Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH3:12])[NH:7][C:6](=S)[C:5]([CH2:10][CH3:11])([CH3:9])[NH:4]1)[CH3:2].[OH-].[Na+].OO.[OH:17]S([O-])=O.[Na+]>O>[CH2:1]([C:3]1([CH3:12])[NH:7][C:6](=[O:17])[C:5]([CH2:10][CH3:11])([CH3:9])[NH:4]1)[CH3:2]
Reactant: O=S([O-])O
Reactant: CCC1(C)NC(=S)C(C)(CC)N1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1(C)NC(=O)C(C)(CC)N1
Temperature: 1 °C
Reaction time: 2 h

Procedure:
A 5 liter 4-necked round-bottomed flask equipped with a mechanical stirrer and thermocouple thermometer was charged with 250 ml water and 43.3 g (0.232 mol) of 2,5-diethyl-2,5-dimethylimidazolidin-4-thione. In order to make the thione dissolve, 1.8 g NaOH was added. The solution was cooled to 0-2° C. with a dry ice-acetone bath. The flask was fitted with two additional funels. Simultaneously, a solution of 16.7 g NaOH in 100 ml water (total of 18.5 g or 0.464 mol of NaOH used) was added through one of the funnels and 105 ml (0.928 mol) of 30% H2O2 was added through the other funnel. The reaction mixture was stirred rapidly and required extensive cooling during the addition. The 5 liter flask was used to provide a large surface area for efficient cooling of the exothermic reaction. The heat of reaction was 269.2 Kcal/mol; 124. The addition was completed in 2 hours; the mixture was stirred an additional half hour. At the end of this time, TLC indicated that no thione remained. Then, 27.9 g of NaHSO3, (0.172 mol) was added to quench excess peroxide; this reaction is also somewhat exothermic (temperature increases from 26 to 43° C.). The reaction mixture was transferred to a 2 liter round-bottomed flask and the solvent removed with a rotary evaporator (aspirator pressure) to give a white residue. The residue was extracted with 850 ml of boiling ethanol. Then, 50 ml of toluene was added to the solution and 130 ml of water/ethanol/toluene azeotrope distilled to remove any remaining water. The solution was cooled and filtered to remove a small amount (˜1 g) of Na2SO4 and then the ethanol was removed on the rotary evaporator to give a syrup that crystallized on cooling to room temperature. The yield was 37.5 g (95%) mp 58-64° C. IR (nujol) 1705, 1659 cm-1. 1H NMR (CDCl3+D2O) ppm (combination of equal amounts of 2 sets of cis-trans pairs) 0.95-0.98 (m, 12H, CH3 on 4 ethyls), 1.27, 1.31, 1.34, 1.38 (4 s, total 12H, 4 CH3), 1.50-1.70 (m, 8H, CH2 on 4 ethyls). The singlets at 1.34 and 1.38 collapse to a singlet in D2O but now integrate 6H.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25].[OH-].[Na+].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([NH:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCC(=O)O
Reactant: COc1ccc(C(=O)Cl)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)NCCCC(=O)O)cc1OCc1ccccc1
Reaction time: 2 h

Procedure:
14.0 g of 3-benzyloxy-4-methoxybenzoyl chloride are added in one portion at 26° C. to 15.6 g of 4-aminobutyric acid, 12.1 g of sodium hydroxide and 160 ml of ion-free water and subsequently 30 ml of tetrahydrofuran are added dropwise within 10 minutes. After 2 hours, the mixture is acidified with concentrated hydrochloric acid at a temperature below 10° C. The precipitate is separated and stirred with ethyl acetate. The mixture is filtered and the filter cake is washed with ethyl acetate. There is obtained 4-[(3-benzyloxy-4-methoxybenzoyl)amino]butyric acid which, after recrystallisation from ethyl acetate, melts at 156°-158° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O.C(OCC)C>[N:30]([CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[CH:17]=[CH:18][CH:19]=2)[O:14]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3cccc(-c4ccccc4Cl)c3O2)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC1CCc2cccc(-c3ccccc3Cl)c2O1
Temperature: 70 °C
Yield: 82 %

