Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[CH:4]1([C:10]2[C:18]3[C:17](=[O:19])[NH:16][C:15]([C:20]4[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=4[O:30][CH3:31])=[N:14][C:13]=3[N:12]([CH3:32])[N:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C>O>[CH:4]1([C:10]2[C:18]3[C:17](=[O:19])[NH:16][C:15]([C:20]4[CH:25]=[CH:24][C:23]([S:26]([N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)(=[O:28])=[O:27])=[CH:22][C:21]=4[O:30][CH3:31])=[N:14][C:13]=3[N:12]([CH3:32])[N:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(S(=O)(=O)N2CCN(C)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.9 %

Procedure:
To a 2 ml anhydrous dichloromethane solution of 87.2 mg (0.2 mmol) of the compound obtained in Example 48, 26.6 μl (0.24 mmol) of N-methylpiperazine and 70 μl (0.5 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 20 hours. Then, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=50/1˜30/1) to obtain 87 mg (87%) of the captioned compound.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3([C:33]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([CH3:52])=[C:40]([C:42]5[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=5)[CH:41]=4)=[O:34])[CH2:32][CH2:31]3)=[CH:29][C:24]=2[O:23][CH2:22]1.CCN(C(C)C)C(C)C>O1CCOCC1>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3([C:33]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([CH3:52])=[C:40]([C:42]5[CH:47]=[CH:46][C:45]([S:48]([N:1]6[CH2:8][CH2:7][CH2:6][C@H:2]6[C:3]([OH:5])=[O:4])(=[O:49])=[O:50])=[CH:44][CH:43]=5)[CH:41]=4)=[O:34])[CH2:32][CH2:31]3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)Cl)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reaction time: 1 h

Procedure:
L-Proline (57 mg, 0.50 mmol) was treated with N,O-bis(trimethylsilyl)acetamide (250 μL, 1.0 mmol) in 1 mL dioxane overnight at 50° C. To this mixture was added 5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-methylbiphenyl-4-sulfonyl chloride (˜35 μmol, 400 μl solution in chloroform) followed by DIEA (100 μl). The reaction mixture was kept at room temperature for 1 h, evaporated, and diluted with DMSO (400 μl). The resulting solution was subjected to preparative HPLC purification. Fractions containing the desired material were combined and concentrated in vacuum centrifuge at 40° C. to provide the trifluoroacetic salt of (S)-1-{5′-[(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2′-methyl-biphenyl-4-sulfonyl}-pyrrolidine-2-carboxylic acid. ESI-MS m/z calc. 548.1, found 549.1 (M+1), retention time 3.40 min; 1H NMR (250 MHz, DMSO-d6) δ 1.04 (m, 2H), δ 1.38 (m, 2H), δ 1.60 (m, 1H), δ 1.80-1.97 (m, 3H) δ 2.16 (s, 3H), δ 3.21 (m, 1H), 3.39 (m, 1H), 4.15 (dd, 1H, J=4.1 Hz, J=7.8 Hz), δ 6.01 (s, 2H), δ 6.89 (s, 2H), δ 6.98 (s, 1H), δ 7.21 (d, 1H, J=8.3 Hz), δ 7.45 (d, 1H, J=2 Hz), δ 7.52 (dd, 1H, J=2 Hz, J=8.3 Hz), δ 7.55 (d, 2H, J=8.3 Hz), δ 7.88 (d, 2H, J=8.3 Hz), δ 8.80 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]1([NH:17][CH2:18][C:19]([F:27])([CH2:25][CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:17]([CH2:18][C:19]([F:27])([CH2:25][CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CCOC(=O)C(F)(CC)CNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(F)(CC)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (1.4 g, 7.2 mmol) in anhydrous acetone (50 ml) at 0° C., was added dropwise a solution of ethyl 2-((cyclopentylamino)methyl)-2-fluorobutanoate (1.38 g, 6 mmol) in acetone (10 mL) over 10 min. After which, potassium carbonate (2.5 g, 18 mmol) was added and the whole was stirred at rt for 18 h. After evaporation in vacuo, the residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with NaHCO3, brine and water, dried over Na2SO4 and concentrated in vacuo to give a red residue which was used directly for next step (2.6 g). [M+H] calc'd for C16H22ClFN4O4, 389; found 389.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=2)=[CH:25][NH:24][N:23]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(F)c1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(F)c4)nc23)cc(C)n1
