Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[CH:28]=[CH:27][C:22]4[N:23]([CH3:26])[N:24]=[N:25][C:21]=4[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[CH:28]=[CH:27][C:22]4[N:23]([CH3:26])[N:24]=[N:25][C:21]=4[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)nnn4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccc4c(c3)nnn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a vial was dissolved (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)benzo[d]thiazol-6-yl)acetate (100 mg, 0.182 mmol) in THF (3 mL) and EtOH (1.5 mL). 1M NaOH (1.5 mL) was added, and the mixture was heated to 50° C. overnight. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting with 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C27H26ClN4O3S: 521.0 (M+H+); Found: 521.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 8.26 (dd, J=8.8, 1.5 Hz, 1H), 7.87 (d, J=9.0 Hz, 2H), 7.70 (dd, J=7.4, 2.4 Hz, 1H), 7.65-7.56 (m, 3H), 5.26 (s, 1H), 4.35 (s, 3H), 2.62 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: S1C=CC=C1.C(O)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=3)[CH2:29][CH2:28]2)=[CH:12][CH:11]=1.[H][H]>[Pt].CO>[NH2:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][CH2:33][N:30]2[CH2:29][CH2:28][CH:27]([NH:26][C:18]3[N:17]([CH2:16][C:13]4[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]=3)[CH2:32][CH2:31]2)=[CH:36][CH:37]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Agent: [Pt]
Solvent: CCO
Solvent: CO
Solvent: c1ccsc1
Product: Nc1ccc(CCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Yield: 42 %

Procedure:
To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol are added 3.3 parts of 1-(4-fluorophenylmethyl)-N-{1-[2-(4-nitrophenyl)ethyl]-4-piperidinyl}-1H-benzimidazol-2-amine and 120 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of methylbenzene and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol, yielding 1.3 parts (42%) of N-{1-[2-(4-aminophenyl)ethyl]-4-piperidinyl}-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine; mp. 195.4° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21].O>CN(C)C=O>[CH2:21]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH:20]=[CH2:19]
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.5 %

Procedure:
(3,4-Difluorophenyl)acetic acid (52 g; 0.3 mol) was dissolved in N,N-dimethylformamid (200 mL). Potassium carbonate (61 g, 0.45 mol) was added and the mixture was stirred at room temperature (rt) for 15 min. Allyl bromide (47 g, 0.39 mol) was added and the suspension was stirred at room temperature for 20 h. The mixture was thrown into water (250 mL) and extracted with diethylether (2×300 mL). The combined organic phases were washed with water (4×100 mL), dried (Magnesium sulphate) and evaporated in vacuo to give 64 g (3,4-Difluoro-phenyl)acetic acid allyl ester as a clear oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH2:17][C:18]([NH2:20])=[O:19])[C:11]([N+]([O-])=O)=[N:12][CH:13]=2)[CH2:4][CH2:3]1.C[O:22][C:23](=O)[C:24]([C:26]1[C:34]2[C:29](=[C:30]([CH3:35])[CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=O.[CH3:37]C([O-])(C)C.[K+]>C1COCC1>[CH3:35][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:29]=1[NH:28][CH:27]=[C:26]2[C:24]1[C:23](=[O:22])[NH:20][C:18](=[O:19])[C:17]=1[C:10]1[C:11]([CH3:37])=[N:12][CH:13]=[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:9]=1
Reactant: COC(=O)C(=O)c1c[nH]c2c(C)cccc12
Reactant: CN1CCN(c2cnc([N+](=O)[O-])c(CC(N)=O)c2)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ncc(N2CCN(C)CC2)cc1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[5-(4-Methyl-piperazin-1-yl)-2-nitro-pyridin-3-yl]-acetamide (96 mg, 0.34 mmol) and (7-Methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (127 mg, 0.58 mmol) in dry THF (8.0 mL) is added at 0° C. under an atmosphere of argon, a solution of 1.0 M KOtBu in THF (1.7 ml, 1.7 mmol). After stirring for 2 h at 0° C., TLC analysis indicated complete consumption of the starting materials. The reaction mixture is diluted with EtOAc and washed with brine. The aqueous phase is extracted with EtOAc and the combined organic layers are washed with brine, dried over Na2SO4, and concentrated at reduced pressure. The residue is purified by FCC (EtOAc/AcOH/H2O 6:1:1) to afford the title compound as an orange powder. 1H NMR (d6-DMSO 400 MHz): δ 2.05 (s, 3H), 2.04-2.11 (m, 4H), 2.46 (s, 3H), 3.06-3.14 (m, 4H), 6.35 (d, J=8.1 Hz, 1H), 6.65 (dd, J=8.1, 7.2 Hz, 1H), 6.84 (d, J=7.2 Hz, 1H), 6.87 (d, J=2.0 Hz,1H), 7.95 (s, 1H), 8.16 (d, J=2.0 Hz, 1H). ES+−MS: 447 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[CH3:21][NH2:22].[BH4-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH:22][CH3:21])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: CN
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CNCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
4-{[4-Chloro-3-(trifluoromethyl)phenyl]oxy}benzaldehyde (3 g, 9.98 mmol) was mixed with a methylamine (1.549 g, 49.9 mmol) alcohol solution. The reaction mixture was stirred at 23° C. overnight. NaBH4 (1.132 g, 29.9 mmol) was added and stirred for additional 2 h. Purification via an ISCO system then provided the title compound as a yellow solid. LCMS: rt=2.53 min, [M+H+]=316.1
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>C(OCC)(=O)C>[ClH:21].[ClH:21].[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(OC2CCNCC2)nc1
Yield: 90 %

