Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=4)=[O:36])=[C:30]([F:45])[CH:29]=3)[CH:24]=[CH:23][N:22]=2)[NH:18][CH:17]=1)=[O:15])[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].CN(C(O[N:55]1N=N[C:57]2C=CC=N[C:56]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(N)C.C1COCC1.Cl>CN(C=O)C.O>[CH2:56]([NH:55][C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=4)=[O:36])=[C:30]([F:45])[CH:29]=3)[CH:24]=[CH:23][N:22]=2)[NH:18][CH:17]=1)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:46])[CH3:57]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O)c[nH]4)c3)cc2F)c1
Agent: CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (2S)-5-tert-butoxy-2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoic acid (80 mg, 0.13 mmol), HATU (57 mg, 0.15 mmol) and N,N-diisopropylethylamine (49 mg, 0.38 mmol) in anhydrous DMF (8 ml) was stirred at room temperature for 10 minutes, followed by addition of 2M ethylamine in THF solution (0.1 ml, 0.2 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 2M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 4˜5% MeOH/CHCl3 to give tert-butyl(4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoate as white solid. Yield: 40 mg, 48%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C=O.O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(O)ccc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Pyridinamine (2.20 g, 23.42 mmol) was added to a stirred solution of 5-hydroxy-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 76; 5.2 g, 21.29 mmol), HOBT (3.59 g, 23.4 mmol) and EDC (4.49 g, 23.42 mmol) in dimethylformamide (100 ml) at room temperature. The reaction mixture was stirred at 25° C. overnight. Water was added, the solid was filtered and washed with ethyl acetate to yield the title compound as a white solid. 3.7 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:27](I)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[N:20]=[CH:21][C:22]([Br:25])=[CH:23][N:24]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(Br)cn2)cs1
Reactant: CCCCCCCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
2-[(4-{2-[(5-Bromopyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (3.27 g) synthesized in Example 162-1 and heptyl iodide (1.77 g) were dissolved in N,N-dimethylformamide (36 mL), potassium tert-butoxide (0.80 g) was added thereto, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (2.80 g) as a colorless oil.
Reaction SMILES: C([O-])=O.[NH4+].C([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[CH:24][C:23]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[N:22]3)=[CH:15][C:14]=1[N+:35]([O-])=O)C1C=CC=CC=1>CO.O.[Pd]>[N:29]1([C:23]2[CH:24]=[N:25][C:26]3[C:21]([N:22]=2)=[CH:20][C:19]([C:16]2[CH:15]=[C:14]([NH2:35])[C:13]([NH2:12])=[CH:18][CH:17]=2)=[CH:28][CH:27]=3)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: O=[N+]([O-])c1cc(-c2ccc3ncc(N4CCOCC4)nc3c2)ccc1NCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(-c2ccc3ncc(N4CCOCC4)nc3c2)cc1N
Yield: 55.3 %

Procedure:
Pd/C (120 mg, 1.13 mmol) and ammonium formate (857 mg, 13.6 mmol) were added to a suspension of N-benzyl-4-[3-(morpholin-4-yl)quinoxalin-6-yl]-2-nitroaniline (1.2 g, 2.7 mmol) in MeOH (120 mL) and water (0.12 mL). The reaction mixture was refluxed for 4 h, then filtered over Celite. After removal of solvent the residue was purified (silica gel, Hexane/EtOAc: 10%->100% EtOAc) giving rise to 480 mg (48%) of the desired product.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][C@H:16](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][N:14]2[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])(=O)=O)=CC=1.[NH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1>C1(C)C=CC=CC=1>[CH3:38][C:35]1[CH:34]=[CH:33][C:32]([S:29]([N:14]2[CH2:15][C@H:16]3[CH2:17][C@@H:13]2[CH2:12][N:39]3[CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)(=[O:30])=[O:31])=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](OS(=O)(=O)c3ccc(C)cc3)CN2S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: NCc1cccnc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2C[C@H]3C[C@@H]2CN3Cc2cccnc2)cc1
Yield: 45.9 %

