Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](O)=O.C(N(CC)CC)C.C(O)C.[NH2:16][C:17]1[N:18]=[N:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=1>O>[Cl:1][C:2]1[N:16]=[C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[N:19][N:18]2[CH:3]=1
Reactant: O=C(O)CCl
Reactant: CC(C)c1ccc(N)nn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc2nc(Cl)cn2n1
Temperature: 25 °C

Procedure:
Chloroacetic acid (0.32 g, 3.3 mmol), triethylamine (0.33 g, 3.3 mmol), ethanol (5.0 ml) and water (5.0 ml) were mixed and 3-amino-6-isopropylpyridazine (0.45 g, 3.28 mmol) was added thereto with stirring at room temperature, and after the mixture was heated at 80 to 90° C. for 5 hours under stirring, the reaction solution was concentrated to dryness. The resulting solids and phosphorus oxychloride (5.0 ml) were stirred at 150° C. for 12 hours in a sealed tube reactor. The reaction solution was left and cooled to room temperature and poured into water (50.0 ml) of 40 to 50° C., to decompose an excess of phosphorus oxychloride. The reaction solution was adjusted to pH 7 with 20% aqueous sodium hydroxide solution and extracted 3 times with ethyl acetate, and the extracts were combined, dried over anhydrous magnesium sulfate and concentrated. The residues were purified by silica gel column chromatography (ethyl acetate:chloroform=1:2), to give the title compound as pale yellow crystals. The yield was 0.15 g (23.4%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C([Cl:8])=O.[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]([NH:23][C@H:24]([C:28]([NH:30][CH:31]([CH:40]([OH:43])[CH2:41][F:42])[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([CH3:11])[C:13]=1[C:21]([NH:23][C@H:24]([C:28]([NH:30][CH:31]([C:40](=[O:43])[CH2:41][F:42])[CH2:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])=[O:29])[CH:25]([CH3:26])[CH3:27])=[O:22]
Reactant: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1c(Cl)c2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
DMSO (0.06 mL, 0.9 mmol) was added to a solution of oxalyl chloride (0.14 mL, 2.0 M, 0.28 mmol, in 4 mL of methylene chloride) and the solution was then stirred for 10 minutes under a nitrogen atmosphere at −78° C. A solution of N-[(1-methylindole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (85 mg, 0.18 mmol) in dry methylene chloride (1 mL), was added dropwise to the reaction mixture and the mixture was stirred for 15 minutes at −78° C. Triethylamine (0.15 mL, 1.08 mmol) was added dropwise to the reaction mixture and the mixture was stirred for 10 minutes at −78° C. and then was allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous layer was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution and brine, dried over sodium sulfate, and concentrated to give a brown foam. The foam was triturated with ether to afford the title product as a light brown powder (64 mg). MS for C24H31,ClFN3O5: (MH)−=494/496.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:17]2[N:16]3[C:11]([C:12]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=4[CH3:26])=[CH:13][CH:14]=[CH:15]3)=[CH:10][C:9]=2[N:8]=[C:7]([CH3:27])[N:6]=1.[C:28]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH:28]1([NH:1][CH2:2][CH2:3][NH:4][C:5]2[C:17]3[N:16]4[C:11]([C:12]([C:18]5[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=5[CH3:26])=[CH:13][CH:14]=[CH:15]4)=[CH:10][C:9]=3[N:8]=[C:7]([CH3:27])[N:6]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(NCCN)c23)c(C)c1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(NCCNC4CCCC4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Treat a solution of (2-aminoethyl)[2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizin-4-yl]amine (0.07 g, 0.19 mmol), cyclopentanone (0.02 mL, 0.19 mmol) and acetic acid (0.01 mL, 0.19 mmol) in dry dichloroethane (3 mL) with sodium triacetoxyborohydride (0.06 g, 0.27 mmol) and stir at ambient temperature for 14 h. Dilute the resulting mixture with CH2Cl2 (20 mL) and wash with saturated aq NaCl (50 mL). Dry the organic portion over Na2SO4, filter, and concentrate under reduced pressure. Purify by preparative TLC (10% MeOH in CH2Cl2 with 0.5% ammonium hydroxide) to obtain the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].O>ClCCl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:9]=[CH:10][C:11]=1[O:12][S:14]([CH3:13])(=[O:16])=[O:15])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc(C=O)ccc1O
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(C=O)ccc1OS(C)(=O)=O
Reaction time: 1 h

