Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].S(=O)(=O)(O)[OH:23].[OH-].[Na+]>O>[C:1]([C:3]1([NH:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)(=[O:23])[NH2:2]
Reactant: CCOC(=O)N1CCC(C#N)(Nc2ccc(F)cc2)CC1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)N1CCC(Nc2ccc(F)cc2)(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
127.5 parts of ethyl 4-cyano-4-(4-fluorophenylamino)-1-piperidinecarboxylate are added dropwise to 360 parts of concentrated sulfuric acid (exothermic reaction: temperature rises to 50° C.). Upon completion, the whole is stirred overnight at room temperature. The reaction mixture is poured onto crushed ice and 250 parts of water are added. The whole is alkalized with sodium hydroxide solution at a temperature of 40°-50° C., whereupon the product is precipitated. It is filtered off, washed with water and taken up in boiling trichloromethane. The latter is washed twice with water, dried and evaporated, yielding 82.1 parts of less pure ethyl 4-carbamoyl-4-(4-fluorophenylamino)-1-piperidinecarboxylate.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[CH:7]=[CH:8][C:9](Cl)=[N:10][CH:11]=1)=[O:5].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[N:10][CH:11]=1)=[O:5]
Reactant: c1c[nH]cn1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CON(C)C(=O)c1ccc(-n2ccnc2)nc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 70.6 %

Procedure:
A suspension of O,N-dimethyl-2-chloropyridine-5-hydroxamic acid (10.0 g, 50 mmol-see Preparation 22(i)), imidazole (4.1 g, 60 mmol) and potassium carbonate (6.9 g, 50 mmol) in N,N-dimethylacetamide (200 ml) was stirred at 140° C. for 24 hours. The mixture was evaporated under reduced pressure and the residue was partitioned between dichloromethane (100 ml) and water (100 ml). The organic phase was washed with water (100 ml) and brine (50 ml) then dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica using gradient elution with ethyl acetate/hexane (1:1,1:0). Fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound (8.2 g, 71%) as an orange oil. A sample was triturated with ether to afford a colourless solid, m.p. 69-70° C.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:27])[C:13]([CH3:26])([O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH3:14])[S:9][CH:10]=1)C.[Li+].[OH-]>C1COCC1.CO.O>[CH3:26][C:13]([O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)([CH3:14])[C:12]([NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:28])=[O:3])[N:7]=1)=[O:27]
Reactant: CCOC(=O)Cc1csc(NC(=O)C(C)(C)Oc2cccc3ccccc23)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Oc1cccc2ccccc12)C(=O)Nc1nc(CC(=O)O)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.6 %

Procedure:
To a solution of {2-[2-Methyl-2-(naphthalen-1-yloxy)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (0.196 g, 5 mmol) in THF (2 ml) and MeOH (1 ml) added a solution of LiOH (0.021 g, 25 mmol) in H2O (1 ml) and stirred at r.t. for 18 h. Solvents were evaporated under reduced pressure and residue was dissolved in water (5 ml) and extracted with ether (2×2 ml). The aqueous phase was acidified with citric acid solution, extracted in EtOAc (2×30 ml), dried over Na2SO4 and the solvent was evaporated under reduced pressure to obtain {2-[2-Methyl-2-(naphthalen-1-yloxy)-propionylamino]-thiazol-4-yl}-acetic acid (0.16 g, 89%). 1H NMR (400 MHz, CDCl3): δ1.72 (s, 6H), 3.42 (s, 2H), 6.34 (s, 1H), 6.74 (d, J=7.2 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.49-7.55 (m, 3H), 7.83-7.85 (m, 1H), 8.23-8.25 (m, 1H), MS (EI) m/z: 371.00 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=2)[N:12]=[C:11]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:23]=2)[C:10]=1[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C:38]1=[O:43].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][C:38]3=[O:43])[CH:17]=2)[N:12]=[C:11]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:23]=2)[C:10]=1[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCN1
