Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[C:10]([OH:21])[CH:9]=1)=[O:7])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:33]1([CH3:40])[CH:38]=[CH:37][C:36](Cl)=[CH:35][CH:34]=1>>[CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[C:10]([O:21][C:36]2[CH:37]=[CH:38][C:33]([CH3:40])=[CH:34][CH:35]=2)[CH:9]=1)=[O:7])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Cl)cc1
Reactant: CC(C)CC(=O)Oc1ccc(C(=O)CNC(C)C)cc1O
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: Cc1ccc(Oc2cc(C(=O)CNC(C)C)ccc2OC(=O)CC(C)C)cc1

Procedure:
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with p-toluyl chloride there is obtained 3-(p-toluyloxy)-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(p-toluyloxy)-4-(isovaleryloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:18]1([CH3:30])[CH:23]=[CH:22][C:21]([S:24]([CH2:27][N+:28]#[C-:29])(=[O:26])=[O:25])=[CH:20][CH:19]=1.[H-].[Na+]>CS(C)=O.C(OCC)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][CH2:3][CH2:2][C:27]([N+:28]#[C-:29])([S:24]([C:21]1[CH:20]=[CH:19][C:18]([CH3:30])=[CH:23][CH:22]=1)(=[O:25])=[O:26])[CH2:2][CH2:3][CH2:4][C:5]([CH3:17])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:10]
Reactant: CCOC(=O)C(C)(CCCBr)c1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: [C-]#[N+]C(CCCC(C)(C(=O)OCC)c1ccccc1)(CCCC(C)(C(=O)OCC)c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 117.8 %

Procedure:
To a solution of ethyl 5-bromo-2-methyl-2-phenyl-pentanoate (25 g, 75.25 mmol), tetra-ii-butylammonium iodide (2.78 g, 7.53 mmol), and p-toluenesulphonylmethyl isocyanide (TosMIC, 7.34 g, 37.63 mmol) in anhydrous DMSO (400 mL) and anhydrous diethyl ether (I150 mL) was added sodium hydride (60% dispersion in mineral oil, 3.80 g, 95 mmol) at rt under N2 atmosphere. The reaction mixture was stirred for 24 h at rt, then carefully hydrolized with ice-water (600 mL), and extracted with diethyl ether (2×300 mL). The organic layer was washed with brine (2×300 mL) dried over anhydrous MgSO4, concentrated in vacuo to furnish crude 2,10-dimethyl-6-isocyano-6-(4-tolyl-sulfonyl)-2,10-diphenyl-undecanedioic acid diethyl ester (28 g) as a brown oil. A solution of this crude intermediate (25 g) was dissolved in CH2Cl2 (500 mL) and concd. HCl (140 mL) and stirred for 2 h at rt. The reaction mixture was diluted with water (500 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×200 mL). The combined layers were washed with saturated NaHCO3 solution (150 mL), and brine (150 mL), dried over MgSO4, and concentrated ill vacuo. The resulting crude oil was purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/20, 1/10) to furnish 2,10-dimethyl-6-oxo-2,10-diphenyl-undecanedioic acid diethyl ester (9.5 g, 50.3%) as a light yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 7.40-7.10 (m, 10H), 4.20-4.05 (m, 4H), 2.38 (m, 4H), 2.05-1.80 (m, 4H), 1.60 (s, 6H), 1.50-1.20 (m, 4H), 1.22 (m, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 210.24, 176.06, 143.71, 128.42, 126.72, 125.97, 60.83, 50.13, 42.97, 38.91, 22.73, 22.47, 19.09, 14.13. HRMS (LSIMS, nba): Calcd. for C29H39O5 (MH+): 467.2797, found: 467.2772.
Reaction SMILES: ON1[C:6]2[CH:7]=[CH:8][CH:9]=C[C:5]=2[N:4]=N1.C(N(CC)CC)C.[C:18]([O:22][C:23]([NH:25][C@H:26]([C:33]([OH:35])=O)[CH2:27][C:28]1[N:29]=[CH:30][S:31][CH:32]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[C:18]([O:22][C:23]([NH:25][C@H:26]([C:33]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:8]1[CH3:9])=[O:35])[CH2:27][C:28]1[N:29]=[CH:30][S:31][CH:32]=1)=[O:24])([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1C(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 323.1 %

