Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C@@H:21]3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:19])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:39][CH2:40][CH3:41].C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][C@@H:21]3[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:19])[CH2:14][CH2:13]2)(=[O:9])=[O:10])=[CH:4][C:3]=1[NH:39][CH2:40][CH3:41]
Reactant: CCNc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N3CCN(C(=O)OC(C)(C)C)C[C@@H]3c3ccccc3)CC2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCNc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N3CCNC[C@@H]3c3ccccc3)CC2)ccc1Cl

Procedure:
(S)-tert-Butyl 4-(trans-4-(4-chloro-3-(ethylamino)phenylsulfonamido)cyclo-hexanecarbonyl)-3-phenylpiperazine-1-carboxylate (Example 1, 77 mg, 0.127 mmol) was stirred in 20% v/v TFA/DCM overnight. The reaction was dilutee with DCM and water and the pH was adjusted to 13 with 1N NaOH. The layers were separated, and the organic layer was concentrated and chromatographed on reverse phase Phenomenex Gemini Axia C18 30×100 mm column using a gradient of 15-100% AcCN in water containing 5 mM ammonium hydroxide. The product was lyophilized to yield the title compound (31.5 mg, 0.62 mmol). MS MH+ 505.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:26])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH3:22])=[CH:16][C:15]=3[N+:23]([O-])=O)=[C:11]([C:27]([OH:29])=[O:28])[N:10]=[N:9]2)=[CH:5][CH:4]=1.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:23][C:15]1[CH:16]=[C:17]([CH3:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:13]([C:12]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=2)[N:9]=[N:10][C:11]=1[C:27]([OH:29])=[O:28])=[O:26]
Reactant: COc1ccc(Cn2nnc(C(=O)O)c2C(=O)c2cc(OC)c(C)cc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nnc(C(=O)O)c2C(=O)c2cc(OC)c(C)cc2N)cc1
Yield: 92 %

Procedure:
Next, 1-(4-methoxybenzyl)-5-(5-methoxy-4-methyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylic acid (c-2': MP) (252 mg, 0.591 mmole) was dissolved in a mixed solvent of ethanol (10 ml) and ethyl acetate (10 ml), and reduced in the presence of 10% palladium on carbon (31 mg) under the hydrogen atmosphere at room temperature overnight to give 5-(2-amino-5-methoxy-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylic acid (c-2: MP) (216 mg, 92%).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:22])[CH3:25]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(R)-Pyrrolidine-2-carboxylic acid tert-butyl ester (16.11 g, 94.1 mmol) in DCM (250 ml) under an inert atmosphere of argon is treated with triethyl amine (26 ml, 188 mmol) and then cooled to 0° C. with a ice bath. To this cooled solution is added dropwise ethyl chloroformate (8.99 ml, 94.1 mmol) and the reaction mixture is left to stir at 0° C. for 3 hours. The reaction mixture is washed with 1M HCl (2×100 ml), water, brine, dried over MgSO4 and concentrated in vacuo to yield the titled compound as a clear oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH:25]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26]1.O>C(Cl)Cl>[CH:25]1([C:29]([NH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:30])[CH2:28][CH2:27][CH2:26]1
Reactant: Nc1ccccc1N1CCc2ccccc21
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccccc1N1CCc2ccccc21)C1CCC1
Temperature: 25 °C

