Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([NH:17][OH:18])=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:1]([O:18][NH:17][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NO
Product: CC(C)(C)OC(=O)NOC(=O)c1ccccc1

Procedure:
[(tert-Butoxy)carbonyl]amino benzoate is prepared from benzoyl chloride and N-tert-butoxycarbonyl hydroxylamine according to Scheme 1 described by Carpino et al. J. Am. Chem. Soc. 1959, 955-957. (7.2 g, 80%), 1H NMR (250 MHz, DMSO-d6) δ ppm 10.89 (1H, br. s.), 7.90-8.12 (2H, m), 7.68-7.82 (1H, m), 7.51-7.65 (2H, m), 1.43 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[CH:14][CH:15]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[Br:25]NC(=O)CCC(N)=O>>[Br:25][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[NH:7][S:8]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[CH:14][CH:15]=1)(=[O:9])=[O:10]
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1cc(NS(=O)(=O)c2ccc(-c3cccc([N+](=O)[O-])c3)s2)on1
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3cccc([N+](=O)[O-])c3)s2)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 136C. Reaction of N-(3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamide (328 g, 0.90 mmol) with N-bromosuccinamide (160 mg, 0.90 mmol) gave the final product. A fraction of this material was further purified by preparative HPLC to give the pure sulfonamide as a brown solid, m.p. 132° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:6][C:5]([CH:18]2[O:22][CH2:21][CH2:20][O:19]2)=[C:4]([N+:23]([O-])=O)[CH:3]=1.[BH4-].[Na+]>[Pd].C(O)C.O.C(OCC)(=O)C>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[C:5]1[C:4]([NH2:23])=[CH:3][C:2]([F:1])=[C:7]([C:8]2[CH:9]=[C:10]([O:16][CH3:17])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=2)[CH:6]=1
Reactant: COc1cc(OC)cc(-c2cc(C3OCCO3)c([N+](=O)[O-])cc2F)c1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1cc(OC)cc(-c2cc(C3OCCO3)c(N)cc2F)c1
Temperature: 90 °C
Yield: 84.3 %

Procedure:
A mixture of 2-(6-fluoro-3′,5′-dimethoxy-4-nitrobiphenyl-3-yl)-1,3-dioxolane (1.8 g, 5.2 mmol), sodium borohydride (587.9 mg, 15.5 mmol) and 10% palladium on carbon (0.2 g) in ethanol/water (33 mL, v/v=10/1) was heated at 90° C. for 1 hour. After that, the mixture was diluted with ethyl acetate (150 mL), and washed by water (50 mL) and brine (50 mL). The organic layer was dried over sodium, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1 to 4/1) to afford the title compound (1.4 g, 88%) as a yellow solid. MS (ES+) C17H18FNO4 requires: 319, found: 320 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[CH3:18][N:19]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].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>[CH3:11][C:9]1[CH:10]=[C:2]([C:18]#[N:19])[C:3]2[CH:4]=[N:5][N:6]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:7]=2[CH:8]=1
Reactant: Cc1cc(Br)c2cnn(C3CCCCO3)c2c1
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C#N)c2cnn(C3CCCCO3)c2c1
Temperature: 100 °C
Yield: 50 %

Procedure:
A mixture of 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.1 g, 3.74 mmol), Zn(CN)2 (873 mg, 7.46 mmol), and Pd(PPh3)4 (646 mg, 0.56 mmol) in NMP (25 mL) under nitrogen was heated at 100° C. overnight. After it was cooled to RT, the reaction mixture was partitioned between EtOAc (300 mL) and water (50 mL). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography using petroleum ether:EtOAc (10:1) as eluting solvents to afford 6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile as white solid (400 mg, 50%). MS (ESI): m/z=242.3 [M+1]+.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][N:6]([C:9](=[O:34])[CH:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:11]([NH:13][S:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)(=[O:16])=[O:15])=[O:12])[CH2:7][CH3:8])C.O.[OH-].[Na+]>C1COCC1>[CH2:27]([CH:10]([C:11]([NH:13][S:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)(=[O:16])=[O:15])=[O:12])[C:9]([N:6]([CH2:7][CH3:8])[CH2:5][C:4]([OH:35])=[O:3])=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CN(CC)C(=O)C(Cc1ccccc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC(=O)O)C(=O)C(Cc1ccccc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 2.5 h
Yield: 89.5 %

