Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:19][CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:19][CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NCC(c2ccccc2)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(NCC(c2ccccc2)c2ccccc2)c2cccc(N)c2)cc1
Yield: 85.4 %

Procedure:
In a similar manner to that described in Example (1b), a solution of [(4-methoxyphenyl)-(3-nitrophenyl)methyl]-(2,2-diphenylethyl)amine (2.54 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (2.76 g) and sodium borohydride (878 mg) were reacted, to afford the title compound (2.02 g) as a clear colorless oil.
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH:3]=[CH2:4].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[S:15])[S-:14].C([NH+](CC)CC)C.Cl.C(OC(C)C)(C)C>C(#N)C.C(OCC)C.C(Cl)Cl>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[S:14])[S:15][CH2:4][CH2:3][C:2](=[O:5])[CH3:1]
Reactant: S=C([S-])Nc1ccccn1
Reactant: C=CC(C)=O
Agent: CC[NH+](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: CC(=O)CCSC(=S)Nc1ccccn1
Reaction time: 2 h
Yield: 53.3 %

Procedure:
A solution of but-3-en-2-one (11.6 g) in anhydrous acetonitrile (15 cc) is added, at a maximum temperature of 5° C., to a suspension of triethylammonium pyrid-2-yldithiocarbamate (45.0 g) in anhydrous acetonitrile (280 cc). The reaction is allowed to proceed for 2 hours at a maximum temperature of 2° C. A 3.5 N solution of anhydrous hydrogen chloride in diethyl ether (47.5 cc) is added at a maximum temperature of 0° C. The triethylamine hydrochloride is filtered off and washed twice with a mixture of acetonitrile and diethyl ether (40 cc and 140 cc, respectively). The solvents are evaporated off under reduced pressure (20 mmHg) at 45° C. The residue is treated with diethyl ether (600 cc). The ethereal solution is washed twice with distilled water (total 240 cc), dried over sodium sulphate and the solvent evaporated off. The residue obtained (30.2 g) is dissolved in methylene chloride (120 cc), silica (0.2-0.5 mm; 25.0 g) is added and the solvent is then evaporated off. The silica impregnated with the product is introduced onto a column of diameter 4 cm, containing silica (0.2-0.5 mm; 300 g). Elution is carried out successively with a mixture of cyclohexane (1,600 cc) and ethyl acetate (400 cc) and then with a mixture of cyclohexane (375 cc) and ethyl acetate (125 cc) and the eluates are discarded. Elution is continued with a mixture of cyclohexane (1,800 cc) and ethyl acetate (600 cc). The eluate is collected and then evaporated to dryness under reduced pressure (20 mmHg) at 45° C. The crystals obtained (24.5 g; m.p. about 65° C.) are treated with a mixture of diisopropyl ether (60 cc) and diethyl ether (60 cc). The crystals are filtered off, washed successively with a mixture of diisopropyl ether (25 cc) and diethyl ether (25 cc) and then twice with diisopropyl ether (50 cc) and dried under reduced pressure (20 mmHg) at 40° C. 3-Oxobutyl pyrid-2-yldithiocarbamate (21.2 g) (structure determined by IR spectroscopy in petroleum jelly), which melts at 74° C., is thus obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:29])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:28])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[CH3:30][O:31][CH2:32][CH2:33][C:34]1([C:39](O)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:29])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:28])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:39]([C:34]1([CH2:33][CH2:32][O:31][CH3:30])[CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:40]
Reactant: COCCC1(C(=O)O)CCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Cl)cn(Cc3ccccc3)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3cc(Cl)cn(Cc4ccccc4)c3=O)cc2)C(=O)OC)CCCC1
Yield: 58.1 %

Procedure:
A solution of 4-(1-benzyl-5-chloro-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (100 mg, 0.25 mmol), 1-(2-methoxyethyl)cyclopentane carboxylic acid (47 mg, 0.28 mmol), DIEA (200 μL, 1.2 mmol) and HBTU (133 mg, 0.35 mmol) in DMF (2 mL) was stirred at room temperature for 18 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation was chromatographed on 25 g of silica gel, eluting with 60:40 ethyl acetate:hexane to give 4-(1-benzyl-5-chloro-2-oxo-3-pyridinyl)-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (80 mg, 63%). LR-Electrospray: m/z 1123 (2M+Na), 1118 (2M+NH4), 573 (M+Na), 568 (M+NH4), 551 (M+H (1 Cl)). HRMS: Obs. Mass 551.2297. Calcd. Mass 551.2313 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH3:25])=[C:12]([NH:21][C:22]([NH2:24])=[S:23])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26](I)[CH3:27]>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH3:25])=[C:12]([NH:21][C:22](=[NH:24])[S:23][CH2:26][CH3:27])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(NC(N)=S)ccc(-n2cccn2)c1CNC(=O)OC(C)(C)C
Reactant: CCI
Solvent: CC#N
Product: CCSC(=N)Nc1ccc(-n2cccn2)c(CNC(=O)OC(C)(C)C)c1C
Yield: 95 %

