Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1.[Cl-].[NH4+]>CC(C)=O.O.[Zn]>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CCC2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CC(C)=O
Product: Clc1ncc2c(n1)C(c1ccccc1)CCC2
Temperature: 90 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A mixture of 2,4-dichloro-8-phenyl-5,6,7,8-tetrahydroquinazoline (51.9 mg, 0.186 mmol), ammonium chloride (13.0 mg, 0.243 mmol) and zinc (130 mg, 1.988 mmol) in acetone (0.75 mL) and water (0.75 mL) was heated at 90° C. with stirring for 2 h. The reaction mixture was filtered through a short plug of diatomaceous earth (Celite®). The solvent was removed in vacuum, and the residue was partitioned between dichloromethane and water. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 2-chloro-8-phenyl-5,6,7,8-tetrahydroquinazoline (24.1 mg, 0.097 mmol, 52.4% yield) as white solid. LC-MS (M+H)+=245.1. 1H NMR (500 MHz, CDCl3) δ ppm 8.39 (1H, s), 7.27 (2H, t, J=7.6 Hz), 7.16-7.23 (1H, m), 6.95 (2H, d, J=7.3 Hz), 4.21 (1H, t, J=6.0 Hz), 2.72-2.91 (2H, m), 2.14-2.26 (1H, m), 1.95-2.06 (1H, m), 1.81-1.93 (1H, m), 1.71-1.81 (1H, m).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([F:41])([F:40])[C:18]([F:39])([F:38])[C:19]([F:37])([F:36])[O:20][C:21]([F:35])([C:26]([F:34])([F:33])[O:27][C:28]([F:32])=[C:29]([F:31])[F:30])[C:22]([F:25])([F:24])[F:23].C(C1C=CC=C(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C=1)#C>O1CCCC1>[F:31][C:29]([F:30])([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH:28]([F:32])[O:27][C:26]([F:33])([F:34])[C:21]([F:35])([O:20][C:19]([F:36])([F:37])[C:18]([F:38])([F:39])[C:17]([F:16])([F:40])[F:41])[C:22]([F:25])([F:24])[F:23]
Reactant: FC(F)=C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: O=Cc1ccc(O)cc1
Agent: C#Cc1cccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=Cc1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc1

Procedure:
In the dry box, tetrahydrofuran (25 mL) and 4-hydroxybenzaldehyde (0.61 g, 0.005 mol) were added to a round bottom flask equipped with a stirrer. Potassium carbonate (0.175 g, 0.00126 mol) was then added to the flask. 1,1,1,2,2,3,3-Heptafluoro-3-(1,1,1,2,3,3-hexafluoro-3-(1,2,2-trifluorovinyloxy)propan-2-yloxy)propane (3.24 g, 0.0075 mol) was then added via the addition funnel and the reaction was placed in an oil bath and heated to a gentle reflux for two hours. The content was analyzed by proton NMR and shown to be 1-ethynyl-3-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)benzene.
