Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2Cl)[CH2:6]1)(=[O:3])[CH3:2].[Cl:27][C:28]1[N:36]=[CH:35][N:34]=[C:33]2[C:29]=1[NH:30][CH:31]=[N:32]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2[N:32]2[CH:31]=[N:30][C:29]3[C:33]2=[N:34][CH:35]=[N:36][C:28]=3[Cl:27])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(Cl)=C(C=O)C[C@@H]32)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4cnc5c(Cl)ncnc54)=C(C=O)C[C@@H]32)C1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of 13 (2.43 g, 6.46 mmol), 6-chloropurine (0.5 g, 3.23 mmol) and TBAF (1.69 g, 6.46) in dry THF (40 mL) was stirred at 50° C. under Ar for 48 h. After cooling to room temperature, the reaction mixture concentrated and poured onto ice-cold water (250 mL) and the resulting precipitate was filtered, washed with water and dried to give a crude product. Purification by FCC [DCM/Methanol (9.7:0.3)] and then recrystallized with hot ethanol to give 0.82 g (51.3%) of pure 21a: mp 140-142° C.; IR (Neat) 2943, 2853, 1729, 1672, 1584, 1556, 1435, 1236, 1032, 939, cm-1; 1H NMR (500 MHz, CDCl3) δ 1.07 (s, 3H, 18-CH3), 1.09 (s, 3H, 19-CH3), 2.04 (s, 3H, 3β-OCOCH3), 4.61 (m, 1H, 3α-H), 5.43 (br, 1H, 6-H), 8.20 (s, 1H, 2′-H), 8.79 (s, 1H, aromatic-H), and 9.53 (s, 1H, 16-CHO).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13](B2OCC(C)(C)CO2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[N:30]=[C:29](Cl)[CH:28]=[C:27]([Cl:32])[N:26]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([C:29]2[CH:28]=[C:27]([Cl:32])[N:26]=[C:25]([NH2:24])[N:30]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1ccc(OCc2ccccc2)cc1B1OCC(C)(C)CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccc(OCc2ccccc2)cc1-c1cc(Cl)nc(N)n1
Temperature: 85 °C
Reaction time: 4 h
Yield: 39.5 %

Procedure:
2-(5-Benzyloxy-2-methylphenyl)-5,5-dimethyl[1,3,2]dioxaborinane (41.5 g) obtained in Step 2 above, 2-amino-4,6-dichloropyrimidine (13.8 g, 84.2 mmol), and dichloroditriphenylphosphine palladium (5.0 g, 7.12 mmol) were placed in a reaction vessel, and then dimethoxyethane (800 ml) and 2N aqueous sodium carbonate solution (63.1 ml, 126.2 mmol) were sequentially added thereto. The resulting mixture was stirred at 85° C. for 4 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (1000 ml), and washed with water (600 ml) and then with a saturated aqueous sodium chloride solution (60 ml). The ethyl acetate solution was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=6:1 to 3:1) to yield 4-(5-benzyloxy-2-methylphenyl)-6-chloropyrimidin-2-ylamine (10.84 g, 40%) as a pale yellow solid material.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[NH2:25].CCOC(C)=O>C(O)(C)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:3]=[CH:4][C:5]3[CH2:11][N:10]([C:12]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH2:9][CH2:8][C:6]=3[N:7]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(N)cc1OC
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncc3c(n2)CCN(C(=O)c2cccnc2)C3)cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 3,4-dimethoxyaniline (0.015 g, 0.100 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature, EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 53% yield (0.019 g, 0.049 mmol).
Reaction SMILES: Cl.[CH2:2]([S:9][C:10]1[S:11][CH:12]([CH2:16][OH:17])[CH:13](O)[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[CH2:2]([S:9][C:10]1[S:11][C:12]([CH2:16][OH:17])=[CH:13][N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCC1SC(SCc2ccccc2)=NC1O
Agent: Cl
Solvent: CCO
Product: OCc1cnc(SCc2ccccc2)s1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
0.2 ml of concentrated hydrochloric acid is added to 3.0 g of 2-benzylsulfanyl-5-hydroxymethyl-4,5-dihydrothiazol-4-ol in 25 ml of ethanol. The mixture is stirred at 50° C. for 12 hours, the solvent is removed in vacuo, and the residue is chromatographed on silica gel (ether:hexane; 1:1). The title compound is obtained in the form of a yellow oil (compound 3.1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[CH:4][C:5]([Br:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:43][C@H:44]1[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:45]1[OH:50].C(N(CC)CC)C>ClCCl>[NH2:1][C:2]1[C:3]([C:13]([NH:43][C@H:44]2[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:45]2[OH:50])=[O:15])=[CH:4][C:5]([Br:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: Nc1c(C(=O)O)cc(Br)c2cccnc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1c(C(=O)N[C@H]2CCCC[C@@H]2O)cc(Br)c2cccnc12
Reaction time: 3 h

