Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC)(=O)C=C.[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:10])[CH:8]=[CH2:9].O[S:21](O)(=O)=O>>[CH2:12]([O:11][C:7](=[O:10])[CH2:8][CH2:9][SH:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=S(=O)(O)O
Reactant: C=CC(=O)OCCCCCCCC
Solvent: C=CC(=O)OC
Product: CCCCCCCCOC(=O)CCS
Yield: 80 %

Procedure:
The procedure was as described in Example 1 but in place of methyl acrylate there were employed 184 grams of octyl acrylate and first there were added 250 ml of dilute H2SO4 (4N) and the later 300 ml of dilute H2SO4. After the fractional distillation there were isolated 174.5 grams (corresponding to a yield of 80%) of 3-mercaptopropionic acid octyl ester.
Reaction SMILES: [BH4-].[Na+].[F:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C:17]3[CH:18]=[C:19]([C:23](=[N:25][OH:26])[NH2:24])[CH:20]=[CH:21][CH:22]=3)=[CH:15][C:10]=2[S:9](=[O:28])(=[O:27])[N:8]=[CH:7]1.Cl>C(O)C>[F:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C:17]3[CH:18]=[C:19]([C:23](=[N:25][OH:26])[NH2:24])[CH:20]=[CH:21][CH:22]=3)=[CH:15][C:10]=2[S:9](=[O:28])(=[O:27])[NH:8][CH2:7]1
Reactant: NC(=NO)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=CN3CCF)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: NC(=NO)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NCN3CCF)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 mg (0.258 mmol) of NaBH4 are added to a suspension of the compound obtained in Step B (75 mg, 0.198 mmol) in 1 ml of ethanol. The suspension is stirred for 30 minutes at ambient temperature and is then cooled in an ice bath. The reaction mixture is neutralised by adding 1N HCl and extracted with ethyl acetate. The organic phase is washed with saturated NaCl solution, dried (MgSO4) and evaporated in vacuo. The evaporation residue is crystallised from CH2Cl2. The expected compound is recovered by filtration.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[N:5]2[N:16]=[C:17]([CH3:20])[C:18]([I:19])=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.[NH:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:35][OH:36]>C(#N)C>[F:15][C:10]1[CH:9]=[C:8]([C:6]2[N:5]3[N:16]=[C:17]([CH3:20])[C:18]([I:19])=[C:4]3[N:3]=[C:2]([N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[CH2:35][OH:36])[CH:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1nn2c(-c3ccc(F)c(F)c3)cc(Cl)nc2c1I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nn2c(-c3ccc(F)c(F)c3)cc(N3CCC[C@H]3CO)nc2c1I
Yield: 85 %

Procedure:
5-Chloro-7-(3,4-difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine (401 mg), DIPEA (0.35 mL) and (S)-2-pyrrolidinemethanol (401 mg) are stirred for 2.5 hours in an acetonitrile (60 mL) solvent at 90° C. The reaction solvent is removed by distillation under reduced pressure. The remainder is purified by column chromatography to yield the target compound (395 mg). 1H NMR (CDCl3, 300 MHz) δ 7.82 (m, 1H), 7.67 (m, 1H), 7.29 (q, J=8.7 Hz, 1H), 6.11 (s, 1H), 4.45 (br, 1H), 3.85 (m, 1H), 3.77 (m, 1H), 3.57 (m, 2H), 2.38 (s, 3H), 2.08-2.01 (m, 3H), 1.70 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][S-:12].[Na+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:12][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1F
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(Cl)cc1C#N
Yield: 96.6 %

