Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.O=C1CCC(=O)N1OC(=O)CCC(NC[CH:20]1[O:24][C:23]2[CH:25]=[CH:26][C:27]([CH2:29][CH:30]([N:32](C)[C:33](=O)C(F)(F)F)[CH3:31])=[CH:28][C:22]=2[O:21]1)=O>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>[CH3:31][CH:30]([NH:32][CH3:33])[CH2:29][C:27]1[CH:26]=[CH:25][C:23]2[O:24][CH2:20][O:21][C:22]=2[CH:28]=1
Reactant: CC(Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)ON1C(=O)CCC1=O)O2)N(C)C(=O)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CNC(C)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 800 mg of bovine serum albumin (BSA) in 8 mL of 50 mM potassium phosphate (pH 7.5) was cooled in an ice-bath. To the solution was added 12 mL of DMSO dropwise, and the reaction mixture was maintained below room temperature. To the protein solution was added a solution of 15 mg of MDMA derivative (1L) in 1 mL of anhydrous DMF dropwise. The reaction mixture was allowed to stir at room temperature 48 hours. The resulting conjugate was placed in a dialysis tube (10,000 MW cut-off) and was dialyzed in 1 L of 70% DMSO in 50 mM potassium phosphate (pH 7.5, 3 changes, at least 3 hours each), 1 L of 50% DMSO in 50 mM potassium phosphate (at least 3 hours), 1 L of 30% DMSO in 50 mM potassium phosphate (at least 3 hours), 1 L of 10% DMSO in 50 mM potassium phosphate (at least 3 hours) at room temperature. The trifluoroacetamido group of the conjugate was deprotected by dialysis of the resulting conjugate against 10% ammonium hydroxide for 3 days (1 L each for approximately 24 hours each), followed by 6 changes with 50 mM potassium phosphate (pH 7.5) at 4° C. (1 L each for at least 6 hours). The protein concentration was determined to be 6.8 mg/mL using BioRad Coomassie blue protein assay (Bradford, M., Anal. Biochem. 72:248, 1976). A total of 38 mL of the conjugate was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:3]([OH:10])([CH2:2][NH:1][S:24]([C:20]1[S:19][CH:23]=[CH:22][CH:21]=1)(=[O:26])=[O:25])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=S(=O)(Cl)c1cccs1
Product: O=S(=O)(NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)c1cccs1

Procedure:
Following the procedure described in the preceeding example but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 2-thienylsulfonylchloride, the title compound was obtained in a similar yield:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=2)=[O:15])[CH2:10][C@H:9]1[CH2:29][C:30](O)=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][NH:34][CH3:35]>>[CH3:33][N:34]([CH3:35])[C:30](=[O:31])[CH2:29][C@@H:9]1[CH2:10][C@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[N:18]([CH:26]([CH3:27])[CH3:28])[N:17]=2)=[O:15])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7]
Reactant: CNC
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)O)N(C(=O)OC(C)(C)C)C2)c2cc(F)ccc21
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)N(C)C)N(C(=O)OC(C)(C)C)C2)c2cc(F)ccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 7 from ((2S,4S)-1-(tert-butoxycarbonyl)-4-{[(5-fluoro-1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidin-2-yl)acetic acid (step 3 of Example 25) and dimethylamine.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[OH:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17][Br:18])=[CH:14][CH:13]=1>C(Cl)Cl.O>[C:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17][Br:18])=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Oc1ccc(CCBr)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetyl chloride (2.01 g, 1.82 mL. 25.6 mmol) was added to a stirred solution of pyridine (2.02 g, 2.07 mL, 25.6 mmol) and 4-hydroxyphenethyl bromide (856.5 mg, 4.26 mmol) in dry CH2Cl2 (17 mL) and the reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (2×40 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford 4-(2-bromoethyl)phenyl acetate. 1H NMR (500 MHz, CHCl3): δ 7.22 (d, J=8.3 Hz, 2 H); 7.04 (d, J=8.3 Hz, 2 H); 3.55 (t, J=7.6 Hz, 2 H); 3.16 (t, J=7.6 Hz, 2 H); 2.29 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.CN(C)C=O.[Br:25]N1C(=O)CCC1=O>O>[Br:25][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[O:2][CH3:1]
Reactant: COc1cc2ccccc2cc1-c1ccccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(-c2ccccc2F)cc2ccccc2c1Br
Temperature: 60 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
13.4 g of 2-methoxy-3-(2-fluorophenyl)naphthalene and 100 mL of N,N-dimethylformamide were placed in a flask. Then, 40 mL of a N,N-dimethylformamide solution of 11.3 g of N-bromosuccinimide was added. The reaction solution was stirred at 60° C. for 8 hours. After cooling to room temperature, 500 mL of water was added. Then, an organic substance was extracted with toluene. The toluene solution was sequentially washed with sodium thiosulfate and saturated saline. After drying with magnesium sulfate, the organic phase was concentrated. Residues were purified by silica gel column chromatography, whereby 15.8 g (yield: 95%) of 1-bromo-2-methoxy-3-(2-fluorophenyl)naphthalene was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][CH2:12][NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])=[N:7][C:6]=2[CH:19]=1.OO.C(=O)([O-])[OH:23].[Na+]>C(O)(=O)C.C(Cl)Cl.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([CH2:11][CH2:12][NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])=[O:23])=[N:7][C:6]=2[CH:19]=1
Reactant: O=C([O-])O
Reactant: CCNC(=O)NCCSc1nc2cc(Cl)ccc2s1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CCNC(=O)NCCS(=O)c1nc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Dissolved in a mixed solution of 5.8 ml of acetic acid and 5.8 ml of methylene chloride were 1.15 g (3.65 mmol) of the compound obtained in Example 21, and 0.41 ml (4.02 mmol) of a 30% aqueous solution of hydrogen peroxide and a catalytic quantity of sodium tungstate were successively added to the solution, which was stirred at room temperature for 1 hour. The reaction solution was poured in 116 ml of water, neutralized with sodium hydrogencarbonate and extracted with 116 ml of chloroform. After separation of the chloroform layer, the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residues were purified by silica gel chromatography to obtain 0.96 g of white crystalline powders (79% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:26])[C:16]2([C:22]([O:24]C)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]>CO.C1COCC1.[OH-].[Na+]>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]([CH3:26])[C:16]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C2(C(=O)OC)CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C2(C(=O)O)CCCCC2)cc1
Reaction time: 16 h

