Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([N:14]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:15]([C@@H:17]([NH:19]C(OC(C)(C)C)=O)[CH3:18])=[O:16])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:14]2[C:15](=[O:16])[C@H:17]([CH3:18])[NH:19][C:3](=[O:2])[C@H:4]2[CH2:5][O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)[C@@H](COCc1ccccc1)N(Cc1ccc(F)cc1)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1NC(=O)[C@@H](COCc2ccccc2)N(Cc2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a solution of (2R)-3-benzyloxy-2-(N-(4-fluorobenzyl)-N-(((1S)-1-(t-butoxy-carbonylamino)ethyl)carbonyl)amino)propanoic acid methyl ester (2.0 g, 4 mmol) in CH2Cl2 (25 mL) was cooled to 0° C. and trifluoroacetic acid (25 mL) was added dropwise over 2 hours. At the end of the addition, the ice bath was removed and the mixture was stirred at ambient temperature. After 2 hours, the mixture was concentrated in vacuo. The residual yellow oil was taken up in ethyl acetate and washed with 1 N aqueous NaHCO3 solution. The organic layer was separated then dried over MgSO4, filtered, and concentrated in vacuo to afford 1.2 g (83% yield) of (2R,5S)-1-(4-fluorobenzyl)-2-(benzyloxy)methyl-5-methylpiperazine-3,6-dione, a compound of formula (R), as a clear oil; NMR (CDCl3) 7.4-7.2 (m, 7), 7.0 (dd, 2), 5.0 (d, 1), 4.5-4.0 (m, 4), 3.9-3.5 (m, 4), 1.5 (d, 3) ppm, MS (LSIMS) 356.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[CH2:10][C:11]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[O:21][CH3:22])([CH3:13])[CH3:12]>C1COCC1.C(OCC)C>[F:20][C:18]1[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[C:14]([C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][OH:8])[CH:19]=1
Reactant: COC(=O)CC(C)(C)c1cc(F)ccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CCO

Procedure:
To a suspension of LAH (1.64 g) in 100 mL of THF stirred under argon was added dropwise over 30 minutes a solution of the above 3-(5-fluoro-2-methoxyphenyl)-3-methylbutyric acid methyl ester in 10 mL of THF (vigorous reaction). The mixture was stirred at room temperature overnight. The reaction was diluted with 200 mL of diethyl ether and quenched by the addition of 3 mL of water (added cautiously) and 3 mL of acetic acid. The mixture was filtered through diatomaceous earth and washed through with diethyl ether. Evaporation of the solvent gave 10.8 g of 3-(5-fluoro-2-methoxyphenyl)-3-methylbutan-1-ol, which was used without additional purification.
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10]1([C@@H:13]2[O:21][CH2:20][C:16]3=[N:17][O:18][CH2:19][C@@H:15]3[CH2:14]2)[CH2:12][CH2:11]1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1I.C([Li])CCC>C1(C)C=CC=CC=1>[CH:10]1([C@@H:13]2[O:21][CH2:20][C@:16]3([C:26]4[CH:25]=[CH:24][C:23]([F:22])=[CH:28][C:27]=4[F:29])[NH:17][O:18][CH2:19][C@@H:15]3[CH2:14]2)[CH2:12][CH2:11]1
Reactant: Fc1ccc(I)c(F)c1
Reactant: C1O[C@@H](C2CC2)C[C@H]2CON=C12
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccc([C@]23CO[C@@H](C4CC4)C[C@H]2CON3)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boron trifluoride diethyl etherate (2.97 mL, 24.1 mmol) was added drop-wise to a solution of rel-(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C18) (1.67 g, 9.99 mmol) in toluene (150 mL) at an internal temperature of −72.5° C. The reaction mixture was stirred at −73° C. to −76° C. for 30 minutes, then treated with 2,4-difluoro-1-iodobenzene (98%, 1.37 mL, 11.2 mmol) in one portion. While the reaction temperature was maintained below −73° C., n-butyllithium (2.5 M in hexanes, 4.24 mL, 10.6 mmol) was added in a drop-wise manner over 15 minutes. The reaction mixture was stirred at −73° C. to −75° C. for 1 hour, then was quenched with saturated aqueous ammonium chloride solution (350 mL) at −74° C. and allowed to warm to room temperature. The resulting mixture was extracted with ethyl acetate (400 mL), and the aqueous layer was extracted with additional ethyl acetate (250 mL and 100 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 30% ethyl acetate in heptane) afforded the product as a white solid after azeotroping twice with dichloromethane. Yield: 2.16 g, 7.68 mmol, 77%. GCMS m/z 281 [M+]. 1H NMR (400 MHz, CDCl3) δ 7.88-7.98 (m, 1H), 6.84-6.93 (m, 1H), 6.79 (ddd, J=11.9, 8.6, 2.4 Hz, 1H), 6.34 (br s, 1H), 4.04 (br d, J=12.7 Hz, 1H), 3.83 (d, J=12.5 Hz, 1H), 3.72 (d, J=7.0 Hz, 1H), 3.54 (dd, J=6.8, 5.1 Hz, 1H), 2.99-3.08 (m, 1H), 2.86-2.95 (m, 1H), 1.99 (br dd, J=13.8, 6.8 Hz, 1H), 1.56-1.68 (m, 1H), 0.88-1.00 (m, 1H), 0.51-0.64 (m, 2H), 0.37-0.47 (m, 1H), 0.24-0.33 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[CH:23]=[N:24][NH:25][CH:26]=1>>[CH3:19][S@:11](=[O:18])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[N:10][C:8](=[O:9])[C:7]1[CH:20]=[C:3]([C:1]#[C:2][C:22]2[CH:23]=[N:24][NH:25][CH:26]=2)[CH:4]=[N:5][CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cn[nH]c2)c1)c1ccccc1

