Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[NH:7]1[CH:14]=[CH:13][C:11]([NH2:12])=[N:10][C:8]1=[S:9]>CCO.[OH-].[Na+]>[NH2:12][C:11]1[CH:13]=[CH:14][N:7]=[C:8]([S:9][CH2:2][CH2:3][CH2:4][C:5]#[N:6])[N:10]=1
Reactant: N#CCCCCl
Reactant: Nc1cc[nH]c(=S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#CCCCSc1nccc(N)n1
Reaction time: 18 h
Yield: 78.6 %

Procedure:
4-Chlorobutyronitrile (0.23 g.) in EtOH (2 ml.) was added to a solution of 2-thiocytosine (0.25 g.) in 0.5 N aqueous NaOH (5 ml.) and the mixture stirred for 18 hours. A further portion of 4-chlorobutyronitrile (0.23 g.) was added and the mixture stirred a further 24 hours. The solution was concentrated in vacuo to 2 ml. and cooled and the crystalline precipitate collected to give 4-[4-aminopyrimid-2-ylthio]butyronitrile (0.3 g.), m.p. 99°-100°.
Reaction SMILES: C(N[C:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH:11]([OH:13])C)=[O:5])C.Cl.[OH-].[Na+].C(=O)(O)[O-:18].[Na+]>>[OH:13][CH2:11][C:10]1[CH:9]=[CH:8][S:7][C:6]=1[C:4]([OH:5])=[O:18]
Reactant: O=C([O-])O
Reactant: CCNC(=O)c1sccc1C(C)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1sccc1CO
Temperature: 25 °C
Yield: 10 %

Procedure:
A solution of 3-(1-Hydroxy-ethyl)-thiophene-2-carboxylic acid ethylamide (298 mg, 1.5 mmol) in 15 ml of aqueous 6N HCl solution is heated at 100° C. for 1.5 h. The reaction mixture is cooled to room temperature and the pH is adjusted to ˜8.5 with 30% aqueous NaOH solution and saturated aqueous sodium bicarbonate solution. The resulting solution is extracted with Dichloromethane. The aqueous layer is collected and acidified with aqueous 6N HCl until the pH ˜1. The resulting solution is extracted with tBuOH-Ether. The combined organic extracts are dried and concentrated to give the title compound (25 mg, 10%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].CN(C=O)C>CC#N.O>[O:22]([CH2:21][CH2:20][O:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCOc1cc([N+](=O)[O-])ccc1C=O
Temperature: 25 °C
Yield: 63.8 %

Procedure:
To a stirred suspension of 2-hydroxy-4-nitrobenzaldehyde (0.500 g, 2.992 mmol) and anhydrous potassium carbonate (0.621 g, 4.488 mmol) in dry MeCN (20 ml) at room temperature was added 2-bromo-1-tert-butyldimethylsiloxyethane (83%, 1.293 g, 4.488 mmol), and the reaction mixture was heated under reflux for 40 min which resulted in the appearance of a thick, dark red precipitate. The reaction mixture was left to cool to room temperature and dry DMF (10 ml) was added. The reaction mixture was heated at 100° C. for 4 h and on cooling was added to water (250 ml) and extracted with EtOAc (3×80 ml). The combined organic extracts were washed with water (3×100 ml), brine (100 ml) and dried (Na2SO4) and the solvent was removed under reduced pressure to give a light brown solid which was purified by flash chromatography (2:1 Hexane/Et2O). Recrystallisation from hexane gave the title compound (0.621 g, 64%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]([CH2:7][CH3:8])([CH2:5][OH:6])[CH2:3][OH:4].[CH3:9][C:10]1[C:11]([O:13][C:14](=O)[C:15]=1[CH3:16])=[O:12]>O>[OH:4][CH2:3][C:2]([N:1]1[C:11](=[O:12])[C:10]([CH3:9])=[C:15]([CH3:16])[C:14]1=[O:13])([CH2:5][OH:6])[CH2:7][CH3:8]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: CCC(N)(CO)CO
Solvent: O
Product: CCC(CO)(CO)N1C(=O)C(C)=C(C)C1=O
Temperature: 70 °C

