Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([F:25])[CH:16]=2)[CH:4]=1.[S:27]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])(=[O:29])[NH2:28]>>[S:27]([C:31]1[CH:32]=[C:33]([NH:37][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:26])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([F:25])[CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:34]=[CH:35][CH:36]=1)(=[O:29])(=[O:30])[NH2:28]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(F)c3)nc12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)c(F)c4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-fluoro-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.16) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 528.0 [(M−H)−]; mp 262° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:17][C:16]([CH3:19])([OH:18])[CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[CH2:26]([C:28]1[NH:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1)[CH3:27].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>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]>[CH2:26]([C:28]1[N:29]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]4[CH2:15][C:16]([CH3:19])([OH:18])[CH2:17]4)[N:8]3[CH3:11])=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:3]=2)[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1)[CH3:27]
Reactant: Cn1c(CCN2CC(C)(O)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3CC(C)(O)C3)n(C)c2n1
Temperature: 120 °C
Yield: 73.4 %

Procedure:
A mixture of 1-[2-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-3-methylazetidin-3-ol (80 mg, 0.22 mmol), 2-ethylbenzimidazole (35 mg, 0.24 mmol), Pd2(dba)3 (5 mg, 2.5 mol %), Xphos (10.4 mg, 10 mol %) and Cs2CO3 (107 mg, 0.33 mmol) in dioxane (2.0 mL) was purged with argon gas then heated at 120° C., for 19 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PCC, 0-10% 2 M NH3/MeOH in DCM) to give 458 (77 mg, 74%) as a pale beige solid. LCMS: (Method I): RT 2.39 min; [M+H]+ 477.2. 1H NMR (400 MHz, CHCl3-d): δ 8.01-7.96 (m, 1 H), 7.76-7.72 (m, 1 H), 7.26-7.22 (m, 2 H), 4.45-4.32 (m, 4 H), 3.86 (t, J=4.8 Hz, 4 H), 3.77 (s, 3 H), 3.40 (d, J=7.3 Hz, 2 H), 3.34 (q, J=7.5 Hz, 2 H), 3.14 (d, J=7.3 Hz, 2 H), 3.02 (t, J=7.3 Hz, 3 H), 2.92 (t, J=7.3 Hz, 2 H), 1.53 (s, 3 H), 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: ClCCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Reactant: C1CCNC1
Product: Brc1cnc2[nH]c(-c3ccc(OCCCN4CCCC4)cc3)nc2c1

Procedure:
The title compound was prepared from 6-bromo-2-[4-(3-chloropropoxy)phenyl]-3H-imidazo[4,5-b]pyridine and pyrrolidine using the method described in Example 46.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:9]1.Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][C:19]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:36][CH2:35]2)=[O:21])=[CH:9]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccccc1N1CCN(C(=O)CCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
Triethylamine (1.46 mL, 10.5 mmol) was added to a mixture of 1H-indole-3-propanoic acid (1.36 g, 7.2 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (1.5 g, 6.55 mmol) and 1-hydroxybenzotriazole (1.33g, 7.86 mmol) in tetrahydrofuran (20 mL) and the mixture was stirred at room temperature for 10 min. 1-(3-Dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (1.89 g, 9.8 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was poured into water and extracted with ethyl acetate. The combined organic fractions were washed with saturated aqueous sodium carbonate and water, dried (MgSO4), and the solvent was evaporated under reduced pressure . The residue was triturated with hexane to give the title compound as a colorless solid (2.1 g, 88%). 1H NMR (360 MHz, CDCl3) δ8.00 (1H, br s), 7.63 (1H, d, J 7.6 Hz), 7.36 (1H, d, J 8.0 Hz), 7.10-7.00 (2H, m), 6.94-6.80 (3H, m), 3.85 (3H, s), 3.80 (2H, t, J 5.0 Hz), 3.52 (2H, t, J 5.0 Hz), 3.14 (2H, m), 2.95 (2H, t, J 5.0 Hz), and 2.77 (4H, m). m/z (ES+) 364 (M+1).
Reaction SMILES: C(Cl)(Cl)=O.[Cl:5][C:6]1[S:10][C:9]([NH:11]C(=O)C)=[C:8]([S:15](=[O:24])(=[O:23])[NH:16][C:17](=S)[NH:18][CH:19]([CH3:21])[CH3:20])[CH:7]=1.C(N(CC)CC)C>O1CCCC1>[Cl:5][C:6]1[S:10][C:9]2[NH:11][C:17]([NH:18][CH:19]([CH3:20])[CH3:21])=[N:16][S:15](=[O:23])(=[O:24])[C:8]=2[CH:7]=1
Reactant: CC(=O)Nc1sc(Cl)cc1S(=O)(=O)NC(=S)NC(C)C
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)NC1=NS(=O)(=O)c2cc(Cl)sc2N1
Temperature: 0 °C

