Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:39][CH2:38][C:37]5[CH:40]=[CH:41][CH:42]=[C:35]([Cl:34])[CH:36]=5)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1
Reactant: NCc1cccc(Cl)c1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4ccnc(NCc5cccc(Cl)c5)n4)cnc23)CC1
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 48 supra) (100 mg, 0.212 mmol) and (3-chlorobenzylamine (120.3 mg, 0.849 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford crude (4-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 80 mg). LC-MS: [M+H]+ 549.
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]C1CC(C(C)C)CCC1=O>>[Br:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]1=[O:14]
Reactant: O=C1CCCCC(c2ccccc2)C1
Reactant: CC(C)C1CCC(=O)C(Br)C1
Product: O=C1CC(c2ccccc2)CCCC1Br

Procedure:
The bromination of 3-phenylcycloheptanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[O:24][CH2:25][C:26]([NH2:28])=[S:27]>C(#N)C.C(O)C.CO>[Cl:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[O:24][CH2:25][C:26]1[S:27][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:28]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: NC(=S)COc1cccc(Cl)c1
Solvent: CO
Solvent: CC#N
Solvent: CCO
Product: CSc1ccc(-c2sc(COc3cccc(Cl)c3)nc2-c2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
A solution of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-bromo-ethanone (1.98 g, 5.84 mmol) (Example 1, Step 3) and 3-chlorophenoxy thioacetamide (1.18 g, 5.85 mmol) in 15 mL of acetonitrile and 10 mL of ethanol was heated to reflux for 16 hours. The solution was diluted with methanol, cooled to 0° C. in an ice bath and a precipitate formed that was removed by filtration. The solid was air dried and then recrystallized from methanol to provide (1.67 g; 65%),of pure 2-((3-chlorophenoxy)methyl)-4-(4-fluorophenyl)-5-(4-methylthiophenyl)thiazole: mp 106°-110° C., 1NMR (CDCl3) 300 MHz 7.50 (m, 2H), 7.30-7.15 (m, 5H), 7.09-6.87 (m, 5H), 5.38 (s, 2H), 2.50 (s, 3H). 19F NMR (CDCl3) -113.58 (m). Mass spectrum M+ =441.
Reaction SMILES: O.NN.[CH3:4][N:5]1[C:9]([C:10]([NH2:12])=[O:11])=[C:8]([N+:13]([O-])=O)[C:7]([CH3:16])=[N:6]1>[Ni].C(O)C>[NH2:13][C:8]1[C:7]([CH3:16])=[N:6][N:5]([CH3:4])[C:9]=1[C:10]([NH2:12])=[O:11]
Reactant: Cc1nn(C)c(C(N)=O)c1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nn(C)c(C(N)=O)c1N
Reaction time: 1.5 h

Procedure:
1.1 ml of hydrazine hydrate are added dropwise at 60° to 75° C. to a suspension of 2.0 g of 1,3-dimethyl-4-nitropyrazole-5-carboxamide and approximately 0.2 g of moist Raney nickel in 15 ml of ethanol; the solution is kept at the boil for 1.5 hours and is filtered. The filtrate is concentrated to dryness in vacuo, and 1.3 g of the hydrochloride, mp 232° to 234° C. (dec.), are precipitated by means of an ethereal solution of hydrogen chloride.
Reaction SMILES: I.[CH3:2][NH:3][C:4](=[NH:7])[S:5][CH3:6].[CH:8]([N:11]([C:15](Cl)=[O:16])[C:12](Cl)=[O:13])([CH3:10])[CH3:9]>>[CH:8]([N:11]1[C:15](=[O:16])[NH:7][CH:4]([S:5][CH3:6])[N:3]([CH3:2])[C:12]1=[O:13])([CH3:10])[CH3:9]
Reactant: CNC(=N)SC
Reactant: CC(C)N(C(=O)Cl)C(=O)Cl
Agent: I
Product: CSC1NC(=O)N(C(C)C)C(=O)N1C