Procedure:
1-t-Butoxycarbonyl-4-(2-pyridoxy)piperidine (6.5 g) was treated with a solution of hydrogen chloride in ethyl acetate (110 mL) for 7 h, and the mixture evaporated to give 4-(2-pyridoxy)piperidine dihydrochloride (7.4 g, 90%).
Reaction SMILES: Cl.[C:2]([C:6]1[N:10]=[CH:9][N:8]([CH2:11]Cl)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:2]([C:6]1[N:10]=[CH:9][N:8]([CH2:11][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CC(C)(C)c1ncn(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ncn(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 33.6 %

Procedure:
1.61 g of 3-t-butyl-1-(chloromethyl)-1H-1,2,4-triazole hydrochloride and 1.24 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 22 ml of N,N-dimethylformamide. 2.13 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.77 g of [(3-t-butyl-1H-1,2,4-triazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (29), hereinafter) shown by below formula.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH3:24])=[O:4].C1C(=O)N([Br:32])C(=O)C1>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH2:24][Br:32])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Solvent: ClCCCl
Product: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Temperature: 25 °C
Yield: 90 %

Procedure:
A mixture of 1-benzenesulfonyl-5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (121 g, 296 mmol), NBS (63 g, 354 mmol) and 1,1-azobis(cyclohexanecarbonitrile) (14.4 g, 59 mmol) in 1,2-dichloroethane (1.2 L) was heated under reflux for 90 minutes. The reaction mixture was allowed to cool to ambient temperature and washed with saturated aqueous sodium thiosulfate solution. The organic layer was dried (Na2SO4) then filtered. The filtrate was stirred with flash silica gel, filtered and the filtrate evaporated under reduced pressure. The resultant residue was triturated with diethyl ether/pentane (1:1) to afford the title compound as a white solid (130 g, 90%). 1H NMR (400 MHz, CDCl3): 8.47-8.46 (m, 4H), 7.64-7.64 (m, 1H), 7.54-7.53 (m, 2H), 5.67 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: C1CC[CH:4]([N:7]=C=NC2CCCCC2)CC1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([F:40])([C:37]([OH:39])=O)[CH:32]([F:36])[CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].FC1C(F)=CC=CC=1C1C=CC(OCCCCCCC)=CC=1.CN(CCN(C)C)C.[Li]CCCC.[C:76](=[O:78])=[O:77]>C(Cl)Cl.C1COCC1.CCCCCC>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:76]([OH:78])=[O:77])=[C:32]([F:36])[C:31]=2[F:40])=[CH:28][CH:29]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:4]([C:31]([CH3:30])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:37][OH:39])#[N:7]
Reactant: O=C=O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCCCCCOc1ccc(C2=CC=CC(F)C2(F)C(=O)O)cc1
Agent: CCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC(C)(C#N)CO
Product: CCCCCCCOc1ccc(-c2ccc(C(=O)O)c(F)c2F)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
At 0° C., 0.1 mol of DCC, dissolved in methylene chloride, is added to a mixture of 0.1 mol of 4'-heptyloxy-2,3-difluorobiphenylcarboxylic acid (preparation: 0.1 mol of 2,3-difluoro-4'-heptyloxybiphenyl and 0.1 mol of TMEDA are dissolved in 200 ml of THF, and the solution is cooled to -78° C. and reacted at this temperature with 0.105 mol of a 1.6N solution of BuLi in hexane. The reaction mixture is stirred at -78° C. for 3 hours and then tipped in one portion onto 200 g of powdered dry ice. After customary work-up, 4'-heptyloxy-2,3-difluorobiphenyl-4-carboxylic acid is obtained), 0.1 mol of optically active 2-cyano-2-methylhexan-1-ol (which can be prepared from optically active ethyl 2-methyl-2-butylcyanoacetate by reduction using LiBH4) and a catalytic amount of 4-N,N'-dimethylaminopyridine (DMAP) in 200 ml of methylene chloride. The mixture is subsequently stirred at room temperature for 12 hours and worked up in a customary manner, and the product is purified by crystallization, to give optically active 2-cyano-2-methylhexyl 4'-heptyloxy-2,3-difluorobiphenyl-4-carboxylate.