Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[C:11](=[O:18])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Na+]>C1COCC1.CO>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[NH:14][C:13](=[O:15])[C:12]([CH3:16])([CH3:17])[C@@H:11]([OH:18])[CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC1(C)C(=O)CC(c2cc(F)cc(F)c2)NC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)C(=O)N[C@H](c2cc(F)cc(F)c2)C[C@@H]1O
Reaction time: 2.5 h

Procedure:
To a solution of 6-(3,5-difluorophenyl)-3,3-dimethylpiperidine-2,4-dione from Step A (20.18 g, 80 mmol) in THF (600 mL) and CH3OH (25 mL) at 0° C. was added NaBH4 (4.57 g, 121 mmol). After 2.5 h, the reaction mixture was quenched with H2O (200 mL) and concentrated in vacuo. The residue was partitioned between H2O (600 mL), saturated aqueous NaHCO3 (200 mL) and EtOAc (1 L). The organic layer was separated and the aqueous layer was extracted with EtOAc (600 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3OH—100:0 to 88:12, to give the title compound, which contained approximately 20% of the corresponding trans-isomer. MS: m/z=256 (M+1).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[CH3:44][S:45]([CH:48]1[CH2:51][NH:50][CH2:49]1)(=[O:47])=[O:46]>>[CH3:32][O:31][C:28]1[N:27]=[CH:26][C:25]([NH:24][C:17]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:23][C:20]([CH2:21][N:50]3[CH2:51][CH:48]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:49]3)=[CH:19][N:18]=2)=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)C1CNC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COc1ccc(Nc2ncc(CN3CC(S(C)(=O)=O)C3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.200 g, 0.346 mmol) and 3-(methylsulfonyl)azetidine (PharmaBlock, Carrboro, N.C.) (0.070 g, 0.519 mmol). 1H NMR (400 MHz, d6-DMSO) δ 11.81 (s, 1H); 8.88 (br. s., 1H); 8.54 (d, J=2.74 Hz, 1H); 8.38 (d, J=1.76Hz, 1H); 8.13 (dd, J=8.90, 2.64 Hz, 1H); 7.77-7.94 (m, 2H); 6.85 (d, J=8.80 Hz, 1H); 4.09-4.58 (m, 7H); 3.85 (s, 3H); 3.12 (s, 3H); 2.44 (s, 3H). m/z (ESI, +ve ion) 456.8 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]3([NH:32]C(=O)C)[CH2:29][O:28]C(C)(C)[O:26][CH2:25]3)=[CH:18][CH:17]=2)=[C:12]([F:36])[CH:11]=1.Cl>C(O)C>[NH2:32][C:24]([CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([S:9][C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])=[CH:11][C:12]=2[F:36])=[CH:21][CH:20]=1)([CH2:29][OH:28])[CH2:25][OH:26]
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Sc4ccc(C)cc4C)cc3F)cc2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(Sc2ccc(-c3ccc(CCC(N)(CO)CO)cc3)c(F)c2)c(C)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
N-(5-{2-[4′-(2,4-Dimethylphenylthio)-2′-fluorobiphenyl-4-yl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl)acetamide (0.26 g) was dissolved in ethanol (4 mL), concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was concentrated, aqueous potassium carbonate solution was added to the residue, and the precipitated crystals were collected by filtration to give the title compound (205 mg) as white crystals.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1COCCN1
Product: O=C(O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Yield: 55.3 %

Procedure:
The title intermediate is prepared from 4-(chlorosulfonyl)benzoic acid (CAS 10130-89-9) (662 mg, 3.0 mmol) and morpholine (522 mg, 6.0 mmol) in a manner substantially similar to Procedure F to provide 450 mg (55%) of the title compound. MS (ES+) 272.3 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8]Cl)=[CH:3][CH:2]=1.[SH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][S:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:3][CH:2]=1
Reactant: COC(=O)CS
Reactant: ClCCc1ccncc1
Product: COC(=O)CSCCc1ccncc1

