Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:22][C:21](=[O:23])[O:20][N:19]=2)=[C:14]([O:24][CH3:25])[CH:13]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[CH3:42]S(OS(C)(=O)=O)(=O)=O>C(#N)C>[CH3:25][O:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10][C:9]2[S:8][C:7]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=3)=[N:6][C:5]=2[CH2:4][CH2:3][CH2:2][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:42]2)[CH:17]=[CH:16][C:15]=1[C:18]1[NH:22][C:21](=[O:23])[O:20][N:19]=1
Reactant: c1ccncc1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCO)ccc1-c1noc(=O)[nH]1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: CC#N
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCN2CCCCCC2)ccc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 150 mg of 3-{4-[4-(3-hydroxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one in 6 mL of acetonitrile were added 0.100 mL of pyridine and 0.200 mL of methanesulfonic anhydride. The resulting mixture was stirred at room temperature for 5 hour then 0.250 mL of hexamethyleneimine was added. The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified by preparative HPLC on normal phase coupled to MS (gradient of methanol 5 in dichloromethane containing NH4OH), then precipitated from dichloromethane/pentane to give 26 mg of 3-{2-methoxy-4-[4-(3-perhydro-azepin-1-yl-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-1,2,4-oxadiazol-5-one as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@H:19]([C:23]([O:25][CH3:26])=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N.CO>C1COCC1.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][C@H:19]([C:23]([O:25][CH3:26])=[O:24])[CH:20]([CH3:21])[CH3:22])(=[O:17])=[O:16])=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2cccc(C#N)c2)cc1)C(C)C
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2cccc(CN)c2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
A suspension of methyl N-[(3′-cyanobiphenyl-4-yl)sulfonyl]valinate obtained in Reference Example 93 (5.00 g, 13.4 mmol), Raney-nickel (5.00 g) and 28% aqueous ammonia (50 mL) in THF (50 ml)-methanol (50 mL) was stirred at room temperature for 15 hr under hydrogen atmosphere (1 atm). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. A mixed solvent of ethyl acetate-hexane was added to the residue, and the precipitated insoluble material was filtered off. The filtrate was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and diethyl ether was added to the residue. The precipitated solid was collected by filtration to give the title compound as a white powder (3.84 g, 76%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[N+](=[CH2:15])=[N-]>CCOCC.CO>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:15])=[O:7]
Reactant: O=C(O)C=Cc1ccccc1O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a stirred mixture of ortho-hydroxycinnamic acid (1.00 g, 6.09 mmol) in 10 mL of ether and 10 mL of methanol was added etheral diazomethane until the mixture became yellowish. The mixture was stirred at room temperature for 15 minutes, and the excess diazomethane was destroyed with the addition of acetic acid. The mixture was concentrated in vacuo and diluted with 100 mL of ethyl acetate. This ethyl acetate solution was washed with saturated sodium bicarbonate solution (3×60 mL) and brine (1×60 mL). The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo to give 1.02 g (94%) of methyl ortho-hydroxycinnamate B.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:18][CH:19]=[C:20]([C:22]([OH:24])=O)[N:21]=2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].CC[N:27]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])=O.[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:18][CH:19]=[C:20]([C:22]([NH2:27])=[O:24])[N:21]=2)[CH2:13][CH2:12]1)(=[O:10])=[O:9]
Reactant: O=C(O)c1csc(N2CCN(S(=O)(=O)c3ccccc3Cl)CC2)n1
Reactant: CCN=C=NCCCN(C)C
Agent: O=C[O-]
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1csc(N2CCN(S(=O)(=O)c3ccccc3Cl)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
2-(4-(2-chlorophenylsulfonyl)piperazin-1-yl)thiazole-4-carboxylic acid (77 mg, 0.02 mmole), EDCI (39 mg, 0.02 mmole), HOBt (31 mg, 0.02 mmole) and ammonium formate (13 mg, 0.02 mmole) were combined in 1 ml of dry DMF. The mixture was treated with 1 equivalent of TEA and stirred at room temperature overnight. The title compound was obtained in yield of 37% after purification on preparative HPLC. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 3.41 (s, 1 H), 3.42-3.44 (m, 3 H), 3.53-3.56 (m, 3 H), 3.57 (s, 1 H), 6.02 (s, 1 H), 6.95 (s, 1 H), 7.38-7.44 (m, 2 H), 7.50-7.53 (m, 2 H), 8.02-8.07 (m, 1 H); ESI-MS: m/z 387.1 (M+H)+.
