Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15]CC3C=CC(OC)=CC=3)[CH2:9]2)=[CH:6][C:5]([C:25]#[N:26])=[CH:4][C:3]=1[NH:27][C:28]1[N:33]=[C:32]([N:34]([CH:44]2[CH2:46][CH2:45]2)CC2C=CC(OC)=CC=2)[C:31]2=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:30]2[N:29]=1.C(N(CC)CC)C.[CH3:59][S:60](Cl)(=[O:62])=[O:61].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([NH:27][C:28]2[N:33]=[C:32]([NH:34][CH:44]3[CH2:46][CH2:45]3)[C:31]3=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:30]3[N:29]=2)=[CH:4][C:5]([C:25]#[N:26])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][S:60]([CH3:59])(=[O:62])=[O:61])[CH2:9]1
Reactant: COc1ccc(CNCC2CN(c3cc(C#N)cc(Nc4nc(N(Cc5ccc(OC)cc5)C5CC5)c5ncc(C#N)n5n4)c3Cl)CCO2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NCC1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CCO1
Temperature: 25 °C

Procedure:
To a round bottom flask charged with (+/−)-2-((2-chloro-5-cyano-3-(2-(((4-methoxybenzyl)amino)methyl)morpholino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (38.9 mg, 0.055 mmol) in tetrahydrofuran (276 μl) was added triethylamine (13.84 μl, 0.099 mmol) and methanesulfonyl chloride (5.59 μl, 0.072 mmol). The reaction mixture was stirred at room temperature ON. The reaction mixture was diluted with ethyl acetate and transferred to a separatory funnel containing saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was taken forward into the deprotection.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[O:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])[CH2:11][CH2:10]1>ClCCl>[Cl:1][C:19]1[CH:20]=[C:15]([CH:12]2[CH2:11][CH2:10][O:9][CH2:14][CH2:13]2)[C:16]([OH:22])=[CH:17][C:18]=1[OH:21]
Reactant: Oc1ccc(C2CCOCC2)c(O)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Oc1cc(O)c(C2CCOCC2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 17 %

Procedure:
2.4 g of N-chlorosuccinimide are added to a solution of 2 g of 4-(tetrahydropyran-4-yl)benzene-1,3-diol (Example 1) in 30 ml of dichloromethane at 0° C. The reaction mixture is stirred at ambient temperature for 16 hours. The reaction mixture is extracted with dichloromethane and then washed with water. The organic phases are combined and then dried over sodium sulphate. The residue is chromatographed on silica gel (75/25 heptane/ethyl acetate). 400 mg of 4-chloro-6-(tetrahydropyran-4-yl)benzene-1,3-diol are obtained. Yield=17%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([NH:15][NH2:16])=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:17][C:18]([F:26])([F:25])[C:19]([OH:24])([CH3:23])[C:20](O)=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.CO>[NH2:1][C:2]1[C:3]([C:13]([NH:15][NH:16][C:20](=[O:21])[C:19]([OH:24])([CH3:23])[C:18]([F:26])([F:25])[F:17])=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Reactant: CC(O)(C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC(O)(C(=O)NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N)C(F)(F)F
Temperature: 0 °C

Procedure:
A cooled (0° C.) solution of 3-amino-6-bromo-5-(trifluoromethyl)picolinohydrazide (Intermediate H) (15 g, 50.2 mmol) in dry NMP (50 ml) was treated with 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (8.72 g, 55.2 mmol), HATU (20.98 g, 55.2 mmol) followed by dropwise addition of TEA (15.38 ml, 110 mmol) over 10 minutes. The orange solution was stirred at 0° C. and allowed to warm to RT and stirred for 3 days. The reaction mixture was partitioned between EtOAc (200 mL) and 1M NaOH (200 mL), shaken and separated. The organic portion washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to give an orange oil. The oil was taken up in methanol (50 mL) and triturated with water (300 mL) to afford the title compound as a yellow solid;
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])[CH2:8][NH2:9])([CH3:4])[CH3:3].[CH3:21][S:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](N)=[O:31])[CH:26]=[CH:27][CH:28]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH2:8][NH:9][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([S:22][CH3:21])[CH:24]=2)=[O:31])[CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])([CH3:1])[CH3:3]
Reactant: COCOc1c(C(C)(C)C)cc(CN)cc1C(C)(C)C
Reactant: CSc1cccc(NC(N)=O)c1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COCOc1c(C(C)(C)C)cc(CNC(=O)Nc2cccc(SC)c2)cc1C(C)(C)C
Yield: 25 %

