Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][C:5](=[O:11])[CH2:6][C:7](=[O:10])[CH2:8][CH3:9].[CH2:12]([O:14][C:15](=[O:18])[CH2:16]Br)[CH3:13].[Cl-].[NH4+]>O1CCCC1>[CH2:12]([O:14][C:15](=[O:18])[CH2:16][CH:6]([C:5](=[O:11])[CH2:4][CH3:3])[C:7](=[O:10])[CH2:8][CH3:9])[CH3:13]
Reactant: CCOC(=O)CBr
Reactant: CCC(=O)CC(=O)CC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C(=O)CC)C(=O)CC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
To a suspension of sodium hydride (5.2 g, 130 mmol, 60% in mineral oil) in tetrahydrofuran (100 mL) at 0° C. was added dropwise a solution of heptane-3,5-dione (16.6 g, 130 mmol) in tetrahydrofuran (30 mL). After 15 minutes, bromo-acetic acid ethyl ester (14.4 mL, 130 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was poured into an aqueous ammonium chloride solution and extracted several times with ethyl acetate. The combined ethyl acetate layers were washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-30% ethyl acetate in heptane) to obtain 4-oxo-3-propionyl-hexanoic acid ethyl ester (19 g, 68%) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[BrH:13].OO.OS([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(C)c1N
Reactant: Br
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: OO
Solvent: O
Product: COC(=O)c1cc(Br)cc(C)c1N

Procedure:
A solution of methyl 2-amino-3-methylbenzoate (142.1 g, 0.843 mol, purity: 98% quantitative NMR) in 240 mL of H2O is gradually admixed at 30° C. with hydrogen bromide (48% of H2O, 149.2 g, 0.885 mol) added dropwise. The suspension obtained is admixed with hydrogen peroxide (30% in H2O, 105.1 g, 0.927 mol) added dropwise over 2 h, and the temperature is kept below 70° C. After 1 hour of subsequent stirring, NaHSO3 (39% in H2O, 33.7 g, 0.126 mol) is added a little at a time (peroxide test was negative). The suspension obtained is adjusted to pH7-8 with Na2CO3 (0.1 eq., 9.0 g, 0.084 mol), which is added a little at a time. Following filtration and drying in a vacuum drying cabinet, methyl 2-amino-5-bromo-3-methylbenzoate is isolated as a pale brown solid. Yield: 204.2 g, 97.7% of theory, purity: 98.5% quantitative NMR).
Reaction SMILES: [CH:1]([N:3](C)[CH:4]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][CH3:13])=O.[ClH:21]>C(OCC)C.CO>[ClH:21].[ClH:21].[CH3:1][NH:3][CH:4]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][CH3:13]
Reactant: CNc1ccccc1CC(c1sccc1C)N(C)C=O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CNc1ccccc1CC(NC)c1sccc1C

Procedure:
N-Formyl-N-methyl-2-methylamino-α-(3-methyl-2-thienyl)benzenethanamine (4.1 g) was treated with 18 ml of 3N hydrochloric acid. After refluxing for 1.5 hours the solution was decanted over ice, basified with 12 ml of a 50% aqueous sodium hydroxide solution and extracted with dichloromethane (3×60 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to an oil. Purification of the oil was accomplished by HPLC (Water's Associates Prep LC/System 500, silica gel, elution with methanol). Concentration of the appropriate fractions afforded a residue which was dissolved in diethyl ether, filtered free of insolubles, and concentrated to afford N-methyl-2-methylamino-α-(3-methyl-2-thienyl)benzeneeethanamine as an oil. The oil was dissolved in methanol and treated with ethereal hydrogen chloride. Dilution with diethyl ether precipitated 2.4 g of the corresponding dihydrochoride salt, mp 191°-192° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH3:23])[CH:16]=3)[CH2:13][O:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.[NH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C1(C)C=CC=CC=1>[F:8][C:6]1[CH:5]=[C:4]([C:9]2([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH3:23])[CH:16]=3)[CH2:13][O:12][C:11]([NH2:14])=[N:10]2)[CH:3]=[C:2]([NH:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:7]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(C2(c3cc(F)cc(Br)c3)COC(N)=N2)cc1C
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1ccc(C2(c3cc(F)cc(Nc4ccccc4)c3)COC(N)=N2)cc1C
Temperature: 105 °C
Yield: 41.7 %

