Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[N:13]=2)[C:8](=[O:16])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][C:27]([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:22]([O:26][C:27]([NH:29][CH:30]1[CH2:34][CH2:33][N:32]([C:12]2[N:13]=[C:14]3[C:9]([C:8](=[O:16])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][N:5]3[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:11]=2)[CH2:31]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)ccc2c1=O
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCC(NC(=O)OC(C)(C)C)C3)ccc2c1=O
Reaction time: 18 h

Procedure:
A solution of Example 73C (0.19 g), 3-(tert-butoxycarbonylamino)pyrrolidine (0.344 g), and potassium carbonate (0.255 g) in dichloromethane (6.2 mL) was refluxed for 4 hours then cooled, stirred for 18 hours, diluted with dichloromethane (50 mL), washed with 0.1M HCl, saturated sodium bicarbonate, and brine, and dried (MgSO4), filtered, and concentrated; and the concentrate was recrystallized from diethyl ether.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]=[O:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]1[O:31][C:30]2[C:25](=[CH:26][CH:27]=[C-:28][CH:29]=2)[O:24]1.[Mg+2].[Br-].C1(C)C=CC=CC=1.O1CCCC1>O1CCCC1>[O:24]1[C:25]2[CH:26]=[CH:27][C:28]([CH:21]([OH:22])[CH2:20][C:10]3[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[N:17]4)=[C:12]([Cl:19])[CH:11]=3)=[CH:29][C:30]=2[O:31][CH2:23]1
Reactant: [c-]1ccc2c(c1)OCO2
Reactant: O=CCc1cc(Cl)c2cccnc2c1OCc1ccccc1
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OC(Cc1cc(Cl)c2cccnc2c1OCc1ccccc1)c1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a stirring solution of [8-(benzyloxy)-5-chloroquinolin-7-yl]acetaldehyde (0.380 mmol) in tetrahydrofuran (4 mL) at −78° C. was dropwise added a 1M solution of 3,4-(methylenedioxy)phenylmagnesium bromide in 1:1 toluene/tetrahydrofuran (0.380 mmol, 1.0 eq.) and stirring at −78° C. was continued for 10 min. The reaction mixture was then allowed to warm to room temperature and was stirred 1 h then quenched with saturated aqueous sodium bicarbonate solution (2 mL). After stirring 15 min the reaction mixture was extracted with ethyl acetate (3×5 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated to give a brown oil that was purified by column chromatography using 30% ethyl acetate/hexanes to give the final product as a white foam (0.126 mmol, 33%). MS (ESI) m/z 434.2; HRMS: calcd for C25H20ClNO4+H+, 434.11536; found (ESI, [M+H]+ Obs'd), 434.1150.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:7](=[O:20])[C:8]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:9]=2[C:17](=[O:19])[CH:18]=1.CO.[C:23](OC(=O)C)(=[O:25])[CH3:24]>S(=O)(=O)(O)O>[C:23]([N:5]([C:6]1[C:7](=[O:20])[C:8]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:9]=2[C:17](=[O:19])[CH:18]=1)[CH2:4][CH2:3][O:2][CH3:1])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COCCNC1=CC(=O)c2sc(C(=O)OC)cc2C1=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COCCN(C(C)=O)C1=CC(=O)c2sc(C(=O)OC)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Five drops of concentrated sulfuric acid was added to a solution of methyl 4,7-dihydro-5-(2-methoxyethyl)amino-4,7-dioxobenzo[b]thiophene-2-carboxylate (1.2 g) in acetic anhydride (20 ml) and the mixture was stirred at room temperature for 1 hour. Methanol (20 ml) was gradually added to the reaction solution and then the solvent was evaporated. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (elution with ethyl acetate-hexane 1:1 solution) to give methyl 5-[N-acetyl-N-(2-methoxyethyl)amino]-4,7-dihydro-4,7-dioxobenzo[b]thiophene-2-carboxylate (0.39 g) as a reddish brown powder.
Reaction SMILES: C1C2CCCCC=2C=CC=1N.[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:22]2[NH:31][C:30](=[O:32])[C:29]3[C:28]4[CH2:33][CH2:34][CH2:35][CH2:36][C:27]=4[CH:26]=[CH:25][C:24]=3[N:23]=2)[CH:21]=1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:22]2[NH:31][C:30](=[O:32])[C:29]3[C:24](=[CH:25][C:26]4[CH2:33][CH2:34][CH2:35][CH2:36][C:27]=4[CH:28]=3)[N:23]=2)[CH:21]=1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc4c(c3c(=O)[nH]2)CCCC4)c1
Agent: Nc1ccc2c(c1)CCCC2
Product: CCOC(=O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)CCCC4)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 131, steps A-B, using 5,6,7,8-tetrahydro-naphthalen-2-ylamine in step A. Step B yielded a 2:1 mixture of the titled compound and 1-(1-oxo-1,2,7,8,9,10-hexahydro-benzo[f]quinazolin-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12]([N:14]1[CH2:17][C:16]([F:19])([F:18])[CH2:15]1)=[O:13])=[O:5])[CH3:2].C1N(CCS(O)(=O)=O)CCOC1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Cl-].[Mg+2].[Cl-].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[OH-].[Na+]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]1[C:12]([N:14]1[CH2:15][C:16]([F:19])([F:18])[CH2:17]1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)N1CC(F)(F)C1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)CCN1CCOCC1
Product: CCOC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)N1CC(F)(F)C1
Yield: 95.4 %

