Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13])=[CH2:2].C(N(CC)CC)C.Br[C:22]1[CH:31]=[CH:30][C:29]2[N:28]=[CH:27][C:26]3[N:32]=[C:33]([CH2:44][CH2:45][O:46][CH3:47])[N:34]([CH2:35][CH2:36][CH2:37][N:38]4[CH2:42][CH2:41][CH2:40][C:39]4=[O:43])[C:25]=3[C:24]=2[CH:23]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:47][O:46][CH2:45][CH2:44][C:33]1[N:34]([CH2:35][CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][C:39]2=[O:43])[C:25]2[C:24]3[CH:23]=[C:22]([CH:2]=[CH:1][N:3]4[C:7](=[O:8])[C:6]5[C:5](=[CH:12][CH:11]=[CH:10][CH:9]=5)[C:4]4=[O:13])[CH:31]=[CH:30][C:29]=3[N:28]=[CH:27][C:26]=2[N:32]=1
Reactant: COCCc1nc2cnc3ccc(Br)cc3c2n1CCCN1CCCC1=O
Reactant: C=CN1C(=O)c2ccccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCc1nc2cnc3ccc(C=CN4C(=O)c5ccccc5C4=O)cc3c2n1CCCN1CCCC1=O
Temperature: 120 °C
Yield: 101.6 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (17 mg, 0.08 mmol), acetonitrile (50 mL), N-vinylphthalimide (716 mg, 4.13 mmol), triethylamine (1.6 mL, 11 mmol), tri-o-tolylphosphine (69 mg, 0.22 mmol) and 1-{3-[8-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one (1.62 g, 3.76 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated at 120° C. in an oil bath for 15 hours. The reaction was cooled to ambient temperature and methanol (50 mL) and chloroform (50 ml) were added. After filtering through a 0.2 micron PTFE membrane, the solution was concentrated under reduced pressure and then purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-8% gradient of methanol in dichloromethane) to provide 2.0 g of 2-(2-{2-(2-methoxyethyl)-1-[3-(2-oxopyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}ethenyl)-1H-isoindole-1,3(2H)-dione as a bright yellow solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=12.[I:14]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[I:14][C:3]1[N:4]2[CH:9]=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: COC(=O)c1ccn2ccnc2c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccn2c(I)cnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of Methyl imidazo[1,2-a]pyridine-7-carboxylate (3.8 g, 21.6 mmol, 1.0 equiv) in DMF (20 ml) was added N-iodosuccinimide (5.8 g, 26 mmol, 1.2 equiv) and the resulting mixture was stirred for 2 h at room temperature. The brown slurry was diluted with water, 10% w/v sodium thiosulfate and sodium carbonate (1M) and the resulting white solid was removed by filtration, washed with ether and dried to afford 4.7 g of product. MS: [M+H]+ 303; 1H NMR (400 MHz, Me-d3-OD): 8.44 (1H, d), 8.25 (1H, s), 7.88 (1H, s), 7.61 (1H, dd), 3.95 (3H, s).
Reaction SMILES: C([O-])(=O)C.[K+].[Br:6]Br.[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[C:16]=2[F:23])[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[CH:10]=1>C(O)(=O)C>[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[C:16]=2[F:23])[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[C:10]=1[Br:6]
