Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=3[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:33]=[C:32](B(O)O)[C:31]([O:37][CH3:38])=[CH:30][C:29]=1[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>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:27][C:28]1[CH:33]=[C:32]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]4[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=4[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[C:31]([O:37][CH3:38])=[CH:30][C:29]=1[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1B(O)O
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
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: [K+]
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Temperature: 50 °C
Yield: 79.8 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-chloroisoquinoline-6-sulfonate (from Step 1 of Example 73, 500 mg, 1.220 mmol), (2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)boronic acid (Intermediate SSSS; 479 mg, 1.709 mmol) potassium carbonate (506 mg, 3.66 mmol), and Pd(Ph3P)4 (141 mg, 0.122 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (4576 μl) and water (1525 μl) were added. The flask was fitted with a reflux condenser and heated in a 50° C. heating bath for 40 min. The mixture was partitioned between water and EtOAc. The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 25-g silica gel loading column, 0-50% EtOAc/Heptane) to give perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (593.7 mg, 0.973 mmol, 80% yield) as a white foam. m/z (ESI) 609.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](Cl)=[O:10])=[CH:4][N:3]=1.[NH:12]([CH3:14])[CH3:13].CCN(CC)CC.O>C(Cl)Cl>[CH3:13][N:12]([CH3:14])[C:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:10]
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 158.8 %

Procedure:
To a solution of 2,4-dichloro-pyrimidine-5-carbonyl chloride (197.7 mg, 0.94 mmol) in CH2Cl2 (9.4 mL) at RT is added Me2NH (2.0 M THF solution, 390 μL, 0.78 mmol) and Et3N (108.6 μL, 0.78 mmol) at 0° C. The reaction mixture is stirred overnight at RT. After adding water, the mixture is extracted with CH2Cl2. The organic layer is dried and concentration under reduce pressure give 2,4-dichloro-pyrimidine-5-carboxylic acid dimethylamide (272.5 mg, quant). ESI-MS m/z: 221 [M+1]+, Retention time 1.94 min (condition B).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([Cl:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1ccc(-c2ccc(Cl)cc2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2ccc(Cl)nn2)cc1

Procedure:
A 269 g. portion of 6-(p-chlorophenyl)-3(2H)-pyridazinone and 1500 ml. of phosphorus oxychloride are heated on a steam bath for 5 hours. The excess phosphorus oxychloride is removed under vacuum. The solid concentrate is diluted with ice water and the resulting solid is recovered by filtration, washed with water and dried. This product is recrystallized twice from dimethylformamide-water yielding 6-(p-chlorophenyl)-3-chloropyridazine as an off-white solid, m.p. 202°-204° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([CH3:8])=[CH:6][S:5][CH:4]=1.C1(C)C=CC=CC=1.[Br:16][CH2:17]CO.OS([O-])(=O)=O.[Na+]>CO>[Br:16][CH2:17][CH2:1][O:2][C:3]1[C:7]([CH3:8])=[CH:6][S:5][CH:4]=1
Reactant: COc1cscc1C
Reactant: OCCBr
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cscc1OCCBr
Yield: 55 %

Procedure:
4.2 g of 3-methoxy-4-methylthiophene was added to a mixture of 40 mL of toluene, 8.2 g of 2-bromo-1-ethanol (Aldrich) and 500 mg of NaHSO4. The resulting mixture was heated until the produced methanol had been distilled off and the temperature rose to 110° C. The product was cooled and washed several times with water and, subsequently, extracted with diethyl ether. The organic phase was dried with magnesium sulfate and then evaporated. The product was purified by column chromatography using silica gel and hexanes as eluent. Yield=55%.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])[CH3:10].Cl.C(OCC)(=O)C>C1COCC1>[OH:11][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C[Zn]Br
Reactant: CC(=O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)(O)c1ccccc1
Yield: 96 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 3.96 g (6.50 mmol, 0.65 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.20 g (10 mmol) of acetophenone in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 25 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL (×2) of hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution. The organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.99 g of the desired product (yield 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:41]=[CH:40][S:39][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([NH:25][C:26]4[CH:38]=[CH:37][C:29]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:28][CH:27]=4)=[O:24])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:41]=[CH:40][S:39][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([NH:25][C:26]4[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:37][CH:38]=4)=[O:24])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nc3scnc23)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2nc(N3CCC(C(=O)Nc4ccc(C(=O)O)cc4)C3)nc3scnc23)cc1OC
Reaction time: 24 h
Yield: 59.8 %

