Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: CO
Reactant: CSc1ccc(CC(=O)O)cc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(SC)c(Cl)c1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid (8.00 g, 36.92 mmol) in methanol (200 mL) was treated slowly with concentrated sulfuric acid (1 mL). The resulting reaction mixture was heated under reflux overnight. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The resulting residue was dissolved with ethyl acetate (50 mL). The organic layer was washed with water (1×50 mL). The water layer was further extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (1×25 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to afford (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (7.28 g, 85.5%) as a yellow oil which was used without further purification: EI-HRMS m/e calcd for C10H11ClO2S (M+) 230.0168, found 230.0166.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1[CH2:14][NH2:15].[CH3:16][S:17]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)(=[O:19])=[O:18]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1[CH2:14][NH:15][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([NH:20][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:22][CH:23]=1
Reactant: CN1CCN(c2ccccc2)CC1CN
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Product: CN1CCN(c2ccccc2)CC1CNC(=O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
In a manner similar to preparation 3, react 1-methyl-4-phenyl-2-piperazinemethanamine with 4-[(methylsulfonyl)amino]benzoyl chloride to obtain the title compound.
Reaction SMILES: CCCCCCCCCCCCCCCC([O:18][CH2:19][C@H:20]([OH:29])[C@H:21]1[O:26][C:24](=[O:25])[C:23]([OH:27])=[C:22]1[OH:28])=O.C([O-])(=O)CCCCCCCCCCCCCCCCC>>[O:25]=[C:24]1[O:26][C@H:21]([C@H:20]([CH2:19][OH:18])[OH:29])[C:22]([OH:28])=[C:23]1[OH:27]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O
Agent: CCCCCCCCCCCCCCCCCC(=O)[O-]
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
Ascorbyl Palmitate or Stearate
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[O:10]=[C:11]([C:22]1[N:23]=[CH:24][NH:25][CH:26]=1)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>O1CCCC1>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:11]([C:22]2[N:23]=[CH:24][NH:25][CH:26]=2)([OH:10])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:5]=1
Reactant: O=C(CCCCc1ccccc1)c1c[nH]cn1
Reactant: Fc1ccc(Br)cc1
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OC(CCCCc1ccccc1)(c1ccc(F)cc1)c1c[nH]cn1
Temperature: 25 °C

Procedure:
0,52 g of magnesium turnings are covered with 60 ml of dry tetrahydrofuran. Then a solution of 1-bromo-4-fluorobenzene (3,8 g) in 60 ml of dry tetrahydrofuran is added dropwise to the mixture at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is refluxed for one additional hour and cooled to room temperature. The reaction mixture is then added dropwise to a solution of 4-(1-oxo-5-phenylpentyl)-1H-imidazole (3,8 g) in 40 ml of tetrahydrofuran at 60° C. After the addition is complete, the reaction mixture is refluxed for 3 hours, cooled and poured into cold water. Tetrahydrofuran is evaporated and conc. hydrochloric acid is added to the solution. The product is extracted as hydrochloric salt into methylene chloride. Combined methylene chloride extracts are then evaporated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:13])[C:6]([C:9]([O:11]C)=[O:10])=[N:7][CH:8]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:13])[C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1
Reactant: COC(=O)c1ncc(OC)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cnc(C(=O)O)c(C)n1
Temperature: 40 °C
Yield: 95.6 %

