Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH3:23])=[O:22].[CH:24](OCC)(OCC)[O:25][CH2:26][CH3:27]>>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([N:1]=[CH:24][O:25][CH2:26][CH3:27])=[C:3]([S:21]([CH3:23])=[O:22])[C:4]([C:19]#[N:20])=[N:5]1
Reactant: CS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: CCOC(OCC)OCC
Product: CCOC=Nc1c(S(C)=O)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbonitrile (4.92 g) in triethyl orthoformate (100 ml) was heated under reflux for two hours, then stirred at 20° C. for 16 hours and evaporated. Trituration with boiling hexane gave 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-[(ethoxymethylene)amino]-4-methylsulfinyl-1H-pyrazole-3-carbonitrile (4.05 g), m.p.93-95° C. By proceeding in a similar manner the following compound was prepared:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH2:14].[Cl:15]NC(=O)CCC(N)=O>C(#N)C>[Cl:15][C:9]1[CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]([NH2:14])=[C:5]([O:4][CH2:3][CH2:2][Cl:1])[CH:10]=1
Reactant: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Reactant: NC(=O)CCC(=O)NCl
Solvent: CC#N
Product: Nc1c(OCCCl)cc(Cl)cc1[N+](=O)[O-]

Procedure:
A solution of 2-(2chloro-ethoxy)-6nitro-phenylamine (1a, 30.0 g, 0.14 mol), N-chlorosuccinamide and acetonitrile (1.3 L) was refluxed for 4 hr. The mixture was concentrated under vacuum and the residue was diluted with ethyl acetate (500 mL). The organic layer was washed with water (2×, 250 mL) and brine (250 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give an orange solid residue. Crystallization from ethyl acetate-hexane gave 33.5 g (95.3%) as orange solid, mp 109-110° C.; MS EI m/e 250/252/254 (M+).
Reaction SMILES: [CH:1]1([C:7]2([C:20]([OH:22])=[O:21])[CH2:13][CH:12]3[N:14](C(OCC)=O)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I:23][Si](C)(C)C>C(Cl)(Cl)Cl>[I-:23].[C:20]([C:7]1([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:8][CH:9]2[NH2+:14][CH:12]([CH2:11][CH2:10]2)[CH2:13]1)([OH:22])=[O:21]
Reactant: CCOC(=O)N1C2CCC1CC(C(=O)O)(C1CCCCC1)C2
Reactant: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: O=C(O)C1(C2CCCCC2)CC2CCC(C1)[NH2+]2
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-cyclohexyl-8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid (1-7) (2.50 g, 8.08 mmol) in 80 mL of chloroform was added iodotrimethylsilane (4.75 mL, 16.8 mmol) dropwise. The mixture was stirred at room temperature overnight and warmed up to 50° C. for additional two hours. After the reaction was completed, the volatiles were removed under vacuum to give (3-1) as a yellow solid.
Reaction SMILES: B.C1COCC1.[Br:7][CH2:8][C:9]([C:11]1[CH:22]=[CH:21][C:14]2[O:15][C:16]([CH3:20])([CH3:19])[O:17][CH2:18][C:13]=2[CH:12]=1)=[O:10].CO>C1COCC1>[Br:7][CH2:8][CH:9]([C:11]1[CH:22]=[CH:21][C:14]2[O:15][C:16]([CH3:19])([CH3:20])[O:17][CH2:18][C:13]=2[CH:12]=1)[OH:10]
Reactant: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)OCc2cc(C(O)CBr)ccc2O1
Reaction time: 1 h
Yield: 84.3 %