Procedure:
A slurry of 1-(2-aminophenyl)indoline hydrochloride (41.44 g) in CH2Cl2 (400 ml) under N2 at 0° C. is treated dropwise with a solution of triethylamine (2.2 equivalents) in CH2Cl2 (80 ml) and then with a solution of cyclobutylcarbonyl chloride (20 g) in CH2Cl2 (50 ml). After warming to room temperature, the product is poured into water (300 ml). The organic layer is washed with 4 N HCl, 2.5 N NaOH, water, dried (Na2SO4), filtered, and concentrated to yield 1-[2-(cyclobutylcarbonyl)aminophenyl]indoline, m.p. 81°-83.5° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([OH:6])=O.OS(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:4](=[O:6])[CH2:3]1
Reactant: Cc1cccc(CC(C)CC(=O)O)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)CC(C)CC2=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Methyl-4-m-tolylbutanoic acid (20.6 g, 107 mmol, dissolved in 125 mL DCM) was added slowly to triflic acid (250 g, 1.7 mol) that was pre-cooled to 0° C. under an Ar atmosphere. After 30 minutes, the volume of the reaction is doubled with DCM and poured slowly onto 1.5 L crushed ice. The resulting icy slurry is allowed to stir and come to room temperature over 1 hour. The resulting aqueous layer was extracted with DCM and the combined organics dried over anhydrous MgSO4 and concentrated in vacuo. The procedure was repeated once and the two lots of crude product were combined and purified via elution on Isco silica gel column chromatography (0-15% EtOAc/hex) to afford 3,6-dimethyl-3,4-dihydronaphthalen-1(2H)-one. LCMS-ESI+ (m/z): [M+H]+ calcd for C12H15O: 175.3. found: 175.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]([N:11]2[CH2:16][CH2:15][N:14](C([O-])=O)[CH2:13][CH2:12]2)=O)[CH:5]=[CH:6][CH:7]=1.B.Cl.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:9][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])N1CCN(C(=O)C(c2cccc(Cl)c2)C2(O)CCCCC2)CC1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: OC1(C(CN2CCNCC2)c2cccc(Cl)c2)CCCCC1
Temperature: 70 °C
Yield: 98.3 %