Reaction SMILES: O[C@H:2]([CH2:35][O:36][Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CS(O)(=O)=O.C(N(CC)CC)C.O>O1CCCC1>[CH3:33][O:32][CH2:31][C@H:30]([CH3:34])[O:29][C:14]1[CH:13]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:6][C@@H:2]([CH2:35][O:36][Si:37]([CH:38]([CH3:40])[CH3:39])([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:42])[CH3:43])[CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][Si:19]([CH:26]([CH3:27])[CH3:28])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:15]=1
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)NC[C@H](O)CO[Si](C(C)C)(C(C)C)C(C)C)[nH]2)c1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=NC[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
N-{(2S)-2-Hydroxy-3-[(triisopropylsilyl)oxy]propyl}-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxamide (10.54 g, 15.6 mmol) synthesized in Example (125e) was dissolved in tetrahydrofuran (160 mL), and anhydrous methanesulfonic acid (5.51 g, 31.6 mmol) and triethylamine (8.70 mL, 62.4 mmol) were added, followed by stirring at room temperature for 3 hours under nitrogen atmosphere, and subsequently the temperature was raised to 60° C., followed by stirring for 3 hours. To the reaction solution, water (200 mL) was added, and extraction was carried out with ethyl acetate (300 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=5%-30%) to afford the desired compound (9.72 g, yield 95%) as a brown oil.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O.[OH-].[Na+:27]>C(O)(C)(C)C>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Na+:27]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
Dispersion B was prepared by using such a facility as shown in FIG. 3. In the tank 30, 87.6 g of behenic acid (Edenor C22-85R, trade name, manufactured by Henkel Co.), 423 mL of distilled water and 120 mL of tert-butanol were added with 49.2 mL of 5 mol/L aqueous solution of NaOH over 5 minutes at 75° C. with stirring, and allowed to react at for 60 minutes to obtain a solution of sodium behenate. Separately, 206.2 mL of an aqueous solution containing 40.4 g of silver nitrate (pH 4.0) was prepared and kept at 10° C. in the tank 29. Further, 600 mL of pure water was measured in the tank 38, and circulated through the pipeline mixer 37, Model LR-1 produced by Mizuho Kogyo Co., Ltd., via the pump 35 at a flow rate of 100 mL/minute. While stirring was performed by operating the pipeline mixer at 10,000 rpm, the aqueous solution of silver nitrate was added at a constant flow rate of 2.9 ml/minute by using the pump 33, and after 5 seconds, addition of the aqueous solution of sodium behenate was started at a constant flow rate of 9.8 mL/minute, so that the solutions were stored in the tank 38. Cooling water at 10° C. was supplied to a jacket of the tank 38 at a flow rate of 2 L/minute, and as a result, the average temperature in the tank was measured to be 30° C.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:25]([O:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:28])([CH3:27])[CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:25]([O:29][C:30](=[O:33])[CH2:31][NH:32][CH2:16][C:13]1[S:12][C:11]([NH:10][C:8]([N:7]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:9])=[N:15][CH:14]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)OC(=O)CNCc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 68.8 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (67 mg. 0.20 mmol), glycine tert-butyl ester hydrochloride (50 mg, 0.30 mmol) and sodium triacetoxyborohydride (59 mg, 0.28 mmol) to afford 62 mg (68%) of the desired product after purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([C:14]([NH2:16]=O)=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.[H][H].[ClH:31]>C(OCC)(=O)C.[Pd]>[ClH:31].[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:11]2([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:20]=1
Reactant: O=C([NH2+][O-])C1(c2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NC(=O)C1(c2ccc(F)cc2)CCNCC1
Temperature: 25 °C

Procedure:
1-Benzyl-4-(4-fluoro-phenyl)-piperidine-4-carboxylic acid amide N-oxide (5.3 g, 16.3 mmol) and 10% palladium-on-carbon (0.6 g) and acetic acid (100 mL) were combined in a pressure vessel. The reaction mixture was treated with hydrogen on a Parr apparatus at an initial pressure of 53 psi of hydrogen. When hydrogen consumption stopped the catalyst was removed by filtration. The filtrate was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (150 mL), acidified by the addition of 12M aqueous hydrochloric acid solution (5 mL), and heated to reflux for 10 minutes. The mixture was cooled to ambient temperature to give a solid which was collected by filtration, rinsed with ethyl acetate, recrystallized from methanol/ethyl acetate to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[N:29]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:28]=[CH:27][CH:26]=3)[N:19]=2)([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:37])[NH:35][NH2:36].Cl.CN(C)CCCN=C=NCC.O>C(Cl)(Cl)Cl>[CH2:39]([O:38][C:34]([NH:35][NH:36][C:14]([C:11]1([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[N:29]([C:30]([CH3:33])([CH3:31])[CH3:32])[N:28]=[CH:27][CH:26]=3)[N:19]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[O:16])=[O:37])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)(C(=O)O)CC1
