Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]([CH3:37])([CH2:34][CH2:35][CH3:36])[CH2:32]O.[K+].[Br-].Cl>>[CH3:30][C:31]([CH3:37])([CH2:34][CH2:35][CH3:36])[CH2:32][O:24][C:23]([C:18]1([C:20]([O:22][CH2:30][C:31]([CH3:37])([CH3:32])[CH2:34][CH2:35][CH3:36])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CCCC(C)(C)CO
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: CCCC(C)(C)COC(=O)C1(C(=O)OCC(C)(C)CCC)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2,2-dimethylpentanol according to the procedure of Example 1 as an off-white solid; 1H NMR(DMSO-d6,400 MHz) 0.8 (m, 18H, 6×CH3), 1.1-1.2 (m, 11H, CH2CH3), 2.6 (m, 1H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 4.0 (s, 4H, OCH2, OCH2), 5.09 (m, 1H, CH), 6.36 (d, J=4.17 Hz, 1H, OH), 6.86 (dd, J=7.9, 1.32 Hz, 1H, Ar--H), 7.07 (s 1H, Ar--H), 7.09 (d, J=8.35 Hz, Ar--H), 7.35-7.42 (m, 3H, Ar--H), 7.48 (s, 1H, Ar--H), 9.84 (brs, 1H, NH), 9.48 (brs, 1H, NH); IR (KBr, cm-1) 3300 (OH), 2900 (NH), 1760 (CO); MS m/e 617 (M+); Analysis for: C34H48ClNO7 ×HCl: Calc'd: C, 62.38; H, 7.55; N, 2.14; Found: C, 62.47; H, 7.51; N, 2.31.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:29][CH2:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[CH:41]([S:43]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=[O:45])=[O:44])=[CH2:42]>C1(C)C=CC=CC=1>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH2:29][CH2:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][CH2:42][CH2:41][S:43]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=[O:44])=[O:45])[CH2:19][CH2:18]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC=C(C(=O)OC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=CS(=O)(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1CC[C@]2(NCCS(=O)(=O)c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC=C(C(=O)OC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 90 °C
Yield: 38.3 %

Procedure:
Methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohexa-1,3-dienecarboxylate (200 mg, 0.366 mmol) and (vinylsulfonyl)benzene (80 mg, 0.476 mmol) were dissolved in toluene (1 mL). The solution was warmed to 90° C. for 9 hours. The crude reaction mixture was applied onto a 12 gm silica gel column, purified with 0-10% ethyl acetate/hexanes as eluent to afford the title compound as a white solid (100 mg, 0.14 mmole, 38.2%). MS: m/e 714.53 (M+H)+, 2.46 min (method 2). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.03-7.89 (m, 2H), 7.73-7.66 (m, 1H), 7.66-7.57 (m, 2H), 7.08-7.01 (m, 1H), 5.83 (d, J=5.5 Hz, 1H), 5.30 (d, J=1.8 Hz, 1H), 4.70 (d, J=2.5 Hz, 1H), 4.65-4.55 (m, 1H), 3.82-3.71 (m, 3H), 3.42-3.24 (m, 2H), 3.03-2.86 (m, 1H), 2.86-2.70 (m, 1H), 2.56-2.40 (m, 3H), 2.40-2.26 (m, 1H), 2.09-2.00 (m, 1H), 1.98-1.85 (m, 1H), 1.85-1.73 (m, 2H), 1.71-1.67 (m, 3H), 1.67-1.38 (m, 7H), 1.37-1.11 (m, 12H), 1.10-1.07 (m, 3H), 1.04-1.01 (m, 3H), 0.98 (d, J=3.3 Hz, 3H), 0.97-0.94 (m, 3H), 0.92-0.89 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH:8]([C:13]([O:15]C)=[O:14])[CH2:7][CH2:6][C:5]=2[N:4]=1.[OH-].[Na+]>CO>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH:8]([C:13]([OH:15])=[O:14])[CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: COC(=O)C1CCc2nc(C(F)(F)F)ccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCc2nc(C(F)(F)F)ccc2C1
Temperature: 90 °C
Yield: 122.4 %