Procedure:
To a solution of methyl 5-methoxy-3-methylpyrazine-2-carboxylate (5.1 g, 28.0 mmol) in MeOH (50 mL) was added sodium hydroxide 1.0 N solution (30.8 mL, 30.8 mmol). The reaction was heated to 40° C. for 2 h. The reaction mixture was concentrated, diluted with water and pH adjusted to 4. The solid that precipitated was filtered and dried. The remaining acidic solution was extracted with EtOAc and DCM. The combined organics were dried with Na2SO4, and concentrated in vacuo to give another batch of solid. The solids were combined and dried to give 5-methoxy-3-methylpyrazine-2-carboxylic acid (4.5 g, 96% yield). 1H NMR (300 MHz, DMSO-d6) δ 13.00 (br. s., 1H), 8.18 (s, 1H), 3.96 (s, 3H), 2.67 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=1.[BH4-].[K+]>C(O)C.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1
Reactant: O=Cc1cnc(Nc2ccccn2)s1
Agent: [BH4-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Product: OCc1cnc(Nc2ccccn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of 2-(pyridin-2-ylamino)thiazole-5-carbaldehyde (410 mg, 2 mmol) in ethanol (15 mL) and DMF (5 mL) was added potassium borohydride (120 mg). The resulting mixture was stirred at RT for 1 h, quenched with 10% sulfuric acid solution and concentrated in vacuo. The residue was extracted with methanol and the methanol solution was concentrated. The crude material was diluted with water, filtered and the solid was washed with water and dried in vacuo to provide compound 9A, [2-(pyridin-2-ylamino)thiazol-5-yl]methanol (385 mg, 93%) as a solid. LC/MS; (M+H)+=208
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14](I)=[CH:15][C:6]1=2.[CH2:22]([O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:26])[C:27]1[CH:32]=[CH:31][C:30]([C:14]2[CH:13]=[N:12][C:7]3[NH:8][CH2:9][C:10](=[O:11])[N:5]([CH2:4][C:3]4[C:2]([Cl:1])=[CH:20][CH:19]=[CH:18][C:17]=4[Cl:21])[C:6]=3[CH:15]=2)=[CH:29][CH:28]=1)[CH3:23]
Reactant: O=C1CNc2ncc(I)cc2N1Cc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(Cc2c(Cl)cccc2Cl)C(=O)CN3)cc1

Procedure:
1-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (231 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4B to give the title compound as a yellow solid. M.p.=226° C., LCMS: m/z=456.52 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.35 (3H, t, J=6.9 Hz), 4.09 (3H, s), 4.33 (3H, q, J=7.1 Hz), 5.47 (2H, s), 7.32 (2H, m), 7.48 (2H, d, J=8.1 Hz), 7.57 (3H, m), 7.63 (1H, m), 7.90 (1H, m), 7.98 (2H, d, J=8.2 Hz), 8.03 (1H, d, J=2.0 Hz).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]2OCC[O:15]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C-]#N.[Na+].O>C1(C)C(C)=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH:14]=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Oc2cccc(C3OCCO3)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: [C-]#N
Solvent: Cc1ccccc1C
Solvent: O
Product: O=Cc1cccc(Oc2ccccc2)c1
Yield: 58 %

Procedure:
A solution of 2-(3-phenoxyphenyl)-1,3-dioxolane prepared according to Example 7 in xylene is treated with an aqueous sulfuric acid solution as described in Example 8. The reaction mixture is cooled and 83 g. of tetrabutylammonium chloride are added followed by a dropwise addition of a solution of 100 g. of sodium cyanide in 500 ml. of water at 10° to 20° C. Thereafter a solution of 48 ml. of concentrated sulfuric acid in 500 ml. of water is added dropwise and the reaction mixture is stirred until no traces of starting compound can be detected by thin layer chromatography. From the xylene phase 196 g. of 3-phenoxybenzaldehyde cyanehydrin are isolated. The purity of the product obtained is better than 95% (determined by NMR spectroscopy). Yield: 58% calculated for 2-(3-chlorophenyl)-1,3-dioxolane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[OH:5].[CH3:18][N:19]1[CH2:23]C[C@@H:21](O)[CH2:20]1>C1(C)C=CC=CC=1>[CH3:18][N:19]1[CH2:20][CH2:21][C@@H:1]([O:2][C:3](=[O:17])[C:4]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)[OH:5])[CH2:23]1
Reactant: CN1CC[C@@H](O)C1
Reactant: COC(=O)C(O)(c1ccco1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CN1CC[C@@H](OC(=O)C(O)(c2ccco2)C2CCCCC2)C1
Yield: 21.2 %

Procedure:
5.0 g (0.021 mol) of 2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid methyl ester were dissolved in 150 ml of dry toluene. To this solution 2.12 g (0.021 mol) of (3R)-1-methylpyrrolidin-3-ol (Intermediate I-19) and 500 mg (0.021 mol) of HNa were added and the mixture was refluxed using a Dean-Stark system for 24 hours. The reaction mixture was cooled, and extracted with HCl 2N. The aqueous layer was basified with K2CO3 and extracted with AcOEt (3×100 ml). The organic layers were combined, dried over Na2SO4 and evaporated to dryness to yield a residue which was purified by chromatography on silica gel eluting with chloroform plus isopropanol (0%→10%). Appropriate fractions were combined and evaporated to give 1.37 g (21%) of the title product as an oil.
Reaction SMILES: O.Cl.BrCCCC[CH:8]1[C:14]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][C:12](=[O:19])[NH:11][C:9]1=[O:10].[N:20]1([C:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:28][N:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(O)(C)C>[S:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:26]([N:20]2[CH2:25][CH2:24][N:23]([CH2:9][CH2:8][CH2:14][CH2:13][N:11]3[C:9](=[O:10])[CH2:8][C:14]([CH2:15][CH3:16])([CH2:17][CH3:18])[CH2:13][C:12]3=[O:19])[CH2:22][CH2:21]2)=[N:27]1
Reactant: CCC1(CC)CC(=O)NC(=O)C1CCCCBr
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CCC1(CC)CC(=O)N(CCCCN2CCN(c3nsc4ccccc34)CC2)C(=O)C1

