Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)=[O:6])C.[OH-].[Na+].Cl>C1(C)C=CC=CC=1>[CH:14]([S:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[C:4]([OH:17])=[O:3])=[CH:8][CH:9]=1)([CH3:16])[CH3:15]
Reactant: CCOC(=O)C(=O)c1ccc(SC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)Sc1ccc(C(=O)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 94.2 %

Procedure:
In a flask (4-isopropylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (4.00 g, 15.85 mmol) was dissolved in toluene (10 mL) and heated to 50° C. in an oil bath. To this heated solution was then added an aqueous sodium hydroxide solution (3 M solution, 6.55 mL, 19.66 mmol) dropwise keeping the temperature of the reaction below 60° C. The reaction was then stirred at 50° C. for 1.5 h. After this time the reaction was removed from the oil bath and concentrated hydrochloric acid (1.52 mL, 18.23 mmol) was added dropwise while the reaction was still at 50° C. It was then allowed to cool to 25° C. and stirred for 16 h. Filter off the solid which turned out to be hygroscopic so the filter paper was washed with methylene chloride and transferred the filterate to a separatory funnel. The aqueous layer was extracted with methylene chloride (3×20 mL) and then the organics were dried over magnesium sulfate, filtered and concentrated in vacuo to afford (4-isopropylsulfanyl-phenyl)-oxo-acetic acid (3.35 g, 94%) as a yellow oily solid (there was a small impurity but the material was carried on without purification).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:16]=[CH:15][C:14]2[NH:13][C:12]3[CH2:17][CH2:18][CH2:19][N:20]([CH:22]=O)[CH2:21][C:11]=3[C:10]=2[CH:9]=1>C1COCC1>[CH3:22][N:20]1[CH2:19][CH2:18][CH2:17][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:8]([CH3:7])=[CH:9][C:10]=3[C:11]=2[CH2:21]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C=O)CCC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2[nH]c3c(c2c1)CN(C)CCC3
Temperature: 55 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a stirred suspension of lithium aluminum hydride (2 g, 52.63 mmol) in dry THF (150 mL) was added portionwise 9-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carbaldehyde (5.9 g, 25.87 mmol) and the reaction mixture stirred at 55° C. for 2 h. The progress of reaction was monitored by TLC. The reaction mixture was quenched with saturated sodium aqueous sulfate solution at 0° C. and then filtered. The filtrate was dried over anhydrous sodium sulfate and evaporated to dryness to afford the title compound (5.2 g). 1H NMR (DMSO) δ (ppm): 7.12-7.05 (m, 2H), 6.80-6.6.76 (d, 1H), 3.65 (s, 2H), 2.90-2.80 (m, 4H), 2.34 (s, 3H), 2.26 (s, 3H), 1.80-1.72 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]#[C:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3ccnc(N)c3)c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(-c2cnn(C)c2)cn2ncc(CCc3ccnc(N)c3)c12
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 4-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]ethynyl}pyridin-2-amine (8.3 mg, 0.024 mmol) in ethanol (1 ml) was added palladium hydroxide on carbon (8 mg, 5.70 μmmol, 20 wt %). The reaction system was placed under an atmosphere of hydrogen (balloon) and stirred at ambient temperature for 7 hours. The mixture was filtered through a 45 min syringe filter and washed with EtOH. The filtrate was concentrated and the residue was purified by preparative HPLC reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to afford 4-{2-[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]ethyl}pyridin-2-amine 1H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 7.87 (d, 1H), 7.73 (s, 1H), 7.56-7.63 (m, 2H), 6.54 (d, 1H), 6.39 (s, 1H), 6.36 (s, 1H), 5.18 (br s, 2H), 3.97 (s, 6H), 3.15 (t, 2H), 2.86 (t, 2H). LRMS (ESI) calculated for C19H21N6O [M+H]+, 349.2; found 349.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1.I[CH:13]([CH3:15])[CH3:14]>>[Cl:1][C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH:13]([CH3:15])[CH3:14])[C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: CC(C)I
Reactant: Clc1cc2[nH]cnc2c(Cl)n1
Product: CC(C)n1cnc2c(Cl)nc(Cl)cc21