Procedure:
A solution of [8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate, prepared in Example 1, step 7 (0.25 g, 0.58 mmol) and sodium azide (0.15 g, 2.3 mmol) in anhydrous dimethyl sulfoxide (9.5 mL) was heated to 70° C. under nitrogen for 16 hours. The cooled reaction mixture was then diluted with diethyl ether (50 mL), washed with water (5×25 mL) and saturated brine (25 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 0.14 g (82%) of 2-azidomethyl-8-(2-chloro-phenyl)-chroman as a colorless oil that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:18]([OH:20])=[O:19])=[N:14][CH:15]=[CH:16][CH:17]=2)[N:4]=1.[CH3:21][C:22](=[N:24]O)[CH3:23].N1C=CC=CC=1.ClOP(=O)(OCl)N(C)C>CN(C)C=O.O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:13]([C:18]([O:20][N:24]=[C:22]([CH3:23])[CH3:21])=[O:19])=[N:14][CH:15]=[CH:16][CH:17]=2)[N:6]=1
Reactant: CC(C)=NO
Reactant: COc1cc(OC)nc(Oc2cccnc2C(=O)O)n1
Agent: CN(C)P(=O)(OCl)OCl
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2cccnc2C(=O)ON=C(C)C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.0 g of 3-(4,6-dimethoxypyrimidin-2-yl)oxypicolinic acid, 3.96 g of acetoxime and 1.71 g of pyridine were dissolved in 20 ml of N,N-dimethylformamide, and then, 3.51 g of dichloro-N,N-dimethylphosphoric acid amide was dropwise added thereto at 0° C. After the dropwise addition, the mixture was stirred at room temperature for 3 hours to complete the reaction. The reaction solution was poured into water. Precipitated crystals were separated by filtration, then washed with water and dried to obtain 2.20 g of the above identified compound as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[C:19](Cl)=[N:20][C:21]([CH3:24])=[N:22][CH:23]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=1[NH2:29]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[C:19]([NH:29][C:28]3[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:27]=3[CH3:26])=[N:20][C:21]([CH3:24])=[N:22][CH:23]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: Cc1ncc(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Nc2nc(C)ncc2S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(C)c1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a solution of 5-(4-benzyloxy-benzenesulfonyl)-4-chloro-2-methyl-pyrimidine (38 mg, 0.106 mmol) and 2-methyl-4-methoxy aniline (31 mg, 0.23 mmol) in toluene (1 mL) was added p-toluenesulfonic acid monohydrate (1.6 mg, 0.0081 mmol). The resulting mixture was heated at reflux under N2 for 1 h and then cooled to room temperature. The mixture was quenched by addition of water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified using preparative TLC on silica (1:1 hexanes/EtOAc) to provide the desired product (46 mg, 95%) as a pale yellow solid: mp 110–114° C.; 1H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 8.61 (s, 1H), 7.86 (d, J=9.1 Hz, 2H), 7.49 (d, J=8.6 Hz, 1H), 7.38–7.33 (m, 4H), 7.07–7.04 (m, 2H), 6.79–6.75 (m, 2H), 5.12 (s, 2H), 3.81 (s, 3H), 2.46 (s, 3H), 2.17 (s, 3H); ESI MS m/z 476 [(M+H)+, calcd for C26H26N3O4S, 476.2].
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][S:7](Cl)(=[O:9])=[O:8].O>C(Cl)Cl>[F:1][CH2:2][CH2:3][CH2:4][O:5][S:7]([CH3:6])(=[O:9])=[O:8]
Reactant: OCCCF
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCCF
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.6 %

