Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([CH3:9])[CH:3]=1.[Mg].II.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[C:26]([C:32]#[N:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[C:32]([CH:26]([C:23]1([C:6]2[CH:5]=[C:4]([CH3:9])[CH:3]=[C:2]([CH3:1])[CH:7]=2)[CH2:22][CH2:21][N:20]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:25][CH2:24]1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])#[N:33]
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CCOC(=O)C(C#N)=C1CCN(Cc2ccccc2)CC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)C1(c2cc(C)cc(C)c2)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
1,3-Dimethyl-5-bromobenzene (15.6 g) was dissolved in anhydrous diethyl ether (60 ml) and added to a vigorously stirred mixture of magnesium turnings (2.2 g) and 2-3 iodine crystals under a nitrogen atmosphere. Gentle heating was applied to initiate formation of the Grignard reagent and once the spontaneous refluxing had subsided the mixture was heated under reflux for a further 30 minutes. The mixture was cooled in an ice-bath and a solution of ethyl 2-(1-benzylpiperidin-4-ylidene)-2-cyanoacetate (8.0 g) (see Preparation 2) in anhydrous tetrahydrofuran (80 ml) added over 20 minutes. The mixture was stirred at 0° C. for 15 minutes before being left to stand at room temperature for 3 days. The mixture was then poured into saturated aqueous ammonium chloride solution (300 ml) and extracted twice with diethyl ether. The organic extracts were combined and the solvent removed under reduced pressure to give a residue which was chromatographed on silca gel eluting with a solvent gradient of 3:0 changing to 3:1, by volume, dichloromethane:diethyl ether to give the title compound (4.7 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][O:13][CH3:14])=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.Br[CH2:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3]([O:11][CH2:12][O:13][CH3:14])=[CH:4][C:5]2[O:10][C:16]([C:17](=[O:19])[CH3:18])=[CH:7][C:6]=2[CH:9]=1
Reactant: COCOc1cc(O)c(C=O)cc1Cl
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCOc1cc2oc(C(C)=O)cc2cc1Cl
Yield: 72.4 %

Procedure:
Using 5-chloro-2-hydroxy-4-(methoxymethoxy)benzaldehyde (1.50 g, 6.94 mmol), acetonitrile (14 mL), bromoacetone (1.57 g, 10.4 mmol) and potassium carbonate (2.87 g, 20.8 mmol), an operation in the same manner as in Reference Example 86 was performed to give the title compound (1.28 g, yield 72%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1.[CH3:15][NH2:16]>CO>[CH3:15][NH:16][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cccc(OCCCCl)c1
Solvent: CO
Product: CNCCCOc1cccc([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 50.6 %

Procedure:
The 1-(3-chloropropoxy)-3-nitrobenzene (1.00 g, 4.65 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH of the solution was adjusted to 6, and impurities were extracted with ether (3-15 mL). The aqueous layer was basified to pH 10 with 10% NaOH solution and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 493 mg (50.6%) of an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:13][CH:14]=[CH2:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].B1C2CCCC1CCC2.C([O-])(=[O:28])C.[Na+].OO>C1COCC1>[OH:28][CH2:15][CH2:14][CH2:13][C:2]([CH3:16])([CH3:1])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: CC(=O)[O-]
Reactant: C=CCC(C)(C)C(=O)OCc1ccccc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(CCCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of benzyl 2,2-dimethylpent-4-enoate (5.74 g, 26.3 mmol, prepared according to Step A) in THF (100 mL) was added a solution of 9-BBN (63.1 mL, 31.6 mmol, 0.5 M in THF) over 20 minutes, while under nitrogen. The reaction was allowed to stir at ambient temperature for 17 hours. An aqueous solution of sodium acetate (7.3 g, 89 mmol, in 18 mL of water) was then added, followed by the slow addition of aqueous hydrogen peroxide (18 mL, 30% by weight solution) with occasional chilling in a 0° C. bath. This mixture was allowed to stir at ambient temperature for 1.5 hours, before being extracted with ethyl acetate. The combined organics were washed with saturated brine. The organics were then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of MeOH:DCM—1:99 to 10:90, to give the title compound. MS: m/z=237 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][N:3]=1.C1COCC1>CO.[Pt]>[NH2:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Br:1])[C:7]=1[OH:8]
Reactant: O=[N+]([O-])c1ccnc(Br)c1O
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccnc(Br)c1O

