Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:41])[NH:14][CH2:15][CH2:16][CH2:17][NH:18][CH:19]([C:23]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](=[O:36])[C:26]2=[C:37]([Cl:40])[CH:38]=[CH:39][N:25]2[N:24]=1)[CH:20]1[CH2:22][CH2:21]1)([CH3:11])([CH3:10])[CH3:9].[CH3:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](Cl)=[O:48])=[CH:45][CH:44]=1>C(Cl)Cl>[C:8]([O:12][C:13](=[O:41])[NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH:19]([C:23]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](=[O:36])[C:26]2=[C:37]([Cl:40])[CH:38]=[CH:39][N:25]2[N:24]=1)[CH:20]1[CH2:21][CH2:22]1)[C:47](=[O:48])[C:46]1[CH:50]=[CH:51][C:43]([CH3:42])=[CH:44][CH:45]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCCNC(c1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nn3ccc(Cl)c3c(=O)n2Cc2ccccc2)C2CC2)cc1
Reaction time: 1.5 h
Yield: 98 %

Procedure:
Triethylamine (0.425 mL, 3.05 mmol) was added to a 0° C. solution of (3-{[(3-benzyl-5-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-cyclopropyl-methyl]-amino}-propyl)-carbamic acid tert-butyl ester (0.74 g, 1.52 mmol) and 4-methylbenzoyl chloride (0.403 mL, 3.05 mmol) in CH2Cl2 (10 mL) and was stirred at 0° for 1.5 h. The reaction mixture was quenched with 1 N HCl (30 mL) and extracted with CHCl3 (3×50 mL). The combined organic extracts were washed with saturated NaHCO3 (1×100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 3/1 hexane/EtOAc to afford the title compound (0.90 g, 98%) as a solid: MS (ESI+) 604 (M++H); HRMS (ESI+) calculated: 604.2691 (M++H). found: 604.2702 (M++H).
Reaction SMILES: Cl[CH2:2][S:3][C:4]#[N:5].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[S:12])=[CH:9][CH:8]=1.O>CO>[S:3]([CH2:2][O:13][C:11](=[S:12])[C:10]1[CH:14]=[CH:15][C:7]([Cl:6])=[CH:8][CH:9]=1)[C:4]#[N:5]
Reactant: OC(=S)c1ccc(Cl)cc1
Reactant: N#CSCCl
Solvent: O
Solvent: CO
Product: N#CSCOC(=S)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
16 g (0.15 mol) of chloromethyl thiocyanate were added dropwise to 31.5 g (0.15 mol) of the K salt of 4-chlorothiobenzoic acid in 200 ml of methanol at 0°-10° and the mixture was then first warmed to room temperature and then to 50°-60°, until the reaction had taken place. The cooled mixture was poured onto 1 liter of cold water, whilst stirring vigorously, and the precipitate was filtered off and dried. Light pink-coloured crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:17]=[C:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:10]3[C:9](=[O:18])[CH:8]=2)=[N:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:29]Br>O1CCCC1>[Br:29][CH:12]1[C:11]2=[N:17][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)=[CH:8][C:9](=[O:18])[N:10]2[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: O=c1cc(-c2ccncn2)nc2n1CCOCC2
Reactant: BrBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1cc(-c2ccncn2)nc2n1CCOCC2Br
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a solution of 5.00 g (20.47 mmol) of pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one in dry tetrahydrofuran (200 mL) under argon at −40° C. was added 22.52 mL (22.52 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The solution was stirred at −40° C. for 10 min and 1.10 mL (21.49 mmol) of bromine was added rapidly. The reaction was stirred at −40° C. during 20 minutes and the reaction mixture was quenched with the addition of a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (cyclohexane/ethyl acetate: 80/20 to 70/30) to afford 2.18 g (33%) of product.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11]C)=[C:5]([CH3:13])[C:4]=1[CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>C(#N)C.O>[CH3:13][C:5]1[C:6](=[O:11])[C:7]([CH3:10])=[C:8]([CH3:9])[C:3](=[O:2])[C:4]=1[CH:14]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: COc1c(C)c(C)c(OC)c(C(CCCCCCO)c2ccccc2)c1C
