Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([N:31]2[CH2:36][CH2:35][CH:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:33][CH2:32]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:9]=2)=[CH:6][CH:7]=1.[CH3:45]B(O)O.C([O-])(=O)C.[K+].O>C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:45][C:2]1[C:3]([N:31]2[CH2:32][CH2:33][CH:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:35][CH2:36]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:30])[CH3:28])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nc(-c3nn(COCC[Si](C)(C)C)c4cnc(-c5cccnc5)cc34)ccc2Cl)CC1
Reactant: CB(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 150 °C

Procedure:
In a microwave reaction vial was charged with tert-butyl 1-(3-chloro-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate from Example 241 (72.1 mg, 0.113 mmol), Methyl boronic acid (34.0 mg, 0.567 mmol), 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (9.25 mg, 0.0113 mmol), 1.00 M of Potassium acetate in Water (0.17 mL, 0.17 mmol), 1.00 M of Sodium carbonate in Water (0.17 mL, 0.17 mmol), and Acetonitrile (3 mL). The reaction mixture was heated under microwave at 150° C. for 3 minutes. Another 5 equivalents of Methyl boronic acid was added and continue heated under microwave at 150° C. for 3 minutes. The same procedure was repeated 2 more times. The mixture was concentrated to afford crude tert-butyl 1-(3-methyl-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate, which was dissolved in 1,4-Dioxane (5 mL) and treated with 4.0 M of Hydrogen chloride in 1,4-Dioxane (5 mL) overnight at room temperature. The mixture was then concentrated, and the residue was purified by reverse phase HPLC to afford 243 as an off-white solid (14.0 mg, 32%). 1H NMR (400 MHz, DMSO) δ 9.24 (d, J=17.9 Hz, 2H), 9.07 (s, 1H), 8.61 (s, 1H), 8.43 (d, J=7.8 Hz, 1H), 8.38 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.56 (d, J=4.6 Hz, 1H), 3.73 (d, J=11.9 Hz, 2H), 3.13 (s, 1H), 3.01 (d, J=11.6 Hz, 2H), 2.32 (s, 3H), 2.02 (d, J=12.0 Hz, 2H), 1.68 (d, J=11.1 Hz, 2H). ESI MS m/z=386.2 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(I)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 124.3 %

