Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:17]1[C:18]2[C:25]([C:26]3[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=3)[C:29]#[N:30])=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1>C(O)CCC>[N:1]1([C:17]2[C:18]3[C:25]([C:26]4[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=4)[C:29]#[N:30])=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1cccc(-c2c[nH]c3ncnc(Cl)c23)c1
Reactant: C1COCCN1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(-c2c[nH]c3ncnc(N4CCOCC4)c23)c1

Procedure:
Morpholine (871 mg, 10 mmol) and N,N-diisopropylethylamine (2.6 g, 20 mmol) were added to a solution of 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (C14) (2.5 g, 9.8 mmol) in n-butanol (100 mL), and the reaction mixture was heated at reflux for 3 hours. Solvents were removed in vacuo and the residue was purified using chromatography on silica gel (Eluent: 1:1 ethyl acetate/petroleum ether). Subsequent recrystallization from ethyl acetate and tert-butyl methyl ether afforded the product as a white solid. Yield: 770 mg, 2.52 mmol, 26%. LCMS m/z 306.0 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 12.34 (br s, 1H), 8.41 (s, 1H), 7.99-8.02 (m, 1H), 7.89 (br d, J=8 Hz, 1H), 7.76 (br d, J=7.5 Hz, 1H), 7.71 (s, 1H), 7.68 (dd, J=7.8, 7.8 Hz, 1H), 3.44-3.50 (m, 4H), 3.11-3.17 (m, 4H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOCc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Clc1ccc(COCCC2CCNCC2)cc1
Reaction time: 8 h
Yield: 445.2 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-[2-(4-chlorobenzyloxy)ethyl]piperidine (760 mg, 0.47 mmol) in MeOH (0.5 mL) was added 2N anhydrous HCl/ether (1.5 mL, 3.0 mmol). The reaction mixture was stirred overnight, then evaporated, and the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2, and the combined organic phases were dried over Na2SO4. After evaporation, 4-[2-(4-chlorobenzyloxy)ethyl]piperidine (531 mg, 97%) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[O:27][CH3:28])=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1[CH:31]=[C:32]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:33]=[CH:34][CH:35]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:15]([N:39]1[CH2:38][CH2:37][N:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([F:29])[CH:31]=3)[CH2:41][CH2:40]1)[N:16]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[O:27][CH3:28])[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: Fc1cccc(N2CCNCC2)c1
Reactant: COC(=O)/C=C/c1cccc(F)c1N=C=Nc1cc(C(F)(F)F)ccc1OC
Solvent: ClCCl
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(F)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
100 mg (0.25 mmol) of methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]-imino}methylene)amino]phenyl}-2-propenoate (Example 18A), 45.7 mg (0.25 mmol) of 1-(3-fluorophenyl)piperazine (Example 15A) and a spatula tip of silica gel are stirred in 15 ml of dichloromethane at room temperature for 1 hour and then under reflux for 20 hours. The target compound is obtained after chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[NH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:18]=2)[CH:11]=[CH:12][CH:13]=1.[Br:23]Br.CC(C)=O.CCCCCC>O.C(Cl)(Cl)Cl>[Br:23][C:17]1[N:18]=[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[CH:9]=2)[NH:15][C:16]=1[C:19]([F:20])([F:21])[F:22]
Reactant: FC(F)(F)c1cnc(-c2cccc(Cl)c2)[nH]1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1[nH]c(-c2cccc(Cl)c2)nc1Br