Solvent: O
Solvent: CC#N
Product: CC1=C(C)C(=O)C(C(CCCCCCO)c2ccccc2)=C(C)C1=O
Reaction time: 0.33 h
Yield: 89.9 %

Procedure:
7-(2,5-Dimethoxy-3,4,6-trimethylphenyl)-7-phenylheptanol (1.85 g, 5.0 mmole) was dissolved in a mixed solution of acetonitrile (12 ml) and water (6 ml), and a cooled solution of ceric ammonium nitrate (8.22 g, 5×3 mmole) in 50% aqueous acetonitrile (16 ml) was added dropwise to the solution, under ice cooling, over the 20-minutes period. After stirring was continued for another 20 minutes under ice cooling, acetonitrile was distilled off under reduced pressure, and isopropyl ether was added to the residue to conduct extraction. The isopropyl ether layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate), and evaporated. The residual solution was chromatographed on a silica gel column, and purification was performed (elution with isopropyl ether) to give 7-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)-7-phenylheptanol (1.53 g, 90%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 9, 10, 35, 36, 46 to 55 and 64 to 67 were prepared.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:7]1[CH:2]([CH3:1])[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5][CH:6]1[CH3:8])[CH3:22]
Reactant: CCOC(=O)CCl
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1C(C)CN(C(=O)OC(C)(C)C)CC1C

Procedure:
2.0 g (9.33 mmol) of tert-butyl (3RS,5SR)-3,5-dimethylpiperazine-1-carboxylate (preparation: Helvetica Chimica Acta 1990, 73 (4), 839-855), 2.3 g (18.67 mmol) of ethyl chloroacetate, 3.9 g (28.00 mmol) of potassium carbonate and 0.5 g (2.80 mmol) of potassium iodide are stirred under reflux overnight in 80 ml of acetonitrile. For the work-up, some of the acetonitrile is removed on a rotary evaporator, and the residue is diluted with ethyl acetate, subsequently washed twice with water and once with a saturated sodium chloride solution. The combined aqueous phases are extracted once with ethyl acetate, the combined organic phases are dried over sodium sulfate, and the solvent is removed completely on a rotary evaporator. The residue is taken up in cyclohexane and after subsequent elution over silica gel 60 using subatmospheric pressure (cyclohexane/ethyl acetate 100/10→80/10→40/10) 2.5 g (88% of theory) of product are obtained.
Reaction SMILES: OO.C(O[C:10]([C:12](F)(F)F)=[O:11])(C(F)(F)F)=O.COC1CCN(CCNC2N=[N+:29]([O-:40])[C:30]3[CH:39]=[C:38]4[C:34]([CH2:35][CH2:36][CH2:37]4)=[CH:33][C:31]=3[N:32]=2)CC1.C(O)(C(F)(F)F)=[O:42]>C(Cl)Cl.N>[N+:29]([C:30]1[CH:39]=[C:38]2[C:34]([CH2:35][CH2:36][CH2:37]2)=[CH:33][C:31]=1[NH:32][C:10](=[O:11])[CH3:12])([O-:40])=[O:42]
Reactant: COC1CCN(CCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)CC1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
