Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[O:2].[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH2:9]([O:1][OH:2])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccccc1
Reactant: O=O
Product: OOCc1ccccc1

Procedure:
750 G of toluene are introduced into a 1.5 liter stainless steel autoclave which is shaken; the toluene is oxidised, at 180°C under a pressure of 20 bars, with air depleted of oxygen until it contains only 8%, with an hourly flow rate of 240 liters (measured under normal temperature and pressure). After 1 hour 30 minutes the reaction mixture is cooled. The hydroperoxide is then purified via its sodium salt. 11.4 G of benzyl hydroperoxide, containing 85% by weight of pure product, are thus obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1.Cl[C:11]1[N:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([N:3]2[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=[C:2]2[CH3:1])=[N:16][CH:15]=1)#[N:18]
Reactant: Cc1nc(C(=O)O)c[nH]1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)O)cn1-c1ccc(C#N)cn1
Temperature: 100 °C

Procedure:
A mixture of 2-methyl-1H-imidazole-4-carboxylic acid (490 mg), 6-chloropyridine-3-carbonitrile (800 mg), and K2CO3 (1.1 g) in DMF (6 mL) is heated to 100° C. overnight. The crude product is purified by HPLC. LC (method 20): tR=0.73 min; Mass spectrum (APCI): m/z=229 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[CH:21]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:27])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(Cl)C1CCCC1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C1CCCC1
Yield: 52.5 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with cyclopentanecarbonyl chloride (0.50 mL, 4.1 mmol) to provide 0.71 g of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclopentanecarboxamide as a white solid, m.p. 168.6-169.8° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:16])[C:7]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:16])[C:7]([N:10]3[CH2:11][CH2:12][N:13]([C:22]([C:21]4[CH:25]=[CH:26][C:18]([I:17])=[CH:19][CH:20]=4)=[O:23])[CH2:14][CH2:15]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(Cl)c1ccc(I)cc1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Yield: 90 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 65 and using 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (1.42 g) described in Preparation Example 96, 4-iodobenzoyl chloride (1.83 g), the title compound (2.63 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([S:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:35]1(/[CH:41]=[CH:42]/[C:43](Cl)=[O:44])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([S:15]([N:18]3[CH2:23][CH2:22][N:21]([C:43](=[O:44])/[CH:42]=[CH:41]/[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:20][CH2:19]3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(S(=O)(=O)N2CCNCC2)s1)c1ccc(Cl)cc1
Reactant: O=C(Cl)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(S(=O)(=O)N2CCN(C(=O)/C=C/c3ccccc3)CC2)s1)c1ccc(Cl)cc1
Yield: 21 %

Procedure:
To a stirred solution of 1 (36 mg, 0.09 mmol) and iPr2NEt (32 μl, 0.189 mmol) in CHCl3 (2 mL) was added [(2E)-3-phenylprop-2-enoyl]chloride (15 mg, 0.09 mmol). After 4 h the reaction mixture was washed with HCl (1 N) and sat. NaCl solution, and dried over MgSO4. The solvent was evaporated and the residue was filtered through silica gel using AcOEt/MeOH 1% as eluent to afford 159 as white solid (10 mg, 20%). M/Z APCI: 531.2 (M+1), 529.1 (M−1). Anal. HPLC: rt.=6.18 min (method a).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:5]2[N:4]=1.C(Cl)Cl.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:5]2[N:4]=1)=[O:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2ccc(-c3ccccc3O)n2n1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(-c3ccccc3O)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
Into a 8-dram vial, 2-(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenol (0.530 g, 2.06 mmol) and Methylene chloride (15 mL, 230 mmol)were added. m-CPBA 70-75% (70:30, m-Chloroperbenzoic acid:3-Chlorobenzoic acid, 0.533 g, 2.16 mmol) was added over 10 minutes. The reaction was stirred at room temperature for 1 hour. The reaction was partitioned with DCM and sat. NaHCO3. The organic was separated, washed with Brine, and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give 2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenol as a yellow solid (0.485 g, 86%).
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1>CN(C=O)C.C(OCC)(=O)C>[CH:37]1([CH2:36][O:1][C:2]2[CH:28]=[CH:27][C:5]3[N:6]=[C:7]([N:9]4[CH2:10][CH2:11][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH3:18])[CH2:13][CH2:14]4)[O:8][C:4]=3[CH:3]=2)[CH2:39][CH2:38]1
Reactant: C[C@@H](COC1CCN(c2nc3ccc(O)cc3o2)CC1)NC(=O)OC(C)(C)C
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(6-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (445 mg) in DMF (3 mL) were added potassium carbonate (471 mg) and (bromomethyl)cyclopropane (0.331 mL), and the mixture was stirred with heating at 60° C. for 7 hr under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The extract was applied to silica gel chromatography (NH, ethyl acetate), and concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (439 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:29])([F:28])[F:27])[N:11]=2)[CH2:4][CH2:3]1.Br[CH2:31][CH2:32][CH2:33]Br>CC(N(C)C)=O>[N:1]1([C@H:2]2[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]3[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:27])([F:28])[F:29])[N:11]=3)[CH2:6][CH2:7]2)[CH2:33][CH2:32][CH2:31]1
Reactant: BrCCCBr
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2Cl)CC1
Solvent: CC(=O)N(C)C
Product: FC(F)(F)Oc1ccccc1CNc1ncc(Cl)c(NC[C@H]2CC[C@H](N3CCC3)CC2)n1
Temperature: 100 °C