Procedure:
(Step 1) A mixture of 5-chloro-2-fluorobenzonitrile (5.0 g) and sodium methanethiolate (2.48 g) was stirred in N,N-dimethylformamide (20 ml) at 60° C. for 1 hr. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-chloro-2-(methylsulfanyl)benzonitrile (5.7 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:11](Cl)[CH:12]=[CH:13][CH3:14].[Mg].[Cl-].[Na+]>CCOCC.O1CCCC1>[C:1]([N:4]1[CH2:9][CH2:8][C:7]([OH:10])([CH:13]([CH3:14])[CH:12]=[CH2:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC=CCCl
Reactant: CC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(C)C1(O)CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.94 g 1-acetyl-4-piperidone in a mixture of ether (80 ml) and tetrahydrofuran (40 ml), was added dropwise at 10° C. or lower 275 ml of a 0.5M Grignard reagent prepared by the usual way from crotyl chloride and magnesium, and the resulting mixture was stirred overnight at room temperature. To the ice-cooled reaction mixture, was slowly added 100 ml of saturated aqueous solution of sodium chloride, and the layers were separated. The aqueous layer was extracted with chloroform, the two organic solutions were each concentrated, and the combined concentrate was subjected to silica gel column chromatography using, as eluent, a mixed solvent of ethyl acetate/n-hexane (1:1 by volume) containing 3% methanol, giving 16.9 g of 1-acetyl-4-hydroxy-4-(1-methyl-2-propenyl)piperidine as oil.
Reaction SMILES: [N+:1]([C:4]1([CH2:18][CH2:19][C:20]([O:22]C)=O)[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]2[CH2:16][CH2:17][CH:5]1[CH:6]=[CH:7]2)([O-])=O>C(O)C.[Ni]>[C:10]1([CH:9]2[C:4]3([CH2:18][CH2:19][C:20](=[O:22])[NH:1]3)[CH:5]3[CH2:17][CH2:16][CH:8]2[CH2:7][CH2:6]3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CCC1([N+](=O)[O-])C2C=CC(CC2)C1c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: O=C1CCC2(N1)C1CCC(CC1)C2c1ccccc1

Procedure:
55 mmoles of methyl β-(2-nitro-3-phenyl-bicyclo[2.2.2]-oct-5-en-2-yl)-propionate in 100 ml of ethanol are hydrogenated, with 3 g of Raney nickel, at 50° C.and under 70 bars. The catalyst is filtered off, the solvent is evaporated off and the residue is recrystallized from isopropanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13]O)=[C:11]([CH3:15])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][N:20]3[C:16](=[O:26])[C:17]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:19]3=[O:21])=[C:11]([CH3:15])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1onc(-c2cccc(F)c2)c1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (5.8 g, 28 mmol) in THF (339 mL) was added phthalimide (5.5 g, 37 mmol) and triphenylphosphine (9.8 g, 37 mmol) at ambient temperature under an argon atmosphere. Then a solution of diethyl azodicarboxylate (40% in toluene, 14.6 mL, 37 mmol) was added and the reaction mixture was stirred for 1 h at room temperature. Concentration and repeated trituration with ethyl acetate afforded the title compound (6.3 g, 66%) as a white solid. MS: m/e=337.1 [M+H]+.
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.[C:50]([O:56][C:57]1([C:60]2[N:61]=[C:62]([CH2:65][N:66]3[N:70]=[C:69]([NH2:71])[CH:68]=[N:67]3)[O:63][CH:64]=2)[CH2:59][CH2:58]1)(=[O:55])[C:51]([CH3:54])([CH3:53])[CH3:52]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:50]([O:56][C:57]1([C:60]2[N:61]=[C:62]([CH2:65][N:66]3[N:70]=[C:69]([NH:71][C:9]([C:7]4[N:8]=[C:4]([CH3:3])[O:5][C:6]=4[C:12]4[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=4)=[O:11])[CH:68]=[N:67]3)[O:63][CH:64]=2)[CH2:59][CH2:58]1)(=[O:55])[C:51]([CH3:54])([CH3:53])[CH3:52]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC(C)(C)C(=O)OC1(c2coc(Cn3ncc(N)n3)n2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3nc(C4(OC(=O)C(C)(C)C)CC4)co3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-methyl-5-(m-tolyl)oxazole-4-carboxylic acid (WO 2009/077990) (92 mg, 0.42 mmol) in CH2Cl2 (2.0 mL) was treated successively with DMAP (13 mg, 0.11 mmol), HOBt (69 mg, 0.51 mmol), EDC.HCl (203 mg, 1.06 mmol) and DIPEA (0.29 mL, 1.69 mmol) and the mixture was stirred at rt for 30 min. A solution of 1-(2-((4-amino-2H-1,2,3-triazol-2-yl)methyl)oxazol-4-yl)cyclopropyl pivalate (129 mg, 0.42 mmol) in CH2Cl2 (2.0 mL) was then added and the reaction mixture was stirred at rt overnight. The reaction mixture was then diluted with CH2Cl2 (10 mL), the layers were separated and the org. layer was washed with water (10 mL), dried over MgSO4, filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound as a white foam: TLC: rf (2:1 hept-EA)=0.25. LC-MS-conditions 06: tR=1.10 min, [M+H]+=505.37.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([F:11])=[C:2]([Br:1])[CH:3]=2)[CH:18]=1)[CH3:13]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(F)c(Br)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(F)c(Br)c2)c1

