Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[CH2:15]([NH2:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23].[OH-:25].[K+]>C(Cl)CCl>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:24][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([O:25][C:2]([F:1])([F:13])[F:14])=[CH:5][CH:6]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: NCCCCCCCCN
Reactant: [OH-]
Agent: [K+]
Solvent: ClCCCl
Product: O=C(NCCCCCCCCNC(=O)c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1

Procedure:
m.p. 164°-165° C., 12.0 g., was prepared as in Example 16 using 4-trifluoromethoxybenzoyl chloride (from 16.5 g. of 4-trifuoromethoxybenzoic acid as in Example 16) in 150 ml. of ethylene dichloride, 7.2 g. of 1,8-octanediamine, 200 ml. of 10% aqueous potassium hydroxide solution, 500 ml. of ethylene dichloride and recrystallization from methanol using decolorizing charcoal.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([NH:13][NH2:14])=[O:12])=[CH:9][N:8]=1.CN1CCOCC1>ClCCl>[Cl:1][CH2:2][C:3]([NH:14][NH:13][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][C:7]([Cl:6])=[N:8][CH:9]=1)=[O:4]
Reactant: NNC(=O)c1ccc(Cl)nc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(CCl)NNC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
Chloroacetyl chloride (2.8 mL, 34.9 mmol) was added dropwise to an ice-cooled solution of 6-chloronicotinic acid hydrazide (5 g, 29.1 mmol) and 4-methylmorpholine (4.8 mL, 43.7 mmol) in dichloromethane (100 mL) and the reaction was stirred at room temperature for 3 hours. The resulting precipitate was then filtered off, slurried with dichloromethane, re-filtered, washed with dichloromethane (×3) and dried to afford the title compound as a beige solid in 57% yield, 4.1 g
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][C@@H:25]([CH3:29])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[C@@H:25]([CH3:29])[CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 4-boc-2-(S)-methyl-piperazine following procedure B. LC-MS showed the product had the expected M+H+ of 403. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (d, 1H) 8.0 (m, 2H) 7.6 (d, 1H) 7.5 (m, 2H) 4.8 (d, 1H) 4.1 (m, 1H) 3.6 (m, 2H) 3.3 (m, 1H) 3.0 (m, 2H) 2.5 (m, 2H) 1.4 (s, 9H) 1.1 (m, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:6]=1[C:7]([O:9]CC)=[O:8])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO>[CH3:2][CH2:1][CH2:5][CH:6]([CH3:12])[CH3:7].[CH2:1]([C:5]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:6]=1[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)ccc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C)C
Product: CCCCc1nc(Cl)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 172.3 %

Procedure:
Ethyl 2-butyl-6-chloronicotinate (395 mg, 1.63 mmol) was stirred in methanol (10 ml) and 2M sodium hydroxide (2 ml, 4 mmol) was added. The solution was stirred at room temperature for 16 hours. The solvent was evaporated and the residue taken up in ice/water (10 ml) and acidified with 2M HCl. The milky solution was extracted with dichloromethane (2×15 ml) and the combined extracts were dried over MgSO4, filtered and evaporated, trituration with isohexane gave 2-butyl-6-chloronicotinic acid (300 mg, 86%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)([Cl:16])=[O:15].[CH2:18]([N:20](CC)CC)[CH3:19]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:20][CH2:18][C:19]([O:8][CH2:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:10][CH:9]=1)=[O:15]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Reactant: CCN(CC)CC
Product: NCC(=O)OCc1ccccc1
