Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:19]C(=O)OC(C)(C)C)[CH2:16][C:17]#[N:18])=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:19][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=1)[CH2:16][C:17]#[N:18]
Reactant: CC(C)(C)OC(=O)NC(CC#N)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#CCC(N)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 120.1 %

Procedure:
HCl (4M) in 1,4-dioxane (0.668 mL, 2.67 mmol) was added in one portion to tert-butyl 1-(4-chlorophenyl)-2-cyanoethylcarbamate (Intermediate 24) (150 mg, 0.53 mmol) in DCM (4 mL) at 20° C. The resulting solution was stirred at 20° C. for 18 hours. The reaction mixture was evaporated to afford 3-amino-3-(4-chlorophenyl)propanenitrile (HCl salt) (115 mg, 99%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([OH:11])(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15].[OH-].[Ca+2:17].[OH-]>>[F:1][C:2]1[C:7]([S:8]([O-:11])(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15].[Ca+2:17].[F:1][C:2]1[C:7]([S:8]([O-:11])(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15]
Reactant: O=S(=O)(O)c1c(F)c(F)c(F)c(F)c1F
Agent: [Ca+2]
Agent: [OH-]
Product: O=S(=O)([O-])c1c(F)c(F)c(F)c(F)c1F

Procedure:
To 1000 g of 5% pentafluorobenzene sulfonic acid aqueous solution stirred at room temperature, 30 g of calcium hydroxide was added. The stirring was continued while measuring the pH value. At the time when the pH value reached 6, approximately, filtration was done by using a 0.4 μm glass filter to remove the insoluble components, so as to obtain a calcium pentafluorobenzenesulfonate aqueous solution.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:23])=[CH:10][C:11]=1[NH:12][C:13]1[N:18]=[C:17]2[N:19]([CH3:22])[CH:20]=[CH:21][C:16]2=[CH:15][CH:14]=1)=O)C.[NH3:24]>CO>[Cl:23][C:9]1[N:8]=[N:7][C:6]([C:4]([NH2:24])=[O:3])=[C:11]([NH:12][C:13]2[N:18]=[C:17]3[N:19]([CH3:22])[CH:20]=[CH:21][C:16]3=[CH:15][CH:14]=2)[CH:10]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1ccc2ccn(C)c2n1
Solvent: CO
Product: Cn1ccc2ccc(Nc3cc(Cl)nnc3C(N)=O)nc21
Reaction time: 2 h
Yield: 100 %

Procedure:
6-Chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-ylamino)-pyridazine-3-carboxylic acid ethyl ester (52 mg, 0.157 mmol) was suspended in 7M ammonia in methanol (2 mL). After 2 h, the reaction mixture was concentrated in vacuo to give 6-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-ylamino)-pyridazine-3-carboxylic acid amide (47 mg, 100%) as a light yellow solid which was used directly in the next step without purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.07 (s, 1H) 9.24 (s, 1H) 8.85 (br. s., 1H) 8.21 (br. s., 1H) 7.99 (d, J=8.3 Hz, 1H) 7.42 (d, J=3.3 Hz, 1H) 6.81 (d, J=8.3 Hz, 1H) 6.45 (d, J=3.3 Hz, 1H) 3.83 (s, 3H); LCMS (EI/CI) m/z: 303 [M+H].
Reaction SMILES: CC([N:5]([C@@H:9]([CH3:13])[CH2:10][CH:11]=[O:12])[C:6](=[O:8])[O-:7])(C)C.[CH3:14][C:15](N([C@@H](C)CC#N)C(=O)[O-])([CH3:17])[CH3:16].[H-].C([Al+]CC(C)C)C(C)C>CCOCC>[CH3:13][C@H:9]([NH:5][C:6](=[O:8])[O:7][C:15]([CH3:17])([CH3:16])[CH3:14])[CH2:10][CH:11]=[O:12]
Reactant: C[C@@H](CC=O)N(C(=O)[O-])C(C)(C)C
Reactant: C[C@@H](CC#N)N(C(=O)[O-])C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: C[C@@H](CC=O)NC(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 30 %

