Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[NH2:3][C:4]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:5]=1[CH:6]([OH:21])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]=1.[CH3:27][C:28]([CH3:32])([CH3:31])[CH:29]=O.C([BH3-])#N.[Na+]>C(OC(=O)C)C.C(O)(=O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:4]([NH:3][CH2:27][C:28]([CH3:32])([CH3:31])[CH3:29])=[C:5]([CH:22]=1)[CH:6]([OH:21])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]=1
Reactant: CC(C)(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(O)c2cc(Cl)ccc2N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)CNc1ccc(Cl)cc1C(O)c1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
To a methanol (4 ml) solution of 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminophenyl) benzyl alcohol (0.4 g) were added trimethyl acetaldehyde (109 mg) and acetic acid (76 mg). The mixture was stirred for 10 minutes at room temperature, to which was added sodium cyano borohydride (79 mg). The mixture was stirred for one hour at room temperature, to which was added acetic acid ethyl ester (50 ml). The mixture was washed with water and dried over anhydrous MgSO4. The solvent was then distilled off, and the residue was purified by means of a silica gel column chromatography to give the object 5-chloro-α-(3-tert-butoxycarbonylaminophenyl)-2-neopentylaminobenzyl alcohol (0.43 g) as a colorless amorphous solid product.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].O.C(O)C.B(O)(O)[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH:23]([S:20]([C:17]1[CH:18]=[CH:19][C:14]([C:2]2[C:3]([NH2:4])=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:15][CH:16]=1)(=[O:21])=[O:22])([CH3:25])[CH3:24]
Reactant: Nc1ccccc1Br
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2ccccc2N)cc1
Temperature: 85 °C
Reaction time: 48 h

Procedure:
To a solution of 2-bromoaniline (1.51 g, 8.78 mmol) in a mixture of benzene (58 mL), H2O (23 mL) and ethanol (3 mL) was added 4-(isopropylsulfonylphenyl)boronic acid (3.00 g, 13.2 mmol) followed by tetrakis(triphenylphoshine) palladium(0) (1.01 g, 0.88 mmol). After stirring 85° C. for 48 h the reaction mixture was poured into H2O (500 mL), extracted with chloroform (three times), dried over MgSO4 and concentrated under vacuum. Purification by silica gel chromatography (20% EtOAc/hexanes—40% EtOAc/hexanes) afforded the desired product.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1>>[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:15]([C:14]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[NH:3][C:2](=[O:1])[C:11]=3[NH:12][CH:13]=2)=[O:17])=[CH:20][CH:19]=1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Reactant: NCc1ccncc1
Product: O=C(NCc1ccncc1)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 43.8 %

Procedure:
This compound is prepared according to synthesis 79 from 75 mg (0.33 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 75) and 37 μL (0.36 mmol) of pyridin-4-ylmethylamine. The precipitate that forms during the reaction is filtered then washed with dimethylformamide and diethyl ether to give 46 mg (44%) of N-(pyridin-4-ylmethyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide in the form of a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1cnc(Cl)c(C)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)n1
Yield: 87.1 %

Procedure:
To a mixture of 2-chloro-3,5-dimethylpyrazine (2.8 g), 1-Boc-piperazine (3.7 g), palladium (II) acetate (225 mg), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (953 mg) and sodium tert-butoxide (2.7 g) was added toluene (40 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 3′,5′-dimethyl-2,3,5,6-tetrahydro[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (5 g). 3′,5′-Dimethyl-2,3,5,6-tetrahydro[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (5 g) was dissolved in chloroform (15 mL), 4N hydrogen chloride/ethyl acetate (15 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added, and the mixture was filtered to give the title compound (3.3 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([N:12]([CH3:51])[CH:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]([CH3:50])[C@@H:21]2[CH2:28][N:27]3[C:29]4[CH:30]=[C:31]([C:42]([O:44]C)=[O:43])[CH:32]=[CH:33][C:34]=4[C:35]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[C:26]3[C:25]3[CH:46]=[CH:47][CH:48]=[CH:49][C:24]=3[O:23][CH2:22]2)[CH2:14]1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][S:9]([N:12]([CH3:51])[CH:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]([CH3:50])[C@@H:21]2[CH2:28][N:27]3[C:29]4[CH:30]=[C:31]([C:42]([OH:44])=[O:43])[CH:32]=[CH:33][C:34]=4[C:35]([CH:36]4[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]4)=[C:26]3[C:25]3[CH:46]=[CH:47][CH:48]=[CH:49][C:24]=3[O:23][CH2:22]2)[CH2:14]1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN1CCC(N(C)S(=O)(=O)NC(=O)OC(C)(C)C)C1)COc1ccccc1-3
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(CCN1CCC(N(C)S(=O)(=O)NC(=O)OC(C)(C)C)C1)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 70 °C

