Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[CH3:2][C:3]1[C:11]2[C:10]([C:12]([O-:14])=O)=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)=[CH:17][CH:16]=3)=[N:7][C:6]=2[N:5]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[N:4]=1.CCN(C(C)C)C(C)C.[C:43]([O:47][C:48]([N:50]1[CH2:57][C:54]2([CH2:56][CH2:55]2)[NH:53][CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl.O>[C:43]([O:47][C:48]([N:50]1[CH2:57][C:54]2([CH2:55][CH2:56]2)[N:53]([C:12]([C:10]2[C:11]3[C:3]([CH3:2])=[N:4][N:5]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[C:6]=3[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)=[CH:17][CH:16]=3)[CH:9]=2)=[O:14])[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCNC2(CC2)C1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)[O-])c12
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC34CC4)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a suspension of 300 mg of 3-methyl-1-(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid sodium salt in 7.5 ml of DCM were added 0.12 ml of Hünig's base, 376 mg of BEP and 146 mg of 4,7-diaza-spiro[2.5]octane-7-carboxylic acid tert-butyl ester. The reaction was stirred overnight at r.t. For workup it was diluted with water and DCM and the layers were separated. The organic layer was washed with water twice, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/EtOAc gradient) to obtain 280 mg (66%) of the title compound.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH:2]1[C:9]([O:11][CH3:12])=[O:10]>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:1]1[CH2:6][CH2:5][S:4](=[O:7])(=[O:8])[CH2:3][CH:2]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C1CS(=O)(=O)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CS(=O)(=O)CCN1
Temperature: 0 °C
Yield: 94.7 %

Procedure:
To a solution of 4-(1,1-dimethylethyl) 3-methyl 3,4-thiomorpholinedicarboxylate 1,1-dioxide (D15; 1.73 g, 5.9 mmol) in 17 ml of anhydrous methylene chloride, trifluoroacetic acid (4.2 ml) was added dropwise while stirring at 0° C. under nitrogen atmosphere. The solution was stirred for 3 h, while allowing it to reach room temperature. The solvent was removed under reduced pressure and the residue was loaded on a SCX cartridge, washed with methanol and eluted with 0.5M methanolic ammonia. The basic fractions were collected and the solvent removed leaving 1.08 g of the target product.
Reaction SMILES: O.[NH2:2][NH2:3].[N+:4]([C:7]1[CH:8]=[C:9]([C:13](SC)=[C:14]([C:17]#[N:18])[C:15]#[N:16])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5]>CO>[NH2:16][C:15]1[NH:3][N:2]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=2)[C:14]=1[C:17]#[N:18]
Reactant: NN
Reactant: CSC(=C(C#N)C#N)c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: CO
Product: N#Cc1c(-c2cccc([N+](=O)[O-])c2)n[nH]c1N
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
0.24 ml (4.8 mmol) of hydrazine hydrate is added dropwise to 1.00 g (4.08 mmol) of 3-(3-nitro-phenyl)-3-methylmercapto-2-cyano-acrylonitrile in 5.3 ml of methanol and the reaction mixture is then boiled for 1.5 hours. The reaction mixture is then cooled in ice-water and the precipitate is filtered off and washed with diethyl ether/isopropanol (2:1), yielding 5-amino-3-(3-nitro-phenyl)-1H-pyrazole-4-carbonitrile; TLC: Rf =0.4 (methylene chloride:methanol=10:1); TRet (Grad20-100)=10.8; MS: (M)+ =229, (M-NO2)+ =183.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:32])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:16]=2)[CH:10]=[CH:11][CH:12]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[C:14]([NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([OH:6])[CH:8]=2)=[O:32])=[C:23]([N+:29]([O-:31])=[O:30])[CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(NC(=O)c2cccc(Oc3ccc(Cl)cc3[N+](=O)[O-])c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cccc(O)c1)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Reaction time: 16 h
Yield: 86.6 %

