Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH:10]1([NH2:13])[CH2:12][CH2:11]1.[Br:14][C:15]1[N:16]=[C:17](Br)[C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1>CC(O)C>[Br:14][C:15]1[N:16]=[C:17]([NH:13][CH:10]2[CH2:12][CH2:11]2)[C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1
Reactant: NC1CC1
Reactant: Brc1cn2ccnc2c(Br)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cn2ccnc2c(NC2CC2)n1
Reaction time: 4.5 h
Yield: 95.3 %

Procedure:
Diisopropylethylamine (2.4 mL, 13.62 mmol) and cyclopropylamine (943 μL, 13.62 mmol) were added to commercially available (Ark Pharm, Inc.) 6,8-dibromoimidazo[1,2-a]pyrazine (2.51 g, 9.08 mmol) dissolved in 2-propanol (9 mL). The solution was placed in an 80° C. oil bath. After 4.5 h, the volatiles were removed in vacuo. The brown residue was partitioned between dichloromethane (50 mL) and water (50 mL). The organic layer was washed further with water (50 mL) and then brine (50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via a filtration over a short plug of silica gel (40% EtOAc/hexanes) and the filtrate was concentrated in vacuo to afford 6-bromo-N-cyclopropylimidazo[1,2-a]pyrazin-8-amine (2.19 g, 95%) as a light brown solid. 1H NMR (CDCl3, 400 MHz) δ: 7.61 (s, 1H), 7.46 (d, 1H, J=1.2 Hz), 7.44 (d, 1H, J=1.2 Hz), 6.26 (bs, 1H), 3.02 (dddd, 1H, J=7.2, 7.2, 7.2, 3.6 Hz), 0.89-0.95 (m, 2H), 0.64-0.69 (m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:10]2[S:26][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:28][C:9]1=2)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:33])[C:9]3=[CH:28][CH:27]([C:29]([O:31][CH3:32])=[O:30])[S:26][C:10]3=[C:11]2[CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1C=C2C(=C(C3CCCCC3)C(c3ccccc3)(c3ccc(Cl)cc3)N2CC(=O)O)S1
Yield: 94 %

Procedure:
A solution (0.04 M) of methyl 4-(2-tert-butoxy-2-oxoethyl)-6-cyclohexyl-5-(4-chlorophenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in DCM/TFA (1:1) was stirred at RT for 3 h. Evaporation of the solvent gave the title compound (94%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].C[Al](C)C.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C@@:24]([OH:50])([CH2:44][N:45]1[CH:49]=[N:48][CH:47]=[N:46]1)[C@H:25]([S:27][C@@H:28]1[CH2:33][O:32][C@@H:31]([C:34]2[CH:43]=[CH:42][C:37]([C:38](OC)=[O:39])=[CH:36][CH:35]=2)[O:30][CH2:29]1)[CH3:26]>>[C:10]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[NH:1][C:38](=[O:39])[C:37]1[CH:42]=[CH:43][C:34]([C@H:31]2[O:30][CH2:29][C@H:28]([S:27][C@H:25]([CH3:26])[C@:24]([C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[F:16])([OH:50])[CH2:44][N:45]3[CH:49]=[N:48][CH:47]=[N:46]3)[CH2:33][O:32]2)=[CH:35][CH:36]=1)#[N:11]
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Reactant: N#Cc1ccc(N)cc1C#N
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(C#N)c(C#N)c3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available 4-aminophthalonitrile (170 mg, 1.2 mmol), trimethylaluminium (1.1 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (129 mg, yield 71%) as a yellow oil which was recrystallized from ethyl acetate-hexane to give pale yellow powdery crystals.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:29]=[CH:30][CH:31]=1)[CH2:18][S:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([OH:25])=[O:24].S(=O)(=O)(O)O.[CH3:37]O>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:29]=[CH:30][CH:31]=1)[CH2:18][S:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([O:25][CH3:37])=[O:24]
Reactant: CO
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CSc2cccc(C(=O)O)c2)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(SCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)c1
Yield: 67 %

