Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][C:9]([CH3:14])=[C:10]([CH2:11][CH:12]=[O:13])[C:6]=2[C:5](=[O:15])[N:4]([CH3:16])[C:3]1=[O:17].S(=O)(=O)([OH:20])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH3:1][N:2]1[C:7]2[S:8][C:9]([CH3:14])=[C:10]([CH2:11][C:12]([OH:20])=[O:13])[C:6]=2[C:5](=[O:15])[N:4]([CH3:16])[C:3]1=[O:17]
Reactant: Cc1sc2c(c1CC=O)c(=O)n(C)c(=O)n2C
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1sc2c(c1CC(=O)O)c(=O)n(C)c(=O)n2C
Reaction time: 2 h

Procedure:
To a solution of Step 7 intermediate (900 mg, 3.57 mmol) and sulphamic acid (693 mg, 7.142 mmol) in acetone (17.8 ml) was added sodium chlorite (484 mg, 5.357 mmol) in water (5.35 ml) and reaction mixture was stirred for 2 h. The solvent was evaporated, diluted with water and acidified with 1N HCl. Solid obtained was filtered and dried to give 375 mg of title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H), 3.20 (s, 3H), 3.42 (s, 3H), 3.80 (s, 2H), 12.19 (br s, 1H); MS (m/z) 249.10 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:17]=[O:18])=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:6]=1.[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:19]1([CH:17]([C:3]2[C:2]([CH3:1])=[CH:6][N:5]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=3)[CH:4]=2)[OH:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of 4-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde (2.3 g) synthesized above in tetrahydrofuran (20 mL) was added dropwise 1M cyclohexylmagnesium bromide-tetrahydrofuran solution (12 mL) at 0° C. After stirring at 0° C. for 1 hr, an aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title compound (1.8 g, 52%) as a colorless solid.
Reaction SMILES: [C:1]([O:9][CH:10]([CH:15]1[CH:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:18]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:17]([CH2:45][O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:16]1[CH2:54]C1C=CC=CC=1)[CH2:11][CH2:12]CO)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC=1>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:9][CH:10]1[CH:15]2[N:16]([CH:17]([CH2:45][O:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH:18]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:19]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:20]2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:54][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC(CCCO)C1C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C(COCc2ccccc2)N1Cc1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CO
Product: O=C(OC1CCCN2C(COCc3ccccc3)C(OCc3ccccc3)C(OCc3ccccc3)C(OCc3ccccc3)C12)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
To a solution of Compound (XV) (0.60 g; 0.74 mmoles) and cyclohexene (5 mL) in methanol (30 mL), Pearlman's catalyst (0.2 g) was added under a nitrogen atmosphere. The suspension was stirred at room temperature for 18 hours, then the catalyst was filtered through Celite and washed with methanol (20 mL). The combined organic layer was evaporated under reduced pressure to yield a crude oil, which was purified via flash chromatography (silica gel; 1:1 as a clear colorless oil (0.34 g) and recovered Compound (XV) (0.10 g; 16% recovery). The N-debenzylated alcohol (0.34 g) was dissolved in pyridine (20 mL) and cooled to -10° C., then methanesulfonyl chloride (0.04 mL) was added, and reaction was continued for 96 hours. The solvent was evaporated under reduced pressure and saturated aqueous sodium bicarbonate solution was added to the residue. After extraction with ether (2×60 mL), the combined organic solution was dried over magnesium sulfate and the solvent evaporated under reduced pressure. The crude product was purified via flash chromatorgraphy (silica gel; 1:1 ethyl acetate:hexane) to yield Octahydro-7,8,9-tris (phenylmethoxy)-6-[(phenylmethoxy)methyl]-2H-quinolizin1-ol benzoate (ester) (XVI) (0.16 g; 50%) as a colorless oil. IR (film from CDCl3) 1718 cm-1 (C=0); MS(CI--CH4) 698 (MH+), 576 (MH+ -PhCO2H); 1H nmr (CDCl3) δ 1.2 (m, 1H), 1.6-1.9 (m, 2H), 2.2 (d, 1H), 2.8 (t, 1H), 3.3-3.4 (m, 2H), 3.5-3.7 (m, 3H), 3.8 (m, 1H), 4.1 (t, 1H), 4.3 (d, 1H), 4.4-4.7 (m, 7H), 4.9 (d, 1H), 5.5 (s, 1H), 7.0-7.4 (m, 22H), 7.5 (m, 1H), 8.1 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH:4]([C:10](=[S:12])[NH2:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O>C(O)C>[CH3:13][CH:2]([CH3:1])[CH2:3][CH:4]([C:10]1[S:12][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)C(CC(C)C)C(N)=S
Solvent: CCO
Product: CCOC(=O)C(CC(C)C)c1nc(-c2ccccc2)cs1