Procedure:
To a solution of 4-[2-(4-iodo-phenoxy)-acetylamino]-thiophene-3-carboxylic acid methyl ester (0.1 g, 0.428 mmol) in a mixture of tetrahydrofuran (21 mL) and water (5 mL) was added 4-fluorophenylboronic acid (40.3 mg, 0.288 mmol) and cesium carbonate (313 mg, 0.96 mmol). The solution was then degassed by bubbling a flux of argon for 20 minutes before adding polymer bound tetrakis(triphenylphosphine)palladium (Aldrich-511579, 12.86 mg, 0.009 mmol). The reaction mixture was then stirred for 90 min at 80° C. under argon atmosphere before allowing to cool down to room temperature and diluting with ethyl acetate. The reaction mixture was then filtered; the filtrate was then washed twice with brine and dried over sodium sulfate before being concentrated in vacuo. The residue was then filtered through a pad of silica (SiO2, EtOAc, 100%) to yield the title compound as a light brown solid (138 mg, 99%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10](Cl)=[O:11].C1C=CC=CC=1.[CH:20]([OH:23])([CH3:22])[CH3:21].N1C=CC=CC=1>O>[CH3:1][C:2]1([CH3:13])[C@@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10]([O:23][CH:20]([CH3:22])[CH3:21])=[O:11]
Reactant: CC(C)O
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C1CCC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)OC(=O)[C@@H]1[C@H](C=C2CCC2)C1(C)C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
8 g of (1R,cis) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylic acid chloride and 10 ml of benzene were added at 10° C. to a solution of 50 ml of benzene, 4 g of isopropanol and 4 g of pyridine and the reaction mixture was stirred for 8 hours. The mixture was poured into iced water and the decanted organic phase was washed with water, with aqueous sodium bicarbonate solution, with water, with N hydrochloric acid and finally with water. The solution was dried and evaporated to dryness under reduced pressure at 45° C. The residue was chromatographed over silica gel and was eluted with an 8-2 petroleum ether (b.p.=60°-80° C.)-isopropyl ether mixture to obtain the fraction with an Rf=0.55. The solution was evaporated to dryness under reduced pressure at 45° C. to obtain 5 g of isopropyl (1R,cis) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylate with a boiling point of 66°~68° C. at 0.1 mm Hg and a specific rotation of [α]D 20 =+74.5° (c=1% in chloroform).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl.[NH:44]1[C@H:48]([C:49]([OH:51])=[O:50])[CH2:47][CH:46]=[N:45]1>C(#N)C>[CH:1]1([CH2:6][C@H:7]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([N:44]2[C@H:48]([C:49]([OH:51])=[O:50])[CH2:47][CH:46]=[N:45]2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)O
Reactant: O=C(O)[C@@H]1CC=NN1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a 1000 ml round bottom flask under N2 was added (2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (Tetrahedron, 2001, 57(36), 7675-7683) (38.1 g, 149 mmol) in acetonitrile (650 mL) at 0° C., followed by N-methylmorpholine (82 mL, 744 mmol) and 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (53.7 g, 164 mmol). The solution was stirred at the same temperature for 2 hours and then (5S)-4,5-dihydro-1H-pyrazole-5-carboxylic acid, hydrochloride (22.4 g, 149 mmol) was added. The solution was allowed to warm up to room temperature and stirring continued overnight. LCMS showed that the reaction was complete. The acetonitrile was removed under reduced pressure, and the residue was taken up in DCM (500 mL) and neutralized by the addition of 2 N HCl. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by Combiflash automated silica gel chromatography (0-5% methanol containing 1% formic acid/DCM) to provide (5S)-1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (27.7 g, 79 mmol, 53% yield) as a clear oil. LCMS: [M+H]+: 353.4.
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][SH:7])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].O.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][C:17]=1[S:25](=[O:28])(=[O:27])[NH2:26]>CCOCC>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([S:7][CH2:6][C@@H:2]([CH3:1])[C:3]([OH:5])=[O:4])=[O:21])=[CH:18][C:17]=1[S:25](=[O:27])(=[O:28])[NH2:26]
Reactant: C[C@H](CS)C(=O)O
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: C[C@H](CSC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
3 g of 2(S)-methyl-3-mercaptopropionic acid is added to a mixture of 3.5 g of potassium carbonate, 60 ml of water and 30 ml of ether with stirring atroom temperature under a nitrogen atmosphere whereupon 6.3 g of 4-chloro-3-sulfamoylbenzoyl chloride is added, and the resulting mixture is stirred at room temperature for 5.5 hours. The aqueous layer is then collected and made acidic with dilute hydrochloric acid, and the separatedoil is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Isopropyl ether is added to the residual oil. The crystals thus obtained are recrystallized from a mixture of ethyl acetate and hexane to give 3-(4-chloro-3-sulfamoylbenzoylthio)-2(S)-methylpropionic acid as white crystalline powder, melting at 152°-153° C. (sinteringat 145° C.).
Reaction SMILES: [CH:1](F)(F)F.[CH2:5]([O:7][C:8](=[O:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([O:17][C:18]2[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[C:20]([Cl:26])[CH:19]=2)[C:11]=1[F:27])[CH3:6].C([Zn]CC)C>>[CH2:5]([O:7][C:8](=[O:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH3:1])=[C:12]([O:17][C:18]2[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[C:20]([Cl:26])[CH:19]=2)[C:11]=1[F:27])[CH3:6]
Reactant: FC(F)F
Reactant: CCOC(=O)Cc1ccc(C)c(Oc2cc(Cl)cc(C#N)c2)c1F
Agent: CC[Zn]CC
Product: CCOC(=O)Cc1ccc(CC)c(Oc2cc(Cl)cc(C#N)c2)c1F

