Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Li+].[CH2:3]([C:5]([NH:30][C:31]([O:33][CH3:34])=[O:32])([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:15][CH:14]=1)C(OCC)=O)[CH3:4].Cl.O>O1CCCC1>[CH2:3]([C:5]1([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:17][CH:18]=2)[CH2:34][O:33][C:31](=[O:32])[NH:30]1)[CH3:4]
Reactant: CCOC(=O)C(CC)(CCc1ccc(OCCCCc2ccccc2)cc1)NC(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(CCc2ccc(OCCCCc3ccccc3)cc2)COC(=O)N1
Reaction time: 8 h
Yield: 64.4 %

Procedure:
Lithium borohydride (0.83 g) was added to a solution of ethyl 2-ethyl-2-methoxycarbonylamino-4-(4-(4-phenylbutyloxy)phenyl)butanoate (5.6 g) in tetrahydrofuran (130 ml) and the mixture was refluxed under heating for 4 hours and allowed to stand at room temperature overnight. 2M Hydrochloric acid (11 ml) and water (400 ml) were added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:1) to give the subject compound (3.0 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][OH:11].C1COCC1.C(=O)(O)[O-].[Na+].[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[OH:11][CH2:10][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[C:30]([O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31]
Reactant: OCC1Cc2ccccc2N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1c2ccccc2CC1CO
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution containing 2,3-dihydro-1H-indol-2-ylmethanol (Preparation 5, 4.31 g) and THF (60 mL) is added to a flask containing sodium bicarbonate (24.27 g) and water (15 mL). Benzylchloroformate (4.5 mL) is slowly added. Once addition is complete, the mixture is stirred overnight. The crude mixture is filtered and washed with a large amount of CH2Cl2. The filtrate is poured into water and the separated organic phase is washed with 5% HCl and brine. The organic layer is dried (Na2SO4), filtering, and concentrated to give a yellow oil. The crude product is chromatographed eluting with EtOAc/heptane (1/1) to give 8.11 g (99%) of the title compound as a pale colored oil. Physical characteristics: MS (ESI+) m/z 284 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:33][C:34]([CH3:36])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@@H:2]([NH:1][CH:34]([CH3:36])[CH3:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][CH2:9]2)=[CH:17][CH:16]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N[C@@H](Cc1ccccc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
(S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-3-phenyl-propan-1-one (0.500 g, 1.15 mmol, Example 52) and acetone (0.084 mL, 1.15 mmol) were mixed in CH2Cl2 (6 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.365 g, 1.72 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (1% MeOH in EtOAc) affording 460 mg (83%) of the pure titled compound as a white foam: mp 45-58° C. APCI-MS m/z 478.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.[CH2:29]([N:32]=[C:33]=[O:34])[CH2:30][CH3:31]>>[CH2:29]([NH:32][C:33]([NH:26][CH2:25][C:24]([C:15]1[NH:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[N:14]=1)([CH3:28])[CH3:27])=[O:34])[CH2:30][CH3:31]
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Reactant: CCCN=C=O
Product: CCCNC(=O)NCC(C)(C)c1nc(-c2ccc3cc(OC)ccc3c2)c(-c2ccncc2)[nH]1
Yield: 49 %

Procedure:
The title compound (12 mg, 49%) was prepared starting from the product of Example 2 and n-propyl isocyanate using the method described in Example 10; MS(ES) m/e 458 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[BH4-]>CC(O)C>[CH2:3]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1ccccc1C=NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Oc1ccccc1CNCc1ccccc1
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Sodium borohydride (0.2 g) was added in small portions to 3 mL of dry 2-propanol in a nitrogen atmosphere. To this mixture was added dropwise a solution of 1.0 g of 2-(benzylimino-methyl)-phenol in 3 mL of 2-propanol. After complete addition, stirring was continued for 1 h. Then water was added in order to decompose excess borohydride, and the volatiles were removed in vacuo. The residue was redissolved in ethyl acetate, washed with water, dried (sodium sulfate) and concentrated yielding 0.9 g of 2-(benzylamino-methyl)-phenol as an oil. EI-MS. 213 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:4].[CH:19]([NH2:22])([CH3:21])[CH3:20]>C(O)(C)C>[CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:22][CH:19]([CH3:21])[CH3:20])=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)N
Reactant: COC(=O)NC=Cc1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: COC(=O)NC=Cc1ccc(OCC(O)CNC(C)C)cc1