Procedure:
A mixture of the compound (47 mg) obtained in Example 7e, ethyl iodide (0.026 ml) and acetonitrile (1 ml) was heated under reflux for 4 hours and then concentrated at reduced pressure. Saturated sodium hydrogencarbonate solution was added to the resulting residue and extraction with chloroform was conducted. The organic layer was dried with anhydrous magnesium sulfate and then concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; chloroform:methanol=15:1) to give the titled compound (yield, 95%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].C([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=C.[Na].FC(F)(F)C([O-])=O>C(O)C>[CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[N:7]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2[nH]c3ccccc3c2C1
Reactant: C=Cc1ccncc1
Agent: O=C([O-])C(F)(F)F
Agent: [Na]
Solvent: CCO
Product: CCN1CCc2c(c3ccccc3n2-c2ccncc2)C1
Yield: 3.6 %

Procedure:
The title compound was prepared according to General Method 3. 2-Ethyl-2,3,4,5-tetrahydro-5-(4-pyridyl)-1H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (See Example 5) (200 mg, 1 mmol), 4-vinylpyridine (0.26 mg, 2.5 mmol), and sodium (15 mg, 0.65 g atom) in ethanol (2 mL) at 150° C. overnight (16 h) to obtain 10 mg of 2-ethyl-2,3,4,5-tetrahydro-5-(4-pyridyl)-1H-pyrido[4,3-b]indole as a trifluoroacetate salt after purification on reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.C1CCCCC=1>[C].[Pd]>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:12])[CH2:3]1
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Agent: [Pd]
Solvent: C1=CCCCC1
Product: CC1CC(C)(C)c2cccc(N)c21
Temperature: 150 °C
Reaction time: 5 h

Procedure:
Into a reaction vessel were charged 6.00 parts by weight of (3R)-1,1,3-trimethyl-4-aminoindane (optical purity of 96.5% ee) and 1.60 parts by weight of 5% palladium-carbon (STD-type, manufactured by N. E. Chemcat Corporation), thereby obtaining a mixture. The reaction vessel was sealed, the gas in the reaction vessel was replaced with nitrogen, and then the mixture was stirred at 150° C. to obtain a reaction mixture. While stirring the obtained reaction mixture, 1.40 parts by weight of cyclohexene was added dropwise thereto over 5 hours. Thereafter, the reaction mixture was cooled and filtered. The obtained solid was washed with 20 parts by weight of 2-propanol. The washing liquid recovered after washing and the filtrate obtained by filtration were combined. The combined mixture was concentrated under reduced pressure to obtain 5.63 parts by weight of 1,1,3-trimethyl-4-aminoindane. The obtained 1,1,3-trimethyl-4-aminoindane had an optical purity of 0.29% ee and a recovery rate of 93.8%.
Reaction SMILES: [CH2:1]([O:3][Si:4]([C:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]=[CH:12]2)([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].C([SiH](CC)CC)C.C(O)C.[C:28]1(C)[CH:33]=CC=[CH:30][CH:29]=1>ClCCl.C1COCC1>[CH2:33]([C:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]=[CH:12]2)[CH2:28][CH2:29][CH3:30].[CH2:6]([O:5][Si:4]([C:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]=[CH:12]2)([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: Cc1ccccc1
Agent: CCO[Si](OCC)(OCC)C12C=CC(CC1)C2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCC12C=CC(CC1)C2
Temperature: 80 °C

