Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[CH3:12]>[Fe].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[CH3:12])[NH2:9]
Reactant: COc1cc([N+](=O)[O-])ccc1C
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cc(N)ccc1C

Procedure:
Prepared according to procedure X using 2-methoxy-1-methyl-4-nitrobenzene (1.66 g, 9.9 mmol), iron powder (1.66 g, 29.8 mmol), and acetic acid (15.0 mL) to give 3-methoxy-4-methylaniline. 1H NMR (500 MHz, DMSO-d6) δ ppm 6.72 (1H, d, J=7.8 Hz), 6.18 (1H, d, J=2.0 Hz), 6.04 (1H, dd, J=7.8, 2.0 Hz), 4.81 (2H, s), 3.67 (3H, s), 1.96 (3H, s).
Reaction SMILES: BrCCBr.[CH2:5](I)[C:6]([CH3:9])([CH3:8])[CH3:7].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[C:22]2=[N:23][C:24]([O:28][CH2:29][C:30]3[N:31]([CH3:35])[N:32]=[CH:33][N:34]=3)=[C:25](Br)[CH:26]=[C:21]2[N:20]=[N:19]1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[C:22]2=[N:23][C:24]([O:28][CH2:29][C:30]3[N:31]([CH3:35])[N:32]=[CH:33][N:34]=3)=[C:25]([CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:26]=[C:21]2[N:20]=[N:19]1
Reactant: Cn1ncnc1COc1nc2c(cc1Br)nnn2-c1ccccc1F
Reactant: CC(C)(C)CI
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(cc1CC(C)(C)C)nnn2-c1ccccc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
A suspension of acid washed zinc dust (0.12 g, 1.80 mmol) and 1,2-dibromoethane (0.015 ml, 10 mol %) in dry DMF (3 ml) was stirred at room temperature under nitrogen for 5 min then warmed to 40° C. A solution of neopentyl iodide (0.25 ml, 1.85 mmol) in dry DMF (1 ml) was added and the mixture was stirred at 40° C. for 3 h. A solution of 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-bromo-1,2,3-triazolo[4,5-b]pyridine (0.15 g, 0.37 mmol) (Example 3, step c), tris(dibenzylideneacetone)dipalladium(0) (0.008 g, 2.5 mol %) and tri-2-furylphosphine (0.017 g, 20 mol %) in dry DMF (2 ml) was stirred at 40° C. under nitrogen for 10 min followed by addition of the organozinc reagent via syringe. The mixture was stirred for 18 h at 40° C. then cooled, diluted with water (60 ml), acidified with 1M aqueous citric acid and extracted with dichloromethane (2×30 ml). The extracts were dried (Na2SO4), filtered and concentrated. Preparative thin layer chromatography on silica gel, eluting with 2% methanol-dichloromethane, and trituration of the product with diethyl ether gave 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4triazol-3-ylmethoxy)-6-(2,2-dimethylpropyl)-1,2,3-triazolo[4,5-b]pyridine (0.060 g, 41%) as a white solid, m.p. 130-133° C. Found: C, 60.03; H, 5.51; N, 24.37. C20H22N7OF.0.25(H2O) requires C, 60.06; H, 5.67; N, 24.52%. δH (360 MHz; CDCl3) 0.93 (9H, s), 2.68 (2H, s), 3.82 (3H, s),5.52 (2H, s), 7.36-7.42 (2H, m), 7.54-7.61 (1H, m), 7.69 (1H, dd, J=7 and 7), 7.86 (1H, s) and 8.10 (1H, s); m/z (ES+) 396 (M+H+).
Reaction SMILES: [Na].[CH3:2][C:3](=O)[CH2:4][CH2:5][C:6](=O)[CH3:7].[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1.O>CO>[CH3:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:2])=[C:10]2[C:11]=1[CH:12]=[CH:13][CH2:14]2
Reactant: C1=CCC=C1
Reactant: CC(=O)CCC(C)=O
Agent: [Na]
Solvent: CO
Solvent: O
Product: Cc1ccc(C)c2c1C=CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
23 g (1.0 mol) of sodium were dissolved in portions in 250 ml of absolute methanol. A mixture of 45.6 g (0.40 mol) of 2,5-hexanedione and 39.7 g (0.60 mol) of cyclopentadiene was then added dropwise at 0° C. in the course of 1 hour. After the mixture had been stirred at room temperature for 1 hours, 50 ml of water were added and the mixture was extracted with about 2 1 of diethylether. The residue which remained after the solvent had been stripped off was chromatographed on 1.4 kg of silica gel 60. 38 g (65%) of 4,6-dimethylindene (yellowish oil) were eluted with hexane/methylene chloride (10:1).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])[C:3]=1[CH3:25].[C:26](OC(C)=O)([CH3:29])([CH3:28])[CH3:27].C([O-])(O)=O.[Na+]>Cl(O)(=O)(=O)=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:4]([CH:19]([O:24][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH3:23])=[O:21])[C:3]=1[CH3:25]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)C(O)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Reaction time: 4.5 h

