Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=2)=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Clc1ccncc1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(Nc2ccncc2)cc1

Procedure:
4.57 g (31 mmol) of 4-chloropyridine and 5.03 g (31 mmol) of ethyl 4-aminobenzoate were dissolved in 100 ml of xylene. 12.7 ml (92 mmol) of triethylamine was added to the obtained solution and the resultant mixture was heated under reflux for 50 hours. The solvent was evaporated, and the residue was diluted with water. After the extraction with dichloromethane followed by washing with saturated Aqueous NaCl solution and drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6](O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>O1CCOCC1>[CH3:1][CH:2]1[CH2:3][C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:5][CH:6]=[CH:7]1
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1C=CC=C(c2ccncc2[N+](=O)[O-])C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of 5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enol (1.0 equiv.) in dioxane (0.1M) was added p-TSA (1.0 equiv.), and the reaction was stirred at 100° C. for 3 h. The solution was cooled to room temperature, then passed through a pad of neutral alumina eluting with EtOAc to yield (+/−)-4-(5-methylcyclohexa-1,3-dienyl)-3-nitropyridine as a yellow oil in 68% yield. LC/MS=217.1 (M+H), LC=3.908 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:17]=1[C:18]([N:20]=[C:21]=[O:22])=[O:19]>C(#N)C>[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:17]=1[C:18]([NH:20][C:21]([NH:14][C:11]1[CH:12]=[N:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:22])=[O:19]
Reactant: Nc1ccc(-c2ccc(Cl)cc2)nc1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: CC#N
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(-c2ccc(Cl)cc2)nc1

Procedure:
6-(4-Chlorophenyl)-3-pyridylamine (70 mg) was dissolved in 45 ml acetonitrile and treated with 2,6-dichlorobenzoyl isocyanate (0.25 gram) under nitrogen at room temperature. A precipitate formed almost immediately and after about 2 hours stirring, the solid was collected and recrystallized from ethanol, yield, 200 mg, m.p. 225°-229° C. The identity of the product was confirmed by NMR.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([CH:15]=2)[C:12](O)=[O:13])[CH:4]=[N:3]1.C(N(C(C)C)CC)(C)C.[CH3:41][C:42]1[C:46]([NH2:47])=[CH:45][O:44][N:43]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH3:41][C:42]1[C:46]([NH:47][C:12](=[O:13])[C:11]2[CH:15]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[C:8]([C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[O:25])=[CH:9][C:10]=2[O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:45][O:44][N:43]=1
Reactant: Cc1nocc1N
Reactant: Cn1cc(-c2cc(C(=O)O)c(OCc3ccccc3)cc2C(=O)N2CCOCC2)cn1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1nocc1NC(=O)c1cc(-c2cnn(C)c2)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-4-yl)-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 26; 44 mg, 0.10 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.04 ml, 0.21 mmol), 3-methyl-4-isoxazolamine (20.48 mg, 0.21 mmol), 1-hydroxy-7-azabenzotriazole (21.32 mg, 0.16 mmol) and EDC (34.0 mg, 0.18 mmol). The reaction was stirred for 18 hours and then the solvent was removed in vacuo. The residue was purified by MDAP to yield the title compound as a white solid. 43 mg.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[N:6]([C@@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)[N:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[H][H].Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.[Na+].[I-]>CN(C=O)C>[CH:1]([C:4]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[N:6]([C@H:12]2[CH2:13][CH2:14][C@@H:15]([O:18][CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:16][CH2:17]2)[N:5]=1)([CH3:2])[CH3:3]
Reactant: ClCCCN1CCCC1
Reactant: CC(C)c1cc(C(C)C)n([C@H]2CC[C@@H](O)CC2)n1
Reactant: [H][H]
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(C)C)n([C@H]2CC[C@@H](OCCCN3CCCC3)CC2)n1
Temperature: 80 °C

Procedure:
Cis-4-(3,5-diisopropyl-pyrazol-1-yl)-cyclohexanol (17.5 mg, 0.068 mmol) was dissolved in dry DMF (2 mL) followed by addition of NaH (excess, 60% in oil) and stirred at room temperature until hydrogen evolution stopped. To the reaction was added 1-(3-Chloro-propyl)-pyrrolidine (20 mg) and catalytic NaI followed by heating to 80° C. overnight. The reaction was cooled, quenched with methanol and concentrated under reduced pressure. The residue was purified by prep HPLC to give the desired product (yield 10.6 mg). LC-MS (C22H39N3O calculated 361) m/z 362 (M+H).
Reaction SMILES: C(OC(=O)N[C@H]1C[C@H:10]([NH:12][C:13]2S[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)C1)(C)(C)C.Cl.[NH2:24][C@H:25]1[CH2:28][C@H:27]([N:29]2[C:33]3=[N:34][CH:35]=[CH:36][CH:37]=[C:32]3[N:31]([CH3:38])[C:30]2=[O:39])[CH2:26]1.ClC1N(C)C2C=CC=CC=2N=1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.CS(C)=O>[CH3:38][N:31]1[C:32]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:29]([C@H:27]2[CH2:28][C@H:25]([NH:24][C:13]3[N:12]([CH3:10])[C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH2:26]2)[C:30]1=[O:39]
Reactant: Cn1c(=O)n([C@H]2C[C@H](N)C2)c2ncccc21
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: Cn1c(Cl)nc2ccccc21
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(N[C@H]2C[C@H](n3c(=O)n(C)c4cccnc43)C2)nc2ccccc21