Reactant: Cc1c(COc2cccc(OCC3CCOCC3)c2)nc2ccc(Br)cc2c1OCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1c(COc2cccc(OCC3CCOCC3)c2)nc2ccc(N3CCCCC3=O)cc2c1OCc1ccccc1
Temperature: 100 °C
Reaction time: 30 h
Yield: 79.4 %

Procedure:
To a solution of 4-(benzyloxy)-6-bromo-3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (400 mg) in dioxane (10 mL) were added piperidin-2-one (90 mg), tris(dibenzylideneacetone)dipalladium(0) (35 mg), cesium carbonate (360 mg), and (9,9-dimethyl-9H-xanthen-4,5-diyl)bis(diphenylphosphine) (65 mg), and the mixture was stirred at 100° C. for 30 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=97/3) to obtain 1-[4-(benzyloxy)-3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinolin-6-yl]piperidin-2-one (328 mg).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH:18]=[C:17]([CH2:19]O)[S:16][C:15]=2[CH:21]=1.S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][CH2:19][C:17]1[S:16][C:15]2[CH:21]=[C:11]([O:10][C:2]3[S:1][C:9]4[C:4]([N:3]=3)=[N:5][CH:6]=[CH:7][CH:8]=4)[CH:12]=[CH:13][C:14]=2[CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2ccc(Oc3nc4ncccc4s3)cc2s1
Solvent: ClCCl
Product: ClCc1cc2ccc(Oc3nc4ncccc4s3)cc2s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
To a cooled (0° C.) solution of [6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzo[b]thiophen-2-yl]-methanol (0.13 g, 0.4 mmol) in DCM (5 mL) was added thionyl chloride (30 μL, 49 mg, 0.4 mmol) and the reaction mixture was stirred (0° C., 3 h). The reaction mixture was partitioned between DCM (20 mL) and saturated NaHCO3 (10 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×20 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound as a yellow solid (0.11 g, 77%). MS (ESI): mass calcd. for C15H9ClN2OS2, 332.0; m/z found, 333.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.57 (dd, J=4.8, 1.6, 1H), 8.07-7.91 (m, 2H), 7.77 (d, J=8.7, 1H), 7.40 (dd, J=8.7, 2.2, 1H), 7.31 (d, J=0.4, 1H), 7.25-7.14 (m, 1H), 4.86 (s, 2H).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[C:5]([O:8][CH2:9][CH2:10][CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1([CH3:18])[CH3:17])(=[O:7])[CH3:6]>C(Cl)Cl>[C:5]([O:8][CH2:9][CH2:10][CH:11]1[CH:16]=[CH:15][C:14]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][Cl:1])=[CH:13][C:12]1([CH3:18])[CH3:17])(=[O:7])[CH3:6]
Reactant: CC(=O)OCCC1C=CC=CC1(C)C
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClCCl
Product: CC(=O)OCCC1C=CC(C(=O)CCCCl)=CC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Charge a flask with aluminum chloride (223 g, 1.68 mol) and methylene chloride (200 mL). Place under a nitrogen atmosphere, cool to 0°-5° C. and add, by dropwise addition, ω-chlorobutyryl chloride (188.6 g, 1.34 mol). After acid chloride addition is complete, add, by dropwise addition, 2,2-dimethylphenethyl acetate (128.0 g, 0.67 mol ), keeping the temperature at approximately 0° C. Continue stirring at 0° C. for 2 hours, quench by slowly pouring over approximately 2L of crushed ice. Add methylene chloride (500 mL) and stir for 5 minutes. Separate the organic phase and extract the aqueous phase with methylene chloride (300 mL). Combine the organic phases and wash with saturated aqueous sodium hydrogen carbonate (3×200 mL), with deionized water (200 mL) and brine (200 mL). Dry (MgSO4) and stir for 30 minutes before filtering. Evaporate the solvent in vacuo and purify by chromatography (ethyl acetate/hexane) to give the title compound as an orange/brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)(c2ccc(F)cc2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1(c2ccc(F)cc2)CCC(O)CC1)OCc1ccccc1
Yield: 91.5 %

Procedure:
1.5 g of [1-(4-Fluoro-phenyl)-4-oxo-cyclohexyl]-carbamic acid benzyl ester (77) were dissolved in 30 mL of dry THF and 182 mg of sodium borohydride were added. When conversion was complete, the mixture was poured into 15 mL of water. pH was adjusted to 2 by addition of 2N HCl and the aqueous layer was extracted with ethyl acetate. The combined organic layer was extracted with brine, dried over magnesium sulfate and evaporated to dryness to give 1.38 g of the desired product as a mixture of cis and trans isomers, the cis isomer (referring to the position of alcohol and Z-amine) being the major one. Rt=2.20 min (Method E). Detected mass: 344.2 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH2:7]([C:9]1[CH:24]=[CH:23][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1)[CH3:8].C([O-])C.[Na+].O>C1COCC1>[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([C:13]2([C:12]3[CH:11]=[CH:10][C:9]([CH2:7][CH3:8])=[CH:24][CH:23]=3)[O:14][CH:2]2[C:3]([O:5][CH3:6])=[O:4])=[CH:16][CH:17]=1)[CH3:22]
Reactant: COC(=O)CCl
Reactant: CCc1ccc(C(=O)c2ccc(CC)cc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(C2(c3ccc(CC)cc3)OC2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A solution of 15 ml (168 mmol) of methyl chloroacetate and 20 g (84 mmol) of 4,4′-diethylbenzophenone in 20 ml of THF was added dropwise to a suspension of 9.1 g (168 mmol) of sodium ethanolate in 80 ml of THF at −10° C. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was added to water and extracted with ether. The organic phase was washed with sodium bicarbonate solution and citric acid solution and dried over magnesium sulfate, and the solvent was distilled off. 15.4 g of a crude oil were isolated and were immediately employed further.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1)=O)(C)(C)C.Cl.C(OCC)C>O1CCOCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1
Reactant: COc1cccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1cccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-[3-(1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(3-methoxy-phenyl) acetamide, prepared as in Intermediate 74, (250 mg, 0.363 mmol) and 4N HCl in dioxane (2 mL) is stirred at RT for 2 h. Diethyl ether (40 mL) is added and the resultant mixture stirred vigorously for 20 min. The solids were allowed to settle and the solvent is decanted. This procedure is repeated three times and the final solid dried by concentration in vacuo to afford the title compound (197 mg) as a white powdery solid: 1H NMR (300 MHz, CDCl3) δ8.05 (d, 1H, J=8.6), 7.76 (d, 1H, J=8.5), 7.67 (t, 1H, J=8.8), 7.5-7.2 (m, 12H), 7.16 (t, 1H, J=6.3), 6.98 (t, 2H, J=7.3), 5.05 (m, 1H, J=6.9), 4.36 (s, br, 2H), 3.94 (t, 1H, J=7.0), 3.82 (s, br, 2H), 3.74 (s, 3H), 1.16 (m, 6H); Low resolution MS (FAB) m/e 588 (M+).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].C(N(CC)CC)C.[CH2:27]([O:29][C:30](Cl)=[O:31])[CH3:28]>O1CCCC1>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[O:13][C:30]([O:29][CH2:27][CH3:28])=[O:31])=[CH:5][C:4]=1[C:16]([F:19])([F:17])[F:18])#[N:2]
Reactant: CCOC(=O)Cl
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)On1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(C#N)cc21
Yield: 90.6 %

Procedure:
A solution of 0.4 g (1.48 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione in 50 ml dry tetrahydrofuran was added 0.2 ml (1.50 mmol) dry triethylamine and 0.15 ml (1.58 mmol) ethylchloroformate. The mixture was refluxed for 45 min., and then evaporated in vacuo. The residue was stirred with water to give 0.46 g (91%) of 7-cyano-1-ethoxycarbonyloxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione. M.p. 190° C. decomp. 1H-NMR (DMSO-d6): 8.33 (1H, s), 7.73 (1H, s), 2.9 (2H, q), 1.2 (3H, t).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:5](=[O:14])[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[C:17]([N+:24]([O-])=O)[CH:16]=2)[C:3]1=[O:27].[OH-].[Na+]>C(O)(=O)C.O.[Zn]>[NH2:24][C:17]1[CH:16]=[C:15]([N:4]2[C:3](=[O:27])[C:2]([CH3:1])([CH3:28])[N:6]([CH2:7][C:8]3[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=3)[C:5]2=[O:14])[CH:20]=[CH:19][C:18]=1[CH:21]([CH3:22])[CH3:23]