Procedure:
N,N-dicyclohexylcarbodiimide (10.83 g, 52.5 mmol), N-hydroxybenzotriazole (2.03 g, 15 mmol) and triethylamine (7.7 ml, 55.2 mmol) were added to a solution (130 ml) of N-(tert-butoxycarbonyl)-3-(thiazol-4-yl)-L-alanine (1) (13.62 g, 50 mmol) obtained by the method described in literatures (J. Am. Chem. Soc. 73, 2935 (1951) and Chem. Pharm. Bull. 38, 103 (1950)) and 2(R)-2-methylpyrrolidine p-toluenesulfonic acid (2) (12.79 g, 50 mmol) obtained by the method described in a literature (Helv. Chim. Acta, 34, 2202 (1951)) in tetrahydrofuran. The mixture was stirred for 20 hours at room temperature. After the precipitates are filtered off, the obtained filtrate was concentrated under reduced pressure. Thus-obtained residue was dissolved in ethyl acetate (200 ml) and the solution were washed with an aqueous solution of sodium hydrogencarbonate and water, successively. The organic layers were dried over magnesium sulfate and concentrated under reduced pressure to give a title compound (3) (16.45 g, 100%) as oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([I:11])[CH:9]=[CH:10][C:2]=1[Br:1]
Reactant: O=C(O)c1cc(I)ccc1Br
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(I)ccc1Br
Temperature: 55 °C

Procedure:
To the solution of 2-bromo-5-iodo-benzoic acid (10 g, 31 mmol) in methanol (100 ml) was added thionyl chloride (5 ml, 68 mmol). The mixture was heated at 55° C. for 12 hours. The solvent and reagent were removed under reduced pressure and the mixture was diluted with EtOAc. The organic solution was washed with saturated sodium bicarbonate, water, and brine, and was dried with sodium sulfate. Concentration gave 2-bromo-5-iodo-benzoic acid methyl ester (10.5 g).
Reaction SMILES: Cl[C:2]1[N:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.O.[NH2:29][NH2:30]>N1C=CC=CC=1>[C:17]([C:8]1[CH:7]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][C:23]([CH:25]([CH3:26])[CH3:27])=[CH:22][CH:21]=3)[NH:30][N:29]=2)[CH:11]=[C:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[C:9]=1[OH:16])([CH3:18])([CH3:19])[CH3:20]
Reactant: NN
Reactant: CC(C)c1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Cl)n1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)c1ccc2c(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n[nH]c2n1

Procedure:
A solution of 4-(2-chloro-6-isopropylnicotinoyl)-2,6-di-tertiary butylphenol and hydrazine hydrate in pyridine is refluxed. After the pyridine is distilled off, to the residue is added water. The resulting crystals are recrystallized from ethanol to give 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-6-isopropyl-1H-pyrazolo[3,4-b]pyridine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCOCC1.O>[CH:16]1([NH:22][C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Clc1nc(Cl)nc(NC2CCCCC2)n1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
2,4,6-Trichloro-1,3,5-triazine (92.2 g) was dissolved in 300 mL of dioxane at room temperature. 53 g of Na2CO3 was dissolved in 300 mL of distilled water and was slowly added into the above solution. Cyclohexylamine (49.95 g) in a dropping funnel was slowly added into the above solution while stirring at 0-5° C. for 2 hr. The stirring was continued for another 3 hr at 0° C., 1 hr at room temperature, and the resultant white precipitate was then filtered and washed with water. The white precipitate was dissolved in methylenechloride (MC) and washed with water and MC was evaporated. Finally, 6-cyclohexylamino-2,4-dichloro-1,3,5-triazine having a substituted cyclohexyl was obtained after drying and solvent removal. The yield was more than 90%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[NH2:11][C:12]([CH3:22])([CH3:21])[C:13]([NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:14].CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][C:6]1[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH:11][C:12]([CH3:22])([CH3:21])[C:13]([NH:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[O:14])[N:7]=1
Reactant: N#Cc1cnc(Cl)nc1Cl
Reactant: CC(C)(N)C(=O)NCC(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(Nc1ncc(C#N)c(Cl)n1)C(=O)NCC(F)(F)F
Temperature: 90 °C

