Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1CCO[CH:3]1[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][C:11](=[O:23])[N:12]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:17]1([N:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([CH:3]=[O:2])[C:8]=3[CH2:9][CH2:10][C:11]2=[O:23])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCc2c(C3OCCO3)cccc2N1c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1cccc2c1CCC(=O)N2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
2N Hydrochloric acid (5 ml) was added to a solution of 5-(1,3-dioxolan-2-yl)-1-phenyl-3,4-dihydro-1H-quinolin-2-one (2.60 g) in THF (30 ml), followed by stirring at room temperature overnight. After distilling off THF under reduced pressure, ethyl acetate-water was added, and the resulting mixture was washed (twice with water and once with a saturated sodium chloride solution), dried (MgSO4), and concentrated under reduced pressure. The obtained solid was recrystallized from chloroform-diethyl ether to thereby obtain 1.93 g (yield: 87%) of 1-phenyl-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a beige powder.
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:17]#[N:18])=[O:13])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH2:31][CH2:32][CH3:33]>CN(C=O)C>[CH2:30]([N:6]1[C:5]([C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=2)[C:17]#[N:18])=[O:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[NH:8][C:7]1=[O:11])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCI
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Temperature: 55 °C
Reaction time: 24 h
Yield: 50.4 %

Procedure:
To a stirred mixture of 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (Compound 1) (2.97 g, 10 mmol) and powdered anhydrous potassium carbonate (1.66 g, 12 mmol) in DMF (20 mL), was added iodobutane (1.37 mL, 12 mmol). The mixture was then stirred in an oil bath (50-60° C.) for 24 hr. and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to afford 1.78 g (50%) of 3-(3-butyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (47) as a white foam. 1H-NMR (200 MHz, CDCl3) δ 0.80 (3H, d, J=3.2 Hz), 0.83 (3H, d, J=3.2 Hz), 1.12 (3H, d, J=7.0 Hz), 1.23 (3H, d), J=7.0 Hz), 1.90 (1H, m), 2.25 (1H, m), 2.53 (3H, s), 2.93 (1H, dd, J=14.2 Hz, J=7.4 Hz), 3.75 (1H, dd, J=14.2 Hz, J=7.4 Hz), 7.80 (1H, s), 7.92 (1H, s), 8.03 (1H, s), 9.03 (1H, s); m/z (EI) 353 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[CH3:18][S:19][CH2:20][CH2:21][OH:22].CNCCNC.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:5]2[N:4]=[CH:3][C:2]([O:22][CH2:21][CH2:20][S:19][CH3:18])=[CH:7][N:6]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(CNc2ncc(Br)cn2)cc1
Reactant: CSCCO
Agent: CNCCNC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2ncc(OCCSC)cn2)cc1
Temperature: 110 °C
Reaction time: 66 h
Yield: 55.3 %

Procedure:
5-Bromo-N-(4-methoxybenzyl)pyrimidin-2-amine (300 mg, 1.02 mmol) was suspended in toluene (20 mL), the suspension was added with cuprous iodide (200 mg, 1.05 mmol), 2-methylthioethanol (1.06 g, 11.5 mmol), N,N′-dimethylethylenediamine (0.83 g, 9.42 mmol) and cesium carbonate (400 mg, 1.22 mmol), and the mixture was stirred at 110° C. for 66 hours in an argon atmosphere. The reaction mixture was separated by silica gel column chromatography (ethyl acetate), and then purified by preparative silica gel thin layer chromatography (hexane:ethyl acetate=1:1) to obtain N-(4-methoxybenzyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (172.4 mg) as colorless amorphous solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]#[N:11])[CH:3]=[CH:2]1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].C1COCC1>ClCCCl.C(Cl)Cl>[C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[C:3]2[CH2:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])#[N:11]
Reactant: C=CC(=O)OCC
Reactant: N#Cc1cccc2cc[nH]c12
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)CCc1c[nH]c2c(C#N)cccc12
Temperature: 120 °C

