Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.C(=O)([O-])O.[Na+].Cl.[NH2:45][OH:46]>C(O)C.O>[OH:46]/[N:45]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][C@H:11]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: NO
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 120 °C
Yield: 102.7 %

Procedure:
To a microwave vial was added (R)-tert-butyl 4-(4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)phenyl)piperidine-1-carboxylate (35 mg, 68.0 μmol), sodium hydrogencarbonate (17.1 mg, 204 μmol) and hydroxylamine hydrochloride (14.2 mg, 204 μmol) in ethanol (1 mL) and water (0.02 mL). The vial was capped and heated at 120° C. for 15 min. The reaction mixture was poured onto aq. sat. sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound (37 mg), which contained ca. 15% of the (Z)-stereoisomer. White foam; MS (ESI+): m/z=: 530.3 [M+H]+).
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=2)=[CH:18][CH:17]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:2]1([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:16]3[CH:31]=[CH:30][C:19]([O:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=4)=[CH:18][CH:17]=3)[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCCNC2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCCC(c4ccccc4)C3)cc2)nc1
Yield: 314.4 %

Procedure:
Using a method similar to Example 345, using 3-phenyl-piperidine hydrochloric acid salt (0.413 g, 2.09 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.50 g, 0.417 mmol), sodium triacetoxyborohydride (0.656 g, 3.10 mmol), and acetic acid (0.172 mL, 3.00 mmol) in 1,2-dichloroethane (20.0 mL) provides, after reverse-phase HPLC, 0.508 g (64%) of the title compound as a white solid: mass spectrum (electrospray): m/z=388.1 (M+1); 1H NMR (DMSO-d6): 8.65 (d, 1H, J=2.2 Hz), 8.29 (dd, 1H, J=2.6, 8.8 Hz), 8.05 (s br, 1H), 7.50 (s br, 1H), 7.39 (d, 2H, J=8.4 Hz), 7.35-7.17 (m, 5H), 7.16-7.06 (m, 3H), 3.55 (s, 2H), 2.91 (d, 2H, J=10.6 Hz), 2.80 (t, 1H, J=11.3 Hz), 2.05 (q, 2H, J=8.4 Hz), 1.86 (d, 1H, J=11.3 Hz), 1.81-1.56 (m, 2H), 1.48 (dq, 1H, J=4.0, 12.1 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:26]([F:29])([F:28])[F:27])([O-:3])=[O:2].FC(F)(F)C(O)=O>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:26]([F:27])([F:28])[F:29])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of tert-butyl 2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)acetate (1 g, 2.39 mmol) in dichloromethane (30 ml) was added trifluoroacetic acid (5 ml). The resulting solution was stirred for 2 hours at room temperature and then concentrated under vacuum. The resulting solution was diluted with dichloromethane (200 ml), washed with water (100 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to afford 800 mg (92%) of 2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)acetic acid as yellow oil. 1H NMR (300 MHz, DMSO): δ 12.5 (broad s, 1H), 8.07 (d, J=9.3 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.07 (s, 1H), 6.87 (dd, J=2.4 Hz, 9.3 Hz, 1H), 4.03 (s, 2H), 3.32-3.46 (m, 2H), 1.91-2.03 (m, 4H), 1.17-1.41 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[S:7](Cl)(=[O:9])=[O:8].[NH2:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>>[Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[S:7]([NH:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])(=[O:9])=[O:8]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cc(Cl)sc1Cl
Yield: 65.6 %

Procedure:
Prepared according to the procedure described for Example 127 using 2,5-dichlorothiophene-3-sulfonyl chloride (0.75 g, 3.0 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (0.73 g, 3.0 mmol) to afford the product (0.9 g); m.p. 189-190° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1C>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([CH3:1])=[CH:3][C:4]=2[N+:9]([O-:11])=[O:10])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: Cc1ccc(Nc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 4-methyl-2-nitroaniline (1.006 g, 6.612 mmol), 4-benzyloxybromobenzene (5.794 g, 22.02 mmol), cuprous iodide (62.9 mg, 0.3306 mmol), potassium carbonate (0.914 g, 6.612 mmol) and anhydrous o-xylene (18 mL) was heated at 150° for 24 hours. Added additional cuprous iodide (30 mg) and heated an additional 6 hours at 160°. The reaction was cooled to room temperature and the solvent removed by rotary evaporation under vacuum. The residue was purified by silica gel flash chromatography using 1:1 methylene chloride/hexanes as eluent to afford the title compound as a red oil which slowly crystallized (1.23 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]([CH2:7][CH2:8][CH3:9])=[N:4][CH:3]=1.[CH3:10][O:11]C(N(C)C)OC.C(N(CC)CC)C.Cl.[OH-].[Na+]>ClC1C=CC=CC=1>[CH2:7]([C:5]1[NH:6][C:2]([Cl:1])=[C:3]([CH:10]=[O:11])[N:4]=1)[CH2:8][CH3:9]
Reactant: CCCc1ncc(Cl)[nH]1
Reactant: COC(OC)N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: CCN(CC)CC
Product: CCCc1nc(C=O)c(Cl)[nH]1
Temperature: 25 °C