Procedure:
[3-(3-Chloro-5-cyano-phenoxy)-4-ethyl-2-fluoro-phenyl]-acetic acid ethyl ester (R-32) was prepared from R-23 using the procedure described for R-31 except diethylzinc was used in place of dimethylzinc.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:18]([NH2:22])[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](O[C:33](=[O:35])[CH3:34])OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[NH2:8][CH2:1][CH2:2][CH2:3][N:22]([CH:18]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:19]([CH3:20])[CH3:21])[C:33](=[O:35])[C:34]1[CH:19]=[CH:18][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)C(N)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)C(c1cc2cc(Cl)ccc2n1Cc1ccccc1)N(CCCN)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a solution of 1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-amine (0.44 mmol) in 10 mL of anhydrous DCM, was added aldehyde (0.44 mmol) and sodium triacetoxyborohydride (0.44 mmol) at 0° C. The mixture was stirred at room temperature overnight. The solution was poured into 10% aq. NaOH, and extracted with EtOAc (×3). The organic layers were combined, washed with H2O (×3), brine (×3), dried (Na2SO4), filtered, and the filtrate was concentrated. The material was purified by flash chromatography (20% EtOAc:hexane) to yield 40 mg of title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:28])[CH2:5][S:6][C:7]=1[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11](C(OCC(Cl)(Cl)Cl)=O)[CH:10]=[CH:9]1.[S]>>[CH3:1][C:2]1[NH:3][C:4](=[O:28])[CH2:5][S:6][C:7]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1
Reactant: COc1ccc2c(c1)C(C1=C(C)NC(=O)CS1)C=CN2C(=O)OCC(Cl)(Cl)Cl
Agent: [S]
Product: COc1ccc2nccc(C3=C(C)NC(=O)CS3)c2c1
Yield: 32.4 %

Procedure:
A mixture of 5-methyl-6-[1-(2,2,2-trichlorethoxycarbonyl)-6-methoxy-1,4-dihydro-4-quinolinyl]-2H-1,4-thiazin-3(4H)-one (0.6 g) and sulfur sublimed (0.3 g) was treated in the same manner as described in Example 3 (ii) to give the titled compound (0.12 g, yield 33%) as pale red crystals. Ethyl acetate was used as a developing eluant.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:19]3=[C:20]4[C:10](=[CH:11][CH:12]=[C:13]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=5)[C:14]4=[CH:15][CH:16]=[C:17]3[CH:18]=1)[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Br:28]N1C(=O)CCC1=O>O1CCCC1>[Br:28][C:11]1[C:10]2[C:20]3=[C:19]4[C:7](=[CH:8][CH:9]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:18]=[C:17]4[CH:16]=[CH:15][C:14]3=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1cc2ccc3ccc(-c4ccc(Cl)cc4)c4ccc(c1)c2c34
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2ccc3c(Br)cc(-c4ccc(Cl)cc4)c4ccc(c1)c2c34
Temperature: 30 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
Then, to a mixed solution of 100.6 g of 7-t-butyl-1-(4-chlorophenyl)pyrene, and 1638 ml of tetrahydrofuran was added 53.5 g of N-bromosuccinimide under a nitrogen stream. This mixed solution was stirred at 30° C. for about 5 hours, and concentrated, 984 ml of methanol was added, and the mixture was stirred for about 1 hour, and filtered. To the resulting solid was added 539 ml of hexane, and the mixture was heated and stirred for about 1 hour, and filtered. After the resultant was vacuum dried, 112.0 g of 1-bromo-7-t-butyl-3-(4-chlorophenyl)pyrene was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:19][C:9]2=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17]Cl)[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH2:1]([O:3][C:4]([C:6]1[NH:19][C:9]2=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCCCCl)cnc2[nH]1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OCCCN3CCCC3)cnc2[nH]1
Yield: 75 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate b), from 5-(3-chloro-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, potassium carbonate, potassium iodide and pyrrolidine to give the desired product as light yellow solid (75%).
Reaction SMILES: C([O:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][S:14]([NH2:17])(=[O:16])=[O:15])[CH3:6])(=O)C.C[O-].[Na+]>CO>[OH:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][S:14]([NH2:17])(=[O:15])=[O:16])[CH3:6]
Reactant: CC(=O)OC(C)c1ccccc1CS(N)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccccc1CS(N)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.5 %

Procedure:
A mixture of 1.9 g (7.4 mmol) of 2-(1-acetyloxyethyl)benzenemethanesulfonamide, 0.18 g of sodium methoxide (3.3 mmol) and 20 ml of methanol was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and 0.1N HCl. The organic layer was dried (MgSO4) and concentrated to give 1.49 g of an oil which slowly solidified.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:9]1)C1C=CC=CC=1.C(N1CCC(O)C1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:23][C:20]([F:21])([F:22])[C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: FC(F)(F)c1cccc(OC2CCN(Cc3ccccc3)C2)c1
Agent: [Pd+2]
Agent: OC1CCN(Cc2ccccc2)C1
Agent: [OH-]
Solvent: CO
Product: FC(F)(F)c1cccc(OC2CCNC2)c1
Reaction time: 8 h
Yield: 85.9 %