Procedure:
BuNB (25.22 g, 0.168 mol), Triethoxysilyl Norbomene (TESNB, CAS 18401-43-9) (4.78 g, 0.019 mol), triethyl silane (0.11 g, 9.32E-05 mol), ethanol (0.10 g, 2.24E-03 mol) and toluene (170.0 g) were combined in a 500 mL serum bottle and heated to 80° C. in an oil bath to form a solution. To this solution were injected Pd1206 (0.018 g, 1.49E-05 mol) in the form of a concentrated solution in dichloromethane. After addition, the resulting mixture was maintained at 80° C. for 9 hours. The copolymer was precipitated by adding methanol drop wise into the vigorously stirred reaction mixture. The precipitated copolymer was collected by filtration and dried in an oven at 60° C. under vacuum After drying, 20.58 g was obtained (69%). The molecular weight of the copolymer was determined by GPC in THF solvent (polystyrene standard) to be Mw=238,000 and Mn=96,000. The composition of the copolymer was determined by 1H-NMR to be (85/15) BuNB/TESNB copolymer. The refractive indices of this polymer were measured by prism coupling method and determined to be 1.5061 in TE mode and 1.5041 in TM mode at a wavelength of 633 nm. The Tg (based on thermomechanical analysis (TMA) measurement) of this polymer was 276° C. The dried copolymer was dissolved insufficient toluene to result in a 30 wt % copolymer solution.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[O:5].Cl[C:27]([O:29][CH3:30])=[O:28]>>[CH3:30][O:29][C:27]([NH:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1)=[O:5])=[O:28]
Reactant: Cc1cc(C)cc(COC(=O)C(N)Cc2c[nH]c3ccccc23)c1
Reactant: COC(=O)Cl
Agent: Cl
Product: COC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OCc1cc(C)cc(C)c1

Procedure:
Following the method of Example 18, 3,5-dimethylbenzyl 2-amino-3-(3-indolyl)propionate hydrochloride and methyl chloroformate gave the title compound after recrystallisation from ethyl acetate/petroleum ether, m.p. 128°-129° C. 1H NMR (360 MHz, CDCl3) δ8.04 (1H, s), 7.52 (1H, d, J=8.0 Hz), 7.32 (1H, d, J=8 Hz), 7.18 (1H, t, J=8 Hz), 7.09 (1H, t, J=8 Hz), 6.95 (1H, s), 6.83 (2H, s), 5.25 (1H, d, J=7.5 Hz), 5.00 (2H, dd, J=12 Hz), 4.73 (1H, m), 3.65 (3H, s), 3.29 (2H, d, J=5 Hz), 2.29 (6H, s).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][C:21](=[O:27])[NH:22]2>>[CH:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[C:20]2[C:19]3[C:23](=[CH:24][CH:25]=[CH:26][C:18]=3[CH3:17])[NH:22][C:21]2=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1C1CCCCC1
Reactant: Cc1cccc2c1CC(=O)N2
Product: COc1ccc(C=C2C(=O)Nc3cccc(C)c32)cc1C1CCCCC1

Procedure:
3-Cyclohexyl-4-methoxybenzaldehyde was condensed with 4-methyl-2-oxindole to give 0.3 g of 3-(3-cyclohexyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:8]([OH:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C1COCC1.C(N(C(C)C)C(C)C)C.[C:41]1([C:47]#[CH:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CCOC(C)=O.[Cu]I>[OH:14][C:8]1[C:9]([CH3:12])([CH3:13])[C:10]2[C:5]([C:6](=[O:26])[C:7]=1[C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[O:16])=[CH:4][CH:3]=[C:2]([C:48]#[C:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH:11]=2
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(Br)ccc2C1=O
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(C#Cc3ccccc3)ccc2C1=O
Temperature: 80 °C

Procedure:
To a mixture of tert-butyl 2-(7-bromo-2-hydroxy-1,1-dimethyl-4-oxo-1,4-dihydronaphthalene-3-carboxamido)acetate (120 mg, 283 μmol, Example 53A-E), palladium dichloride bistriphenylphosphine (20 mg, 28 μmol), and copper(I) iodide (11 mg, 57 μmol) was added THF (1414 μL), N-ethyl-N-isopropylpropan-2-amine (148 μL, 848 μmol), and phenylacetylene (62 μL, 566 μmol). The reaction was heated at 80° C. for 2 hours. The reaction mixture was diluted with 100 mL of EtOAc, washed 2 times with 75 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated to give crude product which was purified via flash chromatography to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH:10]1([CH:16]=[CH:17]B(O)O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:10]1(/[CH:16]=[CH:17]/[C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccc(Br)cn1
Reactant: OB(O)C=CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccc(/C=C/C2CCCCC2)cn1
Temperature: 90 °C
Yield: 75.9 %

