Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1.I[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:21])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1
Reactant: ICC1CCCC1OC1CCCCO1
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1OC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 74.8 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (10.4 mL of a 0.31M stock solution, 3.22 mmol) cooled to −78° C. was treated with 3,4-dichlorophenylacetic acid methyl ester (prepared as in Example 1, 642 mg 2.93 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7.33 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. A solution of 2-(2-iodomethyl-cyclopentyloxy)-tetrahydropyran (1.0 g, 3.22 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) was then added. The reaction mixture was stirred at −78° C. for 2 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). This mixture was poured into water (100 mL) and extracted with methylene chloride 3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-[2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (880 mg, 74.8%) as a pale yellow oil: EI-HRMS m/e calcd for C20H26Cl2O4 (M+) 400.1208. found 400.1203.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH2:22])[C:12]2[N:13]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([NH:22][C@H:11]([C:12]2[N:13]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:15][CH:16]=2)[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: NC(Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cc1cccc(Cl)c1)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of 2-(4-nitropheyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 22,(0.41 g, 1 mmol) 3-chlorophenylacetic acid (0.170 g, 1mmol) and 1-hydroxybenzotriazole (HOBt)(0.07 g, 0.05 mmol) in DMF (5 ml) at 0°, is added 1-(3-dimethylaminoprpyl)-3-ethylcarbodiimide (EDCI) (0.190 g, 1 mmol) followed by triethylamine (0.42 mL, 3 mmol). The mixture is stirred at 0° for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCI, 5% aqueoue NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.290 g (60% yield) of the desired product wich is used without further purification. SEI-MS 428 (M-1).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:22])([F:21])[O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[CH3:23][O:24][C:25]1[CH:66]=[C:65]([O:67][CH3:68])[CH:64]=[CH:63][C:26]=1[CH2:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([S:53]([C:56]3[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][CH:57]=3)(=[O:55])=[O:54])[C:37]([C:39]3[C:47]4[C:42](=[CH:43][C:44]([O:50][CH3:51])=[C:45]([O:48][CH3:49])[CH:46]=4)[N:41]([CH3:52])[CH:40]=3)=[CH:38][C:31]=12.O>ClCCl>[CH3:23][O:24][C:25]1[CH:66]=[C:65]([O:67][CH3:68])[CH:64]=[CH:63][C:26]=1[CH2:27][N:28]([CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([S:53]([C:56]3[CH:57]=[CH:58][C:59]([CH3:62])=[CH:60][CH:61]=3)(=[O:55])=[O:54])[C:37]([C:39]3[C:47]4[C:42](=[CH:43][C:44]([O:50][CH3:51])=[C:45]([O:48][CH3:49])[CH:46]=4)[N:41]([CH3:52])[CH:40]=3)=[CH:38][C:31]=12)[S:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][C:9]([F:22])([F:21])[F:8])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COc1ccc(CNCc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(OC(F)(F)F)cc2)c(OC)c1
Reaction time: 24 h