Procedure:
Following the procedure of Example 15b, 4,6-dichloro-1H-imidazo[4,5-c]pyridine (J. Het. Chem. 1965, 196-201) (0.19 g, 1.0 mmol) was reacted with 2-iodopropane. The residue was purified by silica gel chromatography (25 to 35% ethyl acetate in hexane eluant) to afford the title compound as a solid. MS m/z 230.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.C(=O)([O-])[O-].[K+].[K+].[NH:16]1[CH2:21][CH2:20][CH:19](/[CH:22]=[CH:23]/[C:24]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:25])[CH2:18][CH2:17]1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:16]1[CH2:21][CH2:20][CH:19](/[CH:22]=[CH:23]/[C:24]([C:26]2[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=2)=[O:25])[CH2:18][CH2:17]1
Reactant: O=C(/C=C/C1CCNCC1)c1ccc([N+](=O)[O-])cc1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/C1CCN(Cc2cccc(F)c2)CC1)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 49 %

Procedure:
1.11 g of 3-fluorobenzylbromide and 2.53 g of potassium carbonate were added to 3.0 g of (E)-4-[3-(piperidin-4-yl)propenoyl]nitrobenzene dissolved in 30 ml of dimethylformamide at room temperature, and the mixture was stirred for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 1.06 g of the title compound as pale yellow crystal.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1.C(N(CC)CC)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:6]2[CH2:5][C:4]3([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]3)[S:3][CH:2]2[CH3:1])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC1NCC2(CCN(C)CC2)S1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1SC2(CCN(C)CC2)CN1S(=O)(=O)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]decane (573 mg, 3.08 mmol) was dissolved in dry dichloromethane (2 ml) under an argon atmosphere. Distilled triethylamine (644 μl, 4.62 mmol) was added and the resulting solution was cooled to 0° C. A solution of p-fluorobenzenesulfonyl chloride (600 mg, 3.08 mmol) in dry dichloromethane (2 ml) was added dropwise with a syringe. The reaction flask was allowed to warm to room temperature with stirring, and a white solid started to precipitate. After 1 h of stirring, dichloromethane (50 ml) was added and the resulted solution was washed with water (2×10 ml). The organic phase was dried with anhydrous magnesium sulfate, filtered and evaporated to give the crude mixture as an oil. The crude product was purified by flash chromatography (silica, CH2Cl2/MeOH/NH4OH 93/7/1) to provide AF716 (496 mg, 98.8% chemical purity) as an off-white powder. 1H NMR (CDCl3, 300 MHz) δ 7.89-7.85 (m, 2H, two CHCSO2), 7.27-7.19 (m, 2H, CHCF), 5.02 (q, J=6.12 Hz, 1H, CH—CH3), 3.66 (d, J=11.37 Hz, 1H, CHHNS), 3.48 (d, J=11.37 Hz, 1H, CHHNS), 2.72-2.50 (m, 2H, CH2NCH3), 2.25 (s, 3H, NCH3), 2.16-2.07 (m, 2H, CH2NCH3), 1.95-1.88 (m, 2H, CH2CS), 1.55 (d, J=6.12 Hz, 3H, CH3CH), 1.48 (m, 2H, CH2CS) ppm; 13C NMR (CDCl3, 300 MHz) δ 166.92 and 163.54 (C), 130.05 (CH), 129.93 (CH), 129.58 (C), 116.60 (CH), 116.30 (CH), 60.76 (C), 60.24 (CH), 54.05 (CH2), 53.22 (CH2), 46.03 (CH3), 37.16 (CH2), 37.05 (CH2), 25.56 (CH3) ppm.
Reaction SMILES: [O:1]=[PH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[OH:12]O>>[OH:1][P:2]1(=[O:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=[PH]1CCCc2ccccc21
Reactant: OO
Product: O=P1(O)CCCc2ccccc21

Procedure:
Evaporation of the original chloroform extract, gave colourless crystals (28g). The n.m.r. spectrum of this material indicated the presence of some of the secondary phosphine oxide, 1-oxo-1,2,3,4-tetrahydrophosphinoline. This mixture was again treated with alkaline hydrogen peroxide, and a similar work-up gave a further 25g of crystalline 1-hydroxy-1-oxo-1,2,3,4-tetrahydrophosphinoline, m.p. 142°-4°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11]C(=O)N(C)C)[CH:6]=1.[OH-].[K+].CO>O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([SH:11])[CH:6]=1
Reactant: COC(=O)Cc1cccc(SC(=O)N(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)Cc1cccc(S)c1