Procedure:
((2R,4S)-1-[(4-Methylphenyl)sulfonyl]-4-{[(4-methylphenyl)sulfonyl]oxy}pyrrolidinyl)methyl 4-methylbenzenesulfonate (1.5 g, 2.6 mmol), prepared as described in (J. Med. Chem. (1990) 33, 1344) and 3-(aminomethyl)pyridine (1.0 g, 9.3 mmol) in 20 mL of toluene were heated under reflux for 16 hours. The mixture was cooled, filtered, and the filter cake was washed with 20 mL of toluene. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography (silica gel; hexanes:EtOAc, 9:1 to 1:1) to provide the title compound (410 mg, 46%). 1H NMR (DMSO-d6, 300 MHz) δ 0.86 (d, J=8.5 Hz, 1H), 1.62 (d, J=9.7 Hz, 1H), 2.42 (s, 3H), 2.44 (m, 1H), 2.66 (dd, J=2.4, 9.5 Hz, 1H), 2.99 (dd, J=2.0, 9.5 Hz, 1H), 3.39-3.48 (m, 2H), 3.62-3.41 (d, J=9.5 Hz, 1H), 4.23 (br s, 1H), 4.35 (t, J=5.1 Hz, 1H), 7.31 (m, 1H), 7.43-7.46 (m, 2H), 7.62 (m, 1H), 7.71-7.74 (m, 2H), 8.31-8.43 (m, 2H).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([C:15]([O:17]C)=O)=[CH:13][CH:14]=2)[N:9]=1)[NH2:3].O.[NH2:20][NH2:21]>C(O)C>[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([C:15]([NH:20][NH2:21])=[O:17])=[CH:13][CH:14]=2)[N:9]=1)[NH2:3]
Reactant: NN
Reactant: COC(=O)c1ccc(-c2csc(N=C(N)N)n2)o1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(-c2csc(N=C(N)N)n2)o1
Yield: 97.2 %

Procedure:
A solution of 2-(diaminomethyleneamino)-4-(5-methoxycarbonylfuran-2-yl)thiazole (5.00 g) and hydrazine hydrate (9.40 g) in ethanol (50 ml) was refluxed for 4 hours with stirring. The mixture was cooled and the resulting precipitate was collected by filtration to afford 2-(diaminomethyleneamino)-4-(5-hydrazinocarbonylfuran-2yl)thiazole (4.86 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH2:22]([O:24][C:25](=[O:31])[C@H:26]([C@@H:28]([CH3:30])[OH:29])[NH2:27])[CH3:23].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:22]([O:24][C:25](=[O:31])[CH:26]([NH:27][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[CH:28]([OH:29])[CH3:30])[CH3:23]
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)O
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)C(C)O

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.736 g (10 mmol) of L-threonine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[CH3:32])=[O:25])=[CH:20]1.[F:33][C:34]([Si](C)(C)C)([F:36])[F:35].Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:31][C:29]1[O:30][C:26]([C:24]([C:21]2[CH:22]=[CH:23][O:19][CH:20]=2)([OH:25])[C:34]([F:36])([F:35])[F:33])=[C:27]([CH3:32])[N:28]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1nc(C)c(C(=O)c2ccoc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(O)(c2ccoc2)C(F)(F)F)o1
Temperature: 25 °C

