Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH:48]1[CH2:51][CH:50]([OH:52])[CH2:49]1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([N:48]4[CH2:51][CH:50]([OH:52])[CH2:49]4)=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:3])([CH3:4])[CH3:5]
Reactant: OC1CNC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CC(O)C2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with azetidin-3-ol (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C38H47Cl2N6O4 [(M+H)+] 721.3031, observed 721.3034.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.CO.[CH3:18][C:19]([CH3:21])=O.N1CCCC1>C(OCC)C.O.C(O)(=O)C>[CH3:14][C:8]1([CH3:15])[CH2:9][C:10]([CH3:13])([CH3:12])[CH2:11][CH:6]([C:1]2[CH:2]=[CH:3][C:4](=[C:19]([CH3:21])[CH3:18])[CH:5]=2)[CH2:7]1
Reactant: CC1(C)CC(C2C=CC=C2)CC(C)(C)C1
Reactant: CC(C)=O
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CC(C)=C1C=CC(C2CC(C)(C)CC(C)(C)C2)=C1
Reaction time: 52 h

Procedure:
A 500 mL flask was charged with 1-(cyclopentadienyl)-3,3,5,5-tetramethylcyclohexane (11.87 g, 58.1 mmol), 100 mL methanol, acetone (30 mL, 430 mmol), and pyrrolidine (1.0 mL, 12 mmol). After stirring for 52 hours, 5 mL of acetic acid were added, along with 200 mL water and 100 mL diethyl ether. The organic layer was isolated and the aqueous layer was extracted with diethyl ether (3×50 mL). The combined organic layers were extracted with H2O (3×30 mL) and 10% aqueous NaOH (3×30 mL). The organic layer was dried over MgSO4, filtered, rotavapped, dried in vacuo, and pushed through a short column of alumina to provide the product in quantitative yield as a yellow oil. MS (GC-MS) m/z 244.4 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:18]COC(C)=O.CCCCCCC>CO>[CH3:18][O:12][C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(C)=O
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: CCCCCCC
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a mixture of 2-(4-nitrophenyl)acetic acid (1 g, 5.52 mmol) dissolved in methanol (100 mL) cooled to 0° C., was added thionyl chloride (1.31 mL, 11 mmol) dropwise slowly. The mixture was stirred at 0° C. for 30 min then 25° C. for 1 h. TLC Rf=0.5 PDT (50% EtOAc/heptane; Rf=0.2 for SM). The mixture was concentrated under reduced pressure to afford (4-nitro-phenyl)-acetic acid methyl ester (1.1 g, 100%). 1H NMR (CDCl3) δ 8.2 (d, 1H), 7.5 (d, 1H), 3.79 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].C([Mg]Cl)(C)C.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Mg]Br>C1COCC1.C(Cl)Cl>[NH2:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=1)=[O:5]
Reactant: CON(C)C(=O)c1cc(F)ccc1N
Reactant: Br[Mg]c1ccccn1
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1ccc(F)cc1C(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a −78° C. solution of 2-amino-5-fluoro-N-methoxy-N-methylbenzamide (9.40 g, 47.4 mmol) in THF (39.5 mL) was added isopropylmagnesium chloride 2.0M in THF (47.4 mL, 94.8 mmol) at −40° C. The solution was allowed to rise to −10° C. over 40 min then was lowered back to −40° C. in an acetonitrile/dry ice bath. To the cooled mixture was added 2-pyridylmagnesium bromide, 0.25M in THF (209 mL, 52.2 mmol) and the mixture was allowed to warm to rt. After 22 h, the reaction was diluted with DCM (200 mL) and quenched with satd ammonium chloride solution (200 mL). The aq layer was extracted with DCM (2×100 mL). The organic extract was dried over Na2SO4. The solution was filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtOAc in hexane, to provide (2-amino-5-fluorophenyl)(pyridin-2-yl)methanone as orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65-8.72 (1H, m), 8.02 (1H, td, J=7.7, 1.8 Hz), 7.79 (1H, dt, J=7.8, 1.0 Hz), 7.60 (1H, ddd, J=7.6, 4.9, 1.2 Hz), 7.29-7.36 (1H, m), 7.18-7.29 (3H, m), 6.88 (1H, dd, J=9.2, 4.7 Hz); LC-MS (ESI) m/z 217.