Procedure:
A dried pressure tube was charged consecutively with (RS)-4-(3-bromo-5-fluoro-phenyl)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (Building Block AH, 100 mg, 0.3 mmol), toluene (1.5 mL), sodium tert-butylate (52 mg, 0.5 mmol), and tert-butyl x-phos [di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine] (12 mg, 0.03 mmol). The mixture was purged with argon before [tris(dibenzylidenacetone)dipalladium chloroform complex] (8 mg, 0.008 mmol) and aniline (49 mg, 0.5 mmol) were added. The sealed tube was heated at 105° C. for 15 hours. For the working-up, the reaction mixture was cooled and evaporated under reduced pressure. The residue was directly chromatographed on an Isolute Flash NH2 column using a gradient of heptane/ethyl acetate=100/0 to 100/0 as the eluent. There were obtained 49 mg (47% of theory) of (RS)-4-(3-fluoro-5-phenylamino-phenyl)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine as a white foam; Mass (calculated) C23H22FN3O2 [391]; (found) [M+H]+=392.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C1COCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(Cc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
The ethyl 1-benzylpyrazole-4-carboxylate (5 g, 21.7 mmol) prepared in Example 9 was dissolved in THF (40 ml) and cooled to 0 degrees under inert atmosphere. Lithium Aluminum Hydride (1M in THF, 21.7 ml) was added dropwise. After complete addition, the solution was allowed to warm to room temperature and stirred for 2 hours. Saturated ammonium chloride solution was added slowly until gas evolution ceased. All solvent was removed in vacuo. To the residue was added 100 ml water and 250 ml ethyl acetate and placed in a separatory funnel. The organic layer was washed with water and concentrated to yield [1-benzylpyrazol-4-yl]methan-1-ol (3.8 g, HNMR)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:21])=[CH:13][N:12]=[C:11]([C:22]([NH2:24])=[O:23])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.CO>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:6]2[C:5]3[C:9](=[CH:10][C:2]([NH:1][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[CH:3][CH:4]=3)[NH:8][C:7]=2[C:11]([C:22]([NH2:24])=[O:23])=[N:12][CH:13]=1
Reactant: NC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(N)ccc12
Reactant: O=C(O)c1ccncc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: NC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(NC(=O)c3ccncc3)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.1 %

Procedure:
A mixture of 7-amino-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (25 mg, 0.078 mmol), isonicotinic acid (11.53 mg, 0.094 mmol), BOP (49.7 mg, 0.112 mmol), and N-methylmorpholine (0.037 mL, 0.337 mmol) in DMF (0.25 mL) was stirred at room temperature for 1.5 hr. The mixture was diluted with MeOH (1.5 mL) and subjected to prep LC. reverse phase HPLC purification. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution to pH 9. The precipitating product (10.8 mg, 0.025 mmol, 32.5% yield) was collected as a pale solid by suction filtration. LCMS (M+H)+=426.14. 1H NMR (500 MHz, DMSO-d6) δ: 11.95 (s, 1H), 10.96 (s, 1H), 6.80 (m, 2H), 8.44 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 7.89 (m, 2H), 7.79 (s, 1H), 7.71-7.67 (m, 2H), 7.54-7.48 (m, 2H), 7.42 (dd, J1=8.6 Hz, J2=1.9 Hz, 1H), 7.28 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4].[NH2:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39]>>[CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:30][CH2:31][CH2:32][CH2:33][N:34]2[CH2:38][CH2:37][CH2:36][C:35]2=[O:39])=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(C(=O)OCC)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: NCCCN1CCCC1=O
Product: CCCCn1c(=O)c(C(=O)NCCCN2CCCC2=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 40 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.050 mmol) and 1-(3-aminopropyl)-2-pyrrolidinone (0.05 mL) was prepared 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide (10 mg, 40% yield) as a yellow oil after purification by reverse phase HPLC. This oil was dissolved in diethyl ether, cooled to 0° C., and sodium ethoxide (0.02 mL of a 1 M solution in ethanol, 0.02 mmol) was added. The resulting white suspension was filtered and the white solids were collected to yield sodium 1-butyl-7-[(4-fluorophenyl)methyl]-2-oxo-3-({[3-(2-oxo-1-pyrrolidinyl)propyl]amino}carbonyl)-1,2-dihydro-1,5-naphthyridin-4-olate (11 mg, 42% overall yield) as a white solid. 1H NMR (CDCl3) δ 10.34 (br s, 1 H), 8.56 (s, 1 H), 7.27 (s, 1 H), 7.19-7.15 (m, 2 H), 7.06-7.02 (m, 2 H), 4.14 (s, 2 H), 4.09 (m, 2 H), 3.48-3.37 (m, 6 H), 2.40 (m, 2 H), 2.04 (m, 2 H), 1.88 (m, 2 H), 1.53 (m, 2 H), 1.34 (m, 2 H), 0.91 (m, 3 H); HRMS m/z calcd for: C27H32N4O4F: 495.2408 Found: 495.2397.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:25]=[CH:24][C:23]([F:22])=[C:28]([F:29])[CH:27]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(F)c(F)c1
Product: COc1ccc(-c2nc3cc(-c4ccc(F)c(F)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3,4-difluorophenylboronic acid (134 mg, 0.85 mmol) the subtitle compound was obtained (68 mg, 21%). MS 383 m/z (M+H)+.
Reaction SMILES: [F:1][C:2]([F:37])([C:7]1([O:32][Si](C)(C)C)[C:19]2[N:18](S(C3C=CC(C)=CC=3)(=O)=O)[C:17]3[C:12](=[CH:13][C:14]([C:30]#[N:31])=[CH:15][CH:16]=3)[C:11]=2[CH2:10][CH2:9][CH2:8]1)[C:3]([F:6])([F:5])[F:4].[OH-].[K+]>C1COCC1.O>[OH:32][C:7]1([C:2]([F:37])([F:1])[C:3]([F:4])([F:5])[F:6])[C:19]2[NH:18][C:17]3[C:12](=[CH:13][C:14]([C:30]#[N:31])=[CH:15][CH:16]=3)[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(C#N)ccc42)CCCC3(O[Si](C)(C)C)C(F)(F)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2[nH]c3c(c2c1)CCCC3(O)C(F)(F)C(F)(F)F
Yield: 40.4 %

