Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[C:6]([O:26]CC)(=O)[C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].Cl>C(O)C>[OH:26][C:6]1[CH:7]=[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:3][N:2]=1
Reactant: CCCCCCCCCCCCCCCCC#CC(=O)OCC
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCc1cc(O)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
13.24 g of hydroxylamine hydrochloride were added to a mixture of 130 ml of a 10% w/v aqueous solution of sodium hydroxide and 100 ml of ethanol, whilst ice-cooling. A solution of 5.08 g of ethyl 2-nonadecynoate (prepared as described in Preparation 31) in ethanol (30 ml) was then added dropwise to the resulting mixture, which was then stirred at room temperature for 16 hours. The mixture was then adjusted to a pH value of 3 by adding concentrated hydrochloric acid, and then the mixture was extracted three times with diethyl ether. The combined extracts were washed with water, dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 50 g of silica gel. 4.09 g of the title compound were isolated from the fractions eluted with a 1:1 by volume mixture of methylene chloride and hexane, to give crystals melting at 85°-86° C. (from cold diethyl ether).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:4]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:3]1=[O:21].[OH:22][C@@H:23]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:24]([NH:26][C@H:27]([C:32](O)=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25].CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:18]1([CH2:17][N:4]2[C@H:5]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[CH:6]=[CH:7][CH2:8][C@H:2]([NH:1][C:32](=[O:33])[C@H:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:26][C:24](=[O:25])[C@@H:23]([OH:22])[CH2:35][CH:36]([CH3:37])[CH3:38])[C:3]2=[O:21])[CH2:19][CH2:20]1
Reactant: COc1ccc([C@@H]2C=CC[C@H](N)C(=O)N2CC2CC2)cc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](O)CC(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc([C@@H]2C=CC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)CC(C)C)C(=O)N2CC2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of (3S,7S)-3-amino-1-(cyclopylmethyl)-7-(4-methoxyphenyl)-1,3,4,7-tetrahydro-2H-azepin-2-one (11e) (35 mg) in DCM (3 mL) at 0° C. under N2 was added N-[(2S)-2-hydroxy-4-methylpentanoyl]-L-leucine (7b) (30 mg), HOBt-hydrate (41 mg), EDAC.HCl (35 mg) and N-methyl morpholine (25 mg). The reaction mixture was stirred 1 h at 0° C. and 3H at room temperature, then diluted with 30% Hexanes/EtOAc (100 mL). The organic phase was consecutively washed with H2O, 0.2 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (2% MeOH/DCM) to afford the title compound as an off-white solid (60 mg, 95%). 1H NMR (300 MHz, CDCl3) δ 0.40 (m, 2H), 0.58 (m, 2H), 0.74 (m, 1H), 0.87 (d, 6H), 1.26 (m, 1H), 1.53, (m, 2H), 1.59 (m, 1H), 1.67 (m, 2H), 2.00 (m, 2H), 3.20 (m, 2H), 3.66 (s, 1H), 3.89 (m, 1H), 4.28 (m, 1H), 4.96 (m, 1H), 5.32 (m, 1H), 6.13 (bd, 1H), 6.48 (m, 1H), 6.85-6.94 (m, 4H). MS APCI, m/z=514 (M+1). LC/MS 2.47 min., Method A.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]3[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[C:6]3[CH2:20][CH2:21][N:22](C(OCC(Cl)(Cl)Cl)=O)[CH2:23][C:5]=3[C:4]=2[CH:3]=1.N>C(O)(=O)C.[Zn]>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]3[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C(=O)OCC(Cl)(Cl)Cl)C1
Agent: N
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCNC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 122.8 %