Procedure:
To a solution of 8-amino-5-bromoquinoline-7-carboxylic acid (1.00 g, 3.74 mmol) in 20 mL of dichloromethane was added (1H-1,2,3-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (1.99 g, 4.49 mmol), (1S,2S)-2-aminocyclohexanol (0.517 g, 4.49 mmol), and triethylamine (1.04 mL, 7.49 mmol). After 3 h, a brown solid was collected and washed with dichloromethane and water to provide 8-amino-5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-7-carboxamide that gave a mass ion (ES+) of 365.9 (81Br) for [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[CH:12]1([C:15]2[NH:19][N:18]=[C:17]([O:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][C:22]=3[Cl:32])[CH:16]=2)[CH2:14][CH2:13]1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:19]1[C:15]([CH:12]2[CH2:13][CH2:14]2)=[CH:16][C:17]([O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:29])[F:30])=[CH:23][C:22]=2[Cl:32])=[N:18]1)=[O:11])[CH3:8]
Reactant: CCN=C=O
Reactant: FC(F)(F)c1cc(Cl)c(Oc2cc(C3CC3)[nH]n2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
Potassium carbonate (0.23 g, 1.7 mmol) and ethyl isocyanate (0.11 g, 1.5 mmol) were added to a solution of 5-cyclopropyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)pyrazole (0.51 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a colorless viscous substance of N-ethyl-5-cyclopropyl-3-(2,6-dichloro-4-trifluoromethylpheyloxy)pyrazole-1-carboxamide (0.54 g, yield: 88.2%). 1H-NMR (CDCl3, TMS, ppm): δ 0.70 (m, 2H), 1.07 (m, 2H), 1.20 (t, J=7.3 Hz, 3H), 2.81 (m, 1H), 3.36 (dq, J=6.0 and 7.3 Hz, 2H), 5.45 (s, 1H), 6.60-6.85 (m, 1H), 7.66 (s, 2H).
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.[CH:7]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17](F)[CH:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH2:9][CH2:8]1.C(N(CC)CC)C>CS(C)=O>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:17]1[CH:18]=[C:19]3[C:14]([C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11][N:10]3[CH:7]3[CH2:9][CH2:8]3)=[CH:15][C:16]=1[F:21])[CH2:2]2
Reactant: C1NCC2CC12
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CC4CC4C3)c(F)cc2c1=O
Yield: 33 %

Procedure:
A solution of the hydrochloride salt of 3-azabicyclo-[3.1.0]hexane (157 mg, 1.31 mmol), (prepared in a manner similar to that described in U.S. Pat. No. 4,183,857) in dimethylsulfoxide (13 ml) was treated with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (348 mg, 1.31 mmol) and triethylamine (0.58 ml, 3.9 mmol) and heated for 18 hours. Filtration of the reaction mixture provided a white solid, which was purified by column chromatography (eluant: 1% acetic acid in chloroform, then 5% acetic acid in chloroform, then methanol) to give the title product as a white solid, melting point 290° (186 mg, 0.43 mmol, 33% yield). 1H NMR (DMSO-d6) 8.54 (s, 1H), 7.75 (d, J=14 Hz, 1H), 7.08 (d, J=9 Hz, 1H}, 3.83 (dd, J=4, 10 Hz, 2H), 3.73 (bs, 1H), 3.62 (bd, J=10 Hz, 2H), 1.77 (m, 2H), 1.30 (d, J=6 Hz, 2H), 1.14 (bs, 2H), 0.77 (m, 1H), 0.30 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([S:22]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)(=[O:24])=[O:23])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]O)=[CH:38][CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.ClCCl>[Cl:30][C:27]1[S:26][C:25]([S:22]([N:10]([S:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:8])=[O:9])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:42][C:39]3[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][N:32]([CH3:31])[CH3:44])=[CH:41][CH:40]=3)[N:12]=2)(=[O:23])=[O:24])=[CH:29][CH:28]=1
Reactant: COc1cccc2[nH]nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c12
Reactant: CN(C)CCOc1ccc(CO)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cccc2c1c(N(S(=O)(=O)c1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)s1)nn2Cc1ccc(OCCN(C)C)cc1
Temperature: 65 °C