Procedure:
The above-titled compound was prepared substantially in accordance with the procedure described in Example 6A using 5.2 g (18.5 mmol of 3,5-bis(1,1-dimethylethyl)-4-(methoxymethoxy)benzylamine, 4.62 g (25.4 mmol) of N-[3(methylthio) phenyl]urea (prepared substantially in accordance with the procedure described in Example 5), 1.06 ml of acetic acid and 180 ml of toluene. Such reaction provided 2.06 g of N[[3,5-bis(1,1-dimethylethyl)-4-(methoxymethoxy)phenyl]methyl]N'-[3-(methylthio)phenyl]urea. The methoxymethyl hydroxy protecting group was then removed, substantially in accordance with the procedure described in Example 6B, to provide 444 mg of title compound. m.p. 133°-138° C. (dec).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[C:26]3[NH:33][CH:34]=[CH:35][C:25]=3[C:24]=2[CH:23]=1)=O)(C)(C)C.[CH2:36]([C:38]([O-:40])=[O:39])[CH3:37]>ClC(Cl)C>[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[C:26]3[NH:33][CH:34]=[CH:35][C:25]=3[C:24]=2[CH:23]=1.[CH2:36]([C:38]([O-:40])=[O:39])[CH3:37]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1-c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccccc1-c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
0.5 mL of trifluoroacetic acid is added to a solution of 100 mg (0.22 mmol) of 8-(2-tert-butoxycarbonylaminophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate dissolved in 2 mL of dichloroethane. The solution is stirred at room temperature for 30 minutes then the solvents are evaporated. The residue is triturated with diisopropyl ether then the solid is filtered and washed with dichloromethane. It is taken up in 2 mL of dichloromethane then triethylamine is added to release the amine. Water is added and the compound is extracted with dichloromethane. The organic phases are dried over magnesium sulfate, filtered and evaporated. The solid is triturated with water to give 35 mg (45%) of 8-(2-aminophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([F:24])=[C:19]([Cl:25])[CH:18]=2)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.O>ClCCCl.CO>[Cl:25][C:19]1[CH:18]=[C:17]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:22]=[C:21]([Cl:23])[C:20]=1[F:24]
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)CCN(Cc3ccccc3)C2)cc1Cl
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: O
Solvent: CO
Product: Fc1c(Cl)cc(C2(C(F)(F)F)CCNC2)cc1Cl
Yield: 129.4 %

Procedure:
To a stirred solution of 1-benzyl-3-(3,5-dichloro-4-fluoro-phenyl)-3-trifluoromethyl-pyrrolidine (Preparation 30, 6.1 g, 15.60 mmol) in 1,2-dichloroethane (50 mL) was added 1-chloroethyl chloroformate (3.01 mL, 28.08 mmol) at room temperature. Resulting reaction mixture was refluxed for 3 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to afford brown thick oil. Brown thick oil was dissolved in MeOH (50 mL) and refluxed for 2 hours. Progress of reaction was monitored by TLC. After complete consumption of starting material, reaction mixture was again concentrated to afford brown thick oil, to which water was added (100 mL) and washed with hexane (3×50 mL). Aqueous layer was basified by saturated sodium bicarbonate solution, extracted with ethyl acetate (3×50 mL). Combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford product as brown thick oil (6.1 g, crude). Crude was purified by column chromatography on (100-200 mesh silica). Desired product was eluted in 25% ethyl acetate in hexane to afford brown semi solid (3.8 g, 80.68%). 1H-NMR (400 MHz, DMSO-d6) δ: 2.39-2.46 (m, 1H), 2.53-2.58 (m, 1H), 2.99-3.13 (m, 2H), 3.53 (d, 1H, J=12.84 Hz), 3.65 (d, 1H, J=12.84 Hz), 7.77 (d, 2H J=6.28 Hz). (m/z): 302.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[C:11]([O:13][CH3:14])=[O:12].[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)Cl
Reactant: Oc1ccc(F)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(F)cc1Br
Reaction time: 2 h
Yield: 91.8 %

