Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][CH:11]1[CH2:14][CH2:13][C:12]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH2:1]([O:8][C:9](=[O:16])[NH:10][CH:11]1[CH2:14][CH2:13][CH:12]1[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCC1=O)OCc1ccccc1
Reactant: C1CCNC1
Product: O=C(NC1CCC1N1CCCC1)OCc1ccccc1

Procedure:
The title compound, colorless oil, MS: m/e=275.1 [(M+H)+], were prepared in accordance with the general method of example 1 and 2 from (2-oxo-cyclobutyl)-carbamic acid benzyl ester (CAS 406951-43-7) and pyrrolidine. The 2 diastereomers were not separated.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:39]1[CH:44]=[CH:43][C:42]([C@@H:45]([NH2:48])[CH2:46][OH:47])=[CH:41][CH:40]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:48][C@H:45]([C:42]3[CH:43]=[CH:44][CH:39]=[CH:40][CH:41]=3)[CH2:46][OH:47])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: N[C@@H](CO)c1ccccc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](CO)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 70 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and R-(−)-2-phenylglycinol: yield 70%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:20]=[C:19]([N:21]3[C:25]([C:26]([F:29])([F:28])[F:27])=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:23]=[N:22]3)[CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.O[C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:28][C:26]([F:29])([F:27])[C:25]1[N:21]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([CH2:2][O:1][C:38]4[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=4)=[CH:36][CH:35]=3)[N:20]=2)[N:22]=[CH:23][C:24]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(CO)cc3)n2)c1C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(COc4ccc(C(F)(F)F)cc4)cc3)n2)c1C(F)(F)F
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
To a solution of the title compound from Example 7 Step A (30.0 mg, 0.060 mmol) and 4-hydroxybenzotrifluoride (29.3 mg, 0.181 mmol) in THF (0.400 mL) were added triphenylphosphine (47.5 mg, 0.181 mmol) and diisopropyl azodicarboxylate (0.035 mL, 0.181 mmol). The resulting mixture was stirred at 60° C. After 3.5 h, the mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 50% EtOAc in hexanes, then 50 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 642.3 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[C:6](OC(=O)C)=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])(=O)C.C(O)(=O)C1C=CC(C(O)=[O:29])=CC=1>C(O)(=O)C>[OH:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:29])=[CH:12][CH:11]=1)=[O:9]
Reactant: CC(=O)Oc1cccc(C(=O)c2ccccc2)c1OC(C)=O
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Solvent: CC(=O)O
Product: O=C(c1ccc(O)cc1)c1cccc(O)c1
Temperature: 310 °C
Reaction time: 0.8 h

