Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:18]=[CH:17][C:7]([C:8](=[O:16])[CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[CH:6][CH:5]=1.Cl[CH2:20][C:21]([NH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:22]>CN(C)C=O>[O:29]1[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][NH:23][C:21]([CH2:20][O:3][C:4]2[CH:18]=[CH:17][C:7]([C:8](=[O:16])[CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[CH:6][CH:5]=2)=[O:22])[CH2:31][CH2:30]1
Reactant: CCOC(=O)NCC(=O)c1ccc(O)cc1
Reactant: O=C(CCl)NCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)NCC(=O)c1ccc(OCC(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
31 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to a solution of 156 mg of ethyl N-(p-hydroxyphenacyl)carbamate (prepared as described in Preparation 6) dissolved in 10 ml of dimethylformamide. The mixture was then stirred at room temperature for 30 minute, after which 200 mg of 2-chloro-N-(2-morpholinoethyl)acetamide were added, and the mixture was stirred at 100° to 110° C. for 4 hours. The reaction mixture was then poured into ice-water and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel eluted with ethyl acetate, to give 190 mg of the title compound as pale yellow needles melting at 133°-135° C.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:37])[CH2:17][CH2:18][CH2:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[C:27]([O:29]CC1C=CC=CC=1)=[O:28])=[O:21])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:27]([C@H:23]1[CH2:24][CH2:25][CH2:26][N:22]1[C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:37])([OH:29])=[O:28]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)CCCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CCCN1C(=O)CCCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 45.8 %

Procedure:
440 mg (0.87 mmol) (R)-1-[5-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-5-oxo-pentanoyl]-pyrrolidine-2-carboxylic acid benzyl ester in 100 ml ethanol were hydrogenated in the presence of 40 mg 5% Pd on carbon. Filtration and evaporation of the solvent yielded 130 mg (46%) (R)-1-[5-[(R)-2-carboxy-pyrrolidin-1-yl]-5-oxo-pentanoyl]-pyrrolidine-2-carboxylic acid as colorless oil. MS-ISP: 327 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:19]S(C2C=CC=CC=2)(=O)=O)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:6]=1)#[N:4].CC1CCCO1.[F:39][C:40]([F:56])([F:55])[C:41]1[CH:46]=[C:45]([NH:47][C:48]2[CH2:53][CH2:52][CH2:51][C:50](=[O:54])[CH:49]=2)[CH:44]=[CH:43][N:42]=1>O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:19][C:49]2[C:50](=[O:54])[CH2:51][CH2:52][CH2:53][C:48]=2[NH:47][C:45]2[CH:44]=[CH:43][N:42]=[C:41]([C:40]([F:39])([F:55])[F:56])[CH:46]=2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([S:29]([CH3:32])(=[O:30])=[O:31])[CH:6]=1)#[N:4]
Reactant: O=C1C=C(Nc2ccnc(C(F)(F)F)c2)CCC1
Reactant: CC(C)(C)OC(=O)N(CS(=O)(=O)c1ccccc1)c1ccc(C#N)cc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2ccnc(C(F)(F)F)c2)CCCC1=O)c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 153 mg, 3.84 mmol) is added in portions to a mixture of tert-butyl (4-cyano-2-(methylsulfonyl)phenyl)(phenylsulfonyl)methylcarbamate (step 1, 1.60 g, 3.20 mmol based on 90% purity) and 2-methyltetrahydrofuran (15 mL), and the mixture is stirred at room temperature for 20 min. 3-(2-(Trifluoromethyl)pyridin-4-yl-amino)cyclohex-2-enone (intermediate 55, 940 mg, 3.70 mmol) is added, and the mixture is stirred for 2 h. Water is added, and the phases are separated. The organic layer is washed with water and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient dichloromethane/methanol 99:1 to 97/3). Yield: 2.10 g; ESI mass spectrum [M+H]+=565; Retention time HPLC: 0.67 min (X012_S02).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:21]=[CH:20][C:13]3[N:14]([CH:17]([CH3:19])[CH3:18])[N:15]=[N:16][C:12]=3[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[CH:21]=[CH:20][C:13]3[N:14]([CH:17]([CH3:18])[CH3:19])[N:15]=[N:16][C:12]=3[CH:11]=2)[OH:9])=[CH:6][CH:7]=1
Reactant: CC(C)n1nnc2cc(C(=O)c3ccc(F)cc3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)n1nnc2cc(C(O)c3ccc(F)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a stirred solution of 17 parts of (4-fluorophenyl) [1-(1-methylethyl)-1H-benzotriazol-5-yl]methanone in 80 parts of ethanol were added 3.4 parts of sodium tetrahydroborate. After stirring for 1 hour at room temperature, the reaction mixture was neutralized to pH 7. The reaction mixture was concentrated and the product was extracted with ethyl acetate. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 10.7 parts (62.5%) of α-(4-fluorophenyl)-1-(1-methylethyl)-1H-benzotriazole-5-methanol as a residue (int. 4).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]3)=[CH:16][N:15]=2)=[N:6]1.[H-].[Na+].I[CH3:33].O>CN(C=O)C>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][C@H:22]([O:25][CH3:33])[CH2:21]3)=[CH:16][N:15]=2)=[N:6]1
Reactant: CI
Reactant: O[C@@H]1CCN(c2cnc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H]1CCN(c2cnc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2)C1
Reaction time: 2 h