Procedure:
2-amino-2-ethyl-1,3-propanediol (I-a) (297.9 grams, 2.50 moles) is charged to a reactor and heated to 70° C. under nitrogen. Then, 315.0 grams (2.50 moles) of 2,3-dimethylmaleic anhydride (DMMA) (II-a) is added portionwise with stirring to the reactor. The material is heated to a sufficient temperature (110°-130° C.) to drive off the water of condensation which is collected in a Dean-Stark trap. Once the theoretical amount of water is collected the product is isolated by vacuum distillation (167°-176° C. at 3 mm Hg). This product is used as an intermediate for the formation of polyurethanes and polyesters as will be described in succeeding examples.
Reaction SMILES: C([Li])CCC.[O:6]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[N:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[S:19][CH:20]=3)=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7]1.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[O:29].C1(C)C=CC=CC=1>O1CCCC1.O>[O:6]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[N:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[S:19][C:20]=3[CH:28]([OH:29])[C:27]([O:31][CH2:32][CH3:33])=[O:30])=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C=O
Reactant: c1ccc(-c2nc(-c3ccc4c(c3)CCCO4)cs2)cc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1sc(-c2ccccc2)nc1-c1ccc2c(c1)CCCO2
Reaction time: 0.33 h
Yield: 29 %

Procedure:
Butyl lithium (1.6M, 930 μL, 1.5 mmol) was added at −78° C. to a solution of 4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2-phenyl-1,3-thiazole (9c) (330 mg, 1.12 mmol) in anhydrous tetrahydrofuran (10 mL). After 20 minutes, ethyl glyoxylate 50% in toluene (400 μL, 2 mmol) was added at −78° C. and the mixture was stirred for 2 hours, hydrolyzed with water and concentrated in vacuo. The residue was diluted with ethyl acetate (20 mL) and the organic layer was washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to afford the desired alcohol (9d) as a white solid (130 mg, 0.33 mmol, 29%).
Reaction SMILES: F[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N:11]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=C(CF)c1ccccc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(CN1CCOCC1)c1ccccc1
Temperature: 110 °C

Procedure:
A mixture of 2-fluoroacetophenone (19.9 g), morpholine (21 cc) and potassium carbonate (27.6 g) in dimethyl sulphoxide (32 cc) is heated at 110° C. for 30 hours. The reaction mixture is diluted with water (100 cc) and extracted with ethyl acetate (4×100 cc); the organic solution is washed with distilled water (100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04-0.063 mm, diameter 9 cm, height 40 cm), eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 250 cc fractions. Fraction 24 to 44 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 2-(4-Morpholinyl)acetophenone (4.72 g) is obtained which is used as such for the subsequent syntheses.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34]CC#N)=[CH:30][C:29]=2[CH2:38][CH:39]([CH3:41])[CH3:40])[CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20]CC#N)=[C:16]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.Cl.C(Cl)Cl.CO.CC[O:55][C:56]([CH3:58])=[O:57].[CH3:59][C:60]([OH:62])=[O:61]>CO>[CH2:1]([C:8]1[CH:9]=[C:10]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:58][C:56]([OH:55])=[O:57])=[CH:30][C:29]=2[CH2:38][CH:39]([CH3:41])[CH3:40])[CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:59][C:60]([OH:62])=[O:61])=[C:16]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CC(C)Cc1cc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2Cc2ccccc2)ccc1OCC#N
Reactant: CCOC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Cc1cc(-c2ccc(-c3ccc(CCC(=O)O)cc3CC(C)C)cc2Cc2ccccc2)ccc1OCC(=O)O
Temperature: 0 °C
Yield: 76.67 %