Procedure:
N4-[(trans-4-aminocyclohexyl)methyl]-5-chloro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine (178 mg, 0.41 mmol) was dissolved in DMA (5 mL). To this solution was added 1,3-dibromopropane (208 μL, 2.01 mmol) and NaCO3 (217 mg, 2.01 mmol). The reaction was heated in the microwave at 100° C. for 5 min. The volatiles were removed and the reaction was diluted with EtOAc and poured into H2O. The aqueous phase was separated and extracted two more times with EtOAc. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The crude product was purified on a 2000 micron SiO2 preparative TLC plate, eluting with 10:1 CH2Cl2:MeOH (1% NH4OH) to afford 102 mg (53%) of the title compound, m/z 470.5 [M+1]+.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[S:26][CH:27]=[CH:28][C:29]=2[NH2:30])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([NH:30][C:29]2[CH:28]=[CH:27][S:26][C:25]=2[C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:24]=2)=[O:41])=[CH:35][CH:34]=1
Reactant: Nc1ccsc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)Nc2ccsc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1

Procedure:
The title compound was prepared from 2-(1-trityl-1H-imidazol-4-yl)thiophen-3-amine and 2-(4-methoxyphenyl)acetic acid using protocol B (561 mg, 59%) as a brown solid. Method [7] Retention time 9.46 min by HPLC (MH+ 556).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].Br[CH2:12][C:13]1[S:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=1.[OH-].[Na+].ClCCl>C(O)C>[CH2:9]([O:8][P:1]([CH2:12][C:13]1[S:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=1)([O:2][CH2:3][CH3:4])=[O:5])[CH3:10]
Reactant: O=C(O)c1ccc(CBr)s1
Reactant: CCOP(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(C(=O)O)s1)OCC
Temperature: 160 °C
Yield: 89.9 %

Procedure:
189 g of triethyl phosphite was added to 84 g of 5-bromomethyl-2-thiophenecarboxylic acid obtained above, and the mixture was stirred with heating at 160° C. for 1 hour. The reaction mixture was dissolved in 200 ml of ethanol, and 190 ml of a 4N aqueous solution of sodium hydroxide was slowly added dropwise with ice-cooling and stirring. After stirring the resulting mixture at room temperature for 12 hours, 200 ml of dichloromethane was added for separating the reaction mixture. The obtained aqueous layer was mixed with 300 ml of a 30% aqueous solution of hydrochloric acid and subjected to extraction with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, giving 95 g of 5-[(diethoxyphosphoryl)methyl]-2-thiophenecarboxylic acid as colorless crystals having a melting point of 77-78° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@H:10]1[NH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@H:10]1[NH:20][C:31]([C:26]1[NH:27][C:28]2[C:24]([CH:25]=1)=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=2)=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC[C@@H](N)[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 12 h
Yield: 70.8 %

Procedure:
(1R*,2S*,4R*)-N2-tert-Butoxycarbonyl-4-ethoxycarbonyl-1,2-cyclohexanediamine (4.62 g) was dissolved in dichloromethane (50 ml), 5-chloroindole-2-carboxylic acid (3.63 g), 1-hydroxybenzotriazole monohydrate (2.43 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.45 g) were added at room temperature, and the mixture was stirred for 12 hours. After 0.1N hydrochloric acid was added, and the mixture was extracted with dichloromethane, the resultant organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=2:3) to obtain the title compound (5.3 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[S:23]>CN(C)P(=O)(N(C)C)N(C)C>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[S:23])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: Fc1ccccc1N=C=S
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(=O)c1csc(NC(=S)Nc2ccccc2F)n1