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]([C:19]([O:21]CC)=[O:20])[C:12]3=[O:24])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[OH-].[Na+]>[CH:1]1([S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]([C:19]([OH:21])=[O:20])[C:12]3=[O:24])(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1c[nH]c2ccc(S(=O)(=O)C3CCCC3)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c[nH]c2ccc(S(=O)(=O)C3CCCC3)cc2c1=O
Yield: 94.5 %

Procedure:
Intermediate 5 (10.9 g) was dissolved in ethanol (100 ml) and 2M sodium hydroxide (100 ml), and the mixture was heated under reflux for 3 h. After cooling, the solvent was evaporated in vacuo and the residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified with 2M hydrochloric acid to between pH 5 and pH 6 which caused a precipitate to form. The precipitate was filtered off, washed with water, and dried in vacuo overnight to give the title compound as a beige solid (9.47 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]3[CH2:22][CH2:21][N:20]([CH3:23])[C:19](=[O:24])[C:9]3=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[C:5](=[O:25])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)(Cl)Cl>[CH2:12]([O:11][C:10]1[C:6]2[C:5](=[O:25])[N:4]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:3]=[C:2]([NH:1][C:43](=[O:45])[CH3:44])[C:7]=2[N:8]2[CH2:22][CH2:21][N:20]([CH3:23])[C:19](=[O:24])[C:9]=12)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)Cl
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(N)c32)C1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-amino-2-(4-fluorobenzyl)-10-benzyloxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (21 mg, 47 μmol) and diisopropylethylamine (10 μL, 56 μmol) in anhydrous chloroform (2 mL), acetyl chloride (8 μL, 104 μmol) was added. The mixture was stirred at room temperature for 30 minutes and concentrated under vacuum. The intermediate bisacetylated product was dissolved in methanol, stirred at room temperature overnight, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel. Collection and concentration of appropriate fractions provided the title monoacetylated product.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[C:3](N)[CH:2]=1.Cl.N([O-])=O.[Na+].[O:19]([CH2:23][CH3:24])[C:20]([S-:22])=[S:21].[K+]>O>[C:20]([S:22][C:3]1[CH:2]=[C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=1)(=[S:21])[O:19][CH2:23][CH3:24]
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=S)Sc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1 equiv. of biphenyl-3-amine (1 g, 5.92 mmol) in water (7.3 mL) at 0° C. was added concentrated hydrochloric acid (1 mL). A cold solution of 1.1 equiv. of sodium nitrite (450 mg, 6.5 mmol) in water (3 mL) was added slowly and stirred for 15 min. The cold diazonium solution was added slowly to a solution of 1.3 equiv. of potassium ethyl xanthate (1.16 g, 1.3 mmol) in water (1.3 mL) at 45° C. The reaction mixture was stirred for an additional 30 min at 45° C. and then cooled to RT. The reaction mixture was extracted with diethyl ether (3×50 mL). The combined organic extracts were washed with 1 N NaOH solution (100 mL), water (3×50 mL), brine (50 mL), dried over MgSO4, filtered and evaporated under reduced pressure. The resulting crude xanthate 52a was used directly in the next step without further purification. MS (ESI) m/z 275.0 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O.CO>[C:1]1([C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([CH2:21][OH:22])=[CH:24][CH:25]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(-c2nc3ncccc3cc2-c2ccccc2)cc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: OCc1ccc(-c2nc3ncccc3cc2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(3-phenyl-1,8-naphthyridin-2-yl)benzoic acid (9-1) (100 mg, 0.31 mmole) in dry THF (1.5 mL) was added Et3N (0.056 mL, 0.4 mmole) then isobutyl chloroformate (0.048 mL, 0.37 