Procedure:
A solution of 5-chloro-2-propyl-1H-imidazole (1.45 g, 10 mmol), dimethoxymethyldimethylamine (1.55 g, approximately 92 percent pure, 12 mmol) and triethylamine (0.10 g, 1 mmol) in chlorobenzene (50 ml) was heated for 1 hour at 80° C. and 2.5 hours under reflux, cooled to room temperature and poured into 2M hydrochloric acid (100 ml). The pH was adjusted to pH 1.97 by addition of 30 percent strength sodium hydroxide solution (19 ml) and the mixture was extracted three times, each time with 50 ml of ethyl acetate. The combined organic phases were dried and concentrated on a rotavapor. The yield of the product was 1.27 g (approximately 90 percent pure according to H--NMR), 66 percent based on 5-chloro-2-propyl-1H-imidazole. Other data concerning the product was:
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8](C(OC(C)(C)C)=O)=[N:9][C:5]=2[CH:4]=1.Br[C:22]1[N:27]=[C:26]2[N:28]([CH2:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:29](=[O:31])[NH:30][C:25]2=[N:24][CH:23]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:7]1[C:6]2[CH:17]=[CH:18][C:3]([C:22]3[N:27]=[C:26]4[N:28]([CH2:32][CH:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[C:29](=[O:31])[NH:30][C:25]4=[N:24][CH:23]=3)=[CH:4][C:5]=2[N:9]=[CH:8]1
Reactant: CC(C)(C)OC(=O)c1nc2cc([Sn](C)(C)C)ccc2[nH]1
Reactant: O=c1[nH]c2ncc(Br)nc2n1CC1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=c1[nH]c2ncc(-c3ccc4[nH]cnc4c3)nc2n1CC1CCOCC1
Yield: 10.5 %

Procedure:
6-(1H-Benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-[4,5-b]pyrazin-2(3H)-one hydrochloride. tert-Butyl 5-(trimethylstannyl)-1H-benzo[d]imidazole-2-carboxylate (640 mg, 1.7 mmol), 6-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (See Example 101.B) (420 mg, 1.3 mmol), dichlorobis(triphenylphosphine)palladium(II) (90 mg, 0.13 mmol) in DMF (25 mL) were reacted for 1.5 h at 90° C. The product was purified by reverse-phase semi-preparatory HPLC (30-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). The desired fractions were concentrated, treated with 4N hydrochloric acid in diethyl ether (few drops), and sonicated. This procedure was repeated twice more to provide 6-(1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (48 mg, 10% yield) as the hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) 12.07 (s, 1H), 8.55 (s, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 8.06 (dd, J=8.0, 1.6, 1H), 7.80 (d, J=8.8, 1H), 3.81 (m, 2H), 3.80 (d, J=7.2, 2H), 3.27 (d, J=11.6, 2H), 2.14 (m, 1H), 1.59 (m, 2H), 1.33 (m, 2H); MS (ESI) m/z 351.2 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([NH2:9])=[O:8])=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Br:1][C:2]1[O:6][C:5]([C:7]2[O:8][CH:14]=[C:12]([CH2:11][Cl:10])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(Br)o1
Product: ClCc1coc(-c2ccc(Br)o2)n1
Yield: 23 %

Procedure:
In substantially the same manner as in Reference Example 47, 5-bromo-2-furancarboxamide was allowed to react with 1,3-dichloroacetone to give 2-(5-bromo-2-furyl)-4-chloromethyloxazole. The yield was 23%. Recrystallization from diethyl ether-hexane gave colorless needles, mp 90-92° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl.C(Cl)(Cl)Cl>[C:30]([NH:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1)(=[O:32])[CH3:31]
Reactant: CCOC(=O)CCCCc1c(CN)nn2c(CC)ccc2c1-c1cncc(C)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCCCc1c(CNC(C)=O)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
A mixture of ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (67.6 mg) and acetic anhydride (19.2 mg) in dichloromethane (3 mL) was stirred at ambient temperature for 1 hour. The solution was diluted with chloroform, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-[2-[(acetylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (70 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=1>C(O)C.[Rh]>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2]1
Reactant: CCOC(=O)C=Cc1cccnc1
Agent: [Rh]
Solvent: CCO
Product: CCOC(=O)CCC1CCCNC1
Yield: 62.9 %