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO.[BH4-].[Na+]>C1COCC1>[OH:3][CH:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)c1ccc(C#N)cc1
Reaction time: 0.5 h

Procedure:
4-Acetylbenzonitrile (3 g, 20.67 mmol) was dissolved in THF (5 mL) and MeOH (5 mL) and cooled to 0° C. NaBH4 (0.782 g, 20.67 mmol) was added slowly. The reaction aged at rt for 30 min and was concentrated. 2M aq HCl was added and the solution was extracted with EtOAc. The organic layer was washed with water, dried with Na2SO4, filtered and concentrated to provide the product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[S:5]1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:37]1([C:43]2[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=2[C:45](Cl)=[O:46])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[OH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:45](=[O:46])[C:44]3[CH:48]=[CH:49][CH:50]=[CH:51][C:43]=3[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[S:5]1
Reactant: Nc1ccc(S(=O)(=O)N2C=CC(CCO)Sc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Product: O=C(Nc1ccc(S(=O)(=O)N2C=CC(CCO)Sc3ccccc32)cc1)c1ccccc1-c1ccccc1

Procedure:
Compound 4 as prepared in Example 25 (0.6 g, 1.5 mM) was treated with N,O-bis(trimethylsilyl)acetamide (0.65 g, 3.0 ml) then with 2-phenylbenzoyl chloride (0.39 g,1.8 mM) as described in Example 22 to yield the title product as a white solid. m.p. 1H NMR (300 MHz, CDCl3) δ7.92 (d, J=7.4 Hz, 1H); 7.60-7.04 (m, 17H); 3.76 (m, 2H); 2.89 (m, 1H); 2.08 (m, 1H); 1.90 (m, 1H); 1.64 (m, 4H). m/z (MH+)545
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:24][C:25]2[S:29][N:28]=[C:27]([CH:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)[N:26]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[CH:22][S:23][C:16]=23)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[ClH:45]>C(Cl)Cl.O1CCOCC1>[ClH:45].[ClH:45].[ClH:45].[O:1]([C:8]1[C:9]([NH:24][C:25]2[S:29][N:28]=[C:27]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:26]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[CH:22][S:23][C:16]=23)[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: c1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
tert-butyl 4-(5-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (10 g, 16 mmol) was dissolved in 1:1 CH2Cl2:methanol and 4N HCl in dioxane was added (80 mL). The reaction was stirred for 1 hour and then concentrated in vacuo to afford 3-phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine trihydrochloride (10 g, 100%).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:21][C:15]3[N:16]=[CH:17][NH:18][C:19](=[O:20])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:23]1([NH2:27])[CH2:26][CH2:25][CH2:24]1>CS(C)=O>[CH:23]1([NH:27][C:2]2[C:3]([CH3:22])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:21][C:15]4[N:16]=[CH:17][NH:18][C:19](=[O:20])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCC1
Reactant: Cc1nc2cccc(-c3cc4c(=O)[nH]cnc4[nH]3)c2nc1F
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c(=O)[nH]cnc4[nH]3)c2nc1NC1CCC1
Temperature: 50 °C
Yield: 21.2 %