mmole) at 0° C. After 30 min the mixture was warmed to RT. After 30 min NaBH4 (35 mg, 0.92 mmole) was added then MeOH (1 mL) very slowly (vigorous gas evolution). After 1 hr the mixture was diluted with H2O. The pH was adjusted to 7 and the mixture extracted with CH2Cl2 (5×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The reaction was repeated using 320 mg 4-(3-phenyl-1,8-naphthyridin-2-yl)benzoic acid (9-1). After work-up the crude products were combined then purified by flash column chromatography (gradient, 0–5% MeOH/CH2Cl2) to give the title compound as a yellow foam (9-2): 1H-NMR (500 MHz, CDCl3) δ 9.14 (m, 1 H), 8.24 (m, 1 H), 8.19 (s, 1 H), 7.55 (d, J=7.81 Hz, 2 H), 7.51 (m, 1 H), 7.33 (m, 3 H), 7.27 (m, 4 H), 4.70 (s, 2 H).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[C:13]3[C:12]([C:24]3[CH:25]=[C:26]([CH:47]=[CH:48][CH:49]=3)[CH2:27][NH:28][C:29]([C:31]3[C:32](=[O:46])[N:33]([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=4)[CH:34]=[CH:35][CH:36]=3)=[O:30])=[CH:11]2)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[S:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]1[CH:18]=[C:13]2[C:12]([C:24]3[CH:25]=[C:26]([CH:47]=[CH:48][CH:49]=3)[CH2:27][NH:28][C:29]([C:31]3[C:32](=[O:46])[N:33]([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=4)[CH:34]=[CH:35][CH:36]=3)=[O:30])=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: O=C(NCc1cccc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(-c4cccs4)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(-c4cccs4)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(1-benzenesulfonyl-5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide (0.079 mmol, 0.000079 mol) was dissolved in methanol (1.8 mL, Fisher;) and water (0.60 mL, Fisher). To this was added potassium carbonate (46 mg, 0.00033 mol; Fisher) and the reaction was heated at reflux for 1 hour. The reaction was evaporated, taken up in N,N-dimethylformamide, neutralized with TFA (100 uL) and purified by preparative HPLC chromatography to yield the product in 3.4 mg yield. 1H NMR (500 MHz, CDCl3-MeOH-d4) d ppm 10.244 (s, 1H) 8.734 (s, 1H) 8.550-8.480 (m, 2H) 7.677 (s, 1H) 7.604 (s, 1H) 7.537 (s, 1H) 7.506-7.393 (m, 3H) 7.390-7.326 (m, 2H) 7.144-7.035 (m, 3H) 6.999-6.938 (m, 1H) 6.442 (m, 1H) 5.070 (s, 2H) 4.689 (m, 2H); MS m/z=552.95 M+H.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:9])=[S:8].Br[CH:12]([CH3:20])[C:13](=O)[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[N:9]=[C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:10])[CH3:1])[S:8][C:12]=1[CH3:20]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: CN(C)CCCNC(N)=S
Product: COC(=O)Cc1nc(NCCCN(C)C)sc1C
Yield: 50.8 %

Procedure:
The title compound (854 mg) was prepared from 1.0 g (6.20 mmol) of 3-dimethylaminopropyl thiourea and 1.30 g (6.20 mmol) of methyl 4-bromo-3-oxo-pentanoate according to the method of Intermediate 45: low resolution MS (FAB)m/e 272 (M+).
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:29][C:30]1[C:31]([F:39])=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34].O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][N:21]([C:33](=[O:34])[C:32]4[CH:36]=[CH:37][CH:38]=[C:30]([Cl:29])[C:31]=4[F:39])[CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(O)c1cccc(Cl)c1F
Reactant: CCOC(=O)C1(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)CCN(C(=O)c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 230 mg of ethyl 4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylate in 10 ml of chloroform were added 156 mg of 3-chloro-2-fluorobenzoic acid, 137 mg of hydroxybenzotriazole hydrate and 229 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at room temperature, followed by stirring the reaction mixture at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The resulting ethyl acetate layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=20/1) to give the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:9][C:8]2=[C:10]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH:11]=[CH:12][C:13]([N+:14]([O-])=O)=[C:7]2[O:6]1)[CH3:3]>C(O)(=O)C.[Fe]>[NH2:14][C:13]1[CH:12]=[CH:11][C:10]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[C:8]2[C:7]=1[O:6][CH:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH2:9]2