Procedure:
The flask was charged with 9.57 g of diacetoxybenzophenone (0.032 mole) and 4.98 g of terephthalic acid (0.03 mole) and heated, with stirring, under nitrogen at atmospheric pressure from 238° C. to 310° C. in 48 min. Most of the acetic acid by-product was liberated in this time. Heating at 310° C. continued 22 min. more. Then a vacuum of 0.2 torr (0.0266 kPa) was applied, and a temperature was raised to 325° C. in 8 min. and maintained for 17 min. The cooled polymer had an inherent viscosity, ηinh, of 0.78. Its melt was anisotropic above its flow temperature of 296° C. using the TOT test.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1.C(=O)([O-])O.[Na+].O>CN(C)C=O>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=3)[N:19]=2)[CH:18]=1
Reactant: Cc1ccc(N)nc1
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cn3cc(C)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
A solution of 2-bromo-1-(4-methylphenyl)ethanone (99.3 g, 0.47 mol) in dimethylformamide (250 mL) was added slowly to a solution of 5-methyl-2-pyridinamine (50.4 g, 0.47 mol) in dimethylformamide (250 mL). Sodium hydrogen carbonate (78.3 g, 0.93 mol) was added in portions and the mixture was stirred at room temperature for 15 min., then under reflux for 1.5 h. The mixture was cooled and poured into water (2500 mL). The solid was collected, washed with water (1000 mL) and recrystallised from dimethylformamide (400 mL). The solid was collected and dried in vacuo at 120° C. to give the title compound (89 g, 86%). 1H NMR (360 MHz, DMSO-d6) δ 8.30 (1H, d, J 1.5 Hz), 8.23 (1H, s), 7.84 (2H, d, J 8.0 Hz), 7.47 (1H, d, J 9.2 Hz), 7.25 (2H, d, J 8.0 Hz), 7.09 (1H, dd, J 9.2, 1.5 Hz), 2.33 (3H, s), and 2.28 (3H, s).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([NH:13]S(C(C)(C)C)=O)([CH3:12])[C:6]2[O:7][C:8]([CH3:11])=[N:9][N:10]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1>CO>[CH:1]1([CH2:4][C:5]([C:6]2[O:7][C:8]([CH3:11])=[N:9][N:10]=2)([NH2:13])[CH3:12])[CH2:3][CH2:2]1
Reactant: Cc1nnc(C(C)(CC2CC2)NS(=O)C(C)(C)C)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nnc(C(C)(N)CC2CC2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of N-[2-cyclopropyl-1-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-2-methyl-propane-2-sulfinamide (example 173a, 520 mg, 1.46 mmol) in MeOH (8 ml) was added a 4M solution of hydrochloric acid in dioxane (729 μl, 2.92 mmol). The reaction mixture was stirred at room temperature for 1 hour. Reaction was quenched by addition of potassium carbonate and stirred for 15 minutes. The insolubles were removed by filtration and the filtrate was evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane-methanol gradient to yield the title compound (130 mg, 50%). MS (ESI, m/z): 182.2 (M+H+).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.[CH3:15][C:16]1[C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][NH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.COCCOC>[CH3:14][N:5]1[C:4]2[CH:3]=[C:2]([C:20]3[CH:19]=[N:18][NH:17][C:16]=3[CH3:15])[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(C)N2C
Temperature: 25 °C
Yield: 38.1 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (208 mg, 1.00 mmol), cesium carbonate (489 mg, 1.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. This mixture was refluxed for 18 h. After cooling to room temperature, 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.208 g, 1.00 mmol), Cs2CO3 (0.489 g, 1.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1 mL) were added. The mixture was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.041 g, 0.050 mmol) was added, and the mixture was purged with argon again. The mixture was refluxed for 6 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (100 mL), and the extract was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc). The obtained yellow solid was triturated with EtOAc and collected by filtration to afford the title compound (52.7 mg, 38%) as a pale yellow solid:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([Br:20])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:22](=[O:26])[CH:23]([CH3:25])[CH3:24].O>O1CCCC1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([Br:20])[CH:14]=1)[C:23]([CH3:25])([CH3:24])[CH:22]2[OH:26])=[O:21])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2cc(C)cc(Br)c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(C)cc(Br)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.5 %

Procedure:
To a mixture of 4-{[1-(3-bromo-5-methyl-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (2.5 g, 7.3 mmol) and ytterbium(III) triflate hydrate (0.45 g, 0.73 mmol) in dry tetrahydrofuran (15 mL) at 25° C. was added isobutyraldehyde (0.53 g, 7.3 mmol) and water (0.13 mL, 7.3 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-5-methyl-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.1 g, 100%) as a light yellow oil: LC/MS m/e calcd for C21H24BrNO3 M+: 418.3, observed: 400.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:26]=[CH:25][C:15]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.C(N(CC)CC)C.[N:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]3[CH2:19][CH2:20][CH:21]([NH:24][C:40]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:41])[CH2:22][CH2:23]3)=[O:17])=[CH:25][CH:26]=2)=[N:2]1
Reactant: NC1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Reactant: O=C(Cl)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1)N1CCOCC1
Reaction time: 4 h
Yield: 0.3 %

Procedure:
Compound 64 (500 mg, 1.19 mmol) was dissolved in dichloromethane, and the solution was added with triethylamine (0.498 mL, 3.57 mmol), 4-morpholinecarbonyl chloride (468 mg, 2.62 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (200.2 mg, 1.04 mmol) at 0° C., followed by stirring for 4 hours to obtain Compound 99 (1.5 mg, 0.3%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][CH:39]=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1)(C)(C)C.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[O:30])=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][CH:39]=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2Nc2ncnc3ncccc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2Nc2ncnc3ncccc23)cc1