H2O2 (70%, 3.1 mL, ca. 62.6 mmol) was added dropwise to a stirred solution of TFAA (8.8 mL, 62.6 mmol) in DCM (40 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 42 (2.15 g, 6.3 mmol) and TFA (2.4 mL, 31.3 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give (i) starting material 42 (204 mg, 9%); and (ii) 1,4-dioxide 43 (1.0 g, 44%) as a red solid: mp (MeOH/EtOAc) 148-151° C.; 1H NMR δ 8.11 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.44 (br s, 1H, NH), 3.61-3.66 (m, 2H, CH2N), 3.33 (s, 3H, OCH3), 3.22-3.29 (m, 1H, CHO), 3.10 (br t, J=7.5 Hz, 2H, H-6), 3.05 (br t, J=7.5 Hz, 2H, H-8), 2.75-2.81 (m, 2H, CH2N), 2.68 (br t, J=6.0 Hz, 2H, CH2N), 2.27-2.34 (m, 2H, CH2N), 2.20 (p, J=7.5 Hz, 2H, H-7), 1.87-1.95 (m, 2H, CH2), 1.61-1.70 (m, 2H, CH2); 13C NMR δ 155.6, 149.4, 145.8, 138.0, 129.7, 115.7, 111.6, 75.8, 56.3, 55.5, 50.7 (2), 38.3, 33.4, 32.4, 30.6 (2), 25.6. Anal. calcd for C18H25N5O3.¼H2O: C, 59.4; H, 7.1; N, 19.2. Found: C, 59.2; H, 6.8; N, 19.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[OH:11].[CH3:12][Mg+].[Br-].[NH4+].[Cl-].O>CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:9])[CH3:12])[CH:5]=[C:4]([Cl:10])[C:3]=1[OH:11]
Reactant: C[Mg+]
Reactant: OCc1cc(Cl)c(O)c(Cl)c1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CC(O)c1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A sol. of 2,6-dichloro-4-hydroxymethylphenol (1.635 g, 8.56 mmol) in Et2O (30 mL) was cooled to −78° C. MeMgBr (3M in Et2O, 7.15 mL, 21.5 mmol) was added dropwise to the cooled reaction mixture over 18 min. Et2O (20 mL) was added again during the addition of MeMgBr. Stirring was continued at −78° C. for 1 h, and then the reaction mixture was allowed to warm up to rt over 1 h. The mixture was cooled to 0° C., and aq. sat. NH4Cl (10 mL) was added dropwise. The mixture was allowed to warm up to rt, and additional aq. sat. NH4Cl (35 mL) and water (35 mL) were added. The phases were then separated and the aq. phase was extracted with Et2O. The combined org. extracts were then washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by FC (EtOAc/heptane, 1:1) yielded the title compound (1.683 g, 95%). LC-MS: tR=0.74 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:23]([CH3:30])[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:11]=2[CH:10]=1)=S.C(O)(=O)/C=C/C(O)=[O:38]>C(O)(=O)C.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:23]([CH3:30])[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:11]=2[CH:10]=1)=[O:38]
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=S)NCc3cccc(F)c3)cc21
Reactant: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NCc3cccc(F)c3)cc21
Temperature: 20 °C
Reaction time: 20 h
Yield: 70.4 %

Procedure:
Mercuric acetate (0.80 g) is added to a solution of N-(3-fluorobenzyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide neutral fumarate (1.30 g) in acetic acid (20 cc), and the mixture obtained is stirred for 20 hours at a temperature in the region of 20° C. The black suspension obtained is filtered on sintered glass plugged with celite and the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl acetate (100 cc) and the organic phase is washed successively with normal sodium hydroxide (2×20 cc) and distilled water (2×20 cc) and with aqueous sodium chloride solution (20 cc) and dried over magnesium sulphate. After filtration, the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and a crude yellow oil (0.90 g) is thereby obtained. This residue is dissolved in hot ethanol (3 cc) and treated with fumaric acid (0.25 g) dissolved in ethanol (2 cc). After 4 hours' cooling to 4° C., the crystallized solid is separated by filtration, washed with cold ethanol (2×5 cc) and then dried at 50° C. under reduced pressure (5 mm Hg; 0.7 kPa) to give N-(3-fluorobenzyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide neutral fumarate (0.7 g), m.p. 165° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([CH2:8][CH2:9][N:10]([CH2:15][CH2:16][N:17]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:18][C:19]([OH:21])=[O:20])[CH2:11][C:12]([OH:14])=[O:13])[CH2:5][C:4](=[O:28])[O:3]1.C(N(CC)CC)C.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48]>CN(C)C=O>[C:19]([CH2:18][N:17]([CH2:16][CH2:15][N:10]([CH2:11][C:12]([OH:14])=[O:13])[CH2:9][CH2:8][N:6]([CH2:7][C:2](=[O:1])[NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[CH2:5][C:4]([OH:28])=[O:3])[CH2:22][C:23]([OH:25])=[O:24])([OH:21])=[O:20]
