Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)nc1NC(=S)Oc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3nc(C)c(C)nc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)thiocarbamate (200 mg, 0.69 mmol) and 1-(3,5-dimethoxyphenyl)piperazine (154 mg, 0.69 mmol) were dissolved in anhydrous tetrahydrofuran (25 ml) and thereto DBU (105 mg, 0.69 mmol) was added. The mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: Brc1cccs1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1ccc(-c2cn(-c3cccs3)cn2)cc1
Temperature: 110 °C
Yield: 2.9 %

Procedure:
A suspension of 4-phenyl-1H-imidazole (500 mg, 3.47 mmol), 2-bromothiophene (0.4 ml, 4.16 mmol), CuI (131.9 mg, 0.694 mmol, trans-N,N′-dimethylcyclohexanediamine (0.08 ml, 0.694 mmol), and K2CO3 (1.43 g, 10.4 mmol) in dioxane (5 ml) was heated at 110° C. in a sealed tube for 16 hours. The reaction mixture was then diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by column chromatography using 15-20% ethyl acetate/hexanes to yield the desired 4-phenyl-1-(thiophen-2-yl)-1H-imidazole (23 mg, 3%). The HPLC purity of the final product was 99.7%. LC-MS [M+H] 227 (C13H10N2S+H expected 227.06).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(OCC)(=O)C>C1COCC1>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][C:12]([F:11])([F:21])[F:22])=[CH:15][CH:16]=2)[N:3]=[CH:4][N:5]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1c(Cl)ncnc1Nc1ccc(OC(F)(F)F)cc1
Reaction time: 2 h

Procedure:
To a solution of 4,6-Dichloro-pyrimidine-5-carbaldehyde (3.06 g, 17.5 mmol) in THF (15 mL) was added 4-trifluoromethoxyaniline (3.09 g, 17.45 mmol) at 0° C. The mixture was stirred for 2 h and ethyl acetate (100 mL) was added. The organic layer was separated from brine, dried (Na2SO4) and concentrated to yield crude title compound as yellow solids. The compound was then purified by silica gel column chromatography to give the title compound as yellow crystals. (2.9 g, 55%). MS m/z 318.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:15]2[CH:14]=[N:13]1.C(N(CC)CC)C.Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[CH:39]([O:38][C:36]([N:25]1[CH2:24][CH2:23][CH:22]([O:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=4[F:1])[N:13]=[CH:14][C:15]=23)[CH2:27][CH2:26]1)=[O:37])([CH3:41])[CH3:40]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)c(F)c1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 50 mL round-bottom flask was placed 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (80 mg, 0.2 mmol) and triethylamine (200 μl). DMF (3 mL) was added to completely dissolve the solid material. The reaction flask was immersed in an ice-bath. Isopropyl chloroformate (1.0M in toluene, 0.22 mL) was added to the solution and the mixture was stirred 2 h under N2 at 0° C. After all of the starting amine was completely converted as indicated by LCMS, the reaction was stopped by quenching with water. The reaction mixture was then concentrated under vacuum and purified by preparative HPLC to give 4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (Compound A129). 1H NMR (CDCl3, 400MHz) δ 1.27 (d, 6H), 1.9 (m, 2H), 2.12 (m, 2H), 3.13 (s, 3H), 3.40 (m, 2H), 3.91 (m, 2H), 4.97 (m, 1H), 5.63 (m, 1H), 7.95 (m, 3H), 8.34 (s, 1H), 8.63 (s, 1H). Exact mass calculated for C21H24FN5O5S: 477.15, found 478.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:4][CH:3]=1.O[C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1>ClCCl>[CH2:31]([O:30][C:28]([C:27]1[CH:33]=[CH:34][C:24]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:25][CH:26]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OCCCCCCCCCCCCCOc1ccc(Cl)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OCCCCCCCCCCCCCOc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
