Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:15]([O-])=O)[N:6]=1)(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.CO.[Pd]>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:15])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c([N+](=O)[O-])cccc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)Nc1ccc2c(N)cccc2n1

Procedure:
400 mg (1.7 mmol) of 2-acetylamino-5-nitroquinoline and 105 mg of 10% Pd—C are stirred in 20 ml of ethyl acetate-MeOH (3:1) for 4 hours in a hydrogen atmosphere at room temperature. The batch is filtered, concentrated by evaporation and purified by column chromatography on silica gel with hexane-ethyl acetate: 210 mg of product.
Reaction SMILES: [CH2:1]([O:3][Si:4]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])/[CH:5]=[CH:6]/[Sn](CCCC)(CCCC)CCCC)[CH3:2].[NH2:26][C:27]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][CH3:41])[C:34]=2[F:42])[N:30]=[C:29]([C:43]([O:45][CH3:46])=[O:44])[C:28]=1I>CN(C)C=O.O>[NH2:26][C:27]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][CH3:41])[C:34]=2[F:42])[N:30]=[C:29]([C:43]([O:45][CH3:46])=[O:44])[C:28]=1/[CH:6]=[CH:5]/[Si:4]([O:3][CH2:1][CH3:2])([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25]
Reactant: CCCC[Sn](/C=C/[Si](OCC)(OCC)OCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1I
Solvent: O
Solvent: CN(C)C=O
Product: CCO[Si](/C=C/c1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC)(OCC)OCC
Temperature: 90 °C
Reaction time: 120 h
Yield: 5.4 %

Procedure:
Tetrakis triphenylphosphine palladium(0) (160 mg, 0.14 mmol, 0.10 equiv) and (E)-triethoxy(2-(tributylstannyl)vinyl)silane (990 mg, 2.1 mmol, 1.5 equiv) were sequentially added to a stirred solution of methyl 6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-iodopyrimidine-4-carboxylate (600 mg, 1.4 mmol, 1.0 equiv) in N,N-dimethylformamide (5.5 mL) at room temperature. The heterogeneous yellow mixture was heated at 90° C. and stirred for 5 d. The cooled reaction mixture was diluted with water (300 mL) and extracted with diethyl ether (3×100 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated under vacuum. The product was purified by acid free reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to provide the title compound as a yellow glass (38 mg, 6% yield): IR (thin film) 3315 (w), 3069 (w), 2974 (w), 1657 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.66 (dd, J=9, 8 Hz, 1H), 7.29 (d, J=18.5 Hz, 1H), 7.21 (dd, J=9, 2 Hz, 1H), 6.06 (d, J=18.5 Hz, 1H), 5.39 (br s, 2H), 3.98 (d, J=1 Hz, 3H), 3.92 (s, 3H), 3.89 (q, J=7 Hz, 6H), 1.26 (t, J=7 Hz, 9H); ESIMS m/z 500 [(M+H)+].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])(=[O:3])[CH3:2].[CH3:13][C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])=O.N1CCCC1>C1(C)C=CC=CC=1>[CH3:18][O:17][CH:16]([O:19][CH3:20])[C:14]1([CH3:13])[CH:2]2[O:3][CH:1]2[C:4]2[CH:5]=[C:6]([C:7]#[N:8])[CH:9]=[CH:10][C:11]=2[O:12]1
Reactant: COC(OC)C(C)=O
Reactant: CC(=O)c1cc(C#N)ccc1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: COC(OC)C1(C)Oc2ccc(C#N)cc2C2OC21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
In 100 ml of toluene were dissolved 8.06 g (50 mmole) of 3-acetyl-4-hydroxybenzonitrile and 7.68 g (65 mmole) of pyruvic aldehyde dimethyl acetal; and, then 1.67 ml (20 mmole) of pyrrolidine was added thereto at room temperature. 30 minutes thereafter, the reactants were heated to reflux for 8 hours using Dean-Stark apparatus; the solvent was removed under reduced pressure; and, 50 ml of 2N HCl solution was added thereto. The resultant solution was stirred for 30 minutes at room temperature, extracted with ethyl acetate (100 ml×2), washed with 50 ml of water and with 50 ml of saturated sodium chloride aqueous solution, and purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (4:1) as an eluent to obtain 11.19 g (yield 86%) of the title compound in the form of a white solid.
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:10](=[O:25])[N:9]([CH2:26][C:27]([OH:29])=[O:28])[N:8]=2)C[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:30]C1C=CC=CC=1C(C1C=CC=CN=1)=O.NC1C=CC=CC=1C(C1CCCCC1)=O>>[CH3:22][C:20]([CH3:21])([CH3:23])[C:19](=[O:24])[CH2:18][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][N:30]=2)=[N:8][N:9]([CH2:26][C:27]([OH:29])=[O:28])[C:10]1=[O:25]
Reactant: Nc1ccccc1C(=O)c1ccccn1
Reactant: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: Nc1ccccc1C(=O)C1CCCCC1
Product: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(c2ccccn2)c2ccccc21

