Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:9]([CH:12]=1)[C:10]#[N:11])=[O:4]>CO>[OH:4][CH2:3][C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[C:9]([CH:12]=1)[C:10]#[N:11]
Reactant: N#Cc1cc(C=O)ccc1Oc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cc(CO)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.2 %

Procedure:
NaBH4 (0.39 g, 10.30 mmol) was added to a solution of 5-formyl-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile (5 g, 17.17 mmol) in methanol (30 mL) at 0° C., and then stirred at rt for 30 min. The reaction mixture was quenched by acetone and concentrated. The residue was purified via ISCO (DCM:MeOH=20:1) to afford the title compound as a clear oil (5.5 g, 95% yield).
Reaction SMILES: [CH:1]([NH2:5])([CH2:3][CH3:4])[CH3:2].Cl[CH2:7][CH2:8][O:9][CH:10]([OH:12])[CH3:11]>>[CH:1]([NH:5][CH2:7][CH2:8][O:9][CH:10]([OH:12])[CH3:11])([CH2:3][CH3:4])[CH3:2]
Reactant: CC(O)OCCCl
Reactant: CCC(C)N
Product: CCC(C)NCCOC(C)O
Yield: 60.6 %

Procedure:
In the manner described in Example 8, 131 g of secondarybutylamine and 93 g of 2-chloroethoxyethanol yielded 73 g of secondarybutylaminoethoxyethanol having a b.p. 120° C. (10 mm). Analysis calculated for C8H19NO2 : %N, 8.70: Found: %N, 8.45.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:25])=[C:4]([C:21]([CH3:24])=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>CN1CCCC1=O>[Cl:25][C:3]1[C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:19][CH2:20]4)=[O:17])[N:14]=3)[N:11]=2)=[C:21]([CH3:24])[CH:22]=[CH:23][C:2]=1[NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)c(Cl)c1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)c(Cl)c1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 58.4 %

Procedure:
Using N-[6-(3-amino-2-chloro-6-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.42 mmol), 3-(trifluoromethyl)benzoyl chloride (92 mg, 0.44 mmol) and N-methylpyrrolidone (5.0 mL) as starting materials and in the same manner as in Example 344, the title compound (130 mg, 60%) was obtained as a white powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:5]([Br:18])[CH:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.CCN(CC)CC>C(Cl)Cl>[Br:18][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH:17]=[CH:16][C:6]=1[O:7][CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)COc1ccc(CN)cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1ccc(CNS(=O)(=O)c2ccc(F)cc2)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
To a solution of t-butyl 2-(4-(aminomethyl)-2-bromophenoxy)acetate (6) (88 mg, 1 eq, 0.28 mmol) in DCM (15 mL) was added 4-fluoro-benzenesulfonyl chloride (65 mg, 0.33 mmol, 1.2 eq) and Et3N (56 mg, 0.56 mmol, 2 eq). The mixture was stirred at room temperature for 2 h, filtered, concentrated in vacuo and purified by preparative TLC to give 64 mg (48%) of t-butyl 2-(2-bromo-4-((4-fluorophenylsulfonamido)methyl)phenoxy)acetate (7).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:27][CH2:28][CH3:29])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[CH:9]=O)[CH3:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:27][CH2:28][CH3:29])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[CH2:9][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[CH3:2]
Reactant: CCCc1nc(CC)c(C=O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(CN2CCOCC2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 12 h
Yield: 35 %

Procedure:
To a solution of 4′-[(4-ethyl-5-formyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g) and morpholine (0.17 mL) in acetic acid (10 mL) was added sodium triacetoxyborohydride (0.41 g), and the mixture was stirred for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (0.21 g, 35%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:11]([O:10][C:8]([C:7]1[C:2]2[C:3]([C:13](=[O:15])[N:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:25]=2)=[CH:4][NH:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cncc(C(=O)OCC)c1Cl
Reactant: NNc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1c[nH]cc2c(=O)n(-c3ccccc3)nc1-2

