Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:10][C:11]([C:13]2[C:14]3[CH:21]=[N:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:15]=3[CH:16]=[N:17][CH:18]=2)=[O:12])[CH2:8][CH3:9])[CH2:2]1.CCN(CC)CC.C[Si]([N:40]=[C:41]=[O:42])(C)C>C(#N)C>[C:41]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:10][C:11]([C:13]2[C:14]3[CH:21]=[N:20][N:19]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[C:15]=3[CH:16]=[N:17][CH:18]=2)=[O:12])[CH2:8][CH3:9])[CH2:2]1)(=[O:42])[NH2:40]
Reactant: C[Si](C)(C)N=C=O
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCN(C(N)=O)C1
Reaction time: 4 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (1-piperidin-3-yl-propyl)-amide (0.10 g, 0.26 mmol) in acetonitrile (1 mL) was added Et3N (79 μL, 0.79 mmol) followed by 85% trimethylsilyl isocyanate (125 μL, 0.784 mmol). After 4 hours, the cloudy mixture was filtered and attempts to crystallize the solid proved unsuccessful. The solid and filtrate was combined and diluted with water and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:13])(P(O)(O)=O)[C:6]([OH:8])=[O:7].[C-]#N.[K+].[C:17](O)(=O)[CH3:18]>C(O)C.O>[C:2]([CH2:3][CH2:4][C:5](=[O:13])[C:6]([O:8][CH2:17][CH3:18])=[O:7])#[N:1]
Reactant: CC(=O)O
Reactant: NCCCC(O)(C(=O)O)P(=O)(O)O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=O)CCC#N
Temperature: 25 °C

Procedure:
To a solution of 12.8 g (0.10 mole) of ethyl 2-oxo-3-butenoic acid (prepared as in Example 1) in 100 ml of ethanol and 50 ml of water is added 6.5 g (0.10 mole) of potassium cyanide. The mixture is stirred at 30°-50° for about one hour, during which time a solution of 6.0 g (0.10 mole) of acetic acid in 20 ml of ethanol is slowly dripped in. After addition is complete, the mixture is cooled to room temperature and the solvent is removed under vacuum. The residue is partitioned between water and CH2Cl2, the layers separated, and the water extracted further with CH2Cl2. The combined organic layers are dried (Na2SO4) and the solvent is removed to give the crude product. This is purified by flash chromatography on silica gel to give ethyl 4-cyano-2-oxo-butanoate as an oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1)=[O:3].C(O)C.[H-].[Na+].Cl.[C:17](=O)([O:21]CC)[O:18][CH2:19][CH3:20]>O>[Cl:10][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:17]([O:18][CH2:19][CH3:20])=[O:21])[CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cccc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloroacetophenone (23.9 g, 154 mmol) in diethyl carbonate (150 ml) was added ethanol (0.3 ml), and sodium hydride (60% in oil, 12.4 g, 309 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 2 hrs. To the reaction solution was added 6N hydrochloric acid to stop the reaction, and water (500 ml) was added. Then, the mixture was extracted with ethyl acetate (500 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-5:1) to give the objective substance (24.8 g, 71%).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[N:3]1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:44]([O:46][C:47](=[O:61])[C@H:48]([OH:60])[CH2:49][C@H:50]([NH2:59])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][CH:53]=1)[CH3:45]>CN(C=O)C>[CH2:44]([O:46][C:47](=[O:61])[C@H:48]([OH:60])[CH2:49][C@H:50]([NH:59][C:7]([C:5]1[N:4]=[N:3][N:2]([OH:1])[CH:6]=1)=[O:9])[CH2:51][C:52]1[CH:53]=[CH:54][C:55]([Br:58])=[CH:56][CH:57]=1)[CH3:45]
Reactant: O=C(O)c1cn(O)nn1
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)c1cn(O)nn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.4 %