Procedure:
Combine a mixture of 5-bromo-2-cyano-pyridine (2 g, 10.93 mmol), 2-cyclohexylvinyl boronic acid (2.52 g, 16.39 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (446 mg, 0.546 mmol) and 2M aqueous Na2CO3 (18.2 mL, 36.07 mmol) in 1,4-dioxane (110 mL). Purge with nitrogen and heat at 90° C. overnight. Cool the reaction to room temperature and partition between EtOAc and water. Separate the aqueous phase and extract with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (120 g, pre-packed cartridge) eluting stepwise with hexane/EtOAc (1:0 over 5 min, 49:1 over 5 min and 19:1 over 5 min; 50 mL/min) to obtain the desired intermediate (1.76 g, 76%). MS (APCI+) m/z: 213 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:37])([C:6]1([O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:8]1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:7])C(O)=O>N1C(C)=CC=CC=1C>[F:37][CH:2]([F:1])[C:6]1([O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:8]1[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:7]
Reactant: O=C(O)C(F)(F)C1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: Cc1cccc(C)n1
Product: OC1(C(F)F)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
A stirred solution of 2.57 g of 2-deoxy-2,2-difluoro-4,5,7-tris-O-(phenylmethyl)-D-arabino-3-heptulofuranosonic acid in 25 ml of 2,6-lutidine was refluxed for 2 hours and then concentrated. The residue was subjected to column chromatography on silica gel to give an oil, CMR δ 113.1 (triplet, J=247Hz, CF2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:11]([CH3:16])[C:12]([SH:15])=[N:13][CH:14]=2)[OH:9])=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[N:11]([CH3:16])[C:12]([S:15][CH2:18][CH2:19][CH3:20])=[N:13][CH:14]=2)[OH:9])=[CH:6][CH:7]=1
Reactant: CCCBr
Reactant: Cn1c(C(O)c2ccc(Cl)cc2)cnc1S
Product: CCCSc1ncc(C(O)c2ccc(Cl)cc2)n1C
Yield: 71 %

Procedure:
The product of Example I, Step A (3.35 g) was subjected to the same conditions as described in Example I, Step B except that bromopropane (1.4 mL) was employed as the alkylating agent to provide (4-Chlorophenyl)-(3-methyl-2-propylsulfanyl-3H-imidazol-4-yl)-methanol (2.69 g, 71%). M calc=296; M+H found=297. Calculated for C14H17N2OSCl: C 56.65, H 5.77, 9.44; found C 55.88, H 5.88, N 9.84.
Reaction SMILES: [CH2:1]([N:5](C(=O)C(Cl)Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)[CH:2]=[CH:3][CH3:4].C(O)C.[OH-].[K+]>O>[CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=1)[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCN(C(=O)C(Cl)Cl)c1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC=CCNc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.9 %

Procedure:
64.64 grams (g) (0.198 mole) of N-crotyl-m-trifluoromethyl dichloroacetanilide and 300 milliliters (mL) of absolute ethanol were added to a round-bottomed flask, and stirred at room temperature, followed by the addition of 14.39 g of potassium hydroxide in 20 mL of water dropwise over a period of 10 minutes. After the addition was complete, the reaction mixture solidified with the precipitation of potassium dichloroacetate. The flask was swirled by hand to break up the solidified cake and stirring allowed to continue for an additional 18 hours. At the end of this time, 250 mL of ethylacetate was added and the mixture filtered. The solvent was then removed in vacuo to yield a pale orange-yellow semisolid. This was partitioned between 300 mL of ethylacetate and 300 mL of water and the layers were separated. The organic layer was washed one time with 200 mL of water and one time with 200 mL of a saturated sodium chloride solution. The organic layer was then dried with sodium sulfate and the solvent removed in vacuo to yield a yellow-orange material that was distilled at aspirator pressure to yield 36.6 g (86%) of product, N-crotyl-m-trifluoromethyl aniline.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:9][CH:10]=2)[CH:5]=1)([O-])=O>[Ni].CO>[F:15][C:14]([F:16])([F:17])[C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[CH:13][C:4]([NH2:1])=[CH:5]2)=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc2ccc(C(F)(F)F)cc2c1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc2ccc(C(F)(F)F)cc2c1
Reaction time: 1 h