Procedure:
A mixture of 1H-indole-7-carbonitrile (D2) (3.0 g), FeCl3 (3.4 g) and ethyl acrylate (7.5 mL) in DCE (3 mL) was added into 4 tubes respectively. In the fifth tube was added a mixture of 1H-indole-7-carbonitrile (2.0 g), FeCl3 (2.3 g) and ethyl acrylate (5 mL) in DCE (2 mL). The tubes were sealed and heated at 120° C. for 2 hours. After cooling to room temperature, the combined mixture was diluted with DCM and a little amount of THF. The solid was filtered off through celite. The mixture was washed with 0.5 M HCl solution three times and then brine. The organic solution was dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash chromatography to give Ethyl 3-(7-cyano-1H-indol-3-yl)propanoate (13.4 g). δH (CDCl3, 400 MHz): 1.23 (3H, t), 2.70 (2H, t), 3.10 (2H, t), 4.13 (2H, q), 7.16 (2H, m), 7.51 (1H, dd), 7.83 (1H, d), 8.88 (1H, br s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:18]=1)[C:12]([O:14]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[N:18]=[CH:17][C:16]2[CH2:19][CH:20]([C:21]([O:23][CH3:24])=[O:22])[C:12](=[O:14])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1cnc(OCc2ccccc2)cc1C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1Cc2cnc(OCc3ccccc3)cc2C1=O
Reaction time: 0.5 h

Procedure:
To 75 mL dry THF was added methyl 2-(benzyloxy)-5-(3-methoxy-3-oxopropyl)isonicotinate (2.50 g, 7.59 mmol). The temperature of the solution was lowered to −78° C. To this solution was added 1N sodium bis(trimethylsilyl)amide (15.2 mL, 15.2 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) dropwise over 30 minutes. After completion, the reaction was stirred for an hour and then quenched by addition of 25 mL saturated NH4Cl. The organic layer was extracted with EtOAc and washed with 150 mL water and 100 mL brine, and then dried over MgSO4. The organic solvent was evaporated, and the residue was purified by column chromatography with 15% EtOAc/hexane to give desired product H6.4 (1.90 g, 84.1%). MS ESI (pos.) m/e: 298.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]([O:42][CH3:43])=[O:41])=[N:38][CH:39]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:43][O:42][C:40]([C:37]1[CH:36]=[CH:35][C:34]([CH2:33][NH:32][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[CH:39][N:38]=1)=[O:41]
Reactant: COC(=O)c1ccc(CN)cn1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cn1
Yield: 39.3 %

Procedure:
In a manner similar to the method described in Example 379, a mixture of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (59.2 mg, 0.127 mmol) and methyl 5-(aminomethyl)picolinate (64.4 mg, 0.388 mmol) in N,N-dimethyl formamide (5 mL) were treated with DIPEA (119 mg, 0.916 mmol), HOBt (34.2 mg, 0.253 mmol) and HBTU (96.1 mg, 0.253 mmol) at room temperature to give 5-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-pyridine-2-carboxylic acid methyl ester (30.7 mg, 39%). HRMS (ES+) m/z Calcd C31H30Cl2F2N4O3+H [(M+H): 615.1736. Found: 615.1731.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:7])[CH3:6].[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>C1COCC1>[CH3:3][N:4]([CH2:13][C:12]1[CH:15]=[CH:16][C:9]([F:8])=[CH:10][CH:11]=1)[C:5](=[O:7])[CH3:6]
Reactant: CNC(C)=O
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
To a solution of NaH (6.86 g, 0.172 mole, 60% in mineral oil, 1.3 equiv) in THF (250 mL), add dropwise a solution of N-methylacetamide (11.6 g, 0.159 mole, 1.2 equiv) in THF (90 mL). After about 20 min, add 4-fluorobenzylbromide (25 g, 0.132 mole). Stir for about 62 hours then pour over ice water (300 mL) and extract with ethyl acetate (400 mL and 200 mL). Combine the organic layers and wash with water (300 mL), dry over Na2SO4, filter and concentrate to an oil. Dissolve the oil in acetonitrile and extract with hexane to remove the mineral oil to give 22.79 g N-methyl-N-(4-fluorobenzyl)acetamide: mp=48-54° C.; Rf=0.45 (4% MeOH/methylene chloride); 1H NMR (CDCl3) 7.27-6.93 (m, 4), 4.5 (d, 2), 2.91 (s, 3), 2.14 (s, 3).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>>[F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:18])=[O:6]
Reactant: Cc1ccc(C(=O)O)c(O)c1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c(F)c1O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of 3-fluoro-2-hydroxy-4-methylbenzoic acid (10.5 g) in methanol (50.0 mL) was added sulfuric acid (5.00 mL) at room temperature, and the mixture was stirred at 60° C. for 24 hr. The solvent was evaporated under reduced pressure, to the residue were added water and ethyl acetate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.40 g).
Reaction SMILES: [OH:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4](=[O:13])[C:3]=1[CH:14]=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CCOCC>[C:17]1([NH:16][CH:14]=[C:3]2[C:2](=[O:1])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][CH2:5][C:4]2=[O:13])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: O=CC1=C(O)c2ccccc2OCC1=O
Agent: Cl
Solvent: CCOCC
Product: O=C1COc2ccccc2C(=O)C1=CNc1ccccc1
Reaction time: 0.08 h
Yield: 58 %