Procedure:
A 25 mL flask was charged with methyl 2-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-6-carboxylate (6 mg, 0.02 mmol), methanol (3 mL) and 1 M aqueous sodium hydroxide (0.23 mL, 10 equiv), and the mixture heated in an oil bath at 90° C. The mixture was removed from the heat after 1.5 h, diluted with 1M NaH2PO4 (10 mL), buffered to pH 3 with 1M H3PO4, then extracted with DCM (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford the acid as a white solid (6 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 3.21-3.02 (m, 4H), 2.95-2.84 (m, 1H), 2.42-2.32 (m, 1H), 2.14-2.03 (m, 1H), 1.10 (br s, 11-1); m/z=246.4 (M+H)f.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([CH:7]([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH3:8])=[O:6])[CH3:3].Br[C:18]([CH3:22])([CH:20]=C)[CH3:19]>C(O)C>[CH2:2]([O:4][C:5]([CH:7]([P:9]([O:10][CH2:11][CH3:12])(=[O:16])[O:13][CH2:14][CH3:15])[CH2:8][CH:19]=[C:18]([CH3:22])[CH3:20])=[O:6])[CH3:3]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: C=CC(C)(C)Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CC=C(C)C)P(=O)(OCC)OCC
Reaction time: 1 h

Procedure:
The diethyl 2-ethoxycarbonly-5-methyl-hex-4-ene-2-phosphonate used in this reaction was prepared by the following procedure. 4.8 Parts of sodium metal were dissolved in 200 parts of absolute ethanol and to this solution was added 50 parts of diethyl 1-ethoxycarbonyl-ethylphosphonate. To this stirred reaction mixture at room temperature was added 31.3 parts of 2-bromo-2-methyl-but-3-ene dropwise over 1 hour. On completion of the addition stirring was continued for 1 hour at room temperature and then for 2 hours at 60° C. After cooling, the reaction mixture was filtered free of sodium bromide and the filtrate concentrated under reduced pressure to remove ethanol. The residual oil was taken up in ether, and the ether solution washed with water and evaporated. Fractional distillation of the residue gave diethyl 1-ethoxycarbonyl-4-methyl-pent-3-ene-1-phosphonate b0.3 126°-34° C. with the following percentage composition by weight.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.O[CH2:14][CH2:15][N:16]([CH2:29][CH2:30]O)[C:17](=[O:28])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1.P(=O)(O)(O)O.[OH-].[Na+]>O>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[O:24][CH3:25])[C:17]([N:16]1[CH2:15][CH2:14][N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH2:30][CH2:29]1)=[O:28]
Reactant: COc1ccc(C(=O)N(CCO)CCO)cc1OC
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Yield: 71.4 %

Procedure:
A mixture of 2.7 g of 6-amino-3,4-dihydrocarbostyril, 5.9 g of N,N-bis(2-hydroxyethyl)-3,4-dimethoxybenzamide and 8.6 g of 85% phosphoric acid was reacted at 165° to 175° C. for 4.5 hours while stirring. After allowing to cool, to the reaction mixture was added dropwise about 50 ml of water to dissolve. The solution was neutralized with an aqueous 48% sodium hydroxide solution and extracted with chloroform. After drying the extract over potassium carbonate, chloroform was distilled off. Recrystallization of the residue from ethanol-chloroform gave 4.7 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 238°-239.5° C., colorless granules.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[C:4](=[O:14])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1.C(O)C.[ClH:33]>C(OCC)(=O)C>[ClH:33].[CH3:1][CH:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[C:4](=[O:14])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CC1c2cc3c(cc2C(=O)N1CCC1CCN(C(=O)OC(C)(C)C)CC1)OCO3
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1c2cc3c(cc2C(=O)N1CCC1CCNCC1)OCO3
Reaction time: 1.25 h
Yield: 81 %