Procedure:
A solution of 5.3 g (22.7 mmol) 2-bromo-4-nitro-pyridin-3-ol in 100 ml MeOH:THF=1:2 is hydrogenated in the presence of 0.5 g Pt/C (5%, Engelhard 4709). The reaction mixture is filtered (2 glass fiber filters used) and the filtrate is concentrated in vacuo to afford the crude title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].Cl.C[N:17](C)[CH:18]=[C:19]([N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[C:20]#N>C(O)C>[NH2:17][C:18]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[CH:20][C:19]=1[N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CN(C)C=C(C#N)n1cncn1
Agent: Cl
Solvent: CCO
Product: Nc1c(-n2cncn2)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 95.5 %

Procedure:
19 g (0.075 mole) of 2,6-dichloro-4-trifluoromethyl-phenylhydrazine and 16 g (0.075 mole) of 3-dimethylamino-2-(1,2,4-triazol-1-yl)-acrylonitrile hydrochloride in 200 ml of ethanol are heated at 75° C. to 78° C. for 5 hours, with stirring. For working up, the solvent is distilled off and the residue is triturated with water and dried over clay. 26 g (96% of theory) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(1,2,4-triazol-1-yl)-pyrazole of melting point 170°-174° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15]>>[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][NH:15][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])=[O:9]
Reactant: Cc1ccsc1C(=O)O
Reactant: COc1ccc(CN)c(OC)c1
Product: COc1ccc(CNC(=O)c2sccc2C)c(OC)c1

Procedure:
Prepared in a similar manner to example 4 using 3-methyl-thiophene-2-carboxylic acid and 2,4-dimethoxy-benzylamine. MS (M+H, 292.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22](=[O:31])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:6]([N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][N:15]=2)=O)[CH:7]=1>CO.C([O-])([O-])=O.[K+].[K+]>[CH2:24]([C:23]1[C:22](=[O:31])[C:5]2[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:9]=1[C:11]1[O:12][CH:13]=[CH:14][N:15]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(CCc1ccccc1)c1ccc(Cl)cc1N(C(=O)c1ncco1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=c1c(Cc2ccccc2)c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc12
Yield: 62.8 %

Procedure:
Oxazole-2-carboxylic acid [5-chloro-2-(3-phenyl-propionyl)-phenyl]-phenyl-amide (387 mg) was dissolved in dry MeOH (20 mL) and K2CO3 (100 mg), and heated at reflux for 1.5 h. The product was then cooled, the solvent evaporated, and the residue chromatographed (0-30% MeOH/DCM) to provide 3-benzyl-7-chloro-2-oxazol-2-yl-1-phenyl-1H-quinolin-4-one (Compound 140, 233 mg). mp=219.0-220.0° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:2]1.CCN(C(C)C)C(C)C.[Br:21][C:22]1[CH:23]=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39][C:40]([C:42]3[S:43][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][CH:46]=3)=[O:41])[C:36](O)=[O:37])=[CH:30][CH:29]=2)=[N:26][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:21][C:22]1[CH:27]=[N:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][C@H:35]([NH:39][C:40]([C:42]3[S:43][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][CH:46]=3)=[O:41])[C:36]([N:1]3[CH2:2][CH:3]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:4]3)=[O:37])=[CH:32][CH:33]=2)=[N:24][CH:23]=1
Reactant: CC(C)(C)c1ccc(C(=O)N[C@@H](Cc2ccc(-c3ncc(Br)cn3)cc2)C(=O)O)s1
Reactant: CC(C)(C)OC(=O)C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CN(C(=O)[C@H](Cc2ccc(-c3ncc(Br)cn3)cc2)NC(=O)c2ccc(C(C)(C)C)s2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a stirring solution of tert-butyl azetidine-3-carboxylate (64.55 mg, 0.41 mmol) in DMF (1 mL) were added DIEA (169.6 mg, 1.31 mmol), and (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoic acid (100.0 mg, 0.21 mmol). The solution was cooled to 0° C. at ice bath and then HATU (74.11 mg, 1.31 mmol) in 1 mL DMF solution was slowly added. The reaction was stirred 1 hour at 0° C. and then warmed to RT with stirring for 2 hours. The reaction solution was extracted with DCM (3×10 mL) and aqueous NaHCO3 (3×10 mL). The combined organics were dried over MgSO4 and evaporated. to afford 117.6 mg (85%) of tert-butyl (S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylate INT-38 as a solid powder without further purification for next step. LCMS-ESI (m/z) calculated for C30H35BrN4O4S: 626.2. found 627.2 [M+H]+, tR=3.884 min. (Method 16).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13]>>[N:4]1[CH:3]=[C:2]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:14])[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncnc1
Reactant: C#CCCCCO
Product: OCCCCCCc1cncnc1