Procedure:
Phosgene (0.416 ml, 20% in toluene) was added dropwise to a solution of N-[5-chloro-3-(isopropylthiocarbamoyl)sulfamoylthiophen-2-yl]acetamide(261 mg, 0.73 mmol) and dry triethylamine (0.209 ml, 1.5 mmol) in dry tetrahydrofuran (5 ml) with stirring at 0° C. The mixture was stirred for 1 h at 0° C., and evaporated to dryness. The residue was triturated with 10 ml of water, and the precipitate was isolated by filtration, washed with water and finally deacetylated by stirring in 2 ml of 2 N sodium hydroxide for 90 min at room temperature. The solution was acidified to pH 2 with 4 M hydrochloric acid and the precipitate was filtered off and recrystallised from ethyl acetate with decolorising charcoal affording 44 mg (21%) of the pure title compound; mp 272-274° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ1.16 (d, 6H, 2×CH3), 3.85 (m, 1H NCH), 7.23 (s, 1H, H-7), 7.48 (br d, 1H, NH), 11.12 (s, 1H, NH); MS: m/e 279/281 (M+).
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH3:12]>>[CH3:11][S:8]([C:7]1[C:2]([NH2:12])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:10])=[O:9]
Reactant: N
Reactant: CS(=O)(=O)c1cccnc1Cl
Product: CS(=O)(=O)c1cccnc1N
Temperature: 25 °C