Procedure:
To a reaction vessel, 5 g (0.012 mol) compound XIII, 30 ml ethanol and 100 ml 10% solution of hydrogen chloride in ethyl acetate were added, the reaction was kept at room temperature for 1-1.5 h, filtered, the filter cake was washed with ethyl acetate, dried, and 3.4 g compound II-3 was obtained, with yield of 81%. 1H NMR (D2O): δ 1.24 (d, 3H, J=7.0 Hz), 1.44-1.58 (m, 5H), 1.98 (m, 2H), 2.96 (m, 2H), 3.21-3.25 (m, 1H), 3.44 (d, 2H, J=12.4 Hz), 3.64-3.72 (m, 1H), 4.34 (q, 1H, J=6.6 Hz), 5.94 (s, 2H), 6.72 (s, 1H), 6.79 (s, 1H); MS (ESI): m/z 303 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:33])[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]2[CH:13]=[C:12]([C:20]#[C:21][C:22]3[CH:32]=[CH:31][C:25]([C:26](OCC)=[O:27])=[CH:24][N:23]=3)[CH:11]=[CH:10][C:9]1=2.[H-].C(OCC)(=O)C.[Cl-].[NH4+]>C(OCC)C>[CH3:7][C:8]1([CH3:33])[CH2:17][CH2:16][C:15]([CH3:18])([CH3:19])[C:14]2[CH:13]=[C:12]([C:20]#[C:21][C:22]3[CH:32]=[CH:31][C:25]([CH2:26][OH:27])=[CH:24][N:23]=3)[CH:11]=[CH:10][C:9]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(CO)cn3)ccc21
Temperature: -65 °C
Reaction time: 1 h

Procedure:
A 250 ml 3-necked flask is fitted with a stirrer, a dropping funnel, a nitrogen inlet and a thermometer. In the flask is placed a solution of 379.5 mg (10 mmol) of lithium aluminum hydride in 30 ml of dry diethyl ether. The solution is cooled to -65° C. under nitrogen and a solution of 3.6148 g (10 mmol) of ethyl 6-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]-nicotinoate in 15 ml of dry ether is added dropwise at a rate such that the temperature does not exceed -60° C. The mixture is stirred at -30° C. for 1 hour and the excess hydride is then destroyed by the addition of 300 mg (3.4 mmol) of ethyl acetate. The reaction mixture is then hydrolyzed by adding 3 ml of saturated ammonium chloride solution and allowing the temperature to rise to room temperature. The mixture is then filtered and the residue washed with ether. The ether layer is then washed with saturated sodium chloride solution, dried (MgSO4) and then concentrated in vacuo. The residue is purified by chromatography followed by recrystallization to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22].O>C(Cl)Cl>[C:21]([O:24][CH2:25][C:26]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:3]=1[C:4]#[N:5])=[O:27])(=[O:23])[CH3:22]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCN(CC)c1cccc(N)c1C#N
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CC)c1cccc(NC(=O)COC(C)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(diethylamino)benzonitrile (3 g) in methylene chloride (50 ml) is added pyridine (1.4 ml), and thereto is added dropwise acetoxyacetyl chloride (1.8 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is recrystallized from hexane to give the title compound (1.1 g) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:20]4[CH:24]=[CH:23][O:22][CH:21]=4)[OH:19])[CH:16]=3)[N:11]=[C:10]([O:25][CH3:26])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1>ClC(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:20]4[CH:24]=[CH:23][O:22][CH:21]=4)=[O:19])[CH:16]=3)[N:11]=[C:10]([O:25][CH3:26])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)c3ccoc3)ccc2n1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccoc3)ccc2n1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A mixture of (intermediate 24) (0.0382 mol) and MnO2 (28 g) in trichloromethane (200 ml) was stirred and refluxed overnight. The mixture was cooled to room temperature, filtered over celite and the solvent was evaporated till dryness. The product was used without further purification, yielding 11.5 g (82.7%) of [4-(3-chlorophenyl)-2-methoxy-6-quinolinyl]-3-furanyl-methanone (intermediate 25).
Reaction SMILES: [CH3:1][C:2]([C:5]1[NH:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)([CH3:4])[CH3:3].C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:25])C=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:4][C:2]([C:5]1[NH:13][C:8]2=[N+:9]([O-:25])[CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)([CH3:1])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1cc2cccnc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc2ccc[n+]([O-])c2[nH]1
Temperature: 25 °C

Procedure:
2-(1,1-Dimethylethyl)-1H-pyrrolo[2,3-b]pyridine (10 g, 57 mmol) was dissolved in ethyl acetate:DCM (400 ml, 1:1, v/v), cooled to ˜0° C. in an ice bath and treated by dropwise addition of m-chloroperbenzoic acid (15.85 g, 69.5 mmol). The reaction was warmed to room temperature over 3 hours then treated with 30% potassium carbonate (aq) (150 ml). The organic layer was separated and the aqueous washed with further DCM (2×100 ml). The combined organic layers were washed with a sodium metabisulphite solution, dried then evaporated to give title compound, 11.1 g.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)#[N:2].C([O:15][C@@H:16]1[C@@H:29]([O:30]C(=O)C)[C@H:28]([O:34]C(=O)C)[CH2:27][S:26][C@H:17]1[O:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](Br)[CH:24]=1)(=O)C>>[O:18]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH:24]=1)[C@@H:17]1[S:26][CH2:27][C@@H:28]([OH:34])[C@H:29]([OH:30])[C@H:16]1[OH:15]
Reactant: N#Cc1ccccc1B(O)O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: N#Cc1ccccc1-c1cncc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)c1

