Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(O[C:9]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[O:10])=CC=1)([O-])=O.[F:24][C:25]1[CH:26]=[C:27]([CH:31]2[CH:36]([CH2:37][N:38]([C@@H:46]([C:48]3[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[CH:51]=[CH:50][CH:49]=3)[CH3:47])[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:35][CH2:34][NH:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1.C1COCC1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[C:41]([O:40][C:39]([N:38]([CH2:37][CH:36]1[CH2:35][CH2:34][N:33]([C:9]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)=[O:10])[CH2:32][CH:31]1[C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=1)[C@@H:46]([C:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=1)[CH3:47])=[O:45])([CH3:42])([CH3:43])[CH3:44]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(OC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3cccc(F)c3)C2)c1
Reaction time: 8 h
Yield: 101.8 %

Procedure:
To a suspension of 5.000 g of methyl 3-hydroxybenzoate, 6.955 g of 4-nitrophenyl chloroformate, and 100 mL of toluene was added 4.81 mL of triethylamine at room temperature, followed by stirring overnight. The insolubles were removed by filtration, and as solvent was removed by distillation under reduced pressure to obtain 5.948 g of methyl 3-{[(4-nitrophenoxy)carbonyl]oxy}benzoate as a pale yellow solid. To a mixture of 100 mg of methyl 3-{[(4-nitrophenoxy)carbonyl]oxy}benzoate, 139 mg of tert-butyl {[3-(3-fluorophenyl)piperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate, and 4 ml of THF was added 0.084 mL of triethylamine at room temperature, followed by stirring overnight. A saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 196 mg of 3-(methoxycarbonyl)phenyl 4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidine-1-carboxylate as a pale yellow oily compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([SH:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:19](Br)[CH:20]=[CH2:21]>C(=O)([O-])O.[Na+]>[CH2:21]([S:11][C:4]1[CH:5]=[C:6]([CH:10]=[C:2]([NH2:1])[C:3]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]([OH:9])=[O:8])[CH:20]=[CH2:19]
Reactant: Nc1cc(C(=O)O)cc(S)c1Oc1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCSc1cc(C(=O)O)cc(N)c1Oc1ccccc1

Procedure:
A solution of 5-amino-3-mercapto-4-phenoxybenzoic acid (2.6 g) in saturated sodium hydrogen carbonate (120 ml) is cooled to 4°C. While cooling and stirring, allyl bromide (1 g) is added, and the reaction mixture is kept under nitrogen. After additional stirring for 10 minutes, 3-allylthio-5-amino-4-phenoxybenzoic acid is precipitated by addition of hydrochloric acid until pH 3. After collection by filtration, recrystallisation from aqeuous ethanol, and drying in vacuo, the compound is obtained with a melting point of 142°-143°C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:18][CH2:17][C:10]2[N:11]=[N:12][C:13]([NH:15][NH2:16])=[CH:14][C:9]=2[CH2:8]1)=[O:6])[CH:2]=[CH2:3].[CH3:19][C:20]([CH3:22])=O>>[CH2:1]([O:4][C:5]([N:7]1[CH2:18][CH2:17][C:10]2[N:11]=[N:12][C:13]([NH:15][N:16]=[C:20]([CH3:22])[CH3:19])=[CH:14][C:9]=2[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCc2nnc(NN)cc2C1
Reactant: CC(C)=O
Product: C=CCOC(=O)N1CCc2nnc(NN=C(C)C)cc2C1

Procedure:
A solution of 4 g of 3-hydrazino-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid allyl ester in 40 cc of acetone is heated at reflux on a water bath for 30 minutes. The title compound has a M.P. 134°-136° (decomp.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[CH2:12]([C@@H:14]1[O:16][CH2:15]1)[Cl:13]>>[Cl:13][CH2:12][C@H:14]([OH:16])[CH2:15][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1
Reactant: ClC[C@H]1CO1
Reactant: FC(F)(F)c1cccc(Br)c1
Product: O[C@@H](CCl)Cc1cccc(C(F)(F)F)c1

