Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[C:15](Cl)[N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.CC#N.C(O)(C(F)(F)F)=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[C:15]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH3:29])[N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(Nc1nc(Cl)cc(-n2cnc3ccccc32)n1)c1cccc([N+](=O)[O-])c1
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1ccccc1-c1cc(-n2cnc3ccccc32)nc(NC(C)c2cccc([N+](=O)[O-])c2)n1

Procedure:
The title compound was prepared from 2-[1-(3-nitrophenyl)ethylamino]-4-[benzimidazol-1-yl]-6-chloropyrimidine and 2-methylphenylboronic acid according to the precedure described in EXAMPLE 306, Step C and using [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) as catalyst. Mass spectrum (CH3CN/TFA/NH4O2CH/ESI) 451.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][CH:11]([C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:30]1([C:36]2[O:37][C:38]([C:43]([F:46])([F:45])[F:44])=[C:39]([CH2:41]O)[N:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:30]1([C:36]2[O:37][C:38]([C:43]([F:46])([F:45])[F:44])=[C:39]([CH2:41][O:18][C:17](=[O:19])[C:16]3[CH:20]=[CH:21][C:13]([CH2:12][CH:11]([S:10][CH2:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:27])[Cl:28])=[O:23])=[CH:14][CH:15]=3)[N:40]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: OCc1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1nc(-c2ccccc2)oc1C(F)(F)F)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
To a solution of 4-[2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-2-(2,2,2-trichloro-ethoxy-carbonyl)-ethyl]-benzoic acid (278 mg, 0.58 mmol) and (2-phenyl-5-trifluoromethyl-oxazol-4-yl)-methanol (155 mg, 0.64 mmol) in anhydrous DCM (20 mL) was first added EDCxHCl (144 mg, 0.75 mmol) then DMAP (1.0 mg, 0.006 mol) under nitrogen atmosphere at 0° C. After complete addition the cooling bath was removed and the reaction mixture was stirred at ambient temperature until no starting material was left. The mixture was diluted with water and aq. HCl (2N) and extracted with DCM. The combined organic layers were dried (MgSO4) and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography using n-heptane/EtOAc 4:1 as the eluent to afford the final product as an oil (289 mg, 56.6%). 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 2H), 7.93 (d, 1H), 7.40-7.47 (m, 2H), 7.19-7.29 (m, 4H), 7.02 (dt, 2H), 6.89 (dt, 2H), 5.34 (d, 2H), 4.64 (q, 2H), 3.50 (dd, 1H), 3.18-3.24 (dd, 1H), 2.73-2.98 (m, 5H), 1.1 (s, 2H). Mass Spectrum: M−H+ 703.91.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH2:66][C@@H:67]1[CH:72]2[CH2:73][CH2:74][N:69]([CH2:70][CH2:71]2)[CH2:68]1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][C@@H:67]5[CH:72]6[CH2:73][CH2:74][N:69]([CH2:70][CH2:71]6)[CH2:68]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@H]2CN3CCC2CC3)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (0.11 g, 0.25 mmol, 1 eq), DIPEA (0.17 mL) and TBTU (88 mg, 0.28 mmol, 1.1 eq) were added to 5 mL DCM and the resulting solution stirred at rt for 30 min before the addition of (R)-(+)-3-aminoquinuclidine dihydrochloride (60 mg, 0.30 mmol, 1.2 eq). The RM was then stirred at rt for 16 hours before diluting with DCM and washing sequentially with water (×2), 50% saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was dissolved in the minimum quantity of EtOAc before addition of n-heptane to precipitate (R)-4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide (white solid, 0.13 g, 96%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]([O:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[O:35][CH:34]=[N:33][C:32]=2[C:36](O)=[O:37])[CH:28]=[CH:29][CH:30]=1)([CH3:21])[CH3:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:36]([C:32]3[N:33]=[CH:34][O:35][C:31]=3[C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][CH2:23][O:22][CH:19]([CH3:21])[CH3:20])[CH:26]=3)=[O:37])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC(C)OCCc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(CCOC(C)C)c3)n2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-[3-(2-isopropoxy-ethyl)-phenyl]-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.04 min; [M+H]+=463.35.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=1>>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:7][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: CCOc1ccc(Br)cc1
Product: CCOc1ccc(Cc2cc(Br)c(OC)cc2OC)cc1