Procedure:
To a solution of 86.4 mg (159.78 μmol) 3-(3′-Benzyl-4″-(cyanomethoxy)-2,3″-diisobutyl-1,1′:4′,1″-terphenyl-4-yl)propanenitrile (57) in 6 ml methanol and 6 ml THF 3 ml (24.90 mmol, 155 eq.) 25% aq. NaOH-solution was added. The resulting mixture was refluxed for 24 h and then cooled to 0° C. After acidifying to pH 2 by adding 1 N aq. HCl-solution brine was added and the mixture was extracted with THF. The comb. org. fractions were washed twice with brine, dried over MgSO4 and evaporated. Column chromatography (first CH2Cl2/MeOH (4+1), then EtOAc/HOAc (95+5)) yielded 70.9 mg (122.5 μmol, 76.67%) 3-(3′-Benzyl-4″-(carboxymethoxy)-2,3″-diisobutyl-1,1′:4′,1″-terphenyl-4-yl)propanoic acid (58) as a white solid. Rf (EtOAc/HOAc (95+5))=0.76. 1H-NMR (500 MHz, d4-MeOH+1% d4-HOAc): δ=0.83 (d, 6H, J=6.62 Hz, 2*CH3), 1.02 (d, 6H, J=6.62 Hz, 2*CH3), 1.76 (m, 1H, CH), 2.07 (m, 1H, CH), 2.60 (d, 2H, J=7.25 Hz, CH2), 2.68 (d, 2H, J=7.25 Hz, CH2), 2.77 (t, 2H, J=7.57 Hz, CH2CH2CO2H), 3.06 (t, 2H, J=7.57 Hz, CH2CH2CO2H), 4.14 (s, 2H, CH2Ph), 4.79 (s, 2H, OCH2CO2H), 6.99 (d, 1H, J=8.36 Hz), 7.10 (m, 2H), 7.21-7.33 (m, 10H), 7.39 (d, 1H, J=7.72 Hz). 13C-NMR (125 MHz, d4-MeOH+1% d4-HOAc): δ =20.89, 22.85, 23.04, 29.82, 30.66, 30.92, 31.78, 35.38, 36, 89, 40.01, 40.52, 44.83, 112.38, 126.21, 126.74, 126.81, 128.36, 128.88, 129.30, 129.76, 131.08, 131.17, 131.31, 132.74, 133.18, 135.33, 139.16, 140.26, 140.92, 141.37, 141.81, 142.40, 143.14, 156.93, 160.58, 171.38, 178.30. MS (ESI): 580 (10), 579 (42), 578 (100), 326 (10), 312 (19), 289 (26), 260 (15), 186 (12), 173 (10). HR-MS (FAB): Calcd. for C38H42O5: 578.303225. Found: 578.303100.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Na+].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.S(=O)(=O)(O)O.[OH-].[Na+]>OCC(CO)O>[F:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[N:4]=[CH:15][CH:14]=[CH:19]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: Nc1ccc(F)cc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: OCC(O)CO
Product: Fc1cc(Br)c2ncccc2c1
Temperature: 150 °C
Yield: 416.7 %

Procedure:
To a mixture of 7.0 g of 2-bromo-4-fluoro-aniline, 7.0 g of glycerol and 13.0 g of m-nitrobenzene sulfonic acid sodium salt, 20 ml of 70% sulfuric acid was added drop by drop. The reaction temperature was raised to 150° C. for 4 hr. The mixture was cooled, poured on water neutralized with NaOH and the formed precipitate was filtered to yield 34.7 g of 6-fluoro-8-bromo-quinoline. MS (ES) m/z (relative intensity): 227 (M++H, 100).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]([O:11][C:12]([NH:14][C@H:15]([C:20](N(C)OC)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])([CH3:10])[CH3:9]>CCOCC>[CH:20]([C@@H:15]([NH:14][C:12](=[O:13])[O:11][C:8]([CH3:7])([CH3:10])[CH3:9])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:21]
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of LiAlH4 (0.356 g, 9.38 mmol) in Et2O (20 mL) at 0° C. was added dropwise a solution of N2-{[(1,1-dimethylethyl)oxy]carbonyl}-N1-methyl-N1-(methyloxy)-L-leucinamide (2.34 g, 8.53 mmol) in Et2O (15 mL). The reaction mixture was stirred for 30 min at 0° C. and quenched with EtOAc (6 mL) followed by 5% aq. potassium bisulfate (6 mL). The reaction mixture was washed with 1 M aq. HCl (2×10 mL), saturated aq. NaHCO3 (2×10 mL), and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a clear, colorless oil.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1>CO>[CH3:1][O:2][C:5]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: O=C(O)c1cccnc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1ncccc1C(=O)O
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A stainless steel stirred autoclave was charged sequentially with methanol (2.8 l.), sodium methoxide (259 g.) (in portions, keeping the temperature less than 35° C.), and 2-chloro-3-pyridinecarboxylic acid (190 g.). The autoclave was sealed and the reaction mixture heated at 110° C. (50 psig) for 48 hours. The reaction mixture was cooled to 25° C. and discharged from the autoclave. Solids were recovered by filtration. Concentration of the filtrate gave a second crop. These process steps were repeated until virtually all of the methanol had been removed. The several crops of solids were combined, taken up in 2.5 liters of water and acidified with conc. hydrochloric acid to pH 2.7 keeping the temperature below 20° C. The precipitated product was granulated for 30 minutes at 15° C. and recovered by filtration (141 g.). Purified title product was obtained by recrystallization from ethyl acetate-hexane (120.5 g., m.p. 148°-150° C.).
Reaction SMILES: [NH2:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.C1C(=NNC2C=CC(/C=C/C3C=CC(NN=C4C=CC(=O)C=C4)=CC=3S([O-])(=O)=O)=C(S([O-])(=O)=O)C=2)C=CC(=O)C=1.[Na+].[Na+].[CH3:58][N:59]([CH3:62])[CH:60]=O>>[CH3:58][N:59]([CH:62]=[N:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1)[CH3:60]
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N)S1
Reactant: CN(C)C=O
Agent: O=C1C=CC(=NNc2ccc(/C=C/c3ccc(NN=C4C=CC(=O)C=C4)cc3S(=O)(=O)[O-])c(S(=O)(=O)[O-])c2)C=C1
Agent: [Na+]
Product: CN(C)C=NN1NC=C(c2ncc([N+](=O)[O-])n2C)S1