Procedure:
2,4-dichloropyrimidine-5-carbonitrile (E. F. Godefroi, J. Org. Chem., 1962, 27(6), 2264-6) (0.10 g, 0.57 mmol), 2-amino-2-methyl-N-(2,2,2-trifluoroethyl)propanamide. 1TFA (Meinke, Peter T.; Shih, Thomas L.; Fisher, Michael H., U.S. Pat. No. 6,221,894 B1) (0.171 g, 1.14 mmol) and DIPEA (0.39 mL, 2.29 mmol) were combined in anhydrous THF (5 mL) in a sealed tube and heated to 90° C. for 18 hours, before cooling to room temperature. The solvent was evaporated in vacuo and the residue purified by flash chromatography (40 g SiO2, pentane/ethyl acetate, 30-70% over 14 column volumes) to afford the title compound as a colorless waxy solid (0.036 g, 19.7%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:14]([O:17][C:18]1[CH:35]=[CH:34][C:33]2[C@@H:32]3[C@H:23]([C@H:24]4[C@@:28]([CH2:30][CH2:31]3)([CH3:29])[C:27](=[O:36])[CH2:26][CH2:25]4)[CH2:22][C@@H:21]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:20]=2[CH:19]=1)(=[O:16])[CH3:15].C(OC(C)=C)(=O)C>C(Cl)Cl>[C:14]([O:17][C:18]1[CH:35]=[CH:34][C:33]2[C@@H:32]3[C@H:23]([C@H:24]4[C@@:28]([CH2:30][CH2:31]3)([CH3:29])[C:27]([O:36][C:1](=[O:3])[CH3:2])=[CH:26][CH2:25]4)[CH2:22][C@@H:21]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:20]=2[CH:19]=1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)C[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)c2ccc(OC(C)=O)cc21
Reactant: CC(=O)OC(C)=O
Agent: C=C(C)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(OC(C)=O)=CC[C@@H]23)c2ccc(OC(C)=O)cc21

Procedure:
10.0 g. of 3-hydroxy-6β-ethoxycarbonylmethyl-1,3,5(10)-estratrien-17-one -- produced in accordance with A2 -- is acetylated with 20 ml. of acetic anhydride in 20 ml. of pyridine for 20 hours at room temperature. After precipitation into ice water, filtration, and taking up the precipitate in methylene chloride, the reaction product is dried and evaporated, thus obtaining 11.8 g. of 3-acetoxy-6β-ethoxycarbonylmethyl-1,3,5(10) estratrien-17-one, which is heated to the boiling point with 140 ml. of isopropenyl acetate in the presence of 1.4 g. of p-toluenesulfonic acid and then subjected to a slow distillation. The cooled reaction product is diluted with methylene chloride and washed with sodium bicarbonate solution and water, dried, and evaporated, thus resulting in 13.3 g. of a crude product. After chromatography on silica gel, pure 3,17-diacetoxy-6β-ethoxycarbonylmethyl-1,3,5(10),16-estratetraene is obtained as an almost colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([CH3:27])=[CH:15][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10].[OH-].[K+].O>CO>[CH3:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:16]([CH3:27])=[CH:15][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)C(C)(C)CCCOc1cc(C)c(OCc2ccccc2)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(OCc2ccccc2)c(C)cc1OCCCC(C)(C)C(=O)O
Yield: 921.8 %