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.[CH2:28]([O:30][C:31](=[O:56])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([NH:43][C:44](OCC(Cl)(Cl)Cl)=[O:45])=[CH:41][C:40]([C:52]([CH3:55])([CH3:54])[CH3:53])=[N:39]2)[CH:33]=1)[CH3:29].CCN(C(C)C)C(C)C>O1CCOCC1>[CH2:28]([O:30][C:31](=[O:56])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([NH:43][C:44]([NH:27][C@@H:20]3[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C@H:17]([O:16][C:13]4[CH:14]=[CH:15][C:10]5[N:11]([C:7]([C@@H:3]6[CH2:4][CH2:5][CH2:6][N:2]6[CH3:1])=[N:8][N:9]=5)[CH:12]=4)[CH2:18][CH2:19]3)=[O:45])=[CH:41][C:40]([C:52]([CH3:55])([CH3:54])[CH3:53])=[N:39]2)[CH:33]=1)[CH3:29]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5C)n4c3)c3ccccc32)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A mixture of Intermediate 5c (163 mg, 0.45 mmol), Intermediate 30a (208 mg, 0.45 mmol) in 1,4-dioxane (3 mL) and DIPEA (119 μL, 0.68 mmol) was stirred at 90° C. for 3 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-12% MeOH in DCM, to give the product (291 mg, 96%). A 64 mg portion of this was further purified by HPLC (C18 X-select column, 30-98% MeCN in H2O, 0.1% HCO2H) to give the title compound as a white powder after freeze-drying powder (38 mg). LCMS (Method 5): Rt 3.85 min, m/z 677.3 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26-1.33 (12H, m), 1.80-2.27 (11H, m), 2.30-2.39 (1H, m), 3.09-3.16 (1H, m), 3.99 (1H, br t, J 8.2), 4.32 (2H, q, J 7.1), 4.74-4.83 (1H, m), 5.36-5.41 (1H, m), 6.33 (1H, s), 7.11 (1H, d, J 8.6), 7.19-7.37 (5H, m), 7.66 (1H, t, J 7.9), 7.75 (1H, d, J 9.9), 7.80-7.84 (1H, m), 7.93-7.98 (1H, m), 8.07-8.09 (1H, m), 8.22-8.28 (2H, m).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[O:16])[N:14]=2)[CH2:7]1)(=O)=O.[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>CN(C)C=O>[C:24]([S:26][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)=[O:16])[N:14]=2)[CH2:9]1)(=[O:27])[CH3:25]
Reactant: CC([O-])=S
Reactant: CN1CCN(C(=O)c2csc(N3CC(OS(C)(=O)=O)C3)n2)CC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N3CCN(C)CC3)cs2)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 51.4 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (537 mg, 1.49 mmol) (obtained as described in Reference Example 20(3)) in dimethylformamide (16 ml) was added potassium thioacetate (1.02 g, 8.94 mmol) at room temperature. The mixture was stirred in an oil bath (90° C.) for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 3-acetylthio-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (261 mg, yield 51%) as a pale brown solid.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[O:17]1[CH:19]([CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:18]1.C(Cl)(Cl)Cl.CO>CN(C)C=O>[OH:17][CH:19]([CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:18][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10]
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOCC(O)Cn1cnc2c(N)ncnc21
Reaction time: 20 h
Yield: 32 %

Procedure:
A mixture of adenine (0.829 g, 6.10 mmol), anhydrous potassium carbonate (45 mg) and rac-1,2-epoxy-3-octadecyloxypropane (2.0 g, 6.13 mmol) in anhydrous dimethylformamide (10 mL) is stirred at 70°-75° C. for 20 hours under a nitrogen atmosphere. The reaction mixture is filtered directly without cooling, and the filtrate is concentrated in vacuo to afford a white residue. The residue is stirred with 95:5 (v/v) chloroform-methanol. The insoluble solid is filtered, purified by chromatography, and dried in vacuo to give 0.9 g (31.8%) of 9-[2'-hydroxy-3'-octadecyloxypropyl]-adenine (CPR 1148): Thin-layer Chromatography (TLC); 4×8 cm silica gel 60, 0.25 mm thickness, 10:2:0.2 (v/v/v) CHCl3 -CH3OH-30% aqueous ammonia (Rf value=0.65); mp 151°-152° C.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:34])[C:11]2[O:17][C:16]3[C:18]([Cl:30])=[CH:19][C:20]([NH:22][CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:21][C:15]=3[CH2:14][S:13](=[O:32])(=[O:31])[C:12]=2[CH:33]=1)=[O:7].FC(F)(F)C(O)=O.C([BH3-])#N.[Na+]>CO>[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:34])[C:11]2[O:17][C:16]3[C:18]([Cl:30])=[CH:19][C:20]([N:22]([CH2:1][CH3:2])[CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:21][C:15]=3[CH2:14][S:13](=[O:31])(=[O:32])[C:12]=2[CH:33]=1)=[O:7]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCCC3)cc(Cl)c1O2
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCN(CCN1CCCC1)c1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)OC)cc(C)c1O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Distilled acetaldehyde (0.11 mL, 1.90 mmol) was added to a solution of Example 72k (0.180 g, 0.38 mmol) in dry methanol (15 mL), followed by the addition of trifluoroacetic acid (0.03 mL, 0.38 mmol). The reaction mixture was stirred at 0° C. for 2 h. Sodium cyanoborohydride was added and the reaction mixture was allowed to come to room temperature and then left stirring overnight. It was concentrated, treated with 10% aqueous sodium bicarbonate solution, water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.118 g (62%); 1H NMR (DMSO-d6): δ 1.20 (t, 3H, CH3), 1.90-2.00 (m, 4H, 2CH2), 2.60-2.69 (m, 4H, 2CH2), 2.70 (s, 3H, CH3), 3.45 (q, 2H, CH2), 3.55 (t, 2H, CH2), 3.90 (s, 3H, OCH3), 4.70 (s, 2H, CH2), 6.65 (s, 1H, Ar), 6.75 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.55 (s, 1H, Ar); MS: m/e (ES+) 493 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][C:16]2[C:17]([F:23])=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[C:6]([CH:14]=1)[C:7](N(CC)CC)=[O:8].C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C>C1COCC1>[Br:1][C:2]1[CH:14]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:15][C:16]1[C:17]([F:23])=[N:18][C:19]([Cl:22])=[CH:20][C:21]=1[C:7]2=[O:8]
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc(Cl)nc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: O=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-2-(6-chloro-2-fluoropyridin-3-yloxy)-N,N-diethylbenzamide (120 mg, 0.299 mmol) in 5 mL of dry THF at −78 C was added dropwise lithium diisopropylamide, 2.0 m heptane/tetrahydrofuran/ethylbenzene (158 μL, 1.195 mmol) (0.6 mL of 2M solution) and the reaction was stirred at −78 C for 3 h. The reaction was quenched at −78 C with sat. NH4Cl and was allowed to warm up to RT. The reaction was extracted with EA, dried over Na2SO4, filtered and evaporated to dryness. CC (hexane to H/DCM=1:1 to DCM) gave 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one as an offwhite solid. MS (M+1): 328.