Procedure:
To a stirred solution of tert-butyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-3-carboxamido)benzoate (105 mg, 0.18 mmol) in 10 mL of dichloromethane was added trifluoroacetic acid (5 mL) in one portion at room temperature. Then the reaction mixture was stirred at this temperature for 24 hours. The solvent was evaporated at 37° C. at reduced pressure and the residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 30% acetonitrile/70% water (0.1% TFA V/V) initially, and then proceed to 60% acetonitrile/40% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-3-carboxamido)benzoic acid (56 mg, 59%) as a white solid. 1H NMR (300 MHz, DMSO): δ 10.42 (s, 1H), 9.64 (s, 1H), 8.84 (s, 1H), 7.92-7.73 (m, 6H), 7.48 (brs, 1H), 6.93 (d, 1H, J=9.0 Hz), 3.92-3.36 (m, 11H), 2.29-2.21 (m, 2H). LC-MS: 521 [M+H]+, tR=1.38 min. HPLC: 99.34% at 214 nm, 99.25% at 254 nm, tR=4.75 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[Na+].[Br-]>O>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][O:8][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCCBr
Reactant: Oc1cccc(Cl)c1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1cccc(OCCCCBr)c1
Temperature: 80 °C
Yield: 79 %

Procedure:
A 1 L flask provided with a stirrer was charged with 128.6 g (1.0 mol) of m-chlorophenol (available from Tokyo Chemical Industry Co., Ltd.), 52.0 g (1.3 mols) of sodium hydroxide (available from Wako Pure Chemical Industries Ltd.), 259.1 g (1.2 mols) of 1,4-dibromobutane (available from Tokyo Chemical Industry Co., Ltd.) and 300 g of water. The content was maintained at 80° C. for 4 hours. Then the reaction liquid was cooled to room temperature, and deposited NaBr, produced by side reaction, was filtered off. The organic phase was separated and subjected to distillation under reduced pressure to give 216.9 g of the target m-(4-bromobutoxy)chlorobenzene (yield: 79%, purity: 96%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+].O>C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Cl)cc2Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: Nc1c(CC(=O)O)cccc1Oc1ccc(Cl)cc1Cl
Yield: 73.8 %

Procedure:
A mixture of ethyl 2-[2-amino-3-(2,4-dichlorophenoxy)phenyl]acetate (3.1 g.), sodium hydroxide (730 mg.) and water (40 ml.) was treated in a similar manner to that of Example 5-(2). The resultant residue was pulverized with benzene, collected by filtration and dried to give 2-[2-amino-3-(2,4-dichlorophenoxy)phenyl]acetic acid (2.1 g.). mp 123° to 124° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:8]([C:9](Br)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C([Li])(C)(C)C.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[Br:1][C:2]1[C:3]2[C:8]([C:9]([Si:23]([CH3:26])([CH3:25])[CH3:24])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: C[Si](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c2ccccc2c(Br)c2ccccc12
Temperature: -69 °C
Reaction time: 3 h
Yield: 20.2 %

Procedure:
Under an argon atmosphere, the temperature of a solution of 9,10-dibromoanthracene (5 g, 15 mmol) in dry-THF (50 ml) was cooled to −69° C., and t-butyllithium (18 mmol) was dropped to the solution. After the mixture had been stirred for 3 hours, chlorotrimethylsilane (3 ml, 22.5 mmol) was added to the mixture, and the whole was stirred at −69° C. for an additional 3 hours. After the temperature of the resultant had been increased to room temperature, the resultant was quenched with sodium bicarbonate water, extracted with toluene, and dried with sodium sulfate. Then, the solvent was removed by distillation. The residue was dispersed and washed with hexane, the insoluble matter was removed, and the filtrate was condensed. The condensate was washed with ethanol, and was then subjected to silica gel column chromatography, whereby 1 g of 9-bromo-10-trimethylsilylanthracene was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:29][CH2:30][CH:31]([N:34]6[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]6)[CH2:32][CH2:33]5)=[CH:24][CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CN1CCN(C2CCN(c3ccc(Br)cc3)CC2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(C2CCN(c3ccc(Nc4nc5c(-c6ccc(S(C)(=O)=O)cc6)cccn5n4)cc3)CC2)CC1