Procedure:
Following a procedure similar to that described in Preparation 1. the desired compound was prepared from 15 g of ethyl 2-aminothiazol-4-ylglyoxylate, 17 g of o-fluorophenyl isothiocyanate and 30 ml of hexamethylphosphoric triamide. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>O>[C:10]([C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([CH2:14][CH2:13][C:12]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:15])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])[NH2:11]
Reactant: O=C(O)CCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)NC1=O
Reactant: C1CCNCC1
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=O)C(CCC(=O)O)(CCC(=O)N1CCCCC1)c1ccc(Cl)c(Cl)c1

Procedure:
0.3 g of racemic 3-[3-(3,4-dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionic acid, 1 ml of methanol and 0.5 ml of piperidine are placed at 60° C. for 15 hours in a round-bottomed flask. The reaction medium is diluted with 10 ml of water and acidified with 1 N HCl to pH 2-3. The white crystals formed are filtered, drained and then dried to give 0.3 g of the expected compound.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[O:10]1CC[CH2:12][CH2:11]1.[H-].[Na+]>CO.C(OCC)(=O)C>[N:1]1([CH2:12][CH2:11][OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OCCn1cnc2ccccc21
Reaction time: 0.33 h

Procedure:
To a flask were added 2.3 g benzimidazole and 40 ml tetrahydrofuran and the mixture was cooled to 10 C under nitrogen. 1.0 g Sodium hydride were added in portions and the reaction mixture was stirred for 20 minutes. 4.0 g 2-Todoethanol were added and the mixture was heated to 50 C for 16 hours. The mixture was quenched slowly with 50 ml water, extracted twice with ethyl acetate and dried over sodium sulfate. Following filtration and solvent removal, the product was purified by silica gel chromatography using 25% methanol in ethyl acetate. A solid was obtained that was dissolved in a hot mixture of 10% methanol in ethyl acetate, cooled, filtered and dried giving 1.4 g white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1(OC)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[F:23][C:20]1[CH:21]=[CH:22][C:2]2[N:1]=[C:14]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[C:6]3[C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[S:9][C:5]=3[NH:4][C:3]=2[CH:19]=1
Reactant: CCOC(=O)c1c(Nc2cc(F)ccc2N)sc2ccccc12
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3ccc(F)cc3Nc3sc4ccccc4c32)CC1
Temperature: 25 °C

Procedure:
Ethyl 2-(2-amino-5-fluoroanilino)benzo[b]thiophene-3-carboxylate (24.5 g) and 1-methylpiperazine (135 ml) were dissolved in anisole (400 ml), and titanium tetrachloride (21 ml) was added dropwise while stirring the mixture at room temperature. After the completion of the dropwise addition, the mixture was stirred at 140° C. for 17 hours. The reaction mixture was cooled to 80° C. and poured into ice water. The resultant precipitate was filtrated and the filtrate was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and the obtained oily substance (17 g) was dissolved in ethyl acetate (400 ml). Thereto was added a solution of maleic acid (5.9 g) in ethyl acetate (100 ml) and ethanol (20 ml). The precipitated crystals were collected by filtration and recrystallized from ethanol to give 8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[I]benzothieno[2,3-b][1,5]benzodiazepine.1 maleate (10.2 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19](O)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH:29]1[C@H:38]2[C@@H:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:29]3[C@H:38]4[C@@H:33]([CH2:34][CH2:35][CH2:36][CH2:37]4)[CH2:32][CH2:31][CH2:30]3)=[O:20])[CH:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)O)cs2)CC1
Reactant: C1CC[C@H]2NCCC[C@@H]2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@H]43)cs2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-(4-Carboxy-thiophen-2-yl)-piperidine-1-carboxylic acid t-butyl ester (0.1 g, 0.32 mmol) was dissolved in acetonitrile (2 mL). Triethylamine (0.96 mmol), trans-decahydroquinoline (1:1 mixture of the trans-isomers; 0.35 mmol) and HATU (0.35 mmol) were added and the reaction stirred at room temperature for 5 hours. The solvent was evaporated and the residue was purified by HPLC, eluting with 10%-90% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (0.09 g). 1H NMR (400 MHz, CHCl3-d): δ 7.2 (s, 1H), 6.9 (s, 1H), 4.2 (m, 2H), 3.7 (m, 1H), 3.5-3.3 (m, 2H), 3.0-2.7 (m, 3H), 2.25 (m, 1H), 2.0 (m, 2H), 1.8-1.5 (m, 8H) 1.5 (s, 9H), 1.4-1.0 (m, 6H).
Reaction SMILES: O([C:8]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])C1C=CC=CC=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].Cl>C(O)C>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH:33][C:8]1[C:9](=[CH:13][C:14]([S:24](=[O:26])(=[O:27])[NH2:25])=[C:15]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=1)[C:10]([OH:12])=[O:11]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(Oc2ccccc2)cc1Oc1ccccc1
Reactant: COc1ccccc1CN
Agent: Cl
Solvent: CCO
Product: COc1ccccc1CNc1cc(Oc2ccccc2)c(S(N)(=O)=O)cc1C(=O)O
Temperature: 80 °C