Procedure:
A suspension of 2.3 g (1R,2R)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-oxo-cyclopentanecarboxylic acid ethyl ester in 50.6 mL aqueous buffer (30 mM 2-(N-morpholino)ethanesulfonic acid; 0.5 M D-glucose [2.7 equ.]; 2 mM Magnesium chloride) was adjusted to pH 6.5 at 35° C. Under stirring the reduction was started by the addition of the cofactor NADP (23 mg [0.03 equ.]), the cofactor regeneration enzyme-glucose dehydrogenase (23 mg GDH 102 [Codexis]) and the reductase (23 mg KRED-NADP-131 [Codexis]). During the 17 h reaction time at 35° C. the pH was kept at pH 6.5 by the addition of 8.25 mL 1M NaOH. Under stirring the mixture was mixed with 1.5 g filter aid—Dicalite—and 30 mL ethyl acetate for at least 10 min. at room temperature. Subsequently the filter aid was washed with 30 ml water and 70 mL ethyl acetate. Afterwards the filter aid was discarded. The filtrate was extracted trice with 100 mL ethyl acetate. Treatment of the combined organic phases with sodium sulfate, evaporation and drying over night on a high vacuum yielded in 2.21 g of the title compound. MS: 278.2 (M+H)+; chiral GC: ee 99.5% [BGB-172, 60 m; H2; 10° C./min, 100° C. to 180° C.; 1° C./min, 180° C. to 230° C.].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:20])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:10]=2)[CH2:3][CH2:2]1.N1C(C2C=C(C=CC=2)C(O)=O)=NN=N1.[C:35]([O:39][C:40](N1CCC(N)CC1)=[O:41])([CH3:38])([CH3:37])[CH3:36].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.ClCCl>[C:35]([O:39][C:40]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:20])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[N:16]=[N:17][NH:18][N:19]=3)[CH:10]=2)[CH2:3][CH2:2]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: O=C(NC1CCNCC1)c1cccc(-c2nnn[nH]2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cccc(-c3nn[nH]n3)c2)CC1

Procedure:
In analogy to the procedure described in example 50k), N-piperidin-4-yl-3-(1H-tetrazol-5-yl)-benzamide [prepared from 3-(1H-tetrazol-5-yl)-benzoic acid by reaction with 4-amino-piperidine-carboxylic acid tert-butyl ester, N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride and N,N-dimethyl-4-aminopyridine in dichloromethane at rt in analogy to example 60d) to give 4-[3-(2H-tetrazol-5-yl)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester followed by Boc cleavage in analogy to example 50i)] was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 469.4 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][CH:29]=[C:6]2[C:7]([N:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=3)[CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10](=[O:11])[C:5]=12)=[O:8])([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:31]=[CH:30][CH:29]=[C:6]2[C:7]([N:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=3)[CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10](=[O:11])[C:5]=12)=[O:8]
Reactant: [H][H]
Reactant: CCOc1cc(C(CC(=O)OC)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC(=O)OC)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Yield: 55.4 %