Procedure:
A solution of methyl (7R)-7-[(2-{3-[{[(tert-butoxycarbonyl)amino]sulfonyl}(methyl)amino]pyrrolidin-1-yl}ethyl)(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate in dioxane was treated with aqueous KOH (1M) (3 eq) and heated at 70° C. for 1 h. The residue obtained after evaporation of all volatiles was taken into EtOAc, acidified with HCl (1N), and the organics washed with brine, dried and concentrated in vacuo to get the title compound as a white powder. (ES+) m/z 710 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:3]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>CC(C)=O>[CH3:20][O:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:3]=1
Reactant: CCOC(=O)n1nc(O)c2ccc(C(=O)OC)cc21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)n1nc(OC)c2ccc(C(=O)OC)cc21

Procedure:
1-Ethyl 6-methyl 3-hydroxy-1H-indazole-1,6-dicarboxylate (1.35 g, 5.11 mmol) was suspended in acetone (65 mL). Cesium carbonate (1.75 g, 5.36 mmol) and methyl iodide (1.0 mL, 15 mmol) were added and the reaction was heated to reflux for 23 hours. The reaction was concentrated to dryness. The residue was taken up in dichloromethane (100 mL) and water (100 mL). The layers were separated and the aqueous was extracted again with dichloromethane. The combined organics were dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography gave two regioisomeric products.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[S:7][CH:8]=1)([O-])=O.C([O-])=O.[NH4+]>CCO.C(Cl)Cl.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([S:9]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:25]([F:27])([F:28])[F:26])[C:29]([F:30])([F:31])[F:32])=[CH:20][CH:19]=3)[CH2:16][CH2:17]2)(=[O:10])=[O:11])[S:7][CH:8]=1
Reactant: O=[N+]([O-])c1csc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Product: Nc1csc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Reaction time: 18 h
Yield: 30.5 %

Procedure:
In a 50 mL round bottomed flask a mixture of 2-(4-(4-((4-nitro-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (80 mg, 0.154 mmol), ammonium formate (48.6 mg, 0.770 mmol, Sigma-Aldrich, St. Louis, Mo.), and 10% Pd/C (1.639 mg, 0.015 mmol) in EtOH (10 mL) was stirring under an atmosphere of H2 (1 atm) for 18 h. Afterwards, the reaction mixture was filtered through a plug of Celite® (diatomaceous earth), and the filtrate was concentrated to give the crude product. The crude product was dissolved in CH2Cl2 and filtered through a plug of silica gel. The filtrate was concentrated to give 2-(4-(4-((4-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (23 mg).
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=C1CCC(O)N1
Reactant: CCCCCCCCO
Product: CCCCCCCCOC1CCC(=O)N1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 7.5 g of 5-hydroxy-pyrrolidin-2-one in 10 cm3 of n-octanol and 4 g of Amberlite IR 120 H is agitated at 60° C. for 4 hours. After filtering, and concentrating to dryness, 5.5 g of the expected product is obtained, m.p. 36°-38° C., crystallized from hexane. By re-crystallizing from hexane, m.p.=38°-40° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=[O:13].O>C(Cl)(Cl)(Cl)Cl>[C:2]1([C:1]([C:16]2[O:15][C:14]([C:12]([O:11][CH3:10])=[O:13])=[CH:18][CH:17]=2)=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccco1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(=O)c2ccccc2)o1
Reaction time: 1 h
Yield: 61681.2 %