Procedure:
A mixture of diethyl 4-chloro-3,5-pyridinedicarboxylate (3.09 g, 12.0 mmol) and phenylhydrazine (1.42 ml, 14.4 mmol) in ethanol (100 ml) was degassed by evaporating under vacuum and refilling with nitrogen several times. The mixture was then stirred at reflux for 17 h under nitrogen. The mixture was left to cool in the fridge for a few hours, then filtered from a solid, which was washed with ethanol and ethyl acetate. The combined filtrates were evaporated in vacuo, and the residue was purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) to afford 1.559 g (46%) as an orange solid; 1H NMR (360 MHz, DMSO-d6) δ1.35 (3H t, J 7.1 Hz), 4.34 (2H, q, J 7.1 Hz), 7.18 (1H, t, J 7.3 Hz), 7.44 (2H, t, J 7.5 Hz), 8.14 (1H, s), 8.19 (2H, d, J 7.6 Hz), 8.57 (1H, s), 12.49 (1H, br s).
Reaction SMILES: [C:1]([N:7]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C:8]1=[O:24])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[Li+].CC([N-]C(C)C)C.Br[CH2:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1[Cl:42]>C1COCC1>[Cl:42][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([F:41])[C:35]=1[CH2:34][C@@H:2]([CH2:3][CH:4]=[CH2:5])[C:1]([N:7]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C:8]1=[O:24])=[O:6]
Reactant: C=CCCC(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Reactant: Fc1cccc(Cl)c1CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H](Cc1c(F)cccc1Cl)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Yield: 100.1 %

Procedure:
Dissolve (4S,5R)-3-pent-4-enoyl-4,5-diphenyloxazolidin-2-one (1.0 g, 3.1 mmol) in THF (50 mL) and cool the mixture to −78° C. under N2 with stirring. Add dropwise LDA (2.7 mL, 4.0 mmol, 1.5 M in THF) and stir the mixture for 0.5 hours. Then add 2-(bromomethyl)-1-chloro-3-fluorobenzene (1.39 g, 6.22 mmol). Continue to stir the reaction mixture for one hour until TLC shows that the starting material has been consumed. Add water (50 mL) and extract the aqueous with CH2Cl2 (3×250 mL). Combine the organic layers and dry over Na2SO4. Concentrate and purify by chromatography (Silica gel) to afford (4S,5R)-3-((R)-2-(2-Chloro-6-fluorobenzyl)pent-4-enoyl)-4,5-diphenyloxazolidin-2-one (1.44 g, 75.5%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([OH:28])[CH:6]=[CH:7][C:8]=1[C:9]1[N:13]([CH3:14])[C:12]([C:15]([CH3:27])([O:17][C:18]2[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH3:16])=[N:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([NH2:39])=[O:38].O>CN(C=O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[C:9]1[N:13]([CH3:14])[C:12]([C:15]([CH3:16])([O:17][C:18]2[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH3:27])=[N:11][N:10]=1)[O:28][CH2:36][C:37]([NH2:39])=[O:38]
Reactant: NC(=O)CBr
Reactant: Cn1c(-c2ccc(O)cc2Cl)nnc1C(C)(C)Oc1c(F)cc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(-c2ccc(OCC(N)=O)cc2Cl)nnc1C(C)(C)Oc1c(F)cc(F)cc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
3-chloro-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}phenol monohydrochloride (40 mg) was suspended in DMF (2 ml), potassium carbonate (64 mg) and 2-bromoacetamide (26 mg) were added thereto, followed by stirring at 60° C. for 30 minutes. The reaction solution was cooled to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1 to 100:5). The resulting residue was dissolved in ethyl acetate, 4M hydrogen chloride-ethyl acetate (1 ml) was added thereto and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to obtain 2-(3-chloro-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}phenoxy}acetamide monohydrochloride (17 mg), as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]([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)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([OH:23])=O.[Cl:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:27][CH:26]=1.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:31][CH2:32][N:33]([C:21](=[O:23])[CH2:20][N:3]3[CH2:4][CH2:5][CH2:6][C:7]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]3=[O:1])[CH2:34][CH2:35]2)=[CH:27][CH:26]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Clc1ccc(OC2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 45 h

Procedure:
To a solution of the product of Example 68E (117 mg, 0.38 mmol), 4-(4-chlorophenoxy)piperidine (80.0 mg, 0.378 mmol), and 4-(dimethylamino)pyridine (4.6 mg, 0.038 mmol) in CH2Cl2 (2 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.067 mL, 0.378 mmol) via syringe. The reaction was stirred at ambient temperature for 45 hours. The reaction mixture was diluted with 50 mL CH2Cl2, then washed with 1 N aqueous HCl, saturated aqueous NaHCO3 solution and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Analogix® Intelliflash™ 280; SF15-24 g column; 50% ethyl acetate/hexanes) which yielded the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.36-7.17 (m, 12H), 6.86-6.80 (m, 2H), 4.55-4.45 (m, 1H), 4.40 (d, J=15.6, 1H), 4.09 (d, J=15.6, 1H), 3.80-3.33 (m, 6H), 2.72-2.57 (m, 2H), 2.00-1.74 (m, 6H); MS (ESI+) m/z 503 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](I)[CH3:8].[Br:10][C:11]1[CH:12]=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:14]([O:18][CH2:19][O:20][CH3:21])=[C:15]([OH:17])[CH:16]=1.C(OCC)(=O)C>C(#N)C>[Br:10][C:11]1[CH:16]=[C:15]([O:17][CH2:7][CH3:8])[C:14]([O:18][CH2:19][O:20][CH3:21])=[C:13]([C:22]([CH3:23])([CH3:24])[CH3:25])[CH:12]=1
Reactant: CCI
Reactant: COCOc1c(O)cc(Br)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1cc(Br)cc(C(C)(C)C)c1OCOC
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
Cesium carbonate (10.05 g, 30.9 mmol) and EtI (2.58 ml, 32.2 mmol) were added to a solution of the 5-bromo-3-(tert-butyl)-2-(methoxymethoxy)phenol (7.76 g, 26.8 mmol) in acetonitrile and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added and the reaction mixture was washed with water and brine in that order. The organic layer was dried over anhydrous magnesium sulfate and then the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (6.5 g) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[C:9]([C:16]#[N:17])[CH:8]=2)=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O>>[Br:18][C:8]1[C:9]([C:16]#[N:17])=[C:10]2[N:15]([C:7]=1[C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH2:14][CH2:13][CH2:12][CH2:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cc(-c2ccncc2)n2c1CCCC2
Product: N#Cc1c(Br)c(-c2ccncc2)n2c1CCCC2
Yield: 84 %