Procedure:
A solution R-diphenylprolinol (75 mg) in THF (2 ml) was treated with borane-THF (1M, 20.5 ml) over 20 min at 20° C. under nitrogen. After the addition was complete the solution was kept between 30 and 35° C. for 1 h and then cooled in ice and 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (DE3513885) (3.9 g) in THF (10 ml) was added over 1.5 h keeping the temperature below 5° C. The mixture was stirred under nitrogen for a further 0.5 h and then methanol (4 ml) was added at 0° C. The solvent was removed under reduced pressure and the residue was purified by chromatography on flash silica gel eluting with ethyl acetate-cyclohexane (1:4) to give the title compound (3.31 g) δ (CDCl3) 7.15 (1H, dd, J 8, 2 Hz), 7.03 (1H, br s), 6.82 (1H, d, J 8 Hz), 4.85 (3H, s and m), 3.61 (1H, dd, J 10, 4 Hz), 3.50 (1H, dd, J 10, 9 Hz), 1.54 (6H, s).
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])[N:3]=1.[Na].I[CH3:29]>CO.C(OCC)(=O)C>[CH3:29][O:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])[N:3]=1
Reactant: COC(=O)c1ccc(Cn2nc(O)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Reactant: CI
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(Cn2nc(OC)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Reaction time: 0.08 h
Yield: 28 %

Procedure:
Indazole (T) (1.68 g.) was added to a solution of sodium (0.108 g.) in methanol (1.0 ml.). After stirring for 5 minutes, iodomethane (0.32 ml.) was added and stirring continued for 18 hours. The mixture was diluted with ethyl acetate, washed with water and brine, then dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (130 g.), eluting with 2:98 v/v ethyl acetate:dichloromethane to give methyl 4-[3-methoxy-6-nitroindazol-1-ylmethyl]-3-methoxybenzoate (U) (0.481 g., 28%) as a yellow solid, with satisfactory NMR spectral data.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11](OCC)=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]([NH:4][C:5]1[C:10]([CH2:11][OH:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1NC(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ncc(CO)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
To a solution of ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (16.4 g, 64.4 mmol) in anhydrous THF (100 mL) was added LAH (6.1 g, 0.16 mol) in portions at 0° C. under N2 atmosphere, then the reaction mixture was stirred at r.t. for 30 min. The reaction was quenched by the addition of water (6 mL) followed by aqueous solution of 2N NaOH (6 mL). The suspension was filtered and the filtrate was concentrated to give (4-(isopropylamino)-2-(methylthio)pyrimidin-5-yl)methanol (13.5 g, 98.4% yield), which was used in next step without further purification. 1HNMR (400 MHz, DMSO-d6): δ 7.79 (s, 1 H), 6.37 (d, J=7.6 Hz, 1 H), 5.10 (t, J=5.6 Hz, 1 H), 4.28-4.20 (m, 3 H), 2.38 (s, 3 H), 1.13 (d, J=6.4 Hz, 6 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Reactant: CC(C)(C)c1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1=Cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-tert-butylphenyl borate (0.47 g) and potassium carbonate (0.67 g) in toluene/ethanol/water (30/3/3 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.14 g), and the mixture was refluxed for 16 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:1) and recrystallized from ethyl acetate/diisopropylether to give colorless crystals of methyl 7-(4-tert-butylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (793.6 mg).
Reaction SMILES: [C:1]([O: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][O:22]C1CCCCO1)(=[O:3])[CH3:2].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCO.CCOC(C)=O>[C:1]([O: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][OH:22])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCCCCCCCCCCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)OCCCCCCCCCCCCCCCCCO
Temperature: 55 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
THP ether 39 (1.207 g, 3.03 mmol) was dissolved in 95% EtOH (12 ml) and PPTS (76 mg, 0.3 mmol) was added. Reaction mixture was stirred at 55° C. for 4 h, cooled to room temperature and diluted with EtOAc. Mixture was washed with H2O three times, organic extract was dried over Na2SO4 and evaporated. Residue was chromatographed on silica gel to give 864 mg (91%) of 17-acetoxy-heptadecanol.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:14][C:15](=[O:20])[O:16][CH2:17][CH2:18]Cl>CO.C(O)C>[Cl:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[N:14]1[CH2:18][CH2:17][O:16][C:15]1=[O:20]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)OCCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=C1OCCN1c1ccc([N+](=O)[O-])cc1Cl