Procedure:
0.052 cm3 of triethylamine and 0.265 cm3 of 4-(trifluoromethoxy)benzenesulfonyl chloride are added to a solution of 0.200 g of (2,4-dimethoxybenzyl)[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine in 6 cm3 of dichloromethane, under an argon atmosphere, at a temperature in the region of 20° C. The reaction medium is stirred at this same temperature for 24 hours. 2 cm3 of water are added. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 98/02 by volume as eluent), 0.210 g of N-(2,4-dim ethoxybenzyl)-N-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-4-trifluoromethoxybenzenesulfonamide is obtained, the characteristics of which are as follows:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:14][CH:13]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:14][CH:13]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NCC1CNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A solution of 1-fluoro-4-nitrobenzene (0.61 g, 4.32 mmol) and tert-butyl azetidin-3-ylmethylcarbamate (0.886 g, 4.76 mmol) in dimethylformamide (8.65 ml) was treated with potassium carbonate (0.896 g, 6.48 mmol) and the suspension was heated at 55° C. (12 pm) for 3 hours and at ambient temperature for 16 hours. The reaction was poured into water and the suspension was filtered. The solid was washed with water and dried to provide the title compound.
Reaction SMILES: [Na].[CH2:2]([SH:4])[CH3:3].[CH2:5]([O:7][CH:8]([O:11][CH2:12][CH3:13])[CH2:9]Br)[CH3:6]>C(O)C>[CH2:5]([O:7][CH:8]([O:11][CH2:12][CH3:13])[CH2:9][S:4][CH2:2][CH3:3])[CH3:6]
Reactant: CCS
Reactant: CCOC(CBr)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(CSCC)OCC
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
Sodium (10.7 g, 0.463 mole) was dissolved in ethanol (500 ml) and ice cooled. Ethanethiol (34.4 ml, 0.463 mole) was added, followed after 15 mins. by bromoacetaldehyde diethylacetal (83.8 g, 0.421 mole). The mixture was refluxed 3 hours and the volume reduced to 200 ml by distillation of some of the ethanol at atmospheric pressure. Ether (500 ml) was added and the solution washed with water (3×200 ml), dried over MgSO4 and evaporated at atmospheric pressure. The residue was distilled to provide title compound (70.46 g, 99%) bp 96°-100° C./20 mm Hg.
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH2:8])=[O:7])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][N:13]1[C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22].[S:32](Cl)(O)(=[O:34])=[O:33]>O1CCCC1>[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][N:13]1[C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:8][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])(=[O:34])=[O:33])=[CH:28][CH:27]=1)=[O:22]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(NCCc1ccccc1)N1Cc2ccccc2C1=O
Reactant: CCCCNC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCNC(=O)NS(=O)(=O)c1ccc(CCNC(=O)N2Cc3ccccc3C2=O)cc1
Reaction time: 3 h

Procedure:
4.8 g of butyl urea are dissolved in 100 ml of tetrahydrofurane and, while stirring, 1.5 g of 80% sodium hydride (in oil) are added. The mixture is heated for 3 hours to 60° C. whereupon 7.6 g of 4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzene-sulfochloride in 100 ml of tetrahydrofurane are added while cooling. The temperature is slowly raised to 60°-70° C. and stirring is continued at that temperature for 3 hours. The solvent is removed under reduced pressure, water is added to the residue, the mixture is filtered and the filtrate is acidified with dilute hydrochloric acid. After recrystallization from dilute acetone, the N-(4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]benzenesulfonyl)-N'-butyl-urea melts at 189°-190° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:11].[N+:12]([O-])([OH:14])=[O:13].C1(O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[C:4]=1[OH:11]
Reactant: COc1cccc(O)c1OC
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: Oc1ccccc1
Product: COc1ccc([N+](=O)[O-])c(O)c1OC
Temperature: 5 °C