Procedure:
Preparation was performed in a similar manner as in Preparation Example 3 using 5-bromo-2,4-dimethoxybenzaldehyde and 4-bromophenetole.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:11])[CH:17]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(Br)ccc1N
Reactant: OB(O)c1cccc(Cl)c1
Product: N#Cc1cc(-c2cccc(Cl)c2)ccc1N

Procedure:
Prepared from 2-amino-5-bromobenzonitrile and 3-chlorophenyl boronic acid according to procedure A. Off-white solid: mp 118-119° C.; 1H-NMR (DMSO-d6) δ7.80 (d, 1H, J=2.3 Hz), 7.65-7.72 (m, 2H), 7.57 (d, 1H, J=8.0 Hz), 7.42 (t, 1H, J=7.9 Hz), 7.31 (m, 1H), 6.87 (d, 1H, J=8.7 Hz), 6.29 (br, 2H); Anal. Calc. For C13H9ClN2: C, 68.28, H, 3.97, N, 12.25. Found: C, 67.68, H, 4.06, N, 11.89.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:13]1[CH:14]=[C:15]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=1)[C:16]([O:18]C(C)(C)C)=[O:17].[H-].[Na+]>O1CCCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:13]3[CH:14]=[C:15]([CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[N:25]=3)[C:16]([OH:18])=[O:17])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a vial, 1,4-dioxaspiro[4.5]decan-8-ol (0.400 g, 2.53 mmol) was dissolved in tetrahydrofuran (8.44 mL) with tert-butyl 2-chloro-6-(trifluoromethyl)isonicotinate (0.510 g, 1.81 mmol) and cooled to 0° C. and a 60% mixture of sodium hydride in mineral oil (123 mg, 3.08 mmol) was added and the mixture was stirred for 30 minutes at 0° C. and at 25° C. for 30 minutes at which time TLC analysis showed most of the ester was consumed and a new spot with lower Rf was formed. The reaction was continued for 16 hours. LCMS analysis showed that it consisted mainly of the acid. TLC analysis showed the original product was not present. The reaction was quenched with water and extracted with EtOAc. The crude product was used in the next reaction without further purification. MS (ES): 348 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[CH:5][CH:4]=1.[CH3:17][N:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:19].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7](=[N:19][N:18]([CH3:17])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: CN(N)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CC(=NN(C)c1ccccc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
In 60 ml of acetic acid were dissolved 15 g of ethyl p-methoxybenzoylacetate and 8.25 g of 1-methyl-1-phenylhydrazine and the resulting solution was stirred at room temperature for 12 hours. The reaction mixture was poured into iced water and extracted with ethyl acetate. The extract was washed with aqueous solution of sodium hydrogen carbonate and water in that order, dried over anhydrous magnesium sulfate and concentrated to provide 21.8 g of the desired compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12].C([O-])(O)=[O:14].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([NH2:12])=[O:14]
Reactant: O=C([O-])O
Reactant: N#Cc1c(N)sc2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1c(N)sc2ccccc12
Temperature: 0 °C
Yield: 41 %

Procedure:
A solution of 2-amino-benzo[b]thiophene-3-carbonitrile (50 mg, 0.29 mmol) in concentrated H2SO4 (1.5 mL) was heated at 60° C. for 2 h. The solution was poured into ice-water (5 mL), mixed with saturated NaHCO3 solution (30 mL), and extracted with ethyl acetate (30 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated. Flash chromatography (hexanes/ethyl acetate, 1:1) then provided the title compound (23 mg, 41%) as a white solid: MS (ES) m/z 193 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@H:10]([CH3:11])[CH2:9][N:8]([S:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)(=[O:14])=[O:13])[CH2:7][C@@H:6]1[CH3:25])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:40]>C(#N)C.O>[CH3:25][C@H:6]1[CH2:7][N:8]([S:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)(=[O:13])=[O:14])[CH2:9][C@@H:10]([CH3:11])[N:5]1[C:3](=[O:4])[CH2:2][O:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[O:33][CH3:32]
Reactant: C[C@@H]1CN(S(=O)(=O)c2ccc3ccccc3c2)C[C@H](C)N1C(=O)CCl
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1OCC(=O)N1[C@H](C)CN(S(=O)(=O)c2ccc3ccccc3c2)C[C@@H]1C
Reaction time: 4 h