Procedure:
Anhydrous ferric chloride (0.42 g, 2.6 mmole) and benzoyl chloride (29.6 g, 0.21 mole), were dissolved in CCl4 (40 mL) and added dropwise over 10 min with methyl-2-furoate (25.2 g, 0.20 mmole). The reaction mixture was then heated under reflux for 36 hours, and after cooling was added with water (120 mL). The mixture was stirred for 1 hour and then allowed to sit until it separated into two layers. The water layer and precipitate were extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and then filtered. The solvent of the filtrate was removed under a reduced pressure; the residue was recrystallized from isopropanol to afford 28.4 g of 5-methoxycarbonyl-2-furyl phenyl ketone in a yield of 65.0%.
Reaction SMILES: [NH:1]([C:48]([CH3:50])=[O:49])[C@H:2]([C:6]([NH:8][C@@H:9]([C:26]([NH:28][C@H:29]([C:37]([N:39]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH3:40])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][C:21]([O:23]CC)=[O:22])[CH:12]=1)=[O:7])[C@@H:3]([CH3:5])[OH:4].[OH-].[Na+]>C(O)C>[NH:1]([C:48]([CH3:50])=[O:49])[C@H:2]([C:6]([NH:8][C@@H:9]([C:26]([NH:28][C@H:29]([C:37]([N:39]([CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[CH3:40])=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:27])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][C:21]([OH:23])=[O:22])[CH:12]=1)=[O:7])[C@@H:3]([CH3:5])[OH:4]
Reactant: CCOC(=O)Cn1cc(C[C@@H](NC(=O)[C@@H](NC(C)=O)[C@@H](C)O)C(=O)N[C@@H](Cc2ccccc2)C(=O)N(C)Cc2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N[C@H](C(=O)N[C@H](Cc1cn(CC(=O)O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1)[C@@H](C)O
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of Ac-Thr-D-Trp(CH2CO2Et)-Phe-NMeBzl (0.98 g) in ethanol (25 ml) was added 0.1N sodium hydroxide solution (14.3 ml) under ice-cooling. After stirring two hours, 0.1N sodium hydroxide solution (2.0 ml) was added and the mixture was stirred for additional two hours. The ethanol was evaporated and the solution was extracted twice with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid and extracted twice with ethyl acetate. The extract was washed with sodium chloride solution and concentrated to give Ac-Thr-D-Trp(CH2CO2H)-Phe-NMeBzl as an amorphous solid (0.90 g).
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N>[Ni].CO>[C:1]1([CH:7]([NH2:8])[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH2:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2=NNC(c3ccccc3)C2)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NC(CC(N)c1ccccc1)c1ccccc1

Procedure:
111 g (0.5 mol) of 3,5-diphenyl-2-pyrazoline are hydrogenated with 10 g of freshly prepared Raney nickel in 400 ml of methanol saturated with NH3 for 14 hours at 80° C./100 atmospheres. The catalyst is filtered off and the solvent is removed in a rotary evaporator. Distillation under a high vacuum gives 102 g=90% of theory of a colourless oil1/2.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:20][O:21][CH3:22])[NH:14][C:15]=1[C:16]([O:18][CH3:19])=[O:17])([CH3:10])[CH3:9].[C:23]([N:42]1[C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:53]2[CH:60]=[CH:59][C:56]([CH2:57]Br)=[CH:55][CH:54]=2)=[N:45][N:44]=[N:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C(=O)C>[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:57][C:56]2[CH:55]=[CH:54][C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[C:46]3[N:42]([C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:43]=[N:44][N:45]=3)=[CH:60][CH:59]=2)[C:15]=1[C:16]([O:18][CH3:19])=[O:17])([CH3:9])[CH3:10]
Reactant: COCc1nc(C(C)(C)O)c(C(=O)OC)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCc1nc(C(C)(C)O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
194 mg of potassium t-butoxide were added, whilst ice-cooling, to a solution of 359 mg of methyl 4-(1-hydroxy-1-methylethyl)-2-methoxymethylimidazole-5-carboxylate [prepared as described in Preparation 2(v)] in 5 ml of N,N-dimethylacetamide, and the resulting mixture was stirred for 15 minutes. At the end of this time, a solution of 1.32 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 10 ml of N,N-dimethylacetamide was added. The mixture was first stirred at room temperature for 4 hours and then at 50° C. for a further 2 hours. The reaction mixture was then mixed with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 848 mg of the title compound as crystals, melting at 120°-137° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.ClC1C=C2C3(CCNC3)C[N:31]([C:38](NC3SC(Cl)=CN=3)=[O:39])[C:28]2=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C@@:10]3([CH2:14][CH2:13][N:12]([C:38]([NH:31][CH3:28])=[O:39])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Reactant: O=C(Nc1ncc(Cl)s1)N1C[C@@]2(CCNC2)c2cc(Cl)ccc21
Product: CNC(=O)N1CC[C@@]2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 373, with the exception that the (S)-5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide obtained as an intermediate of Example 52 was used instead of 5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12](B(CC)CC)[CH:11]=1>N1C=CC=CC=1>[I:9][C:4]1[CH:3]=[C:2]([C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([I:8])[CH:5]=1
Reactant: Ic1cc(I)cc(I)c1
Reactant: CCB(CC)c1cccnc1
Solvent: c1ccncc1
Product: Ic1cc(I)cc(-c2cccnc2)c1

Procedure:
The pyridine was prepared as above from 1,3,5-triiodobenzene and 3-pyridyldiethylborane. ##STR97##
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]=1[S:15](=[O:18])(=[O:17])[NH2:16])=O>COCCOC.Cl>[NH2:5][C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]=1[S:15]([NH2:16])(=[O:18])=[O:17]
Reactant: CC(C)(C)C(=O)Nc1ccc2c(c1S(N)(=O)=O)OCO2
Agent: Cl
Solvent: COCCOC
Product: Nc1ccc2c(c1S(N)(=O)=O)OCO2