Procedure:
Using the above procedure 2-(4-pyridyl)ethyl chloride is reacted with methyl 2-mercaptoacetate to yield methyl 2-[2-(4-pyridyl)ethylthio]acetate.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][N:12]1[C:18](=[O:42])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]1[CH2:29][C:28]([F:31])([F:30])[CH2:27][C@@H:26]1[C:32]([O:34]CC1C=CC=CC=1)=[O:33])=[O:24])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:32]([C@H:26]1[CH2:27][C:28]([F:30])([F:31])[CH2:29][N:25]1[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][C:18]([N:12]1[CH2:13][C:14]([F:16])([F:17])[CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:42])([OH:34])=[O:33]
Reactant: O=C(OCc1ccccc1)[C@H]1CC(F)(F)CN1C(=O)CCCCC(=O)N1CC(F)(F)C[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CC(F)(F)CN1C(=O)CCCCC(=O)N1CC(F)(F)C[C@@H]1C(=O)O
Yield: 97 %

Procedure:
0.59 g (0.001 mol) (R)-1-[6-[(R)-2-Benzyloxycarbonyl-4,4-difluoro-pyrrolidin-1-yl]-6-oxo-hexanoyl]-4,4-difluoropyrrolidine-2-carboxylic acid benzyl ester in 20 ml ethanol were hydrogenated at room temperature and atmospheric pressure in the presence of 0.12 g 5% palladium/carbon. After completion of the reaction the catalyst was filtered off, the solvent was distilled off, and the residue was dissolved in dichloromethane. Evaporation gave 0.4 g (97%) (R)-1-[6-[(R)-2-carboxy-4,4-difluoro-pyrrolidin-1-yl]-6-oxo-hexanoyl]4,4-difluoropyrrolidine-2-carboxylic acid as a white foam. ISP-MS: 413 (MH)+; [α]D=+54.2° (c=1% in dimethylsulfoxide).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[S:5][CH:6]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]2[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][S:7][C:4]=2[S:5][CH:6]=1
Reactant: CC(C)=CCSc1cc(C)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1csc2c1C(C)(C)CCS2
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
A solution of 17.36 g (0.088 mol) of the title compound of Step A in 300 mL of methylene chloride was added dropwise to 300 mL of trifluoroacetic acid under nitrogen. After stirring at room temperature overnight, the mixture was evaporated to dryness. The residue was dissolved in 500 mL of methylene chloride, washed with 5% sodium bicarbonate (2×500 mL), dried (MgSO4), filtered, and evaporated to dryness. The crude product was chromatographed on silica gel eluting with hexane to yield 8.26 g of the title compound of Step B as an oil. 1H NMR (CDCl3): δ 1.32 (s,6H), 2.0 (m,2H), 2.3 (s,3H), 3.0 (m,2H), 6.6 (s, 1H).
Reaction SMILES: [OH:1][N:2]([CH3:16])[C:3]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([SH:13])[N:7]2[N:6]=1)=[O:4].CC(O[CH2:21][C:22]1[CH2:31][S:30][C@@H:25]2[C@H:26]([NH2:29])[C:27](=[O:28])[N:24]2[C:23]=1[C:32]([OH:34])=[O:33])=O.B(F)(F)F.CCOCC.ClCCl>ClCCl.S1(CCCC1)(=O)=O>[NH2:29][C@@H:26]1[C:27](=[O:28])[N:24]2[C@@H:25]1[S:30][CH2:31][C:22]([CH2:21][S:13][C:12]1[N:7]3[N:6]=[C:5]([C:3](=[O:4])[N:2]([OH:1])[CH3:16])[N:15]=[C:8]3[N:9]=[C:10]([CH3:14])[CH:11]=1)=[C:23]2[C:32]([OH:34])=[O:33]
Reactant: Cc1cc(S)n2nc(C(=O)N(C)O)nc2n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Solvent: ClCCl
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(C(=O)N(C)O)nc2n1
Temperature: 10 °C
Yield: 73.1 %