Procedure:
1,1-Dimethylethyl[(1S)-1-methyl-3-oxopropyl]carbamate. To a stirred solution of 1,1-dimethylethyl[(1S)-2-cyano-1-methylethyl]carbamate (0.656 g, 3.56 mmol) in anhydrous ether cooled to −40° C. was added dropwise a 1.0 M solution of diisobutylaluminum hydride in hexanes (14.2 mL, 14.2 mmol) over 20 minutes. Stirring was continued at this temperature for an additional 20 minutes. The yellow solution was quenched with Rochelle's salt and the resultant stirred at room temperature for 1 hour. The solids were filtered off through celite and rinsed with EtOAc. The organics were washed with brine, concentrated, and flash chromatographed (10-100% EtOAc/hexanes) to give 1,1-dimethylethyl [(1S)-1-methyl-3-oxopropyl]carbamate (0.193 g, 30%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 1.22 (d, J=6.8 Hz, 3H), 1.41 (s, 9H), 2.53-2.65 (m, 2H), 4.08-4.13 (m, 1H), 4.63 (m, 1H), 9.74-9.75 (m, 1H). b) 1,1-Dimethylethyl[(1S)-3-(cyclopropylamino)-1-methylpropyl]carbamate. The protected diamine was prepared using a modified procedure as described in example Z-32. A solution of 1,1-dimethylethyl[(1S)-1-methyl-3-oxopropyl]carbamate (0.178 g, 0.95 mmol) and cyclopropylamine (197 μL, 2.85 mmol) in anhydrous dichloroethane (10 mL) was treated with acetic acid (272 μL, 4.8 mmol) and stirred for 30 minutes. Sodium triacetoxyborohydride (0.444 g, 2.1 mmol) was added and the solution was stirred for 20 hours. The resultant was subjected to a workup and purification procedure as described in example Z-32 to give 1,1-dimethylethyl [(1S)-3-(cyclopropylamino)-1-methylpropyl]carbamate (0.136 g, 63%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 0.32-0.42 (m, 4H), 1.12 (d, J=6.8 Hz, 3H), 1.39-1.51 (m, 10H), 1.58-1.92 (m, 2H), 2.05-2.10 (m, 1H), 2.67-2.80 (m, 2H), 3.71 (m, 1H), 4.78 (m, 1H). c) [(3S)-3-Aminobutyl]cyclopropylamine dihydrochloride was prepared in a similar manner as described in example Z-29. 1H NMR (400 MHz, CDCl3/CD3OD) δ 0.70-0.75 (m, 2H), 0.90-0.94 (m, 2H), 1.18 (d, J=6.8 Hz, 3H), 1.84-1.94 (m, 1H), 1.97-2.05 (m, 1H), 2.49-2.54 (m, 1H), 2.99-3.04 (m, 2H), 3.23-3.28 (m, 1H), d)
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][C:21]=1[CH2:30][C:31](O)=[O:32]>>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH:23]=[CH:22][C:21]=1[CH2:30][C:31]([NH:17][CH:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:14][CH2:15][CH3:16])=[O:32])[C:26]([O:28][CH3:29])=[O:27]
Reactant: CCCC(N)c1ccccc1N1CCCCC1
Reactant: COC(=O)c1ccc(CC(=O)O)c(OC)c1
Product: CCCC(NC(=O)Cc1ccc(C(=O)OC)cc1OC)c1ccccc1N1CCCCC1

Procedure:
Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 2-methoxy-4-methoxycarbonyl-phenylacetic acid.
Reaction SMILES: [CH2:1]([C:4]1[CH:36]=[CH:35][CH:34]=[CH:33][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]1[CH2:18][O:17][C:16]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[S:15]1)[CH2:2][CH3:3].[OH-].[Li+]>>[CH2:1]([C:4]1[CH:36]=[CH:35][CH:34]=[CH:33][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]1[CH2:18][O:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[S:15]1)[CH2:2][CH3:3]
Reactant: CCCc1ccccc1OCCCCCSCC1COC(CCC(=O)OCC)(CCC(=O)OCC)S1
Agent: [Li+]
Agent: [OH-]
Product: CCCc1ccccc1OCCCCCSCC1COC(CCC(=O)O)(CCC(=O)O)S1