Reactant: NCCCCCCCCCCC(=O)O
Reactant: CCOC(=O)CN(CCN(CCN1CC(=O)OC(=O)C1)CC(=O)O)CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCCCCCCNC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15.33 g (38 mmol) of N3-(2,6-dioxomorpholinoethyl)-N6-(ethoxy-carbonylmethyl)-3,6-diazaoctanedioic acid (Example 13a of EP 0331 616) is suspended in dimethylformamide (DMF) and mixed in an ice bath with 21.07 ml (152 mmol) of triethylamine and 7.65 g (38 mmol) of 11-aminoundecanoic acid. The temperature is allowed to increase to room temperature and the reaction solution is stirred overnight. After completion of the reaction, the possibly still slightly cloudy solution is filtered and the filtrate is concentrated by evaporation in a vacuum. The residue is absorptively precipitated with ether and then recrystallized from water (17.8 g). The ethyl ester is dissolved in 2 N NaOH and is adjusted to pH 7 after 3 hours by adding Amberlite® IR 120 (H+). The ion exchange material is suctioned off, the filtrate is freeze-dried (20.1 g) and then added to H2O/methanol (2:1) on 100 ml of Amberlite® IR 120 (H+) and the acid eluate is concentrated by evaporation and recrystallized from water.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[CH2:30]([O:37][C:38](ON1C(=O)CCC1=O)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>O1CCOCC1.O>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([N:18]([CH2:19][CH2:20][O:21][CH3:22])[C:38](=[O:39])[O:37][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COCCNC1CCC(C(=O)NCc2nccnc2Cl)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: COCCN(C(=O)OCc1ccccc1)C1CCC(C(=O)NCc2nccnc2Cl)CC1
Yield: 99.9 %

Procedure:
To a solution of N-((3-chloropyrazin-2-yl)methyl)-4-(2-methoxyethylamino)cyclohexane-carboxamide (3.15 mmol, 1.03 g) in dioxane (10 ml) and water (10 ml) were added triethylamine (3.36 mmol, 0.47 ml) and N-(benzyloxycarbonyloxy)succinimide (3.31 mmol, 825 mg). After stirring for two hours at room temperature water and 2N hydrochloric acid (1.5 ml) were added and this mixture extracted twice with dichloromethane. The combined organic layers were washed with saturated aqueous sodium hydrogencarbonate solution, dried (sodium sulfate) and concentrated in vacuo to give benzyl 4-((3-chloropyrazin-2-yl)methylcarbamoyl)cyclohexyl(2-methoxyethyl)carbamate (1.45 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC[C@H]1CO)=O)(C)(C)C.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][SH:40])=[CH:37][CH:36]=1.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][S:40][CH2:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(CS)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CSC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1

Procedure:
The procedure described in preparation 5-(2) was repeated, but using 12.16 g of (2S)-1-t-butoxycarbonyl-2-methanesulfonyloxymethylpyrroldine [prepared by the methanesulfonylation of (2S)-1-t-butoxycarbonyl-2-hydroxymethylpyrrolidine], 7.3 ml of 4-methoxybenzyl mercaptan and 2.3 g of sodium hydride (as a 55% w/w suspension in mineral oil) in 100 ml of dry dimethylformamide, to afford 13.93 g of the title compound as an oil.