Procedure:
A solution of 11.25 g of sodium methoxide in 50 ml of methanol was added drop-by-drop to a stirred solution of 58.0 g of 1A in 400 ml of ethanol. The mixture was refluxed for 5 minutes, then the volatile materials were evaporated under reduced pressure. The residue was treated with water and extracted with ether. The extract was dried and concentrated under reduced pressure. The residue was cooled and filtered to give 3-(2-chloro-4-nitrophenyl)-2-oxazolidinone (1B), as a white solid, mp: 94°-96° C.
Reaction SMILES: C1([SeH])C=CC=CC=1.[I:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Se:25][C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([OH:30])=O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[Se:25][C:26]3[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:28](=[O:30])[C:23]=2[CH:24]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([SeH:25])=[CH:21][CH:20]=1.[I:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccccc1[Se]c1ccc(Cl)cc1
Agent: O=C(O)c1ccccc1I
Agent: [SeH]c1ccccc1
Product: Clc1ccc([SeH])cc1
Product: O=c1c2ccccc2[se]c2ccc(Cl)cc12

Procedure:
Thus, e.g. 4-chloro-thiophenol and 2-iodo-benzoic acid are condensed to give 2-carboxy-4'-chlorodiphenylsulfide, which is then cyclized to 2-chloro-thioxanthone (cf. J. O. Jilek, M. Rajsner, J. Pomykacek and M. Protiva, Cesk. Farm. 14, (1965) 294-303). In an analogous manner, 4,5-dichlorothioxanthone is obtained from 2-(o-chlorophenylthio)-3-chlorobenzoic acid (cf. V. G. Kalawar, V. V. Badiger and K. S. Nargund, J. Karnatak Univ. 11, (1966) 37-41). Selenoxanthone is obtained from 2-(phenylseleno)-benzoic acid, made by the condensation of selenophenol with 2-iodobenzoic acid; 2-chloro-selenoxanthone is synthesized from 2-(p-chlorophenylseleno)-benzoic acid, obtained from 4-chloroselenophenol and 2-iodobenzoic acid (cf. K. Sindelar, E. Svatek, J. Metysova, J. Metys and M. Protiva, Collection Czechoslovak Chem. Commun. 34, (1969) 3792-3800). 3-Methoxy xanthone is analogously obtained from 2-carboxy-3'-methoxy diphenyl ether, 3-chloro-6-methoxy-xanthone from 2-carboxy,5-chloro-3'-methoxy diphenyl ether and 3-methyl-xanthone from 2-carboxy,5-methyl diphenyl ether. 3,6-Dimethoxy-xanthone is obtained from the abovementioned 3-chloro,6-methoxy-xanthone by the facile replacement of chloride with methoxy (cf. A. A. Goldberg and A. H. Wragg, J. Chem. Soc. 1958, 4227-4234 and ibid. 4234-4241). Similarly, 3-nitro-xanthone is obtained from 2-carboxy,5-nitrodiphenyl ether and 4-nitroxanthone from 2-carboxy,6-nitro diphenyl ether, whereas 2-nitroxanthone and 2,7-dinitro-xanthone may be obtained by direct nitration of xanthone (cf. A. A. Goldberg and H. A. Walker, J. Chem. Soc. 1953, 1348-1357).
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:29])=[C:23]([NH:25][C:26]([NH2:28])=[O:27])[CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:29][CH2:2][C:3]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)=[O:4])=[C:23]([NH:25][C:26]([NH2:28])=[O:27])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CCl)CC1
Reactant: NC(=O)Nc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)COc2ccc(Cl)cc2NC(N)=O)CC1
Reaction time: 14 h
Yield: 25 %

Procedure:
A solution of the crude tert-butyl 4-(2-chloroacetyl)piperidine-1-carboxylate (one third the material from step 1, approximately 5 mmol) in DMSO (20 mL) was charged with 1-(5-chloro-2-hydroxyphenyl)urea (see N. Hossain et al., WO PCT 2004/005295; 980 mg, 5.25 mmol) and K2CO3 (1.38 g, 10 mmol). The reaction was stirred for ˜14 h and then quenched with water (40 mL). The mixture was extracted twice with EtOAc. The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was purified by flash chromatography to afford tert-butyl 4-(2-(4-chloro-2-ureidophenoxy)acetyl)piperidine-1-carboxylate (550 mg, ˜25% yield) as a solid. LC/MS [M-Boc]+=312.3, [M+Na]+=434.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12](O)[CH2:13][NH:14][C:15](=[O:21])[O:16]C(C)(C)C)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].Cl>CN(C=O)C.O>[CH3:23][C:2]1([CH3:1])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:21])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)NC[C@H](O)c1ccc2c(c1)COC(C)(C)O2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Reaction time: 2 h
Yield: 95.5 %