Procedure:
A solution of 3-fluoro-propan-1-ol (31.2 g, 400 mmol) in 300 mL of CH2Cl2 was treated with methanesulfonyl chloride (55 g, 38 mL, 480 mmol, 1.2 equiv) at 0° C. The resulting reaction mixture was gradually warmed to room temperature and stirred for 1-2 hours. When 1H NMR showed the reaction was complete, the reaction mixture was treated with H2O (100 mL), and the two layers were separated. The aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic layers were washed with H2O (3×100 mL) and dried over MgSO4. The solvent was removed in vacuo to afford the desired methanesulfonic acid 3-fluoro-propyl ester (57.2 g, 91% yield) as a yellow oil.
Reaction SMILES: [CH:1]([CH:3]1[O:7][CH:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)=[O:2].C(=O)([O-])[O-:18].[K+].[K+].OO>>[CH:1]([C:3]1[O:7][C:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]([NH2:14])=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(OC2CCC(C=O)O2)cc1
Agent: OO
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc(C=O)o2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
Combine 4-(5-Formyl-tetrahydro-furan-2-yloxy)-benzonitrile (1.0 g, 4.69 mmol), dimethylsufoxide (100 mL), potassium carbonate (0.32 g, 2.35 mmol), and 1 mL of 30% hydrogen peroxide solution. Stir 18 hours at ambient temperature. Dilute with 300 mL of ice/water, extract with ethyl acetate (3×150 mL). Wash the organic phase with 100 mL of water, and 100 mL of brine. Dry the organic phase over sodium sulfate, filter, and concentrate under vacuum. Purify via ISCO™ 100 c system using a gradient of 75:25 hexane/ethyl acetate to 25:75 hexane/ethyl acetate as eluting solvent to give 0.18 g (18%) of the title compound: 1H NMR (DMSO-d6): 9.38 (s, 1H), 7.6 (d, 1H, J=3.8 Hz), 7.30-7.40 (m, 3H), 6.0 (d, 2H, J=3.7 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[C:5]([CH3:9])[N:4]=1.[CH3:10][I:11]>CCOCC>[I-:11].[CH3:10][N+:7]1[CH:6]=[C:5]([CH3:9])[N:4]=[C:3]([CH2:2][OH:1])[CH:8]=1
Reactant: CI
Reactant: Cc1cncc(CO)n1
Solvent: CCOCC
Product: Cc1c[n+](C)cc(CO)n1
Product: [I-]

Procedure:
2.0 g of 2-hydroxymethyl-6-methylpyrazine (401), prepared by the known method of Klein, et al., J. Org. Chem., 26, 126(1961), was dissolved in 5 ml of ether and 5 ml of methyl iodide added. The flask was stoppered and stored in the dark for 2 weeks. The ether was decanted and the resultant semi-solid material recrystallized from ethanol/ethyl acetate giving 1.8 g of a yellow solid, product (400) m.p. 153°-4°. UV H2O max: 226 (4.13), 287 (3.89). 13C NMR: 163.33, S, 161.73, S (C3, C5); 136.85, D, 133.10, D (C2,C6); 62.79, T (CH2OH); 49.74, Q (NCH3); 22.19, Q (ArCH3). 1HNMR: 8.80, S, 8.76, S (H2, H6): 4.97, S (CH2OH); 4.44, S (NCH3); 2.79, S (ArCH3).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH2:11][CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=[O:22])C=1C#N)#N>O1CCOCC1>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12]([CH2:11][CH2:10][CH2:9][C:8]2=[O:22])=[CH:13][C:14]=1[O:15][CH3:16])(=[O:3])[CH3:2].[C:1]([O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: COc1cc2c(cc1OC(C)=O)CCCC2
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC(C)=O)C(=O)CCC2
Product: COc1cc2ccccc2cc1OC(C)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 62 %
Yield: 23 %