Procedure:
The product of Example 68 was treated with trifluoroacetic acid (3 mL) in methylene chloride (3 mL) at room temperature for 30 minutes. The solvents were removed under vacuum to provide the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) δ ppm: 6.65 (d, J=8.82 Hz, 2 H) 6.97 (d, J=8.46 Hz, 1 H) 7.17 (d, J=8.46 Hz, 2 H) 7.30 (m, 2 H) 7.72 (m, 1 H) 7.91 (m, 3 H) 8.05 (s, 1 H) 8.91 (s, 1 H) 9.12 (d, J=8.46 Hz, 1 H) 9.19 (d, J=3.68 Hz, 1 H) 10.36 (s, 1 H) 11.72 (s, 1 H); MS (ESI+) m/z 543/545 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:39])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18](=[O:38])[C:19]2[CH:24]=[CH:23][C:22](F)=[CH:21][C:20]=2[O:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:6][CH:7]=1.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>>[C:34]([O:33][C:31]([NH:30][CH2:29][CH2:28][CH2:27][O:26][C:20]1[CH:21]=[C:22]([N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C:11]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:39])=[O:38])=[O:32])([CH3:36])([CH3:37])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCCOc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: C1CCNC1
Product: CC(C)(C)OC(=O)NCCCOc1cc(N2CCCC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Yield: 79 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-5-fluoro-2-[4-fluoro-2-(3-tert-butoxycarbonylaminopropoxy)benzoylamino]benzamide (0.4 g, 0.71 mmol) in pyrrolidine (10 mL) was heated at 80° C. for 6 hr. The reaction was concentrated in vacuo and the residue was purified by RPLC (ethyl acetate/hexane 1:4) to give pure product (0.345 g, 79%).
Reaction SMILES: Cl[C:2]1[C:3]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]2)=[N:4][S:5][N:6]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=1.C(C(CCC)[O-])(C)(C)C.[K+].C(O)(C)(C)C>O>[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][C:2]2[C:3]([N:7]3[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]3)=[N:4][S:5][N:6]=2)=[CH:18][CH:17]=1
Reactant: OCc1ccncc1
Reactant: O=C(O)C1CCN(c2nsnc2Cl)CC1
Agent: CCCC([O-])C(C)(C)C
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)C1CCN(c2nsnc2OCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
1-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperidine-4-carboxylic acid (7.99 g, 32 mmol), pyridin-4-yl-methanol (7.39 g, 68 mmol) and a solution of 1M potassium tert-butyl butoxide in tert-butyl alcohol (100 mL, 100 mmol) were combined and stirred at room temperature overnight. The reaction mixture is diluted with H2O (500 mL) and washed with EtOAc (3×). The aqueous phase is concentrated to ˜250 mL and acidified to pH 5-6 with conc'd HCl. The resulting solids are filtered, washed with H2O and dried under high vacuum to give 6.04 g (59%) of 1-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylic acid. 1H NMR (DMSO-d6) 8.57 (d, 2H), 7.41 (d, 2H), 5.51 (s, 2H), 4.03 (m, 2H), 3.00 (m, 2H), 2.46 (m, 1H), 1.91 (m, 2H), 1.63 (m, 2H) ppm. LC-MS (M−)=319.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[CH2:32]([O:23][C:20]1[CH:19]=[CH:18][C:17](/[CH:16]=[CH:15]/[C:9]2[N:10]([CH3:14])[C:11]3[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH2:24][CH3:25])[C:7]=3[N:8]=2)=[CH:22][CH:21]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(O)cc3)n2C)n(CC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCc4ccccc4)cc3)n2C)n(CC)c1=O
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 53.7 %

Procedure:
Compound 184 (100 mg, 0.29 mmol) obtained in Reference Example 181 was dissolved in 2 ml of dimethylformamide. To the solution were added 162 mg (1.17 mmol) of potassium carbonate and 0.28 ml (2.35 mmol) of benzyl bromide, and the mixture was stirred at 80° C. for 2.5 hours. Water was added thereto under ice cooling to dissolve potassium carbonate and the deposited crystals were collected by filtration. The collected crude crystals were dissolved in chloroform, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give 67 mg (yield 53%) of Compound 185 as yellow needles.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH:20]=O)=[CH:12]1.C(OC(=O)C)(=O)C.CCN(CC)CC>>[NH:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH:20]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([OH:10])=[O:9])=[CH:12]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: O=C(O)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 44.3 %

Procedure:
A mixture of phenylacetic acid (0.0376 mol., 5.1 g) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (0.0376 mol., 5.5 g) in acetic anhydride (0.1881 mol., 17.7 ml) and Et3N (0.0376 mol., 5.2 ml) was stirred at 100° C., for 6 hrs. The obtained solution was cooled to 50° C., quenched with conc. hydrochloric acid (10 ml) and extracted with EtOAc. The organic phase was extracted with 1 N NaOH. 3-(1H-Pyrrolo[2,3-b]pyridin-3-yl) -2-phenyl-2-propenoic acid was then precipitated from the aqueous layer with conc. hydrochloric acid with ice-cooling. Filtration and recrystallization from isopropyl alcohol of the crude product afforded 4,4 g of the desired compound as a white solid (44%), m.p. >230° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH2:16][O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:10]=1.O>C1COCC1>[Cl:8][C:9]1[N:14]=[C:13]([O:7][CH2:6][CH:3]2[CH2:5][CH2:4]2)[CH:12]=[C:11]([CH2:16][O:17][CH2:18][C:19]([F:22])([F:20])[F:21])[N:10]=1
Reactant: OCC1CC1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)COCc1cc(OCC2CC2)nc(Cl)n1
Reaction time: 0.08 h