Product: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
As shown in scheme D, reaction of 4-chloro-3-nitrobenzoic acid with thionyl chloride gave 4-chloro-3-nitrobenzoyl chloride, which on further treatment with benzyl glycinate in presence of triethylamine gave benzyl 2-(4-chloro-3-nitrobenzamido)acetate (intermediate 5). The intermediate 5 is treated either with K18F or K19F in the presence of kryptofix[2.2.2] or 18-crown-6 to yield benzyl 2-(4-fluoro-3-nitrobenzamido)acetate, which on further reduction with hydrogen gas or hydrogen source in the presence of Pd/C gave compound 3.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:3]=1.CCCCCCC>CCO.C(Cl)Cl.[Pd]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:1])=[N:3][N:4]2[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[CH:9][CH:8]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCO
Product: Cc1nn(C(=O)OC(C)(C)C)c2cc(N)ccc12
Reaction time: 6 h
Yield: 69.2 %

Procedure:
tert-Butyl 3-methyl-6-nitro-1H-indazole-1-carboxylate (7.40 g, 26.7 mmol) was dissolved in EtOH (534 mL). To the solution was added Pd/C (10 wt %, 1.42 g, 1.33 mmol). The mixture was flushed with H2, and placed under an atmosphere of H2 at atmospheric pressure at rt for about 6 h. The mixture was filtered through Celite® and washed through with MeOH. The solvents were removed under reduced pressure. The residue was purified by column chromatography (120 g silica gel) eluting with 20-80% EtOAc/heptane to give a solid. The solid redissolved in DCM (20 mL) and heptane (50 mL) was added. The mixture was concentrated to remove the DCM. The resulting precipitate was collected by vacuum filtration and washed with heptane (20 mL) to provide tert-butyl 6-amino-3-methyl-1H-indazole-1-carboxylate (4.57 g, 69%): LCMS (Table 2, Method c) Rt=1.81 min.; MS m/z: 248 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ 7.36 (d, J=8.5 Hz, 1H), 7.14 (d, J=1.7 Hz, 1H), 6.59 (dd, J=8.5, 1.9 Hz, 1H), 5.71 (d, J=19.5 Hz, 2H), 2.33 (s, 3H), 1.58 (s, 9H).
Reaction SMILES: [NH:1]([C:8]1[C:13]([CH2:14][O:15][CH2:16][CH3:17])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1[CH:38]=[C:37](C)[O:36][N:35]=1.Cl>CN1C(=O)CCC1>[NH:1]([C:8]1[C:13]([CH2:14][O:15][C:16]2[CH:17]=[C:37]([CH3:38])[O:36][N:35]=2)=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:23][CH:24]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(O)no1
Reactant: CCOCc1cnc(Nc2ccc(OCC(O)CN(C)C)cc2)nc1Nc1ccccc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1cc(OCc2cnc(Nc3ccc(OCC(O)CN(C)C)cc3)nc2Nc2ccccc2)no1
Temperature: 100 °C
Yield: 43.4 %

Procedure:
4-Anilino-5-(ethoxymethyl)-2-{4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]anilino}pyrimidine (Example 86, 100 mg, 0.23 mmol) was dissolved in NMP (2 ml). 3-Hydroxy-5-methylisoxazole (45 mg, 0.46 mmol) and ethereal hydrogen chloride (1.0M; 0.46 ml, 0.46 mmol) were added, and the solution was heated at 100° C. for 20 hours. Volatile material was removed by evaporation, and the residue was dissolved in 10% methanol solution in DCM (3 ml) and loaded on a Varian Mega Bond Elut column. The column was eluted with 0-2.5% methanol solution in DCM containing 0.5% aqueous ammonia solution. Concentration of the appropriate fractions and trituration of the residue with diethyl ether gave the product as a white crystalline solid (49 mg, 44%). NMR: 2.17 (s, 6H), 2.22 (s, 3H), 2.2-2.45 (m, 2H), 3.75-3.9 (m, 3H), 4.73 (br s, 1H), 4.49 (s, 2H), 5.78 (s, 1H), 6.80 (d, 2H), 7.02 (t, 1H), 7.30 (dd, 2H), 7.50 (d, 2H), 7.70 (d, 2H) 8.04 (s, 1H), 8.76 (s, 1H), 9.05 (s, 1H); MS (MH+): 491.5.