Procedure:
The mixture of 800 mg of 2-chloro-3-(methylsulfonyl)pyridine (synthesized according to a method disclosed in J. Org. Chem. 1979, 44, 3080-3082) and 60 mL of aqueous ammonia, was stirred overnight in a sealed-tube at 175° C. After cooling back to room temperature, the mixture was extracted with diethyl ether, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insolubles were filtered. The filtrate was concentrated under reduced pressure, and 473 mg of 3-(methylsulfonyl)pyridine-2-amine [162-1] was obtained as a light orange solid.
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:10]([NH:12]CC)[CH3:11].C(O)(=O)C.[OH-].[Na+]>C(Cl)Cl>[CH:1]1([CH2:7][NH:12][CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCNCC
Reactant: O=CC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNCC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Cyclohexanecarboxaldehyde (38 g), diethylamine hydrochloride (55 g) and acetic acid (29 ml) are dissolved in methylene chloride (500 ml) and thereto is added triacetoxy sodium borohydride (71.8 g) at room temperature and the mixture is stirred at room temperature overnight. To the reaction solution are added a 2N-aqueous sodium hydroxide solution and methylene chloride, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and the mixture is concentrated under reduced pressure to give cyclohexylmethyl-ethyl-amine (40.1 g) as a crude product. MS (m/z): 142 [M+H]+
Reaction SMILES: [CH3:1][N:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3](=[O:19])[O:4][C:5]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:18])[CH:6]=1.[Br:26]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][N:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3](=[O:19])[O:4][C:5]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:18])[C:6]=1[Br:26]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C(=O)Oc1ccn(Cc2ccccc2)c(=O)c1)c1ccccc1
Solvent: ClCCl
Product: CN(C(=O)Oc1ccn(Cc2ccccc2)c(=O)c1Br)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methyl(phenyl)carbamate (0.38 g, 1.13 mmol) in anhydrous CH2Cl2 (7 mL) was added N-Bromosuccinimide (NBS, 0.24 g, 1.34 mmol). The reaction was stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was purified by flash chromatography (silica gel) using EtOAc/hexanes (1:1 v/v). The appropriate fractions were collected according to ES MS (M+H 413) and concentrated. The dried product showed about 14% of di-brominated product by analytical HPLC. The compounds were separated by reverse phase HPLC using a 10-90% acetonitrile in water, 30 min gradient at a 100 mL/min flow rate, to afford (after lyophilization) the salt of the desired compound. The salt was diluted in EtOAc and washed with NaHCO3. The organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford the desired compound (0.271 g, 58%) as a beige solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH2:16]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:24][C:25]([CH3:30])([CH3:29])[O:26]2)=[CH:21][C:20]=1[C:37](=O)[CH3:38])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:24][C:25]([CH3:29])([CH3:30])[O:26]2)=[CH:21][C:20]=1/[C:37](/[CH3:38])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH3:17]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCOc1cc2c(cc1C(C)=O)C(c1ccccc1)=CC(C)(C)O2
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OCC)OC(C)(C)C=C2c1ccccc1

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (0.42 mL, 1.70 mmol) and 1-(7-ethoxy-2,2-dimethyl-4-phenyl-2H-chromen-6-yl)-ethanone (Compound 66, 183 mg, 0.57 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([CH3:29])[CH:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][CH:2]([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:22][C:23]=1[CH3:29]
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Reactant: COc1ccc(Br)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)O4)CC2)cc1C
Yield: 19.5 %

Procedure:
To the toluene (3.1 mL) solution of 1-(2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (400 mg, 1.54 mmol) synthesized in Reference example 56, 4-bromo-1-methoxy-2-methylbenzene (464 mg, 2.31 mmol), palladium acetate (17 mg, 0.077 mmol), BINAP (143 mg, 0.231 mmol) and sodium tert-butoxide (296 mg, 3.08 mmol) were added and irradiated with microwave. The mixture was reacted for 15 minutes at 150° C. To the mixture solution, water was added and extracted with ethyl acetate. The extract solution was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 85:15). The resulting solid was recrystallized from ethanol to obtain the title compound 114 mg (yield 19%). Melting point was 141 to 142° C. (ethanol).
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:11])[CH2:4][S:5][CH2:6][C:7](OC)=[O:8].[H-].[Na+]>O1CCCC1>[CH3:1][CH:2]1[C:3](=[O:11])[CH2:4][S:5][CH2:6][C:7]1=[O:8]
Reactant: CCC(=O)CSCC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1C(=O)CSCC1=O
Reaction time: 3 h
Yield: 76.3 %