Procedure:
A mixture of 5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-N-[4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 10) (0.262 g, 0.5 mmol) and (4-{[2-(dimethylamino)ethyl]oxy}phenyl)methanol (98 mg, 0.5 mmol), triphenylphosphine (197 mg, 0.75 mmol) and di tert-butyl azodicarboxylate (230 mg, 1 mmol) in THF (30 mL) was heated to 65° C. for h. LCMS indicated complete reaction. The mixture was concentrated and the residue was dissolved in methanol and applied to an SCX-2 ion-exchange cartridge (50 g) eluting with methanol, followed by 10% aq. ammonia in methanol. The ammoniacal fractions were combined and evaporated in vacuo to give the crude product (400 mg) as a yellow gum. The mixture was loaded in dichloromethane on a silica cartridge (20 g) and purified by chromatography on Flashmaster using a gradient of 0-15% methanol (containing 1% Et3N)-dichloromethane over 40 min. The appropriate fractions were combined and evaporated in vacuo to give impure product (167 mg) as a colourless gum. The sample was dissolved in 1:1 MeOH-DMSO (2 mL) and purified by MDAP on Xbridge column using acetonitrile water with an ammonium carbonate modifier Appropriate fractions were combined and the solvent was evaporated in vacuo to give the title compound (91 mg, 26%) LCMS (System C) (5 min run) RT=3.76 min, ES+ve m/z 701/703 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4][CH2:3]1.[B-](F)(F)(F)F.[CH3:18][CH2:19][O+](CC)CC>>[CH2:18]([O:6][C:5]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:2]([OH:1])[CH2:3][N:4]=1)[CH3:19]
Reactant: CC[O+](CC)CC
Reactant: O=C1NCC(O)c2ccccc21
Agent: F[B-](F)(F)F
Product: CCOC1=NCC(O)c2ccccc21

Procedure:
In a manner similar to that of Step A of Example 1, ethylation of 4-hydroxy-3,4-dihydroisocarbostyril (21.75 g.) with triethyloxonium fluoborate (0.147 + 0.073/3 mole) and two recrystallizations (the first recrystallization afforded a first crop of 8 g., of which 4.2 g. was recrystallized) of the resulting product from ethanol-ether afforded 1-ethoxy-4-hydroxy-3,4-dihydroisoquinoline (III: Q = C2H5, Y' = OH, Y = Z = Z' = H) fluoborate (3.9 g., m.p. 121°-123° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[C:16](Cl)([N:18]=[C:19]=[O:20])=[O:17]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[C:11]3[O:15][C:19](=[O:20])[NH:18][C:16](=[O:17])[C:12]=3[CH2:13][CH2:14]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: O=C=NC(=O)Cl
Reactant: O=C1CCCC1c1cc(F)c(F)c(F)c1
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1cc(F)c(F)c(F)c1)CC2
Temperature: 130 °C
Yield: 46.4 %

Procedure:
A mixture of 2-(3,4,5-trifluorophenyl)cyclopentanone (2 g, 9.34 mmol) and carbonisocyanatidic chloride (1.773 g, 16.81 mmol) was heated at 58° C. for 1 h and at 130° C. for 2 h. Upon cooling to room temperature, the reaction mixture was dissolved in ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 7-(3,4,5-trifluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (1.227 g, 4.33 mmol, 46.4% yield). LC-MS (M+H)+=284.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 1 was prepared from bis(4-fluorophenyl) acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.39–7.31 (m, 3H), 7.29–7.21 (m, 5H), 7.02–6.96 (m, 4H), 4.80 (s, 1H), 3.40 (q, 2H, J=4.5 Hz), 2.94 (d, 2H, J=10.2 Hz), 2.51–2.38 (m, 4H), 1.97 (dt, 2H, J=1.8, 10.4 Hz), 1.81 (m, 2H), 1.68 (quintet, 2H, J=6.8 Hz,), 1.59 (m, 3H), 1.23 (d, 6H, J=6.9 Hz); ESMS m/e: 534.3 (M+H)+; Anal. Calc. For (HCl salt) C32H37F2N3O2.HCl.0.20 CHCl3: C, 65.11; H, 6.48; N, 7.07. Found: C, 65.30; H, 6.50; N, 6.96.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[N:3]=1.[OH-:23].[K+]>C(O)(C)(C)C>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[N:10]=[C:9]([CH3:22])[N:8]([C:4]3[N:3]=[C:2]([OH:23])[CH:7]=[CH:6][CH:5]=3)[CH:12]=2)[CH:20]=[CH:19][N:18]=1
Reactant: [OH-]
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cccc(F)n1
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cccc(O)n1

Procedure:
The title compound, white cristalline solid, MS: m/e=311.2, 313.2 (M+H+), was prepared in accordance with the general method of example 1a from 2-fluoro-6-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-pyridine and KOH in tert-butanol.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[S:7])[CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[NH:3]1.[C:12](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH3:1][N:2]1[C:6]([S:7][CH3:12])=[CH:5][C:4]([C:8]([F:11])([F:9])[F:10])=[N:3]1
Reactant: Cn1[nH]c(C(F)(F)F)cc1=S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CSc1cc(C(F)(F)F)nn1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.4 %