Procedure:
A mixture of (3-dimethylcarbamoylsulfanyl-phenyl)-acetic acid methyl ester (2.0 g., 7.9 mmol), potassium hydroxide (1.4 g, 24 mmol),methanol (50 mL), and water (5 mL) is stirred at reflux 3 hr. The mixture is concentrated, and product partitioned between 1M aqueous hydrochloric acid (50 mL) and ethyl acetate (3×75 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is taken up in methanol (50 mL), 2 mL concentrated sulfuric acid is added, and the mixture refluxed 3 hr. The mixture is concentrated, and the residue purified by silica chromatography eluting with 7:3 hexanes:ethyl acetate to afford the title compound as a pale yellow oil, 1.0 g, 69%. MS M++1 183. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [CH:1]1([CH2:10][CH:11]=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>CO>[CH:1]1([CH2:10][CH:11]=[N:14][OH:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=CCC1C=Cc2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=CCC1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1H-indene-1-yl)acetaldehyde (1.5 g, 9.5 mmol), hydroxylamine hydrochloride (836 mg, 12.0 mmol), and sodium acetate (1.04 g, 12.7 mmol) were combined in methanol (50 ml) and stirred at ambient temperature overnight. The mixture was evaporated to dryness in vacuo and the residue treated with water and extracted with ether. The ether layer was washed with water, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on a silica gel coulmn eluted with 15% EtOAc in hexane followed by 22% EtOAc in hexane. The product fraction was evaporated to dryness in vacuo to provide 2-(1H-indene-1-yl)acetaldoxime.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N+:11]([C:14]1[C:15]([NH:33][CH2:34][C@H:35]2[CH2:40][CH2:39][C@H:38]([N:41]3[CH2:44][CH:43]([OH:45])[CH2:42]3)[CH2:37][CH2:36]2)=[N:16][C:17]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][C:29]([F:32])([F:31])[F:30])=[N:18][CH:19]=1)([O-:13])=[O:12].CCN(CC)CC.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[N+:11]([C:14]1[C:15]([NH:33][CH2:34][C@H:35]2[CH2:36][CH2:37][C@H:38]([N:41]3[CH2:42][C:43](=[O:45])[CH2:44]3)[CH2:39][CH2:40]2)=[N:16][C:17]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][C:29]([F:31])([F:32])[F:30])=[N:18][CH:19]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N2CC(O)C2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN([C@H]2CC[C@H](CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)C1
Temperature: 25 °C

Procedure:
DMSO (170 μL, 2.4 mmol) was added dropwise to a solution of oxalyl chloride (105 μL, 1.2 mmol) in dry CH2Cl2 (10 mL) cooled in a dry ice/acetone bath. The reaction mixture was stirred with cooling for 30 min. A solution of 1-(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}cyclohexyl)azetidin-3-ol (200 mg, 0.4 mmol) in dry CH2Cl2 was added dropwise and the reaction was allowed to stir for 2 h. Et3N (501 μL, 3.6 mmol) was then added and the reaction mixture was stirred for 16 h and allowed to slowly warm to room temperature. The mixture was diluted with CH2Cl2 and poured into saturated aqueous Na2SO4. The aqueous phase was separated and extracted with CH2Cl2 (×2). The combined organic phase was dried over Na2SO4, decanted and concentrated. The crude product was purified by flash chromatography on a 120 g SiO2 column, eluting with 90:9:1 CH2Cl2:MeOH:NH4OH as an eluent to afford 147 mg (74%) of the title compound, m/z 495.6 [M+1]+.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:19]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:18][C@@:17]2([CH3:26])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][C@H:10]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:11]2=[O:27])[CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[C:34]([O:1][C@@H:2]1[C@@H:19]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:18][C@@:17]2([CH3:26])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][C@H:10]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:11]2=[O:27])[CH2:3]1)(=[O:36])[CH3:35]
Reactant: C[C@]12C[C@H](N3CCCCC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@@H](N3CCCCC3)C[C@@H]12
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)O[C@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)[C@@H](N5CCCCC5)C[C@@H]34)[C@@]2(C)C[C@@H]1N1CCCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 40 g of (2β,3α,5α,16β)-3-hydroxy-2,16-di-(1-piperidinyl)-androstan-17-one in 160 ml of dichloromethane were added 13.5 ml of acetylchloride at 15°-20 ° C. The solution was stirred for 6 h at room temperature and thereafter evaporated to dryness. The residue was dissolved in toluene, the solution again evaporated to dryness and the residue dissolved in dichloromethane. The solution was washed with saturated aqueous sodium carbonate solution, with water and with saturated brine, dried over sodium sulphate, and evaporated to dryness to give 43.5 g of (2β,3α,5α,16β)-3-acetyloxy-2,16-di-(1-piperidinyl)androstan-17-one. Mp 154° C.
Reaction SMILES: ClCCCl.[CH:5]1([C:11]2[C:19]3[C:18](=[O:20])[NH:17][C:16]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]5)=[CH:23][C:22]=4[O:34][CH3:35])=[N:15][C:14]=3[N:13]([CH3:36])[N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:37][NH2:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C(O)(=O)C>[CH:5]1([C:11]2[C:19]3[C:18](=[O:20])[NH:17][C:16]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][CH:30]([NH:38][CH3:37])[CH2:31][CH2:32]5)=[CH:23][C:22]=4[O:34][CH3:35])=[N:15][C:14]=3[N:13]([CH3:36])[N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CN
Reactant: COc1cc(N2CCC(=O)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CNC1CCN(c2ccc(-c3nc4c(c(C5CCCCC5)nn4C)c(=O)[nH]3)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.9 %