Procedure:
A quantity of 10.0g (0.049 mole) of 2,3-dihydro-5-hydroxy-3-oxo-1-benzoxepin-4-carboxaldehyde was added to 15g of aniline. The temperatuure rose to 45° as most solid went into solution. The dark mixture was heated at 105°-110° for 10 minutes and cooled. Ether (500ml) and 300ml of cold 2N hydrochloric acid were added, and the mixture was stirred for 5 minutes. The entire mixture was filtered to remove the dark, suspended insolubles. The ether phase of the filtrate was washed well with water, dried (Na2SO4) and concentrated to give 8.0g (58%) of crude product; m.p. 94°-96°. Recrystallization from ethyl acetate gave pure, orange-tan crystals; m.p. 98°-100°.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[CH2:27][CH2:26][C@H:25]3[C@@H:20]([CH2:21][CH2:22][CH2:23][NH:24]3)[C:19]=2[CH:28]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:24]3[C@@H:25]4[C@H:20]([C:19]5[CH:28]=[C:15]([O:14][CH3:13])[CH:16]=[CH:17][C:18]=5[CH2:27][CH2:26]4)[CH2:21][CH2:22][CH2:23]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: COc1ccc2c(c1)[C@@H]1CCCN[C@H]1CC2
Product: COc1ccc2c(c1)[C@@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 77 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-9-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 77% of theory; LC (method 1): tR=2.61 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([F:14])=[CH:6][C:5]=1[CH2:15]Br.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:14][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([C:10]([F:11])([F:12])[F:13])[CH:8]=1)[C:3](=[O:17])[N:25]([CH2:24][C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=1)[CH2:15]2
Reactant: COC(=O)c1c(CBr)cc(F)cc1C(F)(F)F
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(cc(F)cc2C(F)(F)F)CN1Cc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 323.1 %

Procedure:
A mixture of 4-fluoro-2-bromomethyl-6-trifluoromethyl-benzoic acid methyl ester (0.100 g, 0.32 mmol), 4-trifluoromethyl-benzylamine (0.06 mL, 0.42 mmol), and K2CO3 (0.088 g, 0.64 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-2-(4-trifluoromethyl-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.39 g, 33%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.34 (s, 2H), 4.84 (s, 2H) 7.20-7.50 (m, 6H). GC-MS: m/z 377 (M)+, 356 (M−21)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C:5]([F:31])([F:30])[C@:6]([C:9]2[C:25]([F:26])=[CH:24][C:12]([O:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=3)=O)=[C:11]([N+:27]([O-])=O)[CH:10]=2)([CH3:8])[N:7]=1>[Ni].CO>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH:15]2[NH:27][C:11]3[CH:10]=[C:9]([C@:6]4([CH3:8])[C:5]([F:31])([F:30])[CH2:4][O:3][C:2]([NH2:1])=[N:7]4)[C:25]([F:26])=[CH:24][C:12]=3[O:13][CH2:14]2)=[N:18][CH:19]=1
Reactant: C[C@]1(c2cc([N+](=O)[O-])c(OCC(=O)c3ccc(Cl)cn3)cc2F)N=C(N)OCC1(F)F
Agent: [Ni]
Solvent: CO
Product: C[C@]1(c2cc3c(cc2F)OCC(c2ccc(Cl)cn2)N3)N=C(N)OCC1(F)F