Procedure:
2-Bromo-3-(4-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile is prepared as described in Example 9, from 2.2 g [lacuna] 3-(4-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile and 2.26 g of N-bromosuccinimide. 2.5 g of 2-bromo-3-(4-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile are thus obtained in the form of orange-beige powder melting at 120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[NH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH2:34][CH2:33]2)=[O:9])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Reactant: c1ccc2c(c1)NCCN2
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
A solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (100 mg, 0.35 mmol, 1.0 equiv; Example 31, Step 1) in thionyl chloride (3.28 g, 2 ml, 27.6 mmol, 230 equiv; [CAS RN 7719-09-7]) was heated to 100° C. for 1 h. The reaction mixture was concentrated under reduced pressure, remaining thionyl chloride removed by azotropic distillation with toluene and the residue dissolved in anhydrous DMF (1 mL). To this solution was added N-ethyldiisopropylamine (452 mg, 595 μL, 3.5 mmol, 10.0 equiv; [CAS RN 7087-68-5]) and 1,2,3,4-tetrahydro-quinoxaline (56 mg, 0.42 mmol, 1.2 equiv; [CAS RN 3476-89-9]) and the reaction mixture was stirred at rt for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 17.3 mg (12%) of the title compound. MS (ISP): 400.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:16][S:17]([O:15][CH:12]1[CH2:13][CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)(=[O:19])=[O:18]
Reactant: COc1ccc(C2CCC(O)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(C2CCC(OS(C)(=O)=O)CC2)cc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 75 parts of 4-(4-methoxyphenyl)cyclohexanol and 1000 parts of pyridine are added dropwise 62 parts of methanesulfonyl chloride (exothermic reaction: temperature rises to 40° C.). Upon completion, the whole is heated to 65° C. and stirring is continued for 2 hours, while meantime the mixture is allowed to cool to room temperature. The reaction mixture is evaporated and 1000 parts of water are added to the residue. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 80.5 parts of 4-(4-methoxyphenyl)cyclohexyl methanesulfonate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]2[O:15][C@@H:11]([CH2:12][CH2:13]2)[C@@H:10]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]1C=CC=CC=1.O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O>O1CCOCC1>[C:16]([C@H:10]1[C@H:11]2[O:15][C@H:14]([CH2:13][CH2:12]2)[C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:18])[NH2:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1[C@@H](C(=O)O)[C@@H]2CC[C@H]1O2
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1[C@@H](C(N)=O)[C@@H]2CC[C@H]1O2
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
(1S,2R,3S,4R)-3-(tert-butoxycarbonylamino)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (13) (44 mg, 0.17 mmol) was taken in dioxane when pyridine (1.7 eq) was added followed by addition of BOC2O. The reaction mixture was stirred at rt for 40 min when NH4CO3 (38 mg, 0.49 mmol) was added and the reaction mixture was stirred at rt for 15 h when TLC confirmed formation of product. The reaction mixture was concentrated and purified by column chromatography using silica gel (100-200 mesh) to afford the desired product (43 mg, 95%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:15])[NH:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][C:2]1[C:3](=[O:15])[NH:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)[CH:7]=1
Reactant: Cc1cc(C2CCC(=O)CC2)c[nH]c1=O
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cc1cc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c[nH]c1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of 3-methyl-5-(4-oxo-cyclohexyl)-1H-pyridin-2-one and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[CH2:17][CH3:18])=[C:6]([NH:19][C:20](=O)[CH2:21][C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH:5]=1.Cl.O>O1CCOCC1>[CH2:17]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:10]1[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:28])=[CH:5][C:6]=2[N:19]=[C:20]1[CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[CH3:18]
Reactant: CCC1CCCCC1Nc1ccc(C(=O)OC)cc1NC(=O)Cc1cccs1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCC1CCCCC1n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Temperature: 130 °C
Yield: 86.6 %