Procedure:
Analogously to Example 24, N,S-dimethyl-isothiourea hydroiodide and N-isopropyl-bis-(chlorocarbonyl)-amine (prepared analogously to Synthesis 1970, pages 542-543; boiling point 66-67° C/12 mm Hg yielded 1-isopropyl-3-methyl-4-methylmercapto-tetrahydro-1,3,5-triazine-2,6-dione as a colorless powder of melting point 73°-75° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].F[C:8]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:9]=1[CH:10]=O>>[F:16][C:13]1[CH:14]=[CH:15][C:8]2[S:3][C:2]([C:1]([O:5][CH3:6])=[O:4])=[CH:10][C:9]=2[CH:12]=1
Reactant: COC(=O)CS
Reactant: O=Cc1cc(F)ccc1F
Product: COC(=O)c1cc2cc(F)ccc2s1

Procedure:
In a similar manner to Example 9 Method A, methyl thioglycolate (75.2 g) was reacted with 2,5-difluorobenzaldehyde (101.8 g) to give methyl 5-fluorobenzo[b]thiophene-2-carboxylate which was hydrolysed to give 5-fluorobenzo[b]thiophene-2-carboxylic acid which was decarboxylated to give 5-fluorobenzo[b]thiophene (31 g) as an orange oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:22][C:21]([CH3:23])=[C:20]([C:24]([O:26]C)=[O:25])[CH:19]=3)[CH2:14][C@H:13]2[O:28][CH3:29])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:22][C:21]([CH3:23])=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=3)[CH2:14][C@H:13]2[O:28][CH3:29])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C(=O)OC)c(C)s3)C[C@H]2OC)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C(=O)O)c(C)s3)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl cis(±)-5-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-2-methylthiophene-3-carboxylate obtained in Example (188e) (16 mg) was dissolved in methanol (1 ml) and THF (1 ml). A 2 N aqueous lithium hydroxide solution (1 ml) was added, and the mixture was stirred at room temperature overnight. The organic solvent was evaporated under reduced pressure. Then, the residue was neutralized with 1 N hydrochloric acid, diluted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was recrystallized from an ethyl acetate/hexane solvent to obtain the title compound as crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:37]1([CH2:42][CH2:43]O)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:43][CH2:42][CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCCC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCCC2CCCC2)cc1

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 2-cyclopentyl-1-ethanol in place of 2-ethyl-1-hexanol (yield: 115 mg, 60%). mp 100-101° C. 1H NMR (300 MHz, DMSO-d6) δ 1.00 (m, 2H), 1.38 (m, 2H), 1.57 (m, 7H), 3.30 (s, 3H), 4.42 (t, J=7 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 475 (M+H)+; (APCI−) m/z 509 (M+Cl)−. Anal. calc. for C24H24F2N2O4S.0.25H2O: C, 60.17; H, 5.15; N, 5.84. Found: C, 60.12; H, 5.14; N, 5.76.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[S:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([N+:31]([O-])=O)[CH:25]=2)=[O:16])=[CH:4][C:3]=1[N+:34]([O-])=O.CO.[S-2].[Na+].[Na+]>O>[NH2:34][C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[S:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([NH2:31])[CH:25]=2)=[O:16])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c(N)c2)c(-c2ccc(N)c(N)c2)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a suspension of 21.2 g. (0.076 moles) of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide in 80 ml. of methanol a solution of 22 g. (0.17 moles) of sodium sulfide of 60% purity in 25 ml. of water is added in one hour, under boiling. The reaction mixture is refluxed for 3 hours, and the progress of the reaction is monitored by thin layer chromatography. Thereafter 1 g. of celite is added to the reaction mixture, which is then filtered while hot. The filtrate is diluted with 50 ml. of water, and is slowly cooled to room temperature. The precipitate is filtered off, and the substance remaining on the filter is washed base-free with water. The product is then dried at 50° to 60° C. to yield 17 g. of the title compound, melting at 131° to 132° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)[CH2:4][O:3]1.Cl[C:26]1[N:31]=[C:30]([NH:32][C:33]([C:35]2([C:38]3[CH:48]=[CH:47][C:41]4[O:42][C:43]([F:46])([F:45])[O:44][C:40]=4[CH:39]=3)[CH2:37][CH2:36]2)=[O:34])[CH:29]=[CH:28][C:27]=1[CH3:49]>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[F:46][C:43]1([F:45])[O:42][C:41]2[CH:47]=[CH:48][C:38]([C:35]3([C:33]([NH:32][C:30]4[CH:29]=[CH:28][C:27]([CH3:49])=[C:26]([C:12]5[CH:11]=[CH:10][C:9]([O:8][CH2:7][C@@H:5]6[CH2:4][O:3][C:2]([CH3:1])([CH3:24])[O:6]6)=[CH:14][CH:13]=5)[N:31]=4)=[O:34])[CH2:37][CH2:36]3)=[CH:39][C:40]=2[O:44]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: CC1(C)OC[C@@H](COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)O1
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: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(OC[C@@H]2COC(C)(C)O2)cc1
Temperature: 120 °C
Yield: 78.7 %

