Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:10](OCC)=[O:11].B.CSC.[OH-].[Na+]>CC1CCCO1>[Br:1][C:2]1[N:6]([CH:7]([CH3:8])[CH3:9])[N:5]=[CH:4][C:3]=1[CH2:10][OH:11]
Reactant: CCOC(=O)c1cnn(C(C)C)c1Br
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CSC
Solvent: CC1CCCO1
Product: CC(C)n1ncc(CO)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of ethyl 5-bromo-1-isopropyl-1H-pyrazole-4-carboxylate (163 g, 0.50 mol) in 2-methyl tetrahydrofuran (400 mL) was added borane-DMS (140 mL, 1.50 mol) at 0° C., under argon (effervescence ceased after 50 mL was added). The mixture was stirred at room temperature for 30 minutes and then heated to 70° C. for 2 hours, and then to reflux for 17 hours. Additional portion of borane DMS (40 mL) was added and the mixture was stirred at reflux for an additional 3 hours. The mixture was cooled to room temperature then added gradually to ice-cold methanol (500 mL) with stirring, over a period of 30 minutes. The mixture was stirred at room temperature for 30 minutes then 2 M aqueous sodium hydroxide (1.5 L) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×500 mL). The organic layers were combined, washed with brine (500 mL), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The crude product was purified by dry flash chromatography (0-50% ethyl acetate in heptane) to give (5-bromo-1-isopropyl-1H-pyrazol-4-yl)methanol (70.8 g, 65% over two steps). +ESI (M+H) 220.9; 1H NMR (400 MHz, CDCl3, δ): 7.52 (s, 1H), 4.67 (m, 1H), 4.47 (s, 2H), 2.59 (br. s., 1H), 1.41 (s, 6H).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[C:11]([NH2:12])[C:2]1=2.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[C:17]([Cl:29])=[CH:16][N:15]=1>>[Cl:29][C:17]1[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[N:19][C:14]([NH:12][C:11]2[C:2]3[O:1][CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[CH:8]=[CH:9][CH:10]=2)=[N:15][CH:16]=1
Reactant: Nc1cccc2c1OCCCC2
Reactant: COc1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1ccccc1Nc1nc(Nc2cccc3c2OCCCC3)ncc1Cl

Procedure:
The title compound was prepared from 2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-phenyl)-amine in analogous manner to Example 179. Product was isolated as a light pink solid (20 mg, 30%). LCMS (m/e) 397 (M+H); 1H NMR (DMSO-d6, 400 MHz) δ 8.27 (s, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.86 (d, 1H, J=7.3 Hz), 7.72 (d, 1H, J=7.8 Hz), 7.19 (dd, 1H, J=7.3, 8.3 Hz), 7.12 (d, 1H, J=8.3 Hz), 6.94 (td, 1H, J=7.6 Hz), 6.76 (m, 2H), 3.94 (m, 2H), 3.82 (s, 3H), 2.72 (m, 2H), 1.88 (m, 2H), 1.62 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[C:7]([O:15][CH3:16])=[CH:6][C:3]=1[CH:4]=[O:5].[OH-].[K+].[O-:19][Mn](=O)(=O)=O.[K+]>O1CCOCC1>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[C:7]([O:15][CH3:16])=[CH:6][C:3]=1[C:4]([OH:19])=[O:5]
Reactant: COCCOc1cc(F)c(C=O)cc1OC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCOc1cc(F)c(C(=O)O)cc1OC
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
2-Fluoro-5-methoxy-4-(2-methoxyethoxy)benzaldehyde (0.36 g, 1.6 mmol) was suspended in a mixture of dioxane (1.5 mL) and KOH (16 mL of 0.2 M, 3.2 mmol). KMnO4 (370 mg, 2.4 mmol) was added and the mixture was stirred vigorously for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated to 10 mL (blue soln). HCl (4M, ˜2 mL) was added and the resulting precipitate was filtered and washed with 1M HCl and then water (1 mL) to yield 2-fluoro-5-methoxy-4-(2-methoxyethoxy)benzoic acid (300 mg, 78%) as a white solid. ESI-MS m/z calc. 244.1. found 245.1 (M+1)+. Retention time: 1.01 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 12.96 (s, 1H), 7.30 (d, J=7.0 Hz, 1H), 6.98 (d, J=12.5 Hz, 1H), 4.20-4.13 (m, 2H), 3.78 (s, 3H), 3.71-3.63 (m, 2H), 3.31 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]=[C:33]=[O:34])[CH:27]=1>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:33](=[O:34])[NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:36])[F:35])[CH:27]=3)[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)c1C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64.8 %