Procedure:
To a mixture of the compound (250 mg) obtained by Example 2 in THF (10 mL)/water (3 mL) was added 1 mol/L aqueous sodium hydroxide solution (1.5 mL) at room temperature, and the mixture was stirred for 2.5 hr. After concentration under reduced pressure, the residue was adjusted to pH=1-2 by the addition of 1 mol/L hydrochloric acid and extracted with ethyl acetate (50 mL×2). The organic layer was washed with saturated brine and concentrated under reduced pressure to give the title compound (211 mg) as a white solid.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([C:11]2[O:15][C:14]([C:16]3[N:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:18][CH:17]=3)=[N:13][N:12]=2)=[O:10])=[CH:3][CH:2]=1>CC(O)=O.CCOC(C)=O>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][C:9]([C:11]2[O:15][C:14]([C:16]3[N:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][CH:17]=3)=[N:13][N:12]=2)=[O:10])=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(-c2nnc(C(=O)CCc3ccc(-c4ccccc4)cc3)o2)n1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1cccc(-c2nnc(C(=O)CCc3ccc(-c4ccccc4)cc3)o2)n1
Yield: 100.2 %

Procedure:
The title compound was prepared from 28 (8.7 mg, 0.021 mmol) following general procedure A. Preparative thin layer chromatography (SiO2, 0-4% AcOH-EtOAc) afforded the title compound (8.4 mg, 100%) as a white solid: 1H NMR (DMSO-d6+0.1% TFA, 600 MHz) δ 8.32 (d, 1H, J=7.7 Hz), 8.17 (d, 1H, J=7.8 Hz), 8.01 (t, 1H, J=7.9 Hz), 7.85 (br s, 1H), 7.48 (d, 2H, J=7.4 Hz), 7.45 (d, 2H, J=8.1 Hz), 7.28 (t, 2H, J=7.7 Hz), 7.25 (d, 2H, J=8.1 Hz), 7.18 (t, 1H, J=7.3 Hz), 3.45 (t, 2H, J=7.4 Hz), 3.01 (t, 2H, J=7.4 Hz); 13C NMR (DMSO-d6+0.1% TFA, 150 MHz) δ 188.0, 167.0, 166.1, 165.0, 163.0, 151.1, 144.2, 142.1, 141.2, 140.5, 140.4, 130.6, 130.4, 129.2, 128.8, 128.5, 128.2, 44.7, 29.9; HRMS-ESI-TOF m/z 400.1288 ([M+H]+, C23H17N3O4 requires 400.1292).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCCCO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCC=O
Yield: 66.6 %

Procedure:
A solution of 1.0 g of 6-tert-butoxycarbonylamino-1-hexanol in 20 mL of methylene chloride was combined with 3 g of a 4 angstrom molecular sieve, 808 mg of N-methylmorpholine-N-oxide and a catalytic amount of tetrapropylammonium perruthenate, and stirred for 24 hours. The reaction solution was filtered through Celite, and concentrated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to obtain 660 mg of the desirable compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH2:33][OH:34])[CH:27]=1)[CH2:10][NH:11][C@H:12]([CH3:25])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([O:23]C)=[O:22])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Li+].Cl>O1CCCC1>[Si:1]([O:8][C@H:9]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH2:33][OH:34])[CH:27]=1)[CH2:10][NH:11][C@H:12]([CH3:25])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1cccc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(CO)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
A solution of methyl (3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate (Preparation 37) (7.04 g, 14.4 mmol) in tetrahydrofuran (40 ml) was treated with lithium hydroxide (28.9 ml of a 1M aqueous solution, 28.9 mmol) and the reaction left to stir at room temperature for 16 hours. Hydrochloric acid (28.9 ml of a 1M aqueous solution, 28.9 mmol) was added and then the tetrahydrofuran was removed in vacuo. The remaining aqueous layer was decanted and the residue washed with further water (10 ml). The residue was redisolved in methanol (30 ml) and the solvent removed in vacuo to give the title compound as a colorless foam (5.95 g) which was used without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Cl[C:22]1[C:31]([Cl:32])=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:33][CH3:34])[CH:28]=2)[N:23]=1>>[Cl:32][C:31]1[C:22]([C:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:10]=2)=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:33][CH3:34])=[CH:26][CH:25]=2
Reactant: CCOC(=O)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc2nc(Cl)c(Cl)cc2c1
Product: CCOC(=O)C1CC=C(c2nc3ccc(OC)cc3cc2Cl)CC1