Procedure:
To a 4 ml 1,2-dichloroethane solution of 200 mg (0.46 mmol) of the compound obtained in Example 30, 100 μl (0.92 mmol) of methylamine (30% methanol solution), 146 mg (0.69 mmol) of sodium triacetoxyborohydride, and 26 μl of acetic acid were added, and the mixture was stirred at room temperature for 6 hours. Then, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/chloroform/methanol=10/10/1) to obtain 176 mg (85%) of the captioned compound.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[N-:19]=[N+:20]=[N-:21].[Na+].CCN(C(C)C)C(C)C>CS(C)=O.C(OCC)(=O)C>[N:19]([CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)=[N+:20]=[N-:21]
Reactant: O=[N+]([O-])c1ccc(N2CCN(CCCl)CC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-(2-Chloroethyl)-4-(4-nitrophenyl)piperazine (1 g, 0.0033 mol) was dissolved in dimethylsulphoxide (30 mL) and sodium azide (0.34 g, 0.0052 mol) was added followed by Hunig's base (0.84 g, 0.0065 mol). The mixture was stirred at 80° C. overnight in a sealed tube, then diluted with ethyl acetate and washed with water, dried and evaporated to yield the title compound. LCMS: 90%, t=0.85 min, [MH+]=277.26.
Reaction SMILES: C([O-])(=O)C.[NH4+].[F:6][C:7]([F:39])([CH2:11][C:12]1(O)[C:25]2[CH:24]=[C:23]([O:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[CH:21][C:20]=2[O:19][C:18]2[C:13]1=[CH:14][C:15]([C:32]1[CH:33]=[N:34][CH:35]=[N:36][CH:37]=1)=[CH:16][CH:17]=2)[C:8]([NH2:10])=[O:9]>CC(O)C.O.C(=O)(O)[O-].[Na+]>[F:6][C:7]1([F:39])[C:8](=[O:9])[NH:10][C:12]2([C:25]3[CH:24]=[C:23]([O:26][CH2:27][C:28]([CH3:30])([CH3:31])[CH3:29])[CH:22]=[CH:21][C:20]=3[O:19][C:18]3[C:13]2=[CH:14][C:15]([C:32]2[CH:37]=[N:36][CH:35]=[N:34][CH:33]=2)=[CH:16][CH:17]=3)[CH2:11]1
Reactant: CC(C)(C)COc1ccc2c(c1)C(O)(CC(F)(F)C(N)=O)c1cc(-c3cncnc3)ccc1O2
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)COc1ccc2c(c1)C1(CC(F)(F)C(=O)N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 90 °C