Procedure:
A solution comprised of ethyl 4-methyl-2-thiocarbamoylpentanoate (410 mg, 2 mmol) in ethanol (5 mL) was treated with 2-bromo-1-phenylethanone (400 mg, 2 mmol). The mixture was refluxed for 30 minutes and concentrated to provide ethyl 4-methyl-2-(4-phenylthiazol-2-yl)pentanoate as a crude product. The crude product was dissolved in methanol (5 mL, tech. grade) and the solution was treated with sodium hydroxide (100 mg, 2.5 mmol). The mixture was stirred for 2 hours and diluted with 0.1 M hydrochloric acid solution. The dilution was extracted with ethyl acetate (25 mL) and the extract was washed with water and brine, dried (MgSO4) and concentrated. Product was purified from the residue by flash column on silica gel (60° A) with 33% ethyl acetate in hexane to provide 4-methyl-2-(4-phenylthiazol-2-yl)pentanoic acid (500 mg, 1.8 mmol). Rf 0.33. 1H NMR (DMSO-d6): 0.96 (d, 6H), 1.71-1.79 (m, 3H), 3.61 (m, 1H), 7.12 (s, 1H), 7.32-7.41 (m, 5H). LCMS: 275.91 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[C:17]([F:36])[CH:16]=3)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13]Br)[N:6]2[N:5]=[CH:4][N:3]=1.[CH3:37][O:38][CH2:39][C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[C:17]([F:36])[CH:16]=3)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][N:41]3[CH2:42][CH2:43][CH2:44][C@H:40]3[CH2:39][O:38][CH3:37])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(CCCBr)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Reactant: COC[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC[C@@H]1CCCN1CCCc1cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn12
Temperature: 55 °C
Yield: 65.9 %

Procedure:
1-{4-[4-amino-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (Example 193 step 1) (50 mg, 0.088 mmol) and (2S)-2-(methoxymethyl)pyrrolidine (36 uL, 0.263 mmol) were added to a vial. DMF was added (1 mL) followed by triethylamine (15 uL, 0.109 mmol) and KI (spatula tip). The vial was capped and the reaction heated at 55° C. for two hours. Upon cooling the product precipitated out of solution. The solids were collected by filtration and rinsed with ether to yield 35 mg (65%) of clean product. 1H-NMR (DMSO-d6) δ 9.41 (s, 1H), 9.25 (s, 1H), 8.65 (d, J=7.2 Hz, 1H), 8.26 (t, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.55 to 7.21 (m, 4H), 6.57 (s, 1H), 3.32 (s, 3H), 3.18 to 2.83 (m, 7H), 2.37 to 1.45 (m, 5H); MS [M+H]+=604.2; LCMS RT=2.59
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:24]=1[C:25]#[N:26].C([O:35][C:36]([C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[CH2:43][CH2:44][CH2:45]O)=[O:37])(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([CH3:9])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:45][CH2:44][CH2:43][N:39]2[CH2:40][CH2:41][CH2:42][C@H:38]2[C:36]([OH:37])=[O:35])=[O:7])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:24]=1[C:25]#[N:26]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CCCO
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCCN1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide (30 mg, 0.069 mmol) dissolved in THF (700 μL), (S)-1-(3-hydroxy-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (18 mg, 0.078 mmol), triphenylphosphine (26 mg, 0.1 mmol) and DIAD (20 μL, 0.1 mmol) were added. The mixture was stirred at rt overnight, concentrated, diluted with 1 mL MeOH and purified by prep HPLC. The resulting (S)-1-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester was treated with 50% TFA in DCM (2 mL), stirred at rt for 4 hrs and concentrated yielding (S)-1-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propyl]-pyrrolidine-2-carboxylic acid 50-1. MS: 587.4 (MαH)+, tR=4.34 min (method 3).
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH:18]=[CH2:19])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2]C=C>C1(C)C=CC=CC=1>[N:5]1([C:6]([O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:15])[CH2:1][CH2:2][CH:19]=[CH:18][CH2:17][CH2:16]1
Reactant: C=CCCN(CCC=C)C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC=CCC1
Temperature: 50 °C
Yield: 92.5 %