Reactant: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(F)c2F)n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1nc(-c2ccc(Cl)c(F)c2F)nc(N)c1Br
Temperature: 23 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Potassium acetate (750 mg, 7.6 mmol, 3.0 equiv) and bromine (150 μL, 2.8 mmol, 1.1 equiv) were sequentially added to a stirred suspension of methyl 6-amino-2-(4-chloro-2,3-difluorophenyl)pyrimidine-4-carboxylate (760 mg, 2.5 mmol, 1.0 equiv) in glacial acetic acid (10 mL) at 23° C. The resulting thick orange mixture was stirred at 23° C. for 2 h. The reaction mixture was quenched with saturated sodium thiosulfate solution (˜50 mL) and adjusted to pH=7 using 50% sodium hydroxide solution. The resulting white mixture was diluted with water (150 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated under vacuum. The product was purified by flash chromatography (SiO2, 33% ethyl acetate in hexane) to afford the title compound as a white powder (760 mg, 79% yield): mp 175-178° C.; 1H NMR (300 MHz, CDCl3) δ 7.76 (ddd, 1H, J=9, 7, 2 Hz), 7.23 (ddd, 1H, J=9, 7, 2 Hz), 5.70 (br s, 2H), 4.01 (s, 3H); IR (neat film) 3473 (s), 3317 (s), 3179 (s), 2963 (w), 1740 (s), 1651 (s); ESIMS m/z 378 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](NN)[C:5]([Cl:11])=[CH:4][N:3]=1.Cl[O-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1
Reactant: NNc1c(Cl)cnc(Cl)c1Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Solvent: O
Product: Clc1cnc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
A solution was prepared by dissolving 2.5 grams of 2,3,5-trichloro-4-hydrazinopyridine in 25 milliliters of tetrahydrofuran. To this mixture was added ~10 milliliters of 5.25 percent sodium hypochlorite. The mixture was stirred at ~30° C. for about one hour. The mixture was diluted with water and extracted with methylene chloride. The extract was washed with water and the methylene chloride removed by evaporation. The residue, a dark brown oil, was recovered in a yield of 2.1 grams. The crude 2,3,5-trichloropyridine product was sublimed at ~1 millimeter of mercury and ~50° C. The purified product was obtained in a yield of 1.52 grams (72 percent of theoretical). The structure was confirmed by N.M.R.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccc(Cl)cc1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccc(Cl)cc3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(4-chloro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([CH2:14][CH2:15][CH2:16][S:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C.[OH-].[Na+]>CO.O>[C:10]([O:9][C:7](=[O:8])[CH2:6][CH:5]([CH2:14][CH2:15][CH2:16][S:17][C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:4]([OH:37])=[O:3])([CH3:13])([CH3:11])[CH3:12]
Reactant: CCOC(=O)C(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reaction time: 24 h