Procedure:
2-Chloro-1-((2S,6R)-2,6-dimethyl-4-(naphthalene-2-ylsulfonyl)piperazin-1-yl)ethanone (200 mg, 0.52 moles) was dissolved in 20 mL of acetonitrile. Dry K2CO3 (106 mg, 0.79 moles) was added to the reaction mixture under nitrogen atmosphere and allowed to stir for about ten minutes. 2-methoxyphenol (97 mg, 0.78 moles) was slowly added to the reaction at room temperature and allowed the reaction to continue for another 4 h. The reaction was monitored by TLC and after product formation was observed, the reaction mixture was diluted with cold water (10 mL) and extracted with ethyl acetate (25 mL×2). The combined organic layers were washed with bicarbonate followed by brine & then dried over sodium sulphate. The solvent was evaporated on reduced pressure to afford crude product which was purified by column chromatography to yield the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][N:11]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=[CH2:25])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][N:15]=1
Reactant: CCCCCCCCc1cnc(-c2ccc(O)c(F)c2F)nc1
Reactant: C=CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C=CCCCCCCOc1ccc(-c2ncc(CCCCCCCC)cn2)c(F)c1F
Temperature: 25 °C

Procedure:
A suspension of 2-(2,3-difluoro-4-hydroxyphenyl)-5-octylpyrimidine (1.00 g, 3.07 mmol), 8-bromo-1-octene (0.59 g, 3.07 mmol) and cesium carbonate (1.99 g, 6.14 mmol) in acetone (70 ml) was heated under reflux for 18 h. The reaction mixture was cooled to room temperature, washed with water and the organic layer extracted in ethyl acetate/hexane (3 times, 1:1). The combined extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residues were purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1), Rf 0.30] and recrystallized from hexane to yield colorless crystals.
Reaction SMILES: C(O[CH:5]1[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:8][CH:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:6]1)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14]([CH:7]1[CH2:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH:5]=[CH:6]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1Cc2sccc2C(OC(C)=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C=Cc2ccsc2C1
Yield: 56.7 %

Procedure:
A mixture of 4-acetoxy-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (2.34 g), tosic acid monohydrate (0.13 g), and toluene (50 ml) was stirred at reflux for 2 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and then the separated organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and brine, and dried over MgSO4, and then evaporated in vacuo. After evaporation of the filtrate, the resulting oil was purified by chromatography on silica gel (CHCl3-MeOH as eluent) to give 6-ethoxycarbonyl-6,7-dihydrobenzo[b]thiophene (1.03 g) as an oil.
Reaction SMILES: [CH3:1][O-:2].[K+].Cl[C:5]1[CH:25]=[CH:24][C:8]([C:9]([C:11]2[C:12]([CH3:23])=[C:13]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:7][CH:6]=1>CO>[CH3:1][O:2][C:5]1[CH:25]=[CH:24][C:8]([C:9]([C:11]2[C:12]([CH3:23])=[C:13]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: Cc1c(CCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CO
Product: COc1ccc(C(=O)c2cccc(CCCC(=O)O)c2C)cc1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
17.5 g of 89% potassium methylate were added under an inert atmosphere to a suspension of 7.5 g of 4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyric acid (Example V) in 75 ml of methanol and was then heated at 120°-130° C for 17 hours under pressure. After cooling to room temperature, the mixture was rinsed with water and the methanol was eliminated under reduced pressure. The residue was dissolved in water, treated hot with activated carbon, iced and filtered. The filtrate was acidified to a pH of 1 with hydrochloric acid and the precipitate formed was recovered by filtration, was washed with water until the wash water was neutral and dried. The residue was crystallized from isopropyl ether to obtain 5.35 g of 4-(3'-p-methoxybenzoyl-2'-methyl-phenyl)-butyric acid in the form of colorless crystals melting at 100° C and then 115° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[C:44]([O:43][C:42](=[O:48])[NH:41][C@H:38]1[CH2:37][CH2:36][C@@H:35]([NH:34][C:31]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=2[CH3:30])=[O:33])[CH2:40][CH2:39]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: Cc1c(C(=O)O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: Cc1c(C(=O)N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c2) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:30][C:31](=[O:47])[CH2:32][C:33]1[CH:34]=[C:35]([C:39]2[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][CH:40]=2)[CH:36]=[CH:37][CH:38]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:45][C:42]3[CH:43]=[CH:44][C:39]([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([CH2:32][C:31]([OH:47])=[O:30])[CH:34]=4)=[CH:40][CH:41]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cccc(-c2ccc(C=O)cc2)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)Cc1cccc(-c2ccc(CNc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and (4′-formyl-biphenyl-3-yl)-acetic acid methyl ester. MS (ESI) m/z 601.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][C:10](Cl)=O)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[N:13]12CCC(CO)(CC1)CC2.S([O-])(=O)(=O)C.[C-]#N.[Na+]>CN(C)C=O>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][C:10]#[N:13])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: OCC12CCN(CC1)CC2
Reactant: O=C(Cl)CC12CCN(CC1)CC2
Agent: CS(=O)(=O)[O-]
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCC12CCN(CC1)CC2

