Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[CH3:26])[C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][C:4]=1[CH3:14].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClC(Cl)C.N1C=CC=CC=1>[N:9]1([C:7]2[CH:6]=[CH:5][C:4]([CH3:14])=[C:3]([CH:8]=2)[CH:2]([C:15]2[C:16]([CH3:26])=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][C:24]=2[CH3:25])[O:1][C:39](=[O:40])[C@@H:38]([NH:37][S:34]([C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH3:42])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: COC(=O)c1cc(C)c(C(O)c2cc(-n3ccnc3)ccc2C)c(C)c1
Reactant: C[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)c(C(OC(=O)[C@H](C)NS(=O)(=O)c2ccc(Cl)cc2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Yield: 100.3 %

Procedure:
Methyl (±)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoate (9.2 g) was suspended in dichloroethane (110 ml) and pyridine (3.15 ml), and a solution of (S)-2-(4-chlorobenzenesulfonylamino)propionyl chloride (8.9 g) in dichloroethane (25 ml) was added dropwise over 5 minutes with stirring under ice-cooling. The mixture was stirred at room temperature for 3 hours and the reaction mixture was washed successively with water, 5% citric acid, 5% potassium carbonate and water. The organic layer was separated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 15.7 g of methyl (±)4-[5-(1-imidazolyl)-α-{(S)-2-(4-chlorobenzenesulfonylamino)propionyloxy}-2-methylbenzyl]-3,5-dimethylbenzoate as a pale-yellow oil. This was crystallized from ethyl acetate (27 ml) and isopropyl ether (108 ml) and the obtained crystals were recrystallized from ethyl acetate (15 ml) and isopropyl ether (30 ml) to give 5.2 g of methyl (S)-4-[5-(1-imidazolyl)-α-{(S)-2-(4-chlorobenzenesulfonylamino)propionyloxy}-2-methylbenzyl]-3,5-dimethylbenzoate as white crystals, melting point 126-128° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[O:18].N([O-])=O.[Na+].Cl>O.CN(C)C=O>[CH:13]1[CH:12]=[C:11]([N:16]2[NH:7][N:6]=[N:5][C:17]2=[O:18])[C:10]([Cl:9])=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nn[nH]n1-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
Anhydrous aluminum chloride (1.5 g) was added to N,N-dimethylformamide (20 ml) under ice cooling and the resulting mixture was stirred for fifteen minutes. To the mixture was added sodium azide (0.65 g), followed by a 15 minute-stirring, addition of 2-chlorophenylisocyanate (1.53 g) and heating at 70° to 75° C. for three hours, in that order. After cooling, the reaction mixture was added with stirring to a mixture of sodium nitrite (1 g), water (200 ml) and ice (100 g) and the resulting mixture was acidified was 10% hydrochloric acid (until a potassium iodide starch paper became discolored), followed by extraction with ethyl acetate. The thus obtained ethyl acetate layer was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (eluent: hexane:ethyl acetate = 2:1) to obtain the desired 1-(2-chlorophenyl)-5(4H)-tetrazolinone (1.8 g) having a m.p. in the range of from 124.5° C. to 125.5° C. in a yield of 92% of theory.
Reaction SMILES: C([Li])(C)(C)C.C(O[C:11](=[O:24])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=1)(C)(C)C.[O:25]=[C:26]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][C:39]([F:42])([F:41])[F:40])C(OCC)=O.[Cl-].[NH4+]>C(OCC)(=O)C.O1CCCC1.C(OCC)C.CCCCCCC>[Cl:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[C:20]([F:21])([F:22])[F:23])[NH:12][C:11](=[O:24])[C:26]2([OH:25])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][C:39]([F:40])([F:41])[F:42]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)C(=O)c1ccccc1OC(F)(F)F
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=C1Nc2cc(C(F)(F)F)c(Cl)cc2C1(O)c1ccccc1OC(F)(F)F
Temperature: -40 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
21 mL of a heptane solution of 1.6 mol/L tert-butyllithium was added dropwise under −78° C. cooling to a 30 mL diethyl ether solution of 4.00 g of tert-butyl[4-chloro-3-(trifluoromethyl)phenyl]carbamate, and the reaction mixture was stirred for 1 hour. The temperature was then raised to −40° C., and the reaction mixture was stirred for 2.5 hours at that temperature. The reaction mixture was cooled back down to −78° C., a 15 mL tetrahydrofuran solution of 4.25 g of ethyl oxo[2-(trifluoromethoxy)phenyl]acetate was added dropwise, and the reaction mixture was stirred for 2 hours at the same temperature. The temperature was then raised to room temperature, and the reaction mixture was stirred for 15 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with saturated brine and dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel 60, mobile phase: ethyl acetate/hexane=1/4; v/v) to obtain 3.57 g of the titled compound (colorless powder).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]([CH2:34][CH2:35][CH3:36])[C:14]3[CH:33]=[CH:32][C:17]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]([CH2:34][CH2:35][CH3:36])[C:14]3[CH:33]=[CH:32][C:17]([CH2:18][O:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCN(Cc1nc(-c2ccccc2)cs1)c1ccc(COc2ccc(CCC(=O)OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCCN(Cc1nc(-c2ccccc2)cs1)c1ccc(COc2ccc(CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
To a mixture of methyl 3-[4-({4-[[(4-phenyl-1,3-thiazol-2-yl)methyl](propyl)amino]benzyl}oxy)phenyl]propanoate (240 mg, 0.48 mmol), ethanol (5 mL) and tetrahydrofuran (5 mL) was added 2N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4-4:1 in volume ratio) to give the title compound (75 mg, yield 32%) as colorless prism crystals (recrystallized from acetone-heptane).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH:10]1([OH:16])[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1.C(=O)(O)[O-].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:12]2[CH2:13][CH2:14][CH2:15][C:10](=[O:16])[CH2:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: OC1C=CCCC1
Reactant: COc1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: COc1cccc(C2CCCC(=O)C2)c1
Temperature: 60 °C
Reaction time: 80 h
Yield: 19.6 %