Procedure:
First, 93 g (0.49 mol) of 2-bromo-4-fluorophenol was suspended in 200 ml of water, into which 55 g (0.59 mol) of methyl chloroformate and a solution of 21.5 g (0.51 mol) of sodium hydroxide in 60 ml of water were poured together at IONIC or lower, and the mixture was stirred at the same temperature for 2 hours. The precipitated crystals were collected by filtration, washed with water, and dried in a vacuum oven, which afforded 111.6 g (0.45 mol) of methyl 2-bromo-4-fluorophenoxyformate.
Reaction SMILES: [Si]([O:8][CH:9]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[CH2:10][CH2:11][CH:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH:13]1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:39][C:36]1[CH:35]=[CH:34][C:33]([CH:9]([OH:8])[CH2:10][CH2:11][CH:12]2[C:15](=[O:16])[N:14]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:13]2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.5 g of 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile were dissolved in 65 ml of tetrahydrofuran. 0.74 ml of acetic acid and 8.03 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran were added and the mixture was stirred at room temperature for 2 h. Another 4.82 ml of the tetrabutylammonium fluoride solution were then added, and the mixture was stirred at reflux temperature for another 3 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using n-heptane/ethyl acetate 2/1. This produced 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (4) of molecular weight 430.48 (C26H23FN2O3); MS (ESI): 431.24 (M+H+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([OH:35])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH2:26][O:27]CC3C=CC=CC=3)=[O:23])[CH:17]=2)=[C:8]([NH2:36])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.C1COCC1>[Pd].CO>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([OH:35])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH2:26][OH:27])=[O:23])[CH:17]=2)=[C:8]([NH2:36])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(O)n(Cc3cccc(C(=O)OCCOCc4ccccc4)c3)c2n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1nc(N)c2nc(O)n(Cc3cccc(C(=O)OCCO)c3)c2n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 33.3 %

Procedure:
2-Butoxy-8-hydroxy-9-{3-(2-benzyloxyethoxycarbonyl)benzyl}adenine (0.03 g, 0.06 mmol) obtained by Example 5, 5% Pd/C (60 mg) and concentrated hydrochloric acid (0.1 ml) were added to a mixed solvent of THF (30 ml) and methanol (30 ml), and the mixture was stirred under hydrogen atmosphere at room temperature for 60 hours. The reaction mixture was filtered, neutralized with saturated sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=100/1˜50/1) and washed with methanol to give the captioned compound (0.01 g, 0.02 mmol, yield: 42%) as a white solid.
Reaction SMILES: [H][H].[C:3](OC)(=[O:10])/[CH:4]=[CH:5]\[C:6]([O:8][CH3:9])=[O:7].O1CCCC1>O>[CH2:3]([OH:10])[CH2:4][CH2:5][CH2:6][OH:7].[C:6]1(=[O:7])[O:8][CH2:9][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: COC(=O)/C=C\C(=O)OC
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCCO1
Product: OCCCCO