Procedure:
Tetrabutylammonium fluoride (250 mg) was added to a stirred solution of 2,4-dimethyl-5-oxazolyl 3-furyl ketone (1.7 g) and (trifluoromethyl) trimethylsilane (1.9 g) in dry tetrahydrofuran (30 ml) at -10° C. The mixture was allowed to warm to room temperature. After 45 minutes 6M hydrochloric acid (30 ml) was added. After 1 hour the mixture was basified by the addition of saturated aqueous sodium hydrogen carbonate and then extracted with dichloromethane. The material thus obtained was purified by flash chromatography and recrystallisation from diethyl ether.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[C:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:6](=[O:28])[NH:5]1)([CH3:3])[CH3:2].CC([O:32][CH2:33][C@H:34]1[O:39][C@H:38](Br)[C@H:37]([O:41]C(C)=O)[C@@H:36]([O:45]C(C)=O)[C@@H:35]1[O:49]C(C)=O)=O.[OH-].[Na+]>ClCCl>[C@@H:38]1([O:28][C:6]2[C:7]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])=[C:8]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=2)[O:39][C@H:34]([CH2:33][OH:32])[C@@H:35]([OH:49])[C@H:36]([OH:45])[C@H:37]1[OH:41]
Reactant: COc1ccc(-c2c(Cc3ccc(OC)cc3OC)c(=O)[nH]n2C(C)C)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(-c2c(Cc3ccc(OC)cc3OC)c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn2C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
To a suspension of 1-isopropyl-5-(4-methoxyphenyl)-4-[(2,4-dimethoxyphenyl)methyl]-1,2-dihydro-3H-pyrazole-3-one (0.090 g), acetobromo-α-D-glucose (0.48 g) and benzyl-(n-tributyl)ammonium chloride (0.037 g) in dichloromethane (2 mL) was added sodium hydroxide (5 mol/L, 0.47 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). The obtained semi purified 1-isopropyl-5-(4-methoxyphenyl)-4-[(2,4-dimethylphenyl)-methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole was dissolved in methanol (5 mL), and sodium methoxide (28% methanol solution, 0.45 mL) was added to the solution. The mixture was stirred at room temperature overnight. The solvent of the reaction mixture was removed, and methanol (0.5 mL) and 10% citric acid aqueous solution (5 mL) were added to the residue. The mixture was purified by solid phase extraction on ODS (washing solvent: water, eluent: methanol). Further purification by preparative reverse phase column chromatography (Shiseido CAPSELLPAC C18 UG80, 5 μM, 20×50 mm, flow rate 30 mL/min linear gradient, water/methanol=90/10-10/90) gave the title compound (0.065 g).
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([N:10]1[C:15](=[O:16])[CH2:14][O:13][CH2:12][C@@H:11]1[C@H:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:18])=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[CH2:20]([O:19][C@H:17]([CH3:18])[C@H:11]([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:12][O:13][CH2:14][C:15]([OH:1])=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H]1COCC(=O)N1C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](OCc1ccccc1)[C@@H](COCC(=O)O)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
A 2 N sodium hydroxide solution (250 mL) was added to a methanol (250 mL) solution of (R)-3-((R)-1-benzyloxyethyl)-5-oxomorpholine-4-carboxylic acid t-butyl ester (40 g), and stirring was continued for 3 hours at room temperature. The methanol was removed under a vacuum, and ether was added, and the aqueous layer was partitioned. The aqueous layer was washed with ether, and the pH was adjusted to approximately pH 4 with a 5% citric acid solution. The resultant was extracted twice with ethyl acetate and washed twice with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under a vacuum, and the title compound (42.1 g) was obtained. The physical property values are as follows.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CCN(CC)CC.[CH3:18][O:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH3:10])[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][C:20]([O:19][CH3:18])=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: CCCCCCCNCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCN(CC)C(=O)CCCCC(=O)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3.2 gms of the N-heptyl-N-ethylamine in 96 ml of CH2Cl2 are added 5.7 ml of Et3N followed by 3.63 ml of hexanedioic acid monochloride monomethyl ester. This mixture is stirred at room temperature for 18 hours; and after concentrating under vacuum, the residue obtained is partitioned between ethyl acetate and an aqueous 2N HCl solution. The organic layer is separated and washed with aqueous saturated NaHCO3, then brine, and dried over MgSO4. Following filtration and concentration under vacuum, the residue is flash chromatographed on normal phase silica gel using a 3/1 ratio of hexane and ethyl acetate to yield N-heptyl-N-ethyladipamic acid, methyl ester.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:19]([Mg]Br)[CH:20]([CH3:22])[CH3:21]>O1CCCC1>[CH3:19][CH:20]([CH3:22])[CH2:21][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)[OH:16]
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To a solution of 4′-(trifluoromethyl)biphenyl-4-carbaldehyde (7.0 g, 28 mmol) in tetrahydrofuran (280 mL) was added isobutylmagnesium bromide (21 mL, 2M in THF, 42 mmol) dropwise at −15° C. The reaction was stirred at −10° C. for 2 hours. The reaction was quenched with 1N HCl (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-ol (3.9 g, 45%) as a solid. 1H NMR (400 MHz, CDCl3, δ): 7.62 (s, 4H), 7.52-7.50 (m, 2H), 7.40-7.38 (m, 2H), 4.77-4.73 (m, 1H), 1.75-1.67 (m, 1H), 1.50-1.46 (m, 2H), 0.92-0.90 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH2:7][C:8]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][C:9]=2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.O>S1(=O)(=O)CCCC1>[C:14]([C:12]1[CH:11]=[CH:10][C:9]2[C:17](=[O:19])[C:20]3[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][C:8]=2[CH:13]=1)([OH:16])=[O:15]
Reactant: O=C(O)c1ccc(C(=O)O)c(CCc2ccc(Br)cc2)c1
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)CCc1ccc(Br)cc1C2=O