Procedure:
100 mg (0.21 mmol, purity 80%) of (3S)-1-{2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl}-3-pyrrolidinol (example XIX, step 3) are dissolved in 2 ml of DMF under argon and, while cooling in an ice bath 8 mg (0.33 mmol) of sodium hydride are added. 32 mg (0.23 mmol) of iodomethane are added dropwise to the suspension, likewise while cooling in an ice bath, and the mixture is stirred at this temperature for 2 hours. 0.5 ml of distilled water is added, and the reaction mixture is chromatographed directly on a preparative HPLC. 35 mg (42% of theory) of the product are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C@H:8]2[C@H:17]([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[O:10][CH2:9]2)[CH:2]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1>>[CH3:21][C:22]1[N:23]=[C:24]([CH2:28][O:19][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][CH2:9][C@@H:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C@@H:17]3[OH:18])[CH:25]=[CH:26][CH:27]=1
Reactant: Oc1ccc2c(c1)[C@@H](O)[C@H](Cc1cccnc1)CO2
Reactant: Cc1cccc(CBr)n1
Product: Cc1cccc(COc2ccc3c(c2)[C@@H](O)[C@H](Cc2cccnc2)CO3)n1

Procedure:
By the method of Example 5, 0.50 g (1.95 mmol) of trans-3-(3-pyridylmethyl)-4,6-chromandiol and 400 mg (2.15 mmol) of 2-(bromomethyl)-6-methyl pyridine were converted to present title product, purified by flash chromatography on silica gel using ethyl acetate as eluant to yield purified title product, o.14 g (20%), m.p. 66°-68° C.
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[C:7]([C:33](=[O:41])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:31])[CH3:30])[C:13]([O:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3]C)=[O:2].[OH-].[Na+].Cl>CC(C)=O.O>[C:1]([CH:5]1[O:11][CH:10]2[C:7]([C:33](=[O:41])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:30])[CH3:31])[C:13]([O:15][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:14])[NH:6]1)([OH:3])=[O:2]
Reactant: COC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)C)C2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)O)OC12
Reaction time: 1 h
Yield: 113.9 %

