Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[S:8][CH:9]=1)=[O:4].O.O.[OH-].[Li+]>O1CCCC1>[C:14]([O:13][C:11]([NH:10][C:7]1[S:8][CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
2-tert-Butoxycarbonylamino-thiazole-4-carboxylic acid methyl ester (15.5 g, 60.01 mmol) was dissolved in 4:1 tetrahydrofuran:water (300 mL) followed by the addition of lithium hydroxide monohydrate (5.29 g, 126.07 mmol). The solution was stirred overnight at room temperature. Tetrahydrofuran was removed under vacuum and the salt was neutralized with 2.0 N aqueous hydrochloric acid. The resulting precipitate was filtered and dried to give 2-tert-butoxycarbonylamino-thiazole-4-carboxylic acid (10.4 g, 71%).
Reaction SMILES: [Na].CCO.[F:5][CH:6]([C:12]([O:14]CC)=O)[C:7]([O:9]CC)=O.Cl.[C:18]([NH2:21])(=[NH:20])[CH3:19]>>[OH:9][C:7]1[C:6]([F:5])=[C:12]([OH:14])[N:21]=[C:18]([CH3:19])[N:20]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)C(F)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1nc(O)c(F)c(O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
Part A: A mixture of sodium metal (1.55 g, 67.4 mmol) and EtOH (15.0 mL, 257 mmol) was stirred at RT until nearly all sodium had reacted. Diethyl fluoromalonate (3.54 mL, 22.4 mmol) was added followed by acetamidine hydrochloride (2.14 g, 22.7 mmol). The reaction mixture was heated at reflux for 3 h, cooled to RT and concentrated under reduced pressure. The residue was diluted with water (ca. 50 mL) and acidified (pH=2) with 6M aqueous HCl, and the mixture was stirred at RT for 1 h as a precipitate formed. The solids were collected by suction filtration and washed with water. Excess solvent was removed in vacuo to give 4,6-dihydroxy-5-fluoro-2-methylpyrimidine (2.08 g, 64%) as a light gray solid. LCMS (m/z): 145 (M+H)+
Reaction SMILES: O1CCCC1.[OH:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1.[H-].[Na+].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>C(OCC)(=O)C.O>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:6][CH:7]2[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10]2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(OCc2ccc(F)cc2)C1
Yield: 48.7 %

Procedure:
To a tetrahydrofuran solution (2.0 mL) of tert-butyl 3-hydroxyazetidine-1-carboxylate (87 mg, 0.50 mmol), sodium hydride (33 mg, 0.75 mmol, purity 55%) was added at 0° C. and the resultant solution was stirred for 30 minutes. Subsequently, 4-fluorobenzyl bromide (62.3 μL, 0.50 mmol) was added to the reaction solution and the resultant mixture was stirred at room temperature for 19 hours. After completion of the reaction, water was added to the reaction solution and extraction with ethyl acetate from the resultant mixture was performed three times. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (68.5 mg, yield 49%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:9])[CH3:18]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 4′-bromoacetophenone (50 mmol), ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[CH2:13].O.O.O.[N+]([O-])([O-])=[O:18].[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(Cl)(Cl)Cl>CO>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][C:13](=[O:18])[CH2:8][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: C=C1CCCc2c(OC)cccc21
Reactant: O=[N+]([O-])[O-]
Agent: [Tl+3]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cccc2c1CCCC(=O)C2
Reaction time: 0.02 h

Procedure:
5-Methoxy-1-methylene-1,2,3,4-tetrahydro-naphthalene (23.8 g, 0.137 mol) in 150 mL MeOH added in one portion to freshly prepared solution of thallium(III)nitrate trihydrate (1.0 eq) in 300 mL MeOH. Stirred one minute and 400 mL chloroform added. The solution was filtered and the organics partitioned between dichloromethane and water. The organics were dried (MgSO4) and concentrated. Purification by chromatography (ISCO, 330 g silica cartridge; stepwise elution hexane (5 min) then 7 minute gradient to 100% dicloromethane (20 min) affords the title compound as the most polar of the products as a pale yellow oil (26 g, 97%). 1H-NMR (400 MHz, CDCl3) 7.16 (t, J=7.9 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 6.79 (d, J=7.5 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 2H), 3.05-3.01 (m, 2H), 2.55 (t, J=7.0 Hz, 2H), 2.01-1.96 (m, 2H). LC/MS (ESI+) m/z=191 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([NH2:10])[CH:3]=1.[CH2:11]([O:13][C:14](=[O:18])[CH:15]=[CH:16]O)[CH3:12].[Na]>C(O)(=O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[N:10][C:4]2[C:5]([CH:6]=1)=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)=[O:18])[CH3:12]
Reactant: CCOC(=O)C=CO
Reactant: Nc1cc(Cl)ccc1C=O
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2cc(Cl)ccc2c1
Reaction time: 3 h
Yield: 13 %