Procedure:
A mixture of 2,2,2-trichloroethyl 3,4-dihydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (100 mg, 0.2 mmol) and Zn dust (120 mg, 1.9 mmol) in acetic acid (1.2 ml) was stirred at 25° C. for 12 h. The reaction mixture was basified with saturated aqueous ammonia and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated to obtain 75 mg of 2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole after purification on silica gel (230-400 mesh) chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv.) in anhydrous THF.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1>>[F:24][C:19]1[CH:18]=[C:17]([CH3:16])[CH:23]=[CH:22][C:20]=1[NH:21][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Reactant: Cc1ccc(N)c(F)c1
Product: CCOC(=O)c1cnc2ccnn2c1Nc1ccc(C)cc1F
Yield: 53.5 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (5.0 g, 24.1 mmol) and 4-methyl-2-fluoroaniline (6.04 g, 48.3 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (4.05 g, 53%) was obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][C:15](N(OC)C)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.[Li]CCCC>C1COCC1>[CH:1]1[C:13]2[CH:12]([CH2:14][C:15]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Ic1ccncc1
Reactant: CON(C)C(=O)CC1c2ccccc2-c2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CC1c2ccccc2-c2ccccc21)c1ccncc1

Procedure:
In analogy to example 55, step 2, from 2-(9H-fluoren-9-yl)-N-methoxy-N-methyl-acetamide and 4-iodopyridine using isopropylmagnesium chloride lithium chloride complex in THF at rt (instead of n-BuLi at −70° C.) was prepared the title compound as yellow oil, MS (ESI+): m/z=286.1 ([M+H]+).
Reaction SMILES: O[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[C:4]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:30].C(N(C(C)C)CC)(C)C>CCOC(C)=O>[Cl:30][C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[C:4]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccnc(Cl)c2)c(-c2cccc(C(F)(F)F)c2)c2nncn12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cccc(-c2c(-c3ccnc(Cl)c3)nc(Cl)n3cnnc23)c1
Temperature: 25 °C

Procedure:
5-hydroxy-7-(2-chloro-4-pyridyl)-8-(3-(trifluoromethyl)phenyl)-1,2,4-triazolo[4,3-c]pyrimidine (0.3 g, 0.76 mmol), POCl3 (0.459 g, 3 mmol), and diisopropylethylamine (0.387 g, 3 mmol) in a 50-ml r.b.flask with a stir bar was stirred at 120° C. overnight. The reaction solution was cooled to room temperature and 20 ml of EtOAc and 5 g of SiO2 gel were added into the cooled solution. The solvents were evaporated in vacuo at 40° C. The resulting brown solid was placed on a cake of SiO2 gel (˜20 g) and washed with 250 ml of EtOAc. The brown filtrate was evaporated in vacuo to give 5-chloro-7-(2-chloro-4-pyridyl)-8-(3-(trifluoromethyl)phenyl)-1,2,4-triazolo[4,3-c]pyrimidine; MS m/z (M)+ 410; C17H8Cl2F3N5 requir. 410.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5](C1C=C(OCCCCCCCCCCCCOC2C=CC=CC=2)C=C(O)C=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].BrCCCCCCC1C=CC=C(OCC2C=CC=CC=2)C=1OCC1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[CH2:6][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:38]
Reactant: COC(=O)CN(CC(=O)OC)c1cc(O)cc(OCCCCCCCCCCCCOc2ccccc2)c1
Agent: BrCCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)CNCC(=O)OC

Procedure:
A mixture of 1.7 g (3.2 mmol) of N-[3-hydroxy-5-[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 1.5 g (3.37 mmol) of 1-(6-bromohexyl)-2,3-bis(phenylmethoxy)benzene, 1.3 g (9.6 mmol) of potassium carbonate and 0.96 g (6.4 mmol) of sodium iodide in 60 ml of acetone and 20 ml of DMF was stirred at reflux under argon for 7 days. Theusual workup followed by purification by HPLC using 25% ethyl acetate-hexane gave 2.15 g (74% yield) of N-[3-[6-(2,3-bisphenylmethoxy)phenyl]hexyloxy]-5-[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester as an oil. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].N1CCCCC1>N1C=CC=CC=1>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[C:11]([CH:12]=[C:21]3[S:17][C:18](=[O:23])[NH:19][C:20]3=[O:22])[CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cccc(OCc3ccccc3)c2)S1
Reaction time: 48 h
Yield: 100 %