Procedure:
To a solution of 3-ethoxy-4-hydroxybenzaldehyde (3.0 g, 18.1 mmol, 1.0 equiv) and N,N-dimethylaminopyridine (2.87 g, 23.5 mmol, 1.3 equiv) in dichloromethane (10 mL) under Ar at 0° C. was added methanesulfonyl chloride (1.68 mL, 2.48 g, 21.7 mmol, 1.2 equiv). After the reaction mixture was stirred for 1 h, water (100 mL) was added, the solution extracted with dichloromethane (3×50 mL) and the combined organic phases dried over MgSO4. Removal of the solvent by evaporation under reduced pressure provided the title compound in quantitative yield (4.8 g). 1H NMR (300 MHz, CDCl3): δ 1.42 (t, J=7.0 Hz, 3H), 3.19 (s, 3H), 4.14 (q, J=7.0 Hz, 2H), 7.41 (s, 2H), 7.45 (s, 1H), 9.89 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.53, 38.94, 64.99, 112.20, 124.38, 125.17, 136.01, 142.92, 151.63, 190.65. MS (ISP): 245.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](Cl)=[O:15])[CH2:9]1.[NH2:23][C@@H:24]([CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[CH2:25][NH:26][C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([NH:23][C@@H:24]([CH2:36][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[CH2:25][NH:26][C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])=[O:15])[CH2:9]1
Reactant: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)Cl)C1
Reactant: C[Si](C)(C)CCOC(=O)NC[C@@H](N)CC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CNC(=O)OCC[Si](C)(C)C)CC2CCCCC2)C1
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Crude (R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidine-1-carbonyl chloride (60 mg, 0.184 mmol), 2-(trimethylsilyl)ethyl (S)-2-amino-3-cyclohexylpropylcarbamate (69 mg, 0.23 mmol, 1.25 equiv) and triethylamine (64 μL, 0.46 mmol, 2.5 equiv) were combined in CH2Cl2 (1 mL) at rt and left on the shaker overnight. After concentration, the product was isolated by prep HPLC to afford 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((R)-(3-methoxypropoxy)-(phenyl)methyl)piperidine-1-carboxamido)-3-cyclohexyl-propylcarbamate (85.3 mg, 79%). LC-MS (3 min) tR=2.44 min, m/z 590 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)[CH3:2].C([Li])CCC.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]>O1CCCC1.CCCCCC>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:23]([C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[F:20])[OH:24])[CH3:2]
Reactant: CCOC(OCC)c1ccccc1Br
Reactant: O=Cc1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(OCC)c1ccccc1C(O)c1ccccc1F
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
A solution of 345 g of 2-bromobenzaldehyde diethyl acetal in 3 l of dry tetrahydofuran was cooled to -40° C. In one portion, 913 ml of a 1.6 M solution of butyllithium in hexane were added under vigorous stirring. The resulting solution was stirred for 0.5 h at -25° C., after which a solution of 140 ml of 2-fluorobenzaldehyde in 350 ml tetrahydrofuran was added drop-wise. In a period of 4 h, the mixture was allowed to reach room temperature. The resulting mixture was pored upon ice-water and extracted several times with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulphate and evaporated to dryness under reduced pressure to yield 404 g of 2-(diethoxymethyl)-α-(2-fluorophenyl)-benzenemethanol as an oil, M.S. (C.I.) (M/Z): 305 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:7])[CH2:4][CH2:5][OH:6].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1.C(OCC)(=O)C>[F:21][C:9]([F:8])([F:20])[C:10]1[CH:11]=[CH:12][C:13]([S:16]([O:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH3:7])(=[O:18])=[O:17])=[CH:14][CH:15]=1
Reactant: COC(C)CCO
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(C)CCOS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 42.4 %

