Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][C@H:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])(=[O:3])[CH3:2].[C:32](OCC)(=O)C.CCCCCC>C(Cl)(Cl)Cl>[OH:3][C:1]([C:4]1[C:12]2[O:11][CH2:10][C@H:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])([CH3:32])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OC[C@@H]2c1ccc(C(C)C)cc1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c(C(C)(C)O)c2c1[C@@H](c1ccc(C(C)C)cc1)CO2
Yield: 82 %

Procedure:
Using (+)-N-((3R)-7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 38, the title compound was synthesized in the same manner as in Example 22. Yield: 82%. Melting point: 141-142° C. (ethyl acetate-hexane). [α]D20=+40.8° (c=0.46, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:9]=[C:10]=[O:11])([CH3:8])[CH3:7])=[CH:4][CH:3]=1.[C-]#N.[CH2:16]([NH:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19]>C(C(C)=O)C(C)C>[CH2:16]([N:20]([CH2:21][CH3:22])[C:10]([NH:9][C:6]([CH3:8])([CH3:7])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1)=[O:11])[CH2:17][CH2:18][CH3:19]
Reactant: CC(C)(N=C=O)c1ccc(Cl)cc1
Reactant: CCCCNCC
Agent: [C-]#N
Solvent: CC(=O)CC(C)C
Product: CCCCN(CC)C(=O)NC(C)(C)c1ccc(Cl)cc1
Yield: 86.2 %

Procedure:
A solution of 3.9 g of p-chloro-α,α-dimethylbenzyl isocyanate, prepared from the corresponding cyanide in the same way as in Synthesis Example 1, in 20 ml of methyl isobutyl ketone was added to 2.2 g of N-n-butylethylamine. The solvent was then removed by distillation under reduced pressure and the resulting crystals were recrystallized from n-hexane to obtain 5.1 g of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][CH:7]=1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:27]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:11]=1)=[O:5])[CH3:28]
Reactant: CCOC(=O)C=C(c1ccc(C(=O)N(CC)CC)cc1)c1cccc(OC)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC(c1ccc(C(=O)N(CC)CC)cc1)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 88.8 %

Procedure:
Ethyl 3-(4-diethylcarbamoylphenyl)-3-(3-methoxyphenyl)acrylate (308 mg) synthesized by the method described in WO97/10230 was dissolved in methanol (6 ml), added with 10% palladium/carbon (60 mg) and stirred at room temperature for 22 hours under a hydrogen gas atmosphere. Insoluble solids were removed by filtration, and then the solvent was evaporated under reduced pressure to obtain 275 mg of the title compound. Yield: 89%.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:48]C(OC(C)(C)C)=O)[C:26](=[O:47])[NH:27][C@H:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[C:32]([C:44](=[O:46])[NH2:45])[CH:31]=2)[CH3:29])=[CH:20][CH:19]=1)[P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:13]([O:12][P:10]([CH:9]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][C@H:25]([NH2:48])[C:26](=[O:47])[NH:27][C@H:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[C:32]([C:44](=[O:46])[NH2:45])[CH:31]=2)[CH3:29])=[CH:22][CH:23]=1)[P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8])(=[O:11])[O:15][CH2:16][CH3:17])[CH3:14]
Reactant: CCOP(=O)(OCC)C(c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)c2ccc(OCC3CCCCC3)c(C(N)=O)c2)cc1)P(=O)(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(c1ccc(C[C@H](N)C(=O)N[C@@H](C)c2ccc(OCC3CCCCC3)c(C(N)=O)c2)cc1)P(=O)(OCC)OCC
Reaction time: 0.33 h
Yield: 65.7 %

