Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([CH2:20][CH3:21])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3].[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[CH2:12]([O:11][C:9]1[C:8]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]([CH2:20][CH3:21])=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:10]=1)[CH:13]=[CH2:14]
Reactant: C=CCOc1cc(CC(=O)OC)c(CC)c(OCC=C)c1
Reactant: O=C(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=CCOc1cc(OCC=C)c(C(=O)c2ccccc2)c(CC(=O)OC)c1CC
Temperature: 4 °C
Reaction time: 18 h
Yield: 56.6 %

Procedure:
Methyl 3,5-diallyloxy-2-ethylphenylacetate (0.31 g, 1.3 mmol) obtained in Example 5, Step 3 was dissolved in trifluoroacetic acid (2.0 mL). After the solution was cooled to 4° C., benzoic acid (0.40 g, 3.3 mmol) and trifluoroacetic anhydride (1.0 mL) were added thereto, followed by stirring for 18 hours, while the temperature of the reaction mixture was raised to room temperature. The reaction mixture was gradually added to a saturated aqueous solution of sodium hydrogencarbonate for neutralization, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/4) to obtain methyl 3,5-diallyloxy-2-benzoyl-6-ethylphenylacetate (0.29 g, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.[Cl:28][C:29]1[S:30][C:31]([Cl:37])=[CH:32][C:33]=1[C:34](Cl)=[O:35].CCN(CC)CC>C(Cl)Cl>[Cl:28][C:29]1[S:30][C:31]([Cl:37])=[CH:32][C:33]=1[C:34]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)=[O:35]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Reactant: O=C(Cl)c1cc(Cl)sc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5cc(Cl)sc5Cl)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a mixture of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g, 0.41 mmol) and 2,5-dichlorothiophene-3-carbonyl chloride (0.088 g, 0.41 mmol) in CH2Cl2 was added Et3N (0.086 mL, 0.62 mmol) and the mixture stirred at room temperature under nitrogen for 30 minutes. The mixture was concentrated and purified by silica gel chromatography, eluting with 70% CH2Cl2/(92:7:1 CHCl3/MeOH/concentrated NH4OH) to 100% (92:7:1 CHCl3/MeOH/concentrated NH4OH), to afford the title compound as a light yellow solid (0.177 g, 79%). 1H NMR (300 MHz, DMSO-d6): δ 11.80 (s, 1H), 8.12 (d, J=9.0 Hz, 2H), 7.27 (s, 1H), 7.05 (d, J=9.0 Hz, 2H), 6.69 (d, J=2.3 Hz, 1H), 6.48 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.73-3.82 (m, 2H), 3.38-3.44 (m, 6H). APCI MS m/z 545 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][S:5]([NH:8][C:9]1[N:10]=[CH:11][S:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:7])=[O:6].C(N(CC)C(C)C)(C)C.FC(F)(F)S(O[CH2:37][CH:38]([F:40])[F:39])(=O)=O>C(#N)C>[F:39][CH:38]([F:40])[CH2:37][N:8]([S:5]([CH2:4][C:3]1[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=1[I:1])(=[O:7])=[O:6])[C:9]1[N:10]=[CH:11][S:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1scnc1NS(=O)(=O)Cc1ccccc1I
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1scnc1N(CC(F)F)S(=O)(=O)Cc1ccccc1I
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2.1 g (4.8 mmol) of methyl 4-{[(2-iodobenzyl)sulfonyl]amino}-1,3-thiazole-5-carboxylate were dissolved in 20 ml of acetonitrile, and 0.9 ml (5.3 mmol) of N,N-diisopropylethylamine was added at RT. The reaction mixture was stirred at RT for 5 min and then a solution of 1.54 g (7.2 mmol) of difluoroethyl trifluoromethane-sulfonate in 5 ml of acetonitrile was added dropwise within 10 min. The reaction mixture was stirred at RT for 12 h and then concentrated to dryness. The residue was purified by means of preparative HPLC(C18—SiO2, gradient acetonitrile/water 20:80 to 100:0). This gave 2.09 g of methyl 4-{(2,2-difluoroethyl)[(2-iodobenzyl)-sulfonyl]amino}-1,3-thiazole-5-carboxylate.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[S:30][CH:31]=[C:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[N:28]=3)[CH2:33][CH2:34]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccc(F)cc4)cs3)CC2)cn1
Temperature: 70 °C
Reaction time: 12 h
Yield: 32.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (273 mg, 0.835 mmol), 1-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 12 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (110 mg, 32.9%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:19]([OH:21])=O)[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:28])[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.CN(C)C=O>[C:26]([NH:25][CH2:24][CH2:23][NH:22][C:19]([C:7]1[CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][N:3]=[C:2]2[NH2:1])=[O:21])(=[O:28])[CH3:27]