Procedure:
A glass microwave reaction vessel was charged with 6-(3-fluoro-2-methylquinoxalin-5-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (Example 264; 60 mg, 0.203 mmol) and cyclobutylamine (0.173 mL, 2.032 mmol) in DMSO (0.6 mL). The reaction was heated in an oil bath at 50° C. for 15 min. The mixture was purified by rpHPLC (Phenomenex Gemini C18 column (100×50 mm, 10 μm), 90 mL/min, 5-40% ACN in water with 0.1% TFA). Product-containing fractions were combined and ACN was removed in vacuo. The residual mixture was neutralized with saturated aq. NaHCO3, and the suspension was filtered and dried to give 6-(3-(cyclobutylamino)-2-methylquinoxalin-5-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (15 mg, 0.043 mmol, 21% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 347.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.69 (brs, 1H), 11.97 (brs, 1H), 8.10 (1H, d, J=7.2 Hz), 7.90 (1H, br. s.), 7.66 (1H, d, J=7.0 Hz), 7.47 (1H, br. s.), 7.37 (2H, br. s.), 4.50 (1H, br. s.), 2.58 (3H, br. s.), 2.16-2.28 (2H, m), 1.83-1.97 (2H, m).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[CH:10][C:11]3[O:15]C=[N:13][C:12]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:17].O>CCO.C(Cl)Cl>[ClH:17].[NH2:13][C:12]1[CH:16]=[C:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=[CH:10][C:11]=1[OH:15]
Reactant: c1ccc(Sc2ccc3ocnc3c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Nc1cc(Sc2ccccc2)ccc1O
Reaction time: 2 h

Procedure:
A solution of 5-(phenylthio)benzo[d]oxazole (1.04 g, 4.6 mmol) and conc. HCl (0.97 mL, 11 mmol) under nitrogen in 4.6 mL EtOH in a 50 mL rbf fitted with a water-cooled reflux condensor was placed in a 100° C. bath. After 2 h, the mixture was cooled, concentrated in vacuo and dried to give a yellow solid. The material was sonicated in 10 mL DCM, filtered, rinsing with DCM, and dried to give 2-amino-4-(phenylthio)phenol hydrochloride as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (s, 1H), 8.75 (br. s., 1H), 7.28-7.35 (m, 2H), 7.12-7.25 (m, 5H), 6.99 (d, J=8.0 Hz, 1H), 4.32 (br. s., 2H).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[S:16][C:15]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:14]=2[C:13]=1[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:27][CH:26]=1)=[O:24].Cl.O>C1COCC1.C(Cl)Cl>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:14]2[C:13]([C:23](=[O:24])[C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:29][CH:30]=3)=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH:2]=[O:1])[S:16][C:15]=2[CH:17]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3C3OCCO3)sc2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3C=O)sc2c1