Reactant: NNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)(C(=O)NNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 535 mg of 1-(tert-butoxycarbonyl)-4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid in 10 ml of chloroform were added 214 mg of benzyl carbazate and 291 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at room temperature, followed by stirring the reaction mixture at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with chloroform. The chloroform solution was dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane to hexane/ethyl acetate=10/1) to give the title compound as a pale brown solid.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[N:12]1([C:17]2[CH:45]=[CH:44][C:20]([CH2:21][C:22]3[C:23]([O:42][CH3:43])=[N:24][C:25]4[C:30]([C:31]=3[Cl:32])=[CH:29][C:28]([C:33]([C:35]3[N:39]([CH3:40])[C:38]([CH3:41])=[N:37][CH:36]=3)=[O:34])=[CH:27][CH:26]=4)=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[N:13]1.O>O1CCCC1>[N:12]1([C:17]2[CH:18]=[CH:19][C:20]([CH2:21][C:22]3[C:23]([O:42][CH3:43])=[N:24][C:25]4[C:30]([C:31]=3[Cl:32])=[CH:29][C:28]([C:33]([C:35]3[N:39]([CH3:40])[C:38]([CH3:41])=[N:37][CH:36]=3)([C:11]3[N:7]([CH3:6])[N:8]=[N:9][CH:10]=3)[OH:34])=[CH:27][CH:26]=4)=[CH:44][CH:45]=2)[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1nc2ccc(C(O)(c3cnnn3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
A solution of n-butyllithium in hexanes (2.5 M, 0.32 mL, 0.81 mmol) was added dropwise to a stirring solution of 1-methyl-1H-1,2,3-triazole (70.4 mg, 0.848 mmol, prepared according to PCT Int. Appl., 2008098104) in tetrahydrofuran (1 mL) at −50° C. After 20 minutes, a solution (gently warmed with a heat gun to dissolve the ketone starting material) of (3-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (200 mg, 0.42 mmol, Intermediate 21: step b) in tetrahydrofuran (1 mL) was added dropwise. After 5 minutes, the flask was allowed to warm to 23° C. After 20 minutes, water (1 mL) was added. The biphasic mixture was partitioned between saturated aqueous sodium chloride solution (25 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was dried with sodium sulfate. The dried solution was filtered. Silica gel (2 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with dichloromethane initially, grading to 10% methanol-dichloromethane provided the title compound which was further purified by RP-HPLC eluting initially with 5% acetonitrile-water (containing 0.05% trifluoroacetic acid), grading to 95% acetonitrile-water (containing 0.05% trifluoroacetic acid) to provide the title compound as a white solid after partitioning the purified material between dichloromethane-saturated aqueous sodium bicarbonate solution, separating the layers, drying the organic layer with sodium sulfate, filtering the dried solution, and concentrating the filtrate to dryness. 1H NMR (400 MHz, CDCl3) δ ppm 8.21 (s, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H), 7.60-7.53 (m, 2H), 7.41-7.33 (m, 3H), 7.11 (d, J=1.4 Hz, 1H), 6.46-6.39 (m, 1H), 6.08-6.02 (m, 1H), 4.27 (s, 2H), 4.08 (s, 3H), 3.89 (s, 3H), 3.35 (s, 3H), 2.20 (s, 3H); MS (ESI): mass calcd. for C29H27ClN8O2, 554.2. m/z found, 555.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([NH:15][CH3:16])[N:7]=[C:6]2[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=1.C(N(CC)CC)C.C(O)C.[H][H]>[C].[Pd].O1CCCC1>[NH2:23][C:19]1[CH:18]=[C:17]([C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[C:8]([NH:15][CH3:16])[N:7]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CNc1nc(-c2cccc([N+](=O)[O-])c2)c2cc(OC)c(OC)cc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNc1nc(-c2cccc(N)c2)c2cc(OC)c(OC)cc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.1 %

Procedure:
1.83 g of 6,7-dimethoxy-2-methylamino-4-(3-nitrophenyl) quinazoline obtained in Production Example 4,200 mg of 10% palladium-carbon powder (hydrate) and 1.44 g triethylamine were suspended in a mixed solvent of 10 ml ethanol and 10 ml tetrahydrofuran. After the atmosphere was replaced with hydrogen, the mixture was stirred for 15 hours at ordinary pressure at room temperature. The reaction solution was filtered, then the filtrate was evaporated, and the crude product was purified and separated by silica gel column chromatography (hexane:ethyl acetate=1:3). The product was recrystallized from hexane-ethyl acetate to give 1.22 g of the title compound as pale yellow crystals.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28]I)=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C>[CH2:2]([N:4]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)[CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:22](=[O:23])[C:21]1[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:19]([O:18][CH3:17])[CH:20]=1)[CH3:3]
