Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][C:9]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].Cl.[CH3:21]OC(OC)(C)C>CO.C(Cl)Cl>[CH3:21][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:9]1[NH:10][C:11]2[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=1
Reactant: COC(C)(C)OC
Reactant: Cn1c(=O)c2[nH]c(CCCC(=O)O)nc2n(C)c1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCc1nc2c([nH]1)c(=O)n(C)c(=O)n2C

Procedure:
10 g of theophylline-8-butyric acid are suspended in 50 ml of methanol. For one hour HCl-gas is fed into the suspension. While further feeding HCl-gas into the suspension, heating for one hour under reflux is effected. The feed of HCl-gas is interrupted, and 13.5 ml of 2,2-dimethoxypropane are added to the suspension. Afterwards, for a further 20 minutes HCl-gas is fed into the suspension. After standing over night at room temperature, the suspension is brought to dryness in vacuo. The residue is dissolved in 300 ml of methylenechloride. After having extracted the methylenechloride phase twice with 100 ml of saturated aqueous soda solution and twice with 100 ml of water, it is dried over annealed sodium sulfate and brought to dryness in vacuo. The residue is recrystallized from methanol. In this way 5.15 g (48.4 percent of the theoretically-calculated amount) of the title compound of melting point 200° to 204° C. are obtained.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][CH2:3]1.[C:19]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:11][C:10]([O:9][C:7]([NH:6][C@H:5]([CH2:4][CH2:3][C:2](=[O:1])[C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:28][CH:29]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:8])([CH3:13])[CH3:12]
Reactant: Ic1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized (2.9 g, 16%) following a similar procedure as set out earlier in Description 2 starting from 1-(1,1-dimethylethyl) 2-ethyl (2R)-5-oxo-1,2-pyrrolidinedicarboxylate (D16, 10.5 g 40.8 mmol) and 4-iodophenyl phenylmethyl ether (13.34 g, 43 mmol); Rt (HPLC): 6.37 min; MS: (ES/+) 464 m/z: [M+Na+], C25H31NO6 requires 441; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.92 (d, 2H); 7.29-7.45 (m, 5H); 6.99 (d, 2H); 5.18 (bs, 1H); 5.12 (s, 2H); 4.29-4.4 (bm, 1H); 4.20 (q, 2H); 2.94-3.16 (m, 2H); 2.22-2.33 (m, 1H); 2.00-2.15 (m, 1H); 1.39 (s, 9H); 1.28 (t, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=4)[N:15]=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:4][C@H:3]1[OH:24].[O-]S([O-])(=O)=O.[Na+].[Na+].[O:32]=[C:33]1[CH2:38][S:37][C:36]2[CH:39]=[CH:40][C:41]([CH:43]=O)=[N:42][C:35]=2[NH:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[OH:24][C@@H:3]1[CH2:4][C:5]2([CH2:11][CH2:10][N:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=4)[N:15]=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:6][C@@H:2]1[NH:1][CH2:43][C:41]1[CH:40]=[CH:39][C:36]2[S:37][CH2:38][C:33](=[O:32])[NH:34][C:35]=2[N:42]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2nccc(N3CCC4(CC3)C[C@@H](O)[C@@H](N)C4)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2nccc(N3CCC4(CC3)C[C@@H](O)[C@@H](NCc3ccc5c(n3)NC(=O)CS5)C4)c2n1
Reaction time: 12 h
Yield: 46.9 %

Procedure:
To a solution of (2R,3S)-3-amino-8-[6-(methyloxy)-1,5-naphthyridin-4-yl]-8-azaspiro[4.5]decan-2-ol (40 mg, 0.122 mmol) in DCM-EtOH (1.5 mL, 1:1) at 25° C. were added Na2SO4 (35 mg, 0.244 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (24 mg, 0.122 mmol). After 12 h, NaBH(OAc)3 was added and after stirring an additional 2 h the solution was partitioned between NaHCO3 (sat)-DCM. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 2% MeOH in DCM (1% NH4OH)) yielding the title compound (29 mg, 47%) as a yellow foam: LCMS (ES) m/e 507 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=5.2 Hz, 1H), 8.17 (d, J=9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.83 (d, J=5.3 Hz, 1H), 4.12-4.19 (m, 1H), 4.03 (s, 3H), 3.92 (AB quart., 2H), 3.52-3.67 (m, 4H), 3.47 (s, 2H), 3.21-3.27 (m, 1H), 1.91-2.10 (m, 4H), 1.75-1.78 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]2[NH:12][CH:13]=[C:14]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=3)[C:3]=12.[NH:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]1.C(O)(C(F)(F)F)=O>CCCCO.C(Cl)Cl>[ClH:1].[NH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]3[NH:12][CH:13]=[C:14]([NH:15][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=4)[C:3]=23)[CH2:25]1