Procedure:
3-Iodoanisole (75g), 2-cyclohexen-1-ol (15g), potassium bicarbonate (45 g), tetrabutylammonium chloride (45 g) and palladium acetate (1.8 g) were heated and stirred for 80 hours at an external temperature of 60° C. and under an argon air flow, using acetonitrile (300 ml) as the solvent. After concentrating the reaction solution under reduced pressure, an aqueous ammonium chloride solution was added and extraction was performed with diethyl ether. After washing the organic layer with saturated saline, it was dried with anhydrous magnesium sulfate. The crude product obtained from distilling off the solvent under reduced pressure was separated and purified by silica gel chromatography (n-hexane:ethyl acetate=20:1) to give 6.1 g of 3-(3-methoxyphenyl) cyclohexanone (19.6% yield).
Reaction SMILES: C([Si]([C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>C1COCC1>[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])#[CH:8]
Reactant: CC[Si](C#Cc1ccccc1C(C)C(N)=O)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccccc1C(C)C(N)=O

Procedure:
A cooled (0° C. water/ice bath) solution of 2-(2-((triethylsilyl)ethynyl)phenyl)propanamide I14 (7.17 g, 24.9 mmol) in THF (40 mL) was slowly treated with a 1.0 M solution of tetrabutylammonium fluoride in THF (26.2 mL, 26.2 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 5 minutes before a sat. aq. NaHCO3 solution was added. The mixture was extracted with EtOAc (3 times), the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (Combiflash Rf, 30-80% EtOAc in cyclohexane) to give the title compound K7 as a cream solid (3.69 g, 85%). LCMS-B: rt 3.031 min; m/z 174 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:22]([NH:24][C@@H:25]([C:27]([NH2:29])=[O:28])[CH3:26])=[O:23])[CH2:18][C:19](=[O:21])[OH:20])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=O)(C)(C)C.O.[ClH:31].O1CCOCC1>C(O)(=O)C>[ClH:31].[NH2:8][C@H:9]([C:14]([NH:16][C@H:17]([C:22]([NH:24][C@@H:25]([C:27]([NH2:29])=[O:28])[CH3:26])=[O:23])[CH2:18][C:19](=[O:20])[OH:21])=[O:15])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CSCC[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O