Procedure:
Title product hydrochloride hydrate--Reaction of N-(4-bromobutyl-3,3-diethylglutarimide and 3-(1-piperazinyl)-1,2-benzisothiazole and conversion of the free base to the hydrochloride salt in isopropanol according to the procedure of Example 3 affords 1-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-4,4-diethyl-2,6-piperidinedione hydrochloride hydrate, m.p. 179°-183° C., from acetonitrile.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH2:19][CH:20]=[CH2:21])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1C=CN=C1.[CH3:27][C:28]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:31]([O:1][CH2:2][C@H:3]([CH2:19][CH:20]=[CH2:21])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([C:28]([CH3:30])([CH3:29])[CH3:27])([CH3:33])[CH3:32]
Reactant: C=CC[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-2-(hydroxymethyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (11.5 g, 38.4 mmol), imidazole (7.84 g, 115.2 mmol) and DMAP (234 mg, 1.92 mmol) in CH2Cl2 (200 mL) was added a solution of TBSCl (8.68 g, 57.6 mmol) in CH2Cl2 (100 mL) dropwise. The reaction mixture was stirred at rt for overnight. Water (100 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organic layers was washed with brine (70 mL), then dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by column chromatography to afford (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (9 g, 57%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:10][Si:11]([CH3:26])([CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]1[CH2:19][O:18]1>C(O)C>[CH3:26][Si:11]([CH3:10])([CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])[CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]([OH:18])[CH2:19][NH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Reactant: NCCN1CCOCC1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CNCCN1CCOCC1
Temperature: 70 °C

Procedure:
2-Morpholin-4-yl-ethylamine (4.74 g; 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities and excess 2-morpholin-4-yl-ethylamine.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[Cl:12][C:13]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[S:15][N:14]=1.S(=O)(=O)(O)[OH:23].C(=O)([O-])O.[Na+]>C(O)(=O)C>[Cl:12][C:13]1[C:17]2[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][C:16]=2[S:15][N:14]=1
Reactant: Clc1nsc2c1CCCC2
Reactant: O=S(=O)(O)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCCc2snc(Cl)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of sodium dichromate (4.4 g) in glacial acetic acid (30 mL) was added dropwise over 1 h to a solution of 3-chloro-4,5,6,7-tetrahydro-1,2-benzisothiazole 23a (2.7 g) and concentrated sulfuric acid (1.8 mL) in glacial acetic acid (80 mL). The reaction mixture was stirred at room temperature for an additional 2 h, and neutralized with a saturated solution of sodium hydrogencarbonate. Extraction with ether (3×150 mL), drying and evaporation gave an oil. Column chromatography on silica gel (eluent: toluene-ethyl acetate 1:1) eluted first 3-chloro-4,5,6,7-tetrahydro-1,2-benzisothiazol-7-one (680 mg). The later fractions contained the title compound (780 mg). Mp 84-85° C.
Reaction SMILES: [C:1]([CH2:6][C:7]([S:9][CH2:10][CH3:11])=[S:8])(OCC)=[O:2].C[O-].[Na+].Cl[CH2:16][C:17]#[N:18]>CO>[C:17]([C:16]1[S:8][C:7]([S:9][CH2:10][CH3:11])=[CH:6][C:1]=1[OH:2])#[N:18]
Reactant: CCOC(=O)CC(=S)SCC
Reactant: N#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSc1cc(O)c(C#N)s1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 52.4 %