Procedure:
To a solution of 1-(perfluoroethyl)-9-tosyl-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile (180 mg, 0.3 mmol) in THF (5 mL), KOH (90 mg, 1.6 mmol) in H2O (1 mL) was added. The reaction mixture was refluxed for 20 h, diluted with water and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude residue which was purified by column chromatography [EtOAc-hexane (1:19) as eluant] to afford the title compound as a white solid (40 mg, 40%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.5 (bs, 1H), 7.9 (s, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.44 (d, J=7.5 Hz, 1H), 2.90-2.86 (m, 1H), 2.74-2.56 (m, 1H), 2.56 (s, 1H), 2.33-2.29 (m, 1H), 2.20-2.12 (m, 2H), 2.04-2.03 (m, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6]C(=N)N.O=C1O[C@H]([C@H](CO)O)C(O)=C1O.P([O-])([O-])([O-])=O.N[C@H](C(O)=O)CCCNC(=N)N>O.S([O-])([O-])(=O)=O.[Mn+2].C(#N)C>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH2:6]
Reactant: N=C(N)NCCCC(N)C(=O)O
Agent: [Mn+2]
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: O
Solvent: CC#N
Product: NCCC[C@H](N)C(=O)O
Reaction time: 6 h

Procedure:
1.74 g DL-arginine (50:50) were dissolved in 10 ml water and mixed with 0.21 mg manganese sulfate.H2O, 0.11 mg ascorbic acid and 0.5 mg calf liver L-arginase (Boeringer Mannheim, 97 U/mg. The progress of the reaction was followed with HPLC (amino column; mobile solvent 65:35 acetonitrile:phosphate buffer (pH 6.4). After 6 hours at 25° C., 50% of the original amount of arginine had reacted and a corresponding amount of ornithine had been formed (conversion 100%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][C:11]1[NH:12][C:13]2[CH:19]=[C:18]([O:20]C)[CH:17]=[CH:16][C:14]=2[N:15]=1.[BrH:22]>C(O)(=O)C>[BrH:22].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][C:11]1[NH:12][C:13]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: COc1ccc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: Oc1ccc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c1

Procedure:
A mixture of 0.05 g of 2-(2,6-dichlorophenylamino)-5-methoxybenzimidazole hydrochloride, 0.5 ml of glacial acetic acid, and 0.5 ml of hydrobromic acid (48% strength) was boiled under reflux for 3 hours and the solvent was then distilled off. The solid residue was brought to crystallization under a little EA. 0.02 g of 2-(2,6-dichlorophenylamino)-5-hydroxybenzimidazole hydrobromide was obtained of melting point 265-269° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][C:3]=1[O:19][CH3:20].Cl[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)=[C:3]([O:19][CH3:20])[CH:4]=3)=[C:9]([CH3:18])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1cc(-c2c(C)sc3ncnc(N)c23)ccc1N
Reactant: Clc1ccc2ccccc2n1
Product: COc1cc(-c2c(C)sc3ncnc(N)c23)ccc1Nc1ccc2ccccc2n1
Temperature: 25 °C
Yield: 4.1 %