Procedure:
N-Hydroxy-7-mercapto-N,5-dimethyl-s-triazolo[1,5-a]pyrimidine-2-carboxamide (53 mg) (0.22 mmol) and 54 mg (0.2 mmol) of 7-aminocephalosporanic acid are suspended in 1 ml of dichloromethane/sulpholane (1:1 v/v). 0.5 ml of boron trifluoride diethyl etherate is added thereto at 10° C. while stirring and the mixture is stirred at room temperature for a further 20 hours. Subsequently, about 10 ml of dichloromethane are added thereto, the insoluble material is filtered off under suction, dissolved in water and the product is precipitated by the addition of sodium hydrogen carbonate (pH→4). The precipitate is filtered off under suction and washed with water and ethanol. There are obtained 66 mg of (6R,7R)-7-amino-3-[[[2-(N-hydroxy-N-methylcarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4,2,01oct-2-ene-2-carboxylic acid as a white powder.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH:9]2[CH2:12][N:11]([C:13]3[N:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:14]=3[F:21])[CH2:10]2)[CH2:5][CH2:4]1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([CH:9]2[CH2:12][N:11]([C:13]3[N:18]=[C:17]([CH:19]=[O:20])[CH:16]=[CH:15][C:14]=3[F:21])[CH2:10]2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(C2CN(c3nc(CO)ccc3F)C2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCN1CCN(C2CN(c3nc(C=O)ccc3F)C2)CC1

Procedure:
To a mixed solution of the crude product (402 mg) of (6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)-5-fluoropyridin-2-yl)methanol described in Production Example 7-1 and dichloromethane (10.0 mL) was added Dess-Martin periodinane (787 mg, 1.86 mmol) at room temperature. The resultant mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the resultant solution was extracted with dichloromethane. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure to give a crude product (362 mg) of the title compound. The product was used in the subsequent reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([C:7]1[N:11]=[CH:10][N:9]([CH2:12]O)[N:8]=1)[C:3]([F:6])([F:5])[F:4].S(Cl)([Cl:17])=O>ClCCl>[Cl:17][CH2:12][N:9]1[CH:10]=[N:11][C:7]([C:2]([F:14])([F:1])[C:3]([F:6])([F:5])[F:4])=[N:8]1
Reactant: O=S(Cl)Cl
Reactant: OCn1cnc(C(F)(F)C(F)(F)F)n1
Solvent: ClCCl
Product: FC(F)(F)C(F)(F)c1ncn(CCl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.52 g of 3-(pentafluoroethyl)-1H-1,2,4-triazole 1-ylmethanol was dissolved to 50 ml of dichloromethane, and 2.7 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 1.36 g of 1-(chloromethyl)-3-(pentafluoroethyl)-1H-1,2,4-triazole.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][NH:13][CH3:12])[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1cccc2cc[nH]c12
Reaction time: 3 h
Yield: 88.9 %