Procedure:
192 g of ethyl α-carbethoxy-dithioacetate [Ber., Vol. 100 (1967), p. 1420] were added at 20° C. to a solution of 70 g of sodium methylate in one liter of methanol and after stirring for 5 minutes at 20° C., 76 g of chloroacetonitrile were added thereto. The mixture was stirred for 1 hour at 45° C. and 2 hours at 20° C. and after the addition of a solution of 70 g of sodium methylate in 500 ml of methanol, the mixture was stirred for 4 hours at 20° C. The mixture was evaporated to dryness under reduced pressure and the residue was dissolved in water. Toluene was added to the aqueous phase which was then acidified by addition of concentrated hydrochloric acid and the organic phase was rapidly separated by decanting. The organic phase was iced and vacuum filtered and the recovered crystals were dried to obtain 97 g of 2-cyano-3 -hydroxy-5-ethylthio-thiophene melting at 105° C. A microanalytically pure sample after crystallization from benzene melted at 105° C.
Reaction SMILES: [CH3:1][C@@H:2]([C:11]([O-])=[O:12])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C1COCC1>CO>[OH:12][CH2:11][C@H:2]([CH3:1])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: C[C@H](CC(=O)OC(C)(C)C)C(=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](CO)CC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
Borane-dimethyl sulphide complex (10M, 10.3 ml) was added during 15 minutes to a stirred mixture of 1-tert-butyl (3R)-3-methylsuccinate (12.9 g) and THF (200 ml) which had been cooled to -10° C. and placed under an atmosphere of argon. The mixture was stirred at -10° C. for 30 minutes. The mixture was allowed to warm to room temperature and was stirred for 1 hour. The mixture was recooled to 5° C. and methanol (50 ml) was added portionwise. The mixture was allowed to warm to room temperature and was stirred for 30 minutes. The mixture was evaporated and the residue was partitioned between dichloromethane (100 ml) and water (100 ml). The organic phase was filtered through phase separating paper and evaporated to give tert-butyl (3R)-4-hydroxy-3-methylbutyrate as an oil (11 g); NMR(CDCl3) δ 3.55(2H,m), 2.1-2.4(3H,m), 1.46(9H,s), 0.98(3H,d).
Reaction SMILES: C([N:8](C)[C@@H:9]1[CH2:18][CH2:17][C:16]2[C:15]([OH:19])=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10]1)C1C=CC=CC=1>C1COCC1.[Pd]>[NH2:8][C@@H:9]1[CH2:18][CH2:17][C:16]2[C:15]([OH:19])=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10]1
Reactant: CN(Cc1ccccc1)[C@@H]1CCc2c(O)cccc2C1
Agent: [Pd]
Solvent: C1CCOC1
Product: N[C@@H]1CCc2c(O)cccc2C1
Reaction time: 16 h
Yield: 97 %

Procedure:
A solution of (6R)-6-[Benzyl(methyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol (4.80 g, 18.946 mmol) in THF (150 mL) was added to Pd/C (1.90 g, 10% weight of Pd on activated carbon), and the reaction mixture was stirred under H2 (g) atmosphere for 16 h. It was filtered through Celite washing with AcOEt (1×200 mL) and the solvent was concentrated off to afford 3.0 g of the title product (Rf=0.1 (20% MeOH/CH2Cl2), off-white solid, 97% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](C)([CH2:12][CH:13]=[CH:14][CH2:15][C:16](C(OCC)=O)([CH3:22])[C:17]([O:19][CH2:20]C)=[O:18])[C:7](OCC)=O)=[O:5])C.[OH-].[K+].OS(O)(=O)=O>O>[CH3:22][CH:16]([CH2:15][CH:14]=[CH:13][CH2:12][CH:6]([CH3:7])[C:4]([O:3][CH3:1])=[O:5])[C:17]([O:19][CH3:20])=[O:18]
Reactant: CCOC(=O)C(C)(CC=CCC(C)(C(=O)OCC)C(=O)OCC)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)C(C)CC=CCC(C)C(=O)OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
The mixture of the tetraester compound (B) (9.4 g, 23.5 mmol) and KOH (26.4 g, 47.0 mmol) in H2O (200 mL) was heated to reflux for 2 d. The reaction mixture was cooled to room temperature, and acidified to pH 1 by adding concentrated H2SO4. The resulting mixture was heated to reflux for 3 d, and then cooled to room temperature. The mixture was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product (5.8 g) was dissolved in MeOH (80 mL), and treated with concentrated H2SO4 (3.5 mL). The mixture was then stirred at room temperature for 12 h. Most of the solvent was removed under reduced pressure. The concentrate was dissolved in EtOAc, washed with H2O, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 flash column chromatography (hexanes:EtOAc=4:1) to give the dimethyl ester (C) (4.75 g, 20.9 mmol) in 89% yield.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][F:21].BrC(F)C>O.CS(C)=O>[F:21][CH2:20][CH2:19][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][NH:10][N:9]=[CH:8]1
Reactant: FCCBr
Reactant: c1ccc(-c2cn[nH]c2)cc1
Agent: CC(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: FCCC1(c2ccccc2)C=NNC1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To 2.0 grams of 4-phenyl-1H-pyrazole, 10 mL of dimethyl sulfoxide and 1.5 g of potassium carbonate were added and the solution was stirred at room temperature. Then, 1.5 grams of 1-bromo-2-fluoroethane was added dropwise. After addition of the bromofluoroethane, the mixture was stirred at room temperature for 24 hours, then poured into 100 mL of water. The precipitated product was filtered off, washed with water, and air-dried. There was obtained 2.0 grams of 4-(2-fluoroethyl)-4-phenyl-1H-pyrazole. The compounds summarized in Table 1 were prepared using essentially the same procedure as shown above. Each of the compounds so formed is characterized by its NMR characteristics.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:3]=12.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1>CN1CCCC1=O.O>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:8](=[O:10])[C:7]3[C:2]([C:3]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=4[NH:5][CH:6]=3)=[N:30]2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CCCCCCCC2
Reactant: COc1ccc(NN)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(-n2nc3c4c([nH]cc-3c2=O)CCCCCCCC4)cc1