Procedure:
A solution of 4-chloro-2-aminobenzaldehyde (15 g, 96 mmol, 1 equiv) and 3-hydroxy-acrylic acid ethyl ester, sodium salt (6.65 g, 48 mmol, 0.5 equiv) in glacial acetic acid (175 mL), was heated at reflux for 3 hours. Additional 3-hydroxy-acrylic acid ethyl ester, sodium salt (6.65 grams, 48 mmol, 0.5 equivalents) was added and the reaction was heated at reflux for another 2.5 hours. Additional 3-hydroxy-acrylic acid ethyl ester, sodium salt (4 g, 28.8 mmol, 0.3 equiv) was added and the reaction was heated at reflux for an additional 12 hours. Additional 3-hydroxy-acrylic acid ethyl ester, sodium salt (4 g, 28.8 mmol, 0.3 equiv) was added and the reaction was heated at reflux for 4 hours. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and washed with saturated sodium bicarbonate solution (200 mL). The organic layer was then washed with brine (200 mL), dried over sodium sulfate, and treated with activated charcoal (Darco G-60®) (20 g). The mixture was filtered through diatomaceous earth. Silica gel (15 g) (EM Science, Gibbstown, N.J., 230-400 mesh, 0.04-0.06 mm particle size) was added to the solution and stirred for 3 hours. The slurry was filtered, rinsed with toluene (100 ml) and then 10% ethyl acetate in toluene (200 mL). The combined organic layers were concentrated and the resulting solid was stirred in isopropanol overnight to yield 7-chloro-quinoline-3-carboxylic acid ethyl ester (3 g, 13% yield) as a pale yellow powder.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:22](=[O:38])[CH:23]([N:25]2[CH2:30][CH2:29][C:28]([OH:37])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[CH3:24])[CH:7]=[C:8]([F:21])[C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:22]([OH:38])[CH:23]([N:25]2[CH2:26][CH2:27][C:28]([OH:37])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:29][CH2:30]2)[CH3:24])[CH:7]=[C:8]([F:21])[C:9]=1[O:10][Si:11]([CH:12]([CH3:13])[CH3:14])([CH:15]([CH3:17])[CH3:16])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C(=O)c1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)N1CCC(O)(c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C(O)c1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)N1CCC(O)(c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 30.9 %

Procedure:
A mixture of sodium borohydride (0.16 g, 4.23 mmol) and ethanol (5 mL) was stirred 10 min and then 1-(3,5-difluoro-4-triisopropylsilyloxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-propan-1-one (1.40 g, 2.86 mmol in 20 mL of ethanol) was added. The reaction was stirred at ambient temperature for 3 days. The reaction was quenched with water and stirred 4 h. The white precipitate which formed was collected by filtration and recrystallized from ethanol to afford 0.46 g (32%) of 1R*,2R*1-(3,5-difluoro-4-triisopropylsilyloxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-propan-1-ol which had: NMR δ 7.54 (d, J=7.5 Hz, 2 H), 7.40 (t, J=7.5 Hz, J=8.5 Hz, 2 H), 7.31 (d, J=7 Hz, 1 H), 6.89 (d, J=9 Hz, 2 H), 5.28 (s, 1 H), 4.18 (d, J=9.5 Hz, 1 H), 3.10 (dt, J=2.2, 11.7 Hz, 1 H), 2.73-2.69 (m, 2 H), 2.62-2.51 (m, 2 H), 2.30-2.06 (m, 2 H), 1.90-1.83 (m, 2 H), 1.36-1.20 (m, 3 H), 1.10 (d, J=7 Hz, 18 H), 0.85 (d, J=6.7 Hz, 3 H). Analysis calculated for C29H43F2NO3Si: C, 67.02; H, 8.34; N, 2.69. Found: C, 66.77; H, 8.58; N, 2.71.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[CH3:12][C@H:13]1[C:21]2[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:19][CH:18]=[N:17][C:16]=2[CH2:15][CH2:14]1.[C:28]([O:32][C:33]([N:35]1[CH2:39][CH:38]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([Cl:47])[CH:41]=2)[CH:37]([C:48](O)=[O:49])[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[Cl:47][C:42]1[CH:41]=[C:40]([CH:38]2[CH:37]([C:48]([N:25]3[CH2:26][CH2:27][N:22]([C:20]4[C:21]5[C@H:13]([CH3:12])[CH2:14][CH2:15][C:16]=5[N:17]=[CH:18][N:19]=4)[CH2:23][CH2:24]3)=[O:49])[CH2:36][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:39]2)[CH:45]=[CH:44][C:43]=1[Cl:46]
Reactant: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C(c2ccc(Cl)c(Cl)c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C4CN(C(=O)OC(C)(C)C)CC4c4ccc(Cl)c(Cl)c4)CC3)c21
Reaction time: 2 h