Procedure:
To a mixture of (R)-2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.600 mmol) and N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (183 mg, 0.500 mmol) in DME (3 mL) and 2 M Na2CO3 (1 mL) was added Pd(PPh3)4 (29 mg, 0.025 mmol). The mixture was heated in microwave oven at 120° C. for 30 min. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine and dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to yield (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-5-methylpyridin-2-yl)cyclopropanecarboxamide (212 mg, 79%). MS (ESI) m/e (M+H+) 539.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:4]=2[CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)c(I)nn2C1CCCCO1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Solvent: O
Product: Cn1cc(-c2nn(C3CCCCO3)c3cc(Cl)ncc23)cn1
Temperature: 85 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
A mixture of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (120 mg, 0.33 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.50 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol) and cesium carbonate (320 mg, 0.99 mmol) in 1,4-dioxane (1 mL) and water (0.12 mL) was degassed and sealed. It was stirred at 85° C. for 3 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.10 g). LCMS (M+H)+=318.1.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:33])=[O:5])[S:12][CH:13]=2)=[CH:27][CH:28]=1
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 101.1 %

Procedure:
2-[(4-{2-[(4-Chlorophenyl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (1.1 g) obtained in Example 286-3 was dissolved in dichloromethane (20 mL), trifluoroacetic acid (4.0 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1 to 1:1) to give the title compound (0.99 g) as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.[Br:13][CH2:14][C:15](Br)=[O:16].[CH2:18]([OH:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[Br:13][CH2:14][C:15]([O:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16]
Reactant: CCCCCCCCO
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCCCCCOC(=O)CBr
Reaction time: 8 h

Procedure:
Finely ground potassium carbonate (41.1 g) is added to a stirred dioxane solution of Octyl alcohol (36.9 g) cooled by an ice bath followed by addition over approximately 15 minutes of 2-bromoacetyl bromide (40.0 g). The mixture is stirred overnight, filtered and the dioxane is removed under vacuum. The residue is taken up in dichloromethane, washed with 10% HCl, water, sodium bicarbonate, and dried over magnesium sulfate. After removal of the solvent, the product is obtained as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]2[CH3:22])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[CH3:22])=[CH:28][CH:27]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CNCCN1C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 259.4 %