Procedure:
A mixture of 3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzoic acid (3.20 g), conc. sulfuric acid (1 mL) and methanol (50 mL) was stirred with heating under reflux for 1 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzoate as an oil (2.20 g, yield 67%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][Si:20]([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21])=[CH:4][C:3]=1[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(O)cc(C)c1Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-bromo-3,5-dimethylphenol (2.1 g, 10 mmol) and imidazole (1.50 g, 22 mmol) in DMF (15 mL) was cooled to 0° C. then TBDMSCl (1.66 g, 11 mmol) was added. After the addition, the solution was warmed up to ambient temperature and was stirred for 10 min. The solution was recooled to 0° C. and the reaction was quenched with water. The aqueous layer was extracted with Et2O and the organic layer was washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (10:1) to give (4-bromo-3,5-dimethylphenoxy)-tert-butyl-dimethylsilane as a pale yellow solid.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[C:28]1([CH:34]2[NH:38][C:37](=[O:39])[NH:36][C:35]2=[O:40])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:24][O:23][C:18]1[CH:17]=[C:16]([O:25][CH3:26])[CH:15]=[C:14]2[C:19]=1[C:20](=[O:22])[NH:21][C:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([O:4][CH2:3][CH2:2][N:36]3[C:35](=[O:40])[CH:34]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:38][C:37]3=[O:39])=[C:6]([CH3:27])[CH:7]=1)=[N:13]2
Reactant: O=C1NC(=O)C(c2ccccc2)N1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4C(=O)NC(c5ccccc5)C4=O)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.50 g, 1.35 mmol) in THF (20 mL), were added 5-phenyl-imidazolidine-2,4-dione (0.24 g, 1.35 mmol) and triphenyl phosphine (0.35 g, 1.35 mmol), then diethyl azodicarboxylate (0.43 mL, 2.70 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Solvent was evaporated in vacuo and the residue was washed with dichloromethane and ether. The residue was dissolved in acetic acid and purified by preparative HPLC. The compound was further washed with dichloromethane and ether (1:1, 20 mL) to obtain the title compound as a white solid. Yield: 0.07 g (10%). MP 219.6-221.4° C. 1H NMR (400 MHz, DMSO-d6): δ 8.81 (s, 1H), 7.86 (s, 2H), 7.37 (m, 5H), 6.71 (s, 1H), 6.48 (s, 1H), 3.94 (m, 4H), 3.86 (s, 3H), 3.82 (s, 3H), 2.18 (s, 6H). MS (ES) m/z: 529.29 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CCCCCC.C1(C)C=CC=CC=1>[CH3:40][C:36]1[CH:35]=[C:34]([NH:33][C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:8]3([C:4]4[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=4)[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]4[C:20]3=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:26]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: Brc1cccc(C2(c3ccccc3)c3ccccc3-c3ccccc32)c1
Reactant: Cc1cccc(N)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2cccc(C3(c4ccccc4)c4ccccc4-c4ccccc43)c2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
Into a 200 mL three-neck flask were placed 3.2 g (8.1 mmol) of 9-(3-bromophenyl)-9-phenylfluorene and 2.3 g (24.1 mmol) of sodium tert-butoxide. The air in the flask was replaced with nitrogen. To this mixture were added 40.0 mL of toluene, 0.9 mL (8.3 mmol) of m-toluidine, and 0.2 mL of a 10% hexane solution of tri(tert-butyl)phosphine. The temperature of this mixture was set to 60° C., and 44.5 mg (0.1 mmol) of bis(dibenzylideneacetone)palladium(0) was added to the mixture. The temperature of this mixture was raised to 80° C., and the mixture was stirred for 2.0 hours. After that, the mixture was suction-filtered through Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and alumina to give a filtrate. A solid obtained by concentration of the obtained filtrate was purified by silica gel column chromatography (a developing solvent in which the ratio of hexane to toluene was 1:1) and recrystallized from a mixed solvent of toluene and hexane. Accordingly, 2.8 g of a white solid of the object of the synthesis was obtained in 82% yield. The synthesis scheme of Step 1 above is illustrated in the following scheme (J-1).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29](Cl)[CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1CCNC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2)[C@H](c2cccc(Cl)c2)C1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2)[C@H](c2cccc(N3CCCC3)c2)C1

