Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](CCOS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].C[N:35](C=O)C>>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:35]
Reactant: CN(C)C=O
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1cc2ccccc2[nH]1
Temperature: 80 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
5-(2-Methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.300 g, 0.770 mmol, 1 eq, Example 56, Step D) was suspended in DMF (5 mL) under Ar. K2CO3 (0.425 g, 3.080 mmol, 4 eq) was added followed by the addition of (1S,4S)-(+)-1-Aza-5-oxabicycle[2,2,1]-heptane hydrochloride (0.314 g, 2.320 mmol, 3 eq). The reaction mixture was stirred at 80° C. for 18 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.150 g (50%) of the indole-amine was obtained as a white solid. This was converted to the .HCl salt. LC/MS (ESI+) 391 (M+1); Anal. Calcd for C24H26N2O3.1HCl.0.90H2O: C, 65.05; H, 6.55; N, 6.32; Found: C, 65.05; H, 6.60; N, 6.13.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>>[C:12]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH3:11])[C:8]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35]([CH:37]4[CH2:39][CH2:38]4)=[O:36])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Product: CC(C(=O)NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)(c1ccccc1)c1ccccc1

Procedure:
Example 123 was prepared from 2,2-diphenylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: ESMS m/e: 510.3 (M+H)+.
Reaction SMILES: C(O[CH:4](OCC)[C:5](=[NH:8])OC)C.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[CH2:20][NH2:21]>CO>[CH3:19][C:17]1[CH:16]=[C:15]2[C:4](=[C:13]([CH3:12])[CH:18]=1)[CH:5]=[N:8][C:20]([NH2:21])=[CH:14]2
Reactant: Cc1ccc(CN)c(C)c1
Reactant: CCOC(OCC)C(=N)OC
Solvent: CO
Product: Cc1cc(C)c2cnc(N)cc2c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a solution of methyl 2,2-diethoxyacetimidate (1.5 g, 9.3 mmol) in methanol (4.9 mL) was added (2,4-dimethylphenyl)methanamine (1.2 g, 8.9 mmol) dropwise at ambient temperature. The reaction flask was then placed into a preheated oil-bath and stirred at 70° C. for 16 h, then cooled and the volatiles removed under reduced pressure. The crude material was added dropwise to sulfuric acid (19.7 mL) at ambient temperature and stirred for 72 h. The flask was then placed into an ice-water bath, diluted with water (50 mL), and slowly neutralized to pH=10 with sodium hydroxide (10 N). As the reaction mixture became basic, an orange precipitate formed. This precipitate was filtered, washed with water, and dried to afford 6,8-dimethylisoquinolin-3-amine (1.37 g, 7.95 mmol, 90%). 1H NMR (400 MHz, MeOD) δ ppm 8.82 (s, 1H), 7.17 (s, 1H), 6.90 (s, 1H), 6.72 (s, 1H), 2.61 (s, 3H), 2.37 (s, 3H). MS (LC/MS) R.T.=0.77; [M+H]+=173.15.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].Cl[CH2:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=[O:11]>CO>[C:3]([CH2:2][S:1][CH2:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=[O:11])([OH:5])=[O:4]
Reactant: O=C(O)CC(=O)CCl
Reactant: O=C(O)CS
Solvent: CO
Product: O=C(O)CSCC(=O)CC(=O)O
Temperature: 23.5 °C

