Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:20][CH:21]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[S:31][CH:32]=[CH:33][C:23]=2[NH:22]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:22]2[C:23]3[CH:33]=[CH:32][S:31][C:24]=3[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[CH:21]2[CH3:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1Nc2ccsc2-c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2c3ccsc3-c3ccccc3C2C)cc1
Yield: 55.9 %

Procedure:
A solution of 4-Methoxybenzenesulfonyl chloride (16 g, 77 mmol), triethylamine (25 mL, 180 mmol), and 4-dimethylaminopyridine (0.20 g, 1.6 mmol) in methylene chloride (100 mL) was de-gassed with nitrogen and treated with a de-gassed methylene chloride (100 mL) solution of 5-Methyl4,5-dihydrothieno[3,2-c]isoquinoline (16 g obtained above) at 23° C. After 21 h the reaction mixture was quenched with 1 N aqueous sodium hydroxide (200 mL). The organic layer was separated and the aqueous phase was extracted with methylene chloride (2×200 mL). The combined extracts were washed with 1 N aqueous sodium hydroxide, 1 N aqueous hydrochloric acid, and brine (200 mL each), dried (K2CO3), and concentrated in vacuo to give the crude product (21 g) as a dark oil. The oil was taken up in methylene chloride (ca. 80 mL) and pre-adsorbed on silica gel (80 g). Flash chromatography on silica gel (400 g) eluting 25-, then 50-, and then 75% methylene chloride-hexane gave the product (16 g) as a yellow solid. Further elution with methylene chloride, then 10-, and then 20% ethyl acetate-methylene chloride gave recovered 5-methylthieno[3,2-c]isoquinoline (1.7 g, 14%) from the previous step. Recrystallization of the product from hot ethyl acetate-hexane provided the title compound (15 g, 79% overall based on recovered starting material from Step 1, m.p. 135-36° C.) as shiny yellow-orange prisms.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].Cl[CH2:14][CH:15]=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:3]=1[NH:4][CH2:14][CH:15]=[O:16]
Reactant: Cc1ccc(C(F)(F)F)cc1N
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(C(F)(F)F)cc1NCC=O
Temperature: 150 °C

Procedure:
2-Methyl-5-trifluoromethylaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated to about 150°C for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-methyl-5-trifluoromethylanilino)acetaldehyde.
Reaction SMILES: [NH2:1][C:2]([CH2:8][CH3:9])([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[ClH:10].[CH3:11]O>>[ClH:10].[NH2:1][C:2]([CH2:8][CH3:9])([CH2:6][CH3:7])[C:3]([O:5][CH3:11])=[O:4]
Reactant: CCC(N)(CC)C(=O)O
Reactant: CO
Agent: Cl
Product: CCC(N)(CC)C(=O)OC
Temperature: 25 °C

Procedure:
A solution of 2-amino-2-ethylbutanoic acid (3.00 g, 22.9 mmol) in MeOH (200 mL) was saturated with HCl (g). The resulting mixture was heated at reflux for 24 h, during which time it was allowed to cool to ambient temperature and was again saturated with HCl (g) twice. After 24 h at reflux, the cooled mixture was concentrated in vacuo to provide the title compound. MS: m/z=146 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1)([CH3:4])([CH3:3])[CH3:2].[C:24]([S:28][CH2:29][CH:30]([CH3:34])[C:31](O)=[O:32])(=[O:27])[CH2:25][CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]([O:5][C:6](=[O:23])[C@H:7]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:31](=[O:32])[CH:30]([CH3:34])[CH2:29][S:28][C:24](=[O:27])[CH2:25][CH3:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(=O)SCC(C)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC(=O)SCC(C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
L-Prolyl-L-phenylalanine tert-butyl ester (0.54 g) was added to a solution of 3-propanoylthio-2-methylpropanoic acid (0.30 g) and dicyclohexylcarbodiimide (0.35 g) in dichloromethane (10 ml) cooled in an ice bath. The mixture was stirred in the ice bath for one hour and then at room temperature overnight, followed by concentration under reduced pressure. Ethyl acetate was added to the residue. After cooling, the precipitates were filtered off. The filtrate was washed, dried and concentrated as in Example 26. The residue was chromatographed as in Example 26 to give 1-(3-propanoylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine tert-butyl ester.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH3:27][C:28]1[N:29]=[CH:30][S:31][C:32]=1[C:33]([C:35]1[N:36]=[CH:37][N:38]2[CH:42]=[C:41]([Sn](CCCC)(CCCC)CCCC)[S:40][C:39]=12)=[O:34]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:41]3[S:40][C:39]4=[C:35]([C:33]([C:32]5[S:31][CH:30]=[N:29][C:28]=5[CH3:27])=[O:34])[N:36]=[CH:37][N:38]4[CH:42]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3scnc3C)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: Cc1ncsc1C(=O)c1ncn2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Yield: 50.6 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(4-methylthiazol-5-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (92 mg) was prepared in the same manner as in step a) of Example 1, except that 112 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 165 mg of 7-(4-methylthiazol-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH3:10][NH2:11]>O>[C:1]([NH:4][CH:5]([CH2:9][NH:11][CH3:10])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: C=C(NC(C)=O)C(=O)O
Reactant: CN
Solvent: O
Product: CNCC(NC(C)=O)C(=O)O