Procedure:
A 220 mg (1 mmol) quantity of 6-acetoxy-7-methoxytetralin was dissolved in 1 mL, of dioxane containing 5% water. DDQ (454 mg, 2 mmol) was dissolved in 4 mL of dioxane containing less than 0.01% water. The solution of DDQ was added dropwise over a period of 5 minutes to the stirred solution of 6-acetoxy-7-methoxytetralin at 25° C., under nitrogen. The reaction solution was stirred at 25° C. under nitrogen for 20 hours, after which time the reaction mixture was filtered through a sintered glass funnel and the precipitate (DDHQ) washed with 2 mL dioxane. The residue on evaporation of the filtrate was portioned between 10 mL 5% NaHCO3 (aq) and 80 mL of EtOAc. The EtOAc layer was separated and washed with 5% NaHCO3 (aq)(1×5 mL), water (1×5 mL), and brine (2×5 ml). The organic layer was dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography (hexane: EtOAc, 2.5:1.5) to give two products, 146 mg (62% yield) of 7-acetoxy-6-methoxytetralin-1-one (87) and 50 mg (23% yield) of 2-acetoxy-3-methoxy naphthalene (88). 7-acetoxy-6-methoxytetralin-1-one: mp 118.5-119.5° C.; IR 1769 (C═O str.), 1674, 1613, 1506, 1272, 1210, 1186, 1031 cm−1; 1H NMR (CDCl3) δ7.69 (1H, s, H-8), 6.74 (1H, s, H-5), 3.86 (3H, s, —OCH3), 2.91 (2H, t, J=6.08 Hz, H-2), 2.57 (2H, t, J=6.53 Hz, H-4), 2.28 (3H, s, OCOCH3), 2.11 (2H, qn, J=6.35 Hz, H-3); 13C NMR (CDCl3) δ196.2 (C-1), 168.8, 155.2, 144.5, 138.7, 126.1, 121.5, 111.3, 56.0, 38.4, 29.7, 23.2, 20.4; LRMS EI m/z 234 [M+], 164 [base peak]. 2-acetoxy-3-methoxy naphthalene: mp 114-116° C.; IR 1764 (C═O str.), 1633, 1508, 1483, 1371, 1261, 1201, 1108, 1015 cm−1; 1H NMR (CDCl3) δ7.75 (1H, dd, J=8.13, 1 Hz, H-5 or H-8), 7.73 (1H, dd, J=7.43, 1.1 Hz, H-5 or H-8), 7.50 (1H, s, H-1), 7.44 1H, ddd, J=8.23, 7.55, 1.34 Hz, H-6 or H-7), 7.36 1H, ddd, J=8.14, 7.51, 1.24 Hz, H-6 or H.7), 7.22 (1H, s, H-4), 3.95 (3H, s, —OCH3), 2.38 (3H, s, —OCOCH3); 13C NMR(CDCl3)d 169.2, 150.2, 140.3, 132.5, 128.3, 127.2, 126.5. 124.2, 120.3, 107.3, 55.8, 20.6; LRMS EI m/z 216 [M+], 174 [base peak].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH2:13]([CH:18]([CH2:21]O)[CH2:19][OH:20])[CH2:14][CH2:15][CH2:16][CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([C@@H:18]1[CH2:19][O:20][C@@H:7]([C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=2)[O:8][CH2:21]1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC[C@H]1CO[C@H](c2ccc(C(F)(F)F)cc2)OC1

Procedure:
An equimolar mixture of p-trifluoromethylbenzaldehyde and 2-pentylpropane-1,3-diol in toluene is boiled on a water separator with catalysis by p-toluenesulfonic acid. When the water separation is complete and after conventional work-up, p-(trans-5-n-pentyl-1,3-dioxan-2-yl)-trifluorotoluene, m.p. 44.3°, Δε=+12.9, is obtained.
Reaction SMILES: C1CCCCC1.[CH2:7]([OH:10])[CH2:8][OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH:33]([N+:47]([O-:49])=[O:48])[CH2:34][CH2:35][C:36](=O)[CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>C1C=CC=CC=1>[CH2:7]1[O:10][C:34]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)([CH:33]([N+:47]([O-:49])=[O:48])[CH2:32][C:26]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=2)[O:9][CH2:8]1
Reactant: OCCO
Reactant: COc1ccc(CC(CCC(=O)CCc2ccc(C)cc2)[N+](=O)[O-])cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: C1CCCCC1
Product: COc1ccc(CC([N+](=O)[O-])C2(CCCCc3ccc(C)cc3)OCCO2)cc1OC
Yield: 7.1 %