Procedure:
To [(4-{(S)-2-tert-Butoxycarbonylamino-2-[(S)-1-(3-carbamoyl-4-cyclohexylmethoxy-phenyl)-ethylcarbamoyl]-ethyl}-phenyl)-(diethoxy-phosphoryl)-methyl]-phosphonic acid diethyl ester (2.8 g, 3.5 mmol) in methylene chloride (20 mL) was added TFA (6 mL). The mixture was stirred for 20 min., evaporated to dryness, and dissolved in DMSO (30 mL). Purification by RP HPLC (CH3CN/H2O) and lyophylization yielded a white solid (1.9 g, 2.3 mmol, 66%). MS [M+H]+ 710.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[C:11]([N:14]1[CH2:19][CH2:18][NH:17][CH:16]([CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:15]1)(=[O:13])[CH3:12].[ClH:26]>>[ClH:26].[C:11]([N:14]1[CH2:19][CH2:18][N:17]([C:8](=[O:10])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:16]([CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:15]1)(=[O:13])[CH3:12]
Reactant: O=C(O)Cc1ccccn1
Reactant: CC(=O)N1CCNC(CN2CCCC2)C1
Agent: Cl
Product: CC(=O)N1CCN(C(=O)Cc2ccccn2)C(CN2CCCC2)C1

Procedure:
The compound was prepared by coupling of 2-pyridylacetic acid with 4-acetyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine; mp: (HCl salt) 127-130° C.; 1H NMR (free base, 200 MHz, CDCl3) δ 1.4-1.7 (4H, m), 2.0 (3H, s), 2.2-3.2 (9H, m), 3.4-4.8 (6H, m), 6.8-7.5 (3H, m), 8.4 (1H, m); MS (FAB) 331 (M+H)+; Anal. Calcd. for C18H26N4O2.2HCl.0.5NH4Cl: C, 50.27; H, 7.03; N, 14.65. Found: C, 50.86; H, 6.47; N, 15.79.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12]O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:15]>ClCCl>[Br:15][CH2:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: OCc1nc(-c2ccccc2)cs1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: BrCc1nc(-c2ccccc2)cs1
Temperature: 22 °C
Reaction time: 0.17 h
Yield: 177 %

Procedure:
A solution of (4-phenylthiazol-2-yl)methanol (Example 4C, 0.530 g, 2.77 mmol) in dichloromethane (10 mL) was cooled to 0° C. (ice bath) and treated with PBr3 (0.118 mL, 1.247 mmol) added dropwise over 2 min. A heavy white gum was immediately formed. After 10 min, the bath was removed and the solution was stirred at 22° C. for 4 h. The reaction mixture was quenched with ice (˜10 g) and poured into a mixture of ethyl acetate (150 mL) and saturated sodium bicarbonate (50 mL). The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The solid residue was chromatographed on silica gel (2.5×6 cm, elution toluene) to give the title material (0.561 g, 80%) as a light yellow oil which solidified in the fridge to a pale yellow solid. LC (Method C): 2.062 min. HRMS (ESI) calcd for C10H9BrNS [M+H]+ m/z 253.9634. found 253.9655. 1H NMR (CDCl3, 400 MHz) δ ppm: 4.81 (s, 2H), 7.34-7.39 (m, 1H), 7.41-7.47 (m, 2H), 7.52 (s, 1H), 7.86-7.92 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][C:5]1[C:17]2[C:8](=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:18][CH3:19])=[CH:12][CH:11]=3)[N:7]([CH2:20][C:21]([O:23]CC)=O)[N:6]=1>CO>[NH2:4][C:5]1[C:17]2[C:8](=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:18][CH3:19])=[CH:12][CH:11]=3)[N:7]([CH2:20][C:21]([N:2]([CH3:3])[CH3:1])=[O:23])[N:6]=1
Reactant: CCOC(=O)Cn1nc(N)c2cc3cc(OC)ccc3nc21
Reactant: CNC
Solvent: CO
Product: COc1ccc2nc3c(cc2c1)c(N)nn3CC(=O)N(C)C
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a saturated solution of dimethylamine in 250 ml methanol at 0° C. was added 4.5 g ethyl 3-amino-6-methoxy-1H-pyrazolo[3,4-b]quinolin-1-acetate (Example 20), and the mixture was stirred at 0° C. for one hour, at room temperature for 48 hours and at reflux for two hours. The reaction mixture was cooled to room temperature and the solid product was collected by filtration and chromatographed on silica gel using 95% chloroform/2.5% isopropyl alcohol/2.5% isopropylamine amine as eluant. The appropriate fractions were combined and evaporated to give 2.0 g 3-amino-6-methoxy-N,N-dimethyl-1H-pyrazolo[3,4-b]quinolin-1-acetamide, orange solid, m.p. 251°-253° C.
Reaction SMILES: [C:1]([N:5]1[C:14](=[O:15])[C:13]2[CH:12]=[C:11]([CH3:16])[N+:10]([O-])=[CH:9][C:8]=2[C:6]1=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:20])=O>>[C:1]([N:5]1[C:14](=[O:15])[C:13]2[CH:12]=[C:11]([CH2:16][Cl:20])[N:10]=[CH:9][C:8]=2[C:6]1=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2c(c[n+]1[O-])C(=O)N(C(C)(C)C)C2=O
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)(C)N1C(=O)c2cnc(CCl)cc2C1=O
Reaction time: 3 h