Procedure:
0.31 g of 2-acetamidoacrylic acid was stirred in 200 ml of 40% methylamine in water at 40° C. for 80 hours. Excess methylamine and water were evaporated under reduced pressure, and the residue was held under high vacuum overnight. The residue was recrystallized from a 1:1 v:v mixture of ether and methanol and dried to give 2-acetylamino-3-(methylamino)propionic acid (38A) as a white solid, m.p.: 166.5°-168.5° C. (with decomposition).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[NH:3])[NH2:2].C(=O)([O-])[O-].[Na+].[Na+].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[C:20]([NH:3][C:1]([NH:4][NH:5][C:6](=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[NH:2])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N=C(N)NNC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N=C(NNC(=O)c1ccccc1)NC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A four neck flask (one liter) equipped with a thermometer and a stirrer was charged with 71.3 g (0.4 mole) of N′-amidinobenzoic acid hydrazide (CAS. 3679-92-3), 46.6 g (0.44 mole) of anhydrous sodium carbonate and 360 cc of dimethylformamide. Dropwise added thereto in about 2 hours was 59.0 g (0.42 mole) of benzoyl chloride under stirring while cooling so that the temperature was maintained at 20° C. or lower. After stirring at 20° C. (room temperature) for 12 hours, deposited crystals were filtered off, and the mother liquor was concentrated under reduced pressure. The resulting residue was dissolved in 100 cc of isopropyl alcohol, and the solution was slowly dropwise added to one liter of deionized water to deposit crystals. The resulting crystals were filtered off, sufficiently washed with deionized water and then dried under reduced pressure, whereby the intended compound (pale yellow crystals) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])([O-])=O.[H][H]>C(C(C)=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8]
Reactant: C#CCOC(=O)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Solvent: CCC(C)=O
Product: C#CCOC(=O)c1cccc(N)c1
Reaction time: 14 h
Yield: 65.3 %

Procedure:
In a stirred autoclave, 0.5 g of a catalyst prepared according to Example H1 and containing 0.182 g of Pb(OAc)2 3H2O (corresponding to 2% Pb), and 50 mg (0.5mol %) of FeCl2 4H2O are added to a solution of 10.4 g of propargyl 3-nitrobenzoate in 100 ml of methyl ethyl ketone. The mixture is then hydrogenated for 14 hours at a temperature of 140° C. and at a hydrogen pressure of 20 bar. The catalyst is filtered off, the solvent is distilled off and the remaining mixture is purified by column chromatography to give 5.8 g of propargyl 3-aminobenzoate. The content of allyl 3-aminobenzoate according to 1H--NMR is 18%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(O)=O)[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1.[F:47][C:48]([F:75])([C:65]([F:74])([F:73])[C:66]([F:72])([F:71])[C:67]([F:70])([F:69])[F:68])[CH2:49][CH2:50][CH2:51][CH:52]([CH2:58]CCCCC=C)[C:53]([O:55]CC)=[O:54]>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:58][CH:52]([CH2:51][CH2:50][CH2:49][C:48]([F:47])([F:75])[C:65]([F:73])([F:74])[C:66]([F:71])([F:72])[C:67]([F:70])([F:68])[F:69])[C:53]([OH:55])=[O:54])[C:7]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 13 and the ethyl 2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoate prepared in Example 4, a procedure analogous to that as shown in Example 13 was repeated to give 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoic acid.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].C([Li])CCC.[C:15](Cl)(=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19].[Cl-].[NH4+]>O1CCCC1>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:15](=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: C=CCCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -55 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A solution of (4S)-4-isopropyl-1,3-oxazolidin-2-one (26 g, 0.2 mol) in anhydrous tetrahydrofuran (600 ml) was cooled to −78° C. under a nitrogen atmosphere and treated with n-butyl lithium, 2.5M in hexanes (80 ml, 0.2 mol) keeping the temperature below −65° C. Once the addition was complete the reaction mixture was allowed to warm to −55° C. and stirred at this temperature for 30 minutes. The mixture was cooled back down to −78° C. and treated dropwise with a solution of 4-pentenoyl chloride (23.7 g, 0.2 mol) in anhydrous tetrahydrofuran (100 ml). After stirring at −78° C. for 30 minutes the reaction mixture was allowed to warm to room temperature. Saturated aqueous ammonium chloride solution (1 L) was added and the mixture was extracted with ethyl acetate (2×). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 (pentane:ethyl acetate) gradually changing to 70:30 (pentane:ethyl acetate) to afford the title compound as a yellow oil (36.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:16][C:17]([Cl:21])=[CH:18][CH2:19]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:19][CH:18]=[C:17]([Cl:21])[Cl:16])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: ClCC=C(Cl)Cl
Reactant: N#CC(C#N)Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CC=C(Cl)Cl)Cc1ccc(Cl)cc1
Yield: 66 %