Procedure:
3-Bromo-4-fluorobenzoic acid (123 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:31]([Cl:32])=[CH:30][C:6]([C:7]([NH:9][CH:10]2[CH2:14][CH:13]([CH2:15][OH:16])[N:12](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:11]2)=[O:8])=[C:5]([O:33][CH3:34])[CH:4]=1>CO.[Pd]>[ClH:32].[NH2:2][C:3]1[C:31]([Cl:32])=[CH:30][C:6]([C:7]([NH:9][CH:10]2[CH2:14][CH:13]([CH2:15][OH:16])[NH:12][CH2:11]2)=[O:8])=[C:5]([O:33][CH3:34])[CH:4]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CC(CO)N(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CNC(CO)C1
Yield: 98.2 %

Procedure:
Into a solution of 1.4 g of 4-amino-5-chloro-2-methoxy-N-(1-diphenylmethyl-5-hydroxymethyl pyrrolidin-3-yl) benzamide hydrochloride (Compound of Example 7) in methanol, 0.28 g of 5% palladium/carbon was added and hydrogenation was effected under normal pressure and temperature conditions. At the stage when 63 ml of hydrogen were consumed, the hydrogenation was discontinued and the reaction mixture was filtered to remove the catalyst and then concentrated under reduced pressure to precipitate crystals. The separated crystals were dispersed in aceton and filtered. Thus obtained crude product was recrystallized from ethanol to obtain 0.46 g of 4-amino-5-chloro-2-methoxy-N-(5-hydroxymethyl pyrrolidin 3-yl) benzamid hydrochloride
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]2[C@H:26]3[CH2:31][CH2:30][CH2:29][C@H:27]3[N:28]=[C:3]12.[CH3:32][S:33]SC.[Li+].CC([N-]C(C)C)C>C1COCC1>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:33][CH3:32])[N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:17][CH:18]=3)[N:11]=[C:5]2[N:4]2[C@H:26]3[CH2:31][CH2:30][CH2:29][C@H:27]3[N:28]=[C:3]12
Reactant: CSSC
Reactant: CN1C(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)nc2N2C1=N[C@@H]1CCC[C@@H]12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1c2c(nn1Cc1ccc(-c3cccc(F)n3)cc1)N1C(=N[C@@H]3CCC[C@@H]31)N(C)C2=O
Temperature: 25 °C
Yield: 12.3 %

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-(6-fluoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (50 mg, 0.12 mmol) and methyl disulfide (21.3 μL, 0.24 mmol) are dissolved in 1 mL of anhydrous THF, and then 360 uL of 1.0 M LDA in THF is added dropwise. The reaction mixture is stirred at room temperature for an hour, and then quenched with saline. The mixture is separated with a semi-preparative HPLC to give 6.8 mg of pure product as pale yellow solids. MS (ESI) m/z 463.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](O)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH:15][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([Cl:16])[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNC(=O)c1cccc(Cl)c1

Procedure:
prepared by reaction of (1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester with 3-Chloro-benzoic acid.
Reaction SMILES: [CH:1]([C:7]1[S:8][CH:9]=[C:10]([Br:12])[CH:11]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>>[CH2:1]([C:7]1[S:8][CH:9]=[C:10]([Br:12])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC=Cc1cc(Br)cs1
Reactant: [H][H]
Product: CCCCCCc1cc(Br)cs1