Procedure:
In a manner similar to that describe in Example 431 a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 4-iodopyrazole were reacted to give the title compound as a white film (15 mg, 17%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Br:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[C:1]([C:5]1[CH:10]=[C:9]([Br:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[O:15][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(Br)c([N+](=O)[O-])cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(Br)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a mixture of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) (1.1 g, 4 mmol) and Cs2CO3 (1.56 g, 4.8 mmol) in DMF (8 mL) was added benzyl bromide (500 μL, 4.2 mmol). The mixture was stirred at room temperature for 4 h, diluted with H2O and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After removal of solvent, the residue was purified by column chloromatography (0-5% EtOAc-Hexane) to yield 1-tert-butyl-2-(benzyloxy)-5-bromo-4-nitrobenzene (1.37 g, 94%). 1H NMR (400 MHz, CDCl3) 7.62 (s, 1H), 7.53 (s, 1H), 7.43 (m, 5H), 5.22 (s, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:26])[CH:12]=[CH:13][N:14]2[CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22].[Br:27]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:27][C:12]1[C:11](=[O:26])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[N:14]([CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH:13]=1
Reactant: CCCC(CCC)n1ccc(=O)c2c(-c3ccc(C)cc3C)cccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CCC)n1cc(Br)c(=O)c2c(-c3ccc(C)cc3C)cccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
5-(2,4-Dimethylphenyl)-1-(1-propylbutyl)quinolin-4(1H)-one, (0.21 g, 0.61 mmol), was dissolved in N,N-dimethylformamide (10 mL). The solution was cooled to 0° C. and N-bromosuccinimide (0.11 g, 0.62 mmol) was added. After 10 minutes, the solution was diluted with water, extracted with ethyl acetate, dried (Na2SO4), and concentrated. Flash chromatography (20% ethyl acetate/hexanes) gave 0.136 g (53% yield) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH2:10][CH:11]([CH3:16])[C:12]([CH3:15])([OH:14])[CH3:13]>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:10][CH:11]([CH3:16])[C:12]([CH3:15])([OH:14])[CH3:13])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CC(N)C(C)(C)O
Product: CC(NCc1cccc(Br)n1)C(C)(C)O