Procedure:
To a solution of the compound of example 28 (3.00 g, 5.78 mmol) in methanol (30 mL) and water (10 mL) was added NaOH (1N, 11.6 mL, 11.6 mmol). The mixture was stirred vigorously under ambient conditions. After 24 hours, most of the methanol has evaporated. The residue was portioned between water and ether. The water phase was extracted two times with ether, then acidified with HCl (1N) to pH 1. The water phase was extracted three times with ethyl acetate. The recombined organic phase was dried over sodium sulfate, filtered, and evaporated. The residue was flashed using 5% methanol in chloroform to give the product as a white solid. 1H-NMR(CDCl3, 400 MH: 1.45(s, 9H); 1.35–1.64(m, 4H); 1.58(m, 1H); 2.16(m, 2H); 2.26(m, 1H); 2.64(m, 1H); 4.12(q, J=7.1 Hz, 2H), 7.19–7.29, 7.40(m, 15H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[S:25]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>>[O:31]=[S:25]1(=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:20]1[CH:21]=[CH:22][C:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[C:5]([CH3:24])=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)=[O:16])=[CH:18][CH:19]=1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: O=S1(=O)CCCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 58.5 %

Procedure:
Using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (348 mg) described in Preparation Example 133 and [1,2]thiazinane 1,1-dioxide (141 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (207 mg) was obtained.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24].B(F)(F)F.CCOCC>C(OCC)C>[OH:13][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(C)(C)CO
Agent: FB(F)F
Solvent: CCOCC
Product: COC(=O)C(O)C(OCC(C)(C)C(=O)OC)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
12.7 g (50 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate were dissolved in 50 ml of diethyl ether, 6.6 g (50 mmol) of methyl 3-hydroxy-2,2-dimethylpropionate and 1 ml of BF3.Et2O were added, and the mixture was stirred at room temperature for 18 h. The solvent was evaporated off, and the oily residue was reacted without further purification and characterization.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH3:17][C:18]([S@@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19].O>C(Cl)Cl>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[N:23][S@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)[S@@](N)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[S@](=O)N=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
To a mixture of 3,5-bis(trifluoromethyl)benzaldehyde (5 g, 20.7 mmol) and (S)-2-methylpropane-2-sulfinamide (3 g, 24.8 mmol) in DCM (50 ml) at 0° C., was drop wise added Ti(O-iPr)4 (5.9 g, 24.8 mmol) under N2 atmosphere. After stirring for 20 h at room temperature, the reaction mixture was poured into water (100 mL) with vigorous stirring. The precipitate was filtered and the filtrate was extracted with DCM (2×150 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (6 g, yield: 84%); m/z (ES+): 346 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3]([C:5]1[C:13]2[NH:12][C:11](=[O:14])[CH:10]=[N:9][C:8]=2[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4].I[CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:26]([O:14][C:11]1[N:12]=[C:13]2[C:5]([C:3](=[O:4])[C:2]([CH3:1])([CH3:23])[CH3:24])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1)[CH3:27]
Reactant: CCI
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1

Procedure:
A mixture of 7-(2,2-dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-1,5-dihydro-pyrrolo[2,3-b]pyrazin-2-one (0.080 g, 0.23 mmol), iodoethane (0.018 mL, 0.24 mmol) and potassium carbonate (0.038 g, 0.28 mmol) in 3 mL of acetone was stirred at reflux overnight, then concentrated. The residue was partitioned between 30 mL of ethyl acetate and 30 mL of water. The organic layer was dried over MgSO4, filtered and concentrated to 0.075 g (86%) of crude 1-[2-ethoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow oil that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH3:17])[N:9]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C=O)C>[CH2:26]([O:14][C:12]1[C:11]([CH2:15][CH3:16])=[C:10]([CH3:17])[N:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[N:13]=1)[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: CCc1c(C)nc(-c2ccc(N)cn2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1nc(-c2ccc(N)cn2)nc(C)c1CC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of compound of example 52 (0.200 g, 0.86 mmol) in DMF (3 mL), was added K2CO3 (0.18 g, 1.302 mmol) and stirred at 25° C. for 10 minutes, followed by slow addition of allyl bromide (0.15 g, 1.302 mmol). The reaction mixture was stirred at 25° C. for 1 hour. DMF was removed under vacuum, and the reaction mass was quenched by water, extracted with ethyl acetate (3×20 mL), dried over sodium sulfate and concentrated to obtain the crude product, which was taken for synthesis of compound of example 64 without purification and characterization.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]3[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34]I.[H-].[Na+].Cl>CN(C=O)C>[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([O:23][CH3:34])[CH2:20][N:19]3[C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: O=C(OCc1ccccc1)N1C[C@H](O)C[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1C[C@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)N(C(=O)OCc2ccccc2)C1
Reaction time: 0.17 h

Procedure:
To a solution of benzyl (2R, 4R)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate (400 mg) and CH3I (0.57 mL) in DMF (5 mL) was added NaH (60% oil suspension, 48 mg) at 5° C. The mixture was stirred at the same temperature for 10 minutes, then stirred at room temperature for 30 minutes. The reaction mixture was poured into diluted HCl, and extracted with EtOAc. The organic layer was washed with water, saturated sodium hydrogen carbonate, water and brine, dried (MgSO4), and evaporated in vacuo. The residue was purified by silica gal column chromatography (hexane-EtOAc, 1:1 elution) to give benzyl (2R, 4R)-2-(4,5-diphenyloxazol-2-yl)-4-methoxypyrrolidine-1-carboxylate (402.9 mg).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([O-:6])=[O:5].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(O)=O.[Rh]>[C:21]([NH:1][CH:2]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:3][C:4]([OH:6])=[O:5])([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: NC(CC(=O)[O-])c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Rh]
Solvent: CC(=O)O
Product: O=C(O)CC(NC(=O)OCc1ccccc1)C1CCCCC1
Reaction time: 30 h
Yield: 50.7 %