Procedure:
5-bromopyrimidine and 5-hexyn-1-ol was reacted, as above, to give 5-pyrimidinehexanol as a colorless oil. bp 170°-175° C. (0.6 mm). Analysis Calculated for C10H16N2O: C, 66.63; H, 8.95; N, 15.54. Found: C, 66.62; H, 9.15; N, 15.59.
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]1([CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=4)=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc2c(c1)OCC(c1ccccc1)O2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)OCC(c2ccccc2)O3)nc1

Procedure:
A solution of 2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-ol (80 mg), 2-chloro-5-nitropyridine (56 mg) and potassium carbonate (52 mg) in dimethylformamide (1.0 ml) was stirred at 120° C. for 2 hrs. After cooling the mixture water (10 ml) was added and the precipitated product was filtered, washed with water and 2-propanol and dried under reduced pressure. Yield is 60 mg and mp 163-170° C. 1H NMR (DMSO-d6) δ 4.16 (dd, J 8.5, 11.6 Hz, 1H), 4.47 (dd, J 11.6, 2.6 Hz, 1H), 5.28 (dd, J 2.6, 8.5 Hz, 1H), 6.75 (dd, J 2.6, 8.8 Hz, 1H), 6.88 (d, J 2.6 Hz, 1H), 7.05 (d, J 8.8 Hz, 1H), 7.21 (d, J 9.1 Hz, 1H), 7.39-7.52 (m, 5H), 8.60 (dd, J 2.8, 9.1 Hz, 1H), 9.05 (d, J 2.8 Hz, 1H).
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](OS(C(F)(F)F)(=O)=O)=[CH:21][CH:20]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B([C:36]1[CH:41]=[CH:40][C:39]([C:42]2([C:45]([OH:47])=[O:46])[CH2:44][CH2:43]2)=[CH:38][CH:37]=1)(O)O>>[C:1]1([C@H:7]([O:9][C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[C:19]2[CH:20]=[CH:21][C:22]([C:36]3[CH:41]=[CH:40][C:39]([C:42]4([C:45]([OH:47])=[O:46])[CH2:44][CH2:43]4)=[CH:38][CH:37]=3)=[CH:23][CH:24]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](OC(=O)Nc1cnccc1-c1ccc(OS(=O)(=O)C(F)(F)F)cc1)c1ccccc1
Reactant: O=C(O)C1(c2ccc(B(O)O)cc2)CC1
Product: C[C@@H](OC(=O)Nc1cnccc1-c1ccc(-c2ccc(C3(C(=O)O)CC3)cc2)cc1)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: trifluoro-methanesulfonic acid 4-[3-((R)-1-phenyl-ethoxycarbonylamino)-pyridin-4-yl]-phenyl ester and 1-(4-boronophenyl)cyclopropanecarboxylic acid.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13][N:14](C)C(=O)C>[C-]#N.[Zn+2].[C-]#N.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Zn].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:13]([C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:14]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1cccnc1C#N
Temperature: 120 °C
Yield: 100 %