Procedure:
A solution of 2,2-dimethyl-N-(4-sulfamoyl-benzo[1,3]dioxol-5-yl)-propionamide (800 mg, 2.7 mmol) in 1,2 dimethoxyethan (15 ml) and conc. HCl (15 ml) is stirred at 90° C. for 5 h. The pH is adjusted to 10, the mixture extracted with EtOAc and washed with brine, followed by drying (Na2SO4), evaporation of volatiles and crystallization (CH2Cl2/MeOH) which affords 5-amino-benzo[1,3]dioxole-4-sulfonic acid amide.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[CH:47]=O.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[O:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[CH2:47][N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([I:1])=[CH:11][CH:10]=4)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1
Reactant: O=Cc1ccco1
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCN(Cc3ccco3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 88.4 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), furan-2-carbaldehyde (0.214 mL, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 49 mg (88%) of the title compound as a yellow solid. MS (ESI) m/z 555.4 (M+H)+1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([C@H:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ccnc(N)n1
Solvent: ClCCl
Product: C[C@@H](O)c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)ethanone (Compound 3a) (59.8 g) in N,N-dimethylformide (600 mL) at room temperature was added chloro[(1R,2R)—N-(p-toluenesulfonyl)-1,2-diphenyl-1,2-ethanediamine] (p-cymene)ruthenium (II) (3.35 g). The resulting dark orange solution was then purged with argon and formic acid—triethylamine complex (5:2) (189 g) was added. The reaction was stirred under an atmosphere of argon at room temperature for 1 h then evaporated to dryness under reduced pressure to yield a dark brown residue that was taken up in dichloromethane and the minimal volume of methanol and chromatographed on silica gel eluting with 4-10% methanol in dichloromethane. Fractions containing product were combined and evaporated under reduced pressure to yield the title compound (29.2 g) that was a 2.4%:97.6% ratio of enantiomers by chiral SFC (supercritical fluid chromatography) chromatography.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(N)c(C(N)=O)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc(C)cc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 8.8 mmol) and 2-amino-5-methylbenzamide (3.30 g, 22.0 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-5-methylbenzamide was isolated as white solid (3.30 g, 82% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (s, 3 H), 2.35 (s, 3 H), 6.64 (d, J=4.03 Hz, 1 H), 7.37 (dd, J=8.60, 1.65 Hz, 1 H), 7.46 (d, J=8.05 Hz, 2 H), 7.64 J=1.65 Hz, 1 H), 7.70 (s, 1 H), 7.71 (d, J=4.03 Hz, 1 H), 7.97 (dt, J=8.69, 1.97 Hz, 2 H), 8.19 (s, 1 H), 8.22 (d, J=8.42 Hz, 1 H), 12.02 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[C:9]([CH:15]=O)=[CH:8][CH:7]=1.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C@H:26]2[CH2:29][C@H:28]([NH2:30])[CH2:27]2)=[CH:21][C:20]=1[C:31]([F:34])([F:33])[F:32].CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C@H:26]2[CH2:29][C@H:28]([NH:30][CH2:15][C:9]3[C:10]4[N:11]([CH:12]=[CH:13][N:14]=4)[C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=3)[CH2:27]2)=[CH:21][C:20]=1[C:31]([F:32])([F:33])[F:34]
Reactant: N[C@H]1C[C@H](Oc2ccc(F)c(C(F)(F)F)c2)C1
Reactant: COCOCc1ccc(C=O)c2nccn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COCOCc1ccc(CN[C@H]2C[C@H](Oc3ccc(F)c(C(F)(F)F)c3)C2)c2nccn12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 5-({[(methyloxy)methyl]oxy}methyl)imidazo[1,2-a]pyridine-8-carbaldehyde (34 mg, 0.154 mmol) and trans-3-{[4-fluoro-3-(trifluoromethyl)phenyl]oxy}cyclobutanamine hydrochloride salt (44 mg, 0.154 mmol) in a mixture of DCM (1 mL) and methanol (1 mL) was added DIPEA (0.027 mL, 0.155 mmol) and sodium triacetoxyborohydride (98 mg, 0.463 mmol). The reaction was stirred at ambient temperature for 3.5 hours and then diluted with DCM (10 mL). The solution was then washed with saturated aqueous sodium bicarbonate (10 mL), dried (hydrophobic frit) and concentrated in vacuo. The residue was dissolved in DCM and purified on a silica cartridge (10 g) using a 0-10% methanol-DCM gradient over 40 min. The product containing fractions were combined and evaporated in vacuo to give the title compound as a yellow oil (32 mg).