Procedure:
A solution of 3-benzyloxybenzaldehyde (42.45 g, 200 mmol), 2,4-thiazolidinedione (23.43 g, 200.0 mmol), and piperidine (2 g) in 150 ml pyridine was refluxed for 16 h. The mixture was concentrated in vacuo, and the residue was triturated with 500 ml hot benzene, filtered, and the filtrate left standing at room temperature for two days. The resulting crystals were collected by filtration, washed with petroleum ether, and dried to give the product in 100% yield; mp 233-235° C.; IR (nujol): 1741, 1688 (CO) cm-1 ; NMR (DMSOd6TMS): δ5.19 (s, 2H, ArCH2), 7.15-7.25 (m, 3H), 7.3-7.5 (m, 6H), 7.73 (s, 1H, C=CH); Anal calcd for C17H13NO3, MW 311.36: C, 65.58; H, 4.21; N, 4.50; S, 10.30. Found: C, 65.53; H, 3.91; N, 4.52; S, 10.30. Mass spec m/e 312(M+1).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH:40]4[CH2:42][CH2:41]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH:40]4[CH2:41][CH2:42]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CC4CC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn(CC4CC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH3:31][S:32]([CH:35]1[CH2:39][CH2:38][NH:37][CH2:36]1)(=[O:34])=[O:33]>>[CH3:31][S:32]([CH:35]1[CH2:39][CH2:38][N:37]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)[CH2:36]1)(=[O:34])=[O:33]
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CS(=O)(=O)C1CCNC1
Product: CC1(C)c2cc(N3CCC(S(C)(=O)=O)C3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and 3-methanesulfonylpyrrolidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[CH2:15][C:16]([CH3:19])([CH3:18])[O:17][C:13]=2[CH:12]=[C:11]([C:20](O)=[O:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:33][N:30]1[CH:31]=[CH:32][C:28]([NH:27][C:20]([C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:14]3[CH2:15][C:16]([CH3:19])([CH3:18])[O:17][C:13]=3[CH:12]=2)=[O:21])=[N:29]1
Reactant: Cn1ccc(N)n1
Reactant: CC1(C)Cc2c(OCc3ccccc3)cc(C(=O)O)cc2O1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)c3c(c2)OC(C)(C)C3)n1
Reaction time: 1 h
Yield: 60.1 %

Procedure:
To a solution of 4-benzyloxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (77b) (6.98 g, 23.40 mmol) in CH2Cl2 (100 mL) was added thionyl chloride (2.04 mL, 28.1 mmol), followed by 10 drops of DMF. The mixture was refluxed for 2 h, then concentrated and dried under vacuum. The residue was dissolved in CH2Cl2 (100 mL), and 3-amino-1-methyl-pyrazole (2.73 g, 28.1 mmol) was added at 0° C., followed by triethylamine (6.52 ml, 46.80 mmol). The mixture was stirred at 0° C. to room temperature for 1 hr. The reaction was quenched with H2O, extracted with 3×CH2Cl2. The combined organic layers were dried over Na2SO4, concentrated and purified by flash column chromatography with 1-3% MeOH in CHCl3 to give a white solid (5.31 g, 60% yield). 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1 H) 7.29-7.50 (m, 6 H) 7.09 (d, J=1.01 Hz, 1 H) 6.84 (dd, J=8.08, 1.77 Hz, 2 H) 5.14 (s, 2 H) 3.83 (s, 3 H) 2.95-3.06 (m, 2 H) 1.50 (s, 6H); LCMS for C22H23N3O3 m/z 378.20 (M+H+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CCO>[F:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:12](=[O:13])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:25][CH2:24]2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2cccc(F)c2[N+](=O)[O-])CC1
Yield: 93 %