A mixture of 1-(4-chlorophenoxy)-13-tridecanol (3.27 g.; 0.01 M.), ethyl 4-hydroxybenzoate (2.49 g.; 0.015 M) and dicyclohexylcarbondiimide (3.09 g.; 0.015 M.) was heated at 100°-105° C. for 5 hours with stirring. The reaction mixture was cooled to room temperature, dichloromethane was added and the mixture was filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product (5.95 g.) was chromatographed on silica-gel (250 g.) in dichloromethane to give 1-(4-ethoxycarbonylphenoxy)-13-(4-chlorophenoxy)-tridecane (1.82 g.; 38%). M.P. 75°-7° C.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21]CC)=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.O>C(O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]([OH:21])=[O:20])[CH2:17][CH2:18]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Sodium hydroxide solution (100 ml at 40% w/v) was added to a stirred suspension of the above ester (78.0 g) in ethanol (200 ml)/water (100 ml). Water (100 ml) was added and the reaction mixture heated to reflux and reflux maintained for 30 minutes. The reaction mixture was cooled and the crystalline sodium salt was collected. This sodium salt was suspended in water (350 ml) and glacial acetic acid added to adjust the pH of the solution to 5. The mixture was stirred for 1 hour and the colourless solid collected, washed with water and dried to give, as a colourless solid, 1-(4-bromophenylsulphonyl)piperidine-4-carboxylic acid (68.4 g): m.p. 225-227° C.; microanalysis, found: C, 41.0; H, 3.7; N, 3.9%; C12H14BrNO4S requires: C, 41.4; H, 4.1; N 4.0%; NMR: 1.41-1.63(m, 2H), 1.73-1.93(m, 2H), 2.11-2.30(m, 1H), 2.44(t, 2H); 3.28-3.60(m, 2H), 7.62(d, 2H) 7.89(d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH:11]1[CH:15]=[C:14]([CH2:16][NH2:17])[O:13][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][CH2:16][C:14]2[O:13][CH:12]=[CH:11][CH:15]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: NCc1ccco1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccco1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A solution of 4-chlorobenzoyl chloride (3.2 g, 18.5 mol) in 50 ml dry CH2Cl2 was added over 30 min to a stirred solution of 2-furfurylamine (2 g, 20.6 mol) and iPr2NEt (7 ml, 41 mol) in CH2Cl2 (200 ml) at 0° C. The reaction was allowed to warm to room temperature over 3 h. The mixture was diluted with 200 ml of CH2Cl2, washed twice with HCl aq. (1N) and dried over MgSO4. Evaporation of the solvent afforded 4 g (83%) of the title benzamide as a white solid: 1H NMR: (DMSO-d6) δ 9.05 (t, J=5.7 Hz, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.57 (m, 1H), 7.53 (d, J=8.7 Hz, 2H), 6.40 (dd, J=3.7, 1.1 Hz, 1H), 6.28 (d, J=3.7 Hz, 1H), 4.46 (d, J=5.6 Hz, 2H). M/Z APCI: 236.6 (M+1), 234.8 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:14][C:15]([C:17]2[CH:22]=[C:21]([C:23](OC)=[O:24])[CH:20]=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=2)=[O:16])[CH:7]=[C:8]([C:10](OC)=[O:11])[CH:9]=1)([O-:3])=[O:2].[NH2:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34]>>[N+:1]([C:4]1[CH:5]=[C:6]([NH:14][C:15]([C:17]2[CH:22]=[C:21]([C:23]([NH:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])=[O:24])[CH:20]=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=2)=[O:16])[CH:7]=[C:8]([C:10]([NH:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: NCC(O)CO
Reactant: COC(=O)c1cc(NC(=O)c2cc(C(=O)OC)cc([N+](=O)[O-])c2)cc([N+](=O)[O-])c1
Product: O=C(NCC(O)CO)c1cc(NC(=O)c2cc(C(=O)NCC(O)CO)cc([N+](=O)[O-])c2)cc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