Procedure:
To a solution of methyl 3-(3-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate (2.5 g, 5.8 mmol) in 25 mL of ethyl acetate was added 0.25 g of 10% palladium on carbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford a yellow solid. The crude product was purified by flash column chromatography (silica gel, 7% ethyl acetate/methylene chloride). The resulting solid was recrystallized (60 mL ethyl acetate/20 mL hexane) and was then dried in vacuo (60° C.,<1 mm) to afford 1.28 g (55%) of methyl 3-(3-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate as a yellow solid: mp 134-136° C.; 1H NMR (CDCl3)δ 7.40-7.26 (m, 1H); 7.16-7.01 (m, 3H), 6.86-6.72 (m, 2H), 5.71 (dd, J=6, 9.8 Hz, 1H), 5.28 (br s, 2H), 4.10 (q, J=7 Hz, 2H), 3.83 (s, 3H), 3.73 (dd, J=9).8, 16.5 Hz, 1H), 3.64 (s, 3H), 3.24 (dd, J=6, 16.5 Hz, 1H), 1.44 (t, J=7 Hz, 3H); 13C NMR (CDCl3)δ 171.1, 169.8, 168.3, 148.9, 148.1, 145.3, 134.9, 132.3, 131.3, 120.9, 120.0, 112.5, 112.4, 111.1, 110.8, 64.2, 55.8, 51.8, 50.2, 36.0, 14.6; HPLC (Waters Nova-Pak C18 column, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 50/50, acetonitrile/0.1% aqueous phosphoric acid) 5 min, 100%; Anal. Calcd. for C21H22N2O6. Theoretical: C, 63.31, H, 5.57, N, 7.03. Found: C, 63.11; H, 5.50; N, 6.99.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.Cl.[CH2:13]([NH2:16])[C:14]#[CH:15].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:16][CH2:13][C:14]#[CH:15])=[S:10])[CH:7]=1
Reactant: C#CCN
Reactant: Cc1ccc(Cl)cc1N=C=S
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNC(=S)Nc1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.4 %

Procedure:
5-Chloro-2-methylphenyl isothiocyanate (18.3 g; 0.1 mol) was added dropwise to the mixture of 2-propynylamine hydrochloride (9.2 g, 0.1 mol) and triethyl amine (20 mL) in methylene chloride (200 mL). The mixture was stirred for 18 hours at ambient temperature. The mixture was evaporated to dryness. The residue was stirred in water (200 mL) for 1 hour then filtered. The solid was dissolved in ethyl acetate (300 mL) and washed with 1N hydrochloric acid (2×200 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness to give 16.8 g of N-(5-chloro-2-methylphenyl)-N′-(2-propynyl)thiourea.
Reaction SMILES: C([O:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH3:23])([CH2:20][CH2:21][CH3:22])[O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:24](O)C>[C].[Pd]>[OH:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([CH:13]([CH3:24])[CH2:14][C:15]([CH2:20][CH2:21][CH3:22])([CH3:23])[O:16]2)=[CH:11][CH:10]=1
Reactant: CCO
Reactant: CCCC1(C)C=Cc2ccc(OCc3ccccc3)c(C)c2O1
Agent: [Pd]
Product: CCCC1(C)CC(C)c2ccc(O)c(C)c2O1
Yield: 84.2 %

Procedure:
6.5 Grams of the compound obtained in (3) were subjected to catalytic reduction with 0.5 g. of 10% palladium-carbon and 50 ml of ethanol under atmospheric pressure. The subject compound in amount of 4.0 g. (yield: 84.2%) was thus obtained.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:21][O:22][C:23](=[O:25])[N:24]=2)[CH:15]=1.[CH3:28][C:29]([CH3:35])([CH2:33][CH3:34])[C:30](Cl)=[O:31]>N1C=CC=CC=1>[CH3:28][C:29]([CH3:35])([CH2:33][CH3:34])[C:30]([N:24]1[C:23](=[O:25])[O:22][N:21]=[C:20]1[C:16]1[CH:15]=[C:14]([C:13]([F:12])([F:26])[F:27])[CH:19]=[CH:18][N:17]=1)=[O:31]
Reactant: CCC(C)(C)C(=O)Cl
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(C)(C)C(=O)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Reaction time: 3 h
Yield: 56.2 %