Procedure:
A mixture of 2.00 g of ethyl 4-chloro-5,6,7,8,9,10,11,12-octahydrocyclodeca[b]pyridine-3-carboxylate and 1.12 g of 4-methoxyphenylhydrazine are stirred for eight hours in 20 ml of N-methylpyrrolidinone at 105°. The solution is then diluted with 50 ml of water and twice extracted with ether. The combined ether fractions are extracted twice with 20 ml of 1 N NaOH and the combined alkaline fractions are back-extracted with ether. The alkaline aqueous solution is then treated with an aqueous solution of 2.14 g of ammonium chloride, stirred until a solid forms; the precipitate is filtered off and dried to give 2-(4-methoxyphenyl)-2,3,6,7,8,9,10,11,12,13-decahydrocyclodeca[b]pyrazolo[3,4-d]pyridin-3(5H)-one, m.p. 143°-150°, the compound of example 5/ g.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N-:22]=[C:23]=[O:24].[K+].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:23]([NH2:22])=[O:24])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: [N-]=C=O
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
(R)—N2-indan-1-yl-quinoline-2,6-diamine (100 mg, 0.36 mmol) and potassium isocyanate (32 mg, 0.40 mmol) were stirred in a 1:1 mixture of water and acetic acid (3 mL) at ambient temperature for 2 h. Then a satured solution of sodium bicarbonate was added, the aqueous phase was extracted with ethyl acetate, the organic phase washed with brine and dried over sodium sulfate. Over night the desired product precipitated and subsequently the crystals were collected and dried under vacuum. [2-((R)-Indan-1-ylamino)-quinolin-6-yl]-urea was obtained as a white solid (44 mg; 38%); MS: m/e=319.3 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([N:16]([C:30]([C@H:32]3[CH2:37][CH2:36][C@H:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[C@H:17]3[CH2:22][CH2:21][C@H:20]([O:23]C4CCCCO4)[CH2:19][CH2:18]3)[CH:9]=2)=[CH:3]1>C(O)(=O)C.C1COCC1.O>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([N:16]([C@H:17]3[CH2:18][CH2:19][C@H:20]([OH:23])[CH2:21][CH2:22]3)[C:30]([C@H:32]3[CH2:37][CH2:36][C@H:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[CH:9]=2)=[CH:3]1
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CC(O)CCC3)sc2C(=O)O)[C@H]2CC[C@H](OC3CCCCO3)CC2)CC1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CC(O)CCC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1

Procedure:
A solution of 5-(3-hydroxy-cyclohex-1-enyl)-3-{(trans-4-methyl-cyclohexane-carbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid (4 mg, 0.007 mmol) in acetic acid:THF:H2O (4:2:1) (0.7 mL) was stirred at 45° C. for 3.5 h. The mixture was evaporated to dryness and triturated with CHCl3 and hexane yielding 5-(3-hydroxy-cyclohex-1-enyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (1.6 mg, 47%).