3-Nitro-5-methoxycarbonylphenylaminocarbonyl-(3'-nitro-5'-methoxycarbonylbenzene) (1.21 g, 3.0 mmol) was suspended in aminopropan-2,3-diol (0.55 g, 6.0 mmol) and the mixture was heated to 90° C. After 30 min, the pressure was reduced to 200 mm Hg and heating was continued for 90 min. The product was purified by preparative HPLC. Yield: 0.73 g (47%).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].Br[C:7]1[N:11]([C@H:12]2[O:24][C@@H:23]([CH2:25][O:26]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@@H:13]2[O:14]C(=O)C)[C:10]2[CH:30]=[C:31]([Cl:35])[C:32]([Cl:34])=[CH:33][C:9]=2[N:8]=1.C(O)C>CN(C=O)C>[Cl:34][C:32]1[C:31]([Cl:35])=[CH:30][C:10]2[N:11]([C@H:12]3[O:24][C@@H:23]([CH2:25][OH:26])[C@H:18]([OH:19])[C@@H:13]3[OH:14])[C:7]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[N:8][C:9]=2[CH:33]=1
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)CN
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)CNc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 75 °C
Reaction time: 24 h

Procedure:
Isobutylamine (10 ml ) and 2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.6 g, 1.1 mmol) were combined with absolute ethanol (50 mL) and stirred at 75° C. for 24 h. The reaction mixture was concentrated and purified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:20 methanol:dichloromethane (500 mL), then 1:9 methanol:dichloromethane to give a tan solid (0.39 g, 1.0 mmol. 90%); m.p. 136° C.; [a]20D =(-) 28.4 (c=0.5 DMF).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=O)[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][NH:15]2)=[CH:10][CH:9]=1>>[Cl:3][C:12]1[C:11]2[C:16](=[CH:17][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)[N:15]=[CH:14][C:13]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c[nH]c2cc(OC)ccc2c1=O
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1Cl
Temperature: 25 °C
Yield: 73 %

Procedure:
Phosphorus oxychloride (88 ml) was added to ethyl 7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (58 g, 235 mmol) and the mixture was heated at reflux for 45 minutes under anhydrous conditions. Upon cooling to ambient temperature, phosphorus oxychloride was evaporated and the solid residue was added in portions to a mixture of ammonia (150 ml) and ice (200 g). External cooling as well as further addition of ammonia to maintain the pH around 8 was needed during this hydrolysis step. The aqueous phase was extracted with dichloromethane and the organic phase was washed with water and brine, dried (MgSO4) and concentrated to about 300 ml. Pentane (400 ml) was added and the precipitate formed collected by filtration. Drying under vacuum gave 4-chloro-3-ethoxycarbonyl-7-methoxyquinoline (45.5 g, 73%).
Reaction SMILES: [CH:1]1([NH:6][S:7]([C:10]2[C:11]3[CH:12]=[CH:13][C:14](=[O:27])[NH:15][C:16]=3[CH:17]=[C:18]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:19]=2)(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:35])C(=O)C1>>[Br:35][C:13]1[C:14](=[O:27])[NH:15][C:16]2[CH:17]=[C:18]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:19]=[C:10]([S:7]([NH:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)(=[O:9])=[O:8])[C:11]=2[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(=O)[nH]c2c1
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2cc(Br)c(=O)[nH]c2c1

Procedure:
A solution of N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydroquinoline-5-sulfonamide (100 mg, 0.26 mmol) and NBS (150 mg, 3 equiv) was heated at 80° C. for 1 hour. The reaction mixture was partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and purified on silica gel (rf=0.75 in ethyl acetate) to give 3-bromo-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydroquinoline-5-sulfonamide as a white powder.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)(=O)C>CC(OC)(C)C>[CH2:11]([C@@:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])([OH:4])[CH:2]=[O:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CC(=O)Cl
Solvent: COC(C)(C)C
Product: O=C[C@](O)(Cc1ccccc1)[C@H](O)[C@H](O)CO
Temperature: 35 °C
Reaction time: 8 h

Procedure:
D-Arabinose (50 kg, 330.04 moles) and benzyl alcohol (132.2 kg, 4.33 equivalents) were stirred and heated to 35° C. Acetyl chloride (10.9 kg, 0.42 equivalents), keeping the temperature <45° C., then stirred 50° C. overnight. The mixture was cooled to 20° C. and diluted with MTBE (600 kg). The mixture was stirred for 0.5−5 h. The solids were collected by filtration and washed with MTBE (2×40 kg). The material was dried in a filter drier. 2-Benzyl-D-arabinose was obtained as an off-white solid, 70.9 kg (88.6%). 1H NMR (300 MHz, DMSO-d6): δ 7.32 (m, 5H), 4.76 (s, 1H), 4.66 (d, J=12 Hz, 1H), 4.59 (m, 3H), 4.45 (d, J =12 Hz, 1H), 3.70 (m, 4H), 3.47(dd, J=12, 3 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO.S(OC)(O[CH3:22])(=O)=O>O>[CH3:22][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A mixture of 38 g of 4-phenylphenol, 9 g of sodium hydroxide, 200 ml of methanol and 20 ml of water was heated. 28 g of dimethyl sulfate was dropped in the mixture with stirring at 50° C. After one hour, 20 ml of 10N-sodium hydroxide was dropped in the solution and continued stirring for 2 hours. The crystals were obtained after the solution was cooled to room temperature. After washing with water and methanol for several times, 30 g of 4-methoxybiphenyl (O) was obtained. 154 g of (O) was dissolved with mixed solution of 200 ml of chloroform and 75 ml of carbon tetrachloride, and then 11 g of aluminum chloride powder was added to the solution. 14 g of octanic acid chloride was added to the solution with stirring after changing colour of the solution to greenish blue. 150 ml of ice-water and 5 ml of conc. hydrochloric acid was added, after refluxing 5 hours. The water layer was removed, then the organic layer was washed with 0.1N hydrochloric acid and dehydrated with magnesium sulfate anhydride, and then evaporated after filtration to obtain crude crystals of 4'-nonylcarbonyloxy-4-methoxybiphenyl (P). 13 g of (P), 1 g of 10% palladium-carbon, 130 ml of acetic acid were put into an autoclave and then gave the pressure to 25 kg/cm2 by using hydrogen. (P) was reduced by heating for 3 hours at 80° C. After substituting nitrogen for hydrogen, palladium-carbon was separated by filtrating the reacted solution. 4'-decyl-4-methoxybiphenyl (Q) was obtained after cooling and drying. 8 g of (Q), 90 ml of acetic acid 30 ml of hydrogen bromide water solution were mixed and refluxed for 5 hours to obtain crude crystals. After cooling, the crude crystals were washed with methanol to crystallize 5.5 g of 4-(4'-octylphenyl)phenol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)=[O:23])=[CH:4][CH:3]=1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH:45]([CH3:47])[CH3:46])=[CH:39][CH:38]=1>>[CH2:44]([O:43][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=3[C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]3)=[O:23])=[CH:4][CH:3]=2)=[CH:42][CH:41]=1)[CH:45]([CH3:47])[CH3:46]
Reactant: COC(=O)c1ccc(OCCCc2ccc(O)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Reactant: CC(C)COc1ccc(CCl)cc1
Product: COC(=O)c1ccc(OCCCc2ccc(OCc3ccc(OCC(C)C)cc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Methyl 4-(3-{4-[(4-isobutoxybenzyl)oxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate is prepared in analogy to the process described in Example 34 from methyl 4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate and 1-(chloromethyl)-4-isobutoxybenzene.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([F:9])=[CH:7][CH:8]=1.[NH3:21].CO>C(Cl)Cl>[NH2:21][CH2:2][C:3]1[C:4]([Cl:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([F:9])=[CH:7][CH:8]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CBr)c2Cl)c1
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CN)c2Cl)c1
Yield: 100 %

Procedure:
The title compound was prepared as described herein using 3-{[3-(bromomethyl)-2-chloro-6-fluorophenyl]oxy}-5-chlorobenzonitrile (728 mg, 1.941 mmol) and NH3 in MeOH (27.7 ml, 194 mmol, 7.0 N) in CH2Cl2 (20 ml) to give the title compound as a white solid (602 mg, 100%) which was used for the next step without purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.37-7.43 (1H, m) 7.34 (1H, s) 7.12-7.21 (2H, m) 6.99 (1H, br. s.) 3.98 (2H, br. s.) 1.65-1.89 (2H, m). LCMS: m/z 311 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.CN(C)C=O.[Cl-].[K+].[CH2:23]1[O:25][CH2:24]1>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:23][CH2:24][OH:25])[C:10]1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3=O
Reactant: C1CO1
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCO)C(=O)CCC1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
199 g. (1mole) of 6-methyl-1,2,3,4-tetrahydrocarbazol-1-one dissolved in 2000 ml. of dimethylformamide are taken initially and 5.6 g. (0.1 mole) of potassium chloride dissolved in 200 ml. of water are added. Thereafter 66.1 g.=74.2 ml. (1.5 mole) of ethyleneoxide are added at room temperature and heated up to 50° C. within 30 minutes, a maximum pressure of 0.2 to 0.5 bar being generated. Stirring is done for 20 hours at 50° C., the solvent is distilled off in a vacuum and, the residue is stirred with a mixture of 800 ml. water and 10 ml. of glacial acetic acid; the product (which takes a crystalline form) is filtered with suction, washed with 500 ml. water and dried at 40° C. in vacuo.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:30][CH:19]3[CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:30][CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CC2CN(C(=O)OC(C)(C)C)CC2C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
To a solution of tert-butyl 5-((5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.66 g, 4.01 mmol) in DCM (20 mL) was added a solution of HCl in EtOAc (20 mL, 80 mmol). The reaction mixture was stirred at rt for 1 h and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with saturated Na2CO3 aqueous solution, then extracted with DCM (250 mL×3). The combined organic phases were washed with brine (250 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/5) to give the title compound as a beige solid (505.2 mg, 40.2%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1>[CH3:35][C:20]1[C:21]([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:34])=[CH:22][CH:23]=[CH:24][C:19]=1[C:8]1[C:7]2[C:6]3[C:14](=[CH:15][C:3]([CH2:2][NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:4][CH:5]=3)[NH:13][C:12]=2[C:11]([C:16]([NH2:18])=[O:17])=[CH:10][CH:9]=1
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CN)ccc4c23)cccc1N1Cc2ccccc2C1=O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CNS(C)(=O)=O)ccc4c23)cccc1N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A solution of 7-(aminomethyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 33-1, 60 mg, 0.065 mmol) and TEA (23 μL, 0.163 mmol) in THF (1.3 mL) was treated with methanesulfonyl chloride (5.6 μL, 0.072 mmol) and the mixture was stirred at rt overnight. The mixture was concentrated and purified by preparative HPLC. The appropriate effluent fractions were concentrated and partitioned between EtOAc and NaHCO3 (aq). The organic phase was dried and concentrated, and the residue was purified further by column chromatography (eluting with a gradient from 40:60 hexane-EtOAc to EtOAc) to provide 4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-7-(methylsulfonamidomethyl)-9H-carbazole-1-carboxamide as an off-white solid (7 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ 11.57 (1H, s), 8.19 (1H, br. s.), 8.02 (1H, d, J=7.7 Hz), 7.81 (1H, d, J=7.7 Hz), 7.73 (1H, s), 7.69 (2H, d, J=3.7 Hz), 7.61-7.65 (1H, m), 7.54-7.61 (2H, m), 7.51 (2H, t, J=7.7 Hz), 7.35 (1H, dd, J=7.5, 1.1 Hz), 7.00-7.08 (2H, m), 6.93-6.99 (1H, m), 4.88-5.05 (2H, m), 4.26 (2H, d, J=5.9 Hz), 2.87 (3H, s), 1.84 (3H, s). Mass spectrum m/z 539.2 (M+H)+.