Procedure:
0.15 g Grubb's 2 catalyst was added to a solution of 8 g benzyl dibut-3-enylcarbamate in 680 mL toluene and heated at 50° C. for 5 h. The solvent was removed and the residue was purified by chromatographie on silica gel (ethyl acetate/hexane 1:5) to yield 6.6 g of the desired product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH3:17][S:18]([NH:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:20])=[O:19].C(N(CC)CC)C>C(O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[N:27]1[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22][NH:21][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:29][CH2:28]1
Reactant: CS(=O)(=O)NCCC1CCNCC1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(N3CCC(CCNS(C)(=O)=O)CC3)c2cc1OC
Temperature: 25 °C
Yield: 88 %

Procedure:
4-Chloro-6,7-dimethoxy quinazoline (1.1 g.), 4- (2-methanesulphonamidoethyl)piperidine hydrochloride (1.5 g.) and triethylamine (1.5 ml.) in ethanol (30 ml.) were heated together under reflux for 1.5 hours. The solution was then cooled to room temperature, concentrated in vacuo, suspended in water (70 ml.) and basified to pH 10 with 10% aqueous sodium carbonate solution. The mixture was extracted with chloroform (2×70 ml.), the extracts combined, dried (MgSO4), and taken to dryness in vacuo. The resultant pale yellow oil was triturated with ether (70 ml.) to give a white solid which was collected by filtration. Crystallization of this solid from ethanol yielded 6,7-dimethoxy-4-[4-(2-methanesulphonamidoethyl)-piperidino]quinazoline (1.7 g.), m.p. 162°-164° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:26]=[N:25][C:17]2[NH:18][C:19]3[CH2:24][CH2:23][NH:22][CH2:21][C:20]=3[C:16]=2[CH:15]=1.O>N1C=CC=CC=1>[Cl:13][C:14]1[CH:26]=[N:25][C:17]2[NH:18][C:19]3[CH2:24][CH2:23][N:22]([S:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)(=[O:11])=[O:10])[CH2:21][C:20]=3[C:16]=2[CH:15]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
4-Methoxybenzenesulfonyl chloride (0.04 mL, 0.26 mmol) was added to a solution of 3-chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) in pyridine (2 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was added to water (20 mL), and the resulting precipitate was filtered and dried under vacuum to provide 39 (61 mg, 67% yield) as a yellow solid. LC-MS (M+H=379, obsd.=379).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH:15]=2)O)=[CH:4][CH:3]=1.Cl.[CH3:31][OH:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH:15]2[O:32][CH3:31])=[CH:4][CH:3]=1
Reactant: OC(C1=CCN(Cc2ccccc2)CC1)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CO
Agent: Cl
Product: COC1CN(Cc2ccccc2)CCC1=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A mixture of 50.9 parts of α,α-bis(4-fluorophenyl)-1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinemethanol, 320 parts of methanol and 800 parts of a hydrochloric acid solution 1N was stirred first for 3 hours at reflux temperature and then for 56 hours at room temperature. The whole was evaporated till all traces of methanol were removed. The free base was liberated with ammonium hydroxide. The product was extracted with 1040 parts of dichloromethane. The extract was washed with 100 parts of water, dried, filtered and evaporated. The residue was dissolved in 270 parts of N,N-dimethylformamide. The whole was heated to 60° C. 2.5 Parts of a sodium hydride dispersion 50% were added at 80° C. After stirring for 1 hour at 80° C., the mixture was cooled to room temperature. 