Procedure:
Indole-7-carbaldehyde (500 mg, 3.4 mmol) was dissolved in anhydrous methanol (10 mL). Methylamine (5.1 mL of 2M solution in methanol, 9.55 mmol) was added and the reaction was stirred for 3 hr. The solution was concentrated to a yellow oil and then dissolved into anhydrous methanol (10 mL). Sodium borohydride (131 mg, 3.45 mmol) was added and the mixture was stirred overnight. Water (1 mL) was added and the solution was concentrated. Sodium hydroxide (5 mL, 1N) was added and the indole was extracted with ethyl acetate (3×20 mL), dried over MgSO4 and concentrated to afford the title compound as a yellow oil (484 mg, 92%). 1H NMR (300 MHz, CDCl3) δ 7.54 (s, 1H), 7.29-7.17 (m, 2H), 7.04 (d, J=3.1 Hz, 1H), 6.44 (d, J=3.1 Hz, 1H), 3.84 (s, 2H), 2.46 (s, 3H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][C@@H:4]([CH3:7])[NH:3]1.C([Li])CCC.CO.C(=O)=O.[NH2-].[Li+].CO[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[P:32]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33].C(Cl)(Cl)(Cl)Cl.C(=O)=O.[Cl-].[Na+]>O1CCCC1>[CH3:1][C@@H:2]1[CH2:6][CH2:5][C@@H:4]([CH3:7])[N:3]1[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[P:32]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33]
Reactant: C[C@@H]1CC[C@@H](C)N1
Reactant: COc1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: O=C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: C[C@@H]1CC[C@@H](C)N1c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
In a 300 ml four-necked flask was charged 1.1 g (11 mmol) of (2R,5R)-2,5-dimethylpyrrolidine in a nitrogen stream, and 70 ml of tetrahydrofuran (THF) was added thereto. To the flask was added dropwise 7.7 ml (13.2 mmol) of butyl lithium at -78° C. (methanol-dry ice) over 10 minutes. After maintaining the system at that temperature for 10 minutes, the mixture was stirred at 0° C. for 1 hour to prepare lithium amide. In a separate container 4 g (11 mmol) of 1-methoxy-2-diphenylphosphinylnaphthalene was dissolved in 35 ml of THF, and the lithium amide was slowly added dropwise to the resulting solution cooled to -20° C. (carbon tetrachloride-dry ice), followed by allowing the mixture to react for 4 hours. The reaction was stopped by addition of a saturated sodium chloride aqueous solution, and the reaction mixture was extracted with ethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate. The resulting crude product was purified by silica gel column chromatography using a 1/1 (by volume) mixture of hexane and acetone as an eluent to give 3.24 g of 1-((2R,5R)-2,5-dimethylpyrrolidinyl)-2-diphenylphosphinylnaphthalene in a yield of 69%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13].C([S-])C.[Na+].CN(C=O)C.C(=O)(O)[O-]>O>[NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13]
Reactant: COc1cc(N)c(C(=O)c2ccc(C(C)C)cc2)cc1OC
Agent: CC[S-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2ccc(C(C)C)cc2)c(N)cc1O

Procedure:
A mixture of 1.34 g (4.48 mmol) (2-amino-4,5-dimethoxy-phenyl)-(4-isopropyl-phenyl)-methanone, 1.88 g sodium ethanethiolate and 10 ml DMF are heated for 5 h to 110° C. Saturated aqueous bicarbonate solution (10 ml) and 100 ml water are added. The product is extracted with CH2Cl2 and chromatographed on silica (hexane/ethyl acetate).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]3[CH2:19][CH:20]4[NH:24][CH:23]([C:5]=3[C:4]=2[C:3]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21]4.[C:32]1([S:38](C2C=CC=CC=2)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:32]1([S:38]([C:2]2[CH:10]=[CH:9][C:8]3[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]4[CH2:19][CH:20]5[NH:24][CH:23]([C:5]=4[C:4]=3[C:3]=2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21]5)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)c1c(Br)ccc2c1c1c(n2COCC[Si](C)(C)C)CC2CCC1N2
Reactant: O=S(=O)(c1ccccc1)c1ccccc1
Product: CC(C)(C)OC(=O)c1c(S(=O)(=O)c2ccccc2)ccc2c1c1c(n2COCC[Si](C)(C)C)CC2CCC1N2
Yield: 58 %