Procedure:
A mixture of 103.2 g. of p-bromophenylacetic acid, 77.4 g. of benzene-1,2,4-tricarboxylic anhydride and 1.5 g. of sodium acetate was heated to 275° for 2 hours. The residue was dissolved in 1600 ml of hot dimethylformamide and the solution diluted with 400 ml of water, then cooled. The solution was then filtered to afford a mixture of 3-(p-bromobenzylidene)phthalide-5- and -6-carboxylic acids. 80 g. of this mixture was refluxed for 72 hours in 160 ml of acetic anhydride and 240 ml of 57% aqueous hydriodic acid containing 35.2 g. of red phosphorus. The mixture was cooled in ice and diluted with 1000 water. The solution was filtered and the residue dissolved in 800 ml dimethylformamide and filtered. The filtrate was evaporated to yield a residue which upon recrystallization from benzene: ethanol (3:1) yielded 4-(p-bromophenethyl)benzene-1,3-dicarboxylic acid. The mother liquors were evaporated and the residue recrystallized from ethyl acetate to afford 2-(p-bromophenethyl)benzene-1,4-dicarboxylic acid. 8.5 G. of 2-(p-bromophenethyl)-benzene-1,4-dicarboxylic acid was stirred at 170° for 6 hours in a mixture of 40 ml of polyphosphonic acid and 30 ml of tetrahydrothiophene-1,1-dioxide. The mixture was then poured into water and the product filtered off and recrystallized from aqueous dimethylformamide to yield 2-carboxy-7-bromo-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene mp 252°-254°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH3:11][O:12][C:13](=[O:18])[CH:14]=[CH:15]OC.CC(C)([O-])C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OC)(C)(C)C>[CH3:11][O:12][C:13](=[O:18])[CH2:14][CH:15]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:9]#[N:10]
Reactant: N#CCc1ccccc1Br
Reactant: COC=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)CC=C(C#N)c1ccccc1Br
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A solution of 2-bromo-phenylacetonitrile (6.62 mL, 51.0 mmol) and methyl-3-methoxyacrylate (5.32 mL, 49.5 mmol) in tetrahydrofuran (10 ml) was added to a suspension of sodium tert-butoxide (5.05 g, 51.0 mmol) in tetrahydrofuran (70 mL) at 0° C. over 10 minutes under a stream of nitrogen. The reaction mixture was warmed to room temperature and after 15 minutes diluted with methyl tert-butyl ether (240 mL). To the mixture was added 0.2 N aqueous citric acid until the aqueous layer had a pH of 2 (80 mL). The organic layer was separated and washed with a saturated aqueous solution of sodium chloride (2×80 mL), dried over anhydrous sodium sulfate, filtered through a pad of Celite and silica (4:1) and concentrated in vacuo to provide 4-(2-bromo-phenyl)-4-cyano-but-3-enoic acid methyl ester as a pale yellow oil (13.8 g, 96%). Major isomer 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, 1H, J=7.6, 1.2), 7.57–719 (m, 3H), 6.71 (t, 1H, J=7.1), 3.71 (s, 3H), 3.61 (d, 2H, J=7.1); 13C NMR (100 MHz, CDCl3) δ 169.7, 144.4, 133.7, 131.4, 131.1, 128.3, 122.5, 118.1, 117.3, 115.3, 52.7, 36.6; IR (ATR, neat) 1737, 1434, 1319, 1199, 1171, 1026, 755 cm−1. Minor isomer 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, 1H, J=7.6, 1.0), 7.57–7.19 (m, 3H), 6.9 (t, 1H, J=7.5), 3.64 (s, 3H), 3.06 (d, 2H, J=7.5).
Reaction SMILES: [C:1]([C:3]1[C:4](C)([OH:10])[NH:5][CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2].[CH3:12]O>[Ni].N>[NH2:2][CH2:1][C:3]1[C:4](=[O:10])[NH:5][C:6]([CH3:12])=[CH:7][C:8]=1[CH3:9]
Reactant: CC1=C(C#N)C(C)(O)NC=C1
Reactant: CO
Agent: [Ni]
Agent: N
Product: Cc1cc(C)c(CN)c(=O)[nH]1
Reaction time: 3.5 h