Procedure:
43 g of 2,4-diphenoxy-5-sulfamoyl-benzoic acid (0.1 mol) prepared according to Example 1 (c) were stirred with 80 ml of 2-methoxybenzylamine for 3.5 hours at 140° C. The almost colorless reaction solution which, had been cooled to about 80° C, was then diluted with 150 ml of ethanol, and the solution was introduced while stirring into 1.0 l of 1N hydrochloric acid at room temperature. The reaction product, which had precipitated in crystals, was suction-filtered and washed with water and then boiled up for a short time with 0.3 l of ethanol, during which the major part of it remained undissolved. After cooling to room temperature, it was suction-filtered and washed with ethanol and finally dried on a steam bath.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1>CO>[CH3:1][S:2][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1
Reactant: C[S-]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(SC)c([N+](=O)[O-])c1
Reaction time: 4 h
Yield: 63.5 %

Procedure:
Sodium thiomethoxide (9.1 g) in dry methanol (50 mL) is added dropwise to a stirred solution of methyl 6-chloro-5-nitronicotinoate (25.1 g) in dry methanol (400 mL) and the mixture stirred for 4 hours. The pasty mixture is evaporated to low volume, diluted with water and the product extracted into ethyl acetate. The extacts are washed with water and brine, and finally dried (MgSO4). Evaporation gave methyl 6-methylthio-5-nitronicotinoate (16.8 g) as a yellow solid. The solid can be recrystallised from cyclohexane to give a yellow solid m.p. 115-6° C.
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([S:23]([CH2:26][C@@H:27]([OH:31])[C:28]([OH:30])=O)(=[O:25])=[O:24])[CH:17]=[CH:16]2.[N:32]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:37][CH2:36][CH2:35][CH2:34][C:33]1=[O:38].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([S:23]([CH2:26][C@@H:27]([OH:31])[C:28]([N:42]1[CH2:41][CH2:40][CH:39]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][C:33]3=[O:38])[CH2:44][CH2:43]1)=[O:30])(=[O:24])=[O:25])[CH:17]=[CH:16]2
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: O=C1CCCCN1C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C([C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCC(N2CCCCC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 54 %

Procedure:
WSC (0.19 g) was added to a mixture of (2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropionic acid (0.31 g), 1,4′-bipiperidin-2-one (JP 2001-524466 A) (0.18 g) and HOBt (0.15 g) in DMF (15 mL) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and diluted with dichloromethane and an aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=10/1) to obtain the title compound (0.26 g, 54%) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:21])[CH2:9][NH:10][C:11](=[O:20])/[CH:12]=[CH:13]/[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:21][CH:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:9][NH:10][C:11](=[O:20])/[CH:12]=[CH:13]/[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(/C=C/c1cccnc1)NCC(O)c1cccc(O)c1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(C(O)CNC(=O)/C=C/c2cccnc2)c1
Temperature: 50 °C
Reaction time: 7 h
Yield: 51.3 %

Procedure:
(E)-N-[2-(3-hydroxyphenyl)-2-hydroxyethyl]-3-(3-pyridyl)-2-propenoic acid amide (5.68 g, 20 mmol) and ethyl chloroacetate (5.2 ml, 48 mmol) were dissolved in dimethylformamide (60 ml) and potassium carbonate (8.28 g, 60 mmol) was added and stirred at 50° C. for 7 hours. After allowing to cool, insoluble materials were filtered out and water was added to the filtrate, extracted with ethyl acetate and dried over magnesium sulfate. The solvent was distilled out under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:hexane:methanol=20:2:1) and dried under reduced pressure to yield the titled compound (3.80 g, 51%).