Reaction SMILES: [CH:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].Cl[CH:18](Cl)[C:19]([OH:21])=[O:20].[C:23](=O)([O-])[O-].[K+].[K+].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(O)(C)C.C(Cl)Cl.CO>[CH3:23][O:21][C:19]([CH:18]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]([CH3:2])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16]1)=[O:20]
Reactant: O=C(O)C(Cl)Cl
Reactant: O=C([O-])[O-]
Reactant: CC(c1ccccc1O)c1ccccc1O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Solvent: ClCCl
Product: COC(=O)C1Oc2ccccc2C(C)c2ccccc2O1
Reaction time: 70 h
Yield: 86.6 %

Procedure:
A mixture of 2,2'ethylidenebisphenol (10.0 grams, 0.0467 mol), dichloroacetic acid (3.85 ml, 0.0467 mol) and potassium carbonate (25.8 grams, 0.187 mol) in 200 ml of isopropyl alcohol is heated at reflux for 24 hours with vigorous stirring, after which an additional 3.85 ml of dichloroacetic acid is added and the mixture refluxed with stirring for 70 hours. The isopropyl alcohol is removed by distillation at atmospheric pressure and replaced gradually with H2O. The reaction mixture is cooled, acidified by addition of concentrated HC1 and extracted into chloroform. The chloroform extract is washed with brine, treated with charcoal, dried over MgSO4 and concentrated to afford a quantitative yield of crude acid. This material is then converted to the methyl ester by refluxing in a methanol solution (100 ml) in the presence of conc. H2SO4 (0.6 ml) for 2 hours. The solution is cooled, 50 ml of CH2Cl2 is added and the mixture neutralized by the addition of solid Na2CO3. The inorganic salts are removed by filtration and the filtrate concentrated and taken up into CH2Cl2, washed with brine, dried over MgSO4 and concentrated to afford 11.5 grams of a dark semi-solid. Dry column chromatography (elution with 1:4 EtOAc-hexane) yields 5.0 grams (38 percent) of product as a white solid consisting of a 1:1 mixture of cis and trans isomers: mp 95°-120° C.; IR (thin film) 5.62, 6.7, 6.9, 8.2, 9.25, 10.05, 13.05 cm-1 ; 1H NMR (60 MHz, CDCl3) δ 1.66 and 1.89 (2d, 2, CH3), 3.88 and 3.95 (2s, 3, OCH3), 3.95 and 5.1 (2q, 2, CH), 5.0 and 5.36 (2s, 1, CH), 7.0-7.5 (m, 8, Ar--H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.CC[O:26]CC>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:26]
Reactant: CCOCC
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1cc(C(F)(F)F)ccc1Br
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-5-trifluoromethyl benzonitrile (20.16 mmoles) in methylene chloride (50 ml), under argon at room temperature, was added diisobutylaluminum hydride (25 mmoles, 25 ml hexane) dropwise and the resulting solution was stirred for 30 minutes. The reaction mixture was diluted with ether (50 ml), cooled in ice and quenched by the careful addition of hydrochloric acid (50 ml, 3 N). The ice bath was removed and the mixture was stirred vigorously for 15 minutes. The organic layer was washed with brine (50 ml), treated with magnesium sulfate-charcoal and evaporated. The resulting oil was purified by distillation to give 2-bromo-5-trifluoromethyl benzaldehyde, bp 50°-55° C. at 0.05 mm Hg. A mixture of this compound (16.24 mmoles), 1-phenylocta-1,7-diyne (19.54 mmoles, prepared as in Example 7b), cuprous iodide (0.19 mmoles) and bis(triphenylphosphine) palladium chloride (0.34 mmoles) in triethylamine (50 ml) was refluxed under argon for 30 minutes. The reaction mixture was cooled and filtered. The filtrate was evaporated, taken up in ether (100 ml), washed with hydrochloric acid (50 ml, 3 N) and sodium chloride, and treated with magnesium sulfate-charcoal. Filtration and evaporation left an oil which was purified by flash chromatography (5% ether/hexane) to yield 