Procedure:
Method 1 was followed using 1 eq each of 2,6-difluoronitrobenzene, 4-(N-Boc-amino) piperidine, and TEA in EtOH yielding tert-butyl 1-(3-fluoro-2-nitrophenyl)piperidin-4-ylcarbamate (93%). LCMS (m/z): 340.1 (MH+); LC Rt=3.30 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:29])([C:16]([S:19]CC1C=CC(OC)=CC=1)([CH3:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:29])([C:16]([SH:19])([CH3:17])[CH3:18])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: COc1ccc(CSC(C)(C)C(O)(Cn2cncn2)c2ccc(F)cc2F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)(S)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 85.7 %

Procedure:
To 72.0 g (172 mmol) of (+)-2-(2,4-difluoro-phenyl)-3-((4-methoxyphenyl)methylthio)-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol were added 18.6 g (172 mmol) of anisole and 1010 ml of trifluoroacetic acid in this order, followed by stirring at 70° C. for 1.5 hours. After allowing the mixture to cool, the solvent was removed by distillation under reduced pressure, and the residue was neutralized with a saturated sodium hydrogencarbonate aqueous solution, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution and dried. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography using chloroform as an eluent. The solvent was removed by distillation under reduced pressure, and the residue was recrystallized from a mixed solvent of isopropyl ether and hexane to obtain 44.1 g (86%) of (-)-2-(2,4-difluoro-phenyl)-3-mercapto-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol as a colorless crystal.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH:19]=O)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][CH2:22][CH2:23][CH2:24][P:25](=[O:28])([OH:27])[OH:26].[BH3-]C#N.[Na+]>CO>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:19][NH:21][CH2:22][CH2:23][CH2:24][P:25](=[O:26])([OH:28])[OH:27])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCP(=O)(O)O
Reactant: O=Cc1ccc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=P(O)(O)CCCNCc1ccc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
General Procedure M. To a solution of 5,6-diphenylpyridine-2-carbaldehyde (Compound 54, 95 mg, 0.37 mmol) and (3-amino-propyl)-phosphonic acid (51 mg, 0.37 mmol) in MeOH (3 ml) was added Bu4NOH (0.4 ml, 0.37 mmol, 1M in MeOH) under argon. The mixture was stirred at 50° C. for 30 min. before adding NaCNBH3 (23 mg, 0.37 mmol) to the mixture. The solution was stirred at 50° C. for 3 hours, and then it was concentrated in vacuo. The resulting crude solid was purified MPLC column chromatography (silica gel, 0-100% MeOH in ethyl acetate) to obtain the title compound as a white solid.
Reaction SMILES: C([Mg]Cl)(C)C.[O:6]1CCC[CH2:7]1.Br[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:17]=1.CN(C)C=O>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]#[C:18][C:16]2[CH:17]=[C:12]([CH:7]=[O:6])[CH:13]=[N:14][CH:15]=2)=[CH:21][CH:22]=1
Reactant: C1CCOC1
Reactant: Fc1ccc(C#Cc2cncc(Br)c2)cc1
Agent: CC(C)[Mg]Cl
Solvent: CN(C)C=O
Product: O=Cc1cncc(C#Cc2ccc(F)cc2)c1
Yield: 23.7 %