Procedure:
A solution of 25 g (151 mmol) of 3-amino-3-phenylproprionate in 450 mL of HOAc was charged with 25 g of 5% Rh/Al2O3 and the mixture hyrogenated at 60 psi for 30 hr at 60° C. The reaction was filtered over celite and evaporated in vacuo to a dark oil. The presence of the desired product was confirmed by FD-MS (m/e 172, MH+, 100). The crude reduction product was treated with benzylchloroformate (25.67 g; 151 mmol) under basic conditions substantially according to the procedures of Example 1, A, to afford 23.4 g of N-Cbz-3-amino-3-cyclohexyl propionic acid as a grey solid.
Reaction SMILES: [N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH:7]=[O:8])([O-:3])=[O:2].[CH2:10](O)[CH2:11][OH:12].O>C1C=CC=CC=1>[N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH:7]1[O:12][CH2:11][CH2:10][O:8]1)([O-:3])=[O:2]
Reactant: CC(=CC=O)C[N+](=O)[O-]
Reactant: OCCO
Solvent: O
Solvent: c1ccccc1
Product: CC(=CC1OCCO1)C[N+](=O)[O-]

Procedure:
0.1 Mol of 4-nitro-3-methyl-2-butenal and 0.1 Mol of ethyleneglycol is benzene were refluxed for 1 hour, collecting 0.1 Mol of water in a Dean Stark trap. After cooling the reaction mixture it was quenched in a solution of sat. Sodiumbicarbonate and extracted several times with benzene. The reaction product was purified by Kugelrohr distillation followed by chromotography over silica gel. The product was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=2)=[O:14])[CH:7]=1)[CH3:2].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=3)[N:16]=2)=[O:14])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cccc(Br)n2)c1
Reactant: OB(O)c1cccc(F)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cccc(-c3cccc(F)c3)n2)c1

Procedure:
The pyridyl bromide (77)(100 mg, 0.28 mmol) was coupled to 3-fluoro-phenylboronic acid (42 mg, 0.30 mmol) using Method E. The crude product was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH2:1]([C:4]1([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Cl.[H-].[Na+]>CN(C=O)C>[CH2:1]([C:4]1([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[O:9][C:8](=[O:10])[N:7]([CH2:21][C:20]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:19]=2[Cl:18])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: C=CCC1(c2ccc(F)cc2)CCNC(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(c2ccc(F)cc2)CCN(Cc2ccc(Cl)cc2Cl)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
To a stirred solution of 6-allyl-6-(4-fluorophenyl)-1,3-oxazinan-2-one (15 mg, 0.064 mmol) and 2,4-dichlorobenzyl chloride (25 mg, 0.13 mmol) in dry DMF (0.5 mL) under N2 was added 60% NaH in oil in small portions until gas evolution ceased. The mixture was stirred overnight at rt and quenched with water (0.5 mL). The mixture was applied to a 10-mL Chem-Elut cartridge and eluted with ether (50 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford 6-allyl-3-(2,4-dichlorobenzyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (5.5 mg, 22%). LC-MS Method 1 tR=2.1 min, m/z=394; 1H NMR (CDCl3) 2.30 (2H), 2.60 (m, 2H), 2.96 (m, 1H), 3.08 (m, 1H), 4.44 (d, 1H), 4.65 (d, 1H), 4.75 (1H), 5.06 (m, 2H), 5.67 (m, 1H), 6.86 (d, 1H), 7.08 (3H), 7.30 (3H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C@H:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Br)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a stirred solution of N-Boc-(R)-3-hydroxypyrrolidine (0.936 g, 5 mmol) in THF (25 mL) was added carbon tetrabromide (2.487 g, 7.50 mmol) followed by triphenylphosphine (1.967 g, 7.50 mmol). The resulting suspension was allowed to stir at 60° C. for 1 h. Insoluble material was filtered, and concentrated. The residue was purified by silica gel column chromatography with a gradient of EtOAc (5-30%) in hexanes to afford 72 (1.12 g, 90%) as a colorless oil. LRMS (ESI): calc. 249.0; found 271.9 (MNa)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=[O:3])[CH3:2].[F:17][C:18]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2.[F-].[Cs+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:19]2[C:18]([F:17])=[C:26]3[C:22]([CH:23]=[CH:24][NH:25]3)=[CH:21][CH:20]=2)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc3cc[nH]c3c2F)OC1(C)C
Reactant: COC(=O)c1nc(Cl)cc(NC(C)=O)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1nc(-c2ccc3cc[nH]c3c2F)cc(NC(C)=O)c1Cl
Yield: 95.3 %