Procedure:
To a solution of 3-methoxybutane-1-ol (12) (0.58 g, 4.9 mmol) in pyridine (5 mL) was added p-(trifluoromethyl)-benzenesulfonyl chloride (0.98 g, 4 mmol). The solution was stirred at rt for 3.5 h. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with 1 M HCl (6×25 mL), saturated aqueous NaHCO3 (1×25 mL) and saturated aqueous NaCl (1×25 mL). The organics were dried over Na2SO4 and concentrated to give an oil (13) (0.53 g, 40%). 1H NMR (400 MHz CDCl3) δ 8.03 (d, 2H, J=8.1 Hz), 7.81 (d, 2H, J=8.3 Hz), 4.19 (m, 2H), 3.35 (m, 1H), 3.18 (s, 3H), 1.78 (m, 2H), 1.09 (d, 3H, J=6.0 Hz); 19F δ (s). Anal. Calcd. For C12H15F3O4S: C, 46.15; H, 4.84. Found: C, 45.99; H, 4.64.
Reaction SMILES: Br[C:2]1[C:3]2[C:7]([CH:8]=[CH:9][CH:10]=1)=[N:6][N:5]1[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([Cl:15])=[N:14][C:4]=21.[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[Cl:15][C:13]1[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][N:5]2[N:6]=[C:7]3[C:3]([C:2]([C:27]4[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=4)=[CH:10][CH:9]=[CH:8]3)=[C:4]2[N:14]=1
Reactant: Clc1nc2c3c(Br)cccc3nn2cc1-c1ccccc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cccc3nn4cc(-c5ccccc5)c(Cl)nc4c23)cc1
Temperature: 105 °C
Yield: 26.7 %

Procedure:
400 mg (1.12 mmol) 10-Bromo-2-chloro-3-phenylpyrimido[1,2-b]indazole, intermediate example Int-1-3, 172.1 mg (1.17 mmol) 4-cyanophenylboronic acid, 91 mg (0.112 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) and 354.6 mg (3.35 mmol) sodium carbonate in 12 mL degassed dioxane and 1.68 mL water were heated in the microwave for 45 min. at 105° C. The reaction mixture was poured on a mixture of water/saturated ammonium chloride/dichloromethane and stirred vigorously for 30′. The organic phase was separated, washed twice with brine and dried (sodium sulfate). After filtration and evaporation of the solvent the residue was purified by HPLC yielding 114 mg of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:29])([CH3:28])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[NH:10][C:11]=2[C:12]([F:15])=[CH:13][CH:14]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[F:15][C:12]1[C:11]2[NH:10][CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[C:8]([CH3:29])([CH3:28])[CH2:7][C:6]=2[C:5]([C:3]([OH:4])=[O:2])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(F)c2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2c(C(=O)O)ccc(F)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a stirred mixture solution of 8-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (400 mg, 1.0 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 8-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (345 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25FN2O3 (M+H)+: 385.45, observed: 385.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:5][C:6](=[O:8])[CH:7]=1)=[O:4].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][NH2:19].O>C(O)(=O)C>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][N:19]=[C:3]([OH:4])/[C:2](/[Cl:1])=[CH:7]\[C:6]([OH:5])=[O:8]
Reactant: O=C1C=C(Cl)C(=O)O1
Reactant: COc1ccccc1CCN
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1CCN=C(O)/C(Cl)=C\C(=O)O
Yield: 73.3 %

Procedure:
13.25 g (0.1 mol) of chloromaleic anhydride and 15.2 g (0.1 mol) of 2-(2-methoxyphenyl)-ethylamine are heated to the boiling point in 100 ml of glacial acetic acid for 4 hours. 100 ml of water are then added and the oil which has precipitated is extracted with methylene chloride. The methylene chloride phase is separated off, washed with water, dried and evaporated. The oil which remains crystallizes. 20.8 g (78% of theory) of chloromaleic acid N-[2-(2-methoxyphenyl)-ethyl]-imide are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1.[NH2:16][C:17]([NH2:19])=[S:18]>>[CH3:1][O:2][C:3]([C:4]1[N:16]=[C:17]([NH2:19])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1cccc(Cl)c1
Reactant: NC(N)=S
Product: COC(=O)c1nc(N)sc1-c1cccc(Cl)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-chloro-phenyl)-2-oxo-propionic acid methyl ester with thiourea. LC-MS: tR=0.82 min; [M+H]+=269.2.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([C:28]([CH3:33])([CH3:32])[C:29](O)=[O:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Cl-].[NH4+:35]>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([C:28]([CH3:32])([CH3:33])[C:29]([NH2:35])=[O:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(C(C)(C)C(=O)O)c3)ccc1-2
Reactant: [NH4+]
Agent: [Cl-]
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(C(C)(C)C(N)=O)c3)ccc1-2