Reaction SMILES: [CH3:1][N:2]1[C:14](=[O:15])[N:13]([CH3:16])[C:12](=[O:17])[C:11]2[C:3]1=[C:4]1[N:9]([C:10]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:8][CH2:7][CH:6]=[C:5]1OS(C(F)(F)F)(=O)=O.[Li+].[Cl-].[CH3:34][C:35]1[N:36]=[C:37]([Sn](CCCC)(CCCC)CCCC)[S:38][CH:39]=1>C1COCC1.CCOC(C)=O.[Cu](I)I.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]>[CH3:1][N:2]1[C:3]2=[C:4]3[C:5]([C:37]4[S:38][CH:39]=[C:35]([CH3:34])[N:36]=4)=[CH:6][CH2:7][NH:8][N:9]3[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:11]2[C:12](=[O:17])[N:13]([CH3:16])[C:14]1=[O:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(OS(=O)(=O)C(F)(F)F)=CCN3
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1csc(C2=CCNn3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)n1
Temperature: 25 °C

Procedure:
Trifluoro-methanesulfonic acid 5,7-dimethyl-6,8-dioxo-9-phenyl-1,2,5,6,7,8-hexahydro-1,5,7,9a-tetraaza-fluoren-4-yl ester (step 5) (280 mg, 0.614 mmol), LiCl (2.60 mg, 0.061 mmol), copper iodide (11.68 mg, 0.061 mmol) and 4-methyl-2-tributylstannanyl-thiazole (Intermediate J) (4.45 g, 11.46 mmol) were combined in THF (15 ml) and PdCl2(dppf) (44.9 mg, 0.061 mmol) was added. The mixture was heated at reflux for 1 hour. The reaction mixture was cooled to RT and diluted with EtOAc. The mixture was washed with dil. NH4OH(aq), 1M KF(aq) and brine. The organic phase was dried over sodium sulphate and evaporated under reduced pressure. Purification of the residue by chromatography on silica, eluting with EtOAc/hexane, afforded the title compound as a crude pale brown solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:19]([C:21]1[S:22][CH:23]=[CH:24][C:25]=1Br)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](=[N:40][NH2:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:27](=[N:40][NH:41][C:25]1[CH:24]=[CH:23][S:22][C:21]=1[C:19]([C:11]1[N:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=1)=[O:20])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: O=C(c1sccc1Br)c1nc2ccccc2n1COCc1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(c1sccc1NN=C(c1ccccc1)c1ccccc1)c1nc2ccccc2n1COCc1ccccc1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
A mixture of (1-benzyloxymethyl-1H-benzimidazol-2-yl)-(3-bromothiophen-2-yl)methanone (500 mg, 1.06 mmol, Example 1C), benzophenone hydrazone (276 mg, 1.41 mmol), palladium(II) acetate (13.4 mg, 0.06 mmol), 1,1′-Bis(diphenylphosphino)-ferrocene (57.5 mg, 0.104 mmol), cesium carbonate (570 mg, 1.75 mmol), and toluene (10 mL) under nitrogen is stirred at 90° C. for 15 hours. The dark reaction is cooled to ambient temperature, diluted with ethyl acetate, filtered, and the insolubles washed with ethyl acetate. The combined filtrate and washings were washed with water and brine successively, dried over magnesium sulfate, and then concentrated under reduced pressure to afford a yellow oil. The crude material is chromatographed on silica, eluting with 80% dichloromethane/heptane, to give [3-(N′-benzhydrylidene-hydrazino)-thiophen-2-yl]-(1-benzyloxymethyl-1H-benzoimidazol-2-yl)-methanone as a yellow-orange powder: TLC Rf 0.30 (silica, 80% dichloromethane/heptane); LC/MS: (M+H 543.1, RT=4.68 minutes); 1H NMR [(CD3)2SO), 300 MHz]: δ 11.64 (s, 1H), 8.08 (d, 1H, 5.5 Hz), 7.84-7.13 (m, 20H), 6.00 (s, 2H), 4.46 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C[O-].[Na+]>CO>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: Oc1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1cccnc1Oc1cccc(Cl)c1
Yield: 88.5 %

Procedure:
In the same manner as in Example 1(a), 15.8 grams (0.1 mole) 2-chloronicotinic acid, 64.0 grams (0.5 mole) 3-chlorophenol, 45 grams (0.21 mole) 25% sodium methoxide solution and 100 milliliters methanol were combined to produce 22.1 grams (88.6% of theoretical yield) of 2-(3-chlorophenoxy) nicotinic acid, m.p. 161°-164° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:18][C:19]1[N:20]=[C:21]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[S:22][C:23]=1[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][CH:4]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:24][C:23]2[S:22][C:21]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)=[N:20][C:19]=2[CH3:18])=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(OCC)c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (108 mg, 0.453 mmol) produced in Example 1 (1C) and {4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol (124 mg, 0.453 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@@H:11]1[CH2:15][N:14]([CH:16]([CH3:18])[CH3:17])[CH2:13][C@H:12]1[C:19]([O:21]C)=[O:20]>O1CCCC1>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@@H:11]1[CH2:15][N:14]([CH:16]([CH3:17])[CH3:18])[CH2:13][C@H:12]1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)[C@@H]1CN(C(C)C)C[C@H]1c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Reaction time: 3 h

Procedure:
Lithium hydroxide (171 mg, 7.14 mmol) was added to a solution of methyl (3S,4R)-4-(2,4-difluorophenyl)-1-isopropylpyrrolidine-3-carboxylate, from preparation 32 (1.01 g, 3.59 mmol) in tetrahydrofuran (10 mL) at room temperature. The reaction mixture was stirred for 3 hours and the solvent was removed in vacuo. The residue was dissolved in water (20 mL) and washed with ethyl acetate (2×20 mL). The phases were separated and the aqueous phase was acidified with 2M aqueous hydrochloric acid solution (3.59 mL) and extracted with ethyl acetate (20 mL). The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to afford the desired product as a foam, 686 mg (71%).