Procedure:
A solution of 4-[(3-chlorophenyl)(1-hydroxycyclohexyl)acetyl]piperazine-1-carboxylate (200 mg, 0.46 mmol) in dry tetrahydrofuran (3 mL) under nitrogen was treated dropwise with a solution of borane (1.0 M in tetrahydrofuran, 1.60 mL, 1.60 mmol). The resulting solution was heated at 70° C. for 2 h, after which time the reaction was cooled in an ice bath and was treated dropwise with a 2N aqueous solution of hydrochloric acid (1 mL). The reaction was again heated at 70° C. for 1 h, and was then cooled and treated with methanol (1 mL). After the solvent was removed in vacuo, the resulting residue was dissolved in water (5 mL) and was washed with ethyl acetate (1×4 mL). The aqueous layer was basified with the addition of a 2 N aqueous solution of sodium hydroxide until the pH=10. The product was extracted with ethyl acetate (4×5 mL) and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield 146 mg (99%) 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol as a colorless oil. HRMS: calcd for C18H27ClN2O, 322.1812; found (ESI_FT), 323.18977. 1-[1-(3-Chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol (146 mg) was dissolved in methanol (0.5 mL) and treated with a saturated methanolic solution of hydrochloric acid (0.5 mL) followed by diethyl ether. After crystallizing in the refrigerator for 16 h, the resulting solid was collected, washed with diethyl ether and dried in vacuo to yield 110 mg (60%) 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride as a white solid. MS (ESI) m/z 323/325 ([M+H]+); HRMS: calcd for C18H27ClN2O.2.00 HCl, 394.1345; found (ESI_FT), 323.18831.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=[O:4].[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([O:5][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of N-Boc-Gly (3.0 g) in methylene chloride (100 ml) was added benzyl alcohol (1.6 ml), EDC (4.4 g) and a catalytic amount of DMAP. After 2 hours, the mixture was poured into 1N HCl and extracted with methylene chloride, dried over sodium sulfate, filtered and concentrated to give N-Boc-Gly-OBn (4.5 g). To a solution of N-Boc-Gly-OBn (1.32 g) in THF (10 ml) was added potassium bis(trimethylsilyl)amide (1.19 g) in THF (20 ml) at -78° C. After 30 minutes at -78° C. allyl bromide (0.52 ml) was added to the reaction mixture slowly. The resulting mixture was slowly warmed up to room temperature and stirred for an additional 12 hours. The mixture was poured into 1N HCl and extracted with ether, the combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatotron (hexanes/ethyl acetate=10/1) to give desired product (585 mg). ##STR91##
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][N:7]1[CH2:11][C@H:10]2[C@H:12]([NH:15][C:16](=[O:23])[C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18])[CH2:13][CH2:14][C@H:9]2[CH2:8]1.[N:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[C:30]=[O:31]>ClCCl>[C:32]([NH:29][C:30]([NH:18][C@H:17]([C:16]([NH:15][C@H:12]1[C@H:10]2[C@H:9]([CH2:8][N:7]([CH2:6][C:5]3[CH:24]=[CH:25][CH:26]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:4]=3)[CH2:11]2)[CH2:14][CH2:13]1)=[O:23])[CH2:19][CH:20]([CH3:21])[CH3:22])=[O:31])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)N=C=O
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)NC(C)(C)C)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N1-{(3aS,4R,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide (113 mg, 0.284 mmol) from Example 170 Step B in dichloromethane (0.5 mL) was added 2-isocyanato-2-methylpropane (35.1 μL, 0.313 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction was reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-12). The title compound was eluted with a gradient of 0% to 10% methanol (2 N ammonia)/dichloromethane over 20 minutes: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.74 (d, J=8.3, 1H), 7.73 (s, 1H), 7.57 (d, J=9.5, 2H), 7.44 (t, J=7.7, 1H), 6.56 (d, J=8.6, 1H), 6.33 (s, 1H), 4.88 (td, J=5.6, 8.9, 1H), 4.41-4.33 (m, 1H), 3.56 (d, J=13.5, 1H), 3.41 (d, J=13.6, 1H), 2.71 (dd, J=1.7, 9.2, 1H), 2.55-2.45 (m, 2H), 2.35 (dd, J=6.9, 8.9, 1H), 2.29-2.20 (m, 2H), 2.11 (dq, J=6.1, 12.1, 1H), 1.92-1.77 (m, 3H), 1.73-1.64 (m, 2H), 1.44 (s, 9H), 1.43-1.35 (m, 1H), 0.85 (d, J=3.3, 3H), 0.84 (d, J=3.2, 3H); MS (ESI+) m/z 497 (M+H)+.
Reaction SMILES: C[NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[N:48][C:47]([C:50]([O:52]C)=O)=[N:46]2)=[CH:31][CH:30]=1.N>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[N:48][C:47]([C:50]([NH2:2])=[O:52])=[N:46]2)=[CH:31][CH:30]=1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: COC(=O)c1ncn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1
Agent: N
Product: NC(=O)c1ncn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate and ammonia. 1H-NMR (D6-DMSO, 400 MHZ, d) 8.60 (d, J=6.9 Hz, 1H), 8.41 (s, 1H), 8.17 (s, 1H), 8.03 (s, 1H), 7.83 (d, J=8.5 Hz, 2H), 7.65 (d, J=9.1 Hz, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.35 (t, J=7.9 Hz, 1H), 7.00 (t, J=6.8 Hz, 1H), 6.32 (s, 2H) ppm; m/e 353, 355.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:9])[CH3:8])=[N:3]1.[C:10](Cl)(Cl)=[O:11].Cl.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][NH:34][CH2:35]4)=[CH:30][CH:29]=3)[N:25]=[C:24]([NH2:38])[N:23]=2)[CH2:18][CH2:17]1>>[NH2:38][C:24]1[N:25]=[C:26]([C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][N:34]([C:10]([NH:9][CH:7]([C:4]4[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=4)[CH3:8])=[O:11])[CH2:35]3)=[CH:30][CH:29]=2)[CH:27]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)[N:23]=1
Reactant: CC(N)c1ccn(C)n1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Cl)Cl
Agent: Cl
Product: CC(NC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1)c1ccn(C)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from 1-(1-methyl-1H-pyrazol-3-yl)ethanamine (Ryan Scientific, Cat. #B019558), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=476.1.
Reaction SMILES: [N+](=C[Si](C)(C)C)=[N-].[CH2:8]([Li])CCC.[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[CH:16]=O.Cl[C:24]([O:26][CH3:27])=[O:25]>O1CCCC1>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[C:16]#[C:8][C:24]([O:26][CH3:27])=[O:25]
Reactant: [Li]CCCC
Reactant: COC(=O)Cl
Reactant: O=Cc1c(F)cccc1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)C#Cc1c(F)cccc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
To a mixture of (diazomethyl)trimethylsilane (2.0 M in hexanes, 25 mL, 50 mmol) in tetrahydrofuran (100 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 20 mL, 50 mmol) over 5 minutes. After the addition was complete, the reaction mixture temperature was maintained at about −78° C. for 30 minutes and then 2,6-difluorobenzaldehyde (7.1 g, 50 mmol) was added portionwise. The reaction mixture was maintained at −78° C. for an additional 30 minutes and then allowed to warm to room temperature, during which time gas evolution occurred. The reaction mixture was again cooled to −78° C. and n-butyllithium (2.5 M in hexanes, 28 mL, 70 mmol) was added over 5 minutes. After 15 minutes at −78° C., methyl chloroformate (7.8 mL, 100 mmol) was added to the reaction mixture. After 30 minutes, the reaction mixture was allowed to warm to 0° C., and then partitioned between diethyl ether and saturated ammonium chloride solution. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (0 to 100% gradient of ethyl acetate in hexanes as eluant) to provide the title compound (8.0 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6](Br)[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1.Cl.[F:22][C:23]([F:28])([F:27])[C@@H:24]([NH2:26])[CH3:25].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[Br:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([NH:26][C@@H:24]([CH3:25])[C:23]([F:28])([F:27])[F:22])[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1
Reactant: Fc1cc(F)c(-c2c(Br)nc3ncnn3c2Br)c(F)c1
Reactant: C[C@H](N)C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Br)nc2ncnn12)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.5 %