Yield: 20.2 %

Procedure:
Reaction of 1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (151 mg, 0.5 mmol), prepared from commercially available 3-fluoro-4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (46 mg, 20%). MS (ISP) 455.0 [(M+H)+]; mp 245° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[C:31]2[O:30][CH:29]=[C:28]([Cl:32])[C:27]=2[CH:26]=[CH:25][CH:24]=1>>[ClH:1].[ClH:32].[Cl:32][C:28]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([NH:22][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=4[O:12][CH:13]4[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]4)[N:5]=[CH:4][N:3]=3)[C:31]=2[O:30][CH:29]=1
Reactant: Nc1cccc2c(Cl)coc12
Reactant: COc1cc(OC2CCN(C)CC2)c2c(Cl)ncnc2c1
Product: COc1cc(OC2CCN(C)CC2)c2c(Nc3cccc4c(Cl)coc34)ncnc2c1
Product: Cl

Procedure:
Using an analogous procedure to that described in Example 5, 4-chloro-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline was reacted with 7-amino-3-chlorobenzofuran to give the title compound, a portion of which was treated with a saturated methanolic ammonia solution. The mixture was filtered and the filtrate was evaporated to give the free base; NMR Spectrum: (CDCl3) 2.0-2.4 (m, 6H), 2.33 (s, 3H), 2.9 (m, 2H), 3.93 (s, 3H), 4.6 (m, 1H), 6.56 (s, 1H), 6.9 (s, 1H), 7.3-7.4 (m, 2H), 7.7 (br s, 1H), 8.64 (s, 1H), 8.7 (d, 1H), 10.3 (br s, 1H); Mass Spectrum: M+H+ 439 and 441.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.Cl>O.C1COCC1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([N:8]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH3:7])=[O:27])=[CH:20][CH:21]=1
Reactant: CNc1ccc(C(=O)O)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N(C)c2ccc(C(=O)O)cc2)cc1
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
Aqueous solution (50 ml) of sodium carbonate (23 g) was added to THF solution (50 ml) of 4-(methylamino)benzoic acid (5.0 g), and p-anisoyl chloride (5.6 g) was added dropwise to the solution under ice-cooling, which was stirred for 15 minutes, and then stirred at room temperature for 30 minutes. Concentrated hydrochloric acid was added to the reaction mixture under ice-cooling to make the water layer acidic, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using silica gel column chromatography (development solvent; hexane˜hexane:ethyl acetate=1:2), and recrystallized (ethyl acetate-hexane) to give the titled compound (4.8 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Mg]Br)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:25][C:26]1[CH:27]=[C:28](Br)[CH:29]=[C:30](F)C=1)C1C=CC=CC=1.[Mg].[O:35]1CCCC1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:30]2([OH:35])[CH2:29][CH2:28][CH2:27][CH:26]2[O:25][CH3:18])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Reactant: C1CCOC1
Reactant: Fc1cc(OCc2ccccc2)cc([Mg]Br)c1
Agent: [Mg]
Product: COC1CCCC1(O)c1cc(F)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
After repetition of the above reaction, a solution of 2-methocyclopentanone(12.5 g) in tetrahydrofuran (10 ml) was added to a solution of 3-benzyloxy-5-fluorophenylmagnesium bromide [prepared by heating a mixtureof 3-benzyloxy-5-fluorobromobenzene (31 g), magnesium powder (2.65 g) and tetrahydrofuran (20 ml) to 40° C. for 2 hours] and the mixture was stirred at ambient temperature for 2 hours. The mixture yes evaporated andthe residue was partitioned between diethyl ether and water. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue as purified by column chromatography using a 9:1 v/v mixture of methylene chloride and diethyl ether as eluent. There was thus obtained, as a mixture of diastereoisomers, 1-(3-benzyloxy-5-fluorophenyl)-2-methoxycyclopentanol (21.7 g, 62%), as anoil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:23]2[C:28](Cl)=[N:27][CH:26]=[CH:25][N:24]=2)[NH:16][C:17](=O)[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C(C(N)C2C(Cl)=NC=C[N:46]=2)C=CC=1)C1C=CC=CC=1.CCN(CC)CC.C(Cl)(=O)C(C)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:24]3[CH:25]=[CH:26][N:27]=[C:28]([NH2:46])[C:23]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Reactant: CC(C)(C)C(=O)NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Agent: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(-c2cccc(OCc3ccccc3)c2)c2c(N)nccn12