Procedure:
12.54 Parts of N-t-butoxycarbonyl-L-methionyl-L-aspartyl-D-alanine amide is dissolved in 107 parts by volume glacial acetic acid and 51.66 parts by volume of a 5.6 M solution of HCl/dioxane. The resultant mixture is stirred for 20 minutes and then stripped under reduced pressure to afford a solid. The solid is triturated with ethyl ether, cooled, and the resultant product washed with cold ethyl ether and vacuum dried. This solid is purified by countercurrent distribution to afford L-methionyl-L-aspartyl-D-alanine amide hydrochloride hydrated with 2/3 mole of water per mole, and represented by the following formula.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16](O)=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.S(Cl)([Cl:26])=O.CN(C)C=O>ClCCl>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([Cl:26])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: O=S(Cl)Cl
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)Cl)C(=O)OC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid (mycophenolic acid) (32.0 g) was dissolved in dichloromethane (250 ml), followed by the addition of thionyl chloride (25.9 ml) and dimethylformamide (0.3 ml). The reaction mixture was stirred at room temperature for 3 hours, after which the volatile components were removed under vacuum to afford E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid chloride as an oil.
Reaction SMILES: [Cl-].C([N+]1C=CC=CC=1)CCCCCCCCCCC.O.[C:21](Cl)(Cl)=[O:22].[Cl:25][C:26]1[CH:27]=[C:28]([NH2:35])[C:29](=[CH:33][CH:34]=1)[C:30]([OH:32])=[O:31]>C1(C)C=CC=CC=1>[CH:34]1[C:26]([Cl:25])=[CH:27][C:28]2[NH:35][C:21]([O:31][C:30](=[O:32])[C:29]=2[CH:33]=1)=[O:22]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C(Cl)Cl
Agent: CCCCCCCCCCCC[n+]1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Yield: 67 %

Procedure:
According to the same manner as in Example 4, except that the flask was changed to 300 ml flask, laurylpyridinium chloride was not used, 103 g of water was added, and that amounts of toluene, phosgene and 4-chloroanthranilic acid were changed to 34 g, 40 g and 35 g, respectively, 35.6 g of 7-chloroisatoic anhydride (purity: 73.8%) was obtained. The yield was 67% and the volume efficiency was 9 g/100 ml.
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:27]2[C:28]([CH3:45])=[C:29]([NH:33][CH2:34][C:35]4[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:36]=4[C:37]([OH:39])=O)[CH:30]=[CH:31][CH:32]=2)=[CH:6][N:5]=1)=[CH:15][CH:14]=[C:13]([NH:17][C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH:12]=3)(=[O:3])[NH2:2].CCN(C(C)C)C(C)C.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N:33]4[CH2:34][C:35]5[C:36](=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=5)[C:37]4=[O:39])[C:28]=2[CH3:45])=[CH:6][N:5]=1)=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:19])[O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:12]=3)(=[O:3])[NH2:2]
Reactant: Cc1c(NCc2ccc(Cl)cc2C(=O)O)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(NC(=O)OCC[Si](C)(C)C)ccc3c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(NC(=O)OCC[Si](C)(C)C)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Temperature: 25 °C
Yield: 42 %