Procedure:
To a solution of [2-(2-[1,3]dioxolan-2-yl-phenyl)-6-methoxy-benzo[b]thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (crude) in THF (15 mL), add HCl (2 mL, 5M) and water (2 mL). Heat the mixture to reflux for 30 min. Dilute with CH2Cl2 and quench with aq. NaHCO3. Wash the organic phase with water and brine, dry over MgSO4, filter and concentrate. Purify the crude product by flash chromatography (0-10% (2M NH3 in MeOH)/CH2Cl2) to afford 2-{6-methoxy-3-[4(2-piperidin-1-yl-ethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-benzaldehyde (410 mg) which is contaminated with unidentified byproducts and is used without further purification.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][N:12]=1.C[O:21][C:22]([CH2:24][CH:25]1[NH:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=O.C[O-].[Na+]>CS(C)=O.O=[Pt]=O>[O:21]=[C:22]1[NH:17][C:16]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[N:30]2[CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH:25]2[CH2:24]1
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=[Pt]=O
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN2c3ncccc3NC(=O)CC2C1
Temperature: 95 °C
Reaction time: 54 h

Procedure:
Diisopropylethylamine (3.03 mL, 17.34 mmol) was added to a mixture of 2-chloro-3-nitropyridine (2.75 g, 17.34 mmol) and the product of Example 22B (4.48 g, 17.34 mmol) in dimethyl sulfoxide (20 mL). The mixture was heated at 95° C. under nitrogen for 7 hours and then cooled to room temperature. Ice water (200 mL) was added, and the mixture was extracted with ethyl acetate (2×100 mL). The organic phase was washed with saturated brine (60 mL), dried (MgSO4) and concentrated under vacuum to an oil (6.81 g). This material was dissolved in methanol (400 mL), and PtO2 (25 mg, 0.11 mmol) was added. The flask was evacuated and purged with nitrogen (3 cycles) and then with hydrogen (3 cycles). The suspension was stirred under hydrogen (1 atm) for 54 hours. The flask was evacuated and purged with nitrogen (3 cycles) and the black suspension was filtered through diatomaceous earth with a methanol (2×10 mL) rinse. Sodium methoxide (Aldrich, 25% in methanol, 12.01 g, 55.6 mmol) was added to the filtrate, and the mixture was heated at reflux for 41 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2, eluted with methanol-CH2Cl2 (0:100-5:95), followed by crystallization from ethanol (10 mL) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 2.27-2.40 (m, 1H), 2.78 (dd, J=13.5, 5.9 Hz, 1H), 2.91-3.20 (m, 3H), 3.55-3.68 (m, 1H), 3.69-3.80 (m, 1H), 3.99-4.19 (m, 2H), 6.95 (dd, J=7.7, 5.0 Hz, 1H), 7.23 (dd, J=7.7, 1.4 Hz, 1H), 7.61 (s, 1H), 8.18 (dd, J=5.0, 1.8 Hz, 1H); MS (ESI) m/z 319 (M+H)+.
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:20]([CH:21]4[CH2:23][CH2:22]4)[C:19](Br)=[N:18][C:17]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:32])(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35].C(N(CC)CC)C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:20]([CH:21]4[CH2:23][CH2:22]4)[C:19]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])=[N:18][C:17]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:32])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4F)nc(Br)n3C3CC3)cc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4F)nc(C#C[Si](C)(C)C)n3C3CC3)cc21
Temperature: 25 °C
Yield: 86 %

Procedure:
Combine 1-isopropylsulfonyl-2-amino-6-(1-(cyclopropyl)-2-(bromo)-4-(2-fluorophenyl)-imidazol-5-yl)-benzimidazole (0.332 g, 0.64 mmol), trimethylsilylacetylene (0.36 mL, 2.56 mmol), tetrakis(triphenylphosphine)-palladium (0.150 g, 0.128 mmol), triethylamine (2 mL) and dimethylformamide (4 mL) and heat to 70° C. for 18 hours. Cool to ambient temperature and remove solvents under reduced pressure. Purify the residue on silica gel eluting with acetonitrile/dichloromethane mixtures to provide the title compound (0.295 g). MS(ES+): m/z=536.2 (M+H)+