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
N-[(3-Benzyloxyphenyl)-(3-chloropyrazin-2-yl)-methyl]-2,2-dimethylpropionamide: To a solution of the crude C-(3-benzyloxyphenyl)-C-(3-chloropyrazin-2-yl)-methylamine (444 mg, max. 1.36 mmol) in CH2Cl2 (5 mL), cooled by ice/water, are added NEt3 (210 μL, 152 mg, 1.51 mmol), DMAP (8 mg, 0.07 mmol), and pivaloyl chloride (185 μL, 181 mg, 1.50 mmol), then the cooling bath is removed, and the reaction solution is stirred at ambient temperature for 4.5 h. More pivaloyl chloride (90 μL, 88 mg, 0.73 mmol) and NEt3 (100 μL, 73 mg, 0.72 mmol) are added and also after further 2.5 h, and the solution is stirred overnight at ambient temperature. The reaction mixture is taken up in EtOAc (35 mL), washed with diluted HCl, water, NaHCO3 sol., and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material is chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with hexanes:EtOAc 10:1 (1-17)→3:1 (18-41)→2:1 (42-56)], yielding the title compound as orange oil; 1H NMR (CDCl3, 400 MHz) δ 1.21 (s, 9H), 5.03 (s, 2H), 6.50 (d, J=8.0 Hz, 1H), 6.86-6.90 (m, 1H), 6.93-6.97 (m, 2H), 7.23 (t, J=7.8 Hz, 1H), 7.29-7.43 (m, 6H), 8.32 (d, J=2.4 Hz, 2H), 8.50 (d, J=2.4 Hz, 1H). MS (ES+): m/z 410.1/412.1 (100/36) [MH+], 309.1/311.1 (32/12) [MH+-tBuCONH2].
Reaction SMILES: C1(N[C:8](=[O:35])[C@H:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31]C=3)=O)=[CH:21][CH:20]=2)[NH:10]C(OC(C)(C)C)=O)CCCCC1.Cl.[O:37]1CCOCC1>CCCCCC>[CH2:26]([O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C@@H:9]([C:8]([OH:35])=[O:37])[NH2:10])=[CH:24][CH:23]=1)[C:27]1[CH:29]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCC(=O)c2ccccc2)cc1)C(=O)NC1CCCCC1
Agent: Cl
Solvent: CCCCCC
Product: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the above compound (II) (1.0 g) was added under ice-cooling 4N-hydrogen chloride/dioxane solution (4.5 ml) and the mixture was stirred at room temperature for 30 minutes. Hexane (30 ml) was added to this solution and the precipitated crystalline substance was collected by filtration, washed with ether and then dried under reduced pressure to give quantitatively 4-benzyloxy-L-phenylalanine 4-cis/trans-methylcyclohexylamide hydrochloride (III). On the other hand, triethylamine (0.6 ml) was added to a solution of trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarboxylic acid (0.62 g) dissolved in dry tetrahydrofuran (30 ml) and ethyl chlorocarbonate (0.25 g) was added under ice-cooling, followed by stirring for 30 minutes. To this solution were added the above compound (III) (0.73 g) and triethylamine (1 ml), and the mixture was stirred at room temperature for 3 hours. After evaporation of the solvent, the residue was extracted with ethyl acetate, washed with water and dried to give 0.2 g of N-[trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarbonyl]-4-benzyloxyl-L-phenylalanine 4-cis/trans-methylcyclohexylamide (IV). To the above compound (IV) (0.2 g) was added under ice-cooling 4N-hydrogen chloride/dioxane solution (0.5 ml) and the mixture was stirred at room temperature for 30 minutes. Hexane (20 ml) was added to this solution and the precipitated crystalline substance was collected by filtration, washed with ether and then dried under a reduced pressure to give 0.1 g of N-(trans-4-aminomethylcyclohexylcarbonyl)-4-benzyloxy-L-phenylalanine 4-cis/trans-methylcyclohexylamide hydrochloride.