9 Parts of iodomethane were added dropwise. Upon completion, the whole was stirred and heated for 30 minutes at 40° C. After cooling, the reaction mixture was poured onto 2000 parts of ice-water. The product was extracted twice with 450 parts of methylbenzene. The combined extracts were dried, filtered and evapoated. The oily residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 29.6 parts (57%) of 4-[bis(4-fluorophenyl)methylene]-3-methoxy-1-(phenylmethyl)piperidine as a residue (intermediate 29).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[C:26]([Si:30]([CH3:48])([CH3:47])[O:31][CH:32]1[CH2:37][CH2:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH2:33]1)([CH3:29])([CH3:28])[CH3:27].C([O-])(=O)C.[K+].O>CC#N>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:35]3[CH2:36][CH2:37][CH:32]([O:31][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:47])[CH3:48])[CH2:33][CH:34]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: CC1(C)OB(C2=CCC(O[Si](C)(C)C(C)(C)C)CC2)OC1(C)C
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC1CC=C(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
1H-benzimidazol-2-yl(4-((3-chloro-2-pyrazinyl)oxy)phenyl)methanone (0.50 g, 1.4 mmol), tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-cyclohexen-1-yl)oxy)silane (0.68 g, 2.0 mmol), potassium acetate (1.0 g, 11.0 mmol), and bis[di-tert-butyl(phenyl)phosphane]dichloropalladium (0.066 g, 0.11 mmol) were taken up in 24 mL of 3:1 MeCN:water. The mixture was purged with nitrogen and heated to 100° C. After 18 hours, the mixture was diluted with 30 mL of water and extracted three times with 25 mL of 9:1 chloroform:isopropanol. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 25% EtOAc/hexanes) afforded 1H-benzimidazol-2-yl(4-((3-(4-((tert-butyl(dimethyl)silyl)oxy)-1-cyclohexen-1-yl)-2-pyrazinyl)oxy)phenyl)methanone.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:10][C:7]2[CH:8]=[CH:9][C:2]([Cl:1])=[C:3]([F:11])[C:4]=2[CH:5]=[O:6])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=Cc1c(O)ccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)c(F)c2C=O)CC1
Yield: 106.1 %

Procedure:
In a manner similar to the method described in example 4a, 3-chloro-2-fluoro-6-hydroxy-benzaldehyde (2.07 g, 11.8 mmol) reacted with 4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester (3.51 g, 9.88 mmol, ASTATECH) and K2CO3 in N,N-dimethylformamide to give 4-(4-chloro-3-fluoro-2-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as a brown oil (Yield 3.75 g, 84%).
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:5]=[CH:6][N:1]=1
Reactant: [O-][n+]1ccc(-c2ccncc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc(-c2ccncc2)ccn1
Temperature: 110 °C