Procedure:
(R)-1-chloro-3-(3-trifluoromethylphenyl)-2-propanol was prepared using the same procedure as described for example 2, intermediate (d), but using 3-bromobenzotrifluoride and (R)-epichlorohydrin.
Reaction SMILES: [P:1](Cl)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2].C(N(CC)CC)C.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[P:1]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCSP(=O)(Cl)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCSP(=O)(OC)Oc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of O-methyl S-ethyl chlorothiophosphate (0.03 mole) in methylene chloride (50 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. Triethylamine (0.03 mole) is added and the mixture is cooled to a temperature of about 0° C. A solution of 4-hydroxybenzaldehyde (0.03 mole) in methylene chloride (15 ml) is slowly added with stirring while maintaining the temperature of the reaction mixture at about 0° C. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 1 hour. After this time the reaction mixture is transferred to a separatory funnel and methylene chloride (100 ml) is added. The resulting solution is then washed with water, dilute aqueous sodium hydroxide and again with water. The washed solution is dried over anhydrous magnesium sulfate, is filtered and stripped of solvent under vacuum to yield the desired product O-methyl S-ethyl O-(4-formylphenyl) thiophosphate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)([O-])=O>CN(C=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:18])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(N)c(N)c2)CC1

Procedure:
1-(3,4-Dinitrobenzyl)-4-methylpiperazine (2.8 g, 10 mmol), was dissolved in DMF:MeOH (1:1, 20 mL) and agitated with 10% Pd/C (280 mg) under an atmosphere of H2 for 12 hrs. The reaction was monitored by TLC. The mixture was then filtered and evaporated to give a dark solid which was used immediately without any further purification.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18]/C=C(\C)/CCC(OC)=O)=[C:16]([O:28][CH3:29])[C:15]([CH3:30])=[C:14]2[C:10]=1[C:11](=[O:31])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClCCl.N1C=CC=CC=1.[CH3:41][OH:42]>>[Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:41]=[O:42])=[C:16]([O:28][CH3:29])[C:15]([CH3:30])=[C:14]2[C:10]=1[C:11](=[O:31])[O:12][CH2:13]2)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CO
Reactant: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC=O)C(=O)OC2
Reaction time: 0.75 h

Procedure:
A solution of methyl (E) 6-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (11.0 g) in methanol 125 ml), dichloromethane (125 ml) and pyridine (2 ml) was cooled to -78° C. and a stream of ozonized oxygen was bubbled through. After 45 minutes a blue color developed indicating the presence of unreacted ozone. Dimethyl sulfide (5 ml) was added and the cooling bath was removed. After 16 hours the solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate and then water, then dried and evaporated. The residue was chromatographed on silica gel, eluting with 2:1 hexane:ethyl acetate, so as to produce 2-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)acetaldehyde, mp. 88°-92° C. (ether).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]1.C1N=CN([C:18](N2C=NC=C2)=[O:19])C=1>C1COCC1>[O:19]=[C:18]1[N:4]([C:5]2([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]2)[CH2:3][CH2:2][O:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C1(NCCO)CC1
Solvent: C1CCOC1
Product: CCOC(=O)C1(N2CCOC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.6 %