Procedure:
A dispersion of 2-[4-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-2-nitro-phenoxy]-1-(5-chloro-pyridin-2-yl)-ethanone (160 mg, 349 μmol) and Raney Nickel (30 mg) in methanol (22 ml) was hydrogenated. For the workup, the reaction mixture was filtered through glass fiber paper and the solution was evaporated at reduced pressure. The crude product was purified by flash chromatography on a silica-NH2 phase using a gradient of heptane/ethyl acetate=100:0 to 0 to 100 as the eluent. The (R)-4-[(RS)-3-(5-chloro-pyridin-2-yl)-7-fluoro-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine was obtained as a red solid. MS (ISP): m/z=413.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Br:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[C-:14]#[N:15].[K+]>O>[Br:13][C:11]1[CH:12]=[C:3]([CH2:2][C:14]#[N:15])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: BrCc1cc(Br)c2ncccc2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CCc1cc(Br)c2ncccc2c1
Temperature: 100 °C

Procedure:
DMP (10 mL) and H2O (5 mL) were added to 6-bromomethyl-8-bromoquinoline (3 g) (described in International Patent Publication WO 94/22852) and potassium cyanide (1.6 g). After heating at 100° C. for 1 hour, the resulting mixture was quenched with H2O (100 mL) and extracted with EtOAc. The combined organic extracts were washed with water (3×), brine, dried over MgSO4, filtered and concentrated. Flash chromatography (hexane:EtOAc, 3:1) yielded the (8-Bromo-quinolin-6-yl)-acetonitrile compound as a white solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([NH2:20])=[C:18]([C:21](=[O:24])[CH2:22]Cl)[N:17]=[CH:16]2)[C@@H:6]1[Cl:25])(=[O:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([NH2:20])=[C:18]([C:21](=[O:24])[CH2:22][N:26]=[N+:27]=[N-:28])[N:17]=[CH:16]2)[C@@H:6]1[Cl:25])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N)[C@H](Cl)[C@@H]1OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CN=[N+]=[N-])c2N)[C@H](Cl)[C@@H]1OC(C)=O
Yield: 92 %