Procedure:
Potassium carbonate is made into a paste by adding a few drops of water to 1.3 g (9.4 mol) of the potassium carbonate. The 2-(3-chlorophenyl)-5-trifluoromethylimidazole is dissolved in 100 ml chloroform and added to the flask containing the paste. 1.5 g of bromine is added and stirred. Thin layer chromatography (TLC) on alumina using 50:50 acetone-hexane clearly differentiates starting material from product. Additional bromine is added until starting material is no longer present (0.1 g). Water is added and the organic phase removed. The layer is washed with sodium bisulfite, brine and dried over sodium sulfate. The organic phase is stripped and the residue taken up in 1:1 ether hexane and filtered through silica gel, the filtrate is concentrated to yield 1.7 g product. M.P. 137°-144° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[S:59]1[CH:63]=[CH:62][N:61]=[C:60]1[CH2:64]O>O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:64][C:60]2[S:59][CH:63]=[CH:62][N:61]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OCc1nccs1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2nccs2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.74 mL), 1,3-thiazol-2-ylmethanol (0.48 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was concentrated. The residue was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.96 g, 75%).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C@H:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11].[C:25](=O)(ON1C(=O)CCC1=O)[O:26]N1C(=O)CCC1=O.C(N(CC)CC)C>ClC(Cl)C>[OH:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C@@H:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:25]1=[O:26]
Reactant: CC(C)(C)OC(=O)[C@@H](NCCNCc1ccccc1O)C(C)(C)C
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2O)C1=O)C(C)(C)C
Yield: 67.3 %

Procedure:
A solution of Example 145A (180 mg, 0.521 mmol) and disuccinimidyl carbonate (0.16 g, 0.625 mmol) in dichloroethane (5 mL) was treated with triethylamine (87 μL, 0.625 mmol) at 25° C. for 16 h. The mixture was partitioned between 10% sodium carbonate and dichloromethane. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and the solvents were evaporated to give the crude residue which was purified using silica gel chromatography eluting with a gradient of 100% hexanes to 60% hexanes in ethyl acetate to give the title compound (0.127 g, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([OH:15])=O)[C:7](=[O:16])[N:6]2[CH3:17].[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([NH:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1)=[O:15])[C:7](=[O:16])[N:6]2[CH3:17]
Reactant: COc1ccc2nc(C(=O)O)c(=O)n(C)c2c1
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2nc(C(=O)Nc3nnn[nH]3)c(=O)n(C)c2c1

Procedure:
3,4-Dihydro-6-methoxy-4-methyl-3-oxo-2-quinoxalinecarboxylic acid (1.2 g) and N,N'-carbonyldiimidazole (0.8 g) in tetrahydrofuran (25 ml) and dimethylformamide (20 ml) were heated under reflux for 1 hour. 5-Amino-1H-tetrazole (0.5 g) in dimethylformamide (5 ml) was added and the solution was heated under reflux for 1 hour and allowed to cool. The solid was collected and dried, m.p. 295°-296° (d) (70%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[CH:10][C:2]1=2.Cl.O=C1CC2C(=CC=C(/C=C/C(O)=O)C=2)N1.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:42][NH:43][CH3:44])=[CH:34]1.CC1NC2C(C=1CNC)=CC=CC=2.C(C(O)=O)CC(O)=O>>[O:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[C:13]([N:43]([CH3:44])[CH2:42][C:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]([CH3:32])[CH:34]=3)=[O:15])=[CH:10][C:2]1=2
Reactant: O=C(O)/C=C/c1cnc2c(c1)OCCN2
Reactant: CNCc1cn(C)c2ccccc12
Agent: CNCc1c(C)[nH]c2ccccc12
Agent: Cl
Agent: O=C(O)/C=C/c1ccc2c(c1)CC(=O)N2
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1cnc2c(c1)OCCN2
Yield: 83.3 %

Procedure:
According to the procedure of Example 4, except substituting (E)-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid (0.11 g, 0.53 mmole), from Preparation 7, for the (E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt, and substituting 1-methyl-3-(methylaminomethyl) indole (0.10 g, 0.59 mmole) for the 2-methyl-3-(methylaminomethyl)-1H-indole, the title compound (0.16 g, 82%) was prepared as a light yellow solid: MS (ES) m/e363 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:24]=[C:25]([NH2:30])[CH:26]=[CH:27][C:28]=4[CH3:29])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[C:31]([O:35][N:36]([CH2:40][C:41](O)=[O:42])[C:37]([CH3:39])=[O:38])([CH3:34])([CH3:33])[CH3:32].Cl.CN(C)CCCN=C=NCC.CO>C(Cl)Cl.CN(C)C=O.CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:31]([O:35][N:36]([CH2:40][C:41]([NH:30][C:25]1[CH:26]=[CH:27][C:28]([CH3:29])=[C:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH2:16][C:13]3[CH:12]=[CH:11][C:10]([S:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[CH:15][CH:14]=3)[CH2:18][CH2:19]2)[CH:24]=1)=[O:42])[C:37]([CH3:39])=[O:38])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1ccc(Sc2ccc(CN3CCC(c4cc(N)ccc4C)CC3)cc2)cc1
Reactant: CC(=O)N(CC(=O)O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(Sc2ccc(CN3CCC(c4cc(NC(=O)CN(OC(C)(C)C)C(C)=O)ccc4C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 49.7 %