Reactant: CC(C)c1ccc(N2C(=O)N(Cc3ccncc3)C(C)(C)C2=O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1ccc(N2C(=O)N(Cc3ccncc3)C(C)(C)C2=O)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
2.64 g (6.90 mmol ) 5,5-dimethyl-3-(3-nitro-4-isopropyl-phenyl)-1-pyridin-4-ylmethyl-imidazolidine-2,4-dione were dissolved in 50 ml acetic acid. 7.22 g zinc dust were added in portions while temperature was kept below 45° C. The mixture was stirred for 1 h at RT, then diluted with 100 ml water, made alkaline with 6N sodium hydroxide solution and extracted with methylene chloride. Separating zinc salts were removed by filtration over cellite. Evaporation of the combined organic phases yielded 1.53 g product that were used without further purification.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH2:19]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([C:55]([OH:57])=O)=[C:27]([CH2:42][N:43]3[CH2:48][CH2:47][CH:46]([N:49]4[CH2:54][CH2:53][O:52][CH2:51][CH2:50]4)[CH2:45][CH2:44]3)[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)=[N:29]2)=[CH:24][C:23]=1[S:58]([CH:61]([CH3:63])[CH3:62])(=[O:60])=[O:59])[CH3:20].[F:64][C:65]([F:75])([F:74])[C@H:66]([NH2:73])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.ClCCl.C(=O)(O)[O-].[Na+]>[CH2:19]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([C:55]([NH:73][C@H:66]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[C:65]([F:64])([F:74])[F:75])=[O:57])=[C:27]([CH2:42][N:43]3[CH2:44][CH2:45][CH:46]([N:49]4[CH2:54][CH2:53][O:52][CH2:51][CH2:50]4)[CH2:47][CH2:48]3)[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)=[N:29]2)=[CH:24][C:23]=1[S:58]([CH:61]([CH3:63])[CH3:62])(=[O:59])=[O:60])[CH3:20]
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2cc1S(=O)(=O)C(C)C
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c2cc1S(=O)(=O)C(C)C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
T3P in ethyl acetate (1.273 mL of a 50% solution, 2.001 mmol) was added to a stirred solution of 7-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (1 g, 1.539 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.391 g, 1.847 mmol), and N,N-diisopropylethylamine (0.538 mL, 3.08 mmol) in dichloromethane (10 mL). The reaction mixture was stirred for 16 h, diluted with saturated aqueous sodium bicarbonate, and extracted with methylene chloride (three times). The combined organic extracts were washed with saturated sodium bicarbonate, brine, dried, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 0-5% methanol/methylene chloride) to afford 7-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.450 g, 34% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ10.00 (br. s., 1H), 8.48 (br. s., 1H), 7.97 (s, 1H), 7.86 (d, J=7.55 Hz, 2H), 7.71-7.78 (m, 2H), 7.60-7.68 (m, 2H), 7.42-7.47 (m, 3H), 6.20 (quin, J=8.81 Hz, 1H), 4.39 (q, J=6.80 Hz, 2H), 3.72-3.86 (m, 1H), 3.50 (br. s., 4H), 3.44 (br. s., 1H), 3.18 (br. s., 1H), 2.39 (br. s., 1H), 2.33 (br. s., 1H), 2.26 (br. s., 4H), 2.11 (br. s., 1H), 1.68 (br. s., 2H), 1.53 (br. s., 1H), 1.44 (t, J=6.80 Hz, 3H), 1.12-1.37 (m, 7H), 0.74-0.99 (m, 2H); MS (m/z) 807.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:13][CH2:14][C:15]([F:17])([F:16])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]3.[F:18][C:19]1[C:20]([N:25]2[CH:29]=[C:28]([CH:30]=O)[C:27]([CH2:32][O:33][CH:34]([CH3:36])[CH3:35])=[N:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:13][CH2:14][C:15]([F:16])([F:17])[C:4]=2[CH:3]=1)[CH2:8][CH2:9][N:10]([CH2:30][C:28]1[C:27]([CH2:32][O:33][CH:34]([CH3:36])[CH3:35])=[N:26][N:25]([C:20]2[C:19]([F:18])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:29]=1)[CH2:11][CH2:12]3