Procedure:
Prepare in a similar manner as described in EXAMPLE 90, using a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (2.99 mL, 5.98 mmol), 3-bromo-5-(4-fluorophenylethynyl)-pyridine (1.50 g, 5.43 mmol), (prepared essentially as described in EXAMPLE 96), and anhydrous N,N-dimethylformamide (1.99 g, 27.16 mmol) to give the title compound (0.29 g, 24%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.[I-].C[S+](C)C>CS(C)=O.C(OCC)(=O)C>[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([C:12]2([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=3)[CH2:1][O:13]2)=[CH:10][CH:9]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(I)cc1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Clc1ccc(C2(c3ccc(I)cc3)CO2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Potassium tert-butoxide (18.48 g, 165.0 mmol) was added to a rapidly stirred suspension of 4-chloro-4′-iodobenzophenone (51.38 g, 150.0 mmol) and trimethylsulphonium iodide (33.66 g, 165.0 mmol) in dimethylsulphoxide (200 ml) and the resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate (500 ml), washed with water (3×500 ml) and then with brine (500 ml). The organic layer was separated and the solvent removed in vacuo to afford (RS)-2-(4-chlorophenyl)-2-(4-iodophenyl)oxirane (53.48 g, 100%) as a pale yellow oil that solidified upon standing to afford an off-white solid. 1H NMR (DMSO-d6) 7.76 (2H, d), 7.45 (2H, d), 7.34 (2H, d), 7.12 (2H, d), 3.32 (2H, m). MS: [M−H]− 355.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:9](=[O:28])[N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[NH2:7][C@@H:8]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:9]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]=1)=[O:28].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1c1cccc(Oc2ccccc2)c1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](C(=O)N1CCC[C@H]1c1cccc(Oc2ccccc2)c1)C1CCCCC1
Reaction time: 0.5 h

Procedure:
To a solution of {(S)-1-cyclohexyl-2-oxo-2-[(S)-2-(3-phenoxy-phenyl)-pyrrolidine-1-yl]-ethyl}-carbamic acid tert-butyl ester in CH2Cl2 (20 mL) is added TFA (10 mL) and the mixture is stirred for 30 minutes. The mixture is concentrated under reduced pressures to give (S)-2-amino-2-cyclohexyl-1-[(S)-2-(3-phenoxy-phenyl)-pyrrolidin-1-yl]-ethanone as a TFA salt quantitavely (1.65 g). LCMS m/z 379 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[K].[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[CH2:27]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1oc2cc(O)ccc2c(=O)c1-c1ccccc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CC(C)=O
Product: Cc1oc2cc(OCc3ccccc3)ccc2c(=O)c1-c1ccccc1

Procedure:
10 g of 7-hydroxy-2-methyl-isoflavone, 10 g of anhydrous potassium carbonate, 1 g of potassium iddide and 12.5 g of benzyl chloride are boiled in 200 ml of anhydrous acetone for 2 hours with stirring, under a reflux condenser. On subjecting the mixture to steam distillation, the crude product precipitating from a mixture of 100 ml of methanol and 40 ml of acetone, yielding white needle crystalls of 7-benzyloxy-2-methyl-isoflavone, m.p. 139°-141°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([C:27](O)=[O:28])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.[CH2:50]([NH:54][CH2:55][CH:56]([CH3:58])[CH3:57])[CH:51]([CH3:53])[CH3:52].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([C:27](=[O:28])[N:54]([CH2:55][CH:56]([CH3:58])[CH3:57])[CH2:50][CH:51]([CH3:53])[CH3:52])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:33]=[C:34]([CH3:39])[CH:35]=[C:36]([CH3:38])[CH:37]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CNCC(C)C
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C(=O)O)c(Cl)cc3[nH]c2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C(=O)N(CC(C)C)CC(C)C)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 4-[2-(1-tert-butoxycarbonyl-piperidin-2-yl)-ethoxy]-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinoline-6-carboxylic acid (48 mg in 0.50 mL methylene chloride) was added 12 mg 1-hydroxybenzotriazole (HOBt) followed by 0.020 mL diisobutylamine, 0.025 mL triethylamine and 33 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and the mixture stirred at room temperature. After 22 hours, the mixture was diluted with methylene chloride and washed with 10% aqueous sodium bisulfate and brine. The organics were dried over sodium sulfate and the concentrate purified by flash chromatography on silica gel (chloroform:methanol, 97.5:2.5) to give the title compound (37 mg).