Procedure:
Methyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate (298 mg, 0.71 mmol) was dissolved in t-BuOAc (18.0 mL, 134 mmol) and 7 drops of perchloric acid were added. The reaction was monitored by HPLC and TLC for progress. After 4.5 hours, the mixture was added to icy saturated NaHCO3 and stirred for 10-15 minutes. This mixture was extracted with EtOAc, extracts dried with sodium sulfate and concentrated in vacuo. Purification on silica gel using EtOAc in hexanes gave desired product as well as some starting material. 1H-NMR: (400 MHz, CDCl3): δ 8.39 (d, J=8.8 Hz, 1H); 7.57-7.48 (m, 3H); 7.45-7.42 (m, 1H); 7.35-7.31 (m, 1H); 7.28-7.18 (m, 2H); 5.20 (s, 1H); 3.70 (s, 3H); 2.72 (s, 3H); 0.99 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][N:6]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:7][C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:37][O:36][C:34](=[O:35])[CH2:33][N:1]1[CH2:4][CH:3]([CH2:5][N:6]([CH2:7][C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:2]1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)CC1CNC1
Reactant: COC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1CC(CN(Cc2ncccc2C)Cc2ncccc2C)C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 23.9 %

Procedure:
To a solution of azetidin-3-ylmethyl-bis-(3-methyl-pyridin-2-ylmethyl)-amine (0.4739 g, 1.6 mmol) in CH2Cl2 (16 mL) were added DIPEA (0.56 mL, 3.2 mmol), and methyl bromoacetate (0.18 mL, 1.9 mmol). The mixture was stirred at room temperature for 19 hours, and then saturated NaHCO3 (15 mL) was added and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (100:1:1 CH2Cl2-MeOH—NH4OH) provided 0.1411 g (24%) of (3-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-azetidin-1-yl)-acetic acid methyl ester as a yellow sticky oil. 1H NMR (CDCl3) δ 2.09 (s, 6H), 2.53-2.58 (m, 2H), 2.65-2.78 (m, 3H), 3.10 (s, 2H), 3.51 (t, 2H, J=6.0 Hz), 3.65 (s, 3H), 3.68 (s, 4H), 7.06-7.10 (m, 2H), 7.38 (d, 2H, J=9.0 Hz), 8.35 (d, 2H, J=6.0 Hz).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([S:31]([N:34]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[C:35]4[S:36][CH:37]=[CH:38][N:39]=4)(=[O:33])=[O:32])=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)=[C:17]([OH:49])[CH:16]=1>CN(C=O)C.CCOC(C)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([S:31](=[O:32])(=[O:33])[N:34]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[C:35]4[S:36][CH:37]=[CH:38][N:39]=4)=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)=[C:17]([CH:16]=1)[O:49][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4O)nccc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(F)ccc1-c1nccc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of Cs2CO3 (0.281 g, 0.863 mmol), ethyl bromoacetate (0.048 ml, 0.431 mmol) and 1-(4-fluoro-2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (From Step 1 in Example 189; 0.15 g, 0.288 mmol) in DMF (2.88 ml) was stirred at 60° C. for 16 h. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (2×50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography (25 g column), eluting with EtOAc:Hex: 0-50% to obtain ethyl 2-(5-fluoro-2-(6-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)phenoxy)acetate as light yellow solid. m/z (ESI) 608.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]([CH3:21])([CH3:20])[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>CN(C=O)C>[C:3]1([S:9][C:11]([CH3:21])([CH3:20])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(Cl)C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(Sc1ccccc1)C(=O)c1ccccc1
Temperature: 2 °C