Procedure:
Pd(OH)2 (125 mg) was added to a stirred solution of 1-benzyl-3-(3-trifluoromethyl-phenoxy)-pyrrolidine (prepared according to Step 1 and 5 of the General Scheme from 1-benzylpyrrolidin-3-ol) (125 mg, 0.4 mmol) in MeOH (15 mL) in an inert atmosphere and stirring was continued under H2 gas atmosphere overnight. The reaction mixture was filtered through celite. The filtrate collected was concentrated under reduced pressure to afford 811 mg (85.9% Yield) of 3-(3-Trifluoromethyl-phenoxy)-pyrrolidine.
Reaction SMILES: [Na].[CH3:2][OH:3].F[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1>O>[CH3:2][O:3][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1
Reactant: CO
Reactant: Cc1cccc(F)n1
Agent: [Na]
Solvent: O
Product: COc1cccc(C)n1
Temperature: 25 °C

Procedure:
Sodium (31.0 g, 1.35 mol) was added portionwise to methanol (500 mL) over 30 min with stirring in a flask equipped with a reflux cindenser. After the addition was complete, the reaction mixture was allowed to cool to ambient temperature. 2-Fluoro-6-methylpyridine (50 g, 450 mmol) was added portionwise with stirring. The reaction mixture was then heated to reflux temperature and stirred for 48 h. The mix was then cooled to ambient temperature and solvent was removed in vacuo to provide a yellow oil. The residue was taken up in water (500 mL) and three extractions with ether (200 mL) were performed. The combined organic layers were dried over MgSO4, filtered and solvent was removed in vacuo from the filtrate to give a yellow liquid: 1H-NMR(CDCl3, 300 MHz): δ 7.44 (dd, 1H, J=8, 7), 6.71 (d, 1H, J=7), 6.53 (d, 1H, J=8), 3.91 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]1([NH:15][CH2:16][C:17]#[CH:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:19]([C:22]1[S:23][C:24]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[C:25]([CH3:27])[N:26]=1)=[N+:20]=[N-:21]>>[CH2:31]([NH:30][C:28]([C:24]1[S:23][C:22]([N:19]2[CH:18]=[C:17]([CH2:16][NH:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:21]=[N:20]2)=[N:26][C:25]=1[CH3:27])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Reactant: C#CCNc1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(CNc3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 18 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with phenyl prop-2-ynyl amine to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 18% yield: mp 159-162° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.42-7.35 (m, 5H), 7.30-7.21 (m, 2H), 6.82-6.77 (m, 1H), 6.73-6.69 (m, 2H), 6.18 (t, J=6.0 Hz, 1H), 4.66 (d, J=6.0 Hz, 2H), 4.58 (d, J=6.0 Hz, 2H), 4.32 (br s, 1H), 2.70 (s, 3H); 13C NMR (75 MHz, CDCl3) 160.9, 155.4, 153.1, 147.7, 147.1, 137.4, 129.4, 128.9, 127.9, 127.9, 124.5, 119.3, 118.3, 113.1, 44.3, 39.6, 17.4; MS (ES+) m/z 405.3 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][O:9][P:6]([O:7][CH2:8]1)[O:5][CH2:4]2.[C:11](Cl)(=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:6]12[O:9][CH2:10][C:3]([CH2:2][O:1][C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:8][O:7]1)[CH2:4][O:5]2
Reactant: OCC12COP(OC1)OC2
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)OCC12COP(OC1)OC2
Temperature: 25 °C
Reaction time: 10 h

Procedure:
16.4 g (0.1 mol) of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2,2,2]octane are dissolved in 150 ml of toluene by warming. 30.2 g (0.1 mol) of stearic acid chloride, followed by 10.1 g (0.1 mol) of triethylamine, are added dropwise at room temperature. After the slight evolution of heat has died away, the mixture is stirred for 10 hours under nitrogen at room temperature and the precipitated triethylamine hydrochloride is then filtered off. The filtrate is evaporated with exclusion of moisture, a yellowish oil remaining, which crystallises on being triturated with methanol. After filtering off under suction and drying, stearic acid 1-phospha-2,6,7-trioxabicyclo[2,2,2]oct-4-yl-methyl ester (Stabiliser No. 9), melting point 49°C, is obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=O)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH:25][NH2:26])[CH3:24].C(#N)C>O>[CH2:23]([N:25]1[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)=[C:16]2[C:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:26]1)[CH3:24]
Reactant: CCNN
Reactant: O=C1CCCCC1C(=O)C1CCN(Cc2ccccc2)CC1
Solvent: O
Solvent: CC#N
Product: CCn1nc2c(c1C1CCN(Cc3ccccc3)CC1)CCCC2