Reactant: CC(C)OCc1nn(-c2ncccc2F)cc1C=O
Reactant: FC1(F)COC2(CCNCC2)c2sc(Cl)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)OCc1nn(-c2ncccc2F)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.1 %

Procedure:
To a solution of 2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine] (170 mg, 0.61 mmol) in dichloromethane (2.4 mL), 1-(3-fluoro-2-pyridyl)-3-(isopropoxymethyl)pyrazole-4-carbaldehyde (192 mg) is added. The mixture is stirred 10 min at room temperature. Then, sodium triacetoxyborohydride (268.3 mg) is added, and the reaction is stirred at room temperature overnight. The mixture is diluted with dichloromethane and quenched slowly with sodium bicarbonate (saturated solution). The organic phase is then extracted with more dichloromethane, decanted, dried over magnesium sulfate and solvent evaporated under reduced pressure. The residue is purified by reverse phase HPLC to give 67.9 mg of 2-chloro-4,4-difluoro-1′-[[1-(3-fluoro-2-pyridyl)-3-(isopropoxymethyl)pyrazol-4-yl]methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]. MS (m/z): 527 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].C([O-])(=[O:26])C.[Na+].O.N(S([O-])(=O)=O)(S(O)(=O)=O)O.[K+].[K+]>CO>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:3]1[C:2](=[O:1])[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[C:5](=[O:26])[C:4]=1[CH3:12]
Reactant: CC(=O)[O-]
Reactant: COc1cc(C)c(CCCCCCCCCCO)c(O)c1OC
Agent: O=S(=O)([O-])N(O)S(=O)(=O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Yield: 93.9 %

Procedure:
In methanol (110 l) was dissolved 10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decan-1-ol (6.84 kg). To this solution were added sodium acetate (27.4 kg) and water (110 l). To the mixture was then added dipotassium nitrosodisulfonate (23.5 kg, content 69.9%), which was stirred at 50°±3° C. for 3 hours. After confirming disappearance of the starting material by means of thin-layer chromatography, water (550 l) was added to the mixture, which was stirred at 10° C. or below for 30 minutes or longer, then precipitating crystals were separated by centrifuge. Wet crystals thus collected were dissolved in ethyl acetate (40 l), followed by washing with water (25). The ethyl acetate layer was concentrated under reduced pressure to obtain a crude product 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (6.70 kg, yield 93.9%). Reference examples using dipotassium nitrosodisulfonate (Fremy's salt) are described in Table 3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.[I-].[NH2:18][N+:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][N:11]=3)=[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]3[N:18]=2)=[CH:4][CH:3]=1
Reactant: N[n+]1ccccc1
Reactant: O=C(Cc1ccncn1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: Fc1ccc(-c2nn3ccccc3c2-c2ccncn2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of 1-(4-fluorophenyl)-2-(4-pyrimidinyl)-ethanone (21.6 g, 0.1 mol), 1-aminopyridinium iodide (22.2 g, 0.1 mol) and potassium carbonate (41.4 g, 0.3 mol) in a mixture of water (300 mL) and isopropanol (300 mL) was heated and stirred at 100° C. for 16 h. The isopropanol was removed under vacuum and the resulting aqueous phase extracted with dichloromethane (5×200 mL). The dichloromethane extracts were combined and the solvent evaporated under reduced pressure to leave a red solid which was purified by silica gel chromatography eluting with a hexane/EtOAc to give the title compound as a yellow solid, 9.16 g (32%). 1H NMR (d6-DMSO) δ 7.07 (d, J=5.4 Hz, 1H), 7.14 (t, J=6.8 Hz, 1H), 7.32 (t, J=8.7 Hz, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.60 (dd, J=5.7, 8.7 Hz, 2H), 8.40 (d, J=8.9 Hz, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.83 (d, J=7.1 Hz, 1H), 9.16 (s, 1H), APESI+MS m/z 291 (M+1).