Procedure:
[1-(3,3-Dimethyl-2-oxo-butyl)-2-oxo-5-pyridin-2-yl-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid was prepared using steps a-d of the method employed in the preparation of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d), except that (2-amino-phenyl)-pyridin-2-yl-methanone (G. Semple, et. al. Synth. Commun., (1996), 26, 721) was used in step a instead of (2-amino-phenyl)-cyclohexyl-methanone. 1H NMR (DMSO-d6) 12.50 (1H, br s), 8.57 (1H, m), 7.94 (2H, m), 7.50 (2H, m), 7.16 (3H, m), 4.78 (2H, s), 4.25 (2H, br s), 1.15 (9H, s).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[I:17].C(N(CC)CC)C.[N+:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([O-:27])=[O:26]>O1CCCC1>[N+:25]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([C:7]2[C:2]([I:1])=[C:3]([CH2:8][CH2:9][NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[I:17])[CH:4]=[CH:5][CH:6]=2)=[O:33])=[CH:35][CH:36]=1)([O-:27])=[O:26]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Ic1ccccc1CCNc1ccccc1I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1)c1cccc(CCNc2ccccc2I)c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of 0.90 g of 2-iodo-N-(2-iodophenyl)benzeneethanamine in 4 ml of tetrahydrofuran is added 0.41 g of triethylamine, and 0.57 g of 4-nitrobenzoyl chloride. The mixture is stirred at room temperature for 2 hours and the solvent removed under vacuum. The residue is dissolved in ethyl acetate-di-chloromethane (5:1) and the solution washed with 1N HCl, saturated NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is evaporated and the residual solid triturated with diethyl ether and hexane to give 1.10 g of product as a white solid.
Reaction SMILES: [CH:1]1([C:4](=[C:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][Si](C)(C)C)=[CH:17][C:12]=3[CH2:11][O:10][C:9]3[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:8]2=3)[C:5]#[N:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH:1]1([C:4](=[C:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[CH:19])=[CH:17][C:12]=3[CH2:11][O:10][C:9]3[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:8]2=3)[C:5]#[N:6])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)COc1cc(F)ccc1C2=C(C#N)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccc2c(c1)COc1cc(F)ccc1C2=C(C#N)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
[step 2] 2-Cyclopropyl-2-{3-fluoro-8-[(trimethylsilyl)ethynyl]dibenzo[b,e]oxepin-11(6H)-ylidene}acetonitrile (1.0 g, 2.6 mmol) obtained in step 1 was dissolved in methanol (10 mL), potassium carbonate (0.35 g, 2.6 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction was discontinued with water, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether and collected by filtration to give the title compound (600 mg, 74%, E/Z=1/1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([O:15][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate in dichloromethane (0.13 M) was added triethylamine (1.5 equiv.) followed by methanesulfonyl chloride (1.3 equiv.). The reaction was allowed to stir at room temperature for 15 h. The solution was then quenched with saturated NaHCO3, extracted with dichloromethane, dried with sodium sulfate, and concentrated to give the crude (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-(methylsulfonyl-oxy)piperidine-1-carboxylate in >95% yield. LCMS (m/z): 428.9/328.9 (MH+), Rt=3.81 min.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[CH3:9][O:10][C:11](=[O:21])[C@H:12]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:13].C(N(CC)CC)C>ClCCl>[CH3:9][O:10][C:11](=[O:21])[CH:12]([NH:13][C:5](=[O:6])[CH2:4][CH2:3][S:2][CH3:1])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CSCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccccc1)NC(=O)CCSC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
1.556 g (11 mmol) of 3-methylsulfanyl-propionyl chloride was added slowly to a mixture of 2.20 g (10 mmol) of phenylalanine methyl ester hydrochloride, 4.18 mL (30 mmol) of triethyl amine and 50 mL of dichloromethane and stirred at room temperature for 2 h. The reaction mixture was partitioned between DCM (50 mL) and saturated NaHCO3 solution (100 mL). The aqueous layer was separated and extracted again with dichloromethane (100 mL). The combined organic extracts were dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel gave 2.574 g (92%) of 2-(3-methylsulfanyl-propionylamino)-3-phenyl-propionic acid methyl ester. LCMS: 282 (M+1)+.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C@@H:10]([O:15][CH2:16][C:17]2[C:18]([NH2:32])=[N:19][C:20](=[O:31])[N:21]([CH:30]=2)[C@@H:22]2[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24]([OH:25])[CH2:23]2)[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:33]([O-:35])=[O:34])[CH:3]=1.[CH2:36]([N-:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[C:37]#[CH:38].CCN(CC)CC>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:9][O:8][C:7]1[C:2]([C:38]#[C:37][CH2:36][NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])=[CH:3][C:4]([N+:33]([O-:35])=[O:34])=[C:5]([C@@H:10]([O:15][CH2:16][C:17]2[C:18]([NH2:32])=[N:19][C:20](=[O:31])[N:21]([CH:30]=2)[C@@H:22]2[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24]([OH:25])[CH2:23]2)[C:11]([CH3:13])([CH3:14])[CH3:12])[CH:6]=1
Reactant: C#CC[N-]C(=O)C(F)(F)F
Reactant: COc1cc([C@@H](OCc2cn([C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)nc2N)C(C)(C)C)c([N+](=O)[O-])cc1I
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc([C@@H](OCc2cn([C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)nc2N)C(C)(C)C)c([N+](=O)[O-])cc1C#CCNC(=O)C(F)(F)F
Yield: 91.6 %