Procedure:
1-[1-(4-Bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine was prepared from 1-methyl-4-piperidin-4-yl-piperazine (0.50 g, 2.7 mmol) and 4-bromobenzeneboronic acid (0.50 g, 2.5 mmol) in a manner analogous to Step 49a. The reaction product isolated as a tan solid (0.077 g, 9%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.32 (d, J=7.9 Hz, 2H), 6.79 (d, J=7.7 Hz, 2H), 3.72-3.65 (m, 2H), 2.85-2.35 (m, 14H), 2.00-1.90 (m, 2H), 1.73-1.60 (m, 2H). MS=338, 340 (MH)+. 51b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyri din-2-yl]-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (55.0 mg, 0.191 mmol) and 1-[1-(4-bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine (70.0 mg, 0.207 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (22.0 mg, 0.0402 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as yellow solid (0.014 g, 13%). MP=237-240° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.6 Hz, 1H), 8.23 (d, J=7.7 Hz, 2H), 8.08 (d, J=8.0 Hz, 2H), 7.63 (d, J=7.2 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.01-6.95 (m, 3H), 6.66 (s, 1H), 3.70-3.62 (m, 2H), 3.10 (s, 3H), 2.73-2.32 (m, 11H), 2.30 (s, 3H), 1.98-1.90 (m, 2H), 1.77-165 (m, 2H). MS=546 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:13][C:14]([F:25])([F:24])[O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.C(O)(C(F)(F)F)=O>>[F:13][C:14]([F:24])([F:25])[O:15][C:16]1[CH:17]=[CH:18][C:19]([CH:20]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:22][CH:23]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 38.5 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2.0 g, 12.5 mmol), 4-trifluoromethoxybenzaidehyde (2.4 g, 1 equiv.) and TFA (1.9 mL, 2 equiv.) to give the title compound (1.6 g, 38%) as a white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([CH:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][CH3:51])[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([CH:43]4[CH2:44][CH2:45][N:46]([CH2:49][CH2:50][CH3:51])[CH2:47][CH2:48]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: CCCN1CCC(c2ccc(N)c(OC)c2)CC1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCCN1CCC(c2ccc(Nc3nccc(-c4c(-c5cccc(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OC)c2)CC1
Temperature: 120 °C
Yield: 81.1 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.2 mmol), a different batch of 2-(methyloxy)-4-(1-propyl-4-piperidinyl)aniline (Example 137, step D) (48 mg, 0.19 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 24 hours. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (104 mg, 0.154 mmol, 80%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.41 (d, J=6.59 Hz, 1H), 8.52 (s, 1H), 8.32 (s, 1H), 8.24 (d, J=5.31 Hz, 1H), 8.04 (d, J=7.87 Hz, 1H), 7.80 (d, J=7.87 Hz, 1H), 7.72 (d, J=8.97 Hz, 1H), 7.60 (q, J=7.63 Hz, 2H), 7.44-7.49 (m, 1H), 7.35-7.42 (m, 1H), 7.19 (t, J=8.15 Hz, 2H), 6.99 (t, J=6.96 Hz, 1H), 6.96 (d, J=1.47 Hz, 1H), 6.78 (dd, J=8.24, 1.65 Hz, 1H), 6.52 (d, J=5.31 Hz, 1H), 3.81 (s, 3H), 2.89-2.99 (m, J=8.79 Hz, 2H), 2.39-2.46 (m, 1H), 2.18-2.28 (m, 2H), 1.87-1.98 (m, 2H), 1.64-1.76 (m, 4H), 1.39-1.48 (m, 2H), 0.84 (t, J=7.33 Hz, 3H). MS (ESI): 674 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:7]([CH:8]=[CH:9][C:10]([CH:14]([CH3:16])[CH3:15])=[CH:11][CH:12]=2)=[C:6]([CH2:17][CH3:18])[CH:5]=1)([OH:3])=[O:2].[C:19](Cl)(=O)[C:20](Cl)=O.C(O)C>C1C=CC=CC=1>[CH2:19]([O:2][C:1]([C:4]1[C:13]2[C:7]([CH:8]=[CH:9][C:10]([CH:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=2)=[C:6]([CH2:17][CH3:18])[CH:5]=1)=[O:3])[CH3:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1cc(C(=O)O)c2ccc(C(C)C)ccc1-2
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc(CC)c2ccc(C(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above-mentioned azulene carboxylic acid (3) (4.84 g, 0.002 mole) is suspended in benzene (100 ml), and oxalyl chloride (2.8 g, 0.02 mole) is added dropwise thereto under cooling with ice. The mixture is stirred for 3 hours at room temperature and cooled with ice again. Ethyl alcohol (100 ml) is added dropwise thereto and stirred for 2 hours at room temperature. The mixture is poured into ice-water (300 ml) and extracted with benzene (100 ml). The benzene layer is separated, and then washed with water. The benzene solution is concentrated under reduced pressure, and n-hexane is added thereto to obtain the ethyl ester derivative (2) at a yield of 4.5 g, 83.3%, having a melting point of 48° to 49° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([O:16][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (2 g, 8.8 mmol) cooled at 0° C. was added a solution of Cs2CO3 (2.87 g, 8.8 mmol) in water (12.3 mL). After 30 min stirring, the resulting mixture was concentrated and the residue was suspended in DMF (41 mL). The suspension was cooled to 0° C. and benzylbromide (1.045 mL, 8.8 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at RT for 16 h. DMF was evaporated, the residue was poured in water and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Phase separator) and concentrated under reduced pressure. The residual oil was purified by flash column chromatography on silica gel (c-hexane/EtOAc 10:0 to 8:2) to give the title compound. TLC, Rf (c-hexane/EtOAc 8:2)=0.45; MS (UPLC-MS): 318 [M+H]+; tR (HPLC conditions d): 3.89 min.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8](=O)[CH3:9])(=[O:3])[CH3:2].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.O>C1C=CC=CC=1>[NH:11]1[CH2:16][CH2:15][CH:14]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH:7]=[CH:8][CH3:9])[CH2:13][CH2:12]1
Reactant: C1CCNCC1
Reactant: CC(=O)CCCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CC=CCC(OC(C)=O)C1CCNCC1