Procedure:
10.88 g of a 50% suspension of sodium hydride in paraffin mineral oil are fed into 100 ml of DMF, followed slowly by 25.11 g of thiophenol. When dissolution is complete (65° C.), the solution is cooled to 2° C. and 36.5 g of 2-chloro-2-methylpropiophenone are fed in over 30 minutes maintaining the temperature below 10° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]2)=[CH:7][C:5]=1[NH2:6])([O-])=O>CC(C)=O>[F:11][C:9]1[C:8]([N:12]2[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]2)=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=1
Reactant: Nc1cc(-n2ccc(=O)cc2)c(F)cc1[N+](=O)[O-]
Solvent: CC(C)=O
Product: Nc1cc(F)c(-n2ccc(=O)cc2)cc1N
Yield: 85.6 %

Procedure:
First, 1.065 g of 2-nitro-4-fluoro-5-(4-oxo-4H-pyridin-1-yl)-aniline was dissolved in 45 ml of dimethylformaldehyde by heating and reduced over 195 mg of 10% paradium-carbon catalyst under atmospheric pressure. After the reaction, the reaction mixture was filtered through celite to remove the catalyst, and the mother liquor thus obtained was concentrated to dryness. The residue thus obtained was subjected to column chromatography using 30 g of silica gel, and fractions eluted with a methylene chloride-methanol (20:1) solution were collected. The collected fractions were combined and evaporated. The residue was recrystallized with ethanol to give 802 mg of 4-fluoro-5-(4-oxo-4H-pyridin-1-yl)-1,2-phenylenediamine.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH2:10]([O:13][C:14](Cl)=[O:15])[CH:11]=[CH2:12]>[OH-].[Na+].O>[CH2:10]([O:13][C:14]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)=[O:15])[CH:11]=[CH2:12]
Reactant: O=C(O)C1CCNCC1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOC(=O)N1CCC(C(=O)O)CC1
Reaction time: 1 h

Procedure:
A solution of isonipecotic acid (5.0 g) in 4N sodium hydroxide (9.7 ml) and water (6 ml) was stirred while adding dropwise and simultaneously allylchloroformate (6.0 ml) and 4N sodium hydroxide (16 ml). The reaction mixture was then stirred for 1 hour and washed with ether (50 ml). The aqueous phase was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layers were then washed with water, dried and evaporated to afford the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH3:3].C(O)(=O)[C@@H](C1C=CC=CC=1)O>CC(C)=O>[NH2:1][C@@H:2]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:8][CH2:9]1)[CH3:3]
Reactant: CC(N)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: CC(C)=O
Product: C[C@@H](N)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 19 %

Procedure:
From the mother liquor of the above mentioned first crystallization tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (20 g, 88 mmol) could be isolated (enriched in the other enantiomer). To the material was added (R)-(−)-mandelic acid (14 g, 92 mmol) and acetone (300 mL). The mixture was heated until a clear solution was obtained and allowed to cool to room temperature while stirring. The obtained precipitate was collected, rinsed with some acetone and recrystallized once as described above. After acid base separation, (R)-tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate was obtained (7.5 g, 99+% ee, 19% yield).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:7]([OH:9])=[O:8]>S(=O)(=O)(O)O>[CH3:1][C:6]1([C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CO
Reactant: C1=CCCCC1
Agent: O=S(=O)(O)O
Product: CC1(C(=O)O)CCCC1
Yield: 2.7 %