Procedure:
The product of step A was converted to the phenyl sulfone derivative following the procedure of example 1, step C. The crude material was purified by flash column chromatography (SiO2 98:2 to 65:35 hexane/ethyl acetate) to give tert-butyl 2-phenylsulfonyl-5-[(trimethylsilyl)ethoxy]methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-carboxylate (1.30 g, 58%) as a brown foam: 1H NMR (CDCl3, 300 MHz) δ 8.28 (s, 1H), 8.03-8.09 (m, 2H), 7.75-7.83 (m, 1H), 7.51-7.62 (m, 4H), 5.28-5.49 (m, 3H), 4.66-4.89 (m, 1H), 3.45-3.68 (m, 3H), 2.64 (d, J=16.2 Hz, 1H), 2.45-2.52 (m, 1H), 2.25-2.38 (m, 1H), 2.01-2.11 (m, 1H), 1.64-1.75 (m, 1H), 1.46 (br s, 9H), 0.88-0.95 (m, 2H), −0.11 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:14](Cl)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(O)(=O)C.[F:21][C:22]([F:39])([F:38])[C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][NH:33][CH2:32][CH:31]([C:35]([NH2:37])=[O:36])[CH2:30]2)=[CH:25][CH:24]=1.O>ClCCl>[N:8]1([C:14]([N:33]2[CH2:34][CH:29]([C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:39])([F:38])[F:21])=[CH:28][CH:27]=3)[CH2:30][CH:31]([C:35]([NH2:37])=[O:36])[CH2:32]2)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: NC(=O)C1CNCC(c2ccc(C(F)(F)F)cc2)C1
Reactant: O=C(Cl)N1CCOCC1
Solvent: CC(=O)O
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., 0.56 g (5.52 mmol) of triethylamine and 0.55 g (3.70 mmol) of morpholine-4-carbonyl chloride were added to a solution of 0.61 mg (1.85 mmol) of 5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxamide acetate (Example 51A) in 10 ml of dichloromethane. The reaction mixture was stirred at RT for 1 h. After addition of water and phase separation, the organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. This gave 0.61 g (100% of theory) of crude product in a purity of 77% (LC-MS), which was reacted without any further purification steps.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH:12]3[O:19][CH3:20])[CH2:10]1)[CH2:16]2)(C)(C)C.Br>CCOCC>[CH3:20][O:19][CH:12]1[CH:13]2[CH2:18][C:9]3([CH2:8][NH2:7])[CH2:16][CH:15]([CH2:17][CH:11]1[CH2:10]3)[CH2:14]2
Reactant: COC1C2CC3CC1CC(CNC(=O)OC(C)(C)C)(C3)C2
Agent: Br
Solvent: CCOCC
Product: COC1C2CC3CC1CC(CN)(C3)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 16A (30 mg, 0.10 mmol) in was added HBr (30% in HOAc) 1 mL and the mixture was stirred at rt for 2 h. Ether (10 mL×2) was added and the resulting precipitate was collected and dried under vacuum to give the title compound as hydrogen bromide salts (16). LC-MS (ESR): m/z=196 [M+H]+.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH3:9][C:10](C)([O-])[CH3:11].[K+].ICCC.O>ClCCl>[CH2:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8])[CH2:10][CH3:11]
Reactant: OCCCCCCO
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCCI
Product: CCCOCCCCCCO
Temperature: 75 °C
Reaction time: 1 h
Yield: 24.6 %

Procedure:
a 500-mL, one-necked, round-bottom flask equipped with a magnetic stirrer was charged with 1,6-hexanediol (6.00 g), potassium tert-butoxide (5.413 g) at room temperature. The reaction mixture was stirred for one hour, and then 1-iodopropane (8.63 g) was added. The reaction mixture was heated to 70-80° C. and stirred overnight. The progress of reaction was monitored by TLC (Note 1). After completion of the reaction, water was added to the reaction mixture, and extracted with ethyl acetate (2×100 mL). The combined organic layers were concentrated in vacuo to get the crude product. The crude product was dissolved in dichloromethane and washed with water, and then brine, dried over sodium sulfate. The organic layer was concentrated in vacuo to get the crude product. The crude product was purified by column chromatography using 230-400 mesh silica gel. A solvent gradient of ethyl acetate in hexanes (10-45%) was used to elute the product from the column. All fractions containing the desired pure product were combined and concentrated in vacuo to give pure 6-propyloxy-1-hexanol (lot D-1029-048, 1.9 g, 25%) Completion of the reaction was monitored by thin layer chromatography (TLC); (eluent: 60% ethyl acetate in hexanes).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([CH:12]=[O:13])[C:3]=1[Cl:14].CC(=CC)C.P([O-])([O-])(O)=[O:21].[Na+].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([C:12]([OH:21])=[O:13])[C:3]=1[Cl:14]
Reactant: O=P([O-])([O-])O
Reactant: CCCc1nc(C=O)c(Cl)c(N)c1F
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCc1nc(C(=O)O)c(Cl)c(N)c1F
Temperature: 85 °C