Procedure:
0.59 g 4-(2-Ethyl-cyclohexylamino)-3-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester were reacted with 10 ml of 4M hydrochloric acid in dioxane at 130° C. in a microwave reactor for 20 min. 1 ml water was added and the mixture was heated to 130° C. for 30 min. The reaction was concentrated and the residue purified by chromatography (silica, ethyl acetate/heptane) to yield 0.47 g (88%) of 1-(2-Ethyl-cyclohexyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:22]>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH2:29][CH:25]([CH2:24][NH:23][CH2:21][CH3:22])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCNCC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of 1.00 g (3.53 mmole) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 10 ml of acetonitrile, 0.54 g (3.5 mmole) 1,8-diazobicyclo[5.4.0] undec-7-ene, and 0.48 g (3.7 mmole) of N-ethyl-3-pyrrolidinemethanamine is refluxed one hour, then stirred at room temperature overnight. The reaction mixture is then filtered and the precipitate washed with ethyl ether until dry to yield 1.22 g (88.4%) of the title compound, mp 256°-258° C.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[C:6]1([N:12]2[C:20](=[O:21])[C:19]3[C@@H:18]4[C:22]([CH3:24])([CH3:23])[C@@:15]([CH3:25])([CH2:16][CH2:17]4)[C:14]=3[NH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH:5]1([CH2:4][N:13]2[C:14]3[C@:15]4([CH3:25])[C:22]([CH3:24])([CH3:23])[C@@H:18]([CH2:17][CH2:16]4)[C:19]=3[C:20](=[O:21])[N:12]2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccccc2)n1CC1CC1
Temperature: 100 °C
Yield: 48.5 %

Procedure:
A mixture of (bromomethyl)cyclopropane (263 μL, 2.75 mmol), (4R,7S)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 184 mg, 0.69 mmol) and tetra-n-butylammonium iodide (1.02 g, 2.75 mmol) in N,N-dimethylformamide (4.3 mL) was heated in an oil-bath at 100° C. for 16 h. The solvent was evaporated and dichloromethane (100 mL) and water were added. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with water (5×100 mL) and then with sodium thiosulfate solution (100 mL). The solvent was evaporated and the residue purified on an Isco 120 g column, eluting with 33-100% ethyl acetate/hexanes to give (4R,7S)-1-(cyclopropyl)methyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (108 mg, 49%) as an off-white/tan oil. APCI-MS (M+H) 323.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH:10](O)[C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[O:5][CH:6]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=C=O)=[CH:19][CH:18]=1>C(N(CC)CC)C.C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH:10]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)[C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[O:5][CH:6]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1cc(Br)co1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC(Nc1ccc(Cl)cc1)C(Cl)(Cl)Cl)c1cc(Br)co1

Procedure:
was prepared in accordance with reported methods: see Ulrich, H. et al J Org. Chem., 33, 1968, 2887. A solution of 4-bromo-N-(2,2,2-trichloro-1-hydroxyethyl)furan-2-carboxamide (preparation as for 6 above) (0.566 g, 1.67 mmol), 1-chloro-4-isocyanato-benzene (0.264 g, 1.68 mmol) and triethylamine (2 drops) in benzene (4 mL) was heated at 95° C. for 1.5 h. The mixture was evaporated under reduced pressure. The residue was solvated with chloroform and concentrated onto silica gel. Chromatographic purification on an auto-column with 30% dichloromethane in hexanes gave 4-bromo-N-(2,2,2-trichloro-1-(4-chlorophenylamino)ethyl)furan-2-carboxamide (Compound 33) as a white solid; 422 mg (57%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][C:8]1=[O:16]>C(O)C>[OH:7][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:8]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:16]
Reactant: C1COCCN1
Reactant: O=C1Cc2ccccc2O1
Solvent: CCO
Product: O=C(Cc1ccccc1O)N1CCOCC1
Reaction time: 1 h
Yield: 90.9 %

Procedure:
27.3 g of morpholine are added in a single portion to a solution of 30 g of 2,3-dihydro-2-benzofuranone in 100 ml of ethanol, and the medium is stirred for 1 hour. The solvent is evaporated off under vacuum, the residual gum is taken up in isopropyl ether in the hot state and the medium is allowed to return to room temperature. The crystallized product is filtered, washed with isopropyl ether and dried. 45 g of white crystallized product are obtained.