Procedure:
A mixture of 5,7-dibromo-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine (320 mg, 0.78 mmol), (1S)-2,2,2-trifluoro-1-methylethylamine hydrogen chloride (235 mg, 1.57 mmol), and diisopropylethylamine (260 mg, 2.0 mmol) in 5 mL of N,N-dimethylformamide is stirred at room temperature for 18 h. Water is added to quench the reaction, and the product is extracted with ethyl acetate. The combined organic extracts are washed with saturated sodium chloride (x3), dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of 9:1 hexanes/ethyl acetate to 2:1 hexanes/ethyl acetate. Concentration provides 5-bromo-6-(2,4,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine as a light tan solid (60 mg, mp 95-97° C.). MS: m/z 440.0, 442.0 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C1C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1>[CH2:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCCCCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCCCCCCCn1ccc2ccccc21
Reaction time: 2 h
Yield: 72.3 %

Procedure:
A mixture of indole (1) (0.03 mole, 3.51 g), potassium hydroxide (0.03 mole, 1.97 g) powdered in a mortar, and 18-crown-6 ether (0.001 mole, 250 mg) in benzene (20 cm3) is heated under reflux with vigorous stirring for two hours. A solution of octylbromide (2a), (0.04 mole, 7.72 g) in benzene (10 cm3) is added and reflux is maintained for an additional four hours. The reaction is monitored by TLC and the reaction mixture is filtered on Celite. Evaporation of the solvent yields an orange liquid which is purified by distillation in vacuo. The colourless liquid distilled at 154-156° C. and 1.5 mmHg pressure is shown by 1H nmr to be pure 1-octylindole (3a) (4.98 g, 0.0217 mole, 72% yield).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19]O)[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[CH2:58]([Cl:60])[Cl:59]>>[NH3:1].[CH2:58]([Cl:60])[Cl:59].[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:13][CH:12]=1)[CH3:16]
Reactant: Oc1ccc(CN2CCCCC2)cc1
Reactant: CCN(CC)CCO
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(CN2CCCCC2)cc1
Product: N
Reaction time: 2 h

Procedure:
A suspension of the product of Example 17 (176 mg), 2-Diethylamino-ethanol (0.12 mL), and polymer supported triphenylphosphine (613 mg; loading: 3 mmol/g) in DCM (5 mL) was treated with di-tert-butylazodicarboxylate (316 mg). After 2 h, the resulting mixture was filtered, and the filtrate was evaporated. Chromatography of the residue (3% 2 M methanolic ammonia/DCM) gave the title compound as a pale yellow oil (37 mg). 1H NMR (400 MHz, CDCl3): 7.20 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 4.03 (t, J=6.5 Hz, 2H), 3.40 (s, 2H), 2.87 (t, J=6.5 Hz, 2H), 2.63 (q, J=7.0 Hz, 4H), 2.35 (br s, 4H), 1.59-1.52 (m, 4H), 1.46-1.37 (m, 2H), 1.07 (t, J=7.1 Hz, 6H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[CH3:9][C:10]1[C:15]([OH:16])=[C:14]([CH:17]=O)[C:13]([CH2:19][OH:20])=[CH:12][N:11]=1.Cl.C(=O)([O-])O.[Na+].O>C(O)C>[OH:16][C:15]1[C:10]([CH3:9])=[N:11][CH:12]=[C:13]([CH2:19][OH:20])[C:14]=1[CH:17]1[NH:2][CH:3]([C:6]([OH:8])=[O:7])[CH2:4][S:5]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: Cc1ncc(CO)c(C=O)c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ncc(CO)c(C2NC(C(=O)O)CS2)c1O
Reaction time: 48 h
Yield: 91.8 %