Reactant: Nc1ncnc2c(C(=O)O)cc(-c3cccc(F)c3)cc12
Reactant: CC(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCNC(=O)c1cc(-c2cccc(F)c2)cc2c(N)ncnc12
Temperature: 50 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
To a 4 mL screw-cap vial was added 4-amino-6-(3-fluorophenyl)quinazoline-8-carboxylic acid (0.10 mmol, 28 mg) followed by N-(2-aminoethyl)acetamide (2 equiv., 0.20 mmol, 20 mg), HATU (1.1 equiv., 0.11 mmol, 43 mg), dimethylformamide (0.5 mL), and triethylamine (3 equiv., 0.30 mmol, 0.042 mL). The reaction was capped and shaken at 50° C. for 4 h. The reaction was cooled to room temperature, diluted with 2.5 ml dichloromethane and washed with 1 ml water. Organic was concentrated, then the crude was purified by reverse phase HPLC, yielding 6 mg of desired product. 1H NMR (400 MHz, DMSO) δ 11.17-11.07 (t, J=5.6 Hz, 1H), 8.89-8.75 (m, 2H), 8.54-8.50 (s, 1H), 8.44-8.06 (m, 2H), 8.06-7.99 (t, J=5.5 Hz, 1H), 7.75-7.64 (m, 2H), 7.64-7.53 (m, 1H), 7.35-7.22 (m, 1H), 3.53-3.44 (m, 2H), 3.32-3.26 (m, 2H), 1.85-1.82 (s, 3H). LCMS M/Z (M+H)=368.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.[C:9]1(=[O:16])[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]1.[CH2:17]([O:19][C:20](=[O:25])/[CH:21]=[C:22](\[NH2:24])/[CH3:23])[CH3:18]>C(O)C>[CH2:17]([O:19][C:20]([C:21]1[CH:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[C:10]2[C:9](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]=2[NH:24][C:22]=1[CH3:23])=[O:25])[CH3:18]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: Cn1ccnc1C=O
Reactant: O=C1CCCC(=O)C1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC2=C(C(=O)CCC2)C1c1nccn1C
Yield: 36.6 %

Procedure:
A mixture of N-methyl-imidazole-2-carboxaldehyde (4.9 g, 0.045 mole), 1,3-cyclohexandione (5.8 g, 0.045 mole), and ethyl-3-aminocrotonate (5.04 g, 0.045 mole), in 50 mL of absolute ethanol was refluxed for 24 hours. The reaction mixture was cooled and the separated solid was filtered and recrystallized from a hexane-ethylacetate (1:1) mixture to afford 5.2 g (37% yield) of the title compound, m.p. 271°-272° C.; MS, m/e 315 (M+); NMR (CDCl3) δ 1.0 (t, 3 H, CCH 3), 1.5-2.4 (m, 6 H, cyclohexanone), 2.5 (s, 3 H, =CCH3), 3.9-4.1 (q, 2 H, CH2C), 4.0 (s, 3 H, NCH3), 5.2 (s, 1 H, dihydropyridine-H), 6.3 (d, 1 H, imidazole-H), 6.5 (d, 1 H, imidazole-H) and 9.5 (s, 1 H, NH).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:13]([C:12]2[C:8]([C:7]3[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:16])=[O:15])[CH2:29]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2cccnc2Cl)c1C(=O)O
Reactant: NC1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2cccnc2Cl)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
Combine 3-(2-chloro-pyridin-3-yl)-5-methyl-isoxazole-4-carboxylic acid (0.50 g, 0.0021 mol) with (3-amino-cyclohexylmethyl)-carbamic acid benzyl ester (0.63 g, 0.0021 mol), 1-[3-(dimethyl-amino)propyl]-3-ethylcarbodiimide hydrochloride (0.40, 0.0021 mol), 1-hydroxy-7-azabenzo-triazole (0.29 g, 0.0021 mol), and N,N-diisopropylethyl amine (1.10 mL, 0.0063 mol), in N,N-dimethylformamide (10 mL). Stir over a weekend at ambient temperature. Concentrate in vacuo and take up in water and extract with ethyl acetate. Wash the combined extracts with water, dry over sodium sulfate, and concentrate in vacuo. Elute over silica gel using ethanol/dichloromethane allowing for the isolation of 0.87 g (86%) of the desired amide as a white solid. MS(ES): (M+1)+ 483.1, 485.1 m/z.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:16][CH:17]=[CH2:18])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.[C:28]([CH:33]([CH:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[OH:36])[OH:34])([O:30][CH2:31][CH3:32])=[O:29]>CCOCC>[CH2:16]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:36][CH:35]([CH:33]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[OH:34])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:14])=[CH:8][CH:7]=1)[CH:17]=[CH2:18]
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Reactant: C=CCN(C(=O)C(F)(F)F)c1ccc(CC(=O)Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CCNc1ccc(CC(=O)OC(C(=O)OCC)C(O)C(=O)OCC)cc1

Procedure:
A mixture of 4-[N-trifluoroacetyl-(allylamino)]phenylacetyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g. diethyl tartrate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields diethyl O-[4-(allylamino)phenylacetyl]tartrate as a white, crystalline solid.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH2:25])[CH:23]=2)[CH:18]=[N:17]1>CN(C)C=O>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH:25]/[CH:3]=[C:4]3\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:23]=2)[CH:18]=[N:17]1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1ccc2cn[nH]c2c1
Temperature: 110 °C
Yield: 52.2 %

Procedure:
A mixture of 4-methoxymethylene-4H-isoquinoline-1,3-dione (101.5 mg, 0.5 mmol), 1H-indazol-6-ylamine (66.6 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 1 h. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 79.4 mg (52%) of yellow solid mp >300° C.; MS (ESI) m/z 305.10 (M+1);
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][CH2:10][CH2:11][CH2:12][CH:13]([CH:15]([CH3:17])C)C.[CH3:18][CH2:19]CC(CC(C)C)C.CC(CC(C(C)C)C)C>>[CH2:18]([C:3]1[CH:2]=[C:1]([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=1)[CH2:19][CH2:17][CH2:15][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: Cc1ccccc1O
Reactant: CCCC(C)CC(C)C
Reactant: CCCCC(C)C(C)C
Agent: CC(C)CC(C)C(C)C
Product: CCCCCCCCCc1ccc(O)c(C)c1
Yield: 253.9 %

Procedure:
o-Cresol (108 g, 1 mol), tripropylene (131.74 g), and Amberlyst 15 (8.55 g) were stirred for 20 h at 75° C. and 2 h at 90° C. At ambient temperature the reaction mixture was mixed with heptanes and filtered to remove the catalyst. Removal of the solvent in vacuo gave crude product (225.23 g), which was distilled to obtain pure 4-nonyl-2-cresol (203.76 g) in 87% yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH2:3]1.[Cl:12][C:13]1[CH:22]=[C:21](F)[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>>[ClH:12].[Cl:12][C:13]1[CH:22]=[C:21]([O:8][CH:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4]3[O:11][CH:10]=[CH:9][C:5]2=3)[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(F)cc1Cl
Reactant: CN1Cc2occc2C(O)C1
Product: COC(=O)c1ccc(OC2CN(C)Cc3occc32)cc1Cl
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using methyl 2-chloro-4-fluorobenzoate instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.[N:38]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2N=N1.NC1C=CC=CC=1>ClCCl>[C:42]1([NH:38][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:2][CH:3]=2)=[O:8])[CH:43]=[CH:44][CH:45]=[CH:46][CH:41]=1
Reactant: O=C(O)CCCCCCC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCCCC(=O)c1ccc(-c2ccccc2)cc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
To a solution of carboxylic acid 50h (310 mg, 1 mmol) in dichloromethane (5 mL) stirred at room temperature under nitrogen was added triethylamine (135 μL, 1 mmol), followed by BOP (442 mg, 1 mmol), aniline (108 μL, 1 mmol) and triethylamine (405 μL, 3 mmol). The resulting reaction mixture was stirred for 12 hours at room temperature. The solvent was removed and the mixture was quenched with water (5 mL), extracted with ethyl acetate (3×10 mL), dried (MgSO4), concentrated. Purification by flash silica gel chromatography (5% methanol in dichloromethane) followed by crystallization from acetone afforded the corresponding amide 80 (20% yield). 1H NMR: (300 MHz, CDCl3) δ 8.00 (m, 4H), 7.40-7.60 (m, 10H), 3.00 (m, 2H), 2.60 (m, 2H), 1.60 (m, 4H), 1.20 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([NH:14][CH2:15][CH2:16][Cl:17])=[O:13])[CH2:10][CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1.[OH2:26]>C(O)(=O)C.C(OO)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([NH:14][CH2:15][CH2:16][Cl:17])=[O:13])[CH2:10][CH2:9][N+:8]([O-:26])=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1
Reactant: O=C(NCCCl)N1CCN=C(c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: O
Agent: CC(=O)OO
Solvent: CC(=O)O
Product: O=C(NCCCl)N1CC[N+]([O-])=C(c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
10 Parts of 7-chloro-N-(2-chloroethyl)-5-(o-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-1-carboxamide is dissolved in 50 parts by volume of glacial acetic acid and to this solution 10 parts by volume of 40% peracetic acid is added all at once with stirring. The reaction mixture is stirred at ambient temperature for about 24 hours and then slowly poured into 1000 parts by volume of cold water. The precipitate which forms is extracted with methylene chloride, the extract dried over magnesium sulfate and the solvent removed. The residue crystallizes from ethanol to afford 7-chloro-N-(2-chloroethyl)-5-(o-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-1-carboxamide 4-oxide. This compound is represented by the following formula ##STR37##