Procedure:
Using 0.50 g of (4-chlorobenzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.30 ml of 1,1,3-trichloropropene, and according to the process described in the Production Example 1, there was obtained 0.52 g of 2-(4-chlorobenzyl)-2-(3,3-dichloro-2-propenyl)malononitrile (the present compound (20)).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[C:7]2[C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]2[CH2:23][C@@H:22]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]2)=[O:16])[CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:49]>>[ClH:49].[ClH:49].[CH:1]1([CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[C:7]2[C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]2[CH2:23][C@@H:22]([C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[O:25])[CH2:21][NH:20][CH2:19]2)=[O:16])[CH2:2][CH2:3]1
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCC1CC1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCC1CC1)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3S, 5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (257 mg), 2-cyclopropylethanol (86 mg) and triphenylphosphine (263 mg) in toluene (10 ml) was added diisopropyl azodicarboxylate (506 μl) at room temperature, and the mixture was stirred at the same temperature for 17 hr. The reaction mixture was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give tert-butyl (3S, 5R)-3-[{[1-(2-cyclopropylethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate. The obtained tert-butyl (3S, 5R)-3-[{[1-(2-cyclopropylethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (220 mg).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]2[CH:11]=[C:10]([CH2:12][N:13]3[C:18](=[O:19])[CH2:17][N:16](C(O)=O)[CH2:15][C:14]3=[O:23])[N:9]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=2[N:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][N:9]1[C:7]2[N:8]=[C:3]([C:1]#[N:2])[N:4]=[CH:5][C:6]=2[CH:11]=[C:10]1[CH2:12][N:13]1[C:14](=[O:23])[CH2:15][NH:16][CH2:17][C:18]1=[O:19]
Reactant: CC(C)(C)Cn1c(CN2C(=O)CN(C(=O)O)CC2=O)cc2cnc(C#N)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)Cn1c(CN2C(=O)CNCC2=O)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.3 %

Procedure:
To a solution of 10.5 g (23.9 mmoles) of 4-[2-cyano-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-3,5-dioxo-piperazine-1-carboxylic acid .tert.-butyl ester in 300 ml of CH2Cl2, 52 ml (675 mmoles) of TFA is added at 0° C. The reaction mixture is allowed to warm to ambient temperature and stirred for 6 hours. The reaction mixture is concentrated under reduced pressure, neutralized with sat.NaHCO3 and extracted with CH2Cl2. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: CH2CO2:AcOEt=1:3) give 7.18 g of desired 7-(2,2-dimethyl-propyl)-6-(2,6-dioxo-piperazin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 88.5% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[CH:16]=1)([O-:3])=[O:2].[Cl:17][S:18](O)(=[O:20])=[O:19]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[C:13]([S:18]([Cl:17])(=[O:20])=[O:19])[CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[CH:16]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)oc1ccccc12
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)oc1ccc(S(=O)(=O)Cl)cc12
Temperature: 25 °C
Reaction time: 66 h