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]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH2:40])[CH2:37][CH2:38][CH3:39].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:36]([NH:40][C:28]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][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]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[F:23])=[O:34])[CH2:37][CH2:38][CH3:39]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: CCCCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1F
Yield: 178.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg) was dissolved in toluene (8 ml) and triethylamine (1.0 ml) with heating, and a solution of triphosgene (47 mg) in toluene (1.0 ml) was then added to the solution. The mixture was heated under reflux for 5 min. Next, butylamine (80 mg) was added to the reaction solution, and the mixture was heated under reflux for additional 5 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1) to give 117 mg (yield 81%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:5]2[NH:6][C:7](=[O:24])[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[C:21]([CH2:22]O)=[CH:20][N:19]=[N:18]4)[CH:12]=3)=[N:10][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[Cl-].[CH:36]1([NH2:39])[CH2:38][CH2:37]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:5]2[NH:6][C:7](=[O:24])[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[C:21]([CH2:22][NH:39][CH:36]5[CH2:38][CH2:37]5)=[CH:20][N:19]=[N:18]4)[CH:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: NC1CC1
Reactant: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3nncc3CNC3CC3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from 7-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 63) (218 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with cyclopropylamine in DMF as described in Example 47. Obtained as a light yellow solid (130 mg, 55%).
Reaction SMILES: [N+]([O-])(O)=O.S(=O)(=O)(O)[OH:6].[CH:10]1[C:23]2[C:22](=O)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:25])[C:14]=2[CH:13]=[CH:12][CH:11]=1>>[CH2:22]([C:23]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[C:15]([OH:25])=[O:6])[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: O=C(O)c1ccccc1Cc1ccccc1

Procedure:
A known process involves the oxidation of mixtures of o- and p-benzyl-toluene with dilute nitric acid under pressure at temperatures of 135°-200° C. The reaction mixture is treated with concentrated sulfuric acid to effect the conversion of the o-benzolyl-benzoic acid to anthraquinone; the residual p-benzoyl-benzoic acid is extracted with a soda solution (Acta Chem. Scand. 9, 177-178, 1955; Chem. Abstr. 1956, 4080i). There is no discussion of the purity of the product, in particular with reference to the considerable quantities of nitration by-products. Repetition of the known process lead to the discovery that o-benzyl toluene is unusually susceptible to nitration during the oxidation process with nitric acid. If the oxidation is carried out in the known manner with nitric acid under pressure, only a small amount of the desired o-benzyl-benzoic acid is produced; the reaction product consists primarily of nitration products, in particular nitro-o-benzoyl benzoic acids. For this reason, it is not possible to obtain a pure anthraquinone in good yield with this procedure. If the resultant raw product is treated with sulfuric acid at elevated temperatures, the solution becomes black from the dissociation of the nitro compounds.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[CH3:22][C:23]([CH3:28])=[CH:24][C:25](Cl)=[O:26].N1C=CC=CC=1.O>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:25](=[O:26])[CH:24]=[C:23]([CH3:28])[CH3:22])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)=CC(=O)Cl
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Solvent: O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)=CC(=O)N1CC(NC(=O)OC(C)(C)C)C(=O)Nc2cc(C)ccc21
Yield: 63.2 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Referential Example 7 was suspended in 1,2-dichloroethane (40 ml), 3,3-dimethylacryloyl chloride (941 mg) and pyridine (626 mg) were added, the mixture was refluxed for one hour. The reaction mixture was allowed to cool, water (100 ml) was added, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Isopropylether was added to the residue for trituration, collected by filtration, to thereby obtain 1.62 g of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCCCCC.[CH3:18][C:19](OC(C)=O)=[O:20]>C1(C)C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:19](=[O:20])[CH3:18])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(N)cc(OC)c1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1cc(NC(C)=O)cc(OC)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-dimethoxy-phenylamine (d) (22.0 g, 143.6 mmol) in toluene (100 mL), Ac2O (14 mL) is added slowly at room temperature. After stirring 30 min, hexane (50 mL) is added with stirring at rt. The resulting solid is filtered and washed with hexane (50 mL) to offer the title product e as a white solid.