Procedure:
Phosgene gas is bubbled into 100 ml. of N,N-dimethylformamide at 5°-10° C. until 2.0 g. (0.02 mole) is absorbed and a crystalline suspension is formed. This suspension is added in portions to a stirred mixture of 4.5 g. (0.02 mole) of 2-(2-amino-5-thiadiazolyl)-1-methyl-5-nitroimidazole and 100 ml. of N,N-dimethylformamide at 25° C. After 30 minutes the reaction mixture is diluted with 200 ml. of diethyl ether, and the pale yellow solid is collected, washed with ether, and dried. Treatment of this material with 150 ml. of water and drying affords 5.0 g. (89%) of brilliant yellow solid melting at 230°-232° C.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=[C:18]2[N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO>ClCCl.CN(C=O)C>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21]([C:25]([O:27][CH3:1])=[O:26])=[CH:20][CH:19]=[C:18]2[N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(N(Cc2ccccc2)Cc2ccccc2)c2cc(OCc3ccccc3)ccc12
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(Cc2ccccc2)Cc2ccccc2)c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (2.60 g, 1.79 mL, 20.5 mmol) was added dropwise to a solution of 6-(benzyloxy)-4-(dibenzylamino)-1-naphthoic acid (3.236 g, 6.834 mmol) in dichloromethane (70 mL) and DMF (1 drop). The mixture stirred at RT for 1 h and was concentrated to afford a yellow solid. CH2Cl2 (60 mL) was added followed by the dropwise addition of MeOH(10 mL), and the mixture stirred at RT for 45 min. The mixture was concentrated to afford methyl 6-(benzyloxy)-4-(dibenzylamino)-1-naphthoate as a light brown solid. MS (ESI, pos. ion) m/z: 488.2 (M+H). Mass Calc'd for C33H29NO3: 487.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8]([C:10]2([OH:18])[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11]2)=O)[CH:7]=1.[CH3:20][C:21]([S:24]([NH2:26])=[O:25])([CH3:23])[CH3:22].O>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][C:10]3([CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11]3)[C:8](=[N:26][S:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25])[C:6]=2[CH:7]=1
Reactant: CC(C)(C)S(N)=O
Reactant: COC1CCC(O)(C(=O)c2cc(Br)ccc2F)CC1
Agent: [Ti+4]
Agent: CC[O-]
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC1CCC2(CC1)Oc1ccc(Br)cc1C2=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 21 h
Yield: 64.6 %

Procedure:
To a mixture of 5-bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-one (Intermediate 12, 2.8 g, 9.00 mmol) and 2-methylpropane-2-sulfinamide (2.024 g, 16.20 mmol) in methyl THF (15 mL) was added titanium ethoxide (3.71 mL, 18.00 mmol) and the reaction was heated to reflux. After 21 h the reaction was allowed to cool to r.t. whereafter it was diluted with EtOAc (150 mL). Water (12 mL) was added dropwise over 10 min under vigorous stirring and then the mixture was left standing without stirring for 1.5 h. The solids were filtered off and the organics were evaporated. The crude product was purified by flash chromatography using a gradient of 0%-50% EtOAc in heptane, yielding 2.41 g of the title compound (65% yield): 1H NMR (500 MHz, CDCl3) δ ppm 1.33 (s, 9 H), 1.81 (m, 6 H), 2.12 (d, 2 H), 3.33 (m, 1 H), 3.42 (s, 3 H), 6.94 (d, 1 H), 7.59 (dd, 1 H), 8.53 (m, 1 H); MS (ES+) m/z 415 [M+H]+.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14]>>[C:15]1([CH:13]([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCc1ccccc1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Product: CC(ON1C(C)(C)CC(O)CC1(C)C)c1ccccc1
Temperature: 133 °C
Yield: 45.3 %