Procedure:
To a round bottom flask containing mercaptoacetic acid (0.1 mol) dissolved in methanol (25 mL) is added 4-chloro-3-oxobutanoic acid (0.1 mol). The resulting mixture is heated at reflux temperature for about 2 hours. When the reaction is complete, the mixture is allowed to cool to room temperature (22-25° C.). Volatiles are removed under vacuum and the resulting residue is purified by column chromatography to yield 4-(carboxymethylthio)-3-oxobutanoic acid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S1(=O)CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCS(=O)(=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with thiomorpholine 1,1-dioxide (Syntech) to give the title compound. HR-MS (ES, m/z) calculated for C33H39Cl2N4O4S [(M+H)+] 657.2064, observed 657.2067.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:27])[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:8][C:9](=[N:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>[Pd].CCCCCC>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)[CH:8]=[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=1[OH:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(C)(C)C1=CC(=Nc2ccc(CCC(=O)O)cc2)C=C(C(C)(C)C)C1=O
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)(C)c1cc(Nc2ccc(CCC(=O)O)cc2)cc(C(C)(C)C)c1O
Yield: 77.1 %

Procedure:
A mixture of 4.0 g of 3-[4-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)phenyl]propionic acid, 200 ml of ethanol of 0.1 g of 10% palladium on charcoal catalyst was placed on a Paar apparatus. Hydrogen uptake was complete after 30 minutes. Under a nitrogen atmosphere, the reaction mixture was filtered to remove catalyst. The filtrate was evaporated to give an oil which was coevaporated with hexane to remove all traces of ethanol and then triturated with hexane to give a light orange crystalline solid. This solid was recrystallized from a mixture of ethanol and water to give 3.1 g 3-[N-(3,5-di-tertiary-butyl-4-hydroxyphenyl)-4-aminophenyl]propionic acid, m.p. 140°-142° C. Analysis: Calculated for C23H31NO3 : % C, 74.8; % H, 8.5; % N, 3.8; Found: % C, 74.7; % H, 8.3; % N, 3.9.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8]=[CH:9][C:10]2[C:19]([CH3:20])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[N:6][C:5]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:4]1)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][C:10]2[C:19]([CH3:20])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[N:6][C:5]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[N:4]1)[CH3:2]
Reactant: [H][H]
Reactant: CCn1nc(N2CCCC2)nc1C=Cc1nc2ccccc2nc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCn1nc(N2CCCC2)nc1CCc1nc2ccccc2nc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.8 %

Procedure:
2-(2-(1-ethyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)vinyl)-3-methylquinoxaline (10 mg, 29.9 μmol, Eq: 1.00) was stirred in Ethyl acetate (6 ml) using 5% Pd on Ba2SO4 (3 mg, 30.8 μmol, Eq: 1.00) as catalyst in a hydrogen atmosphere. The mixture was stirred at room temperature for totally 12 h. TLC showed nearly complete conversion. The crude material was applied on silica gel an purified by column chromatography using ethyl acetate/methanol (0-5% methanol) as eluent to give 2-[2-(2-Ethyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-3-methyl-quinoxaline (3.2 mg, 31.8%) as off-white semisolid
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27]([NH:17][C:14]1[S:15][CH:16]=[C:12]([C:4]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=2[Cl:2])[N:13]=1)(=[O:29])=[O:28]
Reactant: Nc1nc(-c2cc([N+](=O)[O-])ccc2Cl)cs1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Agent: Br
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc(-c2cc([N+](=O)[O-])ccc2Cl)cs1

Procedure:
The title compound was prepared from 4-(2-chloro-5-nitrophenyl)-1,3-thiazol-2-amine hydrobromide and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (18.4 mg) with purity >90%. MS (pos) m/z 478.0, 479.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]3O[C:15]([NH2:17])=[N:14][N:13]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH2:18][NH2:19]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]3[N:18]([NH2:19])[C:15]([NH2:17])=[N:14][N:13]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C2(c3nnc(N)o3)CC2)cc1
Solvent: O
Product: COc1ccc(C2(c3nnc(N)n3N)CC2)cc1
Temperature: 190 °C
Yield: 47 %