Reactant: COc1cc(C(=O)OCCCCI)cc(OC)c1OC
Reactant: CCNC1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCN(CCCCOC(=O)c1cc(OC)c(OC)c(OC)c1)C1CCc2cc(OC)ccc2C1

Procedure:
Using 2.0 g of N-ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride, 3.3 g of 4-iodobutyl 3,4,5-trimethoxybenzoate, 0.9 g of anhydrous sodium carbonate and 40 ml of methyl ethyl ketone, the free base, N-ethyl-N-[4-(3,4,5-trimethoxybenzoyloxy)butyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine, was obtained using the procedures described in Example 2 (ii). The free base was treated with methanesulfonic acid to obtain 1.5 g of N-ethyl-N-[4-(3,4,5-trimethoxybenzoyloxy)butyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine methanesulfonate as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[N:12]=[C:13]=[O:14].[CH2:15]([OH:17])[CH3:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:8]([CH3:10])([CH3:11])[CH3:9])[C:3]=1[NH:12][C:13](=[O:14])[O:17][CH2:15][CH3:16]
Reactant: CCO
Reactant: C[Si](C)(C)c1cccc(Cl)c1N=C=O
Product: CCOC(=O)Nc1c(Cl)cccc1[Si](C)(C)C

Procedure:
A mixture of the compound of Example h (10 mmol) and ethanol (75 mL) was refluxed for 1 h. The mixture was concentrated and the residue dissolved in ethyl acatate. The solution was washed twice with water and the solvent removed to yield the crude product, which was recrystallized from hexane. GC/MS showed some remaining isocyanate so the solid was dissolved in ethanol and refluxed again with approx. 0.1 g diazobisbicyclooctane. FID/GC indicated a complete reaction and the ethanol was removed and the title compound recovered. m.p. 109-110° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br-].[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([Zn+])=[N:31][CH:32]=1>O1CCOCC1.[Zn]>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([C:2]2[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([OH:24])([C:16]([F:17])([F:18])[F:19])[C:20]([F:23])([F:21])[F:22])[CH:14]=2)[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])=[N:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: Cc1ccc([Zn+])nc1
Agent: [Br-]
Agent: [Zn]
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(O)(C(F)(F)F)C(F)(F)F)c2)nc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-bromo-5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzoate (1.2 g, 2.8 mmol) in 0.6 mL of dioxane under N2 was added 5-methyl-2-pyridyl zinc bromide (0.5M, 11.3 mL, 5.67 mmol). The reaction was heated to 70° C. for two hours. An additional 0.5 equivalents of zinc reagent was added and the mixture stirred at 70° C. overnight. The mixture was cooled and concentrated. The crude material was taken up in EtOAc and sat. NaHCO3 and sat. Rochelle's salt added. The organic layer was extracted and washed with Rochelle's salt (2×) followed by brine. The final organic layer was dried over Na2SO4, filtered and concentrated to 1.01 g of crude material. Purification using automated flash chromatography (SiO2, 120 g, 0-5% MeOH/DCM) gave, upon concentration, title product. LC-MS (M+H)=436.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].[Br:12][C:13]1[CH:24]=[C:17]2[C:18](OC(=O)[NH:22][C:16]2=[CH:15][CH:14]=1)=[O:19].O.C(OCC)(=O)C>CN(C)C=O>[NH2:22][C:16]1[CH:15]=[CH:14][C:13]([Br:12])=[CH:24][C:17]=1[C:18]([NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=1)=[O:19]
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: COc1ccc(CN)cc1Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc(Br)ccc2N)cc1Cl
Temperature: 25 °C
Yield: 53.5 %

Procedure:
A solution of 3-chloro-4-methoxybenzylamine (234 mg) in N,N-dimethylformamide (5 mL) was added dropwise to a solution of 5-bromoisatoic anhydride (300 mg) in N,N-dimethylformamide (3 mL). The reaction mixture was stirred for an hour at ambient temperature. The mixture was poured into a mixture of water and ethyl acetate. The precipitates were collected by filtration and washed with 2-propanol to give 2-amino-5-bromo-N-(3-chloro-4-methoxybenyl)benzamide (245 mg) as white powders.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26].C([O-])([O-])=O.[Na+].[Na+]>CCO>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: Fc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(Sc2ccccc2F)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
The product from Example 4a (1.50 g, 5.3 mmol) and 2-fluorobenzenethiol (0.56 mL, 5.3 mmol) in EtOH (15 mL) was added aqueous Na2CO3 solution (0.563 g, 5.3 mmol) dropwise at room temperature. The mixture was heated to reflux fluxed for 1 hour, and then evaporated. The residue was diluted with EtOAc, washed with H2O, 5% KOH and brine, dried over MgSO4, filtered and concentrated under vacuum giving the title compound as yellow crystal, which was purified by washing with cold n-hexane to give the title product as yellow crystal (1.15 g, 83%).