Procedure:
The title compound was prepared from the semi-crude (1-benzylpiperidin-4-yl)-(cyclohexanon-2-yl)ketone from step A and 34% aqueous ethylhydrazine in 4:1 acetonitrile and water at room temperature. This provided 8:1 ratio of isomeric ethyl pyrazoles in favor of the title compound. (Note: Use of ethyl hydrazine oxalate in the presence of DIEA gave about 2:1 ratio of the same isomers.) The 1-benzylpiperidine-4-carboxylic acid ethyl ester present in the starting β-diketone was removed after saponification of the crude product with sodium hydroxide in water ethanol mixture flowed by extractive work-up. The desired ethyl isomer is the higher Rf isomer. It was isolated on silica gel chromatography (60˜100% ethyl acetate in hexanes and 5˜20% methanol in ethyl acetate, both with 1% triethylamine).
Reaction SMILES: [NH2:1][CH:2]([C:14]1[C:22]([CH2:23][CH3:24])=[CH:21][C:20]([CH3:25])=[C:19]2[C:15]=1[CH:16]=[CH:17][NH:18]2)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:5]=2[N:4]=1.[CH:26](C1C=C(C)C2N(S(C3C=CC(C)=CC=3)(=O)=O)C=CC=2C=1C=O)(C)C>>[NH2:1][CH:2]([C:14]1[C:22]([CH:23]([CH3:26])[CH3:24])=[CH:21][C:20]([CH3:25])=[C:19]2[C:15]=1[CH:16]=[CH:17][NH:18]2)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:5]=2[N:4]=1
Reactant: CCc1cc(C)c2[nH]ccc2c1C(N)c1nc2cc(C#N)ccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C(C)C)cc(C)c32)cc1
Product: Cc1cc(C(C)C)c(C(N)c2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12

Procedure:
The title compound was synthesized following the same procedures that led to 2-(amino(5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 96) starting from 5-Isopropyl-7-methyl-1-tosyl-1H-indole-4-carbaldehyde (Example 50-A). 1H NMR (400 MHz, ACETONITRILE-d3 with about 5 μL TFA) δ ppm 9.50 (br. s., 1H), 8.00 (s, 1H), 7.60 (d, J=8.30 Hz, 1H), 7.56 (dd, J=1.50, 8.30 Hz, 1H), 7.05-7.20 (m, 2H), 6.55 (s, 1H), 5.71-5.88 (m, 1H), 3.33-3.48 (m, 1H), 2.52 (s, 3H), 1.36 (d, J=6.82 Hz, 3H), 1.21-1.33 (m, 3H). HRMS calcd. for C21H21N5 (M+H)+ 344.1870. found 344.1865.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[C:8](SC)[CH2:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[C:4]([CH3:20])=[N:3]1.[CH2:21]([NH2:24])[C:22]#[CH:23]>C(O)C>[CH3:1][N:2]1[C:6]2[N:7]=[C:8]([NH:24][CH2:21][C:22]#[CH:23])[CH2:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[C:4]([CH3:20])=[N:3]1
Reactant: CSC1=Nc2c(c(C)nn2C)C(c2ccccc2)=NC1
Reactant: C#CCN
Solvent: CCO
Product: C#CCNC1=Nc2c(c(C)nn2C)C(c2ccccc2)=NC1

Procedure:
A mixture of 2.9 g. of 1,6-dihydro-1,3-dimethyl7-(methylthio)-4-phenylpyrazolo[3,4-e][1,4]diazepine (prepared as disclosed in U.S. Pat. No. 3,770,762), 1.5 g. of 2-propynylamine and 50 ml. of ethanol is heated at reflux for 48 hours, then evaporated at reduced pressure to give a residue of 1,6-dihydro-1,3-dimethyl-4-phenyl-7-(2-propynylamino)pyrazolo[3,4-e][1,4]diazepine; m.p. 193°-195° C. after crystallization from ether.