Procedure:
To ethyl 2chloronicotinate (15.0 g, 81 mmol) in anhydrous N,N-dimethylacetamide (75 ml) was added zinc cyanide (5.71 g, 48.6 mmol), Pd2(dba)3 (742 mg, 0.81 mmol), zinc (636 mg, 9.72 mmol), and 1,1′bis(diphenylphosphino)ferrocene (898 mg, 1.62 mmol), and the resulting mixture heated at 120° C. for 1 hour. The mixture was cooled to room temperature and partitioned between water (300 ml) and diethyl ether (150 ml), the mixture was filtered through Celite™ and the phases separated. The aqueous phase was further extracted with diethyl ether (2×100 ml), the combined diethyl ether layers washed with saturated NaCl, dried over Na2SO4, filtered and evaporated to give the title compound (14.26 g, 100%).
Reaction SMILES: NC1C=C(Br)SC=1C(N)=O.Cl.N12CCC(CC1)C[C@H]2C(O)=O.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:56][C:57]1[S:61][C:60]([C:62](=[O:64])[NH2:63])=[C:59]([NH:65][C:66]([C@@H:68]2[CH2:73][CH:72]3[CH2:74][CH2:75][N:69]2[CH2:70][CH2:71]3)=O)[CH:58]=1>CN(C)C=O.O>[N:69]12[CH2:75][CH2:74][CH:72]([CH2:71][CH2:70]1)[CH2:73][C@H:68]2[C:66]1[NH:63][C:62](=[O:64])[C:60]2[S:61][C:57]([Br:56])=[CH:58][C:59]=2[N:65]=1
Reactant: NC(=O)c1sc(Br)cc1NC(=O)[C@@H]1CC2CCN1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=c1[nH]c([C@@H]2CC3CCN2CC3)nc2cc(Br)sc12
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a solution of 3-amino-5-bromothiophene-2-carboxamide (600 mg) produced in Example 1, step D, (2S)-1-azabicyclo[2.2.2]octane-2-carboxylic acid hydrochloride (520 mg), and N-ethyl-N-(1-methylethyl)propan-2-amine (1.19 mL) in N,N-dimethylformamide (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.24 g) at 0° C., and the reaction system was stirred at 70° C. for 20 hr. Water was added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a mixture of (2S)—N-(5-bromo-2-carbamoylthiophen-3-yl)-1-azabicyclo[2.2.2]octane-2-carboxamide and the title compound. A mixed solution of (2S)—N-(5-bromo-2-carbamoylthiophen-3-yl)-1-azabicyclo[2.2.2]octane-2-carboxamide and the title compound produced above in ethanol (4.0 mL) and 2M aqueous sodium hydroxide solution (2.7 mL) was stirred at 70° C. for 2 hr. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give the title compound (220 mg) as a yellow solid.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.[CH2:9]([N:16]=[C:17]=[S:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)(=O)C>[CH2:9]([NH:16][C:17]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:17](=[S:18])[NH:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:2][CH:1]=1)=[S:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(N)cc1
Reactant: S=C=NCc1ccccc1
Solvent: CCOC(C)=O
Product: S=C(NCc1ccccc1)Nc1ccc(NC(=S)NCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
p-Phenylenediamine (2.707 g, 25 mM) was dissolved in 20 ml of ethyl acetate, and 2 equivalents of benzylisothiocyanate (7.461 g, 50 mM) were added. The mixture was stirred at 80° C. for 30 minutes. After cooling, the reaction mixture was filtered, and washed with ethylacetate/n-hexane to obtain 6.26 g (61.6% yield) of a colorless crystal of compound A-25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([CH:18]=O)[C:15]([OH:20])=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([Cl:31])[CH:22]=3)[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([NH:36][CH2:18][C:16]1[C:15]([OH:20])=[C:14]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:28])[F:30])=[C:23]([Cl:31])[CH:22]=2)[CH:13]=[C:12]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([Cl:1])[CH:3]=2)[CH:17]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: O=Cc1cc(-c2ccc(C(F)(F)F)c(Cl)c2)cc(-c2ccc(C(F)(F)F)c(Cl)c2)c1O
Reactant: CC(C)(C)N
Product: CC(C)(C)NCc1cc(-c2ccc(C(F)(F)F)c(Cl)c2)cc(-c2ccc(C(F)(F)F)c(Cl)c2)c1O

Procedure:
5′-((tert-Butylamino)methyl)-3,3″-dichloro-4,4″-bis(trifluoromethyl)-[1,1′:3′,1″-terphenyl]-4′-ol was prepared as a white solid using the procedure described in Example 5 from 3,3″-dichloro-4′-hydroxy-4,4″-bis(trifluoromethyl)-[1,1′:3′,1″-terphenyl]-5′-carbaldehyde and tert-butylamine.
Reaction SMILES: [F:1][C:2]1[C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][CH:5]=[C:4]([F:16])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25]C)=[O:24])[CH:20]=[CH:19][C:18]=1[F:27].[CH3:28]B(O)O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>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>[F:1][C:2]1[C:7]([CH3:28])=[CH:6][CH:5]=[C:4]([F:16])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[CH:19][C:18]=1[F:27]
Reactant: CB(O)O
Reactant: COC(=O)c1ccc(F)c(-c2c(F)ccc(OS(=O)(=O)C(F)(F)F)c2F)n1
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+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(F)c(-c2nc(C(=O)O)ccc2F)c1F
Temperature: 100 °C
Yield: 97 %