Procedure:
To a stirred solution of methyl 1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]cyclohexanecarboxylate (4.6 g, 12.1 mmol) in methanol:THF (4:1, 100 ml), 10 N sodium hydroxide (15 ml) was added at room temperature. The reaction was stirred for 16 h and evaporated to dryness in vacuo and the residue was dissolved in 100 mL water. The pH was adjusted to 1 with 5N hydrochloric acid solution and the mixture was extracted with chloroform, washed with water, dried and concentrated to give 1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]cyclohexanecarboxylic acid as a yellow solid. Yield: 4 g (88%); mp 124-6° C. Electrospray Mass Spec 364(M−H)−.
Reaction SMILES: [ClH:1].Cl.[C:3]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]2[N:27]=[C:26]([N:28]3[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:13]1)=[O:11].N1C=CC=CC=1.[C:47](OC(=O)C)(=[O:49])[CH3:48]>C(Cl)(Cl)Cl>[ClH:1].[C:47]([N:31]1[CH2:32][CH2:33][CH2:34][N:28]([C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([NH:17][C@H:14]3[CH2:15][CH2:16][N:12]([C:10](=[O:11])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:13]3)[N:27]=2)[CH2:29][CH2:30]1)(=[O:49])[CH3:48]
Reactant: O=C(Cc1ccccc1-c1ccccc1)N1CC[C@H](Nc2nc(N3CCCNCC3)c3ccccc3n2)C1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCN(c2nc(N[C@H]3CCN(C(=O)Cc4ccccc4-c4ccccc4)C3)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 113.9 %

Procedure:
t-Butyl 4-(2-((S)-1-(2-biphenyl-2-ylethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)-[1,4]diazepane-1-carboxylate (0.53 g) synthesized in the same manner as in Example 1 was dissolved in ethyl acetate (3 mL), followed by addition of a solution (2.2 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred overnight. Precipitated solids were collected by filtration and then washed with hexane to obtain 2-biphenyl-2-yl-1-((S)-3-(4-[1,4]diazepan-1-ylquinazolin-2-ylamino)pyrrolidin-1-yl)ethanone dihydrochloride (0.15 g). (2) 2-Biphenyl-2-yl-1-((S)-3-(4-[1,4]diazepan-1-ylquinazolin-2-ylamino)pyrrolidin-1-yl)ethanone di hydrochloride (40 mg) was suspended in chloroform (3 mL), followed by addition of pyridine (12 mg) and acetic anhydride (8.5 mg), and the mixture was stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform/methanol=10:1) to obtain the title compound (compound 1-210) (46 mg). The resulting purification product was dissolved in ethyl acetate (1.0 mL), followed by addition of a solution (0.015 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred to obtain the title compound (compound 1-212) (12 mg).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=1[CH:5]=2.[Cl:16][CH2:17][CH2:18][CH2:19][S:20][C:21]1[N:22]([CH3:37])[C:23]([C:26]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:27]=2[CH:28]=[CH:29][C:30]([CH3:36])=[N:31]3)=[N:24][N:25]=1>>[ClH:16].[CH3:1][C:2]1[O:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][N:10]([CH2:17][CH2:18][CH2:19][S:20][C:21]3[N:22]([CH3:37])[C:23]([C:26]4[CH:35]=[CH:34][CH:33]=[C:32]5[C:27]=4[CH:28]=[CH:29][C:30]([CH3:36])=[N:31]5)=[N:24][N:25]=3)[CH2:11][CH2:12][C:6]=1[CH:5]=2
Reactant: Cc1nc2cc3c(cc2o1)CCNCC3
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6nc(C)oc6cc5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-methyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (0.82 mmol) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline and was obtained as a faint yellow slightly hygroscopic solid (0.46 mmol).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH:19]([CH3:21])[CH3:20].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH2:18]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CI
Reactant: COC(=O)c1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1OCC(C)C