Procedure:
9.4 g (0.038 mol) of 1-[p-(2-methoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane are dissolved in 200 ml of isopropanol, 3.25 ml (0.038 mol) of isopropylamine are added and thereafter the mixture is heated to the boil for 3 hours, under a reflux condenser. It is then evaporated in vacuo and the resulting crude base is crystallised from acetone-ether. 1-[p-(2-Methoxycarbonylaminovinyl)-phenoxy]-2-hydroxy-3-isopropylamino-propane of melting point 128°-129° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[O:11])=[CH:8][CH:7]=1.[CH3:23][C:24]1C=CC(OC2C=CC(C(C=CC(O)=O)=O)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH:12]=[CH:13][C:14]([O:16][CH2:23][CH3:24])=[O:15])=[O:11])=[CH:8][CH:7]=1
Reactant: Cc1ccc(Oc2ccc(C(=O)C=CC(=O)O)cc2)cc1
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)cc1
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)cc1

Procedure:
The procedure in Example 17(1) was followed, except that 6.74 g of 3-[4-(3,4-dichlorophenoxy)benzoyl]acrylic acid were used in place of 3-[4-(4-methylphenoxy)benzoyl]acrylic acid, to give 5.42 g of ethyl 3-[4-(3,4-dichlorophenoxy)-benzoyl]acrylate.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH3:11])[C:2]=1[O:1][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]=[O:7]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(C=O)cc(C)c1OCc1ccccc1
Yield: 88.4 %

Procedure:
A mixture of 4.6 g (30.6 mmol) of 4-hydroxy 3,5-dimethyl benzaldehyde (Example E), 4.4 g (35 mmol) of benzyl chloride and 4.8 g (35 mmol) of anhydrous potassium carbonate in 100 mL of acetonitrile, is stirred at reflux for 18 hours overnight. The reaction flask and the inorganic salts are washed with fresh acetonitrile and the solvent is removed on a rotary evaporator. A diethyl ether solution of the residue is washed with 2×25 mL of 1N potassium hydroxide solution, brine, dried (magnesium sulfate) and evaporated. Distillation through a short path apparatus affords 6.5 g of the title compound; bp 149°-152° C./0.50 mm (190°-195° C).
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:3]1[NH:14][C:15]([NH:17][C:18]([O:20][CH3:21])=[O:19])=[S:16].I[CH2:23][CH2:24][CH2:25][CH3:26].CN(C)C=O.[OH-].[Na+]>O>[NH:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:3]1[NH:14][C:15](=[N:17][C:18]([O:20][CH3:21])=[O:19])[S:16][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)NC(=S)NC1C(=N)C=CC=C1Cc1ccco1
Reactant: CCCCI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCSC(=NC(=O)OC)NC1C(=N)C=CC=C1Cc1ccco1
Reaction time: 0.5 h