Procedure:
A solution of compound 66 (245 mg, 0.4 mmol), N-propargyltrifluoroacetylamide (603 mg, 4.0 mmol), tetrakis(triphenylphosphine)-palladium(0) (92 mg, 0.8 mmol), CuI (30 mg, 0.16 mmol), and Et3N (240 μL, 1.7 mmol) in anhydrous DMF (5.0 mL) was stirred at 50° C. for 12 hours. The mixture was concentrated in vacuo and purified by silica gel column chromatography to yield 5-{(S)-1-[5-methoxy-4-(3-trifluoroacetamido-1-propynyl)-2-nitrophenyl]-2,2-dimethyl-propyloxy}methyl-2′-deoxycytidine 67 (230 mg, 91%). 1H NMR (400 MHz, MeOD-d4): δ 7.98 (s, 1H, Ph-H), 7.92 (s, 1H, H-6), 7.19 (s, 1H, Ph-H), 6.15 (t, 1H, J=6.4 Hz, H-1′), 5.21 (s, 1H, Ph-CH), 4.41 (d, 1H, J=13.2 Hz, 5-CH2a), 4.33 (m, 3H, H-3′ and CH2), 4.27 (d, 1H, J=13.2 Hz, 5-CH2b), 3.96 (s, 3 H, OCH3), 3.88 (m, 1H, H-4′), 3.72 (m, 2H, H-5′), 2.30 (m, 1H, H-2′a), 2.12 (m, 1H, H-2′b), 0.84 (s, 9H, C(CH3)3).
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:14]([O:16][CH:17]([O:21][CH2:22]C)[CH2:18][C:19]#[N:20])C.C[O-].[Na+]>CO>[CH3:14][O:16][CH:17]([O:21][CH3:22])/[C:18](=[CH:4]/[C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[C:2]=1[CH3:1])/[C:19]#[N:20]
Reactant: Cc1c(C=O)cccc1C(F)(F)F
Reactant: CCOC(CC#N)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)/C(C#N)=C/c1cccc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-3-(trifluoromethyl)benzaldehyde (3.0 g, 16 mmol) and 3,3-bis(ethyloxy)propanenitrile (2.3 g, 20 mmol) in methanol (10 mL) was added a 25% sodium methoxide in methanol over 20 minutes. The mixture was stirred at room temperature overnight. Most of solvent was evaporated in vacuo and the residue was dissolved with ethyl acetate (30 mL) and water (15 mL). Two layers were separated. Organic layer was separated, washed with brine (15 mL), dried and solvent was evaporated in vacuo. The residue was then purified to give product. (3.66 g, 64%); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.40 (s, 3H) 2.94 (m, J=11.37 Hz, 1H) 3.08 (m, J=4.80 Hz, 1H) 3.20 (s, 1H) 3.43 (d, J=10.36 Hz, 1H) 3.42 (d, J=11.12 Hz, 6H) 3.45-3.52 (m, 1H) 4.60 (d, J=4.80 Hz, 1H) 7.39 (t, J=7.71 Hz, 1H) 7.59 (dd, J=17.18, 7.83 Hz, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:9]([Cl:10])=[C:8](Cl)[S:7][C:6]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2].C(N(CC)CC)C.[H][H]>[Pd].CO>[C:1]([NH:4][C:5]1[C:9]([Cl:10])=[CH:8][S:7][C:6]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)c1sc(Cl)c(Cl)c1NC(C)=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1scc(Cl)c1NC(C)=O