Procedure:
1-Hydroxy-1H-1,2,3-triazole-4-carboxylic acid (163 mg, 1.3 mmol),), HCTU (523 mg, 1.3 mmol), and DMF were combined and stirred for 5 minutes at room temperature. DIPEA (661 μL, 3.8 mmol) and (2R,4R)-4-amino-5-(4-bromophenyl)-2-hydroxypentanoic acid ethyl ester (4 mg, 1.3 mmol) were added and the resulting mixture was stirred for 10 minutes. The reaction mixture was evaporated under reduced pressure and purified (C18 column; 20-70% MeCN in water with 0.05% TFA) to yield the title compound (330 mg).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([OH:22])=O)[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[F:30][C:31]([F:39])([F:38])[C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([NH:37][C:34]2[S:35][CH:36]=[C:32]([C:31]([F:39])([F:38])[F:30])[N:33]=2)=[O:22])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: Nc1nc(C(F)(F)F)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C(F)(F)F)cs2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (270 mg, 0.639 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (116 mg, 0.703 mmol) in the presence of EDCI hydrochloride (245 mg, 1.278 mmol) and DMAP (72 mg, 0.639 mmol) in a mixture of THF and DMF (1:1, 6 mL) to give 127 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.02 (s, 9H), 3.56 (s, 2H), 7.17 (t, J=74.1 Hz, 1H), 7.20-7.31 (m, 2H), 7.42-7.45 (m, 1H), 7.52 (d, J=15.9 Hz, 1H), 7.67-7.69 (m, 1H), 7.81 (d, J=16.2 Hz, 1H), 8.06-8.10 (m, 2H), 13.01 (br s, 1H); APCI-MS (m/z) 573.26 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N:7][CH:6]=[CH:5]3)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc2cnccc2c1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc3cnccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
6-Aminoisoquinoline (3.348 g, Synthesis, 733 (1975)) was dissolved in pyridine (30 ml). To the mixture was added 4-toluenesulfonyl chloride (5.13 g), followed by stirring at room temperature overnight. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was recrystallized from ethanol, to give the title compound (5.958 g, 85%) as pale yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.CC(O)=[O:12].OO>O>[CH:5]1[CH:6]=[N+:1]([O-:12])[CH:2]=[C:3]([CH2:7][C:8]#[N:9])[CH:4]=1
Reactant: CC(=O)O
Reactant: N#CCc1cccnc1
Agent: OO
Solvent: O
Product: N#CCc1ccc[n+]([O-])c1
Reaction time: 72 h

Procedure:
A solution of 3-pyridylacetonitrile (11 g, 93.1 mmol), HOAc (55 mL), and 30% H2O2 (17 mL) was heated at 95° C. overnight, and at room temperature for 72 hours. H2O (50 mL) was added to the reaction mixture and the resulting solution was concentrated. This was repeated with additional H2O (100 mL). Toluene (2×100 mL) was used to remove residual H2O, and the resulting white solid was dried under vacuum overnight affording a waxy white solid: mp 120-125° C.; MS(+)APCI m/z 135 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[S:14][C:15]4[C:16]([N:21]=3)=[N:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][C:6]=2[O:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH:28]12[NH:35][CH:32]([CH2:33][CH2:34]1)[CH2:31][N:30]([C:36](=[O:38])[CH3:37])[CH2:29]2>CC#N.CN(C=O)C>[S:14]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:21]=[C:13]1[O:12][C:10]1[CH:9]=[CH:8][C:7]2[C:3]([CH2:2][N:35]3[CH:28]4[CH2:34][CH2:33][CH:32]3[CH2:31][N:30]([C:36](=[O:38])[CH3:37])[CH2:29]4)=[CH:4][O:5][C:6]=2[CH:11]=1
Reactant: CC(=O)N1CC2CCC(C1)N2
Reactant: ClCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(=O)N1CC2CCC(C1)N2Cc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.9 %