Procedure:
The title compound was prepared according to the procedure in Example 45, Step 1 using 6-bromopyridine-2-carbaldehyde (0.20 g, 1.08 mmol) and 3-amino-2-methylbutan-2-ol (0.11 g, 1.08 mmol) as the starting materials.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([OH:14])([CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15](Cl)([Cl:17])=[O:16]>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([O:14][C:15]([Cl:17])=[O:16])([CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cl
Reactant: CC1(O)CCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C)(OC(=O)Cl)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-hydroxy-3-methylpyrrolidine-carboxylic acid tert-butyl ester (200 mg, 1.00 mmol) in THF (4 mL) was slowly treated with phosgene 20% in toluene (0.954 mL). After stirring at rt for 16 h, solvents were removed under reduced pressure and co-evaporate with CH2Cl2. The crude 3-chlorocarbonyloxy-3-methylpyrrolidine-carboxylic acid tert-butyl ester was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=O)[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=[S:30])[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(Br)c3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)OC(=S)Nc2ccc(-c3cccc(Br)c3)cc21
Temperature: 110 °C
Yield: 122.9 %

Procedure:
A mixture of 6-(3-bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (3 g, 9.04 mmol) and Lawesson's Reagent (1.83 g, 4.51 mmol) in toluene (30 mL) was heated to 110° C. for 24 hours. The reaction was cooled, the toluene removed in vacuo and the residue purified via flash chromatography (silica gel, 20% ethyl acetate/hexane) to give 6-(3-bromophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione (1.93 g, 61%) as a yellow solid: mp 191-193° C.; 1H-NMR (DMSO-d6) (12.3 (s, 1H), 7.92 (s, 1H), 7.72-7.65 (m, 3H), 7.57-7.54 (m, 1H); 7.45-7.39 (m, 1H), 7.14-7.11 (m, 1H), 1.7 (s, 6H); MS (ES) m/z 347 ([M−H]−, 100%); Anal. Calcd. For C16H14BrNOS: C, 55.18; H, 4.05; N, 4.02 Found: C, 55.17; H, 3.93; N, 3.97.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.O.C(=O)(O)[O-].[Na+].[F:23][C:24]([F:35])([F:34])[C:25]([F:33])([F:32])[C:26]([F:31])([F:30])[C:27](O)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[CH:6][C:5]2[NH:15][C:27]([C:26]([F:30])([F:31])[C:25]([F:32])([F:33])[C:24]([F:35])([F:34])[F:23])=[N:16][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(-c2ccc(Cl)cc2)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)c1nc2cc(Cl)c(-c3ccc(Cl)cc3)cc2[nH]1
Yield: 62 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (50 g, 289.74 mmol) in AcOH (200 ml) was added NIS (63 g, 280.02 mmol) with stirring overnight at room temperature. Then the solids were collected by filtration and washed with water (50 ml). The solid was dried in an oven under reduced pressure to afford 5-chloro-4-iodo-2-nitroaniline as a yellow solid (70 g, 81%). Next, to a solution of 5-chloro-4-iodo-2-nitroaniline (15 g, 50.26 mmol) in dioxane (200 ml) and water (20 ml) was added (4-chlorophenyl)boronic acid (15.7 g, 100.40 mmol), K3PO4 (21.2 g, 99.87 mmol) and Pd(PPh3)4 (3 g, 2.60 mmol) with stirring for 6 h at 95° C. maintained with an inert atmosphere of nitrogen. Then the resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 5%˜10% ethyl acetate in petroleum ether to afford 5-chloro-4-(4-chlorophenyl)-2-nitroaniline as a yellow solid (9 g, 63%). To a solution of 5-chloro-4-(4-chlorophenyl)-2-nitroaniline (12 g, 42.39 mmol) in ethanol (150 ml) was added hydrogen chloride (conc, 10 ml) to this was followed by the addition of Zn powder (16.6 g, 253.34 mmol) in portions at room temperature. The resulting solution was stirred for 4 h at 85° C. Then the resulting mixture was concentrated under vacuum, dissolved in water (200 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layers was dried and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-chlorophenyl)benzene-1,2-diamine as an off-white solid (8.7 g, 81%). Finally, a solution of 4-chloro-5-(4-chlorophenyl)benzene-1,2-diamine (7 g, 27.65 mmol) in heptafluorobutanoic acid (70 ml) was stirred for 1.5 h at 120° C. Then the mixture was poured into water (200 ml), adjusted pH value of the solution to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×200 ml). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 5% ethyl acetate in petroleum ether to afford 5-chloro-6-(4-chlorophenyl)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as an off-white solid (7.3977 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[CH2:14]([NH2:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:14]([NH:22][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: O=C(NCCc1ccccc1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and phenethylamine. The product was purified by mass directed purification to give the title compound as an orange solid. δH (CD3OD): 2.94 (2H, t), 3.63 (2H, t), 7.00 (1H, s), 7.15–7.30 (5H, m), 7.64 (1H, s), 8.57 (1H, s); m/z (ES+)=300 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[Br:12][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1c(Br)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 107.4 %