Procedure:
The title compound, MS: m/e=547.4 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3-(3-chloro-phenyl)-4-phenyl-piperidin-1-yl]-methanone, pyrrolidine and biphenyl-2-yl-dicyclohexyl-phosphane as ligand.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][C:13]([OH:16])([CH3:15])[CH3:14]>>[C:13]([O:16][C:10](=[O:11])[NH:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)([CH3:15])([CH3:14])[CH3:12]
Reactant: CC(C)(C)O
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 84 %

Procedure:
A solution of 3,5-dichloro-phenyl isocyanate (5 g, 26.6 mmol) in t-BuOH (100 mL) was heated at 80° C. for 16 h. The mixture was concentrated by rotary evaporation to give a white solid which was triturated with toluene and evaporated to dryness. Addition of toluene and concentration under vacuum gave (3,5-dichloro-phenyl)carbamic acid-tert-butyl ester as a white solid (6 g, 22.9 mmol, 84%). 1H NMR (300 MHz, CDCl3): δ 7.42 (s, 2H), 7.18 (s, 1H), 6.6 (br s, NH), 1.62 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O)=O.O=[C:8]1[CH2:27][CH2:26][C:11]2[C:12]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:13]=3[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[CH2:9]1.O>CN(C)C=O>[CH3:1][N:2]([CH3:3])[CH:8]1[CH2:27][CH2:26][C:11]2[C:12]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:13]=3[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[CH2:9]1
Reactant: CNC
Reactant: O=C1CCC2=C(C1)c1ccccc1Oc1ccc(Cl)cc12
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: O
Product: CN(C)C1CCC2=C(C1)c1ccccc1Oc1ccc(Cl)cc12

Procedure:
To a mixture of 10 ml of dimethylamine and 3.1 ml of 98% formic acid at -10°C a solution of 11.5 g of 2-keto-6-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine in 30 ml of dimethylformamide are added dropwise. The mixture is refluxed for 10 hours. After cooling, the mixture is poured into water and extracted into ether. The ether layer is then washed with 300 ml of 2 N HCl. The acidic water layer is made alkaline with 2 N NaOH, after which the alkaline aqueous solution is extracted with ether once more. The ether layers are collected, dried and then evaporated. The oil obtained crystallizes as maleate: melting point 171°C.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([O:14]CC)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH-].[Na+]>CN1C(=O)CCC1.Cl.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:20][CH:19]=1
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)c1nc2ccccc2nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)c1nc2ccccc2nc1Oc1ccc(F)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
Ethyl 3-chloroquinoxaline-2-carboxylate (473.3 mg, 2.0 mmol), 4-fluorophenol (448.4 mg, 4.0 mmol) and Cs2CO3 (1.30 g, 4.0 mmol) in NMP (5 mL) was stirred at 80° C. for 16 hours. The reaction mixture was poured into water and the pH adjusted to 4 with aqueous 1N HCl. The resulting precipitate was filtered off, taken up in MeOH (3 mL). Water (0.3 mL) and NaOH (320.0 mg, 8.00 mmol) were added and the reaction mixture was stirred at 40° C. for 1 hour. The reaction mixture was diluted with 1N HCl. The resulting precipitate was filtered, washed with ether, and dried to give 3-(4-fluorophenoxy)quinoxaline-2-carboxylic acid (120 mg, 21%) as a white solid. ESI-MS m/z calc. 284.06, found 285.3 (M+1)+; Retention time: 1.29 minutes (3 minutes run).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[OH:45][C:44]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:10][C:41](=[O:42])[C:40]=1[S:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH:30]([CH3:32])[CH3:31]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using 4'-methylacetophenone (2.02 mL, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (3.11 g, 10.0 mmol) m.p. 191-193° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 2.39 (s, 3H), 3.41 (m, 1H), 6.84 (s, 1H), 6.92 (m, 1H), 7.10 (m, 2H), 7.27 (m, 1H), 7.37 (m, 2H), 7.75 (d, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[CH:29]([B-](F)(F)F)=[CH2:30].[K+].C(Cl)Cl>C(O)CC.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]>[CH:29]([C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1)=[CH2:30]
Reactant: C=C[B-](F)(F)F
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCCO
Solvent: ClCCl
Product: C=Cc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 100 °C
Yield: 22.4 %