Procedure:
Cyclohexene (25 ml, 0.246 mol) was treated with conc. sulphuric acid (100 ml) and formic acid (18.9 ml, 0.5 mol) at 5° C. for two hours. The mixture was poured onto ice and extracted twice with EtOAc. The organic extracts were washed with brine, then extracted with 2M KOH. The basic extract was acidified with 2M HCl and extracted with CHCl3, filtered (Whatman® 1 PS phase separator) and evaporated. The resultant brown oil was purified by bulb-to-bulb distillation (125° C./oil pump) to give the title compound as a colourless oil (860 mg, 2%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: COc1ccc2ccc(C3(O)CCNCC3)cc2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Product: COc1ccc2ccc(C3(O)CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)cc2c1
Yield: 72.1 %

Procedure:
Beginning with 0.334 gm (1.77 mMol) (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 0.455 gm (1.77 mMol) of 4-hydroxy-4-(7-methoxynaphth-2-yl)piperidine, 0.570 gm (72%) of the title compound was recovered as a white solid by the procedure described in Example 9.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[N:4][N:3]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>>[CH2:23]([N:20]1[CH2:21][CH2:22][CH:17]([NH:16][C:2]2[C:11]3[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[N:4][N:3]=2)[CH2:18][CH2:19]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1cc(OC)c2cnnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: COc1cc(OC)c2cnnc(NC3CCN(Cc4ccccc4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 2.4 by reacting 1-chloro-5,7-dimethoxyphthalazine with 4-amino-1-benzylpiperidine.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.[CH3:29][CH:30](Cl)[CH2:31][N:32]([CH3:34])[CH3:33]>>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH:30]([CH3:29])[CH2:31][N:32]([CH3:34])[CH3:33])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1
Reactant: CC(Cl)CN(C)C
Reactant: Cc1cccc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)c1
Product: Cc1cccc(-c2nc3ccc(OC(C)CN(C)C)cc3n2Cc2ccccc2C(F)(F)F)c1

Procedure:
The title compound was prepared essentially as described above except that the compound of Example 120 was reacted with 1-methyl-2-(N,N-dimethylamino)ethyl chloride, yielding the title product as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]=[CH:15][C:14](=[O:17])[CH2:13][CH:12]1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH:12]1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH3:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(F)ccc1C1CC(=O)C=CN1C(=O)OCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1C1CC(=O)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.9 %

Procedure:
In 4600 ml of acetic acid was dissolved 190 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydro-2H-pyridine, and added thereto was 91 g of zinc powder and the mixture was stirred at room temperature for 24 hours. From the reaction mixture was removed insoluble matters by filtration, and the solvent was removed by distillation under reduced pressure. To the residue was added 400 ml of ethyl acetate, and the mixture was washed with an aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1), to give 166 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine as shown in Table 125 below.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:19]1[C:23]([NH2:24])=[CH:22][NH:21][N:20]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O>[NH:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]=[C:11]1[C:19]1[C:23]([NH:24][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:9])=[CH:22][NH:21][N:20]=1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Reactant: O=C(O)C1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: ClCCCl
Product: O=C(Nc1c[nH]nc1-c1nc2ccccc2[nH]1)C1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.3 %

Procedure:
A mixture of cyclohexanecarboxylic acid (36 mg, 0.28 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.25 mmol), EDC (58 mg, 0.30 mmol) and HOBt (41 mg, 0.30 mmol) in DMSO (2 ml) was stirred at ambient temperature for 24 h. The reaction mixture was partitioned between EtOAc (40 ml) and water (40 ml) and the organic portion dried (MgSO4), filtered and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-petrol (1:4, 1:3, 1:2, 1:1)] affording cyclohexanecarboxylic acid [3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-amide as an off-white solid (25 mg, 32%). (LC/MS: Rt 3.59, [M+H]+ 310.16).
Reaction SMILES: Br[C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:31]#[N:32])/[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1.[F:33]C1N=C(C=O)C=CC=1>>[C:31](/[C:9](=[CH:8]\[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:33])[N:7]=1)/[C:10]([NH:12][CH:13]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16])=[O:11])#[N:32]
Reactant: O=Cc1cccc(F)n1
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Product: CCCC(NC(=O)/C(C#N)=C/c1cccc(F)n1)c1ccc(OCCN(CC)CC)cc1
Yield: 61 %