Procedure:
3.87 g of compound (8-5) and 4.40 g of potassium carbonate were suspended in 100 ml of acetonitrile. The suspension was stirred at room temperature for 15 minutes. A solution of 3.62 g of methyl iodide in 10 ml of acetonitrile was added dropwise, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. After water was added to the residue, the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce 3.60 g of 1-methyl-5-methylthio-3-(trifluoromethyl)pyrazole (14).
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10]1([CH:16]2[CH2:21][C:20](O)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][CH2:18][N:17]2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:10]1([CH:16]2[CH2:21][C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:19][CH2:18][N:17]2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(c2ccccc2)CC1C1CCCCC1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC=C(c2ccccc2)CC1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of BF3.OEt2 (4.93 ml, 38.9 mmol) in CH2Cl2 (30 ml) was added to a stirred solution of benzyl 2-cyclohexyl-4-hydroxy-4-phenylpiperidine-1-carboxylate (5 g, 12.71 mmol) in CH2Cl2 (244 ml) at 0° C. The mixture was stirred at room temperature for 15 minutes. Saturated sodium bicarbonate (100 ml) was added after 15 minutes. Extracted twice with CH2Cl2 and the combined organics were dried and concentrated. The crude product was not purified.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:23])[S:13][C:14]=2[CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:5]=1.[C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH3:26].[Li]>>[C:29]([O:28][C:25](=[O:27])[CH2:26][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:23])[S:13][C:14]=2[CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:5]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-c2nc(C)sc2COC2CCCCO2)c1
Agent: [Li]
Product: Cc1nc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(COC2CCCCO2)s1

Procedure:
3-[2-Methyl-5-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-benzoic acid methyl ester was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-oxo-3-[3-[2-methyl-5-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-phenyl]-propionic acid tert-butyl ester (5.45 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[CH:10]=2)=[O:8])=[CH:5][N:4]=[CH:3]1.[N:19]1([C:24]2[CH:43]=[CH:42][C:27]([CH2:28][C:29]3[C:30]([Cl:41])=NC4C([C:38]=3[Cl:39])=CC(Br)=CC=4)=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[N:20]1.O=P(Cl)(Cl)Cl.[NH4+].[OH-]>>[N:19]1([C:24]2[CH:25]=[CH:26][C:27]([CH2:28][C:29]3[C:30]([Cl:41])=[N:15][C:12]4[C:13]([C:38]=3[Cl:39])=[CH:14][C:9]([C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)=[O:8])=[CH:10][C:11]=4[CH3:18])=[CH:42][CH:43]=2)[CH:23]=[CH:22][CH:21]=[N:20]1
Reactant: Cc1cc(C(=O)c2cncn2C)ccc1[N+](=O)[O-]
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Temperature: 105 °C

Procedure:
A heterogeneous mixture of (4-amino-3-methylphenyl)(1-methyl-1H-imidazol-5-yl)methanone (1.0 g, 4.6 mmol, Intermediate 14: step c), 2-(4-(1H-pyrazol-1-yl)benzyl)malonic acid (1.3 g, 4.6 mmol, Intermediate 3: step b) and POCl3 (4.3 mL) was heated at 105° C. for 18 hours then cooled to room temperature. The mixture was poured into ice water and treated with aqueous NH4OH solution (kept adding ice during addition) to a basic pH 8-9. The aqueous layer was extracted with DCM, washed with a saturated aqueous solution of NaCl, dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-100% EtOAc/DCM) to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@@H:4]([NH:10]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C@H:5]([N:7]=[N+:8]=[N-:9])[CH3:6].C(O)(C(F)(F)F)=O.C(Cl)[Cl:39]>Cl>[ClH:39].[CH3:1][O:2][C:3](=[O:30])[C@@H:4]([NH2:10])[C@H:5]([N:7]=[N+:8]=[N-:9])[CH3:6]
Reactant: ClCCl
Reactant: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)N=[N+]=[N-]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)[C@@H](C)N=[N+]=[N-]
Reaction time: 2.5 h
Yield: 97 %

Procedure:
A solution of Trt-Azido-Thr-OMe (3) (4.8 g, 12.0 mmol) was dissolved in a 95% TFA/DCM solution (60 ml) at rt with stirring. After 2.5 h, the reaction was complete by LCMS. The bright yellow solution was diluted with 0.5 N aq. HCl (300 ml). The aqueous layer was extracted with DCM (2×30 ml) and then lyophilized to dryness. The white solid was dissolved in AcCN/water (50:50) (100 ml) and again lyophilized to dryness to produce a consistent powder and remove as much of the TFA as possible. The azido-Thr-product (4), 2.26 g (97% yield, 95% pure) of a white solid, was obtained as the HCl salt.