Procedure:
The suspension of 4,4′-bipyridine-1-oxide (8.50 g, 49.36 mmol) in phosphorus oxychloride (80 mL) was heated to 110° C. overnight. The mixture was concentrated and the residue was treated with saturated aqueous NaHCO3 solution (150 mL) slowly and then Na2CO3 solution (2M) until it was basic. The alkaline solution was extracted with chloroform (4×300 mL). The combined organic layer was dried, treated with activated carbon and filtered through celite. The filtrate was concentrated and the resulting solid was purified by flash column chromatography (4% MeOH in CH2Cl2) to give 2-Chloro-4,4′-bipyridine (3-2) as a off-yellow solid. 1H NMR (CDCl3) δ 8.77 (dd, 2H, J=4.5, 1.6), 8.53 (d, 1H, J=5.1), 7.58 (s, 1H), 7.52 (dd, 2H, J=4.7, 1.7), 7.46 (dd, 1H, J=5.2, 1.5).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:24][CH:23]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:22]2[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:23]=2)=[CH:9][CH:8]=1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: CCOC(=O)COc1ccc(O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(OCC(=O)O)cc2)cc1)c1ccccc1
Yield: 13.72 %

Procedure:
Compound 117 was synthesized from Intermediate 13 (0.22 g, 1.020 mmol) and ethyl (4-hydroxyphenoxy)acetate (0.20 g, 1.020 mmol) by following the procedure described in scheme 41 (0.060 g, yield: 13.72%); Purity: 97.98%.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH:3]1[CH2:7][N:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:5]([C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=2)=O)[CH2:4]1.[H-].[Na+]>C1COCC1>[CH3:1][N:2]([CH3:28])[CH:3]1[CH2:7][N:6]2[C:8](=[O:17])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=3)[N:5]2[CH2:4]1
Reactant: CSc1nccc(C(=O)N2CC(N(C)C)CN2C(=O)Cc2ccc(F)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2CC(N(C)C)C3)n1
Temperature: 0 °C

Procedure:
1-[4-Dimethylamino-2-(2-methylsulfanyl-pyrimidine-4-carbonyl)-pyrazolidin-1-yl]-2-(4-fluorophenyl)-ethanone, 23, (4.0 g, 10 mmol) is dissolved in THF (75 mL). This solution is then added dropwise via cannula to a suspension of NaH (0.440 g of a 60% dispersion in mineral oil, 11 mmol) at −30° C. The reaction is allowed to gradually warm to 0° C. over 3 hours. The reaction is quenched with NH4Cl (sat. aq.) (15 ml ). The mixture is stirred at room temperature, then concentrated in vacuo. The residue is diluted with tetrahydrofuran (250 mL) and the mixture filtered through Celite. The filtrate is concentrated in vacuo to give an oil. The crude product is purified over silica (100% ethyl acetate to 5% to 10% to 20% methyl alcohol/ethyl acetate) to afford the desired product.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19]C)=[O:18])[C:9]2=[O:21])(=[O:4])=[O:3].Cl>O1CCOCC1.O>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([OH:19])=[O:18])[C:9]2=[O:21])(=[O:3])=[O:4]
Reactant: COC(=O)CN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.6 %

Procedure:
To a solution of methyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (obtained as described in Example 30, Step 3, theoretical amount 1.622 mmol) in dioxane (10 ml), a 36% solution of HCl in water (10 ml) was added, and the mixture was stirred for 3 hours at room temperature. The volatiles were evaporated and the resulting crude was purified by flash chromatography on silica gel (eluent: DCM/MeOH 95:5). The title compound was obtained as a pale yellow solid (230 mg, 0.772 mmol, 47.6% yield over 2 steps, MS/ESI+ 299.1 [MH]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O.C(OC)(=O)[CH2:14][C:15](OC)=[O:16].[H-].[Na+]>[Fe]>[CH3:9][O:8][C:5]1[CH:4]=[C:3]2[C:2]([CH2:14][C:15](=[O:16])[NH:10]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)CC(=O)OC
Agent: [Fe]
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)NC(=O)C2
Yield: 18.4 %

Procedure:
In a manner similar to the method described in example 167a, 1-chloro-4-methoxy-2-nitro-benzene (19 g, 0.1 mol) was reacted with dimethyl malonate (16 g, 0.2 mol), NaH and iron power to give 6-methoxy-1,3-dihydro-indol-2-one (3 g, 18%).