Procedure:
The title compound was synthesized following the procedure described for INTERMEDIATE 10, using 3-(trans-3-aminocyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one hydrochloride (0.147 g, 0.577 mmol), 2-chloro-1-methyl-1 h-benzoimidazole (0.096 g, 0.577 mmol), diisopropylethylamine (1 ml, 5.75 mmol) and 4-dimethylaminopyridine (7.05 mg, 0.058 mmol) in DMSO (0.5 mL) and purified by ISCO on silica gel column using 0-80% EtOAc/hexanes to afford 1-methyl-3-(trans-3-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)cyclobutyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.103 g, 0.296 mmol, 51.2% yield). m/z: 366.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ: ppm 8.04 (dd, J=5.28, 1.17 Hz, 1 H), 7.50 (dd, J=7.82, 1.17 Hz, 1 H), 7.19-7.24 (m, 1 H), 7.13-7.18 (m, 1 H), 7.10 (dd, J=7.73, 5.18 Hz, 1 H), 7.02 (d, J=6.46 Hz, 1 H), 6.88-6.98 (m, 2 H), 5.32 (t, J=8.41 Hz, 1 H), 4.51-4.69 (m, 1 H), 3.56 (s, 3 H), 3.26-3.40 (m, 5 H), 2.41-2.57 (m, 2 H).
Reaction SMILES: [C:1]([O:18]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:27]([N:26]([CH2:25][CH2:24][O:23][CH2:22][CH2:21][OH:20])[C:1](=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCCCCCCNCCOCCO
Reactant: CCCCCCCCCCCCCCCC(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(CCOCCO)C(=O)CCCCCCCCCCCCCCC
Temperature: 120 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
Into a 250 ml-flask equipped with reflux condenser, were introduced 14.3 g of methyl palmitate and 16.5 g of N-(2-hydroxyethoxy)ethyl-n-hexadecyl amine prepared in Example 1, and thereto was added 2.6 g of sodium carbonate. Then, the mixture was stirred violently for 3 hours at 120° C. After the termination of the reaction, the mixture was cooled to a room temperature and 100 ml of chloroform was added thereto to be dissolved. The precipitates were removed and the solvent was evaporated off under reduced pressure. The produced solid was recrystallized from hexane to give 23.2 g of the title compound(Yield: 82%) as white powder, which was identified by IR and NMR. The results are shown in Table 1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23]C(OC(OC(OC(C)(C)C)=O)=O)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:14]([N:11]1[C:6]2[N:7]=[C:8]([CH2:9][CH3:10])[C:3]([CH2:2][NH:1][CH3:23])=[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[C:5]=2[CH:13]=[N:12]1)[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To the solution of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-amine (0.303 g, 1.0 mmol) in THF (1 mL) was added Boc2O (0.229 g, 1.05 mmol). This mixture was stirred at room temperature for 30 mins and then LAH (5.0 mL, 1.0 M in THF) was added, and that mixture heated with a microwave machine at 100° C. for 30 mins. The reaction was then quenched with Na2SO4 (sat. aq.) slowly, filtered, dried over Na2SO4, filtered, and concentrated to afford 0.252 g (79%) of the title compound. LC-MS m/z 318 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=2[CH3:33])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:34]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:34]3[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]3)=[O:31])[C:25]=2[CH3:33])(=[O:11])=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)O
Reactant: OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)N1CCC(O)CC1

Procedure:
5-[5-(3,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.24 mmol) was coupled with piperidin-4-ol (30 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) in DMF (25 mL) to give the titled compound.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:16][C@H:15]([CH2:17]O)[O:14][C:13]3=[O:19])=[CH:8][C:7]=2[F:20])[CH:5]=[CH:4][N:3]=[CH:2]1.ClC(Cl)(Cl)COC([NH:27][C:28]1[CH:32]=[CH:31][O:30][N:29]=1)=O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[O:30]1[CH:31]=[CH:32][C:28]([NH:27][CH2:17][C@@H:15]2[O:14][C:13](=[O:19])[N:12]([C:9]3[CH:10]=[CH:11][C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)=[C:7]([F:20])[CH:8]=3)[CH2:16]2)=[N:29]1
Reactant: O=C(Nc1ccon1)OCC(Cl)(Cl)Cl
Reactant: O=C1O[C@@H](CO)CN1c1ccc(-n2ccnc2)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1O[C@@H](CNc2ccon2)CN1c1ccc(-n2ccnc2)c(F)c1
Reaction time: 18 h
Yield: 158.5 %

