Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[NH:27][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([NH2:26])[CH:20]=4)[C:13]=3[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[CH:29]1([C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][N:2]([CH3:28])[C:3]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[NH:27][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([NH:26][C:36](=[O:37])[C:35]5[CH:39]=[CH:40][C:32]([CH:29]6[CH2:31][CH2:30]6)=[CH:33][CH:34]=5)[CH:20]=4)[C:13]=3[CH:12]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: O=C(Cl)c1ccc(C2CC2)cc1
Reactant: CN(C)C(=O)N1CC=C(c2cc3c(-c4ccc(F)c(N)c4)ncnc3[nH]2)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CN(C)C(=O)N1CC=C(c2cc3c(-c4ccc(F)c(NC(=O)c5ccc(C6CC6)cc5)c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Intermediate 10 (80 mg, 0.210 mmol), 4-cyclopropyl-benzoyl chloride (J. Med. Chem., 52(14), 4329-4337; 2009) (76 mg, 0.421 mmol), and DMAP (2.6 mg, 0.021 mmol) in pyridine (2 ml) was stirred at r.t. overnight. The mixture was evaporated to dryness, then sat. aqueous NaHCO3 was added, and the mixture was extracted with DCM. The organic layer was dried, filtered, and evaporated to dryness. The residue was purified by flash chromatography (silica gel, EtOAc/MeOH/NH3 gradient) to obtain Example 20.
Reaction SMILES: [CH2:1]([N:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])[CH2:16][C:17](=O)[CH3:18])=[CH:10][C:9]=1[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:28][C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][CH:39]=1)[O:32][CH2:33][C:34]([NH2:36])=O.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1(C)C(C)=CC=CC=1.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[CH2:1]([N:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:15](=[O:20])[CH:16]=[C:17]([CH3:18])[N:36]=[C:34]2[CH2:33][O:32][C:31]2[CH:37]=[CH:38][CH:39]=[C:29]([F:28])[CH:30]=2)=[CH:10][C:9]=1[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN(CCCCCC)c1ccc(NC(=O)CC(C)=O)cc1F
Reactant: NC(=O)COc1cccc(F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: CCCCCCN(CCCCCC)c1ccc(-n2c(COc3cccc(F)c3)nc(C)cc2=O)cc1F
Temperature: 165 °C
Reaction time: 24 h
Yield: 26.3 %

Procedure:
To a mixture of N-(4-(dihexylamino)-3-fluorophenyl)-3-oxobutanamide (2.67 g, 7.05 mmol), and 2-(3-fluorophenoxy)acetamide (2.37 g, 14.0 mmol) in xylene (20 mL) was added titanium tetraisopropanolate (5.97 g, 21.0 mmol) and the mixture was stirred at 165° C. for 24 h. The mixture was cooled to rt and 120 mL of toluene and 150 mL of saturated NH4Cl aqueous solution were added. The resulting mixture stirred at rt overnight and filtered and the filtrate was extracted with DCM (150 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a yellow solid (0.95 g, 26%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]([CH2:20][CH3:21])=[O:19].[OH-].[Na+]>CO>[C:2]1([CH2:1][O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[CH:17][C:18](=[O:19])[CH2:20][CH3:21])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)=O
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(=O)C=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Benzyloxybenzaldehyde (100 g) and 43.2 g of methylethyl ketone were added to 1.2 1 of methanol and stirred at 15°-20° C. during which 125 ml of sodium hydroxide (50%) was added dropwise. Following completion of the addition of sodium hydroxide, the mixture was stirred at room temperature for about 8 hours. The resultant solid was collected and washed with water and recrystallized from acetone to yield the desired subtitled intermediate, m.p. 123°-125° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[N:11]([CH2:14][CH3:15])[CH:12]=[O:13])(=[O:8])[CH3:7].O>ClCCl>[Cl:4][CH2:7][C:6]([C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[N:11]([CH2:14][CH3:15])[CH:12]=[O:13])=[O:8]
Reactant: CCN(C=O)c1ccccc1C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCN(C=O)c1ccccc1C(=O)CCl
Reaction time: 4 h