Procedure:
tert-Butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate, (86.37 g) in DMF (600 ml) was added dropwise to a stirred suspension of sodium hydride (60% oil dispersion, 11.9 g) in DMF (160 ml) with cooling such that the internal temperature remained at 0° under nitrogen. The mixture was stirred at 21° for 2 h. The mixture was recooled to 0° and 2M HCl (134 ml) was added. The mixture was diluted with water and the product was extracted with ethyl acetate twice. The solution was washed with brine twice, dried (MgSO4) and evaporated to give the title compound (63.55 g) LCMS RT=2.66 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31].[CH3:34][N:35]([CH3:38])[CH:36]=[O:37]>CN(C)C1C=CN=CC=1.O>[CH3:28][N:29]([CH3:33])[C:30]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[C:17]([O:20][C:36](=[O:37])[N:35]([CH3:38])[CH3:34])[CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)=[O:31]
Reactant: CN(C)C(=O)Cl
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2cc(O)ccc2c2oc3cc(O)ccc3c12
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1ccc2c(c1)[nH]c(=O)c1c3ccc(OC(=O)N(C)C)cc3oc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 450 ml of dry N,N-dimethylformamide was dissolved 21 g of 3,9-dihydroxy-5H-benzofuro[3,2-c]quinolin-6-one. To the solution were added successively 55 ml of triethylamine, 41 g of dimethylcarbamyl chloride and 500 mg of 4-dimethylaminopyridine, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water. The precipitates were collected by filtration, washed with water and ether, and dried to obtain 30 g of 3,9-bis(N,N-dimethylcarbamoyloxy)-5H-benzofuro[3,2-c]quinolin-6-one as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@@H:4]([NH2:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25](O)=[O:26])[N:16]=1>>[CH3:1][O:2][C:3](=[O:14])[C@@H:4]([NH:13][C:25]([C:17]1[N:16]=[CH:15][C:24]2[C:19]([CH:18]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1cc2ccccc2cn1
Yield: 100.1 %