Reactant: O=C(Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12)c1cccnc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCCCO
Product: Cl
Product: N[C@@H]1CCCN(c2c(C(F)(F)F)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
N-(4-Chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (80 mg, 0.2 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.14 g, 0.70 mmol) in n-BuOH (3 mL) were stirred at 143° C. (bath) for 32 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-80% CH3CN/water gradient; 30 CV) to give a solid. This solid was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 30 minutes. The solvent was removed. The residue was dissolved in DCM (1 mL) and 2N HCl in ether (2 mL) was added. The solid formed was collected by filtration to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (0.047 g, 39% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.43 (d, 1H), 10.54 (s, 1H), 9.42 (d, 1H), 8.98 (dd, 1H), 8.88 (d, 1H), 8.53 (s, 1H), 8.25 (br s, 3H), 7.97 (dd, 1H), 7.74 (d, 1H), 3.36-3.29 (m, 1H), 3.12-3.05 (m, 2H), 3.04-2.95 (m, 2H), 1.94-1.84 (m, 1H), 1.67-1.57 (m, 1H), 1.54-1.42 (m, 1H), 1.33-1.19 (m, 1H); LCMS (APCI+) m/z 405.1 (M+H)+.
Reaction SMILES: [Si]([O:8][C@H:9]([C:46]1[CH:47]=[C:48]([OH:53])[CH:49]=[C:50]([OH:52])[CH:51]=1)[CH2:10][NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C@@H:30]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:31][CH2:32][N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH:24]=2)=[CH:16][CH:15]=1)(C(C)(C)C)(C)C.CCN(CC)CC.F.F.F>CO.O1CCCC1>[NH3:11].[CH:37]([N:33]([CH:34]([CH3:36])[CH3:35])[CH2:32][CH2:31][C@@H:30]([C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]([C:46]3[CH:47]=[C:48]([OH:53])[CH:49]=[C:50]([OH:52])[CH:51]=3)[OH:8])=[CH:19][CH:18]=2)[CH:28]=[CH:27][C:26]=1[OH:29])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([CH3:38])[CH3:39]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3cc(O)cc(O)c3)cc2)ccc1O)C(C)C
Agent: F
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2ccc(CCNC[C@H](O)c3cc(O)cc(O)c3)cc2)ccc1O)C(C)C
Product: N
Reaction time: 8 h

Procedure:
5-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-({2-[4-(2-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}ethoxy)phenyl]ethyl}amino)ethyl]benzene-1,3-diol (Preparation 44, 174 mg, 0.23 mmol) was dissolved in methanol (5 ml) and tetrahydrofuran (10 ml), and triethylaminetrihydrofluoride (0.23 ml, 1.4 mmol) added. The mixture was stirred overnight and then the solvent removed in vacuo. The residue was dissolved in methanol (10 ml) and 880 ammonia (1 ml) and the solvent removed under reduced pressure. This was repeated and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (95/5/0.5 to 80/20/2.0 by volume) to furnish the title compound as a foam, 83 mg.
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[NH:33][C@H:34]([C:38]([OH:40])=[O:39])[CH:35]([CH3:37])[CH3:36]>CCOCC>[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[NH:33][C@H:34]([C:38]([OH:40])=[O:39])[CH:35]([CH3:37])[CH3:36].[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[NH:33][CH:34]([CH:35]([CH3:37])[CH3:36])[C:38]([O:14][CH2:13][C:9]1[NH:10][CH:11]=[CH:12][C:8]=1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:39]
Reactant: OCc1[nH]ccc1Cc1ccccc1
Agent: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)OCc1[nH]ccc1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-benzylpyrrolylmethyl alcohol (0.99 mmol) and triethylamine (0.14 g, 1.38 mmol) in ether (about 15 ml), under nitrogen, is added by syringe a solution of the acid chloride of N-(2-chloro-4-trifluoromethylphenyl)valine (1.5 mmol) in ether. The mixture is stirred for 30 minutes and then quenched with saturated aqueous sodium bicarbonate. The ether phase is washed with aqueous sodium bicarbonate, water and brine and filtered through silica. Evaporation of solvent, followed by thin layer chromatography using a circular chromatography, eluting with 20% ether/hexane, gives the 3-benzylpyrrolylmethyl ester of N-(2-chloro-4-trifluoromethylphenyl)valine, [3-benzylpyrrolylmethyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate].