Procedure:
A solution of 7.8 g (2.1 mmol) of 5-[2,5-dimethyl-4-(phenylmethoxy)phenoxy]-2,2-dimethylpentanoic acid, methyl ester (Example 13), 3.5 g (3×21 mmol) of potassium hydroxide, 10 mL of water and 100 mL of methanol is stirred at reflux for 12 hours. The methanol is removed and the residual aqueous solution is diluted with 150 mL of water then back-extracted with diethyl ether. The aqueous layer is acidified with 15 mL of 6N hydrochloric acid solution and the product is isolated with diethyl ether. The diethyl ether solution is washed with brine, dried (magnesium sulfate) and evaporated leaving 6.9 g of a dark brown crystalline residue. Recrystallization from 30 mL of acetonitrile in the presence of charcoal affords 4.0 g of the title compound as tan, dense crystals; mp 104°-106° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].C(Cl)(Cl)Cl.[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]([C:29](Cl)=[O:30])[C:22]2[O:27][CH2:26][CH2:25][O:24][C:23]=2[CH:28]=1)(=[O:18])=[O:17]>C(Cl)(Cl)Cl.O>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:29]([C:21]1[C:22]2[O:27][CH2:26][CH2:25][O:24][C:23]=2[CH:28]=[C:19]([S:16](=[O:18])(=[O:17])[NH:15][CH3:14])[CH:20]=1)=[O:30])[CH3:2]
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Reactant: CCN1CCCC1CN
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)NC)cc2c1OCCO2
Yield: 66.1 %

Procedure:
82 g of dextrorotatory 1-ethyl-2-aminomethylpyrrolidine, 600 ccm of chloroform and, gradually, at a temperature of from 5°-10° C, 200 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were introduced into a balloon flask with an agitator and a thermometer. After the addition of a liter of water chloroform was distilled and then the remaining solution was filtered. The base was precipitated by the addition of 60 cm3 of 20% ammonia. The crystals formed were dried off, washed with water and then dried. 162 g of dextrorotatory N-(1-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 136°-137° C.; yield: 66%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][C:13]=1[N+:26]([O-:28])=[O:27].ClCCl>C(O)(=O)C>[C:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][C:13]=1[N+:26]([O-:28])=[O:27])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC(=O)NN=C1c1ccc(NCCN)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)NCCNc1ccc(C2=NNC(=O)CC2C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.40 ml (4.23 mmol) of acetic anhydride is added to a solution of 1.00 g (3.43 mmol) of 6-[4-(2-aminoethyl)amino-3-nitro-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone in 10 ml of glacial acetic acid and the solution is stirred at room temperature for 20 hours. The precipitated solid is suction filtered and washed with 5 ml of dichloromethane. The mother liquor is concentrated by evaporation under vacuum and the residue obtained is stirred up with 5 ml of dichloromethane and filtered. The two crystal fractions are recrystallized together from ethanol (99.7%). 0.86 g (75%) of orange coloured crystals, m.p. 222° C., are obtained.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:34]=[CH:33][C:13]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=4)[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[OH-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:9][C:10]1[CH:34]=[CH:33][C:13]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([Cl:1])=[C:28]([O:31][CH3:32])[CH:29]=4)[CH2:24][CH2:23]3)[CH2:20][CH2:21]2)=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Cl)CCN2C1CCN(CCc2ccc(F)cc2)CC1
Yield: 21 %

Procedure:
N-Chlorosuccinimide (0.15 g) was added at room temperature to a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindoline (0.39 g) in methylene chloride (5 ml) and the resultant mixture was stirred for 20 min. Then a 5 N aqueous solution of sodium hydroxide and ethyl acetate were added to the reaction solution and the layers were separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The resulting residue was purified by silica gel column chromatography (methylene chloride/ethanol system) followed by conversion into a hydrochloride to give the hydrochloride (0.10 g) of the title compound as apale red powder (yield: 21%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:25]([OH:27])=[O:26])[CH:21]=2)[N:16]=1.[CH3:28]O>Cl.O1CCOCC1>[CH3:28][O:26][C:25]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:3]1[CH:4]=[C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:9])[CH:6]=[CH:7][C:2]=1[OH:1])[CH:24]=[CH:23]2)=[O:27]
Reactant: CO
Reactant: O=C(O)c1ccc2nc(-c3cc(C(=O)N4CCCC4)ccc3O)ccc2c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc(C(=O)N4CCCC4)ccc3O)ccc2c1
Temperature: 60 °C