Procedure:
A mixture of 5-[1-(4-methoxyphenyl)cyclopropyl]-1,3,4-oxadiazol-2-amine (0.60 g, 2.6 mmol), and hydrazine (0.64 mL, 20 mmol) in water (2.0 mL) was heated at 190° C. for 3 h. After cooling to RT, the mixture was further cooled with ice-water. The crystalline solid formed was collected by filtration, washed with water, and dried under high vacuum to yield the desired product (300 mg, 47.1%). Analytical LCMS: (M+H)+=246.1.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C(O[C@@H:13]1[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@@H:24]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:14]1[O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)C.C[Si](N[Si](C)(C)C)(C)C.Cl[Sn](Cl)(Cl)Cl>C(#N)C>[C:16]([O:15][C@@H:14]1[C@H:24]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:34]([CH2:36][O:37][C:38](=[O:45])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:35][C@H:13]1[N:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC#N
Product: O=C(OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 83.1 %

Procedure:
0.56 g. (5 mmol) of uracil, 2.52 g. (5 mmol) of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose were agitated in 75 ml. of absolute acetonitrile with 0.65 g. (4 mmol) of HMDS, 0.43 g. (4 mmol) of TCS, and 1.56 g. (6 mmol) of SnCl4 for 2 hours at 24° C. The mixture was worked up as set forth in Example 1, yielding 83.1% of crystalline uridine tribenzoate.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15][NH2:16]>O1CCCC1>[CH3:15][NH:16][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: CN
Solvent: C1CCOC1
Product: CNc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A solution of 21.5 g (99.5 mmol) of methyl 2-chloro-3-nitrobenzoate in 300 mL of tetrahydrofuran (THF) was treated with drop wise addition of 300 mL (597 mmol) of methylamine (2M solution in THF) and was stirred overnight at room temperature. The reaction was concentrated to dryness, dissolved in dichloromethane, and washed with aqueous sodium bicarbonate and water. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give 20.8 g (100%) of the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:16][O:17][C:18](=[O:21])[CH2:19][NH2:20].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:16][O:17][C:18](=[O:21])[CH2:19][N:20]=[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)CN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 205.1 %

Procedure:
A 500 mL, 1-necked rbf equipped with a magnetic stirrer, and a Dean-Stark apparatus with a nitrogen inlet was charged with benzophenone (58.0 g, 0.318 mol), glycine methyl ester hydrochloride (20 g, 0.159 mol) and toluene (100 mL). The resulting white suspension was heated to reflux and DIEA (56 mL, 0.318 mol) was added over three hours using a syringe pump. The resulting pale yellow solution was stirred at reflux for an additional 1 h. Upon reaction completion, the reaction mixture was cooled to rt. The reaction mixture was then washed with water (50 mL). The layers were separated and the organic solution was washed with water (50 mL) and concentrated in vacuo at 35-40° C. to give (Benzhydrylideneamino)-acetic acid methyl ester (82.59 g). In a similar fashion, (benzhydrylideneamino)-acetic acid ethyl ester was prepared.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]([CH:8]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][N:9]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O)[CH3:2].C([O-])(=O)C.[NH4+:33]>C(O)C>[NH2:33]/[C:6](/[CH:8]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:11][CH2:10][N:9]1[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[CH:5]\[C:4]([O:3][CH2:1][CH3:2])=[O:28]
Reactant: CCOC(=O)CC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)/C=C(\N)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 103 %

Procedure:
To a solution of bis(1,1-dimethylethyl) 2-[3-(ethyloxy)-3-oxopropanoyl]-1,4-piperazinedicarboxylate (may be prepared as described in Intermediate 3; 7.2 g) in ethanol (250 mL) was added ammonium acetate (6.93 g). The reaction mixture was heated to reflux for 7 hours and then left to stand at room temperature overnight. The reaction mixture was evaporated and then partitioned between 2× EtOAc and water. The combined organic phases were washed with water, dried through a hydrophobic frit and evaporated to give the title compound as a yellow oil (7.40 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[N:3][CH:2]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1>COC(C)(C)C>[N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[N:9]/[CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)=[N:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=Cc1ccncn1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC(/N=C/c2ccncn2)CC1
Reaction time: 2.5 h