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 33 except that 6-fluoropicolinaldehyde was used instead of 6-bromopicolinaldehyde. This produced crude product which was purified by flash silica gel column chromatography, eluting with 4:96 methanol/dichloromethane, to give 34 (105 mg, 61%) as a yellow oil: MS (ES+) m/z 439.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)c2ccc(C)cc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.1 %

Procedure:
A mixture of 4-methyl-1-[(4-methylphenyl)sulfinyl]benzene (1.15 g, 5.00 mmol), N-bromosuccinimide (1.08 g, 6.00 mmol), 2,2′-azobis-(2-methylpropionitrile) (100 mg, 0.600 mmol), and CCl4 (25.0 mL) as solvent was stirred for 5 min at room temperature and then heated to reflux for 12 h. The reaction mixture was cooled to room temperature and filtered and the solvent was removed in vacuo, affording a crude product which was used in the next step without any further purification (1.21 g, 78.1% yield). 1H NMR (CDCl3) δ 7.71-7.57 (m, 2H), 7.57-7.40 (m, 4H), 7.36-7.16 (m, 2H), 4.46 (s, 2H), 2.37 (s, 3H).
Reaction SMILES: O(C(C)(C)C)[K].[CH2:7]([OH:10])[CH2:8][OH:9].Br[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1>C(Cl)Cl>[N:14]1[CH:13]=[C:12]([O:9][CH2:8][CH2:7][OH:10])[CH:17]=[N:16][CH:15]=1
Reactant: OCCO
Reactant: Brc1cncnc1
Agent: CC(C)(C)O[K]
Solvent: ClCCl
Product: OCCOc1cncnc1
Yield: 6 %

Procedure:
KO-t-Bu (7.70 g, 68.6 mmol) was added to ethylene glycol (10.45 g, 168.4 mmol) under stirring. The mixture was gently heated in order to consume all KO-t-Bu. 5-Bromopyrimidine (8.45 g, 53.1 mmol) was added to the light brownish mixture. After 8 h of stirring at 130° C., CH2Cl2 (50 mL) was added to the brownish reaction mixture and two layers were formed. The CH2Cl2 layer was saved and the other layer was extracted with additional portions of CH2Cl2. The combined CH2Cl2 layers were concentrated in vacuo and the oily residue purified by column chromatography on silica gel using CHCl3/MeOH (9: 1) as eluent to give 0.45 g (6%) of the title product as an oil sufficiently pure for the next step. HRMS m/z calcd for C6H8N2O2 (M)+ 140.0586, found 140.0589.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][N:5]=1.C(N(CC)CC)C.[N:23]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:28]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:30])=[O:29])[CH2:12][CH2:11]2)[CH:7]=[CH:6][N:5]=1
Reactant: O=S(=O)(Cl)N1CCCC1
Reactant: COCc1nccc(N2CCNCC2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1nccc(N2CCN(S(=O)(=O)N3CCCC3)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-methoxymethyl-4-piperazin-1-yl-pyrimidine (prepared according to the method of Preparation One, 2.08 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in tetrahydrofuran (20 mL) was added N-pyrrolidinesulfonyl chloride (1.69 g, 10 mmol) at 0° C. and stirred for 3 h at ambient temperature. The mixture was diluted with ethyl acetate and washed twice with water. The organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to an oil which was purified by flash chromatography (95:5 dichloromethane:methanol) to give the title compound of Example 121, Step A as a clear oil, 3.24 g (93%). 1H NMR (COCl3, 300 MHz) δ 1.81-1.85 (m, 4H), 3.12-3.18 (m, 8H), 3.59 (s, 3H), 3.81 (m, 4H), 4.43 (s, 2H), 6.71 (d, 1H), 8.18 (d, 1H); MS (TS) 342 (MH+).