Reaction SMILES: [C:1]1([S:7]([CH2:10][F:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(OCC)(OCC)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([CH3:43])([CH3:42])[CH2:39]C=O)=[CH:34][CH:33]=1.[Cl-].[NH4+].Cl>O1CCCC1.C(OCC)(=O)C>[F:11][C:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])=[CH:42][C:38]([CH3:43])([C:35]1[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=1)[CH3:39]
Reactant: CC(C)(CC=O)c1ccc(Cl)cc1
Reactant: O=S(=O)(CF)c1ccccc1
Agent: CCOP(=O)(Cl)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C=C(F)S(=O)(=O)c1ccccc1)c1ccc(Cl)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, 25.0 grams (0.14 mole) of distilled fluoromethyl phenyl sulfone (prepared by the method of J. R McCarthy et al., Org. Syn. 1993, 72, 209), 24.8 grams (0.14 mole) of diethyl chlorophosphate, and 300 mL of anhydrous tetrahydrofuran are placed in a reaction vessel. The stirring mixture is cooled to about -70° C., and a solution of 310 mL (0.31 mole) of lithium bis(trimethylsilyl)amide (commercially available-1M in tetrahydrofuran) is added dropwise during a 15 minute period. Upon completion of addition, the reaction mixture is stirred at about -70° C. for one hour. After this time a solution of 19.7 grams (0.10 mole) of 3-(4-chlorophenyl)-3-methylbutyraldehyde in 65 mL of tetrahydrofuran is added via a syringe. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred for about two hours. The reaction mixture is then poured into an ice-cold mixture of 250 mL of ethyl acetate, 250 mL of saturated aqueous ammonium chloride, and 30 mL of concentrated hydrochloric acid. The organic layer is separated, and the aqueous o layer is extracted with ethyl acetate. The extract and the organic layer are combined, washed with 100 mL of saturated aqueous sodium chloride, and dried with magnesium sulfate. The mixture is filtered, and the filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel. The product-containing fractions are combined and concentrated under reduced pressure, yielding 1-fluoro-1-phenylsulfonyl-3-methyl-3-(4-chlorophenyl)-1-butene.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][SH:5].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[C:8]=1F.O>CN(C)C=O>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[C:8]=1[S:5][CH3:4]
Reactant: CS(=O)(=O)c1c(C(=O)O)ccc(Cl)c1F
Reactant: CS
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1c(Cl)ccc(C(=O)O)c1S(C)(=O)=O
Reaction time: 2 h
Yield: 55 %

Procedure:
Lithium hydroxide monohydrate (1.26 g) was added to a solution of methyl mercaptan (0.72 g) in dimethyl formamide. To this mixture was added 4-chloro-3-fluoro-2-(methylsulphonyl)benzoic acid (3.7 g). The mixture was stirred for 2 hours then poured into water and acidified to pH1. It was extracted with ether, washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with n-hexane and filtered to give 4-chloro-3-(methylsulphenyl)-2-(methylsulphonyl)benzoic acid (2.26 g) as a white solid, NMR (CDCl3) 2.5(s,3H), 3.45(s,3H), 7.5(d,1H), 7.7(d,1H).