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:23]1[N:28]=[C:27]([NH2:29])[N:26]=[C:25]2[NH:30][N:31]=[CH:32][C:24]=12.C(N(C(C)C)CC)(C)C.O>CC(N(C)C)=O>[C:1]1([S:7]([N:10]2[CH2:16][CH2:15][CH:14]([NH:17][C:23]3[N:28]=[C:27]([NH2:29])[N:26]=[C:25]4[NH:30][N:31]=[CH:32][C:24]=34)[CH2:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCN(S(=O)(=O)c2ccccc2)c2ccccc2C1
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc(NC2CCN(S(=O)(=O)c3ccccc3)c3ccccc3C2)c2cn[nH]c2n1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
To a solution of 1-(phenylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-amine in anhydrous dimethylacetamide (1 mL) was added 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (135 mg, 1.0 mmol) and diisopropylethylamine (0.4 mL, 2.30 mmol). The mixture was stirred at 120° C. for 20 hours. After cooling to room temperature the mixture was poured into water (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organics were dried over sodium sulfate and concentrated to a residue which was purified by reverse phase chromatography on a preparative LC/UV/MS system using a mass triggered fractionation. Compounds were eluted from the HPLC column (Maccel 120-10-C18 SH 10 μm 20 mmID×50 mm) at 88 ml/min with 5-95 acetonitrile/water gradient using 0.1% TFA as modifier to yield N4-(1-(phenylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (13.4 mg).
Reaction SMILES: [I-].C(OC([NH:9][CH:10]1[C:54](=[O:55])[N:12]2[C:13]([C:38]([O:40]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:39])=[C:14](/[CH:17]=[CH:18]/[CH2:19][N+:20]3([CH3:37])[CH2:28][C:27]4[C:22](=[CH:23][C:24]([O:33][C:34](=[O:36])[CH3:35])=[C:25]([O:29][C:30](=[O:32])[CH3:31])[CH:26]=4)[CH2:21]3)[CH2:15][S:16][C@H:11]12)=O)(C)(C)C.[C:56]([OH:62])([C:58]([F:61])([F:60])[F:59])=[O:57]>C(OC(C)C)(C)C>[F:59][C:58]([F:61])([F:60])[C:56]([O-:62])=[O:57].[NH2:9][CH:10]1[C:54](=[O:55])[N:12]2[C:13]([C:38]([OH:40])=[O:39])=[C:14](/[CH:17]=[CH:18]/[CH2:19][N+:20]3([CH3:37])[CH2:28][C:27]4[C:22](=[CH:23][C:24]([O:33][C:34](=[O:36])[CH3:35])=[C:25]([O:29][C:30](=[O:32])[CH3:31])[CH:26]=4)[CH2:21]3)[CH2:15][S:16][C@H:11]12
Reactant: CC(=O)Oc1cc2c(cc1OC(C)=O)C[N+](C)(C/C=C/C1=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)[C@H]3SC1)C2
Reactant: O=C(O)C(F)(F)F
Agent: [I-]
Solvent: CC(C)OC(C)C
Product: CC(=O)Oc1cc2c(cc1OC(C)=O)C[N+](C)(C/C=C/C1=C(C(=O)O)N3C(=O)C(N)[C@H]3SC1)C2
Product: O=C([O-])C(F)(F)F

Procedure:
Diphenylmethyl 7-t-butoxycarbonylamino-3-[(E)-3-(5,6-diacetoxy-2-methyl-2-isoindolinio)-1-propen-1-yl]-3-cephem-4-carboxylate iodide (Va) (610 mg, 0.69 mmol) was treated with TFA (6 ml) at room temperature for 30 min. The reaction mixture was diluted with isopropyl ether. The resulting precipitate was collected by filtration to yield 502 mg (quantitative yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][N:7]2[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15].[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][N:7]2[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(CCC)n1ccc(=O)c2c(Br)cccc21
Reactant: Cc1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(CCC)n1ccc(=O)c2c(-c3ccc(C)cc3C)cccc21
Temperature: 90 °C
Yield: 84.4 %

Procedure:
A mixture of 5-Bromo-1-(1-propylbutyl)quinolin-4(1H)-one (0.096 g, 0.30 mmol), 2,4-dimethylbenzeneboronic acid (0.067 g, 0.45 mmol), potassium carbonate (0.124 g, 0.89 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol) were put under nitrogen gas. Dioxane (4 mL) was added followed by water (27 μL 1.5 mmol). The reaction was heated at 90° C. overnight. The solution was cooled and concentrated. Flash chromatography (60% ethyl acetate/hexanes) gave 0.088 g (85% yield) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([O:16]C)=O.[CH3:18]OC(OC)N(C)C.[CH2:26]([O:28][CH:29]([O:41][CH2:42][CH3:43])[CH2:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=1[O:39][CH3:40])[CH3:27]>C(O)C>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:14](=[O:16])[N:36]([C:35]4[CH:37]=[CH:38][C:32]([O:31][CH2:30][CH:29]([O:28][CH2:26][CH3:27])[O:41][CH2:42][CH3:43])=[C:33]([O:39][CH3:40])[CH:34]=4)[CH:18]=[N:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: CCOC(COc1ccc(N)cc1OC)OCC
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N
Reactant: COC(OC)N(C)C
Solvent: CCO
Product: CCOC(COc1ccc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1OC)OCC
Temperature: 90 °C

Procedure:
To a solution of methyl 3-amino-5-(4-chlorophenyl)-2-thiophenecarboxylate (2.0 g, 7.47 mmol, Maybridge, Inc) in ethanol (20 mL) was added dimethylformamide dimethyl acetal (2.5 mL, 2.5 eq, Aldrich). The reaction mixture was refluxed in a 90° C. oil bath for 3 h at which point the solvents were removed by rotary evaporation. Coevaporation with toluene removed the excess dimethylformamide dimethyl acetal. To the resulting residue was added ethanol (20 mL) and 4-(2,2-diethoxyethoxy)-3-methoxyaniline (2.3 g, 1.2 eq, Example H1). The reaction mixture was heated to 100° C. for 36 hours. The solvent was removed by rotary evaporation and the product purified by column chromatography followed by recrystallization from hot MeOH yielding the intermediate (0.82 g, 22%). 1H NMR (CDCl3) δ 1.22 (6H, t), 3.63-3.83 (4H, m), 3.90 (3H, s), 4.14 (2H, d, J=5.3 Hz), 4.92 (1H, t, J=5.2 Hz), 6.97 (2H), 7.06 (1H, d, J=8.5 Hz), 7.46 (2H, d, J=8.5 Hz), 7.58 (1H, s), 7.68 (2H, d, J=8.4 Hz), 8.24 (1H, br, s). LCMS m/z=501 (m+H+).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl[C:8]1[N:17]=[C:16](Cl)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[H-].[Na+].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN(C)C=O.C(OCC)(=O)C.O1CCOCC1>[CH:1]1([O:6][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:17]=2)[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: OC1C=CCC1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: C1CNCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: C1=CC(Oc2nc(N3CCNCC3)nc3ccccc23)CC1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
To a solution of 2-cyclopenten-1-ol [cf. J. Org. Chem., 40, 1864 (1975)] (996 mg) and 2,4-dichloroquinazoline (2.36 g) in dimethylformamide (10 ml) is added 60% sodium hydride (in oil) (568 mg) with stirring at room temperature, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with ethyl acetate, and washed with water 5 times. The ethyl acetate solution is dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting residue is briefly purified with medium pressure column chromatography (eluent, chloroform) to give a crystalline substance. The crystalline substance is added to a solution of piperazine (4.02 g) in dioxane (26 ml) with stirring at 70° C., and the mixture is stirred at the same temperature for one hour. The reaction mixture is diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The resulting residue is purified by medium pressure liquid column chromatography (eluent, chloroform:methanol=10:1, 5:1, v/v) to give 4-[(cyclopent-2-en-1-yl)oxy]-2-(1-piperazinyl) quinazoline (1.57 g) as crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][C:22]([N:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([Cl:32])[N:27]=3)[CH3:25])=[CH:23][C:16]=2[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:34][C:35]1[CH:36]=[C:37]([S:41]([NH2:44])(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1>C(O)C.Cl>[ClH:32].