Procedure:
A mixture of 0.5 moles of 1-acetoxypentan-4-one and 0.5 moles of piperidine in benzene is refluxed using a water separator until no more water distills from the reaction mixture. The reaction mixture is then cooled, washed and dried to afford the 4-piperidyl-1-acetoxypent-3-ene (XIX). A mixture of 5 g. of XIX in 100 ml. of dioxane is treated with an excess of methyl iodide at 20°C for 18 hours and then heated at 70°C for 6 hours. The reaction mixture is concentrated to a small volume, diluted with water and 1-acetoxy-3-methylpentan-4-one isolated by extraction with ethyl acetate. A mixture of 0.5 g. of this ketone, 100 mg. of p-toluenesulfonic acid, 3 ml. of ethyleneglycol and 100 ml. of benzene is refluxed using a water separator for 24 hours. The reaction mixture is cooled and then 100 ml. of ethanol and 2 g. of potassium hydroxide are added. This mixture is refluxed for 6 hours, cooled, diluted with water and the corresponding ethylene ketal is isolated by extraction with ethyl acetate. A solution of 0.1 moles of the ketal in 50 ml. of dimethylformamide containing 0.1 moles of triphenylphosphine is reacted with 0.1 moles of carbon tetrabromide at room temperature for 18 hours. The mixture is diluted with water and extracted with ether. The ether extracts are combined, washed with water, dried and evaporated. The residue is chromatographed on 400 g. of alumina eluting with hexane-benzene and benzene to give the ethylene ketal of 1-bromo-3-methylpentan-4-one. ##EQU16##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:13][C:9]1[CH:8]=[C:7]([C:6]2[S:5][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][C:2]=2[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:19]#[N:20])[CH:26]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cc(Br)c(-c2cccc(Cl)c2)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(-c2cccc(C#N)c2)c(-c2cccc(Cl)c2)s1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Under argon, 3.20 g (9.26 mmol) of the compound from Example 10A are provided in 100 ml of 1,2-dimethoxyethane, and 1.36 g (9.26 mmol) of 3-cyanophenylboronic acid, 9.05 g (27.8 mmol) of cesium carbonate, 309 mg (0.65 mmol) of dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane and 62.4 mg (0.28 mmol) of palladium(II) acetate are added. The mixture is stirred at 50° C. for three hours. The reaction mixture is subsequently diluted with water and extracted with dichloromethane, and the organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate gradient) on silica gel. 1.71 g (50% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13]([C:15]3[N:16]=[CH:17][N:18]4[CH:22]=[CH:21][S:20][C:19]=34)=[O:14])[CH:10]=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>>[C:1]1([C:7]2[CH:8]=[C:9]([C:13]([C:15]3[N:16]=[CH:17][N:18]4[CH:22]=[C:21]([Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])[S:20][C:19]=34)=[O:14])[CH:10]=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: O=C(c1cncc(-c2ccccc2)c1)c1ncn2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncc(-c4ccccc4)c3)c2s1

Procedure:
7-(5-Phenylpyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole (297 mg) was prepared in substantially the same manner as in step c) of Synthesis Example 1, except that 275 mg of 7-(5-phenylpyridin-3-yl)carbonylimidazo[5,1-b]thiazole, 0.330 ml of tri-n-butylstannyl chloride, and 1.80 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution were used as the starting materials.