Procedure:
A solution of 2-((3-(1-carbamoyl-7-((2-(trimethylsilyl)ethoxy)carbonylamino)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-chlorobenzoic acid (0.343 g, 0.533 mmol), DIPEA (0.279 mL, 1.599 mmol), N-methylmorpholine (0.469 mL, 4.26 mmol) and BOP (0.613 g, 1.386 mmol) in DMF (5.33 mL) under nitrogen was heated at 45° C. for 45 min. The reaction was cooled to room temperature, dissolved in EtOAc (100 mL) and washed with water (3×25 mL) and brine (25 mL), dried over MgSO4, and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 40 g column eluting with 30-75% EtOAc/hexanes. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.140 g, 0.224 mmol, 41.9% yield) as a light orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=O.Cl.[CH3:11][NH:12][CH3:13].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(=O)(O)[O-].[Na+].C(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:6]([CH2:7][N:12]([CH3:13])[CH3:11])[CH:5]=[N:4][CH:3]=1
Reactant: CNC
Reactant: O=Cc1cncc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
5-Bromonicontinaldehyde (XXV) (5.01 g, 26.9 mmol) and dimethylamine hydrochloride (4.39 g, 53.8 mmol) were suspended in 1,2-dichloroethane (108 mL). Triethylamine (7.50 mL, 53.8 mmol) was added, and the reaction was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (8.56 g, 40.4 mmol) was added, and the reaction was further stirred at room temperature overnight. The reaction was diluted with saturated sodium bicarbonate solution and DCM. The organic layer was separated, washed sequentially with water and brine, dried over MgSO4, filtered and concentrated to give 1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (LIV) (1.19 g, 23.9 mmol, 89% yield) as a brown oil: 1H NMR (DMSO-d6) δ ppm 8.59 (d, J=3 Hz, 1H), 8.47 (d, J=2 Hz, 1H), 7.94 (s, 1H), 3.43 (s, 2H), 2.15 (s, 6H); ESIMS found for C8H11BrN2 m/z 215 (M+H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[N:12]([C@H:20]3[CH2:25][CH2:24][C@@H:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)[N:11]=2)=[CH:6][C:5]=1[F:33])[CH3:2].[C:34]1([CH3:43])[CH:39]=[CH:38][CH:37]=[C:36]([N:40]=[C:41]=[O:42])[CH:35]=1>N1C=CC=CC=1>[NH2:19][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:12]([C@H:20]3[CH2:25][CH2:24][C@@H:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)[N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[C:41]([NH:40][C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([CH3:43])[CH:35]=4)=[O:42])=[C:5]([F:33])[CH:6]=3)[C:18]=12
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCNc1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1F
Solvent: c1ccncc1
Product: CCN(C(=O)Nc1cccc(C)c1)c1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
cis-3-[4-(Ethylamino)-3-fluorophenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.177 mmol) was dissolved in pyridine (3 mL) then cooled to 0° C. m-Tolylisocyanate (26 mg, 0.194 mmol) was added to the reaction and stirring was continued at 0° C. for 2.5 hours. The reaction mixture was warmed to room temperature and stirred overnight. Additonal m-tolylisocyanate (13 mg, 0.101 mmol) was added to the reaction mixture and stirring was continued for 1 week. The reaction mixture was concentrated under reduced pressure to give the crude product as a light yellow oil (110 mg). Purification was achieved by RP-HPLC (Waters PrepLC 4000, flow rate: 10 mL/min. λ=254 nm Gradient: 10% to 30% acetonitrile/0.1M aqueous ammonium acetate gradient over 40 minutes; Deltapak C18, 300A, 15 μm, 40×100 mm column). cis-N-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-N-ethyl-N′-(3-methylphenyl)urea was collected as a white solid (10 mg). HPLC-RT: 13.18 min. (flow rate: 1 mL/min λ=254 nm Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300A, 5 μm, 150×3.9 mm column); m/z (MH+)=586.5.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=[CH:9][C:8]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28]C(=O)C)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=[CH:9][C:8]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(OCCCCCOC(C)=O)c(CCC(=O)OCC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCOc1ccc(OCCCCCO)c(CCC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 66.4 %