Procedure:
To a solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 94 mg, 0.298 mmol) in methylene chloride (6.0 mL) was added trifluoro-m-tolyl isocyanate (82 μL, 0.596 mmol) at room temperature under nitrogen. The resulting light brown solution was stirred at room temperature for 40 minutes. The reaction mixture was diluted with water (˜25 mL) and the resulting mixture was extracted with methylene chloride (3×25 mL). The combined organic layers were washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated to a yellow-orange film. Silica gel chromatography (20-25% ethyl acetate in hexanes) provided {6-fluoro-3-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (97 mg, 65%) as a colorless film. MS cald. for C27H27F4N2O3 [(M+H)+]: 503, obsd. 503.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.I[CH3:19].[H-].[Na+]>C1COCC1>[CH3:19][O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CI
Reactant: COC(=O)c1cc(CCO)cc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1cc(C(=O)OC)c2ccccc2c1

Procedure:
Methyl 3-(2-hydroxyethyl)-1-naphthalenecarboxylate (1 eq.) from the previous step and iodomethane (19 eq.) were taken up in THF (0.3 M). To this solution was then added sodium hydride (60% w/w dispersion in oil, 1 eq.) and the resulting suspension was stirred at RT in darkness for 18 h. The volatiles were then removed in vacuo and the resulting residue partitioned between ether and 1 N aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed further with 1 N aq. NaOH, water and brine. This was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford a yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 19:1 (v/v) Hex:EtOAc→1:1 (v/v) EtOAc:Hex) afforded the title compound as a pale yellow oil.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15].C[O:19][B:20](C)[O:21]C.Cl>CCCCCC.C1COCC1>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([B:20]([OH:21])[OH:19])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15]
Reactant: COB(C)OC
Reactant: Cc1ccc(Br)cc1C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
At −78° C., 9.2 ml (1.5 g, 23.0 mmol) of a 2.5M solution of n-butyllithium in hexane were initially charged in 30 ml of THF. 5.0 g (20.9 mmol) of 4-methyl-3-(trifluoromethyl)bromobenzene were dissolved in 15 ml of THF and slowly added dropwise. 3.3 g (31.4 mmol) of trimethylboronic acid were then added dropwise. The mixture was stirred at −78° C. for 2 h, and 11 ml of 2 N hydrochloric acid were then added. The mixture was allowed to warm to RT, and the organic phase was separated off. The solvent was removed under reduced pressure and the residue was recrystallized from n-heptane. Yield: 2.6 g (60% of theory)
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=1.O>CN(C=O)C>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])=[CH:18][N:17]=1
Reactant: CN1CC(=O)NC1=NC(=O)O
Reactant: COc1ccc(N)cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(NC(=O)N=C2NC(=O)CN2C)cn1