Procedure:
To 1 ml of pyridine were added 0.3 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.26 g of 2,2-dimethylbutanoyl chloride was added at room temperature. After stirring for 3 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.24 g of 4-(2,2-dimethylbutanoyl)-3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (11)).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]([C:8]1[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1Cl)=[O:7].Cl.[C:17]([O-])(O)=[O:18].[Na+]>C1COCC1.CCOC(C)=O>[CH3:4][O:5][C:6]([C:8]1[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[O:18][CH3:17])=[O:7]
Reactant: O=C([O-])O
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1nnc(Cl)cc1OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (25 wt % I methanol, 1.1 mL) is added to a stirred solution of 4,6-dichloro-pyridazine-3-carboxylic acid methyl ester (1.03 g, 5 mmol) in THF (25 mL) cooled to 0° C. The reaction mixture is stirred at room temperature overnight and then poured into 1N HCl (8 mL). The resulting solution is then neutralized by saturated NaHCO3. EtOAc (20 mL) is added and the layers are separated. The aqueous layer is extracted twice with EtOAc (20 mL) and the combined extracts are washed with brine (25 mL), dried (Na2SO4) and evaporated. The residue is then purified by flash column chromatography (silica gel, eluted with 2:1 Hexane:EtOAc) to give 6-chloro-4-methoxy-pyridazine-3-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[N:31]1([CH2:37][CH2:38][N:39]2[CH2:44][C:43]3[CH:45]=[C:46](/[CH:49]=[CH:50]/[C:51](O)=[O:52])[CH:47]=[N:48][C:42]=3[NH:41][C:40]2=[O:54])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9])[C:51](=[O:52])/[CH:50]=[CH:49]/[C:46]1[CH:47]=[N:48][C:42]2[NH:41][C:40](=[O:54])[N:39]([CH2:38][CH2:37][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH2:44][C:43]=2[CH:45]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Reactant: CNCc1oc2ccccc2c1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCN2CCOCC2)C(=O)N3)oc2ccccc12
Yield: 91 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzofuran-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.26 g, 91%) was prepared as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 10.75 (br s, 1H), 10.11 (s, 1H), 8.39 (d, J=7.5 Hz, 1H), 7.99 (t, J=9.0 Hz, 1H), 7.59-7.47 (m, 3H), 7.29-7.17 (m, 3H), 5.01-4.57 (m, 4H), 3.97-3.95 (m, 2H), 3.81-3.71 (m, 4H), 3.60-3.51 (m, 2H), 3.41-3.31 (m, 2H), 3.21-2.91 (m, 5H), 2.26 (s, 3H); MS (ESI) m/e 490 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([N+:14]([O-:16])=[O:15])[C:10]([CH3:17])=[CH:9][N:8]=1.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.C(#N)C>[Cl:3][CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([N+:14]([O-:16])=[O:15])[C:10]([CH3:17])=[CH:9][N:8]=1
Reactant: Cc1cnc(CO)c(C)c1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cnc(CCl)c(C)c1[N+](=O)[O-]
Temperature: 12.5 °C

Procedure:
8.0 ml (0.11 mole) of thionyl chloride in 20.0 ml of methylenechloride was added to a solution of 20.0 gms 2-hydroxymethyl-3,5dimethyl-4-nitropyridine, of formula-II obtained in step-(a), at temperature of 10-15° C. over a period of 1 hr. The reaction is maintained at 10-15° C. for further 30 min. Aqueous 10% solution of sodium carbonate was slowly added to the reaction mixture at 10-15° C. and pH adjusted to 8.0 to 8.5. The organic base (compound) is over anhydrous sodium sulfate and solvent was removed under vacuum to obtain crude product. (purity 85%) Pure compound is isolated by re-crystallization from acetonitrile.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21]([OH:22])=[C:16]2[CH:15]=[N:14]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([O:22][C:21]2[N:20]=[CH:19][N:18]=[C:17]3[N:13]([C:4]4[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:8][C:3]=4[N:2]([CH3:23])[CH3:1])[N:14]=[CH:15][C:16]=23)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CN(C)c1cc(S(C)(=O)=O)ccc1-n1ncc2c(O)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN(C)c1cc(S(C)(=O)=O)ccc1-n1ncc2c(OC3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1-(2-Dimethylamino-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (66 mg, 0.200 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (61 mg, 0.300 mmol) and triphenylphosphine (52 mg, 0.200 mmol) were dissolved in toluene (5 mL) and the mixture stirred at 0° C. for 15 min. Diisopropyl azodicarboxylate (28 μL, 0.200 mmol) was then added and the reaction kept going at rt for 16 h. The solvent was removed under reduced pressure and the crude was purified by HPLC. Compound A100 was obtained as a yellowish solid. Exact mass calculated for C24H32N6O5S 516.22, found 517.3 (MH+, 100%). 1H NMR (400MHz CDCl3) δ (ppm): 8.50 (s, 1H); 8.22 (s, 1H); 7.42 (m, 3H); 5.52 (m, 1H); 3.81 (m, 2H); 3.26 (m, 2H); 3.03 (s, 3H); 2.47 (s, 6H); 2.03 (m, 2H); 1.80 (m, 2H); 1.42 (s, 9H).
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.C([O-])([O-])=O.[Na+].[Na+].[CH:35]([C:37]1[CH:41]=[CH:40][O:39][C:38]=1B(O)O)=[O:36].B(O)O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:25]([O:24][C:22](=[O:23])[CH2:21][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)[C:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]1[C:38]1[O:39][CH:40]=[CH:41][C:37]=1[CH:35]=[O:36])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=Cc1ccoc1B(O)O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)OC(C)(C)C)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OBO
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3occc3C=O)n(CC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Yield: 38 %