Procedure:
To a solution methyl 6-(2,6-difluoro-3-(trifluoromethylsulfonyloxy)phenyl)-5-fluoropicolinate (1.0 equiv.) in dioxane and water (10:1, 0.15 M) was added methyl boronic acid (3.0 equiv.) and potassium carbonate (3.0 equiv.). The reaction was degassed with nitrogen for 10 min, then Pd(PPh3)4 (0.1 equiv.) was added to the solution and heated to 100° C. for 3 hours. LC/MS of the reaction at this point indicated complete conversion to the carboxylic acid product (M+H=268). Cooled to room temperature and added water and ethyl acetate. The two layers were separated, the aqueous phase was acidified with concentrated HCl to pH=1 and extracted with ethyl acetate. The organic phase was dried with sodium sulfate, filtered, and concentrated under vacuo to give 6-(2,6-difluoro-3-methylphenyl)-5-fluoropicolinic acid as a clear oil in 97% yield. LC/MS=268.1 (M+H), Rt=0.82 min.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([C:10]([CH3:12])=O)[C:7]([CH3:9])=O)=[O:5].[NH2:13][C:14]([NH2:16])=[O:15].Cl>C(O)C>[OH:15][C:14]1[N:16]=[C:10]([CH3:12])[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[C:7]([CH3:9])[N:13]=1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(C)nc(O)nc1C
Temperature: 90 °C

Procedure:
A mixture of ethyl diacetoacetate (17.22 g, 100 mmol), urea (9.61 g, 160 mmol) and HCl (10 M, 4 ml) in ethanol (400 ml) was heated to 90° C. for 12 hours. The mixture was concentrated to remain 200 ml and then was cooled to −20° C. to allow precipitation. The mixture was filtered at room temperature to obtained 6a as solid granulate (5.32 g, 2.71 mmol, 27%).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[C:6]([N:16]=1)=[N:7][CH:8]=[C:9]([C:11](OCC)=[O:12])[CH:10]=2.CSC1SC2C=C(C(OCC)=O)C=CC=2N=1>>[CH3:1][S:2][C:3]1[S:4][C:5]2[C:6]([N:16]=1)=[N:7][CH:8]=[C:9]([CH2:11][OH:12])[CH:10]=2
Reactant: CCOC(=O)c1cnc2nc(SC)sc2c1
Agent: CCOC(=O)c1ccc2nc(SC)sc2c1
Product: CSc1nc2ncc(CO)cc2s1

Procedure:
(2-(Methylthio)thiazolo[4,5-b]pyridin-6-yl)methanol was synthesized as a white solid (404 mg, 67%) using a procedure analogous to that described in Step 3 of Example 36, substituting ethyl 2-(methylthio)thiazolo[4,5-b]pyridine-6-carboxylate from the previous step for ethyl 2-(methylthio)benzo[d]thiazole-6-carboxylate used in Example 36. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, J=1.9 Hz, 1H), 8.42 (d, J=1.9 Hz, 1H), 5.44 (t, J=5.7 Hz, 1H), 4.63 (d, J=5.7 Hz, 2H), 2.82 (s, 3H); LCMS (ESI) m/z 213 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C(=O)C)=[CH:14][CH:13]=1.Cl.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:27](Cl)=O>>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH2:27][NH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)c(F)c1
Reactant: COc1ccc(C=Cc2ccc(OC(C)=O)cc2)c(N)c1
Agent: Cl
Product: COc1ccc(C=Cc2ccc(O)cc2)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Yield: 67.6 %

Procedure:
Synthesized from acetic acid 4-[2-(2-amino-4-methoxyphenyl)vinyl]phenyl ester (240 mg) and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (660 mg) according to an analogous synthetic method to Example 152, the title compound (273 mg) was obtained.