Procedure:
A mixture of 4-chloro-2-nitrobenzenamine (5.1 g, 30 mmol) and N-bromosuccinimide (6.2 g, 36 mmol) in acetonitrile (50 mL) was heated at reflux for overnight. It was cooled to room temperature and diluted with ethyl acetate (50 mL). The mixture was washed with saturated aqueous K2CO3 solution (100 mL×2). The organic phase was separated, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 109a as a yellow solid (8.1 g, 100%). LCMS: [M+H]+ 253. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J=2.5 Hz, 1H), 7.71 (d, J=2.5 Hz, 1H), 6.64 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:15]2[S:24][C:23]3[C:22]4[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[CH:28][C:21]=4[O:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)[N:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[N:6]=1.Cl.[NH2:33][CH:34]1[CH2:37][O:36][CH2:35]1>>[O:36]1[CH2:37][CH:34]([NH:33][C:29]([C:27]2[CH:26]=[CH:25][C:22]3[C:23]4[S:24][C:15]([C:4]5[N:5]([C:7]6[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=6[F:14])[N:6]=[C:2]([NH2:1])[N:3]=5)=[CH:16][C:17]=4[CH2:18][CH2:19][O:20][C:21]=3[CH:28]=2)=[O:30])[CH2:35]1
Reactant: Nc1nc(-c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)n(-c2ccc(F)cc2F)n1
Reactant: NC1COC1
Agent: Cl
Product: Nc1nc(-c2cc3c(s2)-c2ccc(C(=O)NC4COC4)cc2OCC3)n(-c2ccc(F)cc2F)n1

Procedure:
Similarly to as described in General Procedure D, 2-[5-Amino-2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carboxylic acid was reacted with 3-aminooxetane hydrochloride to give 297 as a colorless solid after reverse phase HPLC (146 mg). LCMS: 496.1
Reaction SMILES: C(O[C:4]([CH2:6][NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=[O:5])C.C(O[C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:51]=[CH:50][C:49]([C:52](O)=O)=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=O)(C)(C)C>>[OH:5][CH2:4][CH2:6][N:7]([CH2:52][C:49]1[CH:48]=[CH:47][C:46]([CH:43]2[CH2:44][CH2:45][N:40]([CH3:38])[CH2:41][CH2:42]2)=[CH:51][CH:50]=1)[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: CCOC(=O)CNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(N(CCO)Cc2ccc(C3CCN(C)CC3)cc2)c1
Yield: 45.1 %

Procedure:
Synthesized from pivalic acid (R)-6-[2-(ethoxycarbonylmethylamino)-4-methoxyphenyl]-5,6,7,8-tetrahydronaphthalen-2-yl ester (35 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (73 mg) according to an analogous synthetic method to the above-mentioned Preparation Example 86 and Example 337,the title compound (18 mg) was obtained.
Reaction SMILES: C1(S(N=N[C:12]2[CH:13]=[C:14]([N:19]([CH3:23])[C:20](=[O:22])[CH3:21])[CH:15]=[C:16]([Br:18])[CH:17]=2)(=O)=O)C=CC=CC=1.[K].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1)([O-:27])=[O:26].O>CS(C)=O>[Br:18][C:16]1[CH:15]=[C:14]([N:19]([CH3:23])[C:20](=[O:22])[CH3:21])[CH:13]=[C:12]([S:34][C:31]2[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=2)[CH:17]=1
Reactant: CC(=O)N(C)c1cc(Br)cc(N=NS(=O)(=O)c2ccccc2)c1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [K]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)N(C)c1cc(Br)cc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 40 °C
Reaction time: 18 h
Yield: 103.5 %