2-(8-phenyloctadiyn-1,7-yl)-5-trifluoromethyl benzaldehyde as an oil. A solution of this compound (13.26 mmoles) in ethyl acetate (100 ml) was treated with charcoal for 30 minutes and then filtered. The solution was then shaken under 50 psi of hydrogen with 10% palladium on charcoal (502 mg) for about 90 minutes. Thin layer chromatography of the reaction mixture indicated about 50% reduction of the aldehyde to the alcohol. To re-oxidize the alcohol, the palladium catalyst was filtered off and manganese dioxide (20 g) was added. This mixture was then stirred at room temperature under argon for 18 hours. Filtration and evaporation gave an oil which was purified by flash chromatography (2% ether/hexane) to afford 2-(8-phenyloctyl)-5-trifluoromethyl benzaldehyde as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([P:19]([CH2:24][CH2:25][CH3:26])([CH2:21][CH2:22][CH3:23])=[O:20])[CH:14]=2)[N:3]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([C@H:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][CH2:40]2)=[C:32]2[C:36]=1[C:35](=[O:37])[N:34]([CH3:38])[CH2:33]2>>[CH2:21]([P:19]([C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C@H:39]4[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][CH2:40]4)=[C:32]4[C:36]=3[C:35](=[O:37])[N:34]([CH3:38])[CH2:33]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)[CH:18]=[CH:17][CH:16]=1)([CH2:24][CH2:25][CH3:26])=[O:20])[CH2:22][CH3:23]
Reactant: CCCP(=O)(CCC)c1cccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c1
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Product: CCCP(=O)(CCC)c1cccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)c1

Procedure:
The title product was prepared according to the procedure for Example 102 using 4-chloro-N-[3-(dipropylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (Compound 168B) and 7-amino-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one. 1H NMR (400 MHz, DMSO-d6) δ 0.93 (t, J=7.33 Hz, 6H), 1.24-1.40 (m, 4H), 1.42-1.58 (m, 4H), 1.79 (d, J=12.88 Hz, 2H), 1.82-1.89 (m, 2H), 1.89-1.98 (m, 4H), 3.08 (s, 3H), 3.42-3.54 (m, 1H), 4.54 (s, 2H), 4.64 (br. s., 1H), 7.26 (br. s., 1H), 7.63-7.72 (m, 2H), 7.79 (d, J=6.57 Hz, 2H), 8.52 (s, 1H), 8.62 (br. s., 1H), 10.14 (s, 1H), 10.59 (br. s., 1H). MS (ES+): m/z=630.27 [MH+]. HPLC: tR=3.17 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([NH:23]C(C)(C)C)(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:28])=[N:6][CH:7]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:28])=[N:6][CH:7]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnc(-c2ccc(-c3ccccc3S(N)(=O)=O)cc2F)cn1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A solution of 4′-(5-aminopyrazin-2-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide (130.0 g, 298.0 mmol), anisole (97.4 mL, 894.0 mmol), and TFA (228.0 mL, 2.98 mol) was stirred at 60° Celsius for 16 hours. The reaction was cooled to rt, concentrated to dryness, and partitioned between 600 mL H2O and 600 mL acetone. 750 mL sat. NaHCO3 (aq), was added over 30 min. The resulting precipitate was isolated via filtration and rinsed with 300 mL H2O then 300 mL acetone. The precipitate was triturated with 1.5 L acetone at 50° Celsius for 16 hours. After cooling to room temperature the solid was collected by filtration and rinsed twice with 250 mL acetone then dried in a vacuum oven at 50° Celsius for 16 hours yielding the title compound (74.3 g, 72.4%). MS (ESI): mass calcd. for C16H13FN4O2S, 344.07; m/z found, 345.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.44-8.36 (s, 1H), 8.10-8.02 (m, 2H), 7.92-7.85 (m, 1H), 7.69-7.59 (m, 2H), 7.43-7.35 (m, 3H), 7.35-7.27 (m, 2H), 6.77-6.69 (s, 2H). Elemental analysis: calcd. for C16H13FN4O2S, C, 55.80; H, 3.81; N, 16.27; measured: C, 55.43; H, 3.54; N, 16.22.