Procedure:
3-(4-Hydroxyphenyl)-(2S)-[(isoquinoline-3-carbonyl)-amino]-propionic acid methyl ester (807 mg, 90%) was prepared from (2S)-amino-3-(4-hydroxy-phenyl)-propionic acid methyl ester (500 mg, 3.0 mmol) and isoquinoline-3-carboxylic acid (530 mg, 2.3 mmol) according to general procedure A.
Reaction SMILES: O=P(Cl)(Cl)Cl.[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3([C:18]([NH:20][C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:24]5)=[O:19])[CH2:17][CH2:16]3)=[CH:14][C:9]=2[O:8][CH2:7]1.CN([CH:37]=[O:38])C>>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3([C:18]([NH:20][C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])=[C:24]5[CH:37]=[O:38])=[O:19])[CH2:17][CH2:16]3)=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
POCl3 (12 g, 80 mmol) was added dropwise to DMF (40 mL) held at −20° C. After the addition was complete, the reaction mixture was allowed to warm to 0° C. and was stirred for 1 h. 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclopropanecarboxamide (3.0 g, 8.0 mmol) was added and the mixture was warmed to 25° C. After stirring for 30 minutes the reaction mixture was poured over ice and stirred for 2 h. The mixture was then heated at 100° C. for 30 min. The mixture was cooled and the solid precipitate was collected and washed with water. The solid was then dissolved in 200 mL dichloromethane and washed with 200 mL of a saturated aq. NaHCO3. The organics were dried over Na2SO4 and evaporated to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-formyl-1H-indol-5-yl)cyclopropane-carboxamide (2.0 g, 61%). ESI-MS m/z calc. 404.5. found 405.5 (M+1)+; retention time 3.30 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 10.39 (s, 1H), 8.72 (s, 1H), 8.21 (s, 1H), 7.35-7.31 (m, 2H), 7.04-7.03 (m, 1H), 6.97-6.90 (m, 2H), 6.03 (s, 2H), 1.53 (s, 9H), 1.42-1.39 (m, 2H), 1.05-1.03 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:34][C:35]3[N:39]([CH2:40][C:41](=[O:49])[NH:42][CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[C:38]4[CH:50]=[CH:51][C:52]([C:54]([NH2:56])=[NH:55])=[CH:53][C:37]=4[N:36]=3)[C:22](=[O:33])[C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)(Cl)[Cl:65]>>[ClH:65].[ClH:65].[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:34][C:35]3[N:39]([CH2:40][C:41](=[O:49])[NH:42][CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[C:38]4[CH:50]=[CH:51][C:52]([C:54]([NH2:56])=[NH:55])=[CH:53][C:37]=4[N:36]=3)[C:22](=[O:33])[C:23]3[CH:24]=[CH:25][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:28]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1
Reactant: COC(=O)c1ccc(C(=O)N(Cc2nc3cc(C(=N)N)ccc3n2CC(=O)NC2CCCCC2)c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Reactant: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C(=O)N(Cc2nc3cc(C(=N)N)ccc3n2CC(=O)NC2CCCCC2)c2ccc(OC3CCNCC3)cc2)cc1
Product: Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[N-[4-(1-tert-butoxycarbonylpiperidin-4-yloxy)phenyl]-N-(4-methoxycarbonylbenzoyl)aminomethyl]-1-(cyclohexylcarbamoylmethyl)-benzimidazole-5-carboxamidine (201 mg) in chloroform (1 ml) was added trifluoroacetic acid (1 ml), and the mixture was stirred for 5 min. After completion of the reaction, the solvent was evaporated and to the obtained residue was added a 1N hydrogen chloride-diethyl ether solution. The obtained solid was collected by filtration and dried under reduced pressure to give the title compound (175 mg).
Reaction SMILES: [NH2:1][C:2]([CH3:29])([CH3:28])[CH2:3][NH:4][CH:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([Cl:27])=[CH:14][CH:15]=2)[N:10]=1)[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=O)=[CH:40][C:39]=1[CH3:47]>ClCCl>[CH2:19]([N:18]1[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([Cl:27])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:5]([N:4]1[CH2:3][C:2]([CH3:29])([CH3:28])[N:1]=[C:42]1[C:41]1[CH:45]=[CH:46][C:38]([F:37])=[C:39]([CH3:47])[CH:40]=1)[CH:6]([CH3:8])[CH3:7])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cc(C(=O)Cl)ccc1F
Reactant: CC(C)C(NCC(C)(C)N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C2=NC(C)(C)CN2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)ccc1F
Temperature: 25 °C
Yield: 42.6 %

Procedure:
To a solution of (±)-2-[1-(2-amino-2-methyl-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-quinazolin-4-one (250 mg, 0.61 mmol) in dichloromethane (10 mL) was added triethylamine (295 μL, 2.12 mmol), followed by 4-fluoro-3-methylbenzoyl chloride (105 mg, 0.61 mmol). The resultant solution was stirred at ambient temperature for 2 hours, then evaporated under reduced pressure to a crude white solid. The resultant solid was treated with glacial acetic acid (10 mL) then the resultant suspention was heated at reflux for 48 hours. The reaction was cooled to ambient temperature then evaporated under reduced pressure to a crude oil. The oil was quenched with saturated aqueous sodium bicarbonate (10 mL) and brine (5 mL). The aqueous layer was extracted with dichloromethane (2×5 mL) and the combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-10% ethyl acetate/hexanes) to furnish (±)-3-benzyl-7-chloro-2-{1-[2-(4-fluoro-3-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-imidazol-1-yl]-2-methyl-propyl}-3H-quinazolin-4-one (138 mg, 43%) as a white solid: LCMS 531 (M++H)