Procedure:
A solution of 101.3 g (0.57 mole) of methyl 2-(3-methylacetonylmercapto)acetate in 2.3 liter of dry tetrahydrofuran is added dropwise over a period of 3 hours to a stirred suspension of 0.57 mole of sodium hydride (27.4 g of 50% mineral oil suspension) in 1.1 liter of dry tetrahydrofuran at room temperature under nitrogen. Stirring is continued for an additional 3 hours. The resulting yellow reaction mixture is concentrated to a small volume at temperature below 40° C. under reduced pressure, poured into ice-cold water and then extracted with ether. The aqueous layer is acidified at pH 2-3 with dilute hydrochloric acid and extracted several times with chloroform. The extracts are washed with a small portion of an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the residue is crystallized from methylene chloride - ether to give 62.7 g (75.6% yield) of 4-methyltetrahydrothiopyran-3,5-dione, mp. 131°-133° C. Recrystallization from acetone - ether gives an analytical specimen, mp. 132.5°-133° C. IR: νmaxCHCl3 cm-1 : 1735, 1705, 1631; νmaxNujol cm-1 :1635, 1553. UV: λmax95%EtOH mμ (ε): 275 (9500), 315 (2400); λmaxN-HCl mμ (ε): 272 (9900); λmaxN-NaOH mμ (ε): 289 (11600), 316 (12900). NMR: ppm (CDCl3): 1.28 (doublet, 3H, J = 7, Me), 3.44 (singlet, 4H, 2-H2 and 6-H2), 3.73 (quartet, 1H, J = 7, 4-H); ppm (CD3OD): 1.69 (broad singlet, 3H, vinyl-Me), 3.34 (broad singlet, 4H, 2-H2 and 6-H2). Anal. Calcd. for C6H8O2S (%): C, 49.98; H, 5.59; S, 22.24. Found (%): C, 50.17; H, 5.50; S, 22.14.
Reaction SMILES: [C:1]1([CH:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:8]([N:10]2[CH:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:34][CH3:35])[C:16]=3[O:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=3)[CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.C1COCC1.[Pd]>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:16]2[C:15]([O:34][CH3:35])=[CH:14][CH:13]=[C:12]3[C:17]=2[CH2:18][CH:19]([C:20]([O:22][CH3:23])=[O:21])[N:10]([C:8](=[O:9])[CH:7]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11]3)=[CH:26][CH:27]=1
Reactant: COC(=O)C1Cc2c(ccc(OC)c2Oc2ccc([N+](=O)[O-])cc2)CN1C(=O)C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1Cc2c(ccc(OC)c2Oc2ccc(N)cc2)CN1C(=O)C(c1ccccc1)c1ccccc1
Yield: 99 %

Procedure:
A solution of 0.80 g (1.45 mmole) of the nitrobenzene derivative of Example 43 in 50% methanol-THF is reduced with 5% palladium-on-carbon catalyst. The filtered solution is concentrated at reduced pressure to give 0.75 g of pure product as a solid foam; mass spectrum (EI) 522 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH:38](=O)[CH3:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: CC=O
Reactant: COc1cc(-c2nn(C3CCNCC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN1CCC(n2nc(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
N2-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (250 mg, 0.503 mmol), acetaldehyde (44 mg, 1.007 mmol) and sodium triacetoxyborohydride (212 mg, 1.007 mmol) were mixed in 1,2-dichloroethane (6 mL). The reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified by reverse phase preparative HPLC using acetonitrile/water (50 mM ammonium acetate buffer) as mobile phase to give N2-{4-[4-amino-1-(1-ethyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (247 mg, 93%). 1H NMR (DMSO-d6) δ 1.04 ((t, J=7.15 Hz, 3H), 1.92 (m, 2H), 2.08 (m, 2H), 2.25 (m, 2H), 2.40 (q, J=7.15 Hz, 2H), 3.03 (m, 2H), 3.96 (s, 3H), 4.04 (s, 3H), 4.68 (m, 1H), 7.13 (m, 1H), 7.33 (m, 4H), 7.58 (d, J=8.00 Hz, 1H), 7.70 (d, J=7.95 Hz, 1H), 8.11 (d, J=8.15 Hz, 1H), 8.25 (s, 1H), 9.44 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 0.8 mL/min.): RT=2.08 min. MH+=525.3.
Reaction SMILES: C([NH:4][CH2:5][CH:6]([C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=1)[CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][NH:9]C(=O)C)(=O)C.[OH-].[Na+]>>[NH2:4][CH2:5][CH:6]([C:19]1[CH:20]=[CH:21][C:22]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=1)[CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][NH2:9]
Reactant: CC(=O)NCC(c1ccccc1)C(CNC(C)=O)c1ccc(N(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CN(C)c1ccc(C(CN)C(CN)c2ccccc2)cc1