Procedure:
Following the procedure for 240, 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propionic acid was reacted with ammonium chloride to give 439. MS(ESI+) 464.1. 1H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 8.32 (d, J=8.3, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.50 (dd, J=8.3, 1.8, 1H), 7.39 (d, J=1.7, 1H), 7.17 (br, 1H), 6.79 (br, 1H), 5.93-5.74 (m, 1H), 4.39 (t, J=5.0, 2H), 3.45 (t, J=5.0, 2H), 1.75 (s, 6H), 1.56 (d, J=6.6, 6H)
Reaction SMILES: [N:1]1([C:7]2[CH:25]=[CH:24][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[C:9]([Cl:26])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.N1C2C=CC=CC=2CCC[CH2:30]1.[Na].[Na]>C(OCC)(=O)C>[CH3:30][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:25]=[CH:24][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[C:9]([Cl:26])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=C(c1ccc(N2CCNCC2)cc1Cl)N1CCCCc2ccccc21
Reactant: c1ccc2c(c1)CCCCN2
Agent: C=O
Agent: [Na]
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(C(=O)N3CCCCc4ccccc43)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a mixture of 1-[4-(1-piperazinyl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g), 37% formaldehyde (0.45 g) and sodium tetrahydro-1H-benzazepine (0.25 g), 37% formaldehyde (0.45 g) and sodium (0.12 g) under ice-cooling, and the mixture is stirred at room temperature for one hour. To the reaction solution is added ethyl acetate, and the mixture is washed with a 2N aqueous sodium hydroxide solution and distilled water. The organic layer is dried over magnesium sulfate, filtered, and concentrated, and the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=10:1) to give 1-[4-(4-methyl-1-piperazinyl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.10 g) as white powder.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[Cl:15][C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:16]([Cl:15])(=[O:18])[O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[Si](C)(C)CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOC(=O)Cl
Reaction time: 0.25 h

Procedure:
To a solution of 2-trimethylsilylethanol (5.0 g, 42.3 mmol) in dichloromethane (35 mL) at 0° C. was added triethylamine (4.7 g, 46.5 mmol). To this stirred solution was added dropwise a solution of triphosgene (4.40 g, 14.8 mmol) in dichloromethane (15 mL); a white precipitant was formed immediately. The mixture was stirred at low temperature for 15 minutes, the ice bath removed, and the mixture was stirred for an additional 1 hour at room temperature. After 1 hour, the white precipitant was filtered and washed with dichloromethane (˜60 mL). The combined filtrate and washings were concentrated. The resultant oily carbonochloridate was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20](Cl)=[O:21])=[CH:16][CH:15]=1.ClCCl.C(N(CC)CC)C>C1COCC1>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:20](=[O:21])[CH2:19][O:18][C:17]2[CH:23]=[CH:24][C:14]([Cl:13])=[CH:15][CH:16]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(Br)ccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-amino-5-bromobenzoate (3.03 mL, 17.4 mmol) in THF (28 mL) was added 2-(4-chlorophenoxy)acetyl chloride (3.92 g, 19.1 mmol) to form a suspension. An additional 30 mL of dichloromethane was added. The reaction was then cooled to 0° C. and triethylamine (5.32 mL, 38.3 mmol) was added dropwise. The cold bath was removed and the reaction was stirred at room temperature for 2 hours. Analysis showed the reaction to be incomplete, so additional 2-(4-chlorophenoxy)acetyl chloride (0.5 mL, 3.22 mmol) was added and reaction solution was stirred for 1 hour then transferred to a reparatory funnel with dichloromethane dilution. The organic phase was washed with water and saturated aqueous NH4Cl solution, then dried (MgSO4), filtered, and concentrated to yield the title compound.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8]1)=[O:6])[CH3:3].[CH:16]1[C:21]([OH:22])=[CH:20][CH:19]=[C:18]([CH3:23])[CH:17]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[OH:8][CH:7]([CH:9]([O:22][C:21]1[CH:20]=[CH:19][C:18]([CH3:23])=[CH:17][CH:16]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6]
Reactant: CC(C)NC(=O)C1OC1c1ccccc1
Reactant: Cc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(OC(c2ccccc2)C(O)C(=O)NC(C)C)cc1