Procedure:
The dialkyl maleate produced in the second esterification stage 13 is fed to a hydrogenation stage 17. For the hydrogenation, hydrogen 19 is also introduced into the hydrogenation stage 17. In the hydrogenation stage 17, the dimethyl maleate is reacted with the hydrogen to form tetrahydrofuran and optionally 1,4-butanediol and/or γ-butyrolactone with simultaneous formation of alkanol and water, as described, for example, in WO 88/00937, WO 91/01960, WO 03/006446 or WO 05/058855. The alkanol formed in the hydrogenation is the same alkanol as that which was introduced in the first esterification stage 9 and second esterification stage 13.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.Cl[C:34](OC1C=CC([N+]([O-])=O)=CC=1)=[O:35].[NH2:46][CH2:47][C:48]([CH3:51])([OH:50])[CH3:49].C(N(CC)CC)C>O1CCCC1>[F:27][C:24]([F:25])([F:26])[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:13]2[CH2:12][CH2:11][CH:10]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:34]([NH:46][CH2:47][C:48]([OH:50])([CH3:51])[CH3:49])=[O:35])=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:18][CH:19]=1)([OH:32])[C:28]([F:31])([F:29])[F:30]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(O)CN
Reactant: CC(c1ccc(N)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(c1ccc(NC(=O)NCC(C)(C)O)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
2-(4-((4-(1-(4-Aminophenyl)ethyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (0.178 mmol, 82 mg) and 4-nitrophenyl chloroformate (0.178 mmol, 35.9 mg) were combined in tetrahydrofuran (2 mL) and the reaction stirred at room temperature for 1 hour. 1-Amino-2-methylpropan-2-ol (0.178 mmol, 15.87 mg) and triethylamine (0.534 mmol, 54.1 mg) were added and the mixture stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue purified by silica gel column chromatography (eluting with dichloromethane to 10% methanol/dichloromethane) to afford the title compound (16 mg). MS (ESI) m/z 576.2 [M+H]+
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH2:6][NH:7][C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.CC(C)([O-])C.[K+].[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=1[CH2:40]Br>C1COCC1>[F:18][C:17]([F:19])([F:20])[C:15]1[CH:14]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:16]=1)[CH2:6][N:7]([CH2:40][C:31]1[CH:32]=[C:33]([C:36]([F:37])([F:39])[F:38])[CH:34]=[CH:35][C:30]=1[Br:29])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: FC(F)(F)c1ccc(Br)c(CBr)c1
Reactant: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (3.9 g, 12 mmol) in THF (50 mL) at room temperature was added potassium tert-butoxide (KOtBu) (13.2 ml of 1M solution, 13.2 mmol) followed by 1-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene (4 g, 12.6 mmol). The mixture was stirred at room temperature for 16 hours. Additional KOtBu in THF (13.2 mL of 1M solution, 13.2 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (3×50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (silica gel) (eluted with 3:1 hexane-ethyl acetate) to yield the title compound (4.72 g). 1H NMR (400 MHz, CDCl3) δ 4.2 (s, 3H) 4.8 (s, 2H) 4.9 (s, 2H) 7.4 (dd, J=8.2, 1.7 Hz, 1H) 7.5 (d, J=1.7 Hz, 1H) 7.7 (m, 3H) 7.8 (s, 1H). MS (ES+) Calc: 561.02, Found: 561.7 (M+1).
Reaction SMILES: [NH:1]1[C:6]2[S:7][C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:5]=2[C:4](=[O:14])[O:3][C:2]1=[O:15].[C:16](=O)([O-])[O-].[K+].[K+].CN(C=O)C.CI>O>[CH3:16][N:1]1[C:6]2[S:7][C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:5]=2[C:4](=[O:14])[O:3][C:2]1=[O:15]
Reactant: O=c1[nH]c2sc3c(c2c(=O)o1)CCCC3
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1c(=O)oc(=O)c2c3c(sc21)CCCC3
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.5 %