Procedure:
From said spectra it was determined that 2-(n-hex-1-enyl)-4-bromothiophene was still present in the reaction product. The reaction product was again treated with Wilkenson's Catalyst and hydrogen, overnight. The re-treated reaction mixture was passed through a silica gel plug and eluted with hexane to yield 2.1 gms of a clear, colorless liquid having the following NMR spectra: 7.01 (s, 1H), 6.71 (s, 1H), 2.77 (t=7 Hz, 2H), 1.65 (m, 2H), 1.29-1.35 (m, 6H), 0.89 (t, J=7 Hz, 3H).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:23](=[O:24])[N:14]2[CH:15]([C:20]([OH:22])=[O:21])[C:16]([CH3:19])([CH3:18])[S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25]O>C(O)(=O)C.[O-][Mo]([O-])(=O)=O.[Na+].[Na+]>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:23](=[O:24])[N:14]2[CH:15]([C:20]([OH:22])=[O:21])[C:16]([CH3:19])([CH3:18])[S:17](=[O:25])[C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OO
Reactant: CC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Agent: O=[Mo](=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(C)C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S1=O

Procedure:
6-(2-phenoxyacetamido)-2,2-dimethylpenam-3-carboxylic acid (1.0 g.) was suspended in glacial acetic acid (3 cc) and sodium molybdate (0.01 g.) was added thereto. To the stirred mixture was added, dropwise, 30% hydrogen peroxide (0.7 cc) while cooling in an ice bath over a period of 5 minutes. One hour later, the precipitate was collected by filtration, washed with water and dried to yield colorless crystals (0.85 g) of 6-(2-phenoxyacetamido)-2,2-dimethylpenam-3-carboxylic acid-1-oxide, m.p. 166.5° C.
Reaction SMILES: [CH3:1][C:2](Cl)([CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6].[C:9]1([CH2:15][CH:16]([CH3:19])[CH2:17][Cl:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(Cl)Cl>[CH3:1][C:2]([C:12]1[CH:13]=[CH:14][C:9]([CH2:15][CH:16]([CH3:19])[CH2:17][Cl:18])=[CH:10][CH:11]=1)([CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(CCl)Cc1ccccc1
Reactant: CCCCC(C)(C)Cl
Solvent: ClC(Cl)Cl
Product: CCCCC(C)(C)c1ccc(CC(C)CCl)cc1
Temperature: 50 °C
Reaction time: 14 h
Yield: 73.8 %

Procedure:
342 g of 1,1-dimethylpentyl chloride were added dropwise to a mixture of 428 g of 3-phenyl-2-methylpropyl chloride and 40.6 g of FeCl3 at 35° C., and the mixture was stirred for 7 hours at 50° C. and for 14 hours at room temperature. The crude product was dissolved in 2 l of CHCl3, and the solution was washed with dilute HCl and water, dried over Na2CO3 and concentrated. Distillation of the residue gave 500 g of (XII) of boiling point 126°-132° C./0.2 mbar.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:18]([O:17][C:15]([NH:14][C@H:10]1[C@H:11]([CH3:13])[CH2:12][NH:8][CH2:9]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Yield: 93.3 %