Procedure:
To 5.0 g (0.0165 mole) of 1-imino(2-furylmethyl)-2-(3-carbomethoxythioureido)benzene and 3.6 g (0.01975 mole) of iodobutane in 80 ml. of N,N-dimethylformamide is added 0.7 g (0.0175 mole) of sodium hydroxide in 20 ml of water. The resulting mixture is stirred for 1/2 hour and the yellow precipitate that formed is separated by filtration, washed with 50 ml of water and dried to give 3.4 g of crude product, m.p. 86°-7° C. Recrystallization from ether-hexane affords 1-imino(2-furylmethyl)-2-(3-carbomethoxy-S-butylisothioureido)benzene m.p. 84°-85° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[C:9]([CH3:15])[C:8]=2[C:16]=1[O:17][CH3:18])(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:30][O:31][C:32](=[O:54])[C@@H:33]([NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=2)=[CH:43][CH:42]=1)(=[O:40])=[O:39])[CH:34]([CH3:36])[CH3:35]>N1C=CC=CC=1>[CH3:30][O:31][C:32](=[O:54])[C@@H:33]([NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:48]=[CH:49][C:50]([NH:53][C:12]([C:10]3[O:11][C:7]4[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:16]([O:17][CH3:18])[C:8]=4[C:9]=3[CH3:15])=[O:14])=[CH:51][CH:52]=2)=[CH:43][CH:42]=1)(=[O:40])=[O:39])[CH:34]([CH3:36])[CH3:35]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Reactant: COc1c(C(C)=O)ccc2oc(C(=O)O)c(C)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(C(C)=O)c(OC)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
To 75 mg (0.3 mmol) of 5-acetyl-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 1 mL of oxalyl chloride and the mixture was refluxed for 2.5 h in the presence of a catalytic amount of DMF, then the excess oxalyl chloride was removed under vacuum. The residue was dissolved in 1 mL of dichloromethane and was added to a mixture of 163 mg (0.46 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester and 2 mL of pyridine in an ice/water bath. The mixture was stirred at room temperature overnight. All the solvents were removed under vacuum. Column chromatography on silica gel gave 54 mg (31% yield) of (S)-2-{4′-[(5-acetyl-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[S:8]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CCC>O>[S:8]1[CH:12]=[CH:11][C:10]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:9]1
Reactant: Brc1cccnc1
Reactant: OB(O)c1ccsc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: c1cncc(-c2ccsc2)c1
Temperature: 100 °C
Yield: 92 %

Procedure:
Into a glass reaction vessel equipped with a cooling apparatus were added 0.015 mmol of bis(dicyclopentyl(2-methoxyphenyl)phosphine)dichloropalladium(II), 1.5 mmol of 3-bromopyridine, 2.25 mmol of 3-thiopheneboronic acid, 3.0 mmol of potassium phosphate and 4 mL of n-butanol. The resultant mixture was stirred with heating at 100° C. for 4 hours. The resultant reaction mixture was cooled down to room temperature, 20 mL of water was added, and the mixture was extracted with 20 mL of diethyl ether twice. The resultant organic layers were mixed, and dried over anhydrous magnesium sulfate, then, filtrated, to obtain a solution. This solution was concentrated, and purified by silica gel column chromatography, to obtain 3-(3-thienyl)-pyridine with a yield of 92%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[S:25]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:26]4[CH2:27][CH2:28][CH2:29][CH2:30][S:25]4(=[O:32])=[O:31])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=S1(=O)CCCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 48.9 %

Procedure:
Using (4-bromo-2-fluorophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (196 mg) described in Preparation Example 114 and [1,2]thiazinane 1,1-dioxide (68 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (109 mg) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].C(=O)(O)[O-].[Na+]>>[CH3:29][O:28][C:24]1[CH:23]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[C:25]=1[O:26][CH3:27])[C:20]([N:9]1[CH2:10][CH2:11][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:21]
Reactant: OCCC1(c2ccncc2)CCNC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccncc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 5.2.2 using 3-(pyrid-4-yl)-3-(2-hydroxyethyl)-pyrrolidine, 3,4,5-trimethoxybenzoyl chloride, and sodium bicarbonate to give the title compound: Rf=0.42 (silica gel, 8% methanol/dichloromethane).
Reaction SMILES: [CH3:1][N:2]([CH3:44])[CH2:3]/[CH:4]=[CH:5]/[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[C:28]([CH3:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:22][N:21](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]3=[N:19][CH:20]=2)[CH:10]=1)=[O:7].O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:44][N:2]([CH3:1])[CH2:3]/[CH:4]=[CH:5]/[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[C:28]([CH3:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)[CH:10]=1)=[O:7]
Reactant: COc1cc(F)c(C)cc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(NC(=O)/C=C/CN(C)C)c3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(F)c(C)cc1-c1c[nH]c2ncc(-c3cccc(NC(=O)/C=C/CN(C)C)c3)cc12
Temperature: 60 °C