Procedure:
To a solution of 11.3 g of diphenylmethyl α-(3ξ-carbomethoxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 230 ml of acetone is added a solution of 900 mg of sodium hydroxide in 36 ml of water under ice-cooling, and the mixture stirred for 1 hour, then diluted with water, acidified with hydrochloric acid, and then extracted with methylene chloride. The extract is washed with water, dried on magnesium sulfate and concentrated under reduced pressure to yield 12.54 g of diphenylmethyl α-(3ξ-carboxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as crude product.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11]([NH:14][C:15]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]2[C:18]([C:19]3[CH:31]=[CH:30][O:29][C:20]=3[CH2:21][O:22]2)=[CH:17][CH:16]=1)(=[O:13])=[O:12].[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl>C1COCC1>[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11]([N:14]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])[C:15]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]2[C:18]([C:19]3[CH:31]=[CH:30][O:29][C:20]=3[CH2:21][O:22]2)=[CH:17][CH:16]=1)(=[O:12])=[O:13]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occc1-2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.304 g) was added to a stirred solution of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 7, 2.93 g) in THF (30 mL). The resultant mixture was stirred at room temperature for 5 minutes until effervescence had ceased. 2-(trimethylsilyl)ethoxymethyl chloride (1.27 g) was added and the solution was stirred at room temperature for one hour. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-20% to give methyl 7-[(2-bromo-4-fluorobenzenesulfonyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-4H-furo[2,3-c]chromene-6-carboxylate (3.51 g) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([S:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]2[C:26](O)=[O:27])(=[O:19])=[O:18])[CH2:13][CH2:12]1.Cl.[CH2:30]([O:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN1CCOCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:30]([O:37][NH:38][C:26]([C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][N:20]1[S:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12][CH2:13]1)(=[O:18])=[O:19])=[O:27])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NOCc1ccccc1)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (0.46 g, 1.12 mmol) [prepared as described Step 2 above] in methylene chloride (10 ml) was added O-benzylhydroxylamine hydrochloride salt (0.54 g, 3.36 mmol), followed by 4-dimethylaminopyridine (0.15 g, 1.23 mmol), 4-methylmorpholine (0.38 ml, 3.47 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimlide (0.43 g, 2.24 mmol). The reaction was stirred at RT for 2 h, diluted with methylene chloride (50 ml) and washed with 1M HCl. The organic layer was washed with brine, dried over MgSO4, and concentrated to give N-benzyloxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (95%) as a clear oil. This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1>C1COCC1>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:17](=[O:18])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
The mixture of 2-amino-4-nitrophenol (5 g, 32.44 mmol) and CDI (6.3 g, 38.93 mmol) in THF (60 mL) was heated at refluxing for 16 h. Cooled to room temperature, the solvent was removed under reduced pressure, the residue was dissolved in DCM (100 mL) and poured into 2N HCl solution (200 mL) with stirring, after 30 min, collected the solid and washed with water (50 mL×2), dried in vacuo to get compound 39-1 as a yellow solid (5.1 g, yield 87%).
Reaction SMILES: Cl[O-].[Na+].[CH2:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13](=[O:15])C)[CH:11]=2)[CH2:6][CH2:5]1.C([O-])(O)=[O:17].[Na+]>>[CH2:6]1[C:7]2[C:12](=[CH:11][C:10]([C:13]([OH:15])=[O:17])=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: CC(=O)c1ccc2c(c1)CCC2
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1ccc2c(c1)CCC2
Temperature: 55 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a stirred aqueous sodium hypochlorite solution (2230 ml, 1.80 mmol, 6%) at 55° C. was added 1-(2,3-dihydro-1H-inden-6-yl)ethanone (120.0 g,0.75 mol) and the mixture was stirred at 55° C. for 2 h. After cooling to room temperature, saturated NaHCO3 solution was added until the solution became clear. The produced precipitate was filtered, washed several times with water and dried to afford the desired product (120.0 g, 99%). 1H NMR (CDCl3, 300 MHz) δ 2.07-2.17 (m, 2H), 2.96 (t, J=7.5 Hz, 4H), 7.30 (d, J=7.8, 1H,), 7.91 (d, J=7.8, 1H), 7.96 (s, 1H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:29])=O>>[CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([Cl:29])=[O:23])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(=O)O)cc2)nc1
Product: CCCCCCCCCCOc1cnc(-c2ccc(C(=O)Cl)cc2)nc1

Procedure:
4-(5-n-Decyloxypyrimidine-2-yl)benzoic acid (1.50 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 4-(5-n-decyloxypyrimidine-2-yl)benzoic acid chloride.
Reaction SMILES: C([O:8][C:9](=[O:45])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[N:17]1[CH2:21][C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:19]([CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([N:35]([CH2:42][CH:43]=[CH2:44])[C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[CH2:31][CH2:30]2)[CH2:18]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:42]([N:35]([CH:32]1[CH2:33][CH2:34][N:29]([CH2:28][C@@H:19]2[C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][N:17]([C@@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]3[CH2:10][C:9]([OH:45])=[O:8])[CH2:18]2)[CH2:30][CH2:31]1)[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)[CH2:43][CH3:44]
Reactant: [H][H]
Reactant: C=CCN(c1cccnc1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)OCc3ccccc3)C[C@@H]2c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCCN(c1cccnc1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)O)C[C@@H]2c2ccccc2)CC1
Yield: 94.8 %