Procedure:
31.5 g of N-tert-butyl-6-methylpyridine-3,4-dicarboximide-1-oxide from 6.004 are added a little at a time to 300 ml of phosphorus oxychloride, and the mixture is heated stepwise until it refluxes and is stirred for 3 hours. The reaction mixture is evaporated down under reduced pressure, the residue is taken up in methylene chloride and the solution is stirred into ice water. The organic phase is washed several times with water, dried, filtered over alumina and evaporated down under reduced pressure. 28.9 g of the title compound of melting point 62°-64° C. are obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1)=[O:17].C(OCC)(=O)C.[ClH:50]>>[ClH:50].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[O:26])[CH2:22][NH:21][CH2:20]1)=[O:17]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)cc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)cc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (83.4 mg) was dissolved in 4N hydrogen chloride-ethyl acetate (3 ml), and the mixture was WO2009/154300 PCT/JP2009/061438 stirred at room temperature for 1.5 hr. The reaction mixture was concentrated to give the object product (67 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O.[OH-].[Na+].O>C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[C:12](=[O:14])/[CH:13]=[CH:20]/[C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)/C=C/c1ccc(C(C)C)cc1
Reactant: O=Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc(/C=C/C(=O)/C=C/c2cccs2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
A mixture of 7.9 grams (0.042 mol) of E-4-(p-isopropylphenyl)-3-butene-2-one, 4.7 grams (0.042 mol) of 2-thiophene carboxaldehyde, 2 mL of 10% sodium hydroxide, 30 mL of water, and 75 mL of ethanol was stirred at ambient temperature for 15 hours. The product was collected by filtration and air dried to give 10.2 grams (86% of theoretical yield) of E,E-1-(p-isopropylphenyl)-5-(2-thienyl)-l,4-pentadien-3-one as a yellow solid. Melting point was determined to be 100°-101° C. Proton nuclear magnetic resonance (1H NMR) was conducted in CDCl3 : d 7.84 (d, 1H, J=16 Hz), 7.69 (d, 1H, J=16 Hz) , 7.53 (AA'BB', 2H) , 7.39 (m, 1H) , 7.32 (m, 1H), 7.25 (AA'BB', 2H) , 7.06 (dxd, 1H, J= 3.6, 5 Hz), 6.96 (d, 1H, J=16 Hz), 6.87 (d, 1H, J=16 Hz), 2.90 (septet, 1H, J=7 Hz), 1.23 (d, 6H, J=7 Hz). Infrared spectroscopy was conducted using a KBr pellet: 2960, 1650, 1585, 1180, and 705 cm-1. Field desorption mass spectral analysis (FDMS) was consistent with the proposed formula (C18H18OS) m+ /z 316.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]=[C:9]3[N:17]4[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]4[CH2:15][O:14][C:10]3=[N:11][C:12]=2[CH:13]=1)([O-])=O.[H][H]>[Pd].O1CCOCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:8]=[C:9]3[N:17]4[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]4[CH2:15][O:14][C:10]3=[N:11][C:12]=2[CH:13]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2nc3c(nc2c1)OCC1CCCCN31
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc2nc3c(nc2c1)OCC1CCCCN31