Procedure:
L-Cysteine hydrochloride (8.00 g, 45.6 mmol), pyridoxal hydrochloride (8.80 g, 43.25 mmol), and sodium hydrogen carbonate (7.60 g, 90.5 mmol) were added to a mixed solvent of water (60 ml) and ethanol (120 ml), and the mixture was at stored −20° C. for 2 days. The precipitated solid was collected by filtration, and dried under reduced pressure to give 2-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]thiazolidine-4-carboxylic acid as a pale-yellow solid (10.73 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17]C(OC(C)(C)C)=O)[CH:12]=2)[O:8][N:7]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:17][C:13]1[CH:12]=[C:11]([C:9]2[O:8][N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:10]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cc(-c2cccc(NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2cccc(N)c2)on1
Yield: 200.3 %

Procedure:
5-(3-tert-butoxycarbonylamino-phenyl)-isoxazole-3-carboxylic acid ethyl ester (2.63 g, 0.00791 mole) in methylene chloride. (5 mL) was treated with trifluoroacetic acid (2.5 mL) at ambient temperature for 4 hours. The mixture was concentrated in vacuo to provide the titled compound (3.68 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=O)[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=3)[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12)[CH3:2].CCOCC>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:19]=3)[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1
Reaction time: 18 h
Yield: 32.2 %

Procedure:
Ethyl [4-(4,9-diethoxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate (33 g, 73 mmol) and zinc (90 g, 1.38 mol) were refluxed in acetic acid for 66 h. An additional quantity of zinc (25 g, 0.38 mol) was added and reflux continued for 18 h. The mixture was filtered hot and the filtrate was evaporated to a yellow solid. The solid was purified by 800 g Biotage column eluting with 20% ethyl acetate/hexane to give a white solid, which was triturated in ether to give a white solid. A further fraction was obtained by crystallisation from the ether residues. A total of 10.2 g, 32% of the title compound was obtained.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[C:11]=1[C:12]#[N:13].[CH:19](OC)=[O:20].O>C1COCC1>[F:9][C:10]1[C:17]([CH:19]=[O:20])=[CH:16][CH:15]=[C:14]([I:18])[C:11]=1[C:12]#[N:13]
Reactant: COC=O
Reactant: N#Cc1c(F)cccc1I
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(I)ccc(C=O)c1F
Reaction time: 1 h
Yield: 71.9 %

Procedure:
LDA (24.3 mL, 2.0 M solution in THF) was added dropwise to a stirred solution of 2-fluoro-6-iodobenzonitrile (10.0 g, 40.5 mmol) in THF (200 mL) at −78° C., and the mixture was stirred for 1 h. Methyl formate (5.0 mL, 81.0 mmol) was added via syringe and the resulting mixture was stirred at −78° C. for 30 min then at rt for 1 h. H2O was added and the mixture was extracted with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20-25% EtOAc/hexanes to give the desired product (8.01 g). MS (ESI(+)) m/e 274.9 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[N:23]1([C:29]([CH:31]2[CH2:35][CH2:34][CH2:33][O:32]2)=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:26]5[CH2:27][CH2:28][N:23]([C:29]([C@H:31]6[CH2:35][CH2:34][CH2:33][O:32]6)=[O:30])[CH2:24][CH2:25]5)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: O=C(C1CCCO1)N1CCNCC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN(C(=O)[C@H]2CCCO2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with piperazin-1-yl(tetrahydrofuran-2-yl)methanone (1.2 equiv) to give 184 (19.3 mg, M+1 480.1)