Procedure:
Pyrimidine-4-carbaldehyde (C12) (23.00 g, 212.8 mmol) was added to a mixture of tert-butyl 4-aminopiperidine-1-carboxylate (42.61 g, 212.8 mmol) in tert-butyl methyl ether (1.52 L). After 2.5 hours, the reaction was filtered, and the filtrate was concentrated in vacuo to provide an amber oil, which was generally taken directly to the following step. Yield: 56.30 g, 193.9 mmol, 91%. 1H NMR (400 MHz, CDCl3) partial spectrum, characteristic peaks: δ 1.49 (s, 9H), 7.95 (dd, J=5.2, 1.5 Hz, 1H), 8.36 (s, 1H), 8.81 (d, J=5.2 Hz, 1H), 9.28 (d, J=1.5 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:28]1[S:32][CH:31]=[C:30]([C:33](O)=[O:34])[CH:29]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[NH2:36][CH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>C(Cl)Cl>[CH:37]1([NH:36][C:33]([C:30]2[CH:29]=[C:28]([C:7]3[C:8]4[C:15](=[O:16])[N:14]5[C@H:10]([C:9]=4[N:17]=[C:18]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]5)[S:32][CH:31]=2)=[O:34])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38]1
Reactant: NC1CCc2ccccc21
Reactant: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1cc(C(=O)O)cs1)C(=O)N1CCC[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1cc(C(=O)NC3CCc4ccccc43)cs1)C(=O)N1CCC[C@@H]21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-{(9aS)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl}-3-thiophenecarboxylic acid (0.100 g, 0.202 mmol) was dissolved in CH2Cl2. 1-aminoindane (0.039 mL, 0.328 mmol) was added followed by EDCI (0.047 g, 0.243 mmol) and HOBt (0.033 g, 0.243 mmol). After 14 h of stirring at ambient temperature the reaction mixture was poured onto 5% HCl solution and extracted with CH2Cl2. The organics were washed with sat'd NaHCO3, brine and then dried (Na2SO4), filtered and concentrated to a brown residue. Chromatography on silica gel using 3:1 EtOAc:Hexanes eluted the product to provide the title compound upon concentration as a white solid (0.085 g, 0.139 mmol, 69% yield): 1H NMR (CDCl3, 400 MHz) δ 8.08 (s, 1H), 7.46 (s, 1H), 7.35–7.31 (m, 1H), 7.28–7.20 (m, 3H), 7.16 (dd, J=8.5, 5.5 Hz, 2H), 6.97 (t, 2H), 6.17 (m, 1H), 5.67 (dd, J=15.5, 7.8 Hz, 1H), 4.69 (dd, J=10.4, 6.2 Hz, 1H), 4.19 (dd, J=14.3, 7.0 Hz, 2H), 3.76–3.69 (m, 1H), 3.42–3.36 (m, 1H), 3.19–2.99 (m, 5H), 2.96–2.87 (m, 1H), 2.74–2.64 (m, 1H), 2.51–2.43 (m, 1H), 2.39–2.27 (m, 2H), 1.96–1.86 (m, 1H), 1.41–1.34 (m, 1H), 1.09 (t, 7.0 Hz); ESMS m/z 610 (M+H)+, 608 (M−H)+; Anal. Calcd. For C35H32FN3O4S.½H2O: C, 68.44; H, 5.33; N, 6.84; found: C, 68.42; H, 5.50; N, 6.78.
Reaction SMILES: COCCOC.[H-].[Na+].[O:9]=[C:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11]P(=O)(OC)OC.[CH:23](=O)[C:24]1[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[C:26]([O:27][CH3:28])[CH:25]=1>O>[CH3:28][O:27][C:26]1[CH:25]=[C:24]([CH:23]=[CH:11][C:10](=[O:9])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:33]=[CH:32][C:29]=1[O:30][CH3:31]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: COc1ccc(C=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCCCC(=O)C=Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under cooling with ice, to 70 ml of dry 1,2-dimethoxyethane containing 0.87 g of sodium hydride (50% mineral oil) was added dropwise 30 ml of dry 1,2-dimethoxyethane containing 4.0 g of dimethyl 2-oxoheptylphosphonate. Then, the mixture was stirred at room temperature for 1 hour and, after that, cooled at -30° C. Then, 3 ml of dry 1,2-dimethoxyethane containing 3.0 g of veratraldehyde was added dropwise. After dropping, the temperature was restored slowly to room temperature. Then, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried with magnesium sulfate. The solvent was removed by distillation to obtain crude product. After purification of the crude product by means of column chromatography (silica gel/hexane:ethyl acetate=3:1), 1.3 g of the above caption compound was obtained.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:16]([CH2:29][CH3:30])[CH2:17][CH2:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([CH:24]([OH:26])[CH3:25])=[CH:22][CH:21]=1)[CH3:15]>>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:26][CH:24]([CH3:25])[C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:16]([CH2:29][CH3:30])[CH2:14][CH3:15])=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CCOc1ccc(C(C)O)cc1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Product: CCN(CC)CCOc1ccc(C(C)Oc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Yield: 37.2 %