Procedure:
To the solution of 295 mg (0.81 mmol) of Compound 19 in 3 mL of methanol, 1 mL of 4M HCl/dioxane was added, and the mixture was heated at 60° C. overnight. The reaction mixture was then evaporated to dryness to give Compound 20 in quantitative yield. MS: 377.18 (M+H+).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:8](=[O:19])[C:9]2[CH:14]=[C:13]([S:15](=[O:18])(=[O:17])[NH2:16])[S:12][C:10]=2[N:11]=1)(=O)C.CO.Cl>O>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:7]1[C:8](=[O:19])[C:9]2[CH:14]=[C:13]([S:15](=[O:17])(=[O:18])[NH2:16])[S:12][C:10]=2[N:11]=[C:6]1[CH2:5][OH:4]
Reactant: CC(=O)OCc1nc2sc(S(N)(=O)=O)cc2c(=O)n1-c1ccccc1Cl
Agent: Cl
Solvent: CO
Solvent: O
Product: NS(=O)(=O)c1cc2c(=O)n(-c3ccccc3Cl)c(CO)nc2s1
Yield: 74.2 %

Procedure:
To 9.3 g of 3,4-dihydro-2-acetoxymethyl-3-(2-chlorophenyl)-4-oxo-6-sulfamoylthieno[2,3-d]pyrimidine were added 200 ml of methanol, 30 ml of water and 14.3 ml of conc. hydrochloric acid, and the mixture was stirred under reflux for 2 hours. The reaction mixture was concentrated, and the residue was crystallized from methanol to give 6.2 g of pale yellow crystals, which was recrystallized from methanol to afford 2.6 g of the title compound, m.p. 259° C. (decomposition).
Reaction SMILES: ClCCN1CCOCC1.CS(OC1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([OH:67])[C:36]2[N:45]=[C:44]([NH:46][C:47]3[CH:51]=[C:50]([CH3:52])[NH:49][N:48]=3)[C:43]3[C:38](=[CH:39][C:40]([O:53][CH:54]4[CH2:59][CH2:58][N:57](C(OC(C)(C)C)=O)[CH2:56][CH2:55]4)=[CH:41][CH:42]=3)[N:37]=2)=[CH:31][CH:30]=1.Cl.O1CCOCC1>>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH:35]([C:36]2[N:45]=[C:44]([NH:46][C:47]3[CH:51]=[C:50]([CH3:52])[NH:49][N:48]=3)[C:43]3[C:38](=[CH:39][C:40]([O:53][CH:54]4[CH2:55][CH2:56][NH:57][CH2:58][CH2:59]4)=[CH:41][CH:42]=3)[N:37]=2)[OH:67])=[CH:33][CH:34]=1
Reactant: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc23)n[nH]1
Agent: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: Cl
Agent: ClCCN1CCOCC1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3cc(OC4CCNCC4)ccc23)n[nH]1
Reaction time: 20 h
Yield: 0.4 %