[C:1]([O:5][C:6](=[O:33])[N:7]([C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][C:22]([N:24]([CH3:25])[C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([S:41](=[O:43])(=[O:42])[NH2:44])[CH:36]=4)[N:27]=3)=[CH:23][C:16]=2[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CN(c1ccc2c(c1)nc(N(C(=O)OC(C)(C)C)c1ccccc1)n2C)c1ccnc(Cl)n1
Agent: Cl
Solvent: CCO
Product: CN(c1ccc2c(c1)nc(N(C(=O)OC(C)(C)C)c1ccccc1)n2C)c1ccnc(Nc2cccc(S(N)(=O)=O)c2)n1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a solution of {5-[(2-Chloro-pyrimidin-4-yl)-methyl-amino]-1-methyl-1H-benzoimidazol-2-yl}-phenyl-carbamic acid tert-butyl ester (100 mg, 0.22 mmol) and 3-amino-benzenesulfonamide (38 mg, 0.22 mmol) in ethanol was added HCl (1 drop, 1M in diethyl ether), and the reaction was heated to 70° C. After 20 h, the reaction was filtered to give the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 10.15 (s, 1H), 8.44 (s, 1H), 7.84 (d, J=6.6 Hz, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.61 (s, 1H), 7.27-7.39 (m, 10H), 5.79 (d, J=5.1 Hz, 1H), 3.78 (s, 3H), 3.51 (s, 3H), 1.41 (s, 9H). MS (ESI) m/z=601 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a solution of (RS)-tert-butyl 4-[(4-chlorobenzenesulfonyl)-(2,5-difluorophenyl)-methyl]-piperidine-1-carboxylate (0.75 g, 1.5 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (5 ml) and the mixture was stirred at room temperature for 30 minutes. The mixture was washed with sodium hydroxide solution (1N, 5 ml), water (5 ml), dried (MgSO4) and evaporated under reduced pressure to yield (RS)-4-[(4-chlorobenzenesulfonyl)-(2,5-difluorophenyl)methyl]-piperidine as a white solid (0.5 g, 83%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][N:13]=[C:12]([C:15]([OH:17])=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CN(C(ON1N=N[C:28]2[CH:29]=[CH:30][CH:31]=N[C:27]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([N:45]([CH:48]([CH3:50])[CH3:49])CC)(C)C>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][N:13]=[C:12]([C:15]([NH:45][C@H:48]([C:49]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH3:50])=[O:17])[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc(-c2ccc3[nH]ncc3c2)on1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cc(-c2ccc3[nH]ncc3c2)on1)c1ccccc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
5-(1H-Indazol-5-yl)isoxazole-3-carboxylic acid (36 mg, 0.16 mmol, Example 71A), was dissolved in N,N-dimethylformamide (1.0 mL) followed by the addition of HATU (60 mg, 0.16 mmol) dissolved in N,N-dimethylformamide (0.5 mL). Then a solution of(S)-1-phenylethanamine (22 mg, 0.18 mmol), dissolved in N,N-dimethylformamide (0.6 mL) was added, followed by diisopropylethylamine (56 μL, 0.32 mmol) dissolved in N,N-dimethylformamide (0.2 mL). The resulting mixture was shaken for 3 hours at 40° C. The reaction was filtered, checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase HPLC (Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm), 50 mL/min, 10-100% acetonitrile/0.1% trifluoroacetic acid in water) to provide the title product. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 1.50 (d, 3H), 5.06-5.22 (m, 1H), 7.23-7.29 (m, 2H), 7.34-7.38 (m, 2H), 7.40-7.45 (m, 2H), 7.70-7.75 (m, 1H), 7.87-7.92 (m, 1H), 8.25-8.27 (m, 1H), 8.39-8.41 (m, 1H), 9.28 (d, 1H). MS (ESI+) m/z 333 (M+H)+; (ESI−) m/z 331 (M−H)−.