Procedure:
A solution of ethyl 3-[pyrid-3-yl]prop-2-enoate (60 g, 0.34 mol) in ethanol (600 ml) was treated with 5% rhodium on alumina powder (17.2 g). The mixture was placed under a hydrogen atmosphere (55 psi) for five hours at 60° C. The reaction was stopped by removing the hydrogen and the reaciton mixture was filtered through a layer of CELITE™. The residue was washed with hot ethanol. The filtrate was concentrated and purified by flash chromatography to provide 39.6 grams (63%) of the desired title product. IR, NMR, and IR were consistent with the proposed title structure.
Reaction SMILES: C[O-].[Na+].C([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1)(=O)C1C=CC=CC=1>CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][OH:12])=[N:15][CH:16]=1
Reactant: O=C(OCc1ccc(Cl)cn1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
Sodium methoxide (1M in MeOH) (0.162 mL, 0.162 mmol) was added to a solution of (5-chloropyridin-2-yl)methyl benzoate Part C (200 mg, 0.808 mmol) in MeOH (47.5 mL) and stirred at RT for 2.0 h. The solvent was removed in vacuo and the crude product was subjected to flash chromatography (silica gel/DCM-MeOH 100:0 to 90:10 gradient) to afford (5-chloropyridin-2-yl)methanol 16D (68 mg, 59% yield) as an off-white solid. LC-MS, [M+H]+=144. 1H NMR (400 MHz, DMSO) δ 8.51 (1H, d, J=2.2 Hz), 7.91 (1H, dd, J=8.4, 2.6 Hz), 7.49 (1H, d, J=8.4 Hz), 5.53 (1H, t, J=5.9 Hz), 4.54 (2H, d, J=6.2 Hz). HPLC-Method 8; 0.76 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.C([Li])CCC.[CH2:14]([CH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C@H:22]2[CH2:21][CH2:20][C@H:19]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:24][CH2:23]2)[CH:3]=1
Reactant: CCCCCC1CCC(=O)CC1
Reactant: Fc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCC[C@H]1CC[C@H](c2cccc(F)c2)CC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
1-Bromo-3-fluorobenzene (s1) (60.0 g) and THF (1,000 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. n-Butyllithium (1.57M in n-hexane; 218 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 4-Pentylcyclohexanone (s2) (57.7 g) dissolved in THF (150 ml) was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The resulting reaction mixture was poured into a vessel containing an aqueous solution of ammonium chloride (500 ml) and ethyl acetate (500 ml), and mixed with them. The mixture was allowed to stand and separate into organic and aqueous layers, and the latter was extracted. The separated organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure. p-Toluenesulfonic acid (2.4 g) and toluene (250 ml) were added to the residue, and the mixture was heated to reflux for 2 hours, while distilled water was removed. After the reaction mixture had been cooled to 30° C., water (500 ml) and toluene (900 ml) were added and mixed with it. The mixture was allowed to stand and separate into two layers of organic and aqueous layers, and the latter was extracted. The separated organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The resulting solution was purified by fractionation using column chromatography with heptane as an eluent and silica gel as a stationary phase powder, and dried. The product was dissolved in toluene (150 ml) and Solmix A-11 (150 ml), to which Pd/C (0.8 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The resulting residue was purified by fractionation using column chromatography with heptane as an eluent and silica gel as a stationary phase powder, and by recrystallization from Solmix A-11, and then dried to give 1-fluoro-3-(trans-4-pentyl cyclohexyl)benzene (s3) (58.4 g). The yield based on the compound (s1) was 68.6%.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[SH:11][CH2:12][CH:13]([OH:15])[CH3:14]>>[OH:15][CH:13]([CH3:14])[CH2:12][S:11][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1
Reactant: CC(O)CS
Reactant: Cc1cc(Br)ccc1C#N
Product: Cc1cc(SCC(C)O)ccc1C#N