Procedure:
To the product from Example 174a (1.5 g, 3.0 mmol) in THF (25 mL) was added tetrabutylammonium fluoride (0.94 g, 3.6 mmol). The reaction was stirred for 16 h. The reaction was poured into water and extracted with ethyl acetate. The organic layer washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (1.0 g, 86%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][C@:11]1([CH3:40])[C@@H:15]([O:16][Si](C(C)(C)C)(C)C)[C@@H:14]([O:24][Si](C(C)(C)C)(C)C)[C@H:13]([N:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[N:34][C:33]2=[O:39])[O:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:6]([O:5][P:4]([CH2:9][O:10][C@:11]1([CH3:40])[C@@H:15]([OH:16])[C@@H:14]([OH:24])[C@H:13]([N:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[N:34][C:33]2=[O:39])[O:12]1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(CO[C@@]1(C)O[C@@H](n2ccc(N)nc2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOP(=O)(CO[C@@]1(C)O[C@@H](n2ccc(N)nc2=O)[C@H](O)[C@@H]1O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of compound 30.4 (288 mg, 0.46 mmol) in THF (20 mL) was added a 1N solution of tetrabutylammonium fluoride in THF (2.7 mL, 2.8 mmol). The mixture was stirred at r.t. for 1 h and concentrated down under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 10% MeOH in CH2Cl2 to give compound 30.5 (114 mg, 63% yield). 1H NMR (300 MHz, CD3OD): δ 1.38 (t, 6H, J=7.0), 1.40 (s, 3H), 3.86 (m, 2H), 4.02 (d, 1H, J=4.9), 4.11 (m, 4H), 4.56 (dd, 1H, J=7.0, 6.7), 5.98 (d, 1H, J=7.4), 6.11 (d, 1H, J=7.0), 7.63 (d, 1H, J=7.6). LRMS (ESI) MH+ C14H24N3O8P requires 394.4. Found 394.1.
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[C:7](/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)\[CH:8]=[O:9])(=[O:3])[CH3:2].CC(=CC)C.[O-:31]Cl=O.[Na+]>CC(O)(C)C.O>[C:1]([O:4][CH2:5]/[C:6](/[C:16]1[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=1)=[C:7](/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)\[C:8]([OH:31])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C(=C(\C=O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(=O)OC/C(=C(\C(=O)O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of the aldehyde from Example 3 (160 mg) and 2-methyl-2-butene (6 mL) in 2-methyl-2-propanol (35 mL) was added a solution of NaClO2 (1 g) and NaH2PO4 (1 g) in 10 mL of H2O. The mixture was stirred for 2 h at r.t., and concentrated. The residue was then taken into 50 mL of pH 7 buffer solution (1M) and extracted with EtOAc (50 mL). The extract was dried over MgSO4 and concentrated. The residue was purified by flash chromatography, eluting with 3:1 EtOAc/hexane containing 1% HOAc to give 150 mg of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([OH:31])=O)=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[CH2:42]([N:45]1[CH:49]=[CH:48][N:47]=[C:46]1[CH2:50][S:51][C:52]1[CH:58]=[CH:57][C:55]([NH2:56])=[CH:54][CH:53]=1)[CH2:43][CH3:44]>O1CCCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:56][C:55]4[CH:57]=[CH:58][C:52]([S:51][CH2:50][C:46]5[N:45]([CH2:42][CH2:43][CH3:44])[CH:49]=[CH:48][N:47]=5)=[CH:53][CH:54]=4)=[O:31])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Reactant: CCCn1ccnc1CSc1ccc(N)cc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCC)cc2)CCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 45.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml) was added one droplet of DMF. Then, thionyl chloride (0.15 ml) was added to the mixture at 0° C., and the mixture was allowed to be at room temperature and stirred for 1 hour under nitrogen atmosphere. This solution was added to a solution of 4-[[(1-propylimidazol-2-yl)methyl]sulfanyl]aniline (515 mg) and triethylamine (5.8 ml) in tetrahydrofuran (15 ml) at 0° C. The mixture was stirred for 1 hour at room temperature under nitrogen atmosphere, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4), and was recrystallized from ethanol-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (483 mg) (Compound 334) as yellow crystals.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[Cl:6][C:7]1[C:8]2[CH:15]=[CH:14][NH:13][C:9]=2[N:10]=[CH:11][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([CH2:2][CH:3]3[CH2:5][CH2:4]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1ncnc2c1ccn2CC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.6 %