Procedure:
A mixture of ethyl 1-((2-hydroxyethyl)amino)cyclopropanecarboxylate (0.180 g, 1.039 mmol) and CDI (0.177 g, 1.091 mmol) in THF (5 mL) was stirred at room temperature for 15 h, then heated to reflux for 15 h. The solvent was removed and the residue was purified with silica gel chromatography to yield ethyl 1-(2-oxooxazolidin-3-yl)cyclopropanecarboxylate (0.2 g). A solution of LiOH (0.048 g) in water (3 mL) was added to a solution of ethyl 1-(2-oxooxazolidin-3-yl)cyclopropanecarboxylate (0.2 g, 1.004 mmol) in THF (5 mL) and the resulting mixture was stirred vigorously at rt for 16 h. The reaction mixture was then diluted with water and washed with EtOAc. The aqueous layer was then acidified with 1N HCl and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated to yield Cap L-5 (60 mg). 1H NMR (500 MHz, DMSO-d6) ppm 12.83 (br. s., 1H), 4.30-4.20 (m, 2H), 3.65-3.56 (m, 2H), 1.41-1.33 (m, 2H), 1.25-1.19 (m, 2H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[CH3:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[N:22]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][NH:27][C:23]2[N:22]=[C:21]([CH3:20])[CH:26]=[CH:25][N:24]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccnc(N)n1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cl
Product: Cc1ccnc(NCc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 4-methylpyrimidin-2-amine. m/e+ 350 for C19H17ClN5[M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.18 (d, J=6.9 Hz, 1H), 7.95 (s, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.20 (m, 1H), 6.76 (dt, J=1.1, 6.9 Hz, 1H), 6.42 (d, J=5.1 Hz, 1H), 5.95 (s, 1H), 5.03 (d, J=5.1 Hz, 2H) 2.28 (s, 3H) ppm.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([O:15][N+:16]([O-:18])=[O:17])[CH2:10][O:11][N+:12]([O-:14])=[O:13])(=O)C.[OH-].[Na+]>C1COCC1.CCO>[N+:12]([O-:14])([O:11][CH2:10][CH:9]([O:15][N+:16]([O-:18])=[O:17])[CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[O:13]
Reactant: CC(=O)OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=[N+]([O-])OCC(CCCCO)O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a solution of 5,6-bis(nitrooxy)hexyl acetate (31.3 g, 118 mmol) in THF-EtOH (1:1, 0.492 M) at 0° C., was added a solution of sodium hydroxide (2 N, 126 mL, 251 mmol, 2.1 equiv) dropwise over 5 min. The reaction was stirred at rt for 2 h. The reaction mixture was quenched with a saturated NaHCO3 solution and extracted 3 times with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The product was purified by combi-flash 2×120 g silica gel cartridge using gradient (0-5% in 5 min, 5-55% in 30 min, 55-70% BA/Hex in 10 min) to afford the desired product (24.5 g, Yield=92%) as a pale yellowish oil. 1H NMR (500 MHz, acetone-d6): δ 5.53-5.47 (m, 1H), 5.00 (dd, 1H), 4.72 (dd, 1H), 3.55 (d, 2H), 3.50 (t, 1H), 1.88-1.80 (m, 2H), 1.58-1.51 (m, 4H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][NH:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:7][N:8]1[C:9]2[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:11][C:2](=[O:3])[C:1]1=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNc1ccccc1N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(=O)[nH]c2ccccc21