Procedure:
In a 500 mL rb flask, 200 mL cyclohexane, 50 mL benzene, 15 g.(0.242 mole) ethylene glycol, 1.5 g p-toluene-sulfonic acid and 19 g (0.049 mole) of 1-(3,4-dimethoxyphenyl)-2-nitro-7-(4-methylphenyl)-5-heptanone were combined and refluxed 24 hours with a Dean-Stark trap. The cooled reaction mixture was poured into cold, sat'd. NaHCO3 and extracted with three 200 mL portions of ethyl acetate. The organic Layer was dried over MgSO4, filtered and concentrated. The residue was triturated with ether and ethyl acetate to give some solid (1.5 g) of mp 89°-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.OS(O)(=O)=O.C1C(=O)N([Br:23])C(=O)C1>O>[Br:23][C:5]1[C:6]([O:8][CH2:9][CH3:10])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ccnc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOc1cc(Cl)ncc1Br
Temperature: 60 °C
Reaction time: 10 h
Yield: 32.1 %

Procedure:
To a mixture of 2-chloro-4-ethoxypyridine (13 g, 82 mmol) and H2SO4 (40 mL, 750 mmol) was added NBS (17.62 g, 99 mmol). Then the mixture was stirred at 60° C. for 10 h. After cooling to rt, the mixture was poured into cold water (300 mL). The mixture was extracted with EA (200 mL×2). The combined organic layer was washed with saturated NaHCO3 solution (200 mL×2) and concentrated. The crude material was purified by silica column chromatography (PE/EA=15:1). All fractions found to contain product by TLC (PE/EA=5:1, Rf=0.6) were combined and concentrated to yield a yellow solid of 5-bromo-2-chloro-4-ethoxypyridine (8.5 g, 26.3 mmol, 32% yield): 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 6.79 (s, 1H), 4.16 (q, J=6.8 Hz, 2H), 1.50 (t, J=6.8 Hz, 3H); ES-LCMS m/z 238 (M+3).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]#[N:19])[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH2:20]>C(O)C.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]([NH2:19])=[O:20])[CH2:11][CH2:12][S:13](=[O:17])(=[O:16])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCS(=O)(=O)CC1
Reactant: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=O)C1(c2ccc([N+](=O)[O-])cc2)CCS(=O)(=O)CC1

Procedure:
A solution of 4-(4-nitro-phenyl)-1,1-dioxo-hexahydro-1λ6-thiopyran-4-carbonitrile (as prepared in the previous step) in ethanol and water is treated with NaBO3 (Synthetic Communications, 20(4), 563-71, (1990)). The mixture is diluted with EtOAc and washed with water. The organic layer is dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography with the appropriate solvent to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[C:7]=2[CH:21]=1)#[N:2].C(O)(=O)C.Cl.[H][H]>C(O)C.[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[C:7]=2[CH:21]=1
Reactant: [H][H]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)Oc2ccc(CN)cc2[C@@H](N2CCCC2=O)[C@@H]1O