Reactant: CN(C)CC1Cc2c(C(=O)OCc3ccccc3)ccc([N+](=O)[O-])c2O1
Agent: [Fe]
Solvent: CC(=O)O
Product: CN(C)CC1Cc2c(C(=O)OCc3ccccc3)ccc(N)c2O1
Reaction time: 2 h
Yield: 96.9 %

Procedure:
Benzyl 2-(dimethylaminomethyl)-7-nitro-2,3-dihydrobenzofuran-4-carboxylate 29f (240 mg, 0.67 mmol) was dissolved in 30 mL of acetic acid followed by the addition of iron powder (189 mg, 3.37 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure, added with 20 mL of water and 20 mL of dichloromethane, then added dropwise with 2 M sodium carbonate solution to adjust pH to about 10 and extracted with dichloromethane (30 mL×3). The combined organic phase was washed with water (20 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the title compound benzyl 7-amino-2-(dimethylaminomethyl)-2,3-dihydrobenzofuran-4-carboxylate 29g (212 mg, yield: 97.2%) as a yellow oil liquid.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)=[CH:6][CH:5]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(-c2nccs2)cc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(-c2nccs2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A solution of 2-phenyl thiazole (200 mg, 1.24 mmol) in conc. sulphuric acid (0.5 ml) was cooled to 0° C. The nitrating mixture (made up of 0.5 ml of conc. nitric acid and 0.5 ml of conc. sulfuric acid) was added dropwise and stirred at 0° C. for 1 hr. The reaction was quenched with ice water and basified with sodium hydroxide solution. The resultant precipitate was filtered and washed with water. Purification by column chromatography over silica gel using EtOAc/pet ether gave 2-(4-nitrophenyl) thiazole (150 mg, 58.6%) as solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[CH3:33][N:34]([CH3:42])[CH:35]([CH3:41])[CH2:36][CH2:37][C:38](O)=[O:39].Cl.C(N=C=NCCCN(C)C)C.CN(C=O)C>CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:33][N:34]([CH3:42])[CH:35]([CH3:41])[CH2:36][CH2:37][C:38]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:39]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: CC(CCC(=O)O)N(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(CCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1,150 mg, 0.342 mmol), 4-(dimethylamino)pentanoic acid (63.6 mg, 0.514 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (131.5 mg, 0.69 mmol), and 4-dimethylaminopyridine (10.5 mg, 0.09 mmol) were added to DMF (3 ml). The reaction was allowed to stir overnight at room temperature followed by addition to EtOAc (40 ml). The precipitate was collected by filtration and then purified by column chromatography 0–5% MeOH/CH2Cl2 to yield a white powder (100 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:21])[C:9]3[C:14]([S:15](=[O:19])(=[O:18])[C:16]=2[CH:17]=1)=[CH:13][CH:12]=[C:11]([CH3:20])[CH:10]=3)(=O)[NH2:2].S(Cl)(Cl)=O>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:21])[C:9]3[C:14]([S:15](=[O:18])(=[O:19])[C:16]=2[CH:17]=1)=[CH:13][CH:12]=[C:11]([CH3:20])[CH:10]=3)#[N:2]
Reactant: Cc1ccc2c(c1)C(=O)c1ccc(C(N)=O)cc1S2(=O)=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1ccc2c(c1)C(=O)c1ccc(C#N)cc1S2(=O)=O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
The amide (0.79 g) of Example 21 was added to a mixture of dimethyl formamide (100 ml) and thionyl chloride (2.0 ml) at -10° C., and stirred at -10° C. for 2 hrs. The mixture was poured on to ice-water and the precipitated product filtered off and washed with water, recrystallised from dimethylformamide, and dried at 155° C./15 mm. Hg, m.p. 290° C. (decomposes).