Procedure:
2,3-Dimethoxyphenol (79) (5.00 g, 0.032 mol) was dissolved in glacial acetic acid (50 ml) and the resultant, stirred solution was cooled to 5° C. A cooled (5° C.) mixture of concentrated nitric acid (10 ml) and water (10 ml) was added in one portion to the phenol solution which immediately turned dark red-brown. The mixture was stirred for a further minute and poured into water (200 ml), this solution was neutralised with saturated sodium bicarbonate solution until all effervescense had ceased. The resultant yellow solution was extracted with several portions of diethyl ether until the ether remained almost colourless. The combined extracts were washed with water until the water remained almost colourless, dried (MgSO4) and the ether evaporated off in vacuo to leave a brown oil. This was purified by column chromatography (10% petrol/dichloromethane) to give a bright yellow solid.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:50])[N:25]([C:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[CH:40][CH:39]=1)[C:26]#[C:27][Si](C(C)C)(C(C)C)C(C)C)([CH3:22])([CH3:21])[CH3:20].O>C1COCC1>[C:19]([O:23][C:24](=[O:50])[N:25]([C:26]#[CH:27])[C:38]1[CH:39]=[CH:40][C:41]([N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[CH:42][CH:43]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)[Si](C#CN(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#CN(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
TBAF (954 mg, 3.02 mmol) was added to a solution of (4-morpholin-4-yl-phenyl)-[(triisopropylsilanyl)-ethynyl]-carbamic acid tert-butyl ester (600 mg, 1.31 mmol) in THF (10 ml) at 0° C. The mixture was stirred for 1 hour at this temperature and was then warmed up to RT. H2O (15 ml) was added and the organic phase was extracted with Et2O (3×15 ml) and dried over Na2SO4. The solvent was removed under reduced pressure and the desired compound was obtained after purification by column chromatography (PE/AcOEt:80/20 to 75/25). The title compound was obtained as yellow solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]([O:17]C)=[O:16].[OH-].[K+]>O1CCOCC1.CO>[CH3:14][O:13][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:1]=[C:2]([C:15]([OH:17])=[O:16])[CH:3]=[CH:4]2)=[O:12]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc2cc(C(=O)O)ccc2c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of dimethyl 2,6-naphthalenedicarboxylate (39.6 g, 162 mmol) in dioxane (1.2 L) was heated to 70-80° C., slowly treated with a solution of KOH (9.1 g, 162 mmol) in methanol (162 mL), heated to 70° C., stirred for 30 minutes, cooled to room temperature, and filtered. The solid was washed sequentially with dioxane and diethyl ether, dissolved in water, adjusted to pH<7 with 1M HCl, and filtered. The solid was washed with water and dried to provide the desired product.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:17][C:18]1[N:23]=[C:22]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=2)[CH:21]=[C:20]([N:33]2[C@H:38]([CH3:39])[CH2:37][O:36][C@H:35]([CH2:40][NH2:41])[CH2:34]2)[N:19]=1>C1COCC1>[NH2:17][C:18]1[N:19]=[C:20]([N:33]2[C@H:38]([CH3:39])[CH2:37][O:36][C@H:35]([CH2:40][NH:41][C:8](=[O:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:34]2)[CH:21]=[C:22]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=2)[N:23]=1
Reactant: C[C@@H]1CO[C@H](CN)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CO[C@H](CNC(=O)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112 %

Procedure:
Triethylamine (48 μL, 0.34 mmol) and benzoyl chloride (31 μL, 0.27 mmol) were added to a solution of 4-{2-amino-6-[(2R,5R)-2-(aminomethyl)-5-methyl-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (77 mg, 0.23 mmol) in THF (5 mL), and the mixture was stirred at room temperature under nitrogen for 30 minutes. The mixture was quenched with saturated aqueous NaHCO3 (15 mL) and extracted with EtOAc (2×10 mL). The extracts were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (115 mg) as a yellow glass. LC-MS (ES) m/z=447 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C@H:4]([NH:11][C:12](/[C:14](/[C:23]#[N:24])=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[SH:25][CH2:26][C@H:27]([C@@H:29]([CH2:31][SH:32])[OH:30])[OH:28]>C(#N)C.C(OCC)(=O)C>[Br:22][C:18]1[N:17]=[C:16]([CH:15]([S:25][CH2:26][CH:27]([OH:28])[CH:29]([OH:30])[CH2:31][SH:32])[CH:14]([C:23]#[N:24])[C:12]([NH:11][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2][CH3:1])=[O:13])[CH:21]=[CH:20][CH:19]=1
Reactant: CCC[C@H](NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccccc1
Reactant: O[C@H](CS)[C@H](O)CS
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCC(NC(=O)C(C#N)C(SCC(O)C(O)CS)c1cccc(Br)n1)c1ccccc1
Yield: 28.6 %

Procedure:
A solution of WP1130 (18; 0.05 g, 0.13 mmol) in acetonitrile (6 mL) was added to a stirred solution of dithiothreitol (2 g, 13 mmol) in acetonitrile (13 mL) at room temp. After 20 hours TLC [Hxa/EtOAc 1:1] showed a single product and no starting material. The mixture was filtered through a short column of silica gel in acetonitrile, and the filtrate stripped of solvent under reduced pressure. A colorless syrup was obtained. The syrup was dissolved in ethyl acetate and flash chromatographed on a column (35×70 mm) of silica gel in ethyl acetate to afford a clear yellow oil (0.02 g) which began to crystallize upon standing. Mass spec ES+; m/z=560, 562 (m+23) and 538, 540 (m+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH2:21][CH2:22][C:23](=O)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.CCOC(C)=O>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][C:23]1[N:1]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH3:11])[C:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[CH:21][CH:22]=1)[CH3:30]
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(OC)cc1
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1ccc(C(=O)O)cc1C
Temperature: 140 °C
Yield: 50.4 %