Procedure:
A solution of sulphuryl chloride (12.7 ml) in dichloromethane (20 ml) was added dropwise to the solution of 2'-acetyl-N-ethylformanilide at 0° and the mixture stirred at 0° for 4 hours. Water (110 ml) was then added whilst maintaining the temperature below 10°. The dichloromethane layer was separated, washed with water (110 ml) and aqueous sodium chloride (6M, 250 ml) and then dried over magnesium sulphate to give a solution of 2'-(2-chloroacetyl)-N-ethylformanilide.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH2:21][CH2:22][OH:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:26][CH:27](Cl)[C:28]1[C:29]([CH3:34])=[CH:30][CH:31]=[CH:32][CH:33]=1.O>C1COCC1>[Cl:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][O:23][CH2:22][CH2:21][NH:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C(Cl)Cl
Reactant: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: ClCc1ccccc1COCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 2-(triphenylmethylamino)ethanol (5.00 g, 16.5 mmol) in THF (20 ml) was added dropwise to a suspension of NaH (60% in oil, 0.79 g, 19.8 mmol) in THF (30 ml) at room temperature and the mixture was stirred for 0.5 hour. α,α-Dichloro-o-xylene (1.56 g, 66.0 mmol) was added and the mixture was stirred for 24 h at reflux temperature. The mixture was poured into water (50 ml) and the whole was extracted with ether (50 ml×2). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=15/1 as eluent) to afford the titled compound as a colorless oil. (1.00 g, 14%)
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][O:7][CH2:6][C@@H:5]1[O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[N+]=[N-]>[Pd].C(O)C>[Si:10]([O:9][C@H:5]1[CH2:6][O:7][CH2:8][C@H:4]1[NH2:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1COC[C@H]1N=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@H]1COC[C@H]1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
A mixture of [(3R,4R)-4-azidotetrahydrofuran-3-yl]oxy-tert-butyl-dimethyl-silane (1.27 g, 5.22 mmol) and 10% palladium on carbon (25 mg, 0.023 mmol) in ethanol (20 mL) is stirred at room temperature under a hydrogen balloon for 16 h. The reaction is filtered through a pad of diatomaceous earth and the filtrate is concentrated in vacuo to give the title compound as a colorless oil (1.0 g, 88%). LC-ES/MS m/z 218 (M+1).
Reaction SMILES: [CH3:1][N:2]([S:17]([C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1)(=[O:19])=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[K+]>O1CCCC1.CO>[CH3:1][N:2]([S:17]([C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1)(=[O:19])=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3nccn3C)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1nccn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
Ethyl 7-{methyl[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}-1H-indole-2-carboxylate (2.87 g) was dissolved in a mixed solvent of tetrahydrofuran (30 mL)-methanol (20 mL). Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (2.0 g) in water (20 mL)) was added to this solution, and the mixture was stirred at room temperature for 16 hr, and concentrated under reduced pressure to evaporate methanol. The obtained residue was acidified with aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.65 g, yield: 100%) as colorless crystals. MS: 335 (MH+). melting point: 241-242° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20].[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][O:2][C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]2[CH2:7][CH2:8][N:9]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(CC(=O)N(C)C)CC2
Yield: 79.4 %

Procedure:
Into a 1-neck round-bottom flask was added 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.5 g, 2.20 mmol), 2-chloro-N,N-dimethyl-acetamide (0.45 mL, 4.41 mmol), potassium iodide (0.18 g, 1.10 mmol), and cesium carbonate (2.16 g, 6.61 mmol), in acetonitrile (15 mL), and the reaction was stirred overnight at reflux. The reaction mixture was next partitioned between water and ethyl acetate, and the layers separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic extracts were washed with water, dried (MgSO4), filtered, and concentrated, and the product was isolated by flash chromatography on SiO2 (MeOH/dichloromethane 0-10%) to give 2-(7-Methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide (537 mg, 79%) as a yellow solid. 1H-NMR (CDCl3) δ 7.67 (s, 1H), 6.82 (s, 1H), 3.95 (s, 3H), 3.30 (s, 2H), 3.09 (s, 3H), 2.98 (s, 3H), 2.85-3.05 (m, 4H), 2.73 (t, J=10.2 Hz, 4H); LC/MS (ESI+): 308.55 (M+H).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1)=[NH:9])[CH:4]([CH3:6])[CH3:5].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>N1C=CC=CC=1>[ClH:18].[CH2:3]([NH:7][C:8](=[NH:9])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[O:27])[CH:12]=1)[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)CNC(=N)Nc1cccc(N)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)CNC(=N)Nc1cccc(NC(=O)Nc2ccc(Cl)cc2)c1
Reaction time: 16 h

Procedure:
To a solution of 1-isobutyl-3-m-aminophenylguanidine dihydrochloride (19.6 g.) in pyridine (100 ml.) is added dropwise a solution of p-chlorophenyl isocyanate (11.5 g.) in pyridine (25 ml.) at room temperature. The mixture is stirred for 16 hours, and the pyridine is removed by distillation under reduced pressure. The residual gum is shaken with a mixture of ether (100 ml.) and 1% aqueous sodium hydroxide solution (10 ml.) to remove pyridine hydrochloride whereafter the product crystallizes. The solid is filtered off, washed with water and ether and dried, and recrystallized from ethanol/petroleum ether b.p. 40°-60° C. to give 1-(3-isobutylguanidino)-3-(3-p-chlorophenylureido)benzene hydrochloride, m.p. 215°-216° C.
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24]O)=[CH:12][N:11]=1)([CH2:3][CH3:4])[CH3:2].C(N(CC)CC)C.CS([Cl:40])(=O)=O.[Cl-].[Li+]>ClCCl>[CH:1]([O:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][Cl:40])=[CH:12][N:11]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C)Oc1cccc(Cc2ncc(CO)c3cc(OC)c(OC)cc23)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)Oc1cccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a stirred solution of [1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinolin-4-yl]-methanol (2.7 g, 7.08 mmol) in dichloromethane (14 mL) was added triethylamine (3.0 mL, 21.2 mmol) and methanesulphonyl chloride (1.24 mL, 15.6 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes and lithium chloride (1.4 g, 33 mmol) was added at this temperature. The reaction mixture was stirred at room temperature for 15 hrs and diluted with dichloromethane (150 mL). The reaction mixture was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 1-(3-sec-butoxy-benzyl)-4-chloromethyl-6,7-dimethoxy-isoquinoline (2.1 g, 74% yield) as a brown oil. The crude product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][CH:11]=2)[OH:9])=[CH:6][CH:5]=[C:4]([CH3:16])[N:3]=1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[C:7]([C:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=[C:4]([CH3:16])[N:3]=1
Reactant: Cc1ccc(C(O)c2cnnn2C)c(C)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)c2cnnn2C)c(C)n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A mixture containing (2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (9.8 g, 44.9 mmol, Intermediate 19: step a) and manganese dioxide (18.8 g, 184 mmol) in dry dioxane (225 mL) was heated to 100° C. with stirring. After 1 hour, the mixture was cooled to 40° C. The cooled mixture was filtered through a 2 cm pad of Celite® and rinsed with tetrahydrofuran (100 mL). The filtrate was concentrated to provide the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:48])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[CH:17](O)[CH2:16][CH:15]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:14]2[CH:27]=[CH:28][CH:29]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH:30]([CH3:35])[CH2:31][C:32]#[C:33][CH3:34])[C:8]=1[O:44][CH2:45][O:46][CH3:47].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:75]>CC#N>[CH3:1][O:2][C:3](=[O:48])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[CH:17]([Cl:75])[CH2:16][CH:15]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:14]2[CH:27]=[CH:28][CH:29]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH:30]([CH3:35])[CH2:31][C:32]#[C:33][CH3:34])[C:8]=1[O:44][CH2:45][O:46][CH3:47]