Procedure:
To a solution of 2-(3-chloromethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine (120 mg, 0.31 mmol) in CH3CN/DMF (4:1, 3 mL) was added K2CO3 (169 mg, 1.2 mmol) followed by 1-(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-ethanone (47 mg, 0.31 mmol) and the reaction mixture was stirred (rt, 48 h). The reaction mixture was partitioned between DCM (10 mL) and sat. NaHCO3 (5 mL). The organic layer was separated and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to provide the title compound as a colorless solid (47 mg, 35%). MS (ESI): mass calcd. for C23H22N4O3S, 434.14; m/z found, 435.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.7, 1H), 8.02 (dd, J=7.9, 1.7, 1H), 7.84 (d, J=8.5, 1H), 7.63-7.56 (m, 2H), 7.29 (dd, J=8.5, 2.1, 1H), 7.21 (dd, J=7.9, 4.8, 1H), 4.20 (dd, J=12.7, 1.5, 1H), 3.72-3.58 (m, 2H), 3.48-3.19 (m, 4H), 2.89 (d, J=12.3, 1H), 2.06 (s, J=2.8, 3H), 2.03-1.93 (m, 2H), 1.72-1.63 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@@H:6]([CH2:15][CH3:16])[N:5]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[N:3]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:33][CH3:34].Cl.C([O-])(O)=O.[Na+]>C(O)C.O>[CH:17]1([N:5]2[C:4]3[N:3]=[C:2]([NH:22][C:23]4[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[CH:25][C:24]=4[O:33][CH3:34])[N:11]=[CH:10][C:9]=3[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@H:6]2[CH2:15][CH3:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC[C@@H]1c2nncn2-c2cnc(Cl)nc2N1C1CCCC1
Reactant: CNC(=O)c1ccc(N)c(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC[C@@H]1c2nncn2-c2cnc(Nc3ccc(C(=O)NC)cc3OC)nc2N1C1CCCC1
Temperature: 90 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a solution of (R)-7-chloro-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine (80 mg, 0.263 mmol) in a mixture ethanol/water (1/4, 5 mL) were added 4-amino-3-methoxy-N-methylbenzamide (72 mg, 0.394 mmol) followed by a catalytic amount of concentrated HCl (0.04 mL). The reaction mixture was stirred at 90° C. for 24 hours, then cooled to room temperature and basified with saturated aqueous solution of NaHCO3. The mixture was extracted with ethyl acetate, the organic layer was dried (MgSO4) and the residue purified by flash chromatography to give the title compound as a colourless solid (92 mg, 78% yield).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:22]3[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[C:14]([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)[N:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[CH3:35][C:32]([CH3:36])([CH2:31][NH:30][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([C:8]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[N:13][C:14]=3[C:17]3[CH:21]=[N:20][NH:19][CH:18]=3)[N:9]=2)=[CH:29][CH:28]=1)[CH2:33][OH:34]
Reactant: O=Cc1ccc(-c2nc3ccnc(-c4cn[nH]c4)c3cc2-c2ccccc2)cc1
Reactant: CC(C)(CN)CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CC(C)(CO)CNCc1ccc(-c2nc3ccnc(-c4cn[nH]c4)c3cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[3-phenyl-5-(1H-pyrazol-4-yl)-1,6-naphthyridin-2-yl]benzaldehyde (1-3) (0.11 g, 0.29 mmol) in NMP (10 mL) was added 3-amino-2,2-dimethylpropan-1-ol (0.030 g, 0.29 mmol) and acetic acid (0.026 g, 0.43 mmol). After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (0.092 g, 0.43 mmol) was added and the reaction was stirred at room temperature for 15 hours. The reaction was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Purification by reverse phase chromatography (5-95% acetonitrile/water/0.1% TFA; Water Sunfire C18) gave 2,2-dimethyl-3-({4-[3-phenyl-5-(1H-pyrazol-4-yl)-1,6-naphthyridin-2-yl]benzyl}amino)propan-1-ol (1-4) as a off white solid. HRMS (M+H)+: calculated 464.2207; found 464.2194
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C:19]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20]1>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C:19]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Reactant: CCOC(=O)C1(N)CC1
Agent: Cl
Product: CCOC(=O)C1(NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)CC1
Yield: 87 %

Procedure:
Prepared as in Example 12-1b from 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) and ethyl 1-aminocyclopropanecarboxylate hydrochloride. Yield 87%, colorless liquid. MS 350 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=1.[CH3:20][O:21][CH:22]([O:39][CH3:40])[C:23]1[C:28]([O:29][CH2:30][O:31][CH3:32])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=[CH:25][C:24]=1[CH2:37]O>>[CH3:40][O:39][CH:22]([O:21][CH3:20])[C:23]1[C:28]([O:29][CH2:30][O:31][CH3:32])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=[CH:25][C:24]=1[CH2:37][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)=[C:2]([F:1])[CH:7]=1
Reactant: COCOc1c(C(F)(F)F)ccc(CO)c1C(OC)OC
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2F)cc1
Product: COCOc1c(C(F)(F)F)ccc(COc2ccc(-c3ccc(CC(=O)OC)cc3)c(F)c2)c1C(OC)OC
Yield: 92 %