Procedure:
A mixture of 5.72 g. of 1,2,3,4,4a,5-hexahydro-9-nitropyrido[1',2':4,5][1,4]oxazino[2,3-b]quinoxaline, 200 ml. of dioxane and 1.5 g. of palladium on carbon catalyst is shaken in a Parr hydrogenator under 45 lb. of hydrogen pressure until reduction is complete. The mixture is filtered and the filtrate concentrated to a residue. The residue is recrystallized from ethanol to give the desired product, m.p. 229°-232° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[H-].[Na+].[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19]>C1COCC1>[F:16][C:17]([F:24])([F:23])[C:18](=[O:19])[CH2:12][C:11]([C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)=[O:13]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a THF suspension of 1-(3-methyl-4-nitro-phenyl)-ethanone (2.0 g), sodium hydride (0.6 g) was slowly added and the mixture was stirred for 1 hour. After adding ethyl trifluoroacetate (1.6 g), the reaction mixture was refluxed for 5 hours. After cooling, the solvent was distilled off under reduced pressure. The residue was suspended in ethyl acetate and washed with 1N aqueous solution of hydrochloric acid. After drying the organic layer with sodium sulfate, the solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain 4,4,4-trifluoro-1-(3-methyl-4-nitro-phenyl)-butane-1,3-dione (2.5 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[O:17])=[C:12]([Cl:25])[CH:11]=1.[F:26][C:27]([F:34])([F:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Cl:25][C:12]1[CH:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][NH:1][S:29]([CH2:28][C:27]([F:34])([F:33])[F:26])(=[O:31])=[O:30])[CH:15]=[CH:14][C:13]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[O:17]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CN)cc1Cl
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CNS(=O)(=O)CC(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 148 (0.18 g, 0.71 mmol) was dissolved in dry pyridine (0.9 mL) and 2,2,2-trifluoroethanesulfonyl chloride (0.12 mL, 1.1 mmol) was added. The solution was stirred at room temperature for 1 h after which it was concentrated in vacuo. The oil was diluted with H2O and the water phase was extracted three times with EtOAc. The combined organic phases were washed with 10% aqueous NaHCO3, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether 1:2 as the eluent to afford the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[CH:4][C:5]([O:8]C)=[N:6][CH:7]=1.C([Li])CCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[CH2:24][C:25](N(OC)C)=[O:26])=[CH:19][CH:18]=1.Cl>O1CCOCC1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[CH2:24][C:25]([C:2]2[C:3]([CH3:10])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=2)=[O:26])=[CH:21][CH:22]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Reactant: COc1cc(C)c(Br)cn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1COCCO1
Product: Cc1cc(=O)[nH]cc1C(=O)CC(c1ccc(Br)cc1)c1ccccc1C

Procedure:
In analogy to example 151, step 1, 5-bromo-2-methoxy-4-methylpyridine was reacted first with n-butyllithium and later with 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4). The product of this reaction was reacted with concentrated aqueous HCl in 1,4-dioxane in analogy to example 162, step 2 to give the title compound as a colorless foam, MS (ESI+): m/z=410.2 [M+H]+.
Reaction SMILES: ClCCl.B(Br)(Br)Br.C[O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][C:17]([CH3:20])([CH3:19])[C:16](=[O:21])[NH:15][C:14]=2[CH:22]=1>O>[OH:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][C:17]([CH3:19])([CH3:20])[C:16](=[O:21])[NH:15][C:14]=2[CH:22]=1
Reactant: COc1ccc2c(c1)NC(=O)C(C)(C)O2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC1(C)Oc2ccc(O)cc2NC1=O
Reaction time: 8 h
Yield: 80 %