Procedure:
A solution of (E)-4-(dimethylamino)-N-(3-(3-(4-fluoro-2-methoxy-5-methylphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide 137 (60 mg, 0.098 mmol) was taken in methanol (7 mL) and water (3 mL) was added potassium carbonate (54.10 mg, 0.392 mmol). The reaction was heated to 60° C. for overnight. The methanol was completely distilled and diluted with water. The organic phase was extracted with ethyl acetate (50 mL) twice. The organic layer was dried over sodium sulphate and filtered and concentrated to get the crude. The crude was purified through flash chromatography by using neutral alumina. The compound was eluted in 2% methanol in chloroform as half white solid (E)-4-(dimethylamino)-N-(3-(3-(4-fluoro-2-methoxy-5-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide 138. MS-ES+458.3, 1H NMR (400 MHz, DMSO): 11.89 (s, 1H), 10.14 (s, 1H), 8.48 (d, 1H), 8.05 (d, 2H), 7.63 (m, 2H), 7.40 (m, 3H), 6.98 (d, 1H), 6.73 (m, 1H), 6.26 (d, 1H), 3.80 (s, 3H), 3.06 (s, 3H), 2.23 (d, 3H), 2.18 (s, 6H).
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:12]([CH2:14][C:15]([NH2:17])=[S:16])#[N:13]>>[CH3:11][C:2]1[S:16][C:15]([CH2:14][C:12]#[N:13])=[N:17][C:3]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CCC(N)=S
Reactant: CC(Br)C(=O)c1ccccc1
Product: Cc1sc(CC#N)nc1-c1ccccc1
Yield: 56 %

Procedure:
This compound was synthesized from 2-bromo-1-phenylpropan-1-one and 2-cyanothioacetamide as described in example 1 step 1 (1.7 g, 56% yield %). MS (ESI) m/z: Calculated for C12H10N2S: 214.06. found: 215.0 (M+H)+.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:15]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccnc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccnc2)sc2ccccc12
Yield: 43.3 %

Procedure:
Methyl thiosalicylate (1.8 g, 10.7 mM) and 3-cyanopyridine (1.1 g, 10.56 mM) were dissolved in toluene (5 ml), and then triethylamine (2 ml, 14.4 mM) was added thereto. After heating the mixture under reflux for 48 hours, the same processes as described in Reference Example 1 were performed to give the title compound as crystals (1.1 g, 43.4%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH2:11])[CH2:8][N:7]1[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:5])[CH3:2].[OH:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[C:27](O)=[O:28]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:27]([C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]=2[OH:16])=[O:28])[CH2:8][N:7]1[CH2:12][CH:13]([CH3:14])[CH3:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](N)CN1CC(C)C
Reactant: O=C(O)c1ccc2ccccc2c1O
Product: CCOC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC(C)C