Procedure:
Intermediate compound (R,S)-tert-butyl 4-(2-((4-fluorophenyl)(hydroxy)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-7-yloxy)piperidine-1-carboxylate was obtained (105 mg) following the procedure described in Example 38 for the synthesis of (R,S)-(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2-morpholinoethoxy)quinazolin-2-yl)methanol, substituting 4-(2-chloroethyl)morpholine in Example 38 with tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate. To the crude tert-butyl 4-(2-((4-fluorophenyl)(hydroxy)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-7-yloxy)piperidine-1-carboxylate (100 mg, 18.2 mmol) in a flask at 0° C. was added 4N HCl/dioxane (5 mL). After stirring for 20 h, the solvent was removed and the residue was shaken with DCM and aq sodium bicarbonate. The solvents were removed, and the remaining residue was extracted with MeOH/DCM. The extracts were concentrated and the residue was chromatographed on reverse phase HPLC to afford (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)-7-(piperidin-4-yloxy)quinazolin-2-yl)methanol as a white solid (32 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (m, 2H) 1.89 (s, 13H) 1.89 (s., 3H) 1.98 (m, 2H) 2.68 (m, 2H) 2.99 (m, 2H) 4.66 (m, 4H) 5.62 (s, 1H) 5.76 (s, 1H) 6.36 (b., 1H) 7.08-7.18 (m, 4H) 7.52 (m, 2H) 8.45 (m., 1H), 10.29 (bs, 1H). LC-MS (ESI) m/z 449 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:15](=[O:16])[C@H:14]3[CH2:17][CH2:18][CH2:19][C@H:13]3[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24][CH2:25][C:26](Br)=[O:27]>>[Br:24][CH2:25][C:26]([N:12]1[C@@H:13]2[CH2:19][CH2:18][CH2:17][C@@H:14]2[C:15](=[O:16])[N:9]([CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:10]2[CH:23]=[CH:22][CH:21]=[CH:20][C:11]1=2)=[O:27]
Reactant: O=C(Br)CBr
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1CCc1ccccc1
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CBr)c2ccccc2N1CCc1ccccc1
Yield: 72 %

Procedure:
Employing (3aR*,10aS*)-9-(2-phenylethyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta-[e][1,4]diazepin-10(1H)-one and bromoacetyl bromide, the titled compound was synthesized by substantially the same procedure as in Working Example 185. Yield 72%. Oily product.
Reaction SMILES: [CH2:1](O)[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH3:10].S(Cl)([Cl:14])=O.N1C=CC=CC=1>O1CCCC1>[CH2:1]([Cl:14])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: COCCOCCOCCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCCOCCOCCCl
Yield: 90 %

Procedure:
101.16 g (≈0.6 mole) of 3,6,9-trioxadecanol are reacted with 44.6 ml (≈0.6 mole) of thionyl chloride and 51.7 ml (≈0.64 mole) of pyridine in a tetrahydrofuran solution by refluxing for 12 hours to give 3,6,9-trioxadecyl chloride ##STR19## The mixture is cooled and then extracted several times with methyl ethyl ketone (MEK), and the MEK phase is then neutralized with NaHCO3 and dried over Na2SO4. After the MEK has been removed, the residue is distilled under 30 Pa and at 30°-37° C. Yield: 90%.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].OB(O)[C:23]1[CH:28]=[C:27]([F:29])[C:26]([O:30][C:31]([F:34])([F:33])[F:32])=[C:25]([F:35])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].O>[F:29][C:27]1[CH:28]=[C:23]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@H:9]3[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]3)=[CH:15][CH:16]=2)[CH:24]=[C:25]([F:35])[C:26]=1[O:30][C:31]([F:32])([F:33])[F:34]
Reactant: OB(O)c1cc(F)c(OC(F)(F)F)c(F)c1
Reactant: CCCCC[C@H]1CC[C@H](COc2ccc(I)cc2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCC[C@H]1CC[C@H](COc2ccc(-c3cc(F)c(OC(F)(F)F)c(F)c3)cc2)CC1

Procedure:
A mixture of 5.0 g (13 mmol) of 4-(trans-4-pentylcyclohexyl) methoxyiodo benzene, 4.1 g (34 mmol) of dihydroxy (3,5-difluoro-4-trifluoromethoxyphenyl) borane, 3.0 g of 5% palladium on activated charcoal and 7.2 g (136 mmol) of sodium carbonate was refluxed in toluene/alcohol/water (1/1/1 v/v, 75 ml) under a nitrogen atmosphere for 3 days. After cooling, the reaction solution was added with water (100 ml) and extracted twice with toluene (100 ml). An organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent therein was distilled off under a reduced pressure. The residue thus obtained was purified by column chromatography (silica gel/heptane:toluene=5:1) and recrystallization (heptane-ethanol) to obtain colorless crystals of 2,6-difluoro-4-(4-(trans-4-pentylcyclohexyl) methoxyphenyl) trifluoromethoxybenzene.