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C[Sn](C)(C)[C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=1>CN1C(=O)CCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([C:2]2[C:3](=[O:17])[CH2:4][CH2:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[N:21][CH:22]=1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)CC2)cc1
Reactant: C[Sn](C)(C)c1ccc(Br)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(Br)cn3)C(=O)CC2)cc1
Temperature: 100 °C

Procedure:
A mixture of 2-bromo-3-(4-(methylsulfonyl)-phenyl)-2-cyclopenten-1-one (700 mg, 2.2 mmol), Pd2 (dba)3 (170 mg, 0.18 mmol), and the total sample of 2-trimethylstannanyl-5-bromopyridine from Step 1 was dissolved in NMP (10 mL) and degassed. The resulting solution was heated to 100° C. for 3.5 h then cooled. The mixture was diluted with EtOAc, washed 2 times with 10% NH4OH and brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (70% EtOAc/hexanes) followed by an EtOAc/Et2O swish to provide 110 mg of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[N:57]=[C:58]([NH:62]C(=O)C)[S:59][C:60]=1[CH3:61])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.COC(=O)[C@@H](NC(C1CC2C=C3OC[C@H](C4C=CC(OCC5C=CC(Cl)=C(Cl)C=5)=CC=4)OC3=CC=2CN1S(C1N=C(N)SC=1C)(=O)=O)=O)CC1C=CC(C2C=CC(C#N)=CC=2)=CC=1>>[NH2:62][C:58]1[S:59][C:60]([CH3:61])=[C:56]([S:53]([N:24]2[CH:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]3[CH:7]=[CH:8][C:9]([C:12]4[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=4)=[CH:10][CH:11]=3)[C:3]([OH:66])=[O:2])=[O:22])[CH2:32][C:31]3[CH:30]=[C:29]4[O:33][CH2:34][C@H:35]([C:37]5[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]6[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=6)=[CH:39][CH:38]=5)[O:36][C:28]4=[CH:27][C:26]=3[CH2:25]2)(=[O:54])=[O:55])[N:57]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1nc(NC(C)=O)sc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1nc(N)sc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: Cc1sc(N)nc1S(=O)(=O)N1Cc2cc3c(cc2CC1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Yield: 63.7 %

Procedure:
(S)-2-({(S)-7-(2-Acetylamino-5-methyl-thiazole-4-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (40 mg) was converted to (S)-2-({(S)-7-(2-amino-5-methyl-thiazole-4-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (28 mg) using General Procedure N. The title compound (24 mg) was prepared by the hydrolysis of (S)-2-({(S)-7-(2-amino-5-methyl-thiazole-4-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (28 mg) using General Procedure B. LCMS (m/z): 912.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[NH:7][N:6]=1)=[O:4].[F:15][C:16]1[CH:17]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>N1C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][S:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=3)(=[O:24])=[O:23])[CH:12]=2)[NH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CNC(=O)c1n[nH]c2ccc(N)cc12
Solvent: c1ccncc1
Product: CNC(=O)c1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Yield: 27.9 %

Procedure:
N-Methyl-5-(3-fluorobenzenesulfonylamino)-1H-indazole-3-carboxamide can be obtained as described in Example 2 from 40 mg of N-methyl-5-amino-1H-indazole-3-carboxamide, 1.2 ml of pyridine and 40 mg of 3-fluorobenzenesulfonyl chloride. 20 mg of N-methyl-5-(3-fluorobenzenesulfonylamino)-1H-indazole-3-carboxamide are thus obtained in the form of an off-white solid melting above 260° C. (Analysis C15H13N4O3S.0.74H2O % calculated C, 51.72; H, 3.76; F, 5.45; N, 16.08; O, 13.78; S, 9.20. % found C, 51.74; H, 3.31; N, 15.71; S, 8.36).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([O-])=O.[ClH:17]>[Pd].O=[Pt]=O.CO>[NH:9]1[CH2:10][CH2:11][CH2:12][C@@H:13]2[C:14]3[CH:15]=[CH:16][C:4]([NH2:1])=[CH:5][C:6]=3[CH2:7][C@H:8]12.[ClH:17]
Reactant: O=[N+]([O-])c1ccc2c(c1)Cc1ncccc1-2
Agent: O=[Pt]=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 7-nitro-9H-indeno[2,1-b]pyridine (3.25 g), 10% palladium on carbon (0.35 g), and methanol (50 mL) is shaken under hydrogen atmosphere (3 bar) at room temperature for 22 h. PtO2 (0.50 g) and 4 M aqueous hydrochloric acid (3.2 mL) are then added and shaking is continued under hydrogen atmosphere (1 bar) at room temperature for another 22 h. The catalysts are separated by filtration and the filtrate is concentrated to give the crude title compound as its hydrochloric acid salt that is used without further purification or transformed to the free base by treatment with aqueous NaOH solution and extraction into ethyl acetate. Yield: 4.20 g (ca. 80% pure); LC (method 1): tR=0.52 min; Mass spectrum (ESI+): m/z=189 [M+H]+.