Reaction SMILES: O[CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.Cl.[NH2:9][CH2:10][CH2:11][SH:12].[BrH:13]>>[BrH:13].[BrH:13].[NH2:9][CH2:10][CH2:11][S:12][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1
Reactant: OCc1cncs1
Reactant: NCCS
Agent: Br
Agent: Cl
Product: NCCSCc1cncs1

Procedure:
The reaction of 5-hydroxymethylthiazole (2.01 g.) with cysteamine hydrochloride (1.99 g.) in aqueous hydrobromic acid by the method described in Example 1(i)(a) gave 5-((2-aminoethyl)thiomethyl)thiazole dihydrobromide (4.85 g.) m.p. 191°-4° (from methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40])[CH2:34]Br>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH2:13][N:12]([CH2:34][C:33]3[CH:36]=[C:37]([O:41][CH3:42])[C:38]([O:39][CH3:40])=[C:31]([O:30][CH3:29])[CH:32]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(C2(CCOC3CCCCO3)CCNC2)cc1Cl
Reactant: COc1cc(CBr)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CN2CCC(CCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 16 h

Procedure:
Combine 4-(3,4-dichloro-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy) -ethyl]-pyrrolidine (10 mmol), K2CO3 (30 mmol), and 3,4,5-trimethoxy-benzyl bromide (10 mmol) in THF/H2O (4/1, 200 mL). Heat to reflux and stir for 16 h. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with H2O. Separate the layers, dry the organic layer over MgSO4, filter, and concentrate in vacuo. Chromatograph on silica gel to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:21][CH2:20][CH:19]3[CH:14]([CH:15]([C:22]([O:24]CC)=[O:23])[CH2:16][CH2:17][CH2:18]3)[CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[OH-].[K+].Cl>O1CCCC1.O.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:21][CH2:20][CH:19]3[CH:14]([CH:15]([C:22]([OH:24])=[O:23])[CH2:16][CH2:17][CH2:18]3)[CH2:13]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCCC2CCN(C(=O)CCc3ccc(F)cc3)CC21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCCC2CCN(C(=O)CCc3ccc(F)cc3)CC21
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
A solution of ethyl (4aSR,8SR,8aSR)-2-[3-(4-fluorophenyl)propanoyl]decahydroisoquinoline-8-carboxylate (385 mg, 1.07 mmol) in tetrahydrofuran (5 mL) was added to a solution of potassium hydroxide (168 mg, 3.0 mmol) in water (5 mL). The resulting solution was stirred at room temperature for 16 hours. Additional potassium hydroxide (385 mg, 1.07 mmol) dissolved in methanol (5 mL) was added, and stirring was continued for an additional 5 hours. The mixture was treated with concentrated aqueous hydrochloric acid until the pH was about 1. The mixture was concentrated to a volume of about 5 mL and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated to provide a white solid (350 mg, 98%). 1H NMR (300 MHz, CDCl3) δ7.11 (m, 2H), 6.90 (m, 2H), 4.66 (m, 1H), 3.80 (m, 1H), 2.85 (m, 2H), 2.7-2.4 (m, 3H), 2.1-1.9 (m, 2H), 1.80 (m, 1H), 1.7-0.9 (m, 9H). Mass spec (ES+) m/z 334.2 (M+H+, 100%).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:15]1([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH2:25])[CH:19]=[CH:18][N:17]=[CH:16]1.CN1CCOCC1.CN(C=O)C>C(Cl)Cl>[N:15]1([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH:25][C:12](=[O:14])[CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: Nc1ccsc1-n1ccnc1
Reactant: O=C(O)Cc1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Cc1cccc2ccccc12)Nc1ccsc1-n1ccnc1
Reaction time: 8 h
Yield: 33 %

Procedure:
To a mixture of 1-naphthyl acetic acid and 2-(1H-imidazol-1-yl)thiophen-3-amine in anhydrous CH2Cl2 was added O-(7-azabenzotriazol-1-yl)-N,N,N,N,-tetramethyl uronium hexafluorophosphate and 4-methymorpholine. A small amount of DMF was added to help starting material reagents go into solution. The reaction mixture was stirred overnight under N2 (g) inlet and evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (silica, 10:90 methanol/methylene chloride) to afford N-(2-(1H-imidazol-1-yl)thiophen-3-yl)2-(naphthalen-1-yl)acetamide (209 mg, 33%). The desired product was purified by preparative HPLC. Method [8] m/z 334.1 (M+H); retention time=4.885. 1H-NMR (CD3OD) δ 8.83 (s, 1H), 7.89-7.80 (m, 2H), 7.77 (d, J=7.8 Hz, 1H), 7.51 (d, J=6.3 Hz, 2H), 7.48-7.32 (m, 5H), 7.17 (d, J=6.3 Hz, 2H), 4.08 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.Br[C:17]1[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([Cl:23])[CH:22]=1>>[CH3:13][C:7]1([CH3:14])[O:8][CH2:9][C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][C:2]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([F:24])[CH:18]=3)=[CH:15][C:6]1=2
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OCC(=O)Nc2ccc(-c3cc(F)cc(Cl)c3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-bromo-5-chloro-1-fluorobenzene generally according to the coupling procedure described in examples 82 and 1. 1H NMR (DMSO-d6): δ 10.01 (s, 1H), 7.61-7.65 (m, 4H), 7.36-7.39 (m, 1H), 7.18 (d, J=8.54 Hz, 1H), 4.26 (s, 2H), 1.62 (s, 6H); MS (ESI) m/z 320/322 ([M+H]+); MS (ESI) m/z 318/320 ([M−H]−). Anal. calcd for C17H15ClFNO2: C, 63.86; H, 4.73; N, 4.38. Found: C, 62.53; H, 4.55; N, 3.50.
Reaction SMILES: C1(OC)C=CC=CC=1.Cl.[NH2:10][C@@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=1)[C:12]([O:14]C(C)(C)C)=[O:13]>C(O)=O>[NH2:10][C@@H:11]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:24][CH:25]=1)[C:12]([OH:14])=[O:13]
Reactant: CC#CCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: O=CO
Solvent: COc1ccccc1
Product: CC#CCOc1ccc(C[C@H](N)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 129.9 %

Procedure:
Formic acid (5 mL), and anisole (20 μL) were added to tert-butyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate HCl salt (200 mg) and the mixture was stirred at room temperature for 18 hours. Completion of the reaction was confirmed by detecting the target product by LCMS (LCMS m/z 234 (M+1), Rt 0.83 min.). The reaction solution was concentrated under reduced pressure to obtain (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionic acid (186 mg).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][CH:14]([C:18]1([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:15]([OH:17])=O.[CH2:36]([O:43][NH2:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl.CN1CCOCC1>C(Cl)Cl>[CH2:36]([O:43][NH:44][C:15](=[O:17])[CH:14]([CH3:13])[C:18]1([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)CC1(C(C)C(=O)O)CCN(CCc2ccccc2)C1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)CC1(C(C)C(=O)NOCc2ccccc2)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
CDI (39.7 mg, 0.245 mmol) is added to a solution of α-methyl-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (74.0 mg, 0.233 mmol) and CH2Cl2 (2.0 mL). The solution is stirred for 1 hour at room temperature. To this is added O-benzylhydroxylamine.HCl (63.2 mg, 0.396 mmol) and N-methylmorpholine (44 μL, 0.40 mmol). The resultant solution is stirred for 16 hours at room temperature. Aqueous workup (CH2Cl2, MgSO4) and purification by flash chromatography (2:1 EtOAc:hexane) gives 88.1 mg (89%) of the title compound as an oil.