Procedure:
0.22 g (0.00055 mol) of N-[3-[2-(phenylsulphonyl)-diazenyl]-5-bromophenyl]-N-methylacetamide was dissolved in 15 ml of dimethyl sulphoxide, treated with 0.185 g (0.000825 mol) of 4-nitrothiophenol potassium salt and stirred at 40° C. for 18 hrs. The reaction mixture was poured into 300 ml of water, extracted with diethyl ether, the organic phase was washed with water and sat. sodium chloride solution, dried over MgSO4, filtered and the filtrate was freed from solvent. The residue was chromatographed on silica gel with 1% MeOH in dichloromethane. There was obtained 0.217 g (100%) of N-[3-bromo-5-(4-nitrophenylsulphanyl)-phenyl]-N-methylacetamide as a yellow oil. MS (EI): me/e=382, 380 (C15H13BrN2O3S+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[S:6].Cl[CH:12]([CH3:16])[C:13](=O)[CH3:14]>CCO.CCOC(C)=O>[CH3:16][C:12]1[N:7]=[C:5]([C:4]2[CH:3]=[C:2]([NH2:1])[CH:10]=[CH:9][CH:8]=2)[S:6][C:13]=1[CH3:14]
Reactant: NC(=S)c1cccc(N)c1
Reactant: CC(=O)C(C)Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(N)c2)sc1C
Temperature: 100 °C

Procedure:
To a solution of 3-amino-thiobenzamide (200 mg, 1.31 mmol, 1 eq.) in EtOH (4 mL) is added 3-chloro-2-butanone (140 mg, 1.31 mmol, 1 eq.). The mixture is heated at 100° C. for 72 h. After cooling to room temperature, the reaction is diluted with EtOAc and sequentially washed with saturated aqueous NaHCO3, H2O and saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (2:1 hexanes/EtOAc) to give 3-(4,5-Dimethyl-thiazol-2-yl)-phenylamine as a yellow oil. [MS: (ES+) 205.1 (M+1)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: C1CCNC1
Product: COc1cccc2cc(C(=O)N3CCCC3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and pyrrolidine to give 2-Pyrrolidinylcarbonyl-7-methoxybenzofuran (Compound 309a). Successively, it was formylated to give 2-pyrrolidinylcarbonyl-4-formyl-7-methoxybenzofuran (Compound 309b), then compound 309b was reacted with methylamine hydrochloride to give compound 309 as a white solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)NC(=O)[C@@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1Cc2ccccc2CN1
Yield: 99.6 %

Procedure:
5.7 kg of benzyl 3(S)-(t-butylcarbamoyl)-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate were dissolved in 40 l of ethanol and hydrogenated in an autoclave in the presence of 1.1 kg of 10% palladium-charcoal at a pressure of 10 bar and an internal temperature of 20°-25°. After approximately 2 hours the hydrogen uptake ceased, whereupon the content of the autoclave was filtered, the autoclave and the filter residue were each rinsed twice with 20 l of ethanol each time and the combined filtrates were evaporated, whereby approximately 3.6 kg of crude N-t-butyl-1,2,3,4-tetrahydro-3(S)-isoquinoline-carboxamide were obtained as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:12]([C:14]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17])C>>[CH3:12][C:14]1[N:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[CH:19][C:15]=1[C:16]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)=[O:17]
Reactant: Nc1ccc2cccnc2c1
Reactant: CCc1nc(C(F)(F)F)ccc1C(=O)O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 45, the title compound was prepared from 7-aminoquinoline (D55) (30 mg, 21 mmol) and 2-ethyl -6-trifluoromethylnicotinic acid (51 mg, 0.25 mmol) as a yellow solid. MS(ES): MH+ 332, M-H+ 330
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([Cl:17])[CH:16]=[C:11]2[C:10]([CH2:18]N(C)C)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22]C(OCC)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([Cl:17])[CH:16]=[C:11]2[C:10]([CH2:18][Cl:22])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CN(C)Cc1cn(C(=O)OC(C)(C)C)c2ncc(Cl)cc12
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1cc(CCl)c2cc(Cl)cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
To 5-chloro-3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (141, 4.20 g, 13.6 mmol) in 100 mL of toluene, ethyl chloroformate (1.48 mL, 15.5 mmol) was added under nitrogen. The reaction was stirred at room temperature for 2 hours, then concentrated under vacuum and combined with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane to provide the desired compound (142, 1.60 g).