Reaction SMILES: N([O-])=O.[Na+].[C:5]([C:7]1[CH:8]=[C:9]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=3)=[CH:18][C:17](N)=[N:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])#[N:6].[ClH:29].C(O)(=O)C>O>[Cl:29][C:17]1[CH:18]=[C:19]([C:20]2[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=2)[N:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([C:5]#[N:6])[CH:8]=2)[N:16]=1
Reactant: Cl
Reactant: COc1ccc(-n2nc(N)cc2-c2ccc(SC)cc2)cc1C#N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(Cl)cc2-c2ccc(SC)cc2)cc1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (0.36 g) in water (0.5 ml) was added to an ice cooled mixture of 1-(3-cyano-4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazol-3-amine (1.08 g), concentrated hydrochloric acid (15 ml) and acetic acid (35 ml). The mixture was stirred at 0° C. for 30 minutes and added portionwise to a mixture of cuprous chloride (1.37 g) and concentrated hydrochloric acid (10 ml) at ambient temperature. The mixture was refluxed for 1 hour, poured into water and extracted with toluene. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with toluene to give 3-chloro-1-(3-cyano-4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazole (0.29 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][CH:40]([NH:1][CH2:2][CH:3]([OH:4])[C:5]4[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=4)[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Product: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(NCC(O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from N-[5-(2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide, and Reference Example 73, N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as a yellow solid; mp 205-218° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.15-1.30 (m, 2H), 1.70-1.90 (m, 2H), 2.50-3.00 (m, 5H), 2.89 (s, 3H), 3.62 (s, 3H), 3.65 (s, 3H), 3.65-3.85 (m 2H), 4.40-4.40 (m, 1H), 6.50-7.10 (m, 8H), 7.45 (d, 2H), 9.11 (s, 1H); MS (ES) m/z: 621.0 (MH+); HRMS Calcd. for C28H37N4O8S2 (MH+): 621.2053. Found: 621.2058.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]>N1C=CC=CC=1>[CH2:1]([S:3]([NH:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cc(C(=O)Nc2ccccc2)ccc1OC
Yield: 90.4 %

Procedure:
Prepared according to the procedure described for Example 121 using ethanesulfonyl chloride (1.5 mL, 15.8 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10 mmol) and pyridine (25 mL) to afford the product (3.023 g); m.p. 175-177° C. after trituration in hexanes/ethyl acetate (1:1).