Procedure:
By using 1.0 g of 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone and 1.1 g of 4-(2-diethylaminoethoxy)-α-methylbenzyl alcohol and similarly to the procedures in Preparation Example 1, a crude product was obtained. The crude product was then purified through column chromatography (eluting with chloroform/methanol=200/5) to obtain 710 mg of the aimed product as an oil.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[S:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)(=[O:9])=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C(Cl)Cl.[C:64]([C:68]1[CH:75]=[CH:74][C:71]([CH2:72][NH2:73])=[CH:70][CH:69]=1)([CH3:67])([CH3:66])[CH3:65]>>[C:64]([C:68]1[CH:69]=[CH:70][C:71]([CH2:72][NH:73][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([S:7]([NH:6][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:8])=[O:9])=[CH:18][CH:17]=2)=[CH:74][CH:75]=1)([CH3:67])([CH3:65])[CH3:66]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)O)cc2)c(OC)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CNC(=O)c2ccc(S(=O)(=O)Nc3nccs3)cc2)cc1
Reaction time: 8 h
Yield: 45.8 %

Procedure:
4-{[(2,4-Dimethoxybenzyl)(1,3-thiazol-2-yl)amino]sulfonyl}benzoic acid (Preparation 99, 1.30E3 mg, 0.00300 mol), HBTU (1400.8 mg, 0.0031671 mol) and Et3N (1.07 mL, 0.00766 mol) were mixed in methylene chloride (10 mL, 0.2 mol). 4-tert-butylbenzylamine (424.1 mg, 0.002598 mol) was added and the reaction stirred overnight. The reaction was washed with saturated sodium bicarbonate (aq) followed by 0.5N HCl. The organic phase was separated and dried over magnesium sulfate, then treated with activated carbon and filtered through a Celite pad. The solvent was removed in vacuo to give an oily residue. The residue was triturated with DCM and the solid collected by filtration. LCMS analysis of the solid revealed cleavage of the dimethoxybenzyl protection group had occurred. The gray solid was saved. The filtrate was purified by column chromatography, chloroform to 10% MeOH in chloroform gradient eluent. Product fractions were combined and evaporated to an oily residue. The residue was triturated with methylene chloride and beige solid collected. The solid products from steps 4 and 5 were combined and dissolved in 1N NaOH (aq). The solution was washed 3× with diethyl ether. The basic aqueous phase was treated with activated carbon and filtered through a Celite pad. The pale yellow filtrate was slowly acidified to pH 2-3 with 6N HCl (aq). The resultant precipitate was collected by filtration. Vacuum drying yielded 511 mg of product as a white powder.