Procedure:
The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 8 (0.80 g, 0.0015 mol) and aqueous lithium hydroxide solution (2 M, 3.0 ml). The product, 0.78 g (89%), was obtained as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCOCC5)c34)cc2C)cn1
Yield: 9 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and morpholine to give the title compound in 9% yield; NMR Spectrum: 2.19 (s, 3H), 2.44 (s, 3H), 2.50 (hidden by DMSO, 4H), 2.81 (t, 2H), 3.55 (br s, 4H), 4.45 (t, 2H), 6.95 (d, 1H), 7.18-7.25 (m, 2H), 7.60 (d, 1H), 7.65 (s, 1H), 8.16 (s, 1H), 8.30 (s, 1H), 8.32 (s, 1H); Mass Spectrum: 462 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH3:25][OH:26].OS(O)(=O)=O>O>[CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[CH:9][N:10]=[C:11]([CH2:25][OH:26])[CH:12]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1ccncc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CCN(CC)Cc1ccnc(CO)c1
Yield: 29 %

Procedure:
Treatment of 4-(N,N-diethylaminomethyl)pyridine (2.0 g, 12.20 mmol) with ammonium persulfate (5.56 g, 24.4 g, 2.0 equiv.), methanol (22 ml), water (11 ml) and concentrated H2SO4 (2.76 g, 28.18 mmol, 2.31 equiv.) as described for Cpd #214 gave 0.697 g (29%) of 4-(N,N-diethylaminomethyl)-2-hydroxymethylpyridine.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][S:9][C:5]=2[CH:4]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[NH2:2][CH2:1][C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][S:9][C:5]=2[CH:4]=1
Reactant: N#Cc1ccc2ncsc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 94 (1.00 eq.) was added to a 0.4M suspension of lithium aluminum hydride (4.00 eq.) in ether at 0° C. The slurry was stirred overnight at ambient temperature. The mixture was returned to 0° C. and quenched with water. The layers were separated. The aqueous phase was adjusted to pH 10-11 and then extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give compound 95 which was used without further purification. ES/MS m/z 214 (MH+), C8H8ClN3S=213 g/mol.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[S:23][CH:24]=2)[N:14]=1.O>CC(N(C)C)=O>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:21]=[C:22]([C:25]([F:26])([F:27])[F:28])[S:23][CH:24]=3)[N:14]=2)[CH:7]=1
Reactant: Fc1cccc(Oc2csc(C(F)(F)F)c2)n1
Reactant: FC(F)(F)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: FC(F)(F)c1cnn(-c2cccc(Oc3csc(C(F)(F)F)c3)n2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 14.9 %