Procedure:
Sodium hydride (19.0 mg, 0.46 mmol) was added to a solution of cyclopropylmethanol (0.037 mL, 0.46 mmol) in dry THF (1 mL) at room temperature. The mixture was stirred for 5 minutes and then a solution of 2,4-dichloro-6-[(2,2,2-trifluoroethoxy)methyl]pyrimidine (120 mg, 0.46 mmol) in dry THF (1 mL) was added. The reaction was stirred at room temperature for 2.5 hours. Water was added and the mixture was extracted with ethylacetate. The organic phase was washed with water, brine, dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with mixtures of 0% to 10% ethyl acetate in heptanes to afford the title compound as a solid, 40 mg, (29%) as yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([CH2:21][CH3:22])[CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH2:21]([C:4]1[CH:3]=[C:2]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]=1[N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:22]
Reactant: CCc1cc(Br)cc(CC)c1-n1ccnc1-c1ccccc1
Reactant: OB(O)c1ccccc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(-c2ccccc2)cc(CC)c1-n1ccnc1-c1ccccc1
Yield: 82.1 %

Procedure:
A 2-necked 250 mL round-bottom flask was charged with 1-(4-bromo-2,6-diethylphenyl)-2-phenyl-1H-imidazole (6.75 g, 19 mmol), phenylboronic acid (4.63 g, 38 mmol), dicyclohexyl (2′,6′-dimethoxy-biphenyl-2-yl)phosphine (0.312 g, 0.76 mmol), and tripotassium phosphate monohydrate (12.1 g, 51 mmol) in 100 mL of toluene and 10 mL of water. The mixture was degassed by bubbling nitrogen directly into solution for 20 min. Pd2(dba)3 was added and the reaction heated to reflux overnight under nitrogen. The organic layer was separated and solvent was evaporated. The material was column purified by silica gel chromatography eluting with 20% ethyl acetate/hexanes. 5.5 g (82% yield) of product was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[NH:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=O)[O:7]C1=O.CCN(C(C)C)C(C)C>C1COCC1>[NH2:5][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]([NH:4][O:3][CH3:2])=[O:7]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CON
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CONC(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
O-Methylhydroxylamine hydrochloride (1.253 g, 15.00 mmol) was added to 1H-3,1-benzoxazine-2,4-dione (isatoic anhydride) (1.631 g, 10 mmol) in THF (50 mL) containing DIPEA (2.79 ml, 16.00 mmol). The resulting solution was stirred at room temperature for 4 hours and then heated to reflux for 17 hours. The mixture was allowed to cool to room temperature, filtered and then evaporated. The residue was dissolved in MeOH (20 mL) and then loaded onto an SCX column. The mixture was eluted first with MeOH and then with a 7N solution of NH3 in MeOH. Fractions containing product were combined and then evaporated to afford 2-amino-N-methoxybenzamide (1.410 g, 85% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 3.67 (3H, s), 6.26 (2H, s), 6.48 (1H, m), 6.70 (1H, dd), 7.15 (1H, m), 7.31 (1H, dd), 11.36 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=167.41.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[F:23])(=O)=O.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]1>CN1C(=O)CCC1.O>[Br:22][C:19]1[CH:20]=[N:21][C:16]([NH:15][C:13]2[CH:12]=[CH:11][C:10]([F:23])=[C:9]([CH:14]=2)[O:8][CH2:7][CH2:6][N:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]2)=[N:17][CH:18]=1
Reactant: COC(=O)C1CCNCC1
Reactant: CS(=O)(=O)OCCOc1cc(Nc2ncc(Br)cn2)ccc1F
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)C1CCN(CCOc2cc(Nc3ncc(Br)cn3)ccc2F)CC1
Temperature: 90 °C

Procedure:
2-(5-(5-bromopyrimidin-2-ylamino)-2-fluorophenoxy)ethyl methanesulfonate 46b (0.24 mmol) and methyl piperidine-4-carboxylate (0.48 mmol) are dissolved in NMP (2 mL) and heated to 90° C. for 3 h. The reaction mixture is cooled to rt and diluted with water and extracted with EtOAc (2×30 mL). The organic layer is washed with water, brine, dried over sodium sulfate, and concentrated to dryness. The crude product is purified by short SiO2 chromatography using DCM:hexane=9:1 as eluant to yield methyl 1-(2-(5-(5-bromopyrimidin-2-ylamino)-2-fluorophenoxy)ethyl)piperidine-4-carboxylate 47 as light brown solid. MS (m/z) (M+1)+: 454.1.