Procedure:
A mixture of 12 g of 98% oxalylchloride in 19.5 ml of triethylamine and 50 ml of toluene was added dropwise to a stirred solution of 8.5 g of o-N-methylamino aniline in 80 ml of toluene. The resulting mixture was heated at reflux for one hour. The precipitate was washed wih ether. The residue was stirred with water and filtered to give 1,2,3,4-tetrahydro-1-methyl-2,3-dioxo-quinoxaline.
Reaction SMILES: [CH2:1]([C:3]1([CH3:21])[N:15]([CH3:16])[C:14]([CH2:18][CH3:19])([CH3:17])[CH2:13][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]2=[O:12])[CH:4]1[CH3:20])[CH3:2].[H-].[Na+].CI.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:3]1([CH3:21])[N:15]([CH3:16])[C:14]([CH2:18][CH3:19])([CH3:17])[CH2:13][C:5]2([N:9]([CH3:26])[C:8](=[O:10])[N:7]([CH3:11])[C:6]2=[O:12])[CH:4]1[CH3:20])[CH3:2]
Reactant: CCC1(C)CC2(NC(=O)N(C)C2=O)C(C)C(C)(CC)N1C
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCC1(C)CC2(C(=O)N(C)C(=O)N2C)C(C)C(C)(CC)N1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.95 g of Compound 64, obtained as described in Example 5, in 10 ml of dimethylformamide was added 0.67 g of 52.9% sodium hydride; the mixture was stirred overnight at room temperature. 2.26 g of methyl iodide were then added and the mixture was heated at 100° C for 15 hours, with stirring. After cooling the mixture, 100 ml of ice-water and 20 ml of a 20% aqueous potassium carbonate solution were added in turn; the mixture was then extracted with ethyl acetate. The extract was washed with water and dried over potassium carbonate. After removing the solvent from the extract, the residue was purified by column chromatography on silica gel (eluent: chloroform containing 2.5% of methanol), giving 2.9 g of Compound 136 as a white powder melting at 77° - 88° C.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])=[CH:4][CH:3]=1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:26][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:18][CH:17]=1
Reactant: Cc1ccc(C(=O)NCCCCCC(=O)O)cc1
Reactant: Nc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCCCCCC(=O)Nc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
A mixture of 6-(4-methylbenzamido)hexanoic acid (498 mg, 2 mmol), o-phenylenediamine (216 mg, 2 mmol), EDCI (383 mg, 2 mmol), HOBt (405 mg, 3 mmol), and triethylamine (404 mg, 4 mmol) in dichloromethane (30 mL) was stirred at room temperature under nitrogen overnight. The reaction mixture was washed with water and brine, dried over Na2SO4, and evaporated. The residue was purified by chromatography on silica gel to give the title compound (227 mg, 33.9%) as a white solid. 1H NMR (DMSO): δ 9.06 (s, 1H), 8.35 (s, 1H), 7.73 (d, J=3.0 Hz, 2H), 7.24 (d, J=3.0 Hz, 2H), 7.14 (1H, J=3.0, d), 6.86-6.89 (m, 1H), 6.70 (d, J=3.0 Hz, 1H), 6.50 (M, 1H), 4.80 (s, 2H), 3.22-3.26 (m, 2H), 2.30-2.35 (m, 5H), 1.53-1.65 (m, 4H), 1.36-1.38 (m, 2H). LC-MS: 340 (MH)+. purity>95%.
Reaction SMILES: O=[C:2]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[N:20]([CH3:21])[C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)[CH:8]=2)[NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.O>C1(C)C=CC=CC=1>[S:33]=[C:2]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[N:20]([CH3:21])[C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)[CH:8]=2)[NH:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(CCCCC1)C(=O)N2
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(CCCCC1)C(=S)N2
Temperature: 80 °C
Yield: 90.5 %

Procedure:
To a solution of 5-(2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1-methyl-pyrrole-2-carbonitrile (0.55 g, 1.8 mmol, 1 eq) in toluene (50 mL) was added Lawesson's reagent (0.47 g, 1.1 mmol, 0.65 eq) and the reaction was heated to 80° C. for 1 hour. The reaction was cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel gave the product as a white solid (0.32 g, 55%). 1H NMR (d6-DMSO, 500 MHz) δ 1.36–1.99 (m, 10 H), 3.7 (s, 3 H), 6.35 (d, 1 H, J=4.2 Hz), 7.05 (d, 1 H, J=4.2 Hz), 7.16 (d, 1 H, J=7.9 Hz), 7.44 (dd, 1 H, J=1.6, 8.1 Hz), 7.83 (d, 1 H, J=1.6 Hz), 12.75 (s, 1 H). MS (ESI) [M−H]−=320. Anal. calcd. for C19H19N3S: C, 70.99; H, 5.96; N, 13.07. Found: C, 68.69; H, 5.36; N, 12.27.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.C1COCC1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[C:29]([CH3:41])=[N:28]1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:26][N:27]1[CH:31]=[C:30]([C:2]2[N:7]=[CH:6][C:5]([CH2:8][C:9]3[C:10]([CH3:20])=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=3)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=2)[C:29]([CH3:41])=[N:28]1
Reactant: COC(=O)c1cc(Cc2ccc(Cl)nc2)c(C)cc1O
Reactant: Cc1nn(C)cc1B1OC(C)(C)C(C)(C)O1
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: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-c3cn(C)nc3C)nc2)c(C)cc1O
Temperature: 85 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of methyl 5-((6-chloropyridin-3-yl)methyl)-2-hydroxy-4-methylbenzoate (0.09 g) in a mixed solvent of THF (2.40 mL)-water (0.80 mL) were added 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.14 g), potassium carbonate (0.17 g) and tetrakis(triphenylphosphine)palladium(0) (0.03 g), and the mixture was stirred overnight at 85° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.09 g).
Reaction SMILES: C([O:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[O:5]1)C.C(#N)C.Cl.[OH-].[Na+]>O>[OH:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[O:5]1
Reactant: CCOC1CCc2ccc(OC)cc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1ccc2c(c1)OC(O)CC2
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 80.9 %