Procedure:
0.114 g of 4-trifluoromethylpyrazole is introduced in 5 ml of dimethylacetamide under nitrogen and at 0° C. 0.028 g of NaH is added. The mixture is allowed to come to RT over 30 min and then 0.2 g of 2-fluoro-6-(2-trifluormethyl-4-thienyloxy)pyridine is added and the mixture is heated at 80° C. for 9 h, cooled to RT and poured into water. After threefold extraction with ethyl acetate the product is washed with water and saturated sodium chloride solution, dried over MgSO4 and concentrated. Chromatographic purification on silica gel with heptane/ethyl acetate (3:7) as eluent gives 0.043 g of 2-(4-trifluoromethylpyrazol-1-yl)-6-(2-trifluoromethyl-4-thienyloxy)pyridine as colorless crystals.
Reaction SMILES: [CH:1]1([C:7]2[N:12]3[N:13]=[C:14]([CH3:19])[C:15]([C:16]([OH:18])=O)=[C:11]3[N:10]=[CH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.C([O:40][C:41](=[O:56])[CH:42]([NH2:55])[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50]C(C)(C)C)=[CH:46][CH:45]=1)(C)(C)C.FC(F)(F)C(O)=O>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.O>[CH:1]1([C:7]2[N:12]3[N:13]=[C:14]([CH3:19])[C:15]([C:16]([NH:55][CH:42]([CH2:43][C:44]4[CH:45]=[CH:46][C:47]([OH:50])=[CH:48][CH:49]=4)[C:41]([OH:56])=[O:40])=[O:18])=[C:11]3[N:10]=[CH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nn2c(C3CCCCC3)c(-c3ccc(F)cc3)cnc2c1C(=O)O
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccc(OC(C)(C)C)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn2c(C3CCCCC3)c(-c3ccc(F)cc3)cnc2c1C(=O)NC(Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
A solution of 36 mg (0.1 mmol) 7-cyclohexyl-6-(4-fluoro-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in 2 mL of dimethylformamide was cooled at 0° C. To the above cold solution was added 0.053 mL (0.3 mmol) of N, N-diisopropylethylamine (DIEA), followed by 38 mg (0.1 mmol) of HA TU, and 37 mg (0.11 mmol) of 2-amino-3-(4-tert-butoxy-phenyl)-propionic acid tert-butyl ester, and a few crystals of 4-dimethylaminopyridine (DMAP), and the resulting mixture was allowed to warm up to rt, and stirred at rt overnight. The reaction mixture was then diluted with ethyl acetate, washed with 0.1 N NaOH solution, water, and brine, dried over sodium sulfate and evaporated to give a residue which was treated with 2 mL of 95:5 trifluoroacetic acid (TFA):water, and stirred at rt for 2.5 h. The mixture was quenched by the addition of 10 mL of 1:1 acetonitrile:water solution, and concentrated to give a residue which was purified via reverse-phase chromatography using Gilson to afford (after lyophilization) 8 mg (16% over 2 steps) of 2-{[7-Cyclohexyl-6-(4-fluoro-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-3-carbonyl]-amino}-3-(4-hydroxy-phenyl)-propionic acid as a white solid (92% purity, entry 517), as indicated by 1H-NMR. (LC-MS calcd for C29H29FN4O4 [M+H]+ 517.22; found 517.2).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:18]=[CH:17][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1)=[O:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[ClH:38].CCOCC>O1CCCC1>[ClH:38].[NH2:1][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=1)=[O:6]
Reactant: COC(=O)COc1ccc(C(=O)CN=[N+]=[N-])cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(C(=O)CN)cc1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
Methyl 4-(azidoacetyl)phenoxyacetate (2.49g.) was added to a stirred solution of triphenylphosphine (2.62g.) in tetrahydrofuran (20ml.) maintained at 40° C. The solution gradually became orange during the addition of the azido compound and was further stirred at 40° C. for 15 minutes after the addition was complete. 1N-Hydrochloric acid (20ml.) was then added and the mixture stirred at 40° C. for 15 minutes. The mixture was cooled to room temperature and then ether (200ml.) was added. The ethereal layer was decanted off and the brown oily residue was dissolved in toluene (20ml.) and the solution obtained was evaporated in vacuo. The solid residue formed was then recrystallised twice from methanol to give methyl 4-(aminoacetyl)phenoxyacetate hydrochloride (0.7g.), m.p. 202°-204° C.
Reaction SMILES: [C:1]1([CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1>[Ru]>[NH2:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][CH:1]([CH2:9][NH2:10])[CH2:2]1
Reactant: NCc1cccc(CN)c1
Agent: [Ru]
Product: NCC1CCCC(CN)C1

Procedure:
By hydrogenating m-xylylenediamine (available from Mitsubishi Gas Chemical Company, Inc., hereinafter referred to as “MXDA”) in the presence of an alumina catalyst supporting 2% by weight of ruthenium, 1,3-bis(aminomethyl)cyclohexane (1,3-BAC) was produced. The hydrogenation was performed in a fixed bed reactor while supplying the starting liquid and hydrogen from the top of the reactor under the following conditions.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]([N:18]=[N+:19]=[N-:20])([CH3:17])[CH2:8][CH2:9][C:10]([O:12]CCCC)=[O:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>>[C:1]([N:5]=[N:6][C:7]([N:18]=[N+:19]=[N-:20])([CH3:17])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOC(=O)CCC(C)(N=NC(C)(C)C)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)N=NC(C)(CCC(=O)O)N=[N+]=[N-]
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
A mixture of 73.3 grams (0.223 moles) of n-butyl 4-t-butylazo-4-azidovalerate and 38.4 grams (0.24 moles) of 25% NaOH in a 250 ml. round bottom flask were warmed to 80° C in an oil bath. The mixture was stirred for 90 minutes at 80° C and then cooled to room temperature. It was then poured into 200 ml. of water and the aqueous solution extracted with 50 ml. of methylene chloride and the methylene chloride layer discarded. The aqueous solution was acidified with concentration HCl to a pH of 3 and then extracted with pentane. The pentane solution was dried over anhydrous sodium sulfate, filtered and the pentane evaporated to leave 48.0g (92.4% yield) of a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=3[CH:25]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[F:28][C:29]1[CH:34]=[C:33]([C:35]([O:37][CH3:38])=[O:36])[CH:32]=[CH:31][C:30]=1B(O)O>>[CH3:38][O:37][C:35]([C:33]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=4[CH:25]=3)[C:10]([F:11])([F:13])[F:12])=[C:4]([Cl:27])[CH:3]=2)=[C:29]([F:28])[CH:34]=1)=[O:36]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)c(F)c1
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 117 from 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 116, step 8) by Suzuki coupling with 2-fluoro-4-methoxycarbonylphenylboronic acid [CAS Reg. No. 603122-84-5]. MS (m/e)=538.3 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>C1COCC1>[O:21]=[C:20]1[N:8]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)c1ccc(Nc2ccccc2N)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2c(=O)[nH]c3ccccc32)cc1
Temperature: 75 °C