Procedure:
Methyl 4-acetamido-3,6-dichloropicolinate (400 mg, 1.520 mmol), 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (437 mg, 1.673 mmol), cesium fluoride (462 mg, 3.04 mmol), and (PPh3)2PdCl2 (107 mg, 0.152 mmol) were charged as solids into a microwave reaction vessel and dioxane (4 mL) and water (1 mL) were added. The reaction vessel sealed and irradiated in a Biotage Initiator microwave at 110° C. for 2 h, with external IR-sensor temperature monitoring from the side. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was filtered and concentrated. The intermediate product was purified by flash chromatography (ISCO 40 g silica 10-75% EtOAc: Hex 16 CV). Fractions containing product were combined and concentrated to give 524 mg of a white solid intermediate methyl 4-acetamido-3-chloro-6-(7-fluoro-1H-indol-6-yl)picolinate (0.524 g, 1.448 mmol) which was subsequently diluted with methanol (10.0 mL). Then acetyl chloride (0.725 mL, 10.20 mmol) was added. The reaction mixture was allowed to stir at room temperature for 18 h. The reaction was concentrated to dryness. The resulting residue was dissolved in ethyl acetate and poured into saturated NaHCO3 solution. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (3×15 mL). The organic extracts were combined, washed with saturated NaCl solution, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified using a Teledyne ISCO purification system with a gradient eluent system of ethyl acetate and hexanes to yield the title compound as a white solid (365 mg, 79%).
Reaction SMILES: C([CH:3]([C:34]([OH:36])=[O:35])[N:4]([CH2:15][P:16]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)=[S:17])[C:5](OCC1C=CC=CC=1)=O)C.Br.[C:38](O)(=O)C>>[CH2:5]([N:4]([CH2:15][P:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)=[S:17])[CH2:3][C:34]([OH:36])=[O:35])[CH3:38]
Reactant: CC(=O)O
Reactant: CCC(C(=O)O)N(CP(=S)(Oc1cccc(Cl)c1)Oc1cccc(Cl)c1)C(=O)OCc1ccccc1
Agent: Br
Product: CCN(CC(=O)O)CP(=S)(Oc1cccc(Cl)c1)Oc1cccc(Cl)c1

Procedure:
Ethyl-N-[bis(metachlorophenoxy)phosphinothioylmethyl]-N-(benzyloxycarbonyl)glycine (1.0 g.) was dissolved in 15 ml. of 35% hydrobromic acid in acetic acid and was stirred for one hour. The reaction mixture was concentrated under vacuum and the residue triturated thoroughly with ether three times, dissolved in benzene and treated with excess propylene oxide. The resultant solution was concentrated in vacuo and the residue chromatographed on silica gel using diethyl ether as an eluant to yield ethyl-N-[bis(metachlorophenoxy)phosphinothioylmethyl]glycine as an oil, ND25 =1.5371, which gave the following analysis.