Procedure:
trans-6-Cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol (5 g, prepared as described in J. Med. Chem. 29, 2194 (1986)), in ethanol (375 ml) and glacial acetic acid (75 ml) containing concentrated HCl (5 ml) was shaken in the presence of 10% Pd/C (1 g) in an atmosphere of hydrogen for 4 h. The catalyst was filtered off and the solution neutralised with 10% aqueous NaOH solution, and the solution evaporated to dryness. Acid-base extraction, and drying of a dichloromethane solution of the residue, furnished, after recrystallisation from ethyl acetate-pentane, 2.03 g of the required aminomethyl compound of example 4 of mp 191°-193° C. as the hemihydrate.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[N+:21]([O-])=O)[CH2:3]1.O.[Cl-].[NH4+]>C(O)C.ClCCl.[Fe]>[F:24][C:2]1([F:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[N:11]=[CH:10][C:9]=2[NH2:21])[CH2:3]1
Reactant: C[Si](C)(C)COCCn1ncc([N+](=O)[O-])c1N1CCCC(F)(F)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)COCCn1ncc(N)c1N1CCCC(F)(F)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of 3,3-difluoro-1-(4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-yl)piperidine (1.4 g, 3.86 mmol) in 20 mL of ethanol was added 40 mL of water, ammonium chloride (0.82 mg, 15.44 mmol), and iron powder (1.08 g, 19.3 mmol). The reaction mixture was stirred at 70° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and filtered through a celite pad, rinsing with more dichloromethane. The filtrate was extracted twice with dichloromethane, then the combined organic extracts were dried over magnesium sulfate and concentrated to afford 1.2 g (93%) of 5-(3,3-difluoropiperidin-1-yl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-amine. LCMS (ESI) m+H=333.1; 1H NMR (400 MHz, CDCl3) δ: 7.09 (s, 1H), 5.38 (m, 2H), 3.74 (m, 6H), 2.01 (s, 1H), 1.96 (s, 2H), 1.52 (m, 2H), 0.92 (m, 2H), 0 (s, 9H).
Reaction SMILES: [N:1]#[C:2]Cl.[C:4]1([C:10]2[N:11]=[CH:12][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.CCOC(C)=O>C(#N)C>[C:4]1([C:10]2[N:11]=[C:12]([C:2]#[N:1])[N:13]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc(Cn2cnc(-c3ccccc3)c2)cc1
Reactant: N#CCl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1nc(-c2ccccc2)cn1Cc1ccccc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Under nitrogen, 2.0 g (0.0325 ml) cyanogen chloride was added to a 5° C. solution of 6.0 g (0.0256 mol) 4-phenyl-1-(phenylmethyl)-1H-imidazole in 100 ml acetonitrile/10 ml DMF. After 18 hour, the dark yellow reaction was warmed at 70° C. for 7 hours. After cooling, 4.5 ml (0.0325 mol) triethylamine was added and the reaction stirred overnight. The reaction was quenched with 300 ml saturated NaHCO3 and extracted into ethyl acetate (3×150 ml). After drying and concentration, a tan oil was obtained. Flash chromatography (500 ml silica gel, EtOAc) gave 3.7 g recovered starting material and 2.26 g of the desired product (84% based on recovered starting material) mp 95°-96° C. (cyclohexane).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[N:13]=O.[CH3:15][CH:16]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[CH3:17].O>C1(C)C=CC=CC=1.[Pd]>[CH3:1][N:2]1[C:3]2[CH:12]=[CH:11][C:10]3[C:5]([C:4]=2[N:13]=[C:23]1[C:22]1[CH:25]=[CH:26][C:19]([O:18][CH:16]([CH3:17])[CH3:15])=[CH:20][CH:21]=1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: CNc1ccc2ccccc2c1N=O
Reactant: CC(C)Oc1ccc(C=O)cc1
Agent: [Pd]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(-c2nc3c4ccccc4ccc3n2C)cc1
Reaction time: 1 h

Procedure:
A solution of 11.16 g (0.06 mole) of 2-methylamino-1-nitrosonaphthalene in 800 cc of toluene is hydrogenated at room temperature and at the atmospheric pressure in the presence of 3 g of Palladium-on-carbon. After one hour, when the theoretical amount of hydrogen has been consumed, 0.06 mole of 4-(1-methylethoxy)-benzaldehyde are added and the obtained reaction mixture is heated to the reflux temperature under an inert atmosphere for about 3 hours. The water which forms during the reaction distillates as binary azeotrope with toluene and is separated through a Dean-Stark apparatus. Then further 1.5 g of 5% Palladium-on-carbon are added and reflux is prolonged for two additional hours. Filtration of the hot solution followed by concentration of the filtrate to dryness under vacuum affords a residue which has been purified by cristallization from ethyl ether. M.p. 144°-5° C.