Procedure:
A mixture of Example 70A (100 mg, 0.35 mmol) and 2-chloroquinoline (62 mg, 0.38 mmol) was heated to 200° C. under nitrogen for 20 minutes, cooled to room temperature, and partitioned between saturated NaHCO3 and dichloromethane. The aqueous phase was extracted three times with dichloromethane and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. The concentrate was triturated with diethyl ether to provide 6 mg (5%) of the desired product. MS(ESI(+)) m/e 414 (M+H)+; 1H NMR (DMSO-d6) δ 9.08 (d, 1H, J=8.2 Hz); 8.70 (s, 1H); 8.28 (s, 1H); 8.08 (d, 1H, J=8.8 Hz); 7.73 (t, 2H, J=8.8 Hz); 7.61-7.56 (m, 1H); 7.44 (d, 1H, J=9.1 Hz); 7.34-7.29 (m, 1H); 7.06 (d, 1H, J=2.0 Hz); 7.02-6.99 (m, 1H); 3.93 (s, 3H); 2.37 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:36]=1)[O:7][CH2:8][C:9]1[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C@H:20]2[CH2:28][N:27]3[C@@H:22]([CH2:23][O:24][CH2:25][CH2:26]3)[CH2:21]2)=[C:15]([N+:29]([O-])=O)[CH:14]=1.C(N(CC)CC)C.Cl[C:45](Cl)([O:47]C(=O)OC(Cl)(Cl)Cl)Cl>[Pt].O1CCCC1.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:36]=1)[O:7][CH2:8][C:9]1[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([C@H:20]3[CH2:28][N:27]4[C@@H:22]([CH2:23][O:24][CH2:25][CH2:26]4)[CH2:21]3)[C:45](=[O:47])[NH:29][C:15]=2[CH:14]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(/C=C2\c3ccccc3COc3cc(F)ccc32)ccc1N[C@@H]1C[C@@H]2COCCN2C1
Agent: [Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(/C=C3\c4ccccc4COc4cc(F)ccc43)ccc2n1[C@@H]1C[C@@H]2COCCN2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
Hydrogenate a mixture of (E)-[4-(3-fluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-((7R,8aR)-hexahydro-pyrrolo[2,1-c][1,4]oxazin-7-yl)-amine (52 g, 0.107 mol), triethylamine (33 mL, 0.237 mol) and 5% platinum on carbon (18 g) in tetrahydrofuran (450 mL) at room temperature at 50 psi for 2 h. Filter off the catalyst, rinse with tetrahydrofuran, and concentrate to obtain a brown foam. Dissolve the foam in anhydrous tetrahydrofuran (500 mL) and cool in an ice bath. Add triphosgene (31.5 g, 0.106 mol) in tetrahydrofuran (450 mL) dropwise over 30 min and stir at room temperature for 16 h. Concentrate the solution, dissolve in 5% methanol in dichloromethane and purify through a short silica gel plug. Concentrate to obtain a brown solid. Suspend the solid in saturated sodium bicarbonate (1.5 L) and stir on the rotary evaporator for one hour. Filter and dry in vacuo. Dissolve in warm 1:1 methanol/dichloromethane (approximately 6 L) and treat with poly (4-vinylpyridine) 2% cross-linked resin (170 g). Stir the slurry for 30 min and filter through diatomaceous earth. Concentrate the filtrate to approximately 1.5 L volume and collect the resulting solids by filtration. Dry at 80° C./20 mm Hg overnight to obtain the title compound as a white solid (38.1 g, 74%). [α]D20−20.5 (c=1.0 in DMSO). 1H NMR (400 MHz, DMSO-d6) δ 1.48 (m, 1H), 2.02 (m, 1H), 2.19 (m, 2H), 2.52 (m, 1H), 2.91 (d, 1H), 3.03 (d, 1H), 3.25 (t, 1H), 3.50 (t, 1H), 3.79 (d, 1H), 3.88 (d, 1H), 4.95 (m, 1H), 5.03 (broad s, 1H), 5.60 (broad s, 1H), 6.59 (m, 2H), 6.78 (m, 2H), 6.97 (s, 1H), 7.02 (d, 1H), 7.25 (t, 1H), 7.38 (t, 1H), 7.48-7.61 (m, 3H), 10.72 (s, 1H, NH). LC-MS m/z 484.0 [M+H]+.
Reaction SMILES: C(N(CCCC)CCCC)CCC.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:22][SiH:23]([Cl:25])[Cl:24]>>[CH2:14]([Si:23]([Cl:25])([Cl:24])[Cl:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: Cl[SiH](Cl)Cl
Solvent: CCCCN(CCCC)CCCC
Product: Cl[Si](Cl)(Cl)Cc1ccccc1
Yield: 28.4 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.090 g (0.5 mmol) of tri-n-butylamine, 0.63 g (5.0 mmol) of benzyl chloride, and 3.41 g (25.2 mmol) of trichlorosilane were reacted at 150° C. for 6 hrs. The resulting mixture was distilled to give 0.32 g of benzyltrichlorosilane (yield; 29%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([OH:27])=[O:26].[CH3:28]S(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].CI>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([O:27][CH3:28])=[O:26]
Reactant: CS(C)=O
Reactant: COc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a 2 L flask was added 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (82.5 g, 187 mmol), DMSO (1249 mL), cesium carbonate (67.2 g, 206 mmol) and methyl iodide (23.44 ml, 375 mmol). The mixture was stirred at room temperature for 2 h. To the resulting slurry was added water (500 mL). The mixture became warm and was cooled with an ice/water bath. Stirring was continued an additional 30 min, then filtered and washed with H2O (2 L). The resulting solid was dried under reduced pressure then azeotroped with toluene two times to afford methyl 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (72.3 g, 85% yield) as a tan solid. MS (m/z) 456 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][C:7]2[CH:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][C:7]2[CH:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(Nc2cc(Nc3ccc(O)cc3)ncn2)c1
Reactant: CN(C)CCCCl
Product: Cc1cccc(Nc2cc(Nc3ccc(OCCCN(C)C)cc3)ncn2)c1
Yield: 13 %