Procedure:
According to a method similar to Example (6-7), from methyl (2′-fluoro-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (1.02 g, 3.94 mmol) obtained in Example (14-1) and [2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)phenyl]methanol (1.71 g, 5.52 mmol) obtained in Example (6-6), methyl (4′-{[2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl]oxy}-2′-fluoro-1,1′-biphenyl-4-yl)acetate was obtained (2.01 g, yield: 92%).
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:46]=[CH:45][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=5)[C:38](OC)=[O:39])[O:32][C:33]=4[CH3:34])=[C:25]([O:47][CH3:48])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].[BH4-].[Li+].O1CCCC1>O>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:46]=[CH:45][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([CH2:38][OH:39])[CH:42]=[CH:43][CH:44]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:47][CH3:48])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(C(=O)OC)c4)oc3C)c(OC)c2)cs1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(CO)c4)oc3C)c(OC)c2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
A mixture of methyl 3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate (212 mg), lithium borohydride (74 mg) and tetrahydrofuran (40 mL) was stirred at room temperature for 12 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:5-1:4, v/v) to give {3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}methanol (143 mg, yield 62%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 130-132° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].ClCCC(C)(C)C(O)=O.Cl[CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]nc(I)c2c1
Reactant: CC(C)(C)C(=O)OCCl
Agent: CC(C)(CCCl)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1nc(I)c2cc(Br)cnc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
5-Bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (4 g, 12.4 mmol) in DMF (50 ml) under nitrogen was stirred at 40° C. for 10 minutes. Sodium hydride (0.9 g, 37 mmol) was added to the DMF solution and the resulting mixture was allowed to stir at 40° C. for 1 hour. Then 2,2-dimethyl-propionic acid chloromethyl ester (chloromethyl pivalate) was added dropwise to the mixture. The reaction was stirred for another 2 hours. The reaction was quenched with saturated NH4Cl (20 ml) and worked up with ethyl acetate, brine, dried with Na2SO4, concentrated to dryness. Silica gel chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2,2-dimethyl-propionic acid 5-bromo-3-iodo-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (5 g, 92% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.07 (s, 9H), 6.37 (s, 2H), 8.30 (s, 1H), 8.77 (s, 1H).
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27]4[C:32]([NH:33][CH:34]([CH3:36])[CH3:35])=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:23][CH2:22]2)=[O:20])=[CH:13]3)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].[CH3:41][C:42]([CH3:44])=O.[OH-].[Na+]>CO.C(O)(=O)C>[CH3:41][CH:42]([N:4]1[CH2:3][CH2:2][N:1]([C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]4[C:32]([NH:33][CH:34]([CH3:36])[CH3:35])=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:25][CH2:26]2)=[O:20])=[CH:13]3)=[O:8])[CH2:6][CH2:5]1)[CH3:44]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc(NC(=O)N4CCNCC4)ccc3[nH]2)CC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc(NC(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1