Procedure:
3-(4-Imidazol-1-yl-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one (693 mg, 2.5 mM, see WO 96-23788) and 3-(2,2,2-trichloroethyloxycarbonylamino)isoxazole (649 mg, 2.5 mM) were suspended by stirring in dry tetrahydrofuran (25 ml) under nitrogen in an ice-bath. Tributylphosphine (808 mg, 4 mM) was added followed by 1,1′-(azodicarbonyl)dipiperidine (945 mg, 3.75 nM) dissolved in tetrahydrofuran (10 ml) over 10 minutes. The mixture was then stirred 18 hours, allowing the temperature to rise to ambient, then filtered, and the filter cake washed with tetrahydrofuran. The combined filtrates were evaporated and the residue purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 5% methanol in dichloromethane. Relevant fractions were combined, evaporated, and the residue triturated with diethyl ether to give the desired product (1.36 g), contaminated with tributylphosphine oxide.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:34])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[OH:34][C@H:24]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH2:23][NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)cc4)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and 4-[(2S)-3-amino-2-hydroxy-propoxy]-phenol (which was obtained in Example 5) according to the procedure of Example 73 as a pale yellowish solid; mp >160° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.35-1.60 (m, 2H), 1.85-2.05 (m, 2H), 2.60-3.50 (m, 7H), 3.67 (brd, J=12.1 Hz, 2H), 3.75-3.95 (m, 3H), 4.57 (dd, J=9.6, 3.8 Hz, 1H), 6.66 (d, J=8.9 Hz, 2H), 6.77 (d, J=8.9 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.6 Hz, 2H), 8.92 (brs, 1H); MS (ES) m/z: 472.0 (MH+); HRMS Calcd. for C24H30N3O5S(MH+): 472.1906. Found: 472.1898.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8]([OH:10])=O)[CH:6]=1)[CH3:2].O[N:23]1[C:27]2C=CC=C[C:26]=2N=N1.C(N)C>CN(C=O)C.ClCCl>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8](=[O:10])[NH:23][CH2:27][CH3:26])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Reactant: On1nnc2ccccc21
Agent: CCN
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)NCC)cc(C(=O)OCC)c1
Yield: 98 %

Procedure:
Stir a solution of 5-(methyl-propylcarbamoyl)-isophthalic acid monoethyl ester (146 mg, 0.5 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), 1-(3-dimethylamninopropyl)-3-ethylcarbodiimide hydrochloride (110 mg, 0.55 mmol), ethylamine (2 N in THF, 0.275 mL, 0.55 mmol) in 0.75 mL DMF at room temperature overnight. Dilute with dichloromethane (15 mL) and wash with water (5 mL), 0.1 N aqueous citric acid (5 mL), saturated aqueous sodium bicarbonate (5 mL), and saturated aqueous sodium chloride (5 mL). Dry (magnesium sulfate) and concentrate to give the title compound (157 mg, 100%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Product: O=C(O)c1ccc(C(F)(F)F)nc1N1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.2 %