Procedure:
(Bromomethyl)cyclopropane (7.6 mL, 78 mmol) was added to a solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 65 mmol) and cesium carbonate (25.4 g, 78 mmol) in DMF (100 mL). The reaction mixture was stirred at room temperature 12 h, filtered, and concentrated in vacuo. Purification by flash column chromatography (silica, 1:9→2:8 EtOAc:hexanes) provided the title compound as a white solid (12.9 g, 95%). MS: 208.5 (MH+); HPLC Rf: 5.21 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([CH3:19])[N:14]1[CH2:20][C:21]([NH:23][CH:24]([CH3:28])[C:25]([OH:27])=[O:26])=[O:22].O[N:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36].C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.ClCCl.O>[O:36]=[C:31]1[CH2:32][CH2:33][C:34](=[O:35])[N:30]1[O:26][C:25](=[O:27])[CH:24]([NH:23][C:21](=[O:22])[CH2:20][N:14]1[CH:15]([CH3:19])[CH2:16][CH2:17][CH2:18][CH:13]1[CH3:12])[CH3:28]
Reactant: CC(NC(=O)CN1C(C)CCCC1C)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(NC(=O)CN1C(C)CCCC1C)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.75 g (25 mMol) p-toluenesulphonic acid were heated under reflux for 1 h in 20 ml toluene using a water separator. After having evaporating the solvent, 6.30 g (25 mMol) 2-[2-(2,6-Dimethyl-piperidin-1-yl) acetylamino]-propanoic acid (27), 2.88 g (25 mMol) N-Hydroxysuccinimide and 5.15 g (25 mMol) N,N′-Dicyclohexylcarbodiimide were added to the residue dissolved in 100 ml dichloromethane. The reaction mixture was stirred for 16 h at room temperature. The solution was filtered and the filtrate was evaporated in vacuo to dryness. The product was recrystallised from diisopropylether.
Reaction SMILES: [F:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[C:5]([N+:13]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[C:5]([NH2:13])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c2c1NCCCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c2c1NCCCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To a solution of 4-fluoro-1-nitro-6,7,8,9-tetrahydro-5-oxa-9-azabenzocycloheptene (158 mg, 0.746 mmol) in EtOAc (10 mL) was added a slurry of 10% Pd/C (30 mg) in IMS (1 mL) and the reaction mixture was stirred at RT under a hydrogen atmosphere for 18 h. The suspension was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo affording the title compound as a brown solid (131.5 mg, 97%). 1H NMR (CDCl3, 300 MHz): 6.46 (1H, dd, J=10.2, 8.6 Hz), 6.35 (1H, dd, J=8.7, 5.1 Hz), 4.25 (2H, t, J=5.8 Hz), 3.36-3.32 (5H, bs & m), 2.06 (2H, quintet, J=5.8 Hz)
Reaction SMILES: C([NH:9][C:10]([NH:12][CH:13]1[C:21]2[CH:20]=[CH:19][S:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)=[O:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>>[S:18]1[CH:19]=[CH:20][C:21]2[CH:13]([NH:12][C:10]([NH2:9])=[O:11])[CH2:14][CH2:15][CH2:16][C:17]1=2
Reactant: O=C(NC(=O)c1ccccc1)NC1CCCc2sccc21
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)NC1CCCc2sccc21

Procedure:
A mixture of 1-benzoyl-3-(4,5,6,7-tetrahydrobenzo-[b]thien-4-yl) urea and 2N aqueous sodium hydroxide solution (5ml) is stirred at reflux for 2.5 hours. The mixture is cooled in ice, the product is collected and washed with water to afford 0.58 g of title compound, m.p. 203° to 207° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[N:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[N:11][N:10]=[C:9]1[N:25]([CH2:27][CH2:28][O:29][CH3:30])[CH3:26].[OH-].[Ca+2].[OH-].C(Cl)(Cl)Cl.[CH3:38][N:39]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N>[CH3:30][O:29][CH2:28][CH2:27][N:25]([C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:38]#[N:39])[C:12]([C:13]2[CH:14]=[N:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[N:11][N:10]=1)[CH3:26]
Reactant: CN1CCCC1=O
Reactant: COCCN(C)c1nnc(-c2ccc(-c3ccccc3)nc2)n1-c1ccccc1Br
Agent: [C-]#N
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COCCN(C)c1nnc(-c2ccc(-c3ccccc3)nc2)n1-c1ccccc1C#N
Temperature: 180 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
[4-(2-Bromophenyl)-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]-N-(2-methoxyethyl)-N-methylamine (436 mg) prepared in the Example 7 was dissolved in N-methyl-2-pyrrolidone (5 ml), followed by addition of zinc cyanide (121 mg), calcium hydroxide (76 mg) and tetrakistriphenylphosphine palladium (326 mg), and stirred at 180° C. for 3 hours. After the reaction solution was cooled to ambient temperature, chloroform was added to the solution, from which insoluble materials were filtered off. The filtrate was washed with saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting solid was recrystallized from ethyl acetate, to afford the entitled compound as white crystal (242 mg, 63%). The physico-chemical values are as follows.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH2:20][O:21][C:22]1[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39].COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[F:33][C:34]([F:44])([F:45])[C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([N:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH2:20][O:21][C:22]1[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:39]
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-ethyl 3-(pyrrolidin-2-ylmethoxy)picolinate bis(trifluoroacetic acid) salt (EXAMPLE 34 Step 1) and 3-trifluoromethylbenzoic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: NCCN1CCCCC1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CC#N
Product: Clc1ccc2c(NCCN3CCCCC3)ccnc2c1

Procedure:
3.57 g of base from 3.96 g of 4,7-dichloroquinoline and 4.8 g of 1-(2-aminoethyl)-piperidine (reaction duration, 5 hours at 140° C.); yellowish crystals from acetonitrile, m.p.: 148°-151° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[C:38]([F:41])([F:40])[F:39])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:42]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:42])=[O:26])=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[C:38]([F:40])([F:39])[F:41])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccc(F)cc1C(F)(F)F
Reactant: N
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccc(F)cc1C(F)(F)F
Temperature: 127.5 °C
Reaction time: 4 h