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:48]2[C:49]([C:54]#[N:55])=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:47])[N:23]([C@H:34]2[CH2:39][CH2:38][C@H:37]([O:40][CH:41]([CH3:46])[C:42]([OH:45])([CH3:44])[CH3:43])[CH2:36][CH2:35]2)[C:24]2[N:25]([N:30]=[C:31]([CH3:33])[N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:54]2[NH:3][C:4](=[O:7])[O:5][N:55]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:47])[N:23]([C@H:34]2[CH2:39][CH2:38][C@H:37]([O:40][CH:41]([CH3:46])[C:42]([OH:45])([CH3:43])[CH3:44])[CH2:36][CH2:35]2)[C:24]2[N:25]([N:30]=[C:31]([CH3:33])[N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2nc(C)nn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.48 g), sodium hydrogen carbonate (0.77 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.27 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.09 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.076 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.19 g, 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[O:38]=[C:39]([NH:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:40][C:41](O)=[O:42].C(Cl)CCl>CN(C=O)C>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH2:40][C:39](=[O:38])[NH:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=3)[S:15][C:8]=12
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Reactant: O=C(O)CC(=O)Nc1ccccc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
To a solution of 46 (333 mg, 0.631 mmol) in DMF (8 mL) at RT was added 3-oxo-3-(phenylamino)propanoic acid (226 mg, 2 eq, 1.262 mmol) and EDC (242 mg, 2 eq, 1.262 mmol), and the reaction mixture was stirred at RT for 24 hours. It was then concentrated to dryness then purified by column chromatography (eluent a gradient of 80% EtOAc in hexane to EtOAc), to afford 47a (357 mg, 82% yield) as a white solid. MS (m/z): 689.4 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=3)[C:8](=[O:19])[C:7]=2[C:6]([NH:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C(Cl)(Cl)Cl>[CH2:26]([N:23]([CH2:24][CH3:25])[CH2:22][CH2:21][NH:20][C:6]1[C:7]2[C:8](=[O:19])[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([O:17][CH3:18])[CH:10]=3)[S:15][C:16]=2[C:3]([CH2:2][NH:1][C:36](=[O:37])[O:38][CH3:39])=[CH:4][CH:5]=1)[CH3:27]
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccc(OC)cc3c(=O)c12
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNc1ccc(CNC(=O)OC)c2sc3ccc(OC)cc3c(=O)c12
Temperature: 25 °C

Procedure:
To a solution of 1.55 g of 4-(aminomethyl)-1-[[2-(diethylamino)ethyl]amino]-7-methoxythioxanthen-9-one in 40 mL of chloroform containing 2 mL of triethylamine chilled to 0° C. was added 0.45 mL of methyl chloroformate and the mixture was stirred at room temperature for several hours. The solvent was removed in vacuo, the residue was purified by flash chromatography (silica gel; eluting with chloroform, then 1% triethylamine in chloroform/hexane (1:1)) affording 1.2 g of methyl N-[[1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9-oxothioxanthen-4-yl]methyl]carbamate which was recrystallized from ethyl acetate to yield 0.79 g of a bright yellow solid, m.p. 131°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16](OCC)=[O:17])=[C:5]2[OH:21].C(N(C(C)C)C(C)C)C.Cl.[NH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8]([CH3:13])([CH3:14])[C:7](=[O:15])[C:6]([C:16]([NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:17])=[C:5]2[OH:21]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)c(Cl)cc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)c(Cl)cc2C(C)(C)C1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
Ethyl 6,7-dichloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (325 mg, 987 μmol) was dissolved in 1,4-dioxane (987 μL) and N-ethyl-N-isopropylpropan-2-amine (516 μL, 2962 μmol). tert-Butyl 2-aminoacetate hydrochloride (248 mg, 1481 μmol) was added, and the reaction was stirred at 80° C. for 4 hours. The reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 20 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (235 mg) as an off-white solid after purification via preparatory LC. MS (m/z)=358(M+H-tBu)+.