Reactant: CC#CCC(C)C(C=CC1C(O[Si](C)(C)C(C)(C)C)CC(O)C1c1cccc(CCCC(=O)OC)c1OCOC)O[Si](C)(C)C(C)(C)C
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: CC#CCC(C)C(C=CC1C(O[Si](C)(C)C(C)(C)C)CC(Cl)C1c1cccc(CCCC(=O)OC)c1OCOC)O[Si](C)(C)C(C)(C)C
Reaction time: 12 h
Yield: 82 %

Procedure:
A mixture of 4-(3-{3-(tert-butyl-dimethyl-silanyloxy)-2-[3-(tert-butyl-dimethyl-silanyloxy)-4-methyl-oct-1-en-6-ynyl]-5-hydroxy-cyclopentyl}-2-methoxymethoxy-phenyl)-butyric acid methyl ester of 506 mg (0.72 mmol), triphenyl phosphine (350 mg, 1.34 mmol), CH3CN (6 ml), pyridine (112 mg, 1.42 mmol), and CCl4 (240 mg, 1.55 mmol) was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and then, subjected to column chromatography on a silica gel to obtain 4-(3-{3-(tert-butyl-dimethyl-silanyloxy)-2-[3-(tert-butyl-dimethyl-silanyloxy)-4-methyl-oct-1-en-6-ynyl]-5-chloro-cyclopentyl}-2-methoxymethoxy-phenyl)-butyric acid methyl ester (426 mg, yield: 82%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2.C(N(CC)CC)C.[CH2:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18]>ClCCl>[CH:4]12[CH2:9][CH:7]([CH:6]=[CH:5]1)[CH2:8][CH:3]2[CH2:2][NH:1][S:19]([CH2:17][CH3:18])(=[O:21])=[O:20]
Reactant: NCC1CC2C=CC1C2
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NCC1CC2C=CC1C2
Reaction time: 24 h
Yield: 83.6 %

Procedure:
An oven-dried, nitrogen-flushed 1 L round bottom flask equipped with an addition funnel, nitrogen inlet, reagent inlet, and a teflon-coated stir bar was charged with 116.3 g 5-aminomethylnorbornene (0.944 mol,) 95.5 g triethylamine (0.944 mol,) and 1 L dichloromethane. The addition funnel was charged with 121.4 g ethanesulfonyl chloride (0.944 mol,) and 500 ml dichloromethane. The contents of the addition funnel were added dropwise to the flask over the course of approx. two hours. During this time, the reaction warmed gradually and finally began a gentle reflux. The reaction was left to stir for approx. 24 hours. The mixture was transferred into a separatory funnel, and the organic layer was washed twice with 300 ml water, 2× with 300 mL dilute sodium bicarbonate, and twice more with 300 ml water. The organic layer was dried over magnesium sulfate, then concentrated to yield an oil. Attempts to crystallize the oil from hexane:ethyl acetate failed. Silica gel column chromatography using hexane:ethyl acetate (60:40) as the eluent gave a clear, straw-colored oil that was further purified by vacuum distillation (140° C. at 5 microns of Hg) to provide 170 g of the desired ethanesulfonamide as a mixture of isomers. The product was identified by 1H and 13C NMR and IR spectroscopy.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=3[F:31])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[CH3:39][O:40][CH2:41][C:42](Cl)=[O:43]>C(Cl)Cl>[F:31][C:22]1[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:21]=1[CH2:20][CH2:19][NH:18][C:12]1[N:13]=[C:14]([O:16][CH3:17])[N:15]=[C:10]([C:6]2[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:42](=[O:43])[CH2:41][O:40][CH3:39])[CH:9]=[CH:8][CH:7]=2)[CH:11]=1
Reactant: COCC(=O)Cl
Reactant: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(CCN)c2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)NCCc1cccc(-c2cc(NCCc3ccc(C(F)(F)F)cc3F)nc(OC)n2)c1
Reaction time: 0.17 h

Procedure:
A solution of {6-[3-(2-amino-ethyl)-phenyl]-2-methoxy-pyrimidin-4-yl}-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine (150 mg, 0.35 mmol) and triethylamine (0.24 mL, 1.73 mmol) in DCM (5 mL) is treated with methoxyacetyl chloride (75 mg, 0.69 mmol) at 10° C. After 10 minutes at 10° C., the mixture is quenched with aqueous NaHCO3 solution (8 mL), and filtered through Chem-Elut with CH2Cl2 washing (10 mL). The filtrate is concentrated, and subjected to chromatography on silica gel eluting with 80% EtOAc in heptane to 5% MeOH in CH2Cl2 to give N-[2-(3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-ethyl]-2-methoxy-acetamide, which is treated with saturated solution of hydrogen chloride in EtOAc followed by lyophilization to afford N-[2-(3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-ethyl]-2-methoxy-acetamide hydrochloride [76 mg, Example 64]. LCMS: RT=2.24 minutes, MS: 507 (M+H). 1H NMR (300 MHz, CDCl3) □9.35 (1H, s), 7.9 (1H, brs), 7.6-7.4 (7H, m), 6.65 (1H, s), 4 (3H, s), 3.76 (3H, s), 3.8-3.7 (2H, m), 3.4 (2H, q, J=6.9 Hz), 3.25 (2H, s), 3.06 (2H, t, J=6.6 Hz), 2.82 (2H, t, J=7.5 Hz). IC50=56 nM
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(N(CC)CC)C.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([F:18])([F:30])[F:31])(=[O:28])=[O:27])[N:3]=1
Reactant: Brc1n[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1C(F)(F)F)n1nc(Br)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a suspension of 3-bromoindazole (500 mg, 2.54 mmol) in 8 ml CH2Cl2 was added triethyl amine (1.06 ml, 7.61 mmol) at room temperature. To this yellow solution was added 2-(trifluoromethyl)benzenesulfonyl chloride (0.392 ml, 2.54 mmol) and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified on SiO2 using 5% to 20% ethyl acetate in heptane to give 3-bromo-1-(2-(trifluoromethyl)phenylsulfonyl)-1H-indazole (894 mg)
Reaction SMILES: C(O[C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]4=[O:27])=[CH:17][CH:16]=3)[C:10](=[O:28])[C:9]=2[N:8]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[N:7]=1)=O)C.[Li+].[BH4-].C(Cl)Cl.P(Br)(Br)Br>C1COCC1.CC(O)=O.[Zn]>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([N:8]2[C:9]3[C:10](=[O:28])[N:11]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][C:22]5=[O:27])=[CH:17][CH:16]=4)[CH2:12][CH2:13][C:14]=3[C:6]([CH3:4])=[N:7]2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(N3CCCCC3=O)cc1)C2=O
Agent: BrP(Br)Br
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C)c3c2C(=O)N(c2ccc(N4CCCCC4=O)cc2)CC3)cc1
Reaction time: 24 h
Yield: 5.8 %

Procedure:
To 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (0.59 g, 1.2 mmol) in THF (25 mL) was added 2M LiBH4 in THF (0.96 mL, 1.9 mmol) and the reaction was heated to reflux for 2.5 h. To the crude alcohol were added CH2Cl2 (25 mL) and PBr3 (0.14 mL) and the reaction was stirred 24 h. Extraction with CHCl3, washing with water, and drying (Na2SO4) afforded a crude bromo-compound. The bromo-compound was heated in AcOH (15 mL) and activated Zn (0.39 g, 6 mmol) at 120° C. for 24 h. Purification by HPLC and freeze-drying afforded 30 mg (58%) of a white solid; High Resolution Mass Spec (M+H)+ for C25H27N4O3 431.2092.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C@H:17]([C:26](O)=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH3:16][C@H:17]([C:26]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC[C@H](C)C(=O)O
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCC[C@H](C)C(=O)Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
{circle around (1)}: A mixture comprising 2.00 g of 4-benzyloxyphenol, 1.86 g of (S)-1-methylnonylcarboxylic acid, 2.06 g of DCC and 20 g of dichloromethane was stirred at room temperature for 30 minutes. Then, a catalytic amount of 4-N,N-dimethylaminopyridine was added to the mixture, and the mixture was further stirred at room temperature for 12 hours. After finishing the reaction, insoluble substances were filtered off, followed by distilling off dichloromethane from the filtrate. The resultant residue was purified by means of silica gel column chromatography, whereby 3.2 g of (S)-4-(1′-methylnonylcarbonyloxy)-1-benzyloxybenzene was obtained.