Procedure:
4-Amino-3-methylbenzoic acid (0.322 g) was mixed with ethyl 7-(4-methoxyphenyl)-4,7-dioxoheptanoate (25C, see scheme 25) (0.498 g) and p-toluenesulfonic acid (49 mg) in dioxane (3 mL). The mixture was heated at 140° C. via microwave over 2 hours. The resultant solution was diluted with EtOAc (20 mL) and washed with 0.5 N HCl (8 mL), Brine (8 mL) and dried over anhydrous Na2SO4. After removal of solvents under reduced pressure, the residue was purified by flash silica gel column chromatography, eluted with 10% MeOH in DCM, to afford 4-(2-(3-ethoxy-3-oxopropyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzoic acid (0.35 g) as a light yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[O:10].[Cl:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1>>[ClH:11].[Cl:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][N:4]3[C:8](=[O:9])[CH2:7][S:6][C:5]3=[O:10])[CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C1CSC(=O)N1CCBr
Product: Cl
Product: O=C1CSC(=O)N1CCN1CCN(c2cccc(Cl)c2)CC1

Procedure:
Reaction of 3-(2-bromoethyl)-2,4-thiazolidinedione with 1-(3-chlorophenyl)piperazine according to the procedure of Example 1(c) affords 3-[2-[4-(3-CHLOROPHENYL)-1-PIPERAZINYL]ETHYL]-2,4-THIAZOLIDINEDIONE HYDROCHLORIDE, m.p. 210°-213° C., from ethanol (43% yield).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/C.[CH:6]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])OCC.[N+]([O-])([O-])=O.[NH4+]>CCO.CCOC(C)=O>[CH2:14]([O:13][CH:6]([O:10][CH2:11][CH3:12])[CH:1]=[CH:2][CH3:3])[CH3:15]
Reactant: CCOC(OCC)OCC
Reactant: C/C=C/C=O
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC=CC(OCC)OCC
Reaction time: 22 h
Yield: 88.7 %

Procedure:
Crotonaldehyde (23.64 mL, 285.35 mmol), triethyl orthoformate (57.02 mL, 342.42 mmol) and ammonium nitrate (2.28 g, 28.54 mmol) were combined in 60 mL EtOH. After 22 h at ambient temperature, the reaction was diluted with EtOAc (60 mL) and washed with saturated sodium bicarbonate solution (40 mL). The aqueous layer was back extracted with EtOAc (20 mL). The combined organics were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 36.5 g (89%) of 1,1-diethoxybut-2-ene. 1H NMR (CDCl3, 400 MHz) 5.84 (m, 1H); 5.54 (m, 1H); 4.82 (d, J=5.7 Hz, 1H); 3.64 (m, 2H); 3.49 (m, 2H); 1.73 (m, 3H); 1.21 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[C:12]2[NH:11][CH:10]([O:13][CH3:14])[CH:9]3[CH2:15][CH:16]=[CH:17][N:8]3[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:19].[C:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30]Cl)=[CH:25][CH:24]=1)([OH:22])=[O:21]>N1C=CC=CC=1>[C:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][O:1][C:2]2[C:12]3[NH:11][CH:10]([O:13][CH3:14])[CH:9]4[CH2:15][C:16]([CH:15]=[CH:9][C:10]([NH2:11])=[O:13])=[CH:17][N:8]4[C:7](=[O:18])[C:6]=3[CH:5]=[CH:4][C:3]=2[CH3:19])=[CH:25][CH:24]=1)([OH:22])=[O:21]
Reactant: COC1Nc2c(ccc(C)c2O)C(=O)N2C=CCC12
Reactant: O=C(O)c1ccc(CCCl)cc1
Solvent: c1ccncc1
Product: COC1Nc2c(ccc(C)c2OCCc2ccc(C(=O)O)cc2)C(=O)N2C=C(C=CC(N)=O)CC12
Reaction time: 12 h