Procedure:
2 g of 4-bromo-2-methylbenzonitrile was reacted with 1-mercapto-2-propanol via Procedure Q to afford 4-(2-hydroxypropylthio)-2-methylbenzonitrile. 950 mg of 4-(2-hydroxypropylthio)-2-methylbenzonitrile was reacted via Procedure T to give 4-(2-hydroxypropylthio)-2-methylbenzoic acid. 1.0 g of 4-(2-hydroxypropylthio)-2-methylbenzoic acid was reacted via Procedure R to give 4-(2-hydroxypropylsulfonyl)-2-methylbenzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-hydroxypropylsulfonyl)-2-methylbenzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)-2-methylbenzamide. MS (Q1) 445.3 (M)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([CH2:10][CH:11]=O)[CH:5]=[CH:6][CH:7]=2)[O:2]1.[CH2:13]1OC2C(=C(C=CC=2)C=O)[O:14]1>>[CH2:1]1[O:9][C:8]2[C:3](=[C:4]([CH2:10][CH2:11][CH:13]=[O:14])[CH:5]=[CH:6][CH:7]=2)[O:2]1
Reactant: O=CCc1cccc2c1OCO2
Reactant: O=Cc1cccc2c1OCO2
Product: O=CCCc1cccc2c1OCO2

Procedure:
Following essentially the same procedure, but substituting 2-(2,3-methylenedioxyphenyl)acetaldehyde for the 2,3-methylenedioxybenzaldehyde, results in the formation of 3-(2,3-methylenedioxyphenyl)propionaldehyde.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[CH:22]([OH:27])[C:23]([O:25][CH3:26])=[O:24].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(O)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(=O)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
To a mixture of methyl 2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (2.5 g, 6.48 mmol) in CH2Cl2 (70 mL) was added Dess-Martin periodinane (3.02 g, 7.13 mmol) and stirred at room temp for 1 h. Then diluted with ethyl acetate (500 mL) and washed with sat. NaHCO3 solution (100 mL), dried (Na2SO4), filtered and concentrated and the residue was purified by silica gel chromatography (5-30% EtOAc/hexane) to afford desired methyl 2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (1.1 g, 2.87 mmol, 44.2% yield) as off-white solid. 44% yield based on 2 steps. 1H NMR (500 MHz, CDCl3) δ 7.77-7.71 (m, 2H), 7.20 (d, J=7.6 Hz, 1H), 7.00 (s, 1H), 4.02 (s, 3H), 2.89-2.83 (m, 4H), 2.64 (s, 3H), 1.86 (dt, J=6.5, 3.3 Hz, 4H). LCMS (M+H)=384.3.
Reaction SMILES: S(=O)(=O)(O)O.C(O)(=[O:8])C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]#[N:19])=[CH:13][CH:12]=1.[OH-].[NH4+]>CCCCCC>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]([NH2:19])=[O:8])=[CH:13][CH:12]=1
Reactant: N#CC(c1ccccc1)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCCC
Product: NC(=O)C(c1ccccc1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 130 °C
Yield: 87 %

Procedure:
A solution of concentrated sulfuric acid (50 mL) and glacial acetic acid (50 mL) was added to bis(4-fluorophenyl)phenylacetonitrile (18.9 g, 0.06 mol) at rt. The resulting orange solution was stirred and heated at 130° C. for 3 h. The reaction was cooled to 0° C., poured into ice water (150 mL) and neutralized with ammonium hydroxide. The organics were extracted with chloroform (3×100 mL), combined and washed with brine (2×50 mL). The organics were dried (Na2SO4) and concentrated under reduced pressure to afford a yellow-orange solid. The solid was stirred with hot hexane (100 ml) for 30 min and filtered. Crystallization from dichloromethane/hexane gave bis(4-fluorophenyl)phenylacetamide (3) as a white crystalline solid (16.9 g, 0.052 mol, 87%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][N:67]([CH2:69][C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)[CH3:68])C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][N:67]([CH2:69][C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)[CH3:68])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: CN(CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1)Cc1ccccc1
Product: CN(CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1)Cc1ccccc1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-[2-(benzyl-methyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=597, obsd.=597).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:46][CH2:45][C:40]3([O:44][CH2:43][CH2:42][O:41]3)[CH2:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[O:41]1[C:40]2([CH2:39][CH2:38][N:37]([C:34]3[CH:35]=[CH:36][C:9]([OH:8])=[C:10]([CH:33]=3)[C:11]([NH:13][C:14]3[CH:26]=[C:25]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:24]=[CH:23][C:15]=3[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[O:12])[CH2:46][CH2:45]2)[O:44][CH2:43][CH2:42]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCC3(CC2)OCCO3)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCC3(CC2)OCCO3)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)benzamido)-4-phenylbenzoate (0.18 g) in methanol (1.5 mL) and ethyl acetate (1.5 mL), 10% palladium-carbon (0.091 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.12 g of tert-butyl 2-(5-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)-2-hydroxybenzamido)-4-phenylbenzoate as a yellow solid.