Procedure:
A 50 mL round-bottom flask was charged with tert-butyl 4-[bis(4-chlorophenyl)methyl]-3-methylpiperazine-1-carboxylate (0.800 g, 1.84 mmol, 1.00 equiv), dichloromethane (15 mL). The mixture was cooled to 0° C. and trifluoroacetic acid (2 mL) was added dropwise. The resulting solution was stirred for 3 hours at room temperature and concentrated under reduced pressure to yield 1.60 g (crude) of 1-[bis(4-chlorophenyl)methyl]-2-methylpiperazine as a light yellow semi-solid. LCMS: (ESI, m/z): 335 [M+H]+.
Reaction SMILES: C([NH:9][C:10]([NH:12][C@@:13]([C:18]1[CH:23]=[C:22]([Br:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])([CH3:17])[CH2:14][CH2:15]O)=[S:11])(=O)C1C=CC=CC=1.Cl.[OH-].[Na+]>O1CCOCC1>[Br:24][C:22]1[C:21]([F:25])=[CH:20][C:19]([F:26])=[C:18]([C@:13]2([CH3:17])[CH2:14][CH2:15][S:11][C:10]([NH2:9])=[N:12]2)[CH:23]=1
Reactant: C[C@@](CCO)(NC(=S)NC(=O)c1ccccc1)c1cc(Br)c(F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(Br)c(F)cc2F)CCSC(N)=N1
Temperature: 100 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
To a solution of (S)-1-benzoyl-3-[1-(5-bromo-2,4-difluoro-phenyl)-3-hydroxy-1-methyl-propyl]-thiourea (41 g, 68 mmoles) in 1,4-dioxane (20 mL) is added an aqueous solution of HCl (5 N, 407 mL, 2.0 moles, 30 equiv). The resulting suspension is warmed to 100° C. After stirring for 20 h, the reaction is concentrated under reduced pressure. The resulting mixture is treated with an aqueous solution of HCl (5 N, 407 mL, 2.0 moles) and stirred at 100° C. for 18 h. The suspension is cooled to 10° C. and the pH is adjusted to pH 10 with a 50% aqueous solution of NaOH. The resulting aqueous solution is extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography eluting with a step gradient of hexane:acetone (4:1) to hexane:acetone (3:1) to give the title compound (57% yield, 85% purity as determined by LCMS): MS (m/z): 321, 323 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[O:14][CH:15]=[CH:16][C:17]=3[CH3:18])[C:10]([CH:11]=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:19]([Mg]Br)#[CH:20].O>O1CCCC1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[O:14][CH:15]=[CH:16][C:17]=3[CH3:18])[C:10]([CH:11]([OH:12])[C:19]#[CH:20])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Mg]Br
Reactant: Cc1ccoc1-c1nn2c(Cl)cccc2c1C=O
Solvent: C1CCOC1
Solvent: O
Product: C#CC(O)c1c(-c2occc2C)nn2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (11.56 g, 44.3 mmol) in tetrahydrofuran (200 mL) at −78° C. was added ethynylmagnesium bromide (133 mL, 0.5 M in tetrahydrofuran, 66.5 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hour. Water was added to the reaction and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was dried over magnesium sulfate, filtered and concentrated to a solid residue, 1-[7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (12.29 g, 97%). 1H-NMR (CDCl3): δ 7.97 (d, 1H), 7.48 (d, 1H), 7.16 (t, 1H), 6.96 (d, 1H), 6.42 (d, 1H), 6.18 (m, 1H), 2.78 (m, 1H), 2.6 (d, 1H), 2.46 (s, 3H). MS m/z 287 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][N:25]1[C:29](=[O:30])[C:28]([CH3:32])([CH3:31])[NH:27][C:26]1=[O:33]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[C:28]([CH3:32])([CH3:31])[C:29](=[O:30])[N:25]([CH3:24])[C:26]4=[O:33])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN1C(=O)NC(C)(C)C1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4(C)C)nc3)CC2)c(C)c1
Yield: 64.2 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127 and 3,5,5-trimethylimidazolidine-2,4-dione (63 mg) described in Preparation Example 218 and by the reaction and treatment in the same manner as in Example 536, the title compound (112 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([OH:28])=[O:27]>>[F:21][C:20]([F:23])([F:22])[CH2:19][N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:33]5[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=5)[C:26]([OH:28])=[O:27])[CH:25]=[CH:24][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: O=C(O)c1cccc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)c1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3-carboxyphenylboronic acid to give 149. MS(ESI+) 473.0. 1H NMR (400 MHz, DMSO) δ 13.05 (br, 1H), 8.42 (d, J=8.3, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 8.00 (d, J=7.8, 1H), 7.96 (d, J=7.8, 1H), 7.65-7.54 (m, 2H), 7.42 (d, J=1.6, 1H), 5.88 (q, J=8.6, 2H), 4.45 (t, J=4.9, 2H), 3.51 (t, J=4.9, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](O)=O)[CH:5]=[CH:6][CH:7]=1.C[NH2:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: O=C(O)Cc1cccc(Cl)c1
Product: NCCc1cccc(Cl)c1

Procedure:
Synthesized according to typical procedures C and D from 3-chlorophenylacetic acid and methylamine.
Reaction SMILES: [C:1]1(=[O:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=[O:13].[Cl:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:15][C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([C:1](=[O:14])[C:2](=[O:13])[N:3]3[CH2:4][CH2:5][CH2:6]2)[CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1C(=O)N2CCCc3cccc1c32
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1C(=O)N2CCCc3cc(Cl)cc1c32
Yield: 47.4 %

Procedure:
A mixture of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione (7.49 g, 0.04 mole) and N-chlorosuccinimide (5.34 g, 0.04 mole) in carbon tetrachloride (40 ml) was refluxed for 23 hours. After cooling, the resultant red precipitate was collected by filteration, washed with water and dried. Recrystallization from acetonitrile afforded 4.2 g (47.4%) of red needles, melted at 188°-189° C.