Procedure:
Ammonium acetate (0.131 g, 1.704 mmol) was added to a solution of 2,2-difluoro-3-(9-hydroxy-2-(neopentyloxy)-7-(pyrimidin-5-yl)-9H-xanthen-9-yl)propanamide (0.04 g, 0.085 mmol) in 2-Propanol (0.852 mL) and the reaction was heated to 90° C. After 30 minutes the reaction was diluted with water and saturated aqueous sodium bicarbonate (50 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were washed with water, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to afford a residue that was purified by silica gel chromatography (1:1 EtOAc in hexane) to provide 4,4-difluoro-2′-(neopentyloxy)-7′-(pyrimidin-5-yl)spiro[pyrrolidine-2,9′-xanthen]-5-one. M=452.1 [M+H].
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=1)[C:43]([NH:45][CH3:46])=[O:44]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:40]2[CH:49]=[CH:48][CH:47]=[C:42]([C:43]([NH:45][CH3:46])=[O:44])[CH:41]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CNC(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CNC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 32.9 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.44 g), 3-bromo-N-methylbenzamide (1.10 g) and tetrakis(triphenylphosphine)palladium(0) (0.21 g), the title compound (1.00 g) was obtained as a pale-yellow amorphous powder.
Reaction SMILES: C([O:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>CC(O)C>[F:20][C:19]([F:21])([F:22])[CH2:18][CH2:17][O:16][CH:13]1[CH2:12][CH2:11][CH:10]([C:9]([OH:23])=[O:8])[CH2:15][CH2:14]1
Reactant: O=C(OCc1ccccc1)c1ccc(OCCC(F)(F)F)cc1
Reactant: [H][H]
Solvent: CC(C)O
Product: O=C(O)C1CCC(OCCC(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
10% Rh—C (14.7 mg) was added to a solution of 4-(3,3,3-trifluoro-propoxy)-benzoic acid benzyl ester (147.3 mg, 0.454 mmol) in iPrOH (1.5 mL). The hydrogen pressure was adjusted to 5 atm, and the mixture was then heated with stirring at 80° C. overnight. The reaction mixture was filtered through celite, and the filtrate was then diluted with ethyl acetate. A saturated aqueous sodium bicarbonate solution was added, and the organic layer and the aqueous layer were separated. The aqueous layer was adjusted to pH 1 with 1 N hydrochloric acid and then extracted with ethyl acetate. The organic layers were sequentially washed with water and saturated brine, and then dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 4-(3,3,3-trifluoro-propoxy)-cyclohexanecarboxylic acid as a colorless transparent oily substance (70.2 mg, 64%).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[CH3:5][O:6][CH2:7][C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)C(=O)C)C>CN(C)C(=O)C>[CH3:5][O:6][CH2:7][C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([CH:2]([CH3:4])[CH3:3])[CH2:10][CH2:9]1
Reactant: COCC1(Nc2ccccc2)CCNCC1
Reactant: CC(C)Br
Agent: CCN(CC)C(C)=O
Solvent: CC(=O)N(C)C
Product: COCC1(Nc2ccccc2)CCN(C(C)C)CC1
Yield: 42.6 %

Procedure:
A mixture of 10 parts of 2-bromopropane, 9 parts of 4-(methoxymethyl)-N-phenyl-4-piperidinamine, 4.9 parts of N,N-diethylethanamide and 72 parts of N,N-dimethylacetamide is stirred and refluxed for 10.25 hours. After cooling, the formed N,N-diethylethanamine hydrobromide is filtered off and the filtrate is diluted with water. The product is extracted with methylbenzene. The extract is washed thoroughly with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 5.7 parts (42.6%) of 4-(methoxymethyl)-1-(1-methylethyl)-N-phenyl-4-piperidinamine as an oily residue.
Reaction SMILES: [CH2:1]([C:3]1[C:8](/[CH:9]=[CH:10]/[O:11]C)=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[N:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=2)[C:23]#[N:24])[S:15][N:14]=1)[CH3:2].Cl>O1CCCC1>[CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=[O:11])=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[N:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:28])[CH3:29])=[C:22]([CH:25]=2)[C:23]#[N:24])[S:15][N:14]=1)[CH3:2]
Reactant: CCc1c(/C=C/OC)cccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Agent: Cl
Solvent: C1CCOC1
Product: CCc1c(CC=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Temperature: 65 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 5-(3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile (D54) (670 mg) in tetrahydrofuran (THF) (20 mL) stirred under nitrogen at room temperature was added 2M hydrochloric acid (0.826 mL). The reaction mixture was stirred at 65° C. for 3 h. After cooling the reaction, the solution was condensed under reduced pressure to give 5-{3-[2-ethyl-3-(2-oxoethyl)phenyl]-1,2,4-thiadiazol-5-yl}-2-[(1-methylethyl)oxy]benzonitrile (D55) (647 mg), which was used directly in the next step without further purification. MS (ES): C22H21N3O2S requires 391. found 392.2 (M+H+).