Procedure:
(2S,4S)-4-[(1-Hydroxy-naphthalene-2-carbonyl)-amino]-1-isobutyl-pyrrolidine-2-carboxylic acid ethyl ester was prepared from (2S,4S)-4-amino-1-isobutyl-pyrrolidine-2-carboxylic acid ethyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C22H29N2O4 [(M+H)+] 385.0, obsd. 385.4.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[CH3:16])[CH:8]2[CH:6]([CH2:7]2)[O:5][NH:4]1.FC(F)(F)C(O)=O>C(O)(=O)C.[Zn]>[NH2:4][C:3]([CH:8]1[CH2:7][CH:6]1[OH:5])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[CH3:16])[CH:2]([F:1])[F:17]
Reactant: Cc1c(F)cccc1C1(C(F)F)NOC2CC21
Agent: [Zn]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1c(F)cccc1C(N)(C(F)F)C1CC1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of 4-(difluoromethyl)-4-(3-fluoro-2-methylphenyl)-2-oxa-3-azabicyclo[3.1.0]hexane (0.81 g, 3.33 mmol) in acetic acid, glacial (7.69 ml, 133 mmol) was added zinc (1.306 g, 19.98 mmol) portionwise at RT followed by trifluoroacetic acid (2.474 ml, 33.3 mmol). The reaction was stirred at RT for 1 hour. The reaction was filtered through a pad of celite and concentrated under vacuum. The residue was dissolved in iced water and the solution was basified by the addition of 5N NaOH to pH 12. The basic aqueous layer was back extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness to afford the title compound 2-(1-amino-2,2-difluoro-1-(3-fluoro-2-methylphenyl)ethyl)cyclopropanol (0.61 g, 2.487 mmol, 74.7% yield). LC/MS (ESI+) m/z=246.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[F:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>N1C=CC=CC=1>[F:12][C:13]1[CH:14]=[C:15]([S:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[I:11])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc2[nH]nc(I)c2c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2[nH]nc(I)c2c1)c1cccc(F)c1
Yield: 10.8 %

Procedure:
3-Fluoro-N-(3-iodo-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 2 from 230 mg of 5-amino-3-iodo-1H-indazole, 5 ml of pyridine and 173 mg of 3-fluorobenzenesulfonyl chloride. 40 mg of 3-fluoro-N-(3-iodo-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a cream solid melting at 189° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([NH2:11])=[CH:9][N:8]=[C:7]([NH:12][CH2:13][CH2:14][C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[N:6]=2)[CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1>CC(N(C)C)=O>[CH:1]1([N:4]2[C:26]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)=[N:11][C:10]3[C:5]2=[N:6][C:7]([NH:12][CH2:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[N:8][CH:9]=3)[CH2:3][CH2:2]1
Reactant: Nc1cnc(NCCc2cccs2)nc1NC1CC1
Reactant: O=Cc1ccncc1
Solvent: CC(=O)N(C)C
Product: c1csc(CCNc2ncc3nc(-c4ccncc4)n(C4CC4)c3n2)c1
Temperature: 140 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
To a solution of 0.032 g (0.12 mmol, 1.0 eq.) of N4-cyclopropyl-N2-(2-(thiophen-2-yl)ethyl)pyrimidine-2,4,5-triamine (I-3) in 5 mL of DMA was added 0.05 mL (0.38 mmol, 3.2 eq.) of 4-pyridinecarboxaldehyde. The mixture was stirred at 140° C. for 16 h and the solvent was removed in vacuo. The residue was purified by flash chromatography (EtOAc) to afford 0.015 g (0.04 mmol, 35%) of 9-cyclopropyl-8-(pyridin-4-yl)-N-(2-(thiophen-2-yl)ethyl)-9H-purin-2-amine (I-4) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([NH2:28])[C:24]=1[C:25]([OH:27])=[O:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:28][C:23]1[C:24](=[C:19]([Cl:18])[CH:20]=[CH:21][CH:22]=1)[C:25]([OH:27])=[O:26])=[O:6]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Cl)c1C(=O)O)c1cccc(F)c1
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
15.9 parts of 3-fluorobenzoyl chloride and 10.1 parts of triethylamine are introduced simultaneously, from 2 feeds, into a solution of 17.1 parts of 6-chloroanthranilic acid in 200 parts of methylene chloride at from 25° to 30° C. The reaction mixture is subsequently stirred for 30 minutes, and is extracted once with 1 N hydrochloric acid and then with water. The organic solution is dried and concentrated, giving 29 parts of N-(3'-fluorobenzoyl)-6-chloroanthranilic acid of melting point 216°-219° C.; yield: 98.6% of theory.