Procedure:
A solution of 2-(R)-(3-(S)-((4-(N-(allyl)-N-(pyrid-3-yl)-amino)-piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid benzyl ester (37 mg, 0.061 mmol from Step C) in 2 mL MeOH was stirred with 13 mg (0.012 mmol) 10% palladium on carbon under 1 atm of hydrogen using a balloon. After 2 h the mixture was filtered and concentrated to provide 30 mg of the title compound. 1H NMR (500 MHz, CDCl3) δ 0.90-0.93 (t, 3H, J=7.5 Hz), 1.1-3.4 (m, 33H), 6.91-6.93 (d, 1H, J=8 Hz), 7.07-7.1 (m, 1H), 7.2-7.35 (m, 5H), 7.92-7.93 (d, 1H, J=4 Hz), 8.08-8.09 (d, 1H, J=2 Hz). ESI-MS. M/z; (M+H)=519.4 (obs), 519.36 (calc.).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](OC)([O:9]C)[CH2:7][CH2:6][O:5][CH2:4]1.Cl>C1COCC1.O>[CH3:1][O:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: COC1COCCC1(OC)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC1COCCC1=O
Reaction time: 1 h

Procedure:
To a solution of 3,4,4-trimethoxytetrahydro-2H-pyran (4 g, 20 mmol) in THF/H2O (60 mL/10mL) was added concentrated HCl (6 mL). After being stirred for 1 h, THF was removed in vacuo. The aqueous solution was extracted with ether (3 ×100 mL). The extracts were dried and concentrated in vacuo to provide the desired product. 1H NMR (CDCl3) δ 4.30-4.10 (2H, m), 3.75-3.65 (2H, m), 3.60-3.50 (1H, m), 3.50 (3H, s), 2.70-2.50 (2H, m).
Reaction SMILES: [F:1]C1C=CC2SC(C(O)=O)=CC=2C=1.F[C:15]1[CH:28]=[CH:27][C:18]2[S:19][C:20]([C:22]([S:24][CH2:25][CH3:26])=[S:23])=[CH:21][C:17]=2[CH:16]=1>>[F:1][C:16]1[C:17]2[CH:21]=[C:20]([C:22]([S:24][CH2:25][CH3:26])=[S:23])[S:19][C:18]=2[CH:27]=[CH:28][CH:15]=1
Reactant: CCSC(=S)c1cc2cc(F)ccc2s1
Reactant: O=C(O)c1cc2cc(F)ccc2s1
Product: CCSC(=S)c1cc2c(F)cccc2s1

Procedure:
The 5-fluoro-2-benzo[b]thiophenecarboxylic acid prepared above in A was converted to ethyl 5-fluoro-2-benzo[b]thiophenecarbodithioate (mp 91-92° C.) using the procedures described above in Examples 2(B)-2(D). NMR confirmed the structure as that of ethyl 5-fluoro-2-benzo[b]thiophenecarbodithioate.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20]/[C:21](=[CH:31]\[S:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)/[C:22](=[S:30])[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[NH4+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[OH:18][CH2:19][CH2:20]/[C:21](=[CH:31]\[S:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)/[C:22](=[S:30])[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](OCC/C(=C\Sc1ccccc1)C(=S)Nc1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCC/C(=C\Sc1ccccc1)C(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 ml of tetra n-butyl ammonium chloride (1 mol/l of tetrahydrofuran solution) was added to 5 ml of tetrahydrofuran solution including 0.4 g of (E)-4-(tert-butyldiphenylsilyloxy)-N-phenyl-2-(phenylthiomethylene)butanethioamide. The resulting solution was stirred at room temperature for 30 minutes and added with saturated ammonium chloride. The solution was extracted with ethyl acetate, dried with anhydrous magnesium sulfate and filtered, concentrated under reduced pressure. Crude (E)-4-hydroxy-N-phenyl-2-(phenylthiomethylene)butanethioamide was obtained. The crude was used in the next reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21].N1C=CC=CC=1>ClCCl>[CH2:20]([NH:22][C:23]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:19])[CH:17]=2)=[O:24])[CH3:21]
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: CCN=C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCNC(=O)Nc1cc2ccc(-c3cc(F)ccc3C)cc2cn1
Temperature: 40 °C