Procedure:
Compound (39) obtained in step (5) above (170 mg) was dissolved in N,N-dimethylformamide (3.4 ml), to which was added sodium azide (45 mg). The resultant mixture was stirred at room temperature for 1 hour to conduct the reaction intended. The reaction solution obtained was concentrated and the residue was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to leave a yellow syrup. The syrup was purified by silica gel column chromatography (developer solvent: toluene-ethyl acetate, 1:2) to afford the titled compound (40) as a colorless solid (159 mg). Yield: 92%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH2:9][C:10]2[CH:15]=[N:14][C:13]([CH3:16])=[CH:12][N:11]=2)[C:4](=[O:17])[CH:3]=1.C1C(=O)N([Cl:25])C(=O)C1>C(O)(=O)C>[Cl:25][C:3]1[C:4](=[O:17])[N:5]([CH2:9][C:10]2[CH:15]=[N:14][C:13]([CH3:16])=[CH:12][N:11]=2)[C:6]([CH3:8])=[CH:7][C:2]=1[OH:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cnc(Cn2c(C)cc(O)cc2=O)cn1
Solvent: CC(=O)O
Product: Cc1cnc(Cn2c(C)cc(O)c(Cl)c2=O)cn1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of 4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-one (1.00 g, 4.3 mmol) in glacial acetic acid (10 mL) was added NCS (0.79 g, 5.94 mmol). The reaction mixture stirred at 60° C. for 6 hours. The solvent was removed under reduced pressure and the resulting residue was triturated with ethyl acetate. The desired product was filtered and dried (0.80 g, 69%). 1H NMR (CD3OD, 400 MHz) δ 8.47 (s, 1H), 8.42 (s, 1H), 6.08 (s, 1H), 5.36 (s, 2H), 2.50 (s, 3H), 2.43 (s, 3H); ES-HRMS m/z 266.0691 (M+H calculated for C12H13N3O2Cl requires 266.0691).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[N:12]=[C:11]([CH3:13])[C:10]([NH2:14])=[CH:9][C:8]=2[C:15]#[C:16][Si](C)(C)C)=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24].BrC1C(O)=NC(C)=CC=1>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[N:12]=[C:11]([CH3:13])[C:10]([NH2:14])=[CH:9][C:8]=2[C:15]#[CH:16])=[CH:4][C:3]=1[C:23]([F:26])([F:24])[F:25]
Reactant: Cc1nc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(C#C[Si](C)(C)C)cc1N
Agent: Cc1ccc(Br)c(O)n1
Product: C#Cc1cc(N)c(C)nc1Oc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
In a 50 ml single-necked round-bottomed flask equipped with a condensor, 35 mg of 2-(4-chloro-3-trifluoromethyl-phenoxy)-6-methyl-5-nitro-3-trimethylsilanylethynyl-pyridine is stirred in 0.50 ml of methanol. Under cooling with an ice/water bath, 0.50 ml of concentrated aqueous HCl is added dropwise by syringe (some precipitation is observed). The ice bath is removed and 77 mg of anhydrous SnCl2 is added in portions. Stirring is continued under heating to reflux for 2 h. After cooling the mixture to ambient temperature, it is concentrated in vacuo to give a brown solid. After adding AcOEt, 5 ml of 4 M aqueous NaOH solution is added (pH 12). Following extraction, the AcOEt phase is dried over Na2SO4, filtered and the solvent removed in vacuo to give 30 mg a brown oil. Purification was done by flash chromatography [silica gel cartridge (5 g, 20 ml) with heptane/ethyl acetate 3:1 (v:v)] to give 7 mg of a 1. fraction (6-(4-chloro-3-trifluoromethyl-phenoxy)-2-methyl-5-trimethylsilanylethynyl-pyridin-3-ylamine) and 15 mg of a 2. fraction of the compound as a brown solid. RP HPLC: Retention time of compound: 1.87 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[H-].[Na+].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CN(C)C=O.O>[CH3:13][S:14]([N:6]([C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2])[S:14]([CH3:13])(=[O:16])=[O:15])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N(c1ccccc1[N+](=O)[O-])S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a cooled (0° C.) solution of 2-nitroaniline (1 g, 7.25 mmol) in dimethylformamide (DMF, 10 mL) was added sodium hydride (608 mg, 25 mmol). After addition was complete methanesulfonyl chloride (1.69 mL, 21.8 mmol) was added and the reaction was warmed to room temperature and stirred for 1 hour. The reaction was then diluted with water and the product extracted with ethyl acetate. The organic layer was concentrated and purified by chromatography to provide N-(methylsulfonyl)-N-(2-nitrophenyl)methanesulfonamide (1.5 g, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.89 (m, 1H), 7.80 (m, 2H), 3.58 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][CH:10]=[O:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[S:22](Cl)(=[O:24])=[O:23].[Cl-].[Na+]>CN(C)C(=O)C.C(#N)C.N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[S:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][CH:10]=[O:11])=[CH:6][CH:7]=1)(=[O:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(NNC=O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: O=CNNc1ccc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2Cl)cc1
Temperature: -5 °C
Yield: 483.4 %

Procedure:
In 90 ml of N,N-dimethylacetamide, 76 ml of acetonitrile, and 19 ml of pyridine were dissolved 35.4 g of 2-(4-aminophenyl)-1-formylhydrazine in a nitrogen gas atmosphere and after cooling the solution to -5° C., 59:9 g of 2-chloro-5-nitrobenzenesulfonyl chloride was gradually added thereto while cooling with stirring so that the liquid temperature was not over -5° C. After further stirring the mixture for 1.5 hours at a temperature below -5° C., the temperature thereof was raised to room temperature and the reaction mixture was poured into 1 liter of a saturated aqueous sodium chloride solution. Crystals formed were collected by filtration and washed with water to provide 63 g of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-methyl-amino)-4-methyl-phenyl]-carbamic acid tert-butyl ester (Example J38) (307 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (330 mg, 52%).