Procedure:
This compound was prepared as in Example 12 from N-(1-methylethyl)-3-phenyl-2-oxiranecarboxamide (6.16 g.), p-cresol (3.3 g.), sodium hydride (50% oil dispersion, 1.5 g.), 18-crown-6 (0.9 g.) and acetonitrile (250 ml.). The product melted at 152°--152°, and amounted to 2.4 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([F:18])[C:16]=1[F:17].C(=O)([O-])[O-].[K+].[K+].CC(O)C>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.C1(C)C=CC=CC=1.O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:12]=[C:11]([F:10])[C:16]([F:17])=[C:15]([F:18])[CH:14]=2)=[C:3]([F:9])[CH:4]=1
Reactant: Oc1ccc(Br)c(F)c1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1ccc(-c2cc(F)c(F)c(F)c2)c(F)c1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
4-Bromo-3-fluorophenol (T-10; 5.00 g), 3,4,5-trifluorophenylboronic acid (5.07 g), potassium carbonate (10.9 g), Pd(Ph3P)2Cl2 (0.552 g), and 2-propanol were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 5 hours. The reaction mixture was cooled to 25° C., and then poured into water (100 ml) and toluene (100 ml) and mixed. Then, the mixture was allowed to stand to be separated into two layers of organic and aqueous layers, and the extraction to an organic layer was carried out. The obtained organic layer was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The product was further purified by recrystallization from a mixed solvent of heptane/Solmix A-11 and dried, whereby 4.79 g of 4-hydroxy-2,3′,4′,5′-tetrafluoro-1,1′-biphenyl (T-11) was obtained. The yield based on the compound (T-1) was 74%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].N1C(C)=CC=CC=1C.Cl/[C:24](=[CH:27]/[C:28]#[N:29])/[C:25]#[N:26].Cl/C(=C\C#N)/C#N>CO>[NH2:29][C:28]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:24]([C:25]#[N:26])[CH:27]=1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N#C/C=C(/Cl)C#N
Agent: N#C/C=C(\Cl)C#N
Solvent: CO
Solvent: Cc1cccc(C)n1
Product: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reaction time: 16 h
Yield: 71 %

Procedure:
A 50 mL round-bottom flask was charged with (2,6-dichloro-4-trifluoromethyl-phenyl)-hydrazine (1.2 g, 4.84 mmol), 2,6-lutidine (0.57 g, 5.32 mmol, 1.1 equiv.) and methanol (10 mL). A mixture of chloromaleonitrile and chlorofumaronitrile (0.82 g, 7.29 mmol) was slowly added at 20-25° C. Stirring was continued for about 16 hours at that temperature. The solution was then concentrated at a pressure of 50 mbar. The residue was purified by flash column chromatography (silica, hexanes/EtOAc 100:0→70:30) to give the product as a off-white solid (1.1 g, 3.43 mmol, 71%), melting point: 117-118° C., 1H-NMR (360 MHz, CDCl3): δ [ppm]=7.78 (d, 2H, J=0.4 Hz); 6.04 (s, 1H); 3.83 (bs, 2H), 13C-NMR (125 MHz, DMSO-d6): δ [ppm]=150.0; 136.0; 135.9; 132.7 (q, J=34 Hz); 126.43; 126.42; 122.4 (q, J=273 Hz); 114.6; 90.8.