Procedure:
A mixture of 25 g of methyl 3-acetylamino-4,5-dichlorothiophene-2-carboxylate, about 10 g of triethylamine, 300 ml of methanol and 1 g of palladium on carbon is, at room temperature and under atmospheric pressure, hydrogenated until the uptake of hydrogen has stopped. The catalyst is filtered off and the mixture is then concentrated by distillation under reduced pressure until crystallization begins, water is then added and the solid is filtered off. Colorless crystals from isopropanol. M.p. 142-147° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH2:13]([Mg]Br)[CH2:14][CH3:15].ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1COCC1>[CH2:13]([C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:14][CH3:15]
Reactant: CCC[Mg]Br
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: C1CCOC1
Product: CCCc1c([N+](=O)[O-])ccc2nc[nH]c12
Temperature: -15 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a solution of 5-nitrobenzimidazole (2.3 g, 14 mmol) was added 14 ml of n-PrMgBr solution (42 mmol) and reaction mixture was stirred for 2 h at −15° C. The reaction was quenched by adding a solution of tetrachloro-1,4-benzoquinone (4 g, 16 mmol) in 10 ml of THF. The reaction mixture was concentrated in vacuo to provide an oil, which was subjected to column chromatographic separation (EtOAc, neat) to provide 1.4 g (7.2 mmol, 52%) of 4-n-propyl-5-nitrobenzimidazole, which was converted to the corresponding amine (1.2 g, >95%) by hydrogenation(H2, Pd/C).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14](Cl)=[O:15].[NH3:22].O>CCOCC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([NH2:22])=[O:15]
Reactant: N
Reactant: CC(OCc1ccc2ccccc2c1)(C(=O)Cl)C(F)(F)F
Solvent: CCOCC
Solvent: O
Product: CC(OCc1ccc2ccccc2c1)(C(N)=O)C(F)(F)F

Procedure:
A solution of (±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chloride (1.3 g.) in ether (10 ml.) is added to a mixture of ammonia (d, 0.90; 10 ml.) and water (100 ml.). The mixture is shaken, and the ether is evaporated. The solid is filtered off and crystallised from light petroleum (b.p. 100°-120° C.) to give (±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionamide (0.76 g.) m.p. 111°-112° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH2:13]([N:20]1[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>CO.O>[CH2:13]([N:20]1[CH2:24][CH2:23][C@H:22]([NH:25][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1ccc(CN2CC[C@H](NCc3ccc4ccccc4c3)C2)cc1
Reaction time: 18 h