Procedure:
By following a procedure analogous to Example 122 starting from 2-cyano-phenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 5-(2-cyanophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=67%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11](/[CH:17]=[C:18]1/[C:19](=[O:33])[N:20]=[C:21]([NH:23][C@@H:24]3[CH2:26][C@H:25]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:22]/1)=[CH:10][CH:9]=2)=[O:4].[OH-].[Na+]>CO>[CH3:16][O:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:17]=[C:18]3/[C:19](=[O:33])[N:20]=[C:21]([NH:23][C@@H:24]4[CH2:26][C@H:25]4[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[S:22]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cnc2ccc(/C=C3\SC(N[C@@H]4C[C@H]4c4ccccc4)=NC3=O)cc2c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C(=O)O)cnc2ccc(/C=C3\SC(N[C@@H]4C[C@H]4c4ccccc4)=NC3=O)cc12
Reaction time: 12 h

Procedure:
To the suspension of 4-methoxy-6-[4-oxo-2-((1R,2S)-2-phenyl-cyclopropylamino)-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carboxylic acid methyl ester (example 1) (50 mg, 0.11 mmol) in methanol (2 mL) was added 1 N aqueous sodium hydroxide solution (0.5 mL, 0.5 mmol). After stirring for 12 hours, the crude product was purified by HPLC (reverse C18, 10%-90% acetonitrile in water in 10 min) to afford 4-methoxy-6-[4-oxo-2-((1R,2S)-2-phenyl-cyclopropylamino)-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carboxylic acid. LC-MS m/e 446 (MH+).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH2:14])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[C:15]([NH:23][C:24]1[S:25][C:26]([C:30](=[O:33])[CH2:31]Br)=[C:27]([CH3:29])[N:28]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(N(CC)CC)C>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][CH2:31][CH:30]([OH:33])[C:26]2[S:25][C:24]([NH:23][C:15](=[O:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:28][C:27]=2[CH3:29])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: Cc1nc(NC(=O)c2ccccc2)sc1C(=O)CBr
Reactant: CCOC(=O)c1ccc(CCN)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CCNCC(O)c2sc(NC(=O)c3ccccc3)nc2C)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-(4-carboethoxyphenyl)ethylamine and stoichiometric amounts of triethylamine with 2-benzoylamino-4-methyl-5-bromoacetyl-thiazole, followed by reduction and purification of the base on a silica gel column using chloroform/methanol=9:1 as eluant and trituration with petroleum ether.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]([CH2:29][CH2:30][Cl:31])=[CH:22][C:10]=1[NH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.CC(O)=O.[Pd]>[CH2:1]([O:8][C:9]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]([CH2:29][CH2:30][Cl:31])=[C:22]2[C:10]=1[NH:11][C:12]([C:18]([F:19])([F:20])[F:21])=[C:13]2[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C=C(Nc1cc(CCCl)c([N+](=O)[O-])cc1OCc1ccccc1)C(F)(F)F
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1c(C(F)(F)F)[nH]c2c(OCc3ccccc3)cc([N+](=O)[O-])c(CCCl)c12
Temperature: 68 °C
Reaction time: 6 h