Procedure:
A mixture of 2-chloro-6-(trifluoromethyl)nicotinic acid (purchased from APOLLO, 5.0 g, 22.2 mmol) and pyrrolidine (40 ml, 562 mmol) was stirred for 24 hours at room temperature according to J. Med. Chem., 2005, 48, 71-90). Then the reaction mixture was evaporated in vacuo to give the title compound (5.5 g, 95%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:5]=1[C:6]([NH:8][C:9]1[C:14]2[O:15][C:16]([CH3:23])=[C:17]([C:18](OCC)=[O:19])[C:13]=2[C:12](CO)=[CH:11][CH:10]=1)=[O:7].[OH2:31].[CH3:32]O>>[Cl:3][C:4]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:5]=1[C:6]([NH:8][C:9]1[C:14]2[O:15][C:16]([CH3:23])=[C:17]([CH:18]([OH:19])[CH2:32][OH:31])[C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: CO
Reactant: CCOC(=O)c1c(C)oc2c(NC(=O)c3c(Cl)cccc3Cl)ccc(CO)c12
Reactant: O
Agent: [BH4-]
Agent: [Na+]
Product: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1C(O)CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium borohydride (7 mg) was added to a solution of 7-(2,6-dichlorobenzoylamino)-3-(1-ethoxycarbonyl)hydroxymethyl-2-methylbenzo[b]furan (76 mg) in methanol (3 ml) at 4° C. The mixture was stirred at ambient temperature for 3 hours and poured into cold water. The separated oil was extracted with ethyl acetate and the extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by colum chromatography on silica gel and the obtained oil was crystallized from diethyl ether to give 7-(2,6-dichlorobenzoylamino)-3-(1,2-dihydroxyethyl)-2-methylbenzo[b]furan (35 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:30][CH2:31][CH:32]=[CH2:33])[CH:28]=[CH2:29]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21][N:30]([CH2:31][CH:32]=[CH2:33])[CH2:27][CH:28]=[CH2:29])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCCN12
Reactant: C=CCNCC=C
Solvent: C1CCOC1
Product: C=CCN(CC=C)Cc1csc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n1
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A solution of 0.81 g (0.002 mol) of (S)-8-chloro-1-(4-chloromethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 5 ml of tetrahydrofuran was treated with 3 ml (0.024 mol) of diallylamine and stirred at 50° for 8 hrs. All volatiles were removed in a water-jet vacuum and the residue was chromatographed over silica gel with methylene chloride/methanol 98:2 as the eluent. After recrystallization from diethyl ether there was obtained 0.52 g (55%) of (S)-8-chloro-1-(4-diallylaminomethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in the form of white crystals; m.p. 186-187° and [α]D20 =-67.5° (MeOH, c=1%).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[Br:25]C1C=C(N2CCNCC2)C2OCCOC=2C=1>>[Br:25][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(O)cc3c2OCCO3)CC1
Reactant: Brc1cc2c(c(N3CCNCC3)c1)OCCO2
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Br)cc3c2OCCO3)CC1

Procedure:
The intermediate 1 -(7-bromo-2,3-dihydro-1,4-benzodioxin-5-yl)-4-(t-butyloxycarbonyl)piperazine was prepared similar to the method described for 1-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-4-(t-butyloxycarbonyl)piperazine (Intermediate 12a) using 1-(7-bromo-2,3-dihydro-1,4-benzodioxin-5-yl)piperazine.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH2:11][Cl:12])=[O:9].[CH3:13][C:14]1[C@@H:31]([O:32][C:33]([C@H:35]([OH:52])[C@@H:36]([NH:43][C:44]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:45])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH2:30][C@:26]2([OH:53])[C:27]([CH3:29])([CH3:28])[C:15]=1[C@@H:16]([O:71][C:72]([CH3:74])=[O:73])[C:17]([C@@:19]1([CH3:70])[C@H:24]([C@@H:25]2[O:54][C:55]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)=[O:56])[C@:23]2([O:65][C:66]([CH3:68])=[O:67])[CH2:63][O:64][C@@H:22]2[CH2:21][C@@H:20]1[OH:69])=[O:18]>ClCCl>[C:72]([O:71][C@@H:16]1[C:15]2[C:27]([CH3:28])([CH3:29])[C@@:26]([OH:53])([CH2:30][C@H:31]([O:32][C:33](=[O:34])[C@H:35]([O:52][C:8]([O:10][CH2:11][Cl:12])=[O:9])[C@@H:36]([NH:43][C:44](=[O:45])[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:14]=2[CH3:13])[C@@H:25]([O:54][C:55](=[O:56])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@H:24]2[C@:23]3([O:65][C:66](=[O:67])[CH3:68])[CH2:63][O:64][C@@H:22]3[CH2:21][C@H:20]([O:69][C:8]([O:10][CH2:11][Cl:12])=[O:9])[C@@:19]2([CH3:70])[C:17]1=[O:18])(=[O:73])[CH3:74]
Reactant: O=C(Cl)OCCl
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C(=O)[C@]2(C)[C@@H](OC(=O)OCCl)C[C@H]3OC[C@@]3(OC(C)=O)[C@H]2[C@H](OC(=O)c2ccccc2)[C@]2(O)C[C@H](OC(=O)[C@H](OC(=O)OCCl)[C@@H](NC(=O)c3ccccc3)c3ccccc3)C(C)=C1C2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.9 %

Procedure:
Pyridine (0.026 g, 23.0 mmol, 2.0 eq) was added to a solution of chloromethyl chloroformate (CMCF) [8](0.02 g, 23.0 mmol, 2.0 eq) in dry dichloromethane under an argon atmosphere at 0° C. At 0° C., a solution of paclitaxel [4114] (0.10 g, 11.7 mmol, 1.0 eq) in dry dichloromethane was added to the above reaction mixture. The reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After 2 h the reaction mixture was diluted with dichloromethane (25 ml), washed with a 10% solution of NaHCO3 (15 ml), brine (10 ml), and then dried over anhydrous sodium sulfate. Evaporation of the solvent under vacuum gave a white solid, [312], (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2-(((chloromethoxy)carbonyl)oxy)-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-4-(((chloromethoxy)carbonyl)oxy)-11-hydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxete-6,12b-diyl diacetate, (0.11 g, 90%)