Procedure:
A mixture of 2.33 g (10.0 mM) of phenyl carbamate 8 and 1.24 g. (10.0 mM) of 5-amino-2-methoxypyridine in 9 ml of anhydrous DMF was heated at 70° C. for 6 hrs., cooled, and poured into 40 ml of water. On cooling in ice, crystals precipitated from the aqueous solution and these were collected and recrystallized from methanol to give 0.5 g of the above urea as pale yellow needles, m.p. 175°-176° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Cl:29][C:30]1[N:31]=[C:32]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:33]2[S:38][C:37]([CH:39]=O)=[CH:36][C:34]=2[N:35]=1>C1COCC1>[Cl:29][C:30]1[N:31]=[C:32]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:33]2[S:38][C:37]([CH:39]=[CH:2][O:3][CH3:4])=[CH:36][C:34]=2[N:35]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
To a suspension of methoxymethyl triphenylphosphonium chloride (7.24 g) in THF (100 mL) at 0° C. was added n-butyllithium (6.76 mL of a 2.M solution in hexanes). The reaction mixture was stirred at 0° C. for 1 h and then a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (2 g) in THF (30 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 h and then quenched with water (80 mL) and extracted with ethyl acetate (2×80 mL). The combined organics were washed with aqueous brine solution (2×80 mL), dried (MgSO4), concentrated and purified using column chromatography to give 2-chloro-6-(2-methoxy-vinyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (mixture of cis/trans isomers) as a yellow solid (2.24 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:10]([O:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22](Cl)=[N:23][CH:24]=[N:25]2)=[CH:20][C:19]=1[O:29][CH3:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN1C(=O)CCC1>[CH2:10]([O:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:23][CH:24]=[N:25]2)=[CH:20][C:19]=1[O:29][CH3:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
Phenol (29.05 g, 309 mmol) was dissolved in NMP (210 ml), sodium hydride (11.025 g, 60% dispersion in mineral oil) was added in portions with cooling and the mixture was stirred for 3 hours. The viscous suspension was diluted with NMP (180 ml) and stirred overnight. The solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline was added and the suspension stirred at 100° C. for 2.5 hours. The suspension was allowed to cool to ambient temperature and poured into water (1.51) with vigorous stirring. The precipitate was collected by filtration, washed with water and dried under vacuum. The residue was dissolved in dichloromethane, washed with brine and filtered through phase separating paper. The filtrate was evaporated under vacuum then triturated with ether to give 7-benzyloxy-6-methoxy-4-phenoxyquinazoline (87.8 g, 83%) as a pale cream solid.
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.F[C:8](F)(F)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:20][C:21]#[N:22])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[C:9]1([CH3:8])[CH:14]=[CH:13][C:12]([C:15]2([CH2:20][C:21]([NH2:22])=[NH:1])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1
Reactant: [NH4+]
Reactant: N#CCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C2(CC(=N)N)CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a stirred suspension of NH4Cl (1.3 g, 23.69 mmol) in dry toluene (30 mL) was added trimethylaluminium (2M solution in toluene) dropwise at 0° C., stirred at 0° C. for 15 min, then stirred at room temperature for 2 h. The solution of [1-(4-trifluoromethyl-phenyl)-cyclopentyl]-acetonitrile (241) (2 g, 7.89 mmol) in toluene (10 mL) was added dropwise at the room temperature and the reaction mixture was heated at 80° C. for 16 h, the reaction mixture was cooled to 0° C., and the reaction mixture was poured into the slurry of silica gel (4 g) in CHCl3 (4 mL), stirred vigorously for 30 min at 0° C., the solid was filtered off through celite and washed with methanol (5×100 mL). The filtrate was concentrated and the crude product was taken up in 10% methanol in dichloromethane (200 mL) and stirred for 30 min. The solid was discarded by filtration and the filtrate was concentrated. The crude product was suspended in ether and a solid was collected by filtration and dried to get 2-(1-p-tolyl-cyclopentyl)-acetamidine (hydrochloride salt) (242) (1.4 g, 65.59%) as a light yellow solid.
Reaction SMILES: [C:1]([CH:5]1[C:11](=[O:12])[CH2:10][C@H:9]2[N:13]([CH3:14])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].[BH4-].[Na+].[ClH:17]>CO.C(O)C>[ClH:17].[C:1]([CH:5]1[CH:11]([OH:12])[CH2:10][C@H:9]2[N:13]([CH3:14])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1C(=O)C[C@@H]2CC[C@H]1N2C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COC(=O)C1C(O)C[C@@H]2CC[C@H]1N2C
Reaction time: 4 h

Procedure:
To a solution of the 2-carbomethoxy-3-tropanone obtained in example 4 (17 g, 85 mmol) in 750 ml methanol cooled to −35° C. was added sodium borohydride (17 g, 450 mmol) and the mixture was stirred for 4 hours. The cooled solution was quenched by slow addition of concentrated hydrochloric acid (40 ml) and the mixture was concentrated in vacuo. Water (400 ml) was added and the pH was adjusted to 3 by addition of concentrated hydrochloric acid. After having washed the water phase three times with diethyl ether pH was adjusted to 11 by addition of concentrated ammonium hydroxide and the water phase was extracted three times with methylene chloride. Concentration in vacuo yielded oil which was dissolved in ethanol and added concentrated hydrochloric acid followed by concentration in vacuo. Freeze drying of the residue yielded the title compound as an amorphous product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[C:26]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)=[O:27]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)=[O:27])=[CH:29][CH:30]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccc(O)cc1)c1ccc2ccccc2c1
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc5ccccc5c4)cc3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 5.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg) and 4-hydroxyphenyl 2-naphthyl ketone (124 mg) obtained in Example 36 were mixed and stirred at 180° C. for 30 minutes. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, and then the chloroform layer was dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, a portion (50 mg) of the resulting residue (227 mg) was purified by thin layer chromatography on silica gel eluting with chloroform/ethyl acetate (5/1) to obtain 11 mg of the title compound (yield: 23%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:26])=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[N:13]=2)[CH:8]=1.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[Cl:25][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[N:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:4]([F:26])[CH:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1cc(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c(Cl)cc1F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-82, 0.300 g), pivaloyl chloride (0.3 mL), TEA (2.0 mL), dry THF (10 mL) to afford 0.050 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 1.12 (s, 9H), 4.31 (d, J=6.8 Hz, 2H), 7.63-7.71 (m, 2H), 8.05-8.07 (m, 1H), 8.16 (m, 1H), 8.55 (d, J=13.2 Hz, 1H), 9.29 (s, 1H), 12.85 (s, 1H); MS (m/z): 472.41 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:23])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(C(F)(F)F)c1Cl