Procedure:
19.1 g of N,N'-diacetyl-1,4-diamino-2-(p-dimethylaminophenyl)-3-phenyl-butane in 80 ml of 15% strength aqueous sodium hydroxide solution are heated to 200° C. in an autoclave for 16 hours. The reaction solution is then concentrated in a rotary evaporator and extracted with chloroform. After removing the chloroform in vacuo, 8.5 g of crystalline crude amine are obtained and this is recrystallised from 35 ml of isopropanol. Yield: 3.8 g of product having a melting point of 145°-146° C. A further 2.0 g of product having a melting point of 145°-146° C. are obtained by concentrating.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]([CH2:22][CH2:23][OH:24])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C:28]1[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:32][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:22][CH2:23][O:24][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:25][CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)c1ccc(CN(CCO)C(=O)c2cccc3cc[nH]c23)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CN(CCOc2cccc(C(F)(F)F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
To a solution of 175 mg (0.5 mmol) of 1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-(2-hydroxy-ethyl)-amide, 91 mg (0.55 mmol) of 3-hydroxy-benzotrifluoride and 144 mg (0.55 mmol) of triphenyl phosphine in 5 ml THF were added dropwise 88 μl (0.55 mmol) azodicarboxylic acid diethyl ester at 0° C. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue purified by column chromatography (20 g silica gel, diethyl ether/heptane 1:1) to yield 182 mg (74%) product as a white solid. MS (ISP) 495.5 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]([OH:25])=O)=[CH:15]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:29][C:28]=1[Cl:39].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:39][C:28]1[CH:29]=[C:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=[CH:32][C:27]=1[NH:26][C:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]([CH3:13])[CH:15]=1)=[O:25]
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(NC(=O)c2cn(C)c3ccccc23)c(Cl)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 30.2 %

Procedure:
In DMF (20 ml), EDC HCl (1.44 g, 7.49 mmol) was added to 1-methyl-3-indolylcarboxylic acid (1.01 g, 5.71 mmol), ethyl 4-amino-3-chlorophenylacetate (1.22 g, 5.71 mmol), HOBt (0.86 g, 6.34 mmol), and DMAP (0.14 g, 1.15 mmol) and the resulting mixture was stirred at 70° C. for 18 hours. After cooling to room temperature, the reaction mixture was added with water, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (1:1, v/v) eluate fractions, ethyl (3-chloro-4-((1-methyl-3-indolylcarbonyl)amino)phenyl)acetate (639 mg, 30%) was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([F:18])[C:15]=2[CH:16]=[O:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].C(Cl)Cl>C1COCC1.O>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([F:18])[C:15]=2[CH2:16][OH:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(-c2cncc(F)c2C=O)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(-c2cncc(F)c2CO)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To the solution of 2-chloro-4-(5-fluoro-4-formylpyridin-3-yl)benzonitrile (45 mg, 0.17 mmol) in THF (3 mL) and water (1 mL) was added sodium borohydride (6.5 mg, 0.17 mmol) at 0° C. This reaction mixture was stirred for 0.5 h at room temperature. After addition of CH2Cl2, the organic layer was washed with saturated NaCl solution and extracted with DCM for five times. The combined extracts were dried over Na2SO4, filtered, and evaporated. The resulting mixture was passed through a pad of silica gel, rinsed with 0-50% EtOAc/heptane, and evaporated to give 2-Chloro-4-(5-fluoro-4-hydroxymethyl-pyridin-3-yl)-benzonitrile (21 mg, 46%) as a white solid. ESI-MS m/z: 263 [M+1]+, Retention time 1.11 min. 1H-NMR (CDCl3, 400 MHz) δ 4.56 (s, 2H), 7.66 (dd, J=8.4, 1.6 Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 8.39 (s, 1H), 8.55 (s, 1H).