Procedure:
3-Cyano-2,4-dimethyl-2-hydroxypyridine (0.3 g, 2.0 mmol) was dissolved in MeOH (5 mL), to which catalytic amount of Raney Ni and of aqueous NH3 (0.3 mL) were added and the reaction mixture was stirred under hydrogen pressure (bladder pressure) for 3-4 h. After completion of the reaction, catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was thoroughly dried to provide the desired product (0.3 g, quantitative yield).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[SH:10][C:11]1[S:12][CH2:13][CH2:14][N:15]=1.Cl[O-].[Na+]>O>[CH:1]1([NH:7][S:10][C:11]2[S:12][CH2:13][CH2:14][N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: SC1=NCCS1
Reactant: NC1CCCCC1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: C1CCC(NSC2=NCCS2)CC1
Yield: 86.7 %

Procedure:
A mixture of 12.3 g (124 mmole) of cyclohexylamine and 30 ml of water was thoroughly stirred in an ice bath, and 30 ml of a 1N sodium hydroxide aqueous solution having dissolved therein 3.57 g (30 mmole) of 2-mercaptothiazoline and 22.3 ml (30 mmole) of a 10% sodium hypochlorite aqueous solution were simultaneously added thereto dropwise. After allowing the mixture to react at room temperature for 1 hour, the reaction mixture was filtered with suction. The resulting solid was washed with water and dried under reduced pressure to obtain 5.61 g (26 mmole) of the titled compound in a percent yield of 87%.
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[C:16]2[C:15]3[N:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][N:8]=1.[C:21](=[O:23])=[O:22]>CCCCC.C1COCC1>[C:7]1([C:21]([OH:23])=[O:22])[C:16]2[C:15]3[N:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][N:8]=1
Reactant: O=C=O
Reactant: Brc1n[nH]c2c1-c1ncccc1CCC2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=C(O)c1n[nH]c2c1-c1ncccc1CCC2
Temperature: 25 °C

Procedure:
7.8 mL of 1.7 M of t-BuLi in pentane is added dropwise under argon to a stirred solution of 1-bromo-3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene (1.4 g) in 75 mL of anhydrous THF at −78° C. After addition, dry carbon dioxide is bubbled into the mixture at the same temperature for 2 hours. The reaction mixture is allowed to warm to room temperature, quenched with 1N HCl solution, and diluted with water. The mixture is basified with 1N NaOH to pH 8-9, and then extracted with EtOAc. The aqueous layer is then acidified with HOAc to pH 4-5 and extracted with CH2Cl2 eight times. The combined extracts are washed with water, dried, and concentrated to give 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid as a tan solid. 1H NMR(DMSO): 1.95(m, 2H), 2.96(m, 2H), 3.07(t, 2H), 7.45(m,1H), 7.97(d,1H), 8.52(d, 2H). LR-MS: MW 229.23, Found: 230.2(M+1). Step 6: A mixture of 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid (80 mg), 1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-ylamine (68 mg), EDCI(85 mg) and DMAP(55 mg) in 10 mL of 1,2-dichloroethane is refluxed overnight, cooled and diluted with CH2Cl2. The mixture is washed with aqueous NaHCO3 solution, water, dried over Na2SO4 and concentrated under vacuum. Purification on a silica gel plate, eluting with 10% MeOH in CH2Cl2 yields 12 mg of 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid [1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-yl]-amide as a colorless foam. 1H NMR (CDCl3): 2.01-2.31(m, 6H), 2.67-2.92(m, 8H), 3.63(m, 2H), 4.17(t, 2H), 6.65(d, 1H), 7.23(m, 1H), 7.33(d, 1H), 7.65(d, 1H), 8.62(d, 1H), 14.13(bs, 1H). LR-MS: MW 391.48, Found: 392.2 (M+1).