Procedure:
To 5,6,7,8-tetrahydro-2H-[1]benzothieno[2,3-d][1,3]oxazine-2,4(1H)-dione (1.5 g) and potassium carbonate (1.4 g) was added DMF (15 mL), and methyl iodide (1.2 m) was added thereto under ice-cooling, followed by stirring at room temperature for 6 hours. Methyl iodide (0.61 mL) was added thereto, followed by stirring at room temperature overnight, water (15 mL) was added to the reaction mixture, and the solid was collected by filtration, washed with water, and dried under reduced pressure to obtain 1-methyl-5,6,7,8-tetrahydro-2H-[1]benzothieno[2,3-d][1,3]oxazine-2,4(1H)-dione (1.3 g).
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]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:51][O:52][C:53]1[CH:61]=[CH:60][C:56]([CH:57]([OH:59])[CH3:58])=[CH:55][CH:54]=1>C(Cl)Cl>[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]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:59][CH:57]([C:56]2[CH:60]=[CH:61][C:53]([O:52][CH3:51])=[CH:54][CH:55]=2)[CH3:58])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: COc1ccc(C(C)O)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(C(C)OC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C)c2C)cc1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (68 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (94 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-methoxy-α-methylbenzyl alcohol (48 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (75 mg, yield 66%).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].C([N+](C[CH2:22][CH2:23][CH3:24])(CCCC)CCCC)CCC.[OH-].[Na+].Cl[CH:28]=CC>O>[CH3:28][C:23](=[CH2:22])[CH2:24][O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCO
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC=CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)COCCCCC
Temperature: 70 °C
Reaction time: 7 h
Yield: 68 %

Procedure:
In a 3000 mL reaction flask was charged 1-pentanol (400 g, 4.5 mol), a 40% by weight in water solution of tetrabutyl ammonium hydroxide (100 g, 0.15 mol), and a 50% by weight solution of NaOH (435 g, 5.4 mol). The mixture was heated to 70° C. and 3-chloro-2-propene (486 g, 5.4 mol) was fed into the reaction over 3 hours. The reaction was aged for 7 hours at 70° C., then cooled to room temperature. The reaction was quenched with 600 mL of water, and the layers separated. The organic layer washed with 600 mL water and 600 mL of brine. The crude product was purified by distillation to give 435 g of ether, a 68% yield.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])=[N:14][CH:13]([N:29]2C(=O)C3=CC=CC=C3C2=O)[C:12]1=[O:40].O.NN.C(OCC)(=O)C>C1COCC1>[NH2:29][CH:13]1[N:14]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]([CH2:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[C:12]1=[O:40]
Reactant: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2F)c2ccccc2N1Cc1nc2ccccc2s1
Agent: NN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC1N=C(c2ccccc2F)c2ccccc2N(Cc2nc3ccccc3s2)C1=O
Temperature: 25 °C
Yield: 11.1 %

Procedure:
To a suspension of (3RS)-1-(benzothiazol-2-yl)methyl-2,3-dihydro-5-(2-fluorophenyl)-3-phthalimido-1H-1,4-benzodiazepin-2-one (1.30 g) in THF (50 ml) was added dropwise hydrazine monohydrate (0.12 g) under stirring at ambient temperature. The mixture was stirred for 2 hours at the same temperature and refluxed under stirring for 2 hours. The reaction mixture was cooled in an ice-bath. The resultant precipitates were filtered off atad washed with THF (30 ml). The filtrate and washing were combined and concentrated in vacuo to afford a crude product. The product was dissolved into ethyl acetate (150 ml) and extracted with 1N-HCl aqueous solution (3×25 ml). The aqueous layer was alkalined with sodium bicarbonate and extracted with ethyl acetate (2×100 ml). The extracts were dried over magnesium sulfate and filtered off by filtration. The filtrate was concentrated in vacuo to afford (3RS)-3-amino-1-(benzo-thiazol-2-yl)methyl-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzo-diazepin-2-one as a colorless crystalline solid (110 mg). The compound was allowed to use in a next reaction step without further purification.