Procedure:
A microwave vial equipped with a magnetic stir bar was charged with 4-amino-3-chloro-6-propyl-5-fluoropicolinaldehyde (15.9 mg, 0.072 mmol) and t-butanol (1.0 mL). The mixture was treated with H2O (0.40 mL), 2-methylbut-2-ene (100 μL, 0.10 mmol), sodium hydrogenphosphate (21.6 mg, 0.100 mmol), and finally sodium chlorite (19.28 mg, 0.206 mmol) was added in one portion. The mixture was heated to 85° C. for 16 h. An aliquot of the reaction mixture was analyzed by LC-MS. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was evaporated to dryness under N2. Purification via reverse phase chromatography yielded 4-amino-3-chloro-6-propyl-5-fluoropicolinic acid (4.7 mg, 27.9%): 1H NMR (400 MHz, CDCl3) δ 11.60 (s, 1H), 4.98 (m, 2H), 2.76 (m, 2H), 1.75 (m, 2H), 0.99 (m, 3H); 19F NMR (376 MHz, CDCl3) δ−139.98; ESIMS m/z 231.2 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH:7]=1.CC1(C)N([O])C(C)(C)CCC1.CC(OC)(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=[O:12])[N:10]=2)[CH:7]=1
Reactant: OCc1nc2ncc(Br)cn2n1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: O=Cc1nc2ncc(Br)cn2n1
Yield: 74.2 %

Procedure:
A slurry of (6-bromo-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-methanol (6.5 g, 28.51 mmol) from step 1 above in dichloromethane (60 mL) was added Phl(OAc)2 (10.1 mg, 31.4 mmol) and with catalytic TEMPO (334 mg, 2.14 mmol). After reaction at room temperature for 3 hours, the reaction is complete. MTBE is added slowly (50 mL) to crystallize the product, filtration followed by drying the product by vacuum oven overnight. The filtrate was concentrated and purified by flash chromatography (2% MeOH in CH2Cl2) to give the desired product as light white solid (combine total 4.8 g, 75% yield). 1H NMR (300 MHz, CDCl3) □ ppm 8.96 (d, J=2.45 Hz, 1H) 9.09 (d, J=2.45 Hz, 1H) 10.22 (s, 1H). MS: (APCI) 228 (M+H).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[C:18]1([CH:16]2[CH2:17][NH:14][CH2:15]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [H][H]
Reactant: c1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(C2CNC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.2 %

Procedure:
Add 20% palladium hydroxide on activated carbon (0.130 g) and ethanol (25 mL) to a Parr pressure vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 kPa), seal the vessel and agitate the mixture at RT for 15 min. Vent the hydrogen from the reaction vessel and purge the reaction vessel with nitrogen. Add 1-benzhydryl-3-phenylazetidine (0.515 g, 0.00172 mol) and ethanol (75 mL) to the pressure vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 kPa), seal the vessel and agitate the reaction at RT for 20 h. Turn off the agitation, vent the excess hydrogen from the vessel, purge the vessel with nitrogen and filter the reaction mixture to remove the palladium on carbon catalyst. Concentrate and purify (silica gel chromatography, eluting with 5:95 to 10:90 2 M ammonia in methanol:DCM) to give the title compound (76 mg, 34%).