Procedure:
Methyl 3-[2-benzyloxy-5-(2-chloroethyl)-4-nitroanilino]4,4,4-trifluoro-2-butenoate (0.035 g, 0.0763 mmol) was dried under high vacuum in a round bottom flask. Palladium II acetate (0.034 g, 0.153 mmol) was added, the flask was then covered with a septum and flushed with N2. Dry dimethyl acetamiide (20 mL) was then added via syringe under N2. The solution was then degassed three times under vacuum for thirty minutes and purged with N2. The solution was then stirred for six hours and fifteen minutes in an oil bath at 68° C. The solution was then diluted with CHCl3 (100 mL) and washed with water three times (100 mL). The organic layer was dried with sodium sulfate, gravity filtered and concentrated on rotovap. The dimethylacetamide was removed under high vacuum Kugelrohr distillation (50° C., 0.25 mm Hg). The residue was purified on silica gel column using methylene chloride as a solvent to yield methyl 7-benzyloxy-4-(2-cloroethyl)-5-nitro-2-trifluoromethylindole-3-carboxylate as a yellow solid. Total yield: 0.010 g (0.022 mmol, 29%). TLC (methylene chloride) Rf320.75.500 MHz 1H-NMR (CDCl3) 9.24 (s br, 1H), 7.46 (m, 5H), 7.44 (s, 1H), 5.26 (s, 2H), 4.01 (s, 3H), 3.82 (t, 7.5, 2H), 3.63 (t, 7.5, 2H). IR (neat) 3036, 2952, 2915, 2850, 1732, 1713, 1695, 1576, 1534, 1503, 1451, 1337, 1259, 865, 802. EI-MS (relative intensity) 456 (M+, 3), 420 (M+−HCl, 3). Accurate mass for C20H16O9N235ClF3: calcd. 456.0700, obsd. 456.0695.
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH2:19][CH:20]=[O:21])[C:3]([NH:5][C:6]1[S:7][C:8]([CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)=[O:4].Cl>O>[CH:11]1([C:8]2[S:7][C:6]([N:5]3[CH:20]([OH:21])[CH2:19][CH2:18][N:2]([CH3:1])[C:3]3=[O:4])=[N:10][N:9]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CN(CCC=O)C(=O)Nc1nnc(C2CCCCCC2)s1
Agent: Cl
Solvent: O
Product: CN1CCC(O)N(c2nnc(C3CCCCCC3)s2)C1=O

Procedure:
The dimethyl acetal of 3-[1-methyl-3-(5-cycloheptyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled resulting in the formation of a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-cycloheptyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:24][O:25][C:26](=[O:46])[CH2:27][CH2:28][CH2:29][N:30]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=1)[C:31]([C@@:33]1([CH3:37])[CH2:36][CH2:35][NH:34]1)=[O:32].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[CH3:24][O:25][C:26](=[O:46])[CH2:27][CH2:28][CH2:29][N:30]([C:31]([C@@:33]1([CH3:37])[CH2:36][CH2:35][N:34]1[C:6]([C:4]1[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[S:1][CH:5]=1)=[O:8])=[O:32])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=1
Reactant: O=C(O)c1csc2ccccc12
Reactant: COC(=O)CCCN(Cc1cccc(Cl)c1)C(=O)[C@@]1(C)CCN1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)CCCN(Cc1cccc(Cl)c1)C(=O)[C@@]1(C)CCN1C(=O)c1csc2ccccc12
Temperature: 20 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
To a suspension of benzo[b]thiophene-3-carboxylic acid (7.12 g, 1.2 eq.) in 210 mL of DCM and 210 mL of THF were added HOBt (5.4 g, 1.2 eq.) EDC.HCl (9.6 g, 1.5 eq.) and TEA (18.5 mL, 4 eq.). The reaction was stirred at 20° C. for 15 h, then a solution of 4-[(3-chloro-benzyl)-((R)-2-methyl-azetidine-2-carbonyl)-amino]-butyric acid methyl ester hydrochloride obtained in step i above (12.5 g, 1 eq.) in 105 mL of DCM and 105 mL of THF was added. The reaction was stirred at 20° C. for 4.5 h. The crude was diluted with DCM. A saturated aqueous solution of NaHCO3 was added. The aqueous layer was extracted three times with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 90/10 to 50/50) to afford 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid methyl ester (14.53 g, yield=87%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][NH2:12].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][NH:12][C:18](=[O:20])[CH3:19]
Reactant: CCCCCC(CCCN)OC1CCCCO1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCC(CCCNC(C)=O)OC1CCCCO1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred, ice cold solution of 4-(2-tetrahydropyranyloxy)nonylamine (7.29 g., 0.03 mole) in pyridine (40 ml.) is added acetic anhydride (3.06 g., 0.03 mole) at such a rate as to maintain the reaction temperature at 5°-10°C. The reaction is then allowed to stand at room temperature for 6 hours, poured into ice water (200 ml.) and extracted with ether (2 × 100 ml.). The ether is extracted with ice cold 5% hydrochloric acid (2 × 20 ml.), washed with brine (2 × 25 ml.), then dried over sodium sulfate. Evaporation in vacuo affords the subject compound as a pale yellow oil.