Procedure:
DIPEA (35.5 mg, 0.275 mmol) was added to a suspension of (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (20 mg, 0.069 mmol), 1-(tert-butoxycarbonyl)-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylic acid (29.7 mg, 0.082 mmol), and O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (31.3 mg, 0.082 mmol) in CH2Cl2 (5 mL) at room temperature. The resulting mixture was stirred for 2 hours, diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NH4Cl. The organic layer was dried (MgSO4) and concentrated. The residue was purified by a silica cartridge (5.0 g), eluted by a mixture of EtOAc and hexanes (60:40) to give the tert-butyl 3-(3,4-dichlorophenyl)-4-(1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-4-carbonyl)pyrrolidine-1-carboxylate as a mixture of diastereomers (34 mg, 88%). LCMS (APCI+) [M-Boc+H]+ 560.0; Rt: 3.59 min.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]1[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:40][CH2:41][C:42]1[C:43]([OH:50])=[N:44][C:45]([CH3:49])=[CH:46][C:47]=1[CH3:48]>O.ClCCl.C(N(CC)CC)C>[OH:50][C:43]1[C:42]([CH2:41][NH:40][C:8]([C:6]2[CH:5]=[CH:4][N:3]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:2](=[O:1])[CH:7]=2)=[O:10])=[C:47]([CH3:48])[CH:46]=[C:45]([CH3:49])[N:44]=1
Reactant: CC(c1ccccc1)n1ccc(C(=O)O)cc1=O
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccn(C(C)c3ccccc3)c(=O)c2)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.7 %

Procedure:
A mixture of 2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylic acid (60 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (95 mg, 0.5 mmol), N-hydroxybenzotriazole (67 mg, 0.5 mmol), triethylamine (0.1 mL) and dichloromethane (5 mL) were stirred at 25° C. for half an hour before 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (50 mg, 0.33 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, was added water (10 ml) and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxamide as a white solid (28 mg, 29%). LRMS (M+H+) m/z: cald. 377.17. found 377. 1H NMR (300 MHz, d6-DMSO): δ 11.47 (s, 1H), 8.55 (t, J=4.5 Hz, 1H), 7.67 (d, J=6.9 Hz, 1H), 7.38-7.27 (m, 5H), 6.79 (s, 1H), 6.54-6.51 (m, 1H), 6.14 (q, J=7.2 Hz, 1H), 5.85 (s, 1H), 4.23 (d, J=4.5 Hz, 2H), 2.12 (d, J=6.6 Hz, 6H), 1.68 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[N:7]=[N:6][N:5]([CH2:1][CH2:2][C:3]#[C:4][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:9]=2[CH3:10])=[CH:16][CH:15]=1
Reactant: C#CCCn1nnc(-c2ccc(F)cc2)c1C
Reactant: Brc1ccccn1
Product: Cc1c(-c2ccc(F)cc2)nnn1CCC#Cc1ccccn1
Yield: 57.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 1-(but-3-ynyl)-4-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole (87 mg, 0.38 mmol, Example 257(B)) and 2-bromopyridine (66 mg, 0.42 mmol). Reaction time: 2 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 68 mg (0.22 mmol, 58%) of 2-(4-(4-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as a white powder (M.P.=130-131° C.).
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][O:12][CH3:13])[O:10][C:6]=2[C:5]([NH2:14])=[CH:4][C:3]=1[CH3:15].[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.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>[CH3:13][O:12][CH2:11][CH:9]1[CH2:8][C:7]2[C:2]([C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)=[C:3]([CH3:15])[CH:4]=[C:5]([NH2:14])[C:6]=2[O:10]1
Reactant: OB(O)c1ccncc1
Reactant: COCC1Cc2c(Br)c(C)cc(N)c2O1
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: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC1Cc2c(c(N)cc(C)c2-c2ccncc2)O1
Temperature: 135 °C
Reaction time: 1 h