Procedure:
A mixture of 2-nitro-7-trifluoromethylnaphthalene (650 mg, 2.7 mmol) and Raney nickel (65 mg) in methanol (10 mL) is stirred under H2 (1 atm) for 1 hour. Filtration of the catalyst and evaporation of the solvent gives 7-trifluoromethyl-2-aminonaphthalene as a yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[C:5]([F:17])=[C:4]([F:18])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:18][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[C:5]=1[F:17]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C1NCCCn2c1cc1c(F)c(F)cc(Br)c12
Product: COc1ccc(-c2cc(F)c(F)c3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, grey solid (82 mg, 96%), MS (ISP) m/z=343.2 [(M+H)+], mp 207.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9,10-difluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 5) (78.8 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6]>CO.[Rh]>[ClH:1].[CH3:2][O:3][C:4](=[O:14])[C@H:5]([NH2:6])[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Agent: [Rh]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](N)CC1CCCCC1
Yield: 97 %

Procedure:
Commercially available D-phenylalanine methyl ester hydrochloride (12 g) was hydrogenated with 5% rhodium on carbon (1.2 g) in 250 mL of methyl alcohol to yield (2R)-2-amino-3-cyclohexyl propanoic acid methyl ester hydrochloride in 97% yield. This (5.0 g, 18.4 mmol) was coupled with Boc-L-proline (3.97 g, 18.4 mmole)by standard methods [(1-hydroxybenzotriazole monohydride (HOBt) (2.74 g, 20 mmol), N-methylmorpholine (NMM) (2.23 mL, 20 mmol) and 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDC) (3.89 g, 20 mmol) as exemplified by the methods described in "Peptide Synthesis" Second Edition, Bodanszky, M; Klausner, Y. S. and Ondetti, M. A., (1976) in 71% yield. The Boc-group was cleaved with 4 N hydrochloric acid in dioxane, and the obtained prolyl-(2R) -2-amino-3-cyclohexylpropanoic acid methyl ester hydrochloride was reacted with N-alpha-Cbz-N-epsilon-Boc-lysine (quantitative yield) according to the method mentioned above. The N-alpha-Cbz group was removed by hydrogenolysis (20%-palladium on charcoal 10% w/w) in acetic acid-isopropanol, and the obtained product was coupled with Boc-(N-methyl)phenylalanine by the above method to obtain N-Boc-(N-methyl) phenylalanyl-lysyl(N-epsilon-Boc)-prolyl-{(2R)-2-amino-3-cyclohexylpropanoic acid methyl ester} in quantitative yield. Finally, the methyl ester (7.33 g, 9.5 mmole) was cleaved by treatment with 1.5 molar equivalents of lithium hydroxide (598 mg, 14.25 mmol) in 115 mL of methanolwater (2:1) mixture to obtain N-Boc-(N-methyl)phenylalanyllysyl (N-epsilon-Boc)-prolyl-{(2R)-2-amino-3-cyclohexylpropanoic acid} in 83% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][C:13](=S)[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:25][CH2:26][C:27]1([CH:32]2[CH2:34][CH2:33]2)OCCO1>COCCO.[Hg]=O>[CH:32]1([C:27]2[N:12]3[N:11]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)[C:16]4[CH:17]=[C:18]5[O:23][CH2:22][O:21][C:19]5=[CH:20][C:15]=4[CH2:14][C:13]3=[N:25][CH:26]=2)[CH2:34][CH2:33]1
Reactant: NCC1(C2CC2)OCCO1
Reactant: O=[N+]([O-])c1ccc(C2=NNC(=S)Cc3cc4c(cc32)OCO4)cc1
Agent: O=[Hg]
Solvent: COCCO
Product: O=[N+]([O-])c1ccc(C2=Nn3c(C4CC4)cnc3Cc3cc4c(cc32)OCO4)cc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A suspension of 0.50 g (1.47 mmol) of 5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8-thione (Example 15D) and 0.42 g (2.94 mmol) of 2-aminomethyl-2-cyclopropyl-1,3-dioxolane in 12 ml of Methyl Cellosolve® with 0.32 g (1.47 mmol) of red mercury oxide is stirred for 12 hours at 110° C. After filtration, the mixture is concentrated by evaporation to a volume of 5 ml and poured into water. The precipitate is suctioned off and dissolved in 10 ml of a 1:1 mixture of concentrated hydrochloric acid and glacial acetic acid and heated to boiling for 1.5 hours. During cooling, the hydrochloride salt of the title compound precipitates.