Procedure:
To a suspension of 2-chloro-3-(trifluoromethyl)benzoic acid (15 g, 67 mmol) and catalytic DMF (0.06 mL, 0.67 mmol) in DCM (150 mL) was added oxalyl chloride (6.8 mL, 80 mmol) dropwise. The reaction was let stir (vigorous bubbling) for 4 h and concentrated to an oily solid which became solid after overnight drying on high vacuum.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[C:31](Cl)(=[O:35])[O:32][CH2:33][CH3:34].C(N(CC)CC)C>O1CCCC1>[F:26][C:25]([F:28])([F:27])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]2[N:5]([CH:30]=[C:2]([NH:1][C:31](=[O:35])[O:32][CH2:33][CH3:34])[N:3]=2)[N:6]=1)=[O:29]
Reactant: CCOC(=O)Cl
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 62 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol), ethyl chlorocarbonate (41 μL, 0.435 mmol), triethylamine (75 μL, 0.544 mmol) and tetrahydrofuran (3 mL) as starting materials and in the same manner as in Example 388, the title compound (109 mg, 62%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][NH2:21])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:23][C:24]([F:37])([F:36])[C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][C:33](=N)[NH2:34])[CH:28]=[CH:29][CH:30]=1>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[NH:34][C:33]([CH2:32][CH2:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:37])[F:36])[CH:26]=4)=[N:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: N=C(N)CCc1cccc(C(F)(F)F)c1
Reactant: NNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1n(Cc2nnc(CCc3cccc(C(F)(F)F)c3)[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 180 °C
Reaction time: 1 h

Procedure:
50 mg (0.16 mmol) of the compound from Example 21A were taken up in 1 ml of DMF, 62 mg (0.24 mmol) of 3-[3-(trifluoromethyl)phenyl]propaneimidamide hydrochloride were added and the mixture was stirred in a microwave oven at 180° C. for 1 h. After cooling, the reaction mixture was diluted with methanol and the solution was directly separated by preparative HPLC [Method 19]. This gave 11 mg (14% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C:4]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:7]=[C:6]([O:21][CH3:22])[C:5]=1[O:23][CH3:24])[CH2:2][CH3:3].[CH2:25](Br)[CH2:26][CH2:27][CH3:28].[OH-].[K+]>CO>[CH2:25]([N:11]1[CH2:10][CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:7]=[C:6]([O:21][CH3:22])[C:5]([O:23][CH3:24])=[C:4]([CH2:1][CH2:2][CH3:3])[C:14]=2[CH2:13][CH2:12]1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCc1c2c(cc(OC)c1OC)C(c1ccccc1)CNCC2
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1CCc2c(cc(OC)c(OC)c2CCC)C(c2ccccc2)C1

Procedure:
A mixture of 4.5 g of 6-propyl-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 0.02 mole of n-butyl bromide and 0.02 mole of potassium hydroxide is dissolved in 120 ml of dry methanol and refluxed for 48 hours. The reaction mixture is evaporated to dryness, taken up in ethyl acetate and filtered to remove inorganic salts. The filtrate is washed with water, dried and evaporated to give 3-n-butyl-6-propyl-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[CH:10][CH:9]=1>>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:15][C:16]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:17][C:18]=2[CH3:19])=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc(-c2sccc2C)cc1
Product: COc1ccc(-c2sc(S(=O)(=O)Cl)cc2C)cc1

Procedure:
The above sulfonyl chloride, EI-MS: M=304.1, was prepared analogous to Example 50 using 2-(4-methoxy-phenyl)-3-methyl-thiophene in the first step.
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[CH:3]/[CH2:4]Cl.[C:7]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:16])[CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10]>>[CH:2]([CH:3]1[CH2:4][C:8]1([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])[C:7]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])=[CH2:1]
Reactant: CCCCOC(=O)CC(=O)OCCCC
Reactant: ClC/C=C/CCl
Product: C=CC1CC1(C(=O)OCCCC)C(=O)OCCCC
Yield: 69 %

Procedure:
Example 3 was repeated except the organic solvent was omitted and the mol ratio of trans 1,4-dichlorobutene-2 to di-n-butyl malonate was 2:1. Di-n-butyl 2-vinylcyclopropane-1,1-dicarboxylate was obtained in 69% yield.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([OH:19])=[O:18].[CH2:20](O)[CH3:21]>O>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCO
Reactant: O=C(O)Cc1ccc2c(c1)CCc1ccccc1S2
Solvent: O
Product: CCOC(=O)Cc1ccc2c(c1)CCc1ccccc1S2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To 70 mg of (10,11-dihydro dibenzo[b,f]thiepin-2-yl)-acetic acid was added 3 ml of ethanol containing 7% hydrogen chloride, and the mixture was stirred under a dry atmosphere at room temperature for 2 hours. To this was added water, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated sodium hydrogen carbonate solution and then with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain a residue, which was chromatographed over 7 g of silica gel and eluted with n-hexane/acetone (10/1), thereby yielding 70 mg (yield: 91%) of ethyl (10,11-dihydro dibenzo[b,f]thiepin-2-yl)-acetate as a yellow oil.