Procedure:
To a stirred solution of 3-(1-{[4-(4-methoxyphenylthio)phenyl]methyl}(4-piperidyl))-4-methylphenylamine (121 mg, 0.289 mmol) in CH2Cl2/dimethylformamide (2.00/0.200 mL) was added 2-[(tert-butoxy)-N-methylcarbonylamino]acetic acid (54.6 mg, 0.289 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (111 mg, 0.578 mmol) and 4-dimethylaminopyridine (5.00 mg). The reaction mixture was stirred at room temperature for 10 h, then partitioned between CH2Cl2 (10 mL) and saturated NaHCO3 solution (10 mL) and the organic phase was separated and washed with water (10 mL), then brine (10 mL), dried over MgSO4 and concentrated in vacuo to give the crude product. Purification by flash column chromatography (eluent: CH2Cl2 then 3% methanol in CH2Cl2) gave 2-[(tert-butoxy)-N-methylcarbonylamino]-N-[3-(1-{[4-(4-methoxyphenylthio)phenyl]methyl}(4-piperidyl))-4-methylphenyl]acetamide (84.7 mg, 50.1% yield) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.S(=O)(=O)(O)O>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[CH:27][C:28]([C:2]3[CH:17]=[N:16][C:5]4[NH:6][C:7]5[CH:12]=[N:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:8]=5[C:4]=4[CH:3]=3)=[CH:29][CH:30]=2)[CH2:21][CH2:20]1
Reactant: CN1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: CN1CCN(c2ccc(-c3cnc4[nH]c5cnc(C(=O)O)cc5c4c3)cc2)CC1
Temperature: 140 °C

Procedure:
A degassed mixture of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid (37.7 mg, 0.13 mmol), 4-(4-methylpiperazin-1-yl)phenylboronic acid, pinacol ester (58.5 mg, 0.194 mmol) and bis(triphenylphosphine)palladium(II) dichloride (4.5 mg, 6.4 μmol) in acetonitrile (2 mL) and aqueous sodium carbonate solution (2 mL) was heated under microwave irradiation at 140° C. for 10 minutes. The cooled reaction mixture was acidified with 10% aqueous sulfuric acid, filtered, and the crude solution was purified by preparative HPLC (0-30% MeCN over 30 min, 35 mL/min) to afford the title compound. 1H NMR (DMSO-D6, 400 MHz): 12.62 (s, 1H), 9.66 (s, 1H), 9.14-8.95 (m, 4H), 7.77 (d, J=8.7 Hz, 2H), 7.18 (d, J=8.9 Hz, 2H), 3.97 (d, J=13.4 Hz, 2H), 3.55 (d, J=11.6 Hz, 2H), 3.20 (q, J=11.1 Hz, 2H), 3.04 (t, J=11.9 Hz, 2H), 2.89 (s, 3H). LCMS (Method D): RT=5.09 min, M+H+=388.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([OH:19])[CH:12]=2)=[CH:5][N:4]=1.Br[CH2:21][CH2:22][CH2:23][NH:24][S:25](=[O:37])([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=1)=[O:26].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:21][CH2:22][CH2:23][NH:24][S:25](=[O:26])([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=3)=[O:37])[CH:12]=2)=[CH:5][N:4]=1
Reactant: COc1ccc(Cc2cnc(N)nc2N)cc1O
Reactant: CC(=O)Nc1ccc(S(=O)(=O)NCCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cc2cnc(N)nc2N)cc1OCCCNS(=O)(=O)c1ccc(NC(C)=O)cc1
Reaction time: 18 h