Procedure:
To a solution of 1-[5-(1-piperazinylcarbonylamino)-indole-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine (EXAMPLE 46, 0.41 g) in methanol (50 ml) is added sodium cyanoborohydride (53 mg) and acetone (1 ml). Additional sodium cyanoborohydride (44.3 mg total) and excess acetone are added in portions until the reaction is complete as judged by TLC on silica gel. The mixture is acidified with acetic acid, neutralized with 50% aqueous sodium hydroxide and concentrated. The residue is dissolved in methylene chloride, washed with water, saturated potassium carbonate solution, and saline and dried over sodium sulfate followed by concentration. The resulting material is purified by chromatography on silica gel (100 ml) packed in methanol/chloroform (1/99) and eluted with a methanol/chloroform gradient (1→5%) to give the title compound, NMR (chloroform-d) 9.14, 7.71, 7.33, 7.17, 6.95, 6.86, 6.74, 4.06, 3.58, 3.20, 2.78, 2.60, 1.27, 1.08 δ.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])(=[O:8])=[O:7])([CH3:4])[CH3:3].C1C(=O)N([Br:25])C(=O)C1>C(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:25][CH2:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]([S:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])(=[O:8])=[O:7])[CH:14]=1
Reactant: COc1ccc(C)cc1S(=O)(=O)NC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: COc1ccc(CBr)cc1S(=O)(=O)NC(C)(C)C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
A mixture of 27 g of N-(1,1-dimethylethyl)-2-methoxy-5-methylbenzenesulfonamide (E. H. Huntress and F. H. Carten, J. Am. Chem. Soc., 62 (1940), 603), 19.6 g NBS and 0.3 g azobisisobutyronitrile in 200 ml CH2Cl2 was refluxed and illuminated with an sun lamp. After 8 hours and the lamp was turned off and the reaction was refluxed for another 24 hr. The reaction was allowed to cool. The reaction mixture was washed with 200 ml of a 1:1:1:1 mixture of brine:sodium sulfite:sodium bicarbonate:water. The organic layer was dried (MgSO4), treated with charcoal and filtered through a 5 g plug of silica gel. The plug was washed with 100 ml of chloroform. The combined organic fractions were evaporated to give 34 g of solid, m.p. 137°-142° C.;
Reaction SMILES: B.[CH2:2]([CH:4]([CH2:18][CH3:19])[CH2:5][O:6][C:7]1[N:12]=[C:11]([C:13](=[O:17])[CH2:14][C:15]#[N:16])[CH:10]=[CH:9][CH:8]=1)[CH3:3].N.CO.C(Cl)Cl>>[NH2:16][CH2:15][CH2:14][C@H:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([O:6][CH2:5][CH:4]([CH2:18][CH3:19])[CH2:2][CH3:3])[N:12]=1)[OH:17]
Reactant: CCC(CC)COc1cccc(C(=O)CC#N)n1
Agent: B
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCC(CC)COc1cccc([C@H](O)CCN)n1

Procedure:
Borane reduction of 3-(6-(2-ethylbutoxy)pyridin-2-yl)-3-oxopropanenitrile following the method described in Example 6 gave after flash chromatography purification (25%-30% 7N NH3/MeOH—CH2Cl2 gradient) Example 30 as a colorless oil. Yield (0.11 g, 25%); 1H NMR (400 MHz, DMSO-d6) δ 7.61 (t, J=7.6 Hz, 1H), 7.0 (d, J=7.6 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 4.57-4.50 (m, 1H), 4.15-4.06 (m, 2H), 2.70-2.58 (m, 2H), 1.84-1.76 (m, 1H), 1.64-1.52 (m, 2H), 1.42-1.28 (m, 4H), 0.85 (t, J=7.2 Hz, 6H); RP-HPLC tR=8.51 min; ESI-MS m/z 253.2 [M+H]+.
Reaction SMILES: CN(CCN(C)C)C.[CH2:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[CH2:10][CH3:11].[Li]CCCC.[O-]S(C(F)(F)[F:44])(=O)=O.F[N+]1C(C)=CC(C)=CC=1C>CCCCCC.C1COCC1>[CH2:9]([C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[C:26]([F:44])[CH:25]=3)=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)[CH2:10][CH3:11]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: CN(C)CCN(C)C
Agent: Cc1cc(C)[n+](F)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(F)(F)F)c(F)c3)cc2)CC1
Temperature: 25 °C

Procedure:
0.01 mol of TMEDA is added to a solution of 0.01 mol of 4-(trans-4-n-propylcyclohexyl)-4'-trifluoromethylbiphenyl in 10 ml of n-hexane. At 0°-5° C. 0.01 mol of n-BuLi is added, and stirring at RT is continued for another half an hour and at 40° C. for half an hour. The mixture is then cooled to 0° C., 20 ml of THF are added, and the fluorinating agent 1-fluoro-2,4,6-trimethylpyridinium triflate (in THF) is added dropwise at this temperature according to scheme 21. Extractive work-up and, as is customary, chromatography and crystallization give 4-(trans-4-n-propylcyclohexyl)-3'-fluoro-4'-trifluoromethylbiphenyl.