Procedure:
In 100 ml of N,N-dimethylformamide are dissolved 10.0 g of methyl salicylate, 18.1 g of potassium carbonate and 11.3 ml of isobutyl iodide. The solution is heated under reflux for 1.5 hours with stirring. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2.0 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5) to obtain 4.2 g of methyl 2-isobutoxybenzoate as a light yellow oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]2[CH2:21][OH:22])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([O:22][CH2:21][C@@H:12]2[CH2:13][C@@H:14]([O:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH2:15][N:11]2[C:9]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=2)=[O:10])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2CO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (8.7 g: 24.2 mmole) in dichloromethane(80 ml) are added triethylamine (4.05 ml), p-toluenesulfonyl chloride (5.08 g) and 4-dimethylaminopyridine (148 mg). The mixture is stirred at room temperature overnight. The reaction mixture is washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene:ethyl acetate=1:1) to give (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (11.75 g). Yield: 95%. NMR δ(CDCl3) ppm: 2.2 to 2.5(m), 2.44(s, 3H), 2.98(s, 3H), 3.4 to 3.6(m, 2H), 3.82(s, 3H), 3.8 to 4.6(m), 5.03, 4.95(ABq, J=12 Hz, 2H), 5.2 (br s, 1H), 6.89(d, J=8.6 Hz, 2H), 7.18 to 7.4(m, 4H), 7.6 to 7.8(m, 2H). IR ν (CHCl3) cm-1 : 1698, 1612.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])=[O:9])=[O:5])[CH3:2].C(N(CC)CC)C.C(Cl)[Cl:28]>>[C:13]([OH:15])(=[O:14])[C:12]1[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:10].[Cl:28][C:8]([CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:9]
Reactant: ClCCl
Reactant: CCOC(=O)CCC(=O)Nc1ccccc1C(=O)O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC(=O)Cl
Product: Nc1ccccc1C(=O)O

Procedure:
In the same way as in Example 15, the intermediate 2 is reacted with 2-(3-ethoxycarbonylpropanoylamino)benzoic acid obtained by reaction of anthranilic acid with ethyl 3-chlorocarbonylpropanoate in CH2Cl2 in the presence of triethylamine, according to a method adapted from Tetrahedron Lett. 50 (1994) 34, 10331. The product is purified by flash chromatography on a column of silica, eluting with the solvent C/A30.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([NH2:17])=[C:13]([NH2:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.O1CCO[CH:23](O)[CH:22]1O>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]3[N:17]=[CH:23][CH:22]=[N:16][C:13]=3[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cc1N
Reactant: OC1OCCOC1O
Solvent: CO
Product: Brc1cccc(Nc2ncnc3cc4nccnc4cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A mixture of 4-(3-bromoanilino)-6,7-diaminoquinazoline (90 mg, 0.27 mmol) and 1,4-dioxane-2,3-diol (0.2 g, 1.6 mmol) [Venuti, M. C.; Synthesis, 1982, 61-63] in MeOH (20 mL) is stirred at room temperature overnight to give a precipitate of 4-(3-bromoanilino)pyrazino[2,3-g]quinazoline (80 mg, 83%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>>[ClH:16].[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[N:14]=1)=[O:20]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CN1CCC(Oc2cccc(N)n2)CC1
Product: CN1CCC(Oc2cccc(NC(=O)c3ccccc3Cl)n2)CC1
Product: Cl
Yield: 153.3 %