Procedure:
A mixture of 2.82 g (0.01 mole) of 2,4-diamino-5-(3'-hydroxy-4'-methoxybenzyl)pyrimidine hydrochloride, 3.36 g (0.01 mole) of N1 -(3-bromopropyl)-N4 -acetylsulfanilamide, 2.76 g of anhydrous K2CO3, and 20 ml of dimethylformamide is heated with stirring at 100° for 18 hr. The mixture is concentrated in vacuo to a dark oil, which is shaken with a mixture of water and chloroform. The oily material which remaines insoluble in the water and chloroform is chromatographed on silica gel. Elution with chloroform-methanol, (85:15) gives fractions containing 0.55 g (11%) of 2,4-diamino-5-{3'-[3"-(N4 -acetylsulfanilamido)propoxy-4'-methoxybenzyl}pyrimidine, m.p. 96°-98°. Spectral data are consistent with the proposed structure.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CN(C)C=O>[OH:25][CH2:24][C:23]([NH:22][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])([CH3:27])[CH3:26]
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CC(C)(N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CO)NC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (1.00 g), 2-amino-2-methylpropan-1-ol (0.55 g), 1H-1,2,3-benzotriazol-1-ol (0.50 g) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.71 g) at 0° C., and the mixture was stirred at 60° C. overnight. Water was added to the reaction mixture and the mixture was acidified with 10% aqueous citric acid solution. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.89 g, yield 74%) as colorless crystals. melting point>217° C. (decomposition).
Reaction SMILES: Br[C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[C:4]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1.CCOCC.O.C[C:40]([N:42](C)C)=O>[C-]#N.[C-]#N.[Zn+2].[Zn].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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:40]([C:2]1[C:3]([N:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)=[C:4]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[C:5]2=[N:6][CH:7]=1)#[N:42]
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Br)cnc32)cc1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: O
Product: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C#N)cnc32)cc1
Yield: 89 %

Procedure:
A solution of tert-butyl 4-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.20 g, 0.398 mmol, see Example 1), Zn(CN)2 (0.0304 g, 0.259 mmol), Zn dust (0.00625 g, 0.0955 mmol), Pd2dba3 (0.00729 g, 0.00796 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (“dppf”) (0.00883 g, 0.0159 mmol) in dimethylacetamide (“DMA”; 5 mL) were heated at 110° C. for 20 hours. Ether (50 mL) and H2O (20 mL) were then added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give tert-butyl 4-(5-cyano-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.16 g, 89%) as a solid. MS APCI (+) m/z 449.1 detected. 1H NMR (400 Hz, DMSO-d6) δ 8.47 (s, 1H), 7.20 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.51 (s, 2H), 3.88 (m, 4H), 3.70 (s, 3H), 3.58 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH:11]([F:13])[F:12])=[CH:4][C:3]=1[F:14].[CH2:15]1[C:20](=[O:21])[O:19][CH2:18][C:16]1=O>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:10][CH:11]([F:13])[F:12])[C:16]2[CH2:18][O:19][C:20](=[O:21])[CH:15]=2)=[CH:4][C:3]=1[F:14]
Reactant: Fc1cc(CNCC(F)F)cnc1Cl
Reactant: O=C1COC(=O)C1
Solvent: CC(=O)O
Product: O=C1C=C(N(Cc2cnc(Cl)c(F)c2)CC(F)F)CO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.1 %