Procedure:
To a stirred mixture of (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (200 mg, 0.44 mmol) from Example 29 in n-PrOH were added potassium vinyltrifluoroborate (117 mg, 0.88 mmol), PdCl2(dppf).DCM (18 mg, 0.022 mmol), and TEA (122 μL, 0.88 mmol). The resulting mixture was purged with argon for 5 min, the reaction vessel was sealed and the mixture was heated at 100° C. overnight. LCMS analysis showed that the reaction was complete. The reaction mixture was cooled to rt and purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-2-((6-((6-vinyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a tan powder (40 mg, 23%). 1H NMR (300 MHz, MeOH-d4) δ 8.50 (d, J=1.7 Hz, 1H), 8.43 (s, 1H), 8.15 (d, J=1.7 Hz, 1H), 7.63 (s, 1H), 7.32-7.41 (m, 1H), 7.25-7.32 (m, 1H), 6.91 (dd, J=10.9, 17.7 Hz, 1H), 5.91 (d, J=17.5 Hz, 1H), 5.53 (s, 2H), 5.35 (d, J=11.1 Hz, 1H), 3.50-3.66 (m, 1H), 3.37-3.49 (m, 1H), 2.14 (d, J=12.1 Hz, 1H), 2.01 (br s, 1H), 1.63-1.82 (m, 2H), 1.13-1.50 (m, 4H). LCMS (ESI) m/z 406 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-])=O)=[CH:5][N:4]=1.[CH3:13]O>[Pd]>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[N:10]=[CH:13][NH:9][C:7]=2[CH:8]=1
Reactant: CO
Reactant: COc1cc(N)c([N+](=O)[O-])cn1
Agent: [Pd]
Product: COc1cc2[nH]cnc2cn1

Procedure:
A solution of 15.51 g of 2-methoxy-5-nitropyridin-4-amine (example E7) in 1.55 I methanol was treated with 4.65 g Pd/C (10% Pd) and hydrogenated for 12 h under atmospheric pressure. The reaction mixture was filtered through a plug of CELITE® (diatomaceous earth) and the filtrate was concentrated under vacuum. The resulting residue was treated with 181 ml formic acid and the mixture was refluxed for 50 h. The formic acid was distilled off and the residue was repeatedly purified by flash chromatography (neutral alumina oxide, ethyl acetate/methanol) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.N1C=CN=C1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][CH2:6]1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CN1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CN1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
Treat a solution of (4-hydroxy-piperidin-1-yl)-acetic acid methyl ester (10.0 g, 57.7 mmol) and imidazole (4.71 g, 69.2 mmol) in DMF (100 mL) with t-butyl-diphenylsilyl chloride (19.04 g, 69.3 mmol) and stir for 16 hours at room temperature. Dilute the reaction with diethyl ether and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 2% methanol in CH2Cl2 to afford 17.38 g (73%) of the titled product. Rf=0.71 (9/1 CH2Cl2/methanol). ES MS (m/z): 412 (M+).
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=2)[C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=3[C:12]=2[CH2:13][O:14][CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCCCC.C(O)C.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=2)[C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=3[C:12]=2[CH2:13][O:14][CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2COC)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCCCCC
Product: COCc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 3-[{[4-({cyclohexyl[5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (1.20 g) synthesized in Example A48(1) was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID×500 mL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/ethanol (200/800), flow rate: 60 mL/min, column temperature: 30° C.). The fraction containing an optically active form having a longer retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give an amorphous form (465 mg, 99.9% ee). To a mixture of the obtained amorphous form, ethanol (5 mL) and tetrahydrofuran (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (415 mg, 37%, 99.9% ee) as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([O:22]C)=[O:21])[CH:17]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[N:15]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+].C1COCC1>O>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[N:15]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1COCCN1c1cc(C(=O)O)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
Methyl 2-[4-(cyclopropylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylate (350 mg) was dissolved in water (15 mL) containing sodium hydroxide (67 mg) and the reaction was allowed to stir at RT for 1 h. A further 2 equivalents of sodium hydroxide were added along with THF (3 mL). The reaction was stirred for another 1 h then the THF removed under reduced pressure and the aqueous solution partitioned with ethyl acetate (15 mL). The aqueous layer was acidified with concentrated hydrochloric acid and the precipitate was filtered and dried in a vac-oven at 50° C. for 18 h to give the desired material (350 mg) as a white solid.