Procedure:
A mixture of 4-bromo-2-(methoxymethyl)-5-methyl-2,3-dihydrobenzofuran-7-amine (8c) (0.85 g, 3.1 mmol), pyridin-4-ylboronic acid (0.76 g, 6.2 mmol), Cs2CO3 (2.5 g, 7.8 mmol), Pd(PPh3)4 (0.18 g, 0.16 mmol) and water (6 mL) in DMF (20 mL) was stirred at 135° C. under N2 for 1 h. It was cooled to ambient temperature, poured into water (50 mL), extracted with EtOAc (60 mL), washed with water, brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (20:1 to 5:1 to 1:1) to give the title compound (8d) as a yellow oil. MS-ESI (m/z): 271 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)O1.C([O-])(O)=O.[Na+]>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.O.C1COCC1>[NH2:41][C:38]1[N:39]=[CH:40][C:35]([C:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12][CH:11]=2)=[CH:36][CH:37]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)C1
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: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)nc2)C1
Temperature: 70 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
In a 250 mL round-bottomed flask, 3-trifluoromethanesulfonyloxy-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (2.3 g, 7.25 mmol, Eq: 1.00) was combined with THF (60 ml) to give a colorless solution. The solution was purged with argon for 10 min. Potassium carbonate (5.06 g, 36.2 mmol, Eq: 5.0), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.91 g, 8.7 mmol, Eq: 1.20), tetrakis(triphenylphosphine)palladium(0) (83.8 mg, 72.5 μmol, Eq: 0.01) and water (1.2 ml) were added. The reaction mixture was heated to 70° C. and stirred for 16 h. The reaction mixture was poured into saturated NaHCO3 and extracted twice with Et2O. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 60 g, 50% (60:10:1 DCM:MeOH:NH4OH)/DCM) to give tert-butyl 3-(6-aminopyridin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.03 g, 54%). LC/MS-ESI observed [M+H]+ 262.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1.C(#N)C.[Br:14]N1C(=O)CCC1=O>>[Br:14][C:7]1[S:6][C:5]([NH2:8])=[N:4][C:3]=1[C:2]([F:10])([F:9])[F:1]
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1nc(C(F)(F)F)c(Br)s1
Temperature: 60 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a 250 mL round-bottomed flask were added 4-(trifluoromethyl)thiazol-2-amine (6 g, 36 mmol), ACN (90 mL, 1723 mmol), and N-bromosuccinimide (4 mL, 43 mmol). The solution was stirred at 60° C. for 3 hours. The reaction was cooled, and the solvent was removed in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of (5%→50% EtOAc in hexane) to provide 5-bromo-4-(trifluoromethyl)thiazol-2-amine (8.1 g, 90% yield), m/z (%): 248.2 (100%, M++H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14].Cl.[NH:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:18]2[CH2:21][CH:20]([OH:22])[CH2:19]2)=[O:8])=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: O=C(O)c1ccc(Br)c(OCC(F)(F)F)c1
Reactant: OC1CNC1
Agent: Cl
Product: O=C(c1ccc(Br)c(OCC(F)(F)F)c1)N1CC(O)C1

Procedure:
Starting with 4-bromo-3-(2,2,2-trifluoroethoxy)benzoic acid and azetidin-3-ol hydrochloride, Int06.05 was prepared analogously to the procedure for the preparation of Int02.03.
Reaction SMILES: I.[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:24]([NH:31][C:32]([N:15]1[CH2:16][CH2:17][CH2:18][CH:13]([N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:3]([Cl:2])[C:4]=3[C:5]3=[N:22][O:21][C:20]([CH3:23])=[C:6]3[C:7]2=[O:19])[CH2:14]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCNC1)c1cccc(Cl)c21
Reactant: O=C=NCc1ccccc1
Agent: I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1onc2c1c(=O)n(C1CCCN(C(=O)NCc3ccccc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a suspension of 9-chloro-3-methyl-5-piperidin-3-yl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide (50 mg, 0.11 mmol) in tetrahydrofuran (3 mL) add benzyl isocyanate (16 μL, 0.12 mmol) and follow by potassium carbonate (23 mg, 0.17). Stir the mixture at room temperature under nitrogen overnight. concentrate the mixture, partition between 20% isopropanol/chloroform and water, and separate. Wash the organic layer with saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–0.5% methanol/chloroform) to give 44.4 mg of the title compound as an orange solid, 88% yield. 1H NMR: consistent with structure. MS (ion spray) 451 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15]O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@@H:12]([CH2:15][N:40]2[C:39](=[O:41])[C:38]3[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=3[C:36]2=[O:46])[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C

Procedure:
cis-(tert-Butoxy)-N-[4-(hydroxymethyl)cyclohexyl]carboxamide (0.5 g, 2.18 mmol) and resin-bound triphenyl phosphine (1.453 g, 4.36 mmol, 3 mmol/g resin) were suspended in 15 mL of dry THF. Phthalimide was added in 5 mL of THF followed by diisopropyl azodicarboxylate (DIAD) (0.858 mL, 4.36 mmol). The reaction was stirred at room temperature and monitored by LC-MS. After overnight stirring at room temperature, the resin was removed by filtration and washed multiple times with 5 mL portions of THF. The filtrate combined with washings was concentrated under reduced pressure. The product was purified using column chromatography on silica gel using 10% ethyl acetate in hexanes as eluent. The product was isolated as a white solid (0.486 g, 1.35 mmol, 62% yield) ES-MS (m/z) 359.