Procedure:
In 120 ml of pyridine were reacted 300 mg of 5,10,11,11a-tetrahydro-9-hydroxy-11-methoxy-8-methyl-5-oxo-1H-pyrrolo-[2,1-C][1,4]benzodiazepine and 1 g of 1-(4-carboxyphenyl)-2-chloroethane, for 12 hr at 50° C. After completion of the reaction, purification and recrystallization were conducted in the same manner as in Example 14 to obtain a light yellow crystal of 5,10,11,11a-tetrahydro-9-[2-(4-carboxyphenyl)-ethoxy]-11-methoxy-8-methyl-5-oxo-1H-pyrrolo-[2,1-C][1,4]benzodiazepine-2-acrylamide having a melting point of 193° to 195° C. Further, this product was converted to a corresponding sodium salt in the same manner as in Example 14. The yield of the sodium salt was 350 mg.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[CH2:9][S:10]([CH3:12])=O.FC(F)(F)C(O)=O>C1C=CC=CC=1>[CH3:12][S:10][CH:9]1[C:8](=[O:13])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1]1
Reactant: CS(=O)CC(=O)c1ccccc1O
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CSC1Oc2ccccc2C1=O

Procedure:
2-Hydroxy-1-[(methylsulfinyl) acetyl]benzene (1.5 g 0.0075m) and trifluoroacetic acid (1.5 g) are refluxed in benzene (25 ml) for one hour under nitrogen. The solvent is removed under reduced pressure to give a pale yellow oil which crystallizes on standing. Recrystallization from ethanol gave white crystals, (0.611 g 45%), m.p. 81°-82° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:24]2[CH2:23][CH2:22][N:21]([C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:20]([CH3:19])[CH2:25]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Reactant: Cc1cccc(N2CCNCC2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4cccs4)n(C(C)(C)C)n3)CC2C)c1

Procedure:
89 mg (99%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 2-methyl-1-m-tolylpiperazine (36 mg, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[S:14][C:13]([C:15]([NH2:17])=O)=[N:12][N:11]=2)[CH:5]=[C:4]([O:18][CH2:19][C@H:20]2[CH2:22][C@@H:21]2[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)[N:3]=1.CCN(CC)CC.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[S:14][C:13]([C:15]#[N:17])=[N:12][N:11]=2)[CH:5]=[C:4]([O:18][CH2:19][C@H:20]2[CH2:22][C@@H:21]2[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)[N:3]=1
Reactant: Cc1ccc([C@H]2C[C@@H]2COc2cc(NCc3nnc(C(N)=O)s3)nc(C)n2)nc1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccc([C@H]2C[C@@H]2COc2cc(NCc3nnc(C#N)s3)nc(C)n2)nc1
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To the solution of 5-((2-methyl-6-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-4-ylamino)methyl)-1,3,4-thiadiazole-2-carboxamide (17-11) (116 mg, 0.15 mmol) in THF was added NEt3 (0.1 mL, 0.7037 mmol) and TFAA (74 mg, 0.35 mmol) at 0° C. The mixture was brought to rt and stirred for 1 h. Then it was concentrated under reduced pressure and purified on silica gel (eluent PE/EA/NEt3=10/1/1%-5/1/1%) to give the product as a pale red solid (40 mg, 70%). 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.38 (dd, J=7.9, 1.7 Hz, 1H), 7.04 (d, J=7.9 Hz, 1H), 5.62 (s, 1H), 5.37 (t, J=5.9 Hz, 1H), 5.05 (d, J=6.2 Hz, 2H), 4.29 (ddd, J=27.7, 11.2, 7.0 Hz, 2H), 2.49 (s, 3H), 2.28 (s, 3H), 2.16-2.03 (m, 1H), 1.96-1.70 (m, 1H), 1.41-1.17 (m, 1H), 1.17-0.94 (m, 1H); LRMS (ESI) calculated M+H for C19H20N7OS: 394.4. Found: 394.1.