Procedure:
A mixture of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (51.3 mg, 203 μmol) and ethyl isocyanate (20 uL, 0.26 mmol) in dichloromethane (2.0 mL) was heated at 40° C. for 4 days. The cooled mixture was treated with pyridine (20 uL, 0.25 mmol) and a further portion of ethyl isocyanate (20 uL, 0.26 mmol) at 40° C. for 24 h and concentrated in vacuo, and the residue purified by reverse phase HPLC (gradient of acetonitrile in water with 0.1% formic acid) to yield the title compound as a white amorphous solid (54.6 mg, 83%). 1H NMR (400 MHz, DMSO) δ 9.07 (s, 2H), 8.09 (s, 1H), 7.97 (s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.37 (t, J=7.2 Hz, 1H), 7.20-7.12 (m, 2H), 7.06-7.00 (s, 1H), 3.19 (dq, J=7, 7 Hz, 2H), 2.25 (s, 3H), 1.10 (t, J=7.2 Hz, 3H). LCMS (Method E): RT=4.885 min, M+H+=324.1.
Reaction SMILES: [P:1]([O:23][CH3:24])([O:21][CH3:22])([O:3][C:4](=[C:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:2].Br[CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>>[P:1]([O:23][CH3:24])([O:21][CH3:22])([O:3][C:4](=[C:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[N:6]=1)=[O:2]
Reactant: COc1ccc2c(C(OP(=O)(OC)OC)=C3CCCC3)n[nH]c2c1
Reactant: CC(C)(C)C(=O)CBr
Product: COc1ccc2c(C(OP(=O)(OC)OC)=C3CCCC3)nn(CC(=O)C(C)(C)C)c2c1

Procedure:
The title compound was prepared from cyclopentylidene(6-methoxy-1H-indazol-3-yl)methyl dimethyl phosphate and 1-bromo-3,3-dimethylbutan-2-one using the procedure described in Method I Step C of Example 1 followed by RP-HPLC purification using 30-100% MeCN gradient without TFA. It was obtained as a solid following lyophilization. LC-MS: 3.56 min. (m/Z=325.2, 451.2, 473.1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].O1CCCC1.Cl[CH2:10][C:11]([N:13]([C:15]1[C:16](=[O:31])[C:17]2[C:22]([C:23](=[O:30])[C:24]=1[NH:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:14])=[O:12].O>O1CCCC1>[CH3:29][O:28][CH2:27][CH2:26][NH:25][C:24]1[C:23](=[O:30])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:31])[C:15]=1[N:13]([CH3:14])[C:11](=[O:12])[CH2:10][N:2]([CH3:3])[CH3:1]
Reactant: COCCNC1=C(N(C)C(=O)CCl)C(=O)c2ccccc2C1=O
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: COCCNC1=C(N(C)C(=O)CN(C)C)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2 M Dimethylamine/tetrahydrofuran solution (3.0 ml) was added to a solution of 2-chloro-N-[1,4-dihydro-3-(2-methoxyethyl)amino-1,4-dioxo-2-naphthalenyl]-N-methylacetamide (0.5 g) in tetrahydrofuran (30 ml) and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was crystallized from ethanol to give N-[1,4-dihydro-3-(2-methoxyethyl)amino-1,4-dioxo-2-naphthalenyl]-N-methyl-2-(dimethylamino)acetamide (0.19 g) as a brown powder.
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[N:9]=[C:4]2[CH:3]=1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCCl>[CH:20]1([NH:26][C:27]([NH:10][C:8]2[N:9]=[C:4]3[CH:3]=[C:2]([CH3:1])[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])[C:5]3=[N:6][CH:7]=2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1cc2nc(N)cnc2n1COCC[Si](C)(C)C
Reactant: O=C=NC1CCCCC1
Solvent: ClCCCl
Product: Cc1cc2nc(NC(=O)NC3CCCCC3)cnc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Yield: 95.3 %

Procedure:
6-Methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamine (58 mg, 0.208 mmol) was dissolved in 1,2-dichloroethane (2.1 mL). Cyclohexylisocyanate (0.54 mL, 4.16 mmol) was added and the reaction mixture was heated to reflux overnight, cooled to RT, concentrated, purified by SiO2 chromatography (12 g SiO2, hexanes/EtOAc 0-50% EtOAc) to give 80 mg of 1-cyclohexyl-3-[6-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as a yellow solid (95% yield).