Procedure:
Followed Scheme 2, Step 1 (see Ex. 8, Step 1) starting from ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate and 2,3-dichloro-6-methoxyquinoline (Intermediate 4).
Reaction SMILES: [CH3:1][O:2][NH2:3].[N+:4](/[C:7](=[CH:9]/[CH3:10])/[CH3:8])([O-:6])=[O:5]>>[CH3:1][O:2][NH:3][CH:9]([CH3:10])[CH:7]([N+:4]([O-:6])=[O:5])[CH3:8]
Reactant: C/C=C(\C)[N+](=O)[O-]
Reactant: CON
Product: CONC(C)C(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
O-Methylhydroxylamine (176 mg, 3.75 mmol) was added to (E)-2-nitro-2-butene (303 mg, 3 mmol) and the resulting mixture was stirred at 25° C. for 10 minutes. Then, the product was isolated and purified by silica gel thin-layer chromatography (eluent: ethyl acetate/hexane=1/5). O-Methyl-N-(α-methyl-β-nitropropyl)hydroxylamine (mixture of diastereomers, yield: 95%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[C:12](=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[C:12](=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccccc1NN1C(=O)c2[nH]c3cc(Cl)ccc3c(=O)c2C1=O
Agent: CS(=O)(=O)O
Solvent: CO
Product: COc1ccccc1-n1nc(O)c2c(=O)c3ccc(Cl)cc3[nH]c2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
A stirred suspension of 6-chloro-2-(2-methoxyanilino)2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]-quinoline-1,3,9-trione (1.78 g, 4.81 mM) in a solution of methanol (285 mL) and methanesulfonic acid (89 mL) was refluxed for 8 hours during which time a tan precipitate formed. The resulting suspension was cooled to room temperature and stirred for 16 hours. The suspension was filtered (the filtrate was saved for use in Example 30) and the collected solids were washed with methanol and then ether to give the title compound (0.889 g, 50%) as a yellow powder, mp 356°-359° C.; MS(CI): 370 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:26][CH2:27]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCNCC4)cc3C2=O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-6-(3-(piperazin-1-yl)propoxy)-2-p-tolyl-1H-inden-1-one (30 mg, 1.2 eq, 0.063 mmol) obtained in Step 2 in CH2Cl2 at 0° C. was added triethylamine (11 mL, 1.5 eq) and methylsulfonyl chloride (4.0 mL, 1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (17 mg, 74% for 2 steps).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:22]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:22][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[N:7][C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: C[C@@H]1CC[C@H](C(=O)N2CCCC2)CN1c1ccc([N+](=O)[O-])c(N)n1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CC[C@H](C(=O)N2CCCC2)CN1c1ccc(N)c(N)n1

Procedure:
A solution of cis-(1-(6-amino-5-nitropyridin-2-yl)-6-methylpiperidin-3-yl)(pyrrolidin-1-yl)methanone (500 mg, 1.50 mmol) in ethanol (20 mL) was added to a suspension of 10% palladium-on-carbon (250 mg) in ethanol under a nitrogen atmosphere. The suspension was hydrogenated using a balloon filled with hydrogen gas for 2 h at room temperature. The mixture was filtered through Celite and the filtrate was used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].[N:19]1([C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[C:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:22]1[CH2:23][CH2:24][N:19]([C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH2:20][CH2:21]1)=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: N#Cc1cnc(N2CCNCC2)s1
Product: CC(C)(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C#N)s2)CC1
Yield: 52 %

Procedure:
Prepared in analogy to example 1 (b) from 2-tert-butoxy-5-methanesulfonyl-benzoic acid (Example A12) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 52%). MS (m/e): 449.3 (M+H+, 50%), 466.4 (M+NH4+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH3:8].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[N+](C1C=CC([O:28][C:29]([C:31]2[CH:32]=[CH:33][C:34]([O:46][CH3:47])=[C:35]3[O:39][C:38]([S:40](=[O:45])(=[O:44])[N:41]([CH3:43])[CH3:42])=[CH:37][C:36]=23)=O)=CC=1)([O-])=O.O>CN(C)C=O>[CH3:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:1][C:29]([C:31]1[CH:32]=[CH:33][C:34]([O:46][CH3:47])=[C:35]2[O:39][C:38]([S:40](=[O:44])(=[O:45])[N:41]([CH3:43])[CH3:42])=[CH:37][C:36]=12)=[O:28]
Reactant: Cc1cnccc1N
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(S(=O)(=O)N(C)C)oc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2ccncc2C)c2cc(S(=O)(=O)N(C)C)oc12
Reaction time: 0.08 h
Yield: 81 %

Procedure:
To a stirred solution of 4-amino-3-methylpyridine (200 mg) in dimethylformamide (8 ml) under an atmosphere of nitrogen at 0° C. was added sodium hexamethyldisilazide (1.0M solution in tetrahydrofuran, 1.9 ml). The reaction mixture was stirred at this temperature for 5 minutes. 2-Dimethylsulfamyl-7-methoxy-benzofuran-4-carboxylic acid 4-nitrophenyl ester (400 mg) was then added and stirring continued for 30 minutes. Water (10 ml) was added and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (150 ml), washed with water (3×50 ml) and washed with brine (50 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography eluting with 10% methanol in ethyl acetate afforded the title compound as a white solid (0.3 g).
Reaction SMILES: F[C:2]1[C:7]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[C:7]([C@@H:8]3[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: O[C@H]1CCC[C@@H](c2cccnc2F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O[C@H]1CCC[C@@H](c2cccnc2Oc2ccc(Nc3ccccn3)cc2)C1
Temperature: 180 °C