Procedure:
317 mg (1.41 mmol) of N-[(6-chloro-5-fluoropyridin-3-yl)methyl]-2,2-difluoroethylamine (III-1) are added to 173 mg (1.69 mmol) of tetronic acid in 400 μA of acetic acid, and the mixture is stirred at room temperature for 6 hours. The reaction mixture is concentrated under reduced pressure, and the residue is then partitioned between dichloromethane and water. The aqueous phase is extracted two more times with dichloromethane. The combined organic phases are washed with 1 N aqueous sodium hydroxide solution and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (3:1) gives 316 mg (64% of theory) of 4-[[(6-chloro-5-fluoropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[NH2:4].[CH2:9]([CH:11]1[O:13][CH2:12]1)[Cl:10]>O>[Cl:10][CH2:9][CH:11]([CH2:12][NH:4][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH2:2][OH:1])[OH:13]
Reactant: NC(CO)(CO)CO
Reactant: ClCC1CO1
Solvent: O
Product: OCC(CO)(CO)NCC(O)CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.1 Grams (0.1 mol) of tris(hydroxymethyl)methylamine (from Aldrich Chemical Co.) is dissolved in 125 ml of water. To this solution is slowly added about 0.12 mole (a 20% excess) of epichlorhydrin (Aldrich Chemical). After stirring for one hour at ambient temperature, the solution is extracted twice using 50 ml of methylene chloride to remove the unreacted epichlorhydrin. The aqueous phase containing the reactive Cl-compound is used immediately.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O1CCCCC1[O:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](CCBr)=[CH:37][CH:36]=1.C(=O)C.[Cl-].[NH4+]>C(#N)C.O1CCCC1.[Pd]>[CH:38]1[CH:37]=[CH:36][C:35]([CH2:34][CH2:33][OH:32])=[CH:40][CH:39]=1
Reactant: BrCCc1ccc(CCOC2CCCCO2)cc1
Agent: [Pd]
Agent: CC=O
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: C1CCOC1
Product: OCCc1ccccc1
Temperature: -40 °C
Reaction time: 18 h

Procedure:
Triphenylphosphine (8.4 g.) and potassium carbonate (4.9 g.) were added to a stirred solution of 2-[p-(2-bromoethyl)phenyl]ethyl tetrahydropyranyl ether (10 g.) in acetonitrile (200 ml.) and the mixture was heated under reflux for 36 hours, cooled and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 10:1 v/v mixture of methylene chloride and methanol as eluant. n-Butyllithium (1.2 ml. of a 1.5 molar solution in hexane) was added to a stirred solution of the phenethyltriphenylphosphonium bromide thus obtained (1.1 g.) in tetrahydrofuran (5 ml.) which was maintained at -40° C. under an atmosphere of argon, and a solution of the above acetaldehyde (0.2 g.) in tetrahydrofuran (5 ml.) was added. The reaction mixture was stirred at -40° C. for 18 hours, allowed to warm up to laboratory temperature and saturated aqueous ammonium chloride solution (10 ml.) was added. The mixture was extracted three times with diethyl ether (10 ml. each time) and the combined extracts were washed with water, dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 3:1 v/v mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether as eluant. The product thus obtained was hydrogenated over a palladium- on-charcoal catalyst by a similar process to that decribed in the second part of Example 3, and the tetrahydropyranyl group was removed by acidic hydrolysis by a similar process to that described in the fifth paragraph of Example 2. There was thus obtained as an oil 2-p-{4-[(1RS, 2SR)-6-methoxy-2-p-methoxyphenyl-1,2,3,4-tetrahydronaphth-1-yl]butyl}(phenylethanol.
Reaction SMILES: CCN=C=NCCCN(C)C.OC(C(F)(F)F)=O.[NH2:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:22].[Br:40][C:41]1[CH:42]=[C:43]([C:50]([F:53])([F:52])[F:51])[CH:44]=[C:45]([CH:49]=1)[C:46](O)=[O:47]>>[Br:40][C:41]1[CH:49]=[C:45]([CH:44]=[C:43]([C:50]([F:51])([F:52])[F:53])[CH:42]=1)[C:46]([NH:19][CH2:20][C:21](=[O:22])[NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:47]
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cc(Br)cc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from the EDCI coupling of 2-amino-N-[1-(4-phenyl-cyclohexyl)-azetidin-3-yl]-acetamide TFA salt (as prepared in Step D of Example 66) and 5-bromo-3-trifluoromethyl-benzoic acid (Aldrich) using the procedure described in Step F of Example 1.