Procedure:
A mixture of 2.22 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{-1-[4-fluoro-2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxylate and 168 ml of a saturated solution of ammonia in methanol is stirred in a microwave vial at 125-130° C. for 4 h in the microwave cavity. The reaction mixture is concentrated to dryness and the resulting residue is purified by flash chromatography [Silica gel, eluent: ethyl acetate/cyclohexane, elution gradient of 0/100 (v/v) to 70/30 (v/v)] to yield the title product.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)=[N:9]1)=O)(C)(C)C.C(OCC)(=O)C.Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:31]([N:28]1[CH2:29][CH2:30][N:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2/[CH:18]=[CH:17]/[C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][N:9]=2)[CH2:26][CH2:27]1)(=[O:33])[CH3:32]
Reactant: CC(=O)N1CCN(c2ccccc2/C=C/c2nn(C(=O)OC(C)(C)C)c3ccccc23)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccccc2/C=C/c2n[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
A solution of (E)-3-{2-[2-(4-acetylpiperazin-1-yl)phenyl]vinyl}indazole-1-carboxylic acid tert-butyl ester (41 mg, 0.094 mmol) obtained in Step 3 in ethyl acetate (1.5 mL) was added with 4.0 mol/L hydrogen chloride-ethyl acetate solution (0.082 mL, 0.32 mmol) and stirred at room temperature for 2.0 hours, followed by stirring under heating and reflux for 2.0 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and ethyl acetate to separate the mixture into organic layer and aqueous layer and the aqueous layer was extracted with ethyl acetate 2 times. All organic layers were gathered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=90/10) to obtain Compound 133 (13 mg, 41%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[O:29][N:28]=[C:27]([CH:30]([CH3:32])[CH3:31])[N:26]=4)[CH2:21][CH2:20]3)[N:17]=[CH:18][C:11]=12.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:30]([C:27]1[N:26]=[C:25]([N:22]2[CH2:23][CH2:24][CH:19]([N:16]3[C:12]4=[N:13][CH:14]=[N:15][C:10]([O:1][C:2]5[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=5)=[C:11]4[CH:18]=[N:17]3)[CH2:20][CH2:21]2)[O:29][N:28]=1)([CH3:32])[CH3:31]
Reactant: CC(C)c1noc(N2CCC(n3ncc4c(Cl)ncnc43)CC2)n1
Reactant: Cc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(c2nc(C(C)C)no2)CC1
Temperature: 160 °C
Yield: 38.9 %

Procedure:
A mixture of 3-hydroxy-2-methylpyridine (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 1.25 mg, 0.011 mmol), 4-chloro-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 22; 4 mg, 0.012 mmol) and potassium carbonate (3 mg, 0.022 mmol) in DMF (0.5 mL) was heated in a microwave at 160° C. for 10 min, but TLC showed no reaction. Potassium carbonate (3 mg, 0.022 mmol) and DMF (0.1 mL) were added and the reaction mixture was heated in a microwave at 180° C. for 15 min. The solvent was evaporated and water was added. The mixture was extracted with ethyl acetate and the extracts were dried, held under high vacuum, and purified by HPLC to give 1-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-4-(2-methyl-pyridin-3-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (1.8 mg, 39%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([Cl:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cu][C:14]#[N:15].CN(C=O)C>CCOC(C)=O>[Cl:12][C:7]1[N:8]=[CH:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([C:14]#[N:15])[CH:11]=2
Reactant: Clc1cc2ccc(Br)cc2cn1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2cc(Cl)ncc2c1
Temperature: 150 °C

Procedure:
To a flask charged with 7-bromo-3-chloroisoquinoline (1.0 g, 4.1 mmol) and a stir bar was added copper(I) cyanide (550 mg, 6.2 mmol) and DMF (50 mL). The mixture was heated to 150° C. for 24 hours under an atmosphere of nitrogen. The reaction was diluted with EtOAc, washed with sat. NH4OAc and brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography (Hexanes:DCM) and the solvent removed to afford the title compound. LC-MS (IE, m/z): 189 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([O:22]C(C)C)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[OH-].Cl>C1COCC1.O>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(C)OC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.8 %

Procedure:
A 3-neck round-bottom flask was charged with a solution of (Z)-isopropyl 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate (3) (130 g, 1.0 eq.) in THF (1.3 L) and treated with a solution of LiOH (69.3 g, 5 eq) in water (1.3 L). The reaction mixture was stirred at ambient temperature for 3-4 h before being diluted with 400 mL water, acidified (pH=2-3) with dilute aqueous HCl and extracted with EtOAc (3×1 L). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 110 g (94% yield) of desired compound (4); Z/E ratio=90.0/8.2 by LCMS.