Procedure:
Using a method similar to example 154, using 6-(1-methyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 60, 200 mg, 0.965 mmol) and 2-chlorobenzoyl chloride (146 μL, 1.16 mmol) yields the title compound (340 mg, 92%). Mass spectrum (ion spray): m/z 346.0 (M+1); Analysis calculated for C18H20N3O2Cl2.0.5H2O. Theory: C, 55.25; H, 5.67; N, 10.74. Found: C, 55.60; H, 5.67; N, 10.74. mp=88-90° C.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[O:18]=[C:19]1[C:27]2([C:31]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:30]=3[O:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[O:18]=[C:19]1[C:27]2([C:31]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:30]=3[O:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: N#Cc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Reactant: BrCc1ccccn1
Agent: Br
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: N#Cc1ccc2c(c1)OCC21C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile was obtained (89%) as a colorless solid: mp 151-153° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J=3.9 Hz, 1H), 7.66 (t, J=7.5 Hz, 1H), 7.34-6.84 (m, 9H), 5.19 (d, J=15.8 Hz, 1H), 5.07 (d, J=9.2 Hz, 1H), 4.97 (d, J=15.8 Hz, 1H), 4.79 (d, J=9.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.3, 160.7, 155.1, 149.7, 142.3, 137.1, 134.8, 131.2, 129.5, 125.8, 124.6, 123.8, 122.9, 121.8, 118.5, 113.8, 113.3, 109.9, 80.21, 77.5, 57.9, 46.1; MS (ES+) m/z 353.9 (M+1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[I:5]N1C(=O)CCC1=O.[C:13]1([N+:19]#[C-:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O.[I-].C[N+](C)(C)C.C(Cl)(Cl)Cl>[I:5][C:20]1[N:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[N:2][N:1]=1
Reactant: [C-]#[N+]c1ccccc1
Reactant: O=C1CCC(=O)N1I
Reactant: [N-]=[N+]=[N-]
Agent: C[N+](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Ic1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
With vigorous stirring, a solution of 9.7 mmol (0.63 g) of sodium azide in 10 ml of water and 0.1 g of tetramethylammonium iodide are added to a mixture, cooled to 0° C., of 9.7 mmol (2.18 g) of N-iodosuccinimide in 10 ml of chloroform. After 5 minutes of stirring, a solution of 9.7 mmol (1 g) of phenyl isocyanide in chloroform is added dropwise, and the reaction mixture is stirred at 0° C. for 45 minutes. The reaction mixture is allowed to warm to room temperature, and a further 10 ml of chloroform are added. The phases are separated, and the organic phase is washed 3 times with water, once with saturated sodium thiosulfate solution, again with water and then with saturated sodium chloride solution. After drying over sodium sulfate, the solvent is distilled off under reduced pressure and the residue is recrystallized from ethanol or petroleum (bp.: 80 . . . 110° C.)/ethyl acetate. This gives 0.2 g (8%) of 5-iodo-1-phenyltetrazole of melting point 123-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([F:27])([F:26])[C:18](=[O:25])[CH:19]=[C:20]1C[CH2:23][CH2:22][S:21]1.C(#[N:30])C>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:30]2[CH2:23][CH2:22][S:21][C:20]2=[CH:19][C:18](=[O:25])[C:17]([F:27])([F:26])[F:16])=[CH:6][CH:7]=1
Reactant: CC#N
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C(C=C1CCCS1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(C=C1SCCN1Cc1ccc(Cl)nc1)C(F)(F)F
Yield: 50 %

Procedure:
2-chloro-5-chloromethylpyridine (80 mg, 0.50 mmol) dissolved in 8 mL of anhydrous acetonitrile, and potassium carbonate (69 mg, 0.50 mmol) were added to 65 mg (0.33 mmol) of 1,1,1-trifluoro-3-(thiaolidin-2-ylidene)propane-2-one obtained by the foregoing method, and the mixture was refluxed under heating for 2 hours. After reaction completion, the reaction mixture was returned to room temperature, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=1:1→1:3), giving 53 mg of the target compound (yield, 50%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([CH:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C(Cl)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[CH2:40][NH2:41]>>[C:29]1([CH:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:41][CH2:40][C:36]2[S:35][CH:39]=[CH:38][CH:37]=2)=[O:18])=[O:7])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NCc1cccs1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CON=C1C[C@@H](C(=O)NCc2cccs2)N(C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and 2-thienylmethylamine the title compound was obtained in 88% purity by LC/MS. MS(ESI+): m/z=448.4.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]([CH3:10])=[N:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[CH2:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1>C1COCC1>[O:25]=[C:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([CH2:15][C:14]3[CH:13]=[C:12]([NH:11][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=4)=[O:8])[CH:28]=[CH:27][CH:26]=3)=[CH:17][CH:18]=2)[NH:22]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cccc(Cc2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(Cc3ccc4c(c3)NC(=O)C4)c2)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
A dry 25 mL flask was charged with 2,5-Dimethyl-2H-pyrazole-3-carbonyl chloride (0.146 g, 0.924 mmol) and THF (2 mL). 6-(3-Amino-benzyl)-1,3-dihydro-indol-2-one (as prepared in Example 91, 0.200 g, 0.840 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (2 mL). The ethanolic solution was treated with 1M NaOH(aq) (1 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The precipitate that formed was filtered and washed with THF (˜2 mL) affording the 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indol-6-ylmethyl)-phenyl]-amide (0.115 g, 0.319 mmol, 38%).