Procedure:
A solution of 1.0 g (2.2 mmol) of 2-[[5-(acetyloxy)pentyl]oxy]-5-(4-ethoxy-4-oxobutoxy)benzenepropanoic acid ethyl ester from the preceding example, and 0.018 g of p-toluenesulfonic acid monohydrate in 10 mL of ethanol was stirred and refluxed for 30 hr and stirred at room temperature for 21 hr. Most of the ethanol was removed in vacuo and the residue was diluted with water and worked-up with ether in the usual manner (the combined ether extracts were additionally washed with saturated aqueous sodium bicarbonate). The product was purified by flash chromatography on silica gel, eluting with 1:1 hexane-ethyl acetate. There was obtained 0.6 g (66.5%) of 2-[(5-hydroxypentyl)oxy]-5-(4-ethoxy-4-oxobutoxy)benzenepropanoic acid ethyl ester as a viscous oil.
Reaction SMILES: [OH-].[K+].[CH3:3]I.[C:5]1([S:11]([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([SH:25])[N:22]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:29][CH:28]=4)[C:21]=3[CH:39]=2)=[O:16])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>CO.O>[C:5]1([S:11]([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([S:25][CH3:3])[N:22]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:31][CH:32]=4)[C:21]=3[CH:39]=2)=[O:16])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(NS(=O)(=O)c1ccccc1)c1ccc2nc(S)n(Cc3ccc(-c4ccccc4)cc3)c2c1
Reactant: CI
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A 20% potassium hydroxide aqueous solution (0.323 g), 2 ml of water and 0.123 g of methyl iodide were added to a solution of 0.310 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-mercaptobenzimidazole in 5 ml of methanol in this order, and the mixture was stirred at room temperature for 2 hours. The reaction solution was adjusted to a pH of from 5 to 6 with 10% hydrochloric acid. The crystals precipitated were separated through filtration, and were dried to give 0.281 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylthiobenzimidazole (237).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][C:7]=1[CH3:16].[OH-].[Na+]>O1CCOCC1>[OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[CH3:16]
Reactant: COC(=O)c1ccc(OCCCO)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1OCCCO
Temperature: 70 °C
Yield: 83 %

Procedure:
To a solution of methyl 4-(3-hydroxypropoxy)-3-methyl-benzoate (0.9 g, 4.01 mmol) in dioxane (8 mL) was added 1N NaOH (5 mL) and the reaction mixture was heated at 70° C. for 22 hours. The solvent was concentrated in vacuo and the crude residue was dissolved in water (20 mL) and extracted with ethyl acetate (1×20 mL). The aqueous layer was acidified with 1 M HCl solution and extracted with ethyl acetate (2×20 mL). The organics were separated, dried with Na2SO4 and concentrated in vacuo to give 4-(3-hydroxypropoxy)-3-methyl-benzoic acid (0.7 g, 87%) as a white solid. ESI-MS m/z calc. 210.0. found 211.0 (M+1)+; Retention time: 0.95 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 12.5 (bs, 1H), 7.97-7.60 (m, 2H), 7.01 (d, J=8.6 Hz, 1H), 4.57 (s, 1H), 4.11 (t, J=6.2 Hz, 2H), 3.59 (t, J=5.5 Hz, 2H), 2.19 (s, 3H), 1.89 (p, J=6.2 Hz, 2H).
Reaction SMILES: ClC1C=[C:10]2[C:5]([CH2:6][CH2:7][N:8](C3C=NC=CC=3)[C:9]2=O)=[CH:4]C=1.[F:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[F:30])[C:26](=[O:31])[NH:25][CH2:24][CH2:23]2.IC1C=NC=CC=1C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[F:30])[C:26](=[O:31])[N:25]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[CH3:4])[CH2:24][CH2:23]2
Reactant: O=C1c2cc(Cl)ccc2CCN1c1cccnc1
Reactant: O=C1NCCc2cc(F)c(F)cc21
Agent: I[Cu]I
Agent: Cc1ccncc1I
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2cc(F)c(F)cc2C1=O
Yield: 24 %

Procedure:
Using analogous conditions as described in example 1 for the preparation of Compound 1A, 6,7-difluoro-3, 4-dihydroisoquinolin-1(2H)-one (I-49d: 300 mg, 1.6393 mmol) was reacted with 3-iodo-4-methyl-pyridine (359 mg, 1.6393 mmol), 1, 4-dioxane (15 mL), copper iodide (31.2 mg, 0.1639 mmol), trans-N,N′-dimethyl-cyclohexyl-1, 2-diamine (77.3 mL, 0.4917 mmol) and potassium phosphate (868.8 mg, 4.0982 mmol) to afford the crude product. Purification by column chromatography on silica gel (80% ethylacetate in hexane) afforded 110 mg of the product (24% yield).