Procedure:
A dichloromethane solution (36 ml) of 2M boron tribromide was added dropwise to a dichloromethane solution of 6-methoxy-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (5.0 g, 26 mmol) under ice cooling and the mixture was stirred overnight. Water was added to the reaction solution to decompose the reagents excessively present. The reaction solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1). The purified product was concentrated to dryness under reduced pressure to obtain 6-hydroxy-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (4.02 g) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12].[CH2:13]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18])[C:14]#[CH:15].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[NH2:12][C:3]1[C:4]2[O:8][CH2:7][O:6][C:5]=2[C:9]([C:15]#[C:14][CH2:13][NH:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])=[CH:10][C:2]=1[Cl:1]
Reactant: C#CCNC(=O)N1CCOCC1
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: Nc1c(Cl)cc(C#CCNC(=O)N2CCOCC2)c2c1OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
5-Chloro-7-iodo-1,3-benzodioxol-4-amine (600 mg, 2.02 mmol) and N-prop-2-yn-1-ylmorpholine-4-carboxamide (406 mg, 2.42 mmol) in ethyl acetate (10 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, and then treated with bis(triphenylphosphine) palladium(II) dichloride (140 mg, 10 mol %) followed by copper(I) iodide (38 mg, 10 mol %) and diisopropylamine (407 mg, 4.03 mmol). The reaction was allowed to warm to room temperature and stirred for 3 hours and then filtered through Celite. The filtrate was purified by column chromatography on silica using ethyl acetate as eluent to give N-[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]morpholine-4-carboxamide (529 mg, 78%) as a pale brown solid; NMR Spectrum:(DMSOd6) 3.28 (m, 4H), 3.54 (m, 4H), 4.05 (d, 2H), 5.47 (s, 2H), 6.05 (s, 2H), 6.78 (s, 1H), 7.01 (t, 1H); Mass Spectrum: M+H+ 338/340.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1.Cl[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[CH2:13][CH2:12]2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(C(=CC2CCNCC2)c2cccc(OC)c2)c1
Reactant: ClCCCCCCCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(=CC2CCN(CCCCCCCCc3cccnc3)CC2)c2cccc(OC)c2)c1
Reaction time: 16 h
Yield: 70.1 %

Procedure:
A mixture of 4-[2,2-bis(3-methoxyphenyl)ethenyl]piperidine (1.65 g), 3-(8-chloroctyl)pyridine (1.13 g), sodium iodide (0.75 g) and anhydrous sodium carbonate (0.53 g) in dimethylformamide (10 ml) was stirred under argon at 75° for 16 hours. The solvent was removed in vacuo and the residue was taken up in a mixture of ethyl acetate and 1N sodium hydroxide solution. The separated aqueous layer was reextracted with three portions of ethyl acetate. The organic layers were washed in turn with water and brine, then were combined, dried over sodium sulfate, decolorized with charcoal and evaporated to give 2.5 g of crude product as an oil. The oil was purified by HPLC (hexane:ethyl acetate:triethylamine; 34:17:1) to give 1.8 g of 3-[8-[4-[2,2-bis(3-methoxyphenyl)ethenyl]-1-piperidinyl]octyl]pyridine, as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([OH:35])[CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33].C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:35][C:28]1[CH:29]=[CH:30][C:31]([N+:32]([O-:34])=[O:33])=[C:26]([F:25])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1NC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])c(F)c3)c2cc1NC(=O)OCc1ccccc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 8.8 %

Procedure:
(4-Chloro-7-methoxyquinolin-6-yl)carbamic acid benzyl ester (1.58 g) was added to 1-methyl-2-pyrrolidone (5 ml), and then 3-fluoro-4-nitrophenol (0.87 g) and N,N-diisopropylethylamine (1.2 ml) were added and the mixture was heated and stirred at 130° C. for 6 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The organic layer was concentrated and the obtained residue was subjected to NH silica gel column chromatography for elution with a solvent (ethyl acetate) to obtain the title compound (188 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][CH2:26][C:16]1([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:28])[CH2:14][CH2:15]1)=[O:6]
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: O=C(NCC1(c2ccc(F)nc2)CCC(F)(F)CC1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and (4,4-difluoro-1-(6-fluoropyridin-3-yl)cyclohexyl)methanamine. LCMS (MH+): m/z=401.2, tR (minutes, Method D)=0.72
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)/[C:5](=[CH:13]/[C:14]([OH:16])=O)/[CH2:4]1)[CH3:2].[Cl:17]CCl>>[CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)/[C:5](=[CH:13]/[C:14]([Cl:17])=[O:16])/[CH2:4]1)[CH3:2]
Reactant: ClCCl
Reactant: CCC1C/C(=C\C(=O)O)c2cc(F)ccc21
Product: CCC1C/C(=C\C(=O)Cl)c2cc(F)ccc21

Procedure:
This compound was prepared in an analogous manner to Example 18h with replacement of (E)-2-(6-fluoro-3-methyl- 1 -indanylidene)acetic acid with (E)-2-(3-ethyl-6-fluoro-1-indanylidene)acetic acid (5.7 g. 25.88 mmol). The product residue was dissolved in dichloromethane and used without purification in Example 26.