Procedure:
A mixture of (rac)-cis-3-(2-fluoropyridin-3-yl)cyclohexanol (250 mg, 1.281 mmol), 4-(pyridin-2-ylamino)phenol (477 mg, 2.56 mmol), and cesium carbonate (834 mg, 2.56 mmol) in NMP (4 ml) was heated in a Biotage™ microwave reactor at 180° C. for 1.5 h. The mixture was partitioned between H2O (15 ml) and CH2Cl2 (30 ml), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×30 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure, and the resulting brown oil was purified by reversed phase HPLC (Gilson Gemini-NX 10u C18 110A, 100×50.0 mm, 10% to 95% H2O/MeCN, 0.1% TFA). The product containing fractions were combined, neutralized by the addition of solid Na2CO3, and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to deliver (rac)-cis-3-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)cyclohexanol as a tan solid. MS (ESI, pos. ion) m/z: 362.0 (M+1). IC50 (uM) 0.011024.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[C:20]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)[CH:21]=[CH:22][CH:23]=4)[CH2:28]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: c1cc2c(c(N3CCOCC3)c1)CNCC2
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2cccc(N3CCOCC3)c2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[CH3:10].S(Cl)([Cl:13])=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:13])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(CO)ccc1Br
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(CCl)ccc1Br
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a stirred solution of 1.1 (2.0 g, 9.947 mmol) in DCM (50 mL) at 23° C. was added thionyl chloride (1.451 mL, 19.89 mmol) and allowed to stir overnight. The reaction was concentrated and then purified by combiflash (0 to 10% EtOAc/hexanes) to provide 1.2 (1.9940 g, 91.32% yield).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C.[C:23](O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)[C:12]([O:14][CH2:15][CH3:23])=[O:13]
Reactant: COC(=O)c1cc(NC(=O)OC(C)(C)C)cc(C(C)(C)C)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(N)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 3-(tert.-butoxycarbonylamino)-5-tert-butylbenzoate (0.42 g) was dissolved in DCM (5 ml). To the resulting solution, TFA (1 ml) was added, the mixture was stirred for 30 min at room temperature and then concentrated in vacuum. The residue was dissolved in DCM and extracted with aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulphate and concentrated in vacuum to yield ethyl 3-amino-5-tert-butylbenzoate (0.28 g), which was used for the synthesis of example 112 without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH2:11][C:12]([O:14]C)=O)[CH2:5][NH:6]2>C1(C)C(C)=CC=CC=1>[NH:6]1[C:7]2[C:3]3[CH:4]([CH2:11][C:12](=[O:14])[NH:1][C:2]=3[CH:10]=[CH:9][CH:8]=2)[CH2:5]1
Reactant: COC(=O)CC1CNc2cccc(N)c21
Solvent: Cc1ccccc1C
Product: O=C1CC2CNc3cccc(c32)N1

Procedure:
1.80 g (8.73 mmol) methyl (4-amino-2,3-dihydro-1H-indol-3-yl)acetate in 100 mL xylene were refluxed for 30 h. The reaction mixture was evaporated down and purified by flash chromatography. The product-containing fractions were combined and evaporated down.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH2:11][C:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14].B.C1COCC1>C1COCC1>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][C:12]([CH3:17])([OH:18])[C:13]([F:16])([F:14])[F:15]
Reactant: CC(O)(CC(=O)Nc1ccc(Cl)cc1N)C(F)(F)F
Agent: B
Solvent: C1CCOC1
Product: CC(O)(CCNc1ccc(Cl)cc1N)C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 28.8 %

Procedure:
To a solution of N-(2-amino-4-chlorophenyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide (2.0 g, 6.75 mmol) in THF (30 mL) was added 1.0 M BH3-THF in THF (10 mL). The mixture was stirred at 50° C. overnight. The reaction was quenched by addition of 1 N HCl (15 mL) and the mixture was stirred at room temperature for 1 hour and then washed with EtOAc (30 mL). The resulting aqueous phase was basified to pH 9 with sat. aqueous solution of NaHCO3 and then extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine and then concentrated in vacuo. The residue was purified with flash column (EA:PE=0:1 to 1:1) to afford 4-[(2-amino-4-chlorophenyl)amino]-1,1,1-trifluoro-2-methylbutan-2-ol (0.55 g, yield: 28.8%).