Procedure:
2-(Quinuclidin-4-yl)acetyl chloride may be made by converting (quinuclidin-4-yl)methanol (vide supra) to the mesylate (methanesulfonylchloride/triethylamine in chloroform) which is then treated with sodium cyanide in dimethylformamide to form (quinuclidin-4-yl)acetonitrile. Heating this in ethanol saturated with hydrogen chloride gas produces the corresponding ethyl ester which is hydrolyzed to the acid by treatment with 6N hydrochloric acid. Finally, the acid is converted to the acid chloride as described above.
Reaction SMILES: C([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:6][CH:5]=1)C.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH:28]([F:30])[F:29]>CN(C=O)C.C(OCC)(=O)C>[F:29][CH:28]([F:30])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:8][CH:9]=1
Reactant: CCOc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)F)cc1

Procedure:
A solution of Step 1 intermediate, Intermediate 10 (400 mg, 1.548 mmol) in DMF (15 ml) was treated with Cs2CO3 (1.513 g, 4.645 mmol) slowly at room temperature. The reaction temperature was raised to 80° C. at which the chloro-difluoro-methane (ClCHF2) gas was passed into the reaction mixture till TLC indicated completion of the reaction. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4 and purified using column chromatography to afford the desired compound; 1H NMR (300 MHz, CDCl3) δ 2.20 (s, 3H), 7.18-7.22 (m, 2H), 7.25 (s, 1H), 7.37-7.40 (m, 2H), 7.55 (d, J=5.1 Hz, 1H), 7.99 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 309.45 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C([BH3-])#N.[Na+]>CO.Cl>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: COC(=O)c1cccc(C(C)=O)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(C(C)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.09 g (6.15 mmol) of methyl 3-acetylbenzenecarboxylate (Example 59A) were initially charged in 28 ml methanol. 0.77 g (12.29 mmol) of sodium cyanoborohydride was added, and the reaction solution was then adjusted to pH 3 using a few drops of 1N hydrochloric acid and stirred at RT overnight. The reaction solution was evaporated, water was then added and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and evaporated.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:17]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:16]3[C:11]([C:12]4[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][C:13]=4[CH2:14][CH2:15]3)=[N:10]2)=[CH:5][C:4]=1[CH3:30])#[N:2].C(O)C.C(=O)=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@@H:17]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[C@@H:16]3[C:11]([C:12]4[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][C:13]=4[CH2:14][CH2:15]3)=[N:10]2)=[CH:5][C:4]=1[CH3:30])#[N:2]
Reactant: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)ccc1C#N
Agent: O=C=O
Solvent: CCO
Product: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4CC[C@@H]3[C@@H]2C2CCCC2)ccc1C#N

Procedure:
The title compound was prepared from the 2-(4-cyano-3-methylphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid prepared in Example 21 using chiral resolution (e.g., Method G (Chiralcel OJ-H 30×250 mm; 50% ethanol/carbon dioxide). First eluting peak: chiral HPLC tR=2.31 minutes (Chiralcel OJ-H 4.6×250 mm; 50% ethanol/carbon dioxide)).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]#[N:15])[CH2:9]1)C1C=CC=CC=1.N1C=CC=CC=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36]>C(Cl)Cl>[C:14]([C:13]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:10]1[CH2:11][CH2:12][N:8]([C:35]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:36])[CH2:9]1)#[N:15]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCN(Cc2ccccc2)C1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC(c1ccccc1)(c1ccccc1)C1CCN(C(=O)Oc2ccccc2)C1
Yield: 46.3 %

Procedure:
To a solution of 47 g (0.13 mole) of α-(1-benzyl-3-pyrrolidinyl)-α,α-diphenylacetonitrile and 10.58 g (0.13 mole) of pyridine in 400 ml of methylene chloride was added, dropwise at 0° C., 62.7 g (0.39 mole) of phenyl chloroformate. The reaction mixture was refluxed for 16 hr. The mixture was cooled and washed 3 times with water and twice with dilute sodium hydroxide solution. The methylene chloride layer was then dried, filtered and concentrated in vacuo. The resulting solid was recrystallized twice from ethyl acetate to give 23 g (50%) of title compound, m.p. 154°-155° C.