Reaction SMILES: C[Al](C)C.[C:5]([N:9]1[C:13]([NH2:14])=[CH:12][C:11]([CH:15]2[CH2:18][C:17]([O:21][CH3:22])([O:19][CH3:20])[CH2:16]2)=[N:10]1)([CH3:8])([CH3:7])[CH3:6].C([O:25][C:26](=O)[C:27]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH3:28])C.[NH4+].[Cl-]>CCCCCCC.C(Cl)Cl>[C:5]([N:9]1[C:13]([NH:14][C:26](=[O:25])[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)([CH3:35])[CH3:28])=[CH:12][C:11]([CH:15]2[CH2:16][C:17]([O:19][CH3:20])([O:21][CH3:22])[CH2:18]2)=[N:10]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: COC1(OC)CC(c2cc(N)n(C(C)(C)C)n2)C1
Reactant: CCOC(=O)C(C)(C)c1ccccn1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCCCCCC
Product: COC1(OC)CC(c2cc(NC(=O)C(C)(C)c3ccccn3)n(C(C)(C)C)n2)C1
Reaction time: 0.25 h

Procedure:
A solution of trimethylaluminum in heptane (2.0 M, 19.5 mL) was added slowly to a solution of 2-tert-butyl-5-(3,3-dimethoxy-cyclobutyl)-2H-pyrazol-3-ylamine (8.98 g) in CH2Cl2 (60 mL) at room temperature. After 15 min, a solution of 2-methyl-2-pyridin-2-yl-propionic acid ethyl ester (6.85 g) in CH2Cl2 (60 mL) was added. The reaction mixture was heated to reflux overnight. Saturated aqueous NH4Cl solution was added and the mixture was extracted with CH2Cl2 (2×). The combined organic layers were dried over Na2SO4 and concentrated to afford N-[2-tert-butyl-5-(3,3-dimethoxy-cyclobutyl)-2H-pyrazol-3-yl]-2-pyridin-2-yl-isobutyramide as an oil that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.Cl>>[ClH:1].[CH:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=2)[C:2]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:12]
Reactant: CC(=O)Nc1cccc(-n2c(Cl)c(C=O)c3ccccc32)c1
Reactant: C1CNCCN1
Agent: Cl
Product: CC(=O)Nc1cccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)c1
Yield: 37 %

Procedure:
N-[3-(2-chloro-3-formyl-indol-1-yl)phenyl]-acetamide is reacted with piperazine as described in Step 2 of Example 29 and subsequently treated with hydrochloric acid as described in Example 44 to afford N-{3-[3-Formyl-2-(piperazin-1-yl)-indol-1-yl]phenyl}-acetamide hydrochloride (37% yield) as a cream solid. ESI/MS 363 (M+H); RT 2.2 min.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH3:13][Si:14]([CH3:29])([CH3:28])[CH2:15][CH2:16][O:17][C:18](ON1C(=O)CCC1=O)=[O:19].C(N(CC)CC)C>ClCCl>[CH3:13][Si:14]([CH3:29])([CH3:28])[CH2:15][CH2:16][O:17][C:18]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:19]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: COC(=O)CCCCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCCCNC(=O)OCC[Si](C)(C)C
Reaction time: 5 h
Yield: 81.6 %

Procedure:
Methyl 7-amino-heptanoate hydrochloride (7.0 g, 35.9 mmol) was dissolved in dichloromethane (75.4 mL), and N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (10.0 g, 38.6 mmol) and triethylamine (10 mL, 71.7 mmol) were then added at room temperature. The mixture was stirred for 5 hours, and then quenched with water (100 mL), and separated. The aqueous layer was extracted with dichloromethane (50 mL). The organic layers were combined, then dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to obtain 8.89 g (29.3 mmol, 82% yield) of methyl 7-(2-trimethylsilanyl-ethoxycarbonylamino)-heptanoate.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].IC.CC(OC)(C)C>CN(C=O)C>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: COC(C)(C)C
Product: COC(=O)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
To a 100 mL round bottom flask was added 3-bromo-2-fluorobenzoic acid (5.00 g, 22.8 mmol, Oakwood), potassium carbonate (3.17 g, 22.9 mmol), and DMF (30 mL). Iodomethane, 2 M in MTBE (11.6 ml, 23.2 mmol) was added and the reaction mixture was stirred at RT for 16 hours. The reaction was filtered and the filtrate concentrated was in vacuo. The resulting brown crude residue was taken up with EtOAc and again filtered and concentrated to give methyl 3-bromo-2-fluorobenzoate (4.76 g, 20.4 mmol, 89.5% yield), as a brown syrup that was used in the Step 2 without further purification.