Procedure:
Using an analogous reaction procedure to that described in Example 23, 4-(4'-hydroxyanilino)-6-(3'-methylanilino)pyrimidine (0.6 g) was reacted with 3-dimethylaminopropyl chloride. The product so obtained was chromatographed on silica and precipitated from a mixture of methylene chloride, methanol and hexane to give 4-[4'-(3-dimethylaminopropoxy)anilino]6-(3'-methylanilino)pyrimidine in 13% yield, m.p. 204°-207° C.;
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[C:13](I)=[CH:12][C:11]([C:15]#[N:16])=[CH:10][C:9]=1[Br:17])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[C:23]#[CH:24])[CH3:20].C(N(CC)CC)C.N1CCCN2CCCCCC=12>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.CN(C=O)C>[C:1]([O:5][C:6]([N:7]1[C:8]2[C:13](=[CH:12][C:11]([C:15]#[N:16])=[CH:10][C:9]=2[Br:17])[CH:24]=[C:23]1[CH:22]([O:25][CH2:26][CH3:27])[O:21][CH2:19][CH3:20])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1c(Br)cc(C#N)cc1I
Reactant: C#CC(OCC)OCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(OCC)c1cc2cc(C#N)cc(Br)c2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
A mixture of (2-bromo-4-cyano-6-iodo-phenyl)-carbamic acid tert-butyl ester (step A) (413 mg, 0.98 mmol), 3,3-diethoxyprop-1-yne (125 mg, 140 μl, 0.98 mmol), triethylamine (395 mg, 544 μl, 3.9 mmol), copper(I)iodide (5.58 mg, 29.3 μmol) and bis(triphenylphosphine)-palladium(II)chloride (34.3 mg, 48.8 μmol) was allowed to stir for 3 h at room temperature. Afterwards 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (297 mg, 292 μl, 1.95 mmol) and DMF (1.58 ml) were added, and the reaction mixture was allowed to stir for 17 h at room temperature, poured into water (10 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine, dried (MgSO4) and evaporated. The crude product (0.51 g) was further purified by flash chromatography on silica gel (heptane/ethyl acetate 0-20%) to yield 7-bromo-5-cyano-2-diethoxymethyl-indole-1-carboxylic acid tert-butyl ester (0.29 g, 64%) as a light yellow oil, MS (EI) m/z=422 [(M)+].