Procedure:
A 500-milliliter egg plant type flask was charged with 5.14 g of 2-ethoxy-7-methoxychroman, 74 ml of acetonitrile and 25 ml of water, and 4.8 ml of a 35% hydrochloric acid aqueous solution was slowly added thereto dropwise at room temperature. The solution was stirred at 60° C. for 20 minutes, and then cooled to 20° C. The reaction solution was neutralized with 39 ml of a 5% sodium hydroxide aqueous solution, and the acetonitrile was removed by distillation in vacuo therefrom. The residue was extracted three times with 50 ml of ethyl acetate, and the organic layer was washed with water. Then, the ethyl acetate was removed by distillation in vacuo therefrom. The resulting residue was purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate 5:1) to obtain 3.60 g of a colorless liquid (yield 81%). Further, 0.77 g of 2-ethoxy-7-methoxychroman was recovered.
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[NH:26][C:25]4[N:33]=[CH:34][CH:35]=[CH:36][C:24]=4[N:23]3[C:37]=2[C:38]2[CH:43]=[CH:42][C:41]([C:44]3([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:47][CH2:46][CH2:45]3)=[CH:40][CH:39]=2)=[CH:16][CH:15]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:8][S:9]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[NH:26][C:25]4[N:33]=[CH:34][CH:35]=[CH:36][C:24]=4[N:23]3[C:37]=2[C:38]2[CH:43]=[CH:42][C:41]([C:44]3([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:53])([CH3:52])[CH3:54])[CH2:45][CH2:46][CH2:47]3)=[CH:40][CH:39]=2)=[CH:18][CH:19]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(N)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(NS(C)(=O)=O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
Et3N (36.6 μL, 0.263 mmol) and methanesulfonyl chloride (7.46 μL, 0.0964 mmol) were added to a solution of tert-butyl (1-{4-[2-(4-aminophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (50.0 mg, 0.0876 mmol) in DCM (1 mL) at 0° C., and stirred at room temperature. After reaction was completed, the mixture was diluted with sat. NaHCO3 and extracted with CHCl3 (3×). The combined organic layers were dried over anhydrous Na2SO4, and concentrated. The residue was purified by PTLC (CHCl3/MeOH=9:1, CHCl3/EtOAc=1:1) to afford desired product (30.9 mg, 54.4%) as pale yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.18-8.12 (m, 1H), 8.04-7.97 (m, 1H), 7.63-7.50 (m, 2H), 7.41-7.33 (m, 2H), 7.33-7.23 (m, 2H), 7.19-7.08 (m, 5H), 6.96 (d, J=7.8 Hz, 1H), 6.80 (d, J=7.8 Hz, 1H), 6.60 (dd, J=7.8, 4.6 Hz, 1H), 6.44 (br s, 1H), 5.69-4.98 (m, 1H), 2.98 (s, 3H), 2.63-2.27 (m, 4H), 2.21-2.06 (m, 1H), 1.96-1.82 (m, 1H), 1.38 (br s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:14][O:15][C:16](=[O:24])[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]2[CH2:17][C:16]([O:15][CH3:14])=[O:24])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CC1CCCCN1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCCCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 1.5 h

Procedure:
A solution of 3,4-dichlorobenzenesulfonyl chloride (1.88 g, 7.65 mmol) in DCM (15 ml) was added at 0° C. to a solution, cooled to 0° C., of piperidin-2-ylacetic acid methyl ester hydrochloride (1.3 g, 8.4 mmol) in DCM (33 ml) and triethylamine (2.66 ml, 21 mmol), and stirring was then carried out for 90 minutes at room temperature. 0.5 M HCl (20 ml) was then added, and stirring was carried out for a further 15 minutes. The organic phase was separated off, washed with water and dried over sodium sulfate. The solvent was removed using a rotary evaporator and the product was used in the next stage without being purified further. Yield: 1.9 g (63%)