Procedure:
To a stirred solution of 100 mg of 3-nitrodibenzofuran in 1.7 mL of dichloromethane at −20° C. under a nitrogen atmosphere was added 0.44 mL chlorosulfonic acid in small portions. The reaction mixture was allowed to slowly warm to room temperature and stirred for 66 hours at room temperature. The reaction mixture was poured into ice-cold water, extracted four times with dichloromethane, dried (magnesium sulfate) and concentrated. Purification on silica gel (dichloromethane) yielded 129 mg of 50a: rf=0.73.
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[CH:9]=[C:8]2[CH2:10][CH2:11][CH:12]3[C:17]([C:19](O)=[O:20])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]3([CH3:22])[CH:7]2[CH2:6][CH2:5]1)[CH3:3].P(Cl)(Cl)[Cl:24].CN(C=O)C>C1COCC1>[CH3:18][C@:17]1([C:19]([Cl:24])=[O:20])[CH:12]2[C@@:13]([CH3:22])([CH:7]3[C:8]([CH:10]=[CH:11]2)=[CH:9][CH:4]([CH:2]([CH3:1])[CH3:3])[CH2:5][CH2:6]3)[CH2:14][CH2:15][CH2:16]1
Reactant: CC(C)C1C=C2CCC3C(C)(C(=O)O)CCCC3(C)C2CC1
Reactant: ClP(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)C1C=C2C=CC3[C@](C)(CCC[C@@]3(C)C(=O)Cl)C2CC1
Yield: 93.3 %

Procedure:
A mixture of dihydroabietic acid (1.0 eq. 9.95 mmol), phosphorous (III) chloride (1.1 eq. 10.95 mmol) and DMF (0.1 ml) is refluxed overnight in THF (20 ml). The reaction mass is filtered under suction and concentrated under vacuum to give 2.98 g (93%) yellow oil. The compound is used immediately for the next step without any purification.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=2)[C:26]([NH:28][CH3:29])=[O:27])[C:19]([Cl:33])=[CH:18][N:17]=1>>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=2)[C:26]([NH:28][CH3:29])=[O:27])=[N:21][C:16]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:17][CH:18]=1
Reactant: CNC(=O)c1cccc(Nc2nc(Cl)ncc2Cl)c1
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Product: CNC(=O)c1cccc(Nc2nc(Nc3ccc4c(c3)CCCC(=O)N4C)ncc2Cl)c1
Yield: 47 %

Procedure:
In an analogous procedure to Example 651, part c, 7-Amino-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide were combined to yield 3-[5-Chloro-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (53.36 mg, 47% yield) as a white powder. 1H-NMR (DMSO-d6) δ 9.39 (s, 1H), 9.03 (s, 1H), 8.39 (d, J=4.4 Hz, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.1 Hz, 1H), 7.47 (m, 1H), 7.44 (br s, 1H), 7.03 (d, J=8.7 Hz, 1H), 3.15 (s, 3H), 2.75 (d, J=4.3 Hz, 3H), 2.39 (m, 2H), 2.08 (m, 2H), 1.94 (m, 2H). LC/MS (ESI+)=451 (M+H). Mp=215-217° C.
Reaction SMILES: Cl.[CH:2]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:48][C:49]1([F:55])[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:2]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:52]3[CH2:53][CH2:54][C:49]([F:55])([F:48])[CH2:50][CH2:51]3)=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCC4)CC3)ccc2[nH]1
Reactant: FC1(F)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Yield: 83 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4,4-difluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown solid (83%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])=[O:35])[CH:28]=[CH:27]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15](/[CH:17]=[CH:18]/[C:19]([N:40]3[CH2:39][CH2:38][N:37]([S:34]([C:29]4[CH:28]=[CH:27][C:26]5[C:31](=[CH:32][CH:33]=[C:24]([Cl:23])[CH:25]=5)[CH:30]=4)(=[O:36])=[O:35])[CH2:42][CH2:41]3)=[O:21])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCc2sc(/C=C/C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1

Procedure:
In a similar manner to Referential Example 12 except for the use of (E)-3-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)acrylic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH:38]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)=[O:39]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:43]3[CH:44]=[CH:45][C:40]([CH:38]=[O:39])=[CH:41][CH:42]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4ccc(C=O)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-methylbenzene from Example 159-(1) and 4-formylphenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-formylphenyl)-2-thienylmethyl)-4-methylbenzene as a colorless solid. APCI-Mass m/Z 640 (M+NH4).