Procedure:
A solution of 2-naphthaldehyde (2.0 g, 12.8 mmol) and (3S)-1-benzyl-3-amino-pyrrolidine (2.37 g, 13.4 mmol) in methanol (30 mL) was stirred under nitrogen at room temperature for 6 hours. Sodium borohydride (969 mg, 25.6 mmol) was added and the reaction mixture left at room temperature for 18 hours. The reaction mixture was diluted with water and extracted into ethyl acetate (×3) and the organics were combined, dried over magnesium sulphate, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with dichloromethane:methanol 100:0 to 97:3 to yield the title product, 4.01 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])=[O:4].[C:14]([CH:16]1[CH2:18][CH2:17]1)#[CH:15].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]#[C:14][CH:16]2[CH2:18][CH2:17]2)=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1[N+](=O)[O-]
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC2CC2)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Firstly bis(triphenylphosphine)palladium(II) chloride (17.6 mg) and then copper(I) iodide (19 mg) were added to a mixture of 5-bromo-3-nitrothiophene-2-carboxylic acid methyl ester (133 mg), ethynylcyclopropane (66 mg), triethylamine (51 mg), triphenylphosphine (3.3 mg) and THF (14 mL). After one hour, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC. The product with the molecular weight of 251.26 (C11H9NO4S) was obtained in this way; MS (ESI): 252 (M+H+).
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:30])[C:5]1[CH:6]=[C:7]([N:11]2[C:16]3[CH2:17][CH2:18][C:19](=[O:20])[C:15]=3[CH:14]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[NH:13][C:12]2=[O:29])[CH:8]=[CH:9][CH:10]=1.[CH3:31]I.O>O1CCCC1>[F:30][CH:4]([F:3])[C:5]1[CH:6]=[C:7]([N:11]2[C:16]3[CH2:17][CH2:18][C:19](=[O:20])[C:15]=3[CH:14]([C:21]3[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=3)[N:13]([CH3:31])[C:12]2=[O:29])[CH:8]=[CH:9][CH:10]=1
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)F)c3)C3=C2C(=O)CC3)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)N(c2cccc(C(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
Sodium hydride (60% in mineral oil, 13 mg, 0.32 mmol) is added to a solution of 4-(1-(3-(difluoromethyl)phenyl)-2,5-dioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)benzonitrile (example 11, 100 mg, 0.26 mmol) in tetrahydrofuran. After 20 min methyl iodide (22 μL, 0.35 mmol) is added and the mixture is stirred at room temperature over night. Water is added and the mixture is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 55 mg; ESI mass spectrum [M+H]+=394; Retention time HPLC: 0.74 min (005_CA01).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[C:33]([NH:38][S:39](Cl)(=[O:41])=[O:40])(=[O:37])[CH2:34][CH2:35][CH3:36].C(N(CC)CC)C>ClCCl>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:39]([NH:38][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])(=[O:41])=[O:40])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CCCC(=O)NS(=O)(=O)Cl
Reactant: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CCC(C)C)C1=O)N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.7 %

Procedure:
A mixture of the product of Example 34B (52.2 mg, 0.110 mmol) and the product of Example 99A (102 mg, 0.55 mmol) in dichloromethane (5 mL) was treated with triethylamine (66.5 mg, 0.658 mmol). The mixture was stirred at r.t. for 15 minutes. The reaction mixture was partitioned between dichloromethane and 1N hydrochloric acid, and the aqueous phase extracted with additional dichloromethane. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by HPLC to give the title compound (38 mg, 59%). 1H NMR (300 MHz, DMSO-d6) δ 0.41 m, 1 H) 0.69 (m, 8 H) 0.79 m, 1 H) 1.37 m, 4 H) 1.56 (s, 3 H) 2.04 m, 1 H) 2.11 (t, J=7.35 Hz, 2 H) 2.22 m, 1 H) 7.48 (dd, J=8.82, 2.21 Hz, 1 H) 7.53 m, 1 H) 7.59 (d, J=2.21 Hz, 1 H) 7.71 (d, J=8.82 Hz, 1H) 7.76 (d, J=4.04 Hz, 2 H) 8.15 (d, J=7.72 Hz, 1 H) 10.95 (s, 1 H) 11.99 (s, 1H) 13.81 (s, 1H). MS (ESI+) m/z 589.1 (M+H)+, 606.1 (M+NH4)+, (ESI−) 587.2 (M−H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc(Cl)c(F)c(Br)c1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(C(C)=O)cc(Cl)c(F)c1Br
Temperature: 60 °C
Yield: 39 %

Procedure:
A mixture of 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (5.3 g, 20 mmol), potassium carbonate (7.2 g, 52 mmol) and methyl iodide (2.7 mL, 44 mmol) in N,N-dimethylformamide (20 mL) was heated at 60° C. for 1 hour. The mixture was filtered and washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 20% ethyl acetate in hexane, to yield the desired product (39% yield). LCMS calculated for C9H8BrClFO2 (M+H)+: m/z=280.9, 282.9. found: 280.8, 282.8.