Procedure:
A suspension of 1-benzyl-trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (4.8 g) and 10% palladium-on-charcoal (1.8 g) in ethanol (40 ml) was shaken with hydrogen were absorbed under elevated pressure (100 kg/cm2) at 50°-70° C. for 6.5 hours. The catalyst was removed by filtration and the filtrate was evaporated to give the title compound (3.09 g) as brown oil. This oil was gradually solidified at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][NH:36][CH2:35][CH2:34][O:33][CH3:32])=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: COCCN
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: COCCNCc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and 2-methoxyethanamine (36.4 mg; 0.48 mmol) to give Example 114 as a white solid. 1H NMR: (CDCl3, 400 MHz) δ 8.73-8.69 (2H, m), 8.05 (2H, d, J=8.0 Hz), 7.66-7.52 (2H, m), 7.46 (2H, d, J=8.0 Hz), 7.40-7.33 (3H, m), 7.18 (1H, t, J=9.1 Hz), 3.88 (2H, s), 3.53 (2H, t, J=5.1 Hz), 3.36 (3H, s), 2.82 (2H, t, J=5.1 Hz). LC/MS (Method C): 472 (M+H)+. HPLC (Method F) Rt 3.07 min (Purity: 96.5%).
Reaction SMILES: C([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:31][CH3:32])[CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[C:5]1=[O:33])C=C.C(#N)C.I([O-])(=O)(=O)=O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC[O:58][C:59]([CH3:61])=[O:60]>O.O.[Ru](Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([C@@H:24]([CH2:31][CH3:32])[CH:25]([OH:30])[C:26]([F:27])([F:28])[F:29])[C:5](=[O:33])[C@@H:4]([CH2:61][C:59]([OH:58])=[O:60])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)C(F)(F)F)C1=O
Reactant: CCOC(C)=O
Agent: Cl[Ru](Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: CC[C@@H](C(O)C(F)(F)F)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
To a rapidly stirring solution of 6.3 mg (0.013 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-1,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-2-one (Example 19, Step B, the diastereomer not used for Example 19 Step B)) (6.30 mg, 0.013 mmol) in a mixture of water (108 μL), acetonitrile (71.9 μL), and CCl4 (71.9 μL) was added sodium periodate (10.7 mg, 0.050 mmol), followed by ruthenium(III) chloride hydrate (0.284 mg, 1.26 μmol). After being stirred vigorously for 18 h, the reaction was acidified (10% citric acid) and diluted (EtOAc). The reaction mixture was filtered through Celite® (J. T. Baker, Phillipsberg, N.J., J. T. Baker, Phillipsberg, N.J., diatomaceous earth). The filtrate was extracted (2×EtOAc). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by reversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 45 to 70% acetonitrile +0.1% TFA in water +0.1% TFA, gradient elution) provided the title compound as a white solid.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[CH:71][N:70]=[C:69]([CH3:73])[CH:68]=2)[C:56]=1[CH3:74].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:72]=[CH:71][N:70]=[C:69]([CH3:73])[CH:68]=4)[C:56]=3[CH3:74])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1cc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)ccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)ccn1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.023 g, 0.047 mmol), 2,5-dimorpholinopyridin-3-amine (0.094 g, 0.35 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(2-methylpyridin-4-yl)quinoline (0.090 g, 0.30 mmol), Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.071 g, 0.74 mmol) in toluene (2.7 mL) at 120° C. for 2 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(2-methylpyridin-4-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.67 (1H, dd, J=4.9, 0.6 Hz), 7.71 (1H, d, J=11.0 Hz), 7.67 (1H, d, J=2.5 Hz), 7.62 (1H, ddd, J=9.4, 2.5, 1.4 Hz), 7.39 (1H, br s), 7.28 (1H, br s), 7.04 (1H, ddd, J=13.4, 8.6, 2.5 Hz), 6.33 (1H, dd, J=2.3, 0.4 Hz), 3.91 (4H, t, J=4.7 Hz), 3.83 (4H, app t, J=4.7 Hz), 3.20 (4H, br. s), 3.03 (4H, app t, J=4.9 Hz), 2.69 (3H, s), 2.13 (3H, s). Mass Spectrum (ESI) m/e=533.2 (M+1).
Reaction SMILES: ClCCl.[CH:4]([C:6]1[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:8]([CH3:19])[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=1)=O.[N+:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([O-:27])=[O:26].CN1CCOCC1.[Cl-].[NH4+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:32]([O:31][C:29](=[O:30])[C:28]([N+:25]([O-:27])=[O:26])=[CH:4][C:6]1[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:8]([CH3:19])[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=1)[CH3:33]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: CCOC(=O)c1c(C=O)cn(COCC[Si](C)(C)C)c1C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1cn(COCC[Si](C)(C)C)c(C)c1C(=O)OCC)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A flask equipped with stirbar was charged with 4 mL tetrahydrofuran and cooled in an ice bath. Titanium(IV) chloride, 1M solution in dichloromethane (2.1 mL, 2.100 mmol) was added by syringe, providing a suspension. After 15 minutes, a solution of Example 93c (0.322 g, 1.034 mmol) and ethyl 2-nitroacetate (0.115 mL, 1.034 mmol) in tetrahydrofuran (0.5 mL) was added. After an additional 15 minutes, a solution of 4-methylmorpholine (0.45 mL, 4.09 mmol) in tetrahydrofuran (0.3 mL) was added dropwise. The solution was allowed to warm to ambient temperature and stirred for 18 hours. The heterogeneous reaction mixture was poured into aqueous ammonium chloride and extracted twice with ether. The combined organics were washed with saturated aqueous sodium chloride then dried over anhydrous magnesium sulfate. Filtration, solvent removal, and chromatography on a 12 g silica gel cartridge eluting with 0-60% ethyl acetate/heptane provided the title compounds as a 2.5:1 mixture of olefin isomers.