Procedure:
A mixture of 17.23 g (0.10 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 106.17 g (1.0 mol) of ethylbenzene under a nitrogen atmosphere is heated at 133° C. for 26 hours. The volatiles are removed in vacuo and the residue is triturated with diethyl ether. The precipitate of 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine is collected by filtration to give 12.57 g of an off-white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26](OC)=[O:27])[CH:21]=[CH:22][C:23]=1[F:24].[H-].[Na+].CCOC(C)=O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[CH2:15][C:26](=[O:27])[CH2:25][C:20]2[CH:21]=[CH:22][C:23]([F:24])=[C:18]([F:17])[CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(F)c(F)c1
Reactant: CC(=O)C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CC(=O)C1CCN(Cc2ccccc2)CC1)Cc1ccc(F)c(F)c1
Yield: 67 %

Procedure:
The title compound was prepared in 67% yield from 2.18 g 1-benzyl-4-acetylpiperidine from the last step, 5.58 g methyl 3,4-difluorophenylacetate from Fisher esterification, and 0.8 g 60% NaH in 15 mL anhydrous THF using a procedure similar to that described in Example 1, Step A Method B. RF: 0.28 (15% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3): δ7.32˜7.35 (m, 4H), 7.26˜7.30 (m, 1H), 7.06˜7.15 (m, 3H), 6.95˜6.98 (m, 1H), 5.47 (s, 1H), 3.57 (s, 2H), 3.54 (br s, 2H), 2.96 (br d, 11.5 Hz, 2H), 2.17˜2.21 (m, 1H), 2.02˜2.10 (m, 2H), 1.70˜1.83 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].C(N(CC)CC)C.[C:19]([NH:21][C:22](Cl)=[N:23][CH3:24])#[N:20]>CO>[C:19]([N:21]=[C:22]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])[NH:23][CH3:24])#[N:20]
Reactant: CN=C(Cl)NC#N
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CCN(CC)CC
Solvent: CO
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Reaction time: 7.5 h
Yield: 22.4 %

Procedure:
To a stirred solution of 2-(5-methylimidazol-4-ylmethylthio)ethylamine (1.0 g) and triethylamine (0.71 g) in methanol (20 ml) was added N-cyano-N'-methylchloroformamidine (0.82 g) and stirred for 7.5 hrs. at 50°-55° C. After evaporation, the residue was subjected to chromatography on SiO2 [eluant: CHCl3 -MeOH (10:1)]. The resulting crude product was added to water (3 ml) and extracted repeatedly with ethyl acetate. Ethyl acetate extracts were dried over anhydrous MgSO4 and concentrated under a reduced pressure to small volume. The resulting crystals were collected by filtration and washed with ethyl acetate to give N"-cyano-N-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine (0.33 g). Yield 22.4%, m.p. 134°-137° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(c1cccc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A suspension of 1-(3-(trifluoromethyl)phenyl)ethanone (0.100 g, 0.532 mmol), tert-butyl piperazine-1-carboxylate (0.148 g, 0.797 mmol), acetic acid (0.046 mL, 0.797 mmol) and sodium cyanoborohydride (0.050 g, 0.797 mmol) in ethanol (0.5 mL) was heated under nitrogen at 75° C. After stirring overnight the reaction was concentrated, saturated sodium bicarbonate (0.7 mL) was added, and the product was extracted into ethyl acetate (2×0.7 mL). The combined organic layers were concentrated, dissolved in a minimal amount of dichloromethane, loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 2% to 20% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)(=O)[CH3:2].O=[C:14]([C:20]([O:22]CC)=[O:21])[C:15](OCC)=[O:16].O.[NH2:26][NH2:27].[OH-].[Na+].Cl>C(O)(C)C>[O:11]1[C:7]2[CH:6]=[CH:5][C:4]([C:1]3[CH:2]=[C:14]([C:20]([OH:22])=[O:21])[C:15](=[O:16])[NH:26][N:27]=3)=[CH:12][C:8]=2[CH:9]=[CH:10]1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CC(=O)c1ccc2occc2c1
Reactant: NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1cc(-c2ccc3occc3c2)n[nH]c1=O
Temperature: 120 °C
Reaction time: 34 h

Procedure:
5-Acetyl-1-benzofuran (536 mg, 3.35 mmol) and diethyl ketomalonate (642 mg, 3.69 mmol) were mixed together, and the mixture was stirred for 34 hours at 120° C. Hydrazine monohydrate (247 mg, 4.93 mmol) was added to a solution of the reaction mixture in isopropanol (8.5 mL), and the resultant mixture was heated with stirring for six hours at 100° C. A 2-mol/L aqueous sodium hydroxide solution (5.2 mL) was added thereto, and the mixture was further stirred for four hours at 100° C. The mixture was cooled with ice, and concentrated hydrochloric acid was added thereto, to thereby acidify the heated system. The formed precipitates were collected through filtration, thoroughly washed with water, and dried, to thereby yield 397 mg of the title compound as a yellow powder (46.2%).