Procedure:
To a solution of methyl 2-bromo-1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in Example 1, Step 1) in dioxane (0.04 M) was added Na2CO3 (5 eq, 2 M aqueous solution), 3-formylfuran-2-boronic acid (1.4 eq) and bis(triphenylphosphine)palladium(II) dichloride (0.2 eq). The mixture was heated at reflux for 20 mins, at which point the heat was removed and the reaction cooled slightly to allow addition of a further 1 eq of boronic acid. The reaction was then heated for a further 1 h at reflux. Again, the reaction was cooled slightly to allow addition of a further 0.5 eq of boronic acid. After heating for a further 30 mins, the reaction was allowed to cool to RT, filtered and the filtrate diluted with EtOAc. The organic phase was washed with H2O and dried (Na2SO4) before being filtered and concentrated in vacuo. The crude was purified by flash chromatography (10-20% EtOAc/PE) to afford the title compound as an oil (38%); MS (ES+) m/z 466 (M+H)+, 488 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([N:14]([CH3:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4].O.O.O.C([O-])(=O)C.[Na+]>ClCCl.FC(F)(F)C(O)=O>[CH3:1][C:2]([CH3:31])([CH3:30])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([N:14]([CH3:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: CN(c1ccccc1)c1cnc2c(n1)c(C(=O)C(C)(C)C)cn2COCC[Si](C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CN(c1ccccc1)c1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1
Reaction time: 15 h
Yield: 60.8 %

Procedure:
A solution of 2,2-dimethyl-1-[2-(methyl-phenyl-amino)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one (0.021 g, 0.048 mmol) in 1 mL of dichloromethane and 1 mL of trifluoroacetic acid was stirred for 1 h, then concentrated. The residue was dissolved in 0.5 mL of ethanol and treated with sodium acetate trihydrate (0.065 g, 0.48 mmol). The mixture was stirred for 15 h, then concentrated to a residue. Column chromatography (50→100% EtOAc/hexanes) afforded 0.009 g (61%) of 2,2-dimethyl-1-[2-(methyl-phenyl-amino)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10]C)=O)[CH2:6][S:5][C:4]2[S:12][CH:13]=[CH:14][C:3]1=2.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C(C)=CC=CC=1>[O:1]=[C:2]1[CH:7]([C:8]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:10])[CH2:6][S:5][C:4]2[S:12][CH:13]=[CH:14][C:3]1=2
Reactant: COC(=O)C1CSc2sccc2C1=O
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccc1)C1CSc2sccc2C1=O
Yield: 89.8 %

Procedure:
A mixture of methyl 5,6-dihydro-4-oxo-4H-thieno[2,3-b]-thiopyran-5-carboxylate (5.7 g, 0.025 mole), aniline (3.5 g, 0.0375 mole) and xylene (180 ml) is refluxed for 2.5 hrs. in a Soxhlet apparatus, the thimble of which contains 20 g of Linde type 4A molecular sieve. The mixture is cooled in an ice bath, and the resulting crystalline precipitate (m.p.155°-158° C.) is collected, dried and recrystallized from methylene chloride and isopropyl ether to give 6.5 g (90%) of off-white crystalline material, m.p. 155°-158° C.