Procedure:
A mixture of ethyl 4-[(2-aminophenyl)amino]benzoate from Step B (442 mg, 1.72 mmol) and 1,1′-carbonyldiimidazole (652 mg, 4.02 mmol) in THF (10 mL) was heated at 75° C. for 3 h. The cooled mixture was partitioned between EtOAc (100 mL) and 10% aqueous citric acid (50 mL). The organic layer was washed with H2O (30 mL), then brine (30 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-95:5 to 75:25, to give the title compound. MS: m/z=283 (M+1).
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4]S(=O)O1.[C:12]([O:21][CH2:22][CH3:23])(=[O:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1(C)C=CC=CC=1>[C:12]([C@H:13]1[C@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:1][C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:4]1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)/C=C/C(=O)OCC
Reactant: O=S1Cc2ccccc2CO1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1Cc2ccccc2C[C@H]1C(=O)OCC
Temperature: 110 °C
Yield: 63.9 %

Procedure:
To a stirred solution of 1,4-dihydro-2,3-benzoxathiin 3-oxide (2.0 g, 11.9 mmol) in toluene (20 mL) was added diethyl fumarate (3.9 mL, 23.8 mmol). Upon completion of addition, the reaction mixture was heated to 110° C. for 16 h under nitrogen. The solvent was removed under vacuum to yield a residue. The residue was purified by silica gel chromatography eluting with 10% ethyl acetate in hexane to yield the title compound (2.1 g, 64%). 13C NMR (400 MHz, CDCl3) δ 174.1, 133.7, 128.3, 126.1, 60.5, 42.3, 42.0, 31.6, 14.3, 14.0. 1H NMR (400 MHz, CDCl3) δ 7.04-7.15 (m, 4H), 4.18 (m, 4H), 3.12 (dd, J=2.6, 12.4 Hz, 2H), 2.87-3.03 (m, 4H), 1.27 (t, J=7.5 Hz, 6H). MS [M+Na]+, 299.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:23][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[C:10]([CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[CH:11]=1)=[O:5].[OH-].[Na+].O.Cl>C(O)C.C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:26]=[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:23][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[C:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:11]=1)=[O:5]
Reactant: COC(=O)CCc1cc(C(=O)c2ccc(OCC(C)C)cc2O)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(CCC(=O)O)c2)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
In 155 ml of ethanol is dissolved 30.9 g of methyl 3-[5-(2-hydroxy-4-isobutoxybenzoyl)-2-isobutoxyphenyl]propanoate, to which is added 44 ml of 5 mol/L solution of sodium hydroxide. The mixture is stirred at ambient temperature for one hour. Water, followed by chloroform, is added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 29.5 g of 3-[5-(2-hydroxy-4-isobutoxybenzoyl)-2-isobutoxyphenyl]-propanoic acid is obtained as a yellow-white colored solid product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CN(C(O[N:31]1[C:36](=[O:37])[CH2:35][CH2:34][C:32]1=[O:33])=[N+](C)C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[O:33]=[C:32]1[CH2:34][CH2:35][C:36](=[O:37])[N:31]1[O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:17]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: O=C(O)CCCCC(=O)OCc1ccccc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCCCC(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(benzyloxy)-6-oxohexanoic acid (3.3 g, 13.97 mmol) in DMF (50 mL) at 0° C. was added TSTU (4.3 g, 14.28 mmol) and DIPEA (2.5 mL, 14.31 mmol). After stirring at 0° C. for 1 hour, the reaction mixture was partitioned between Et2O and water. The organic layer was separated and the aqueous layer was further extracted with ether (2×150 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound. UPLC Method B: calculated for C17H19NO6 333.12, observed m/e: 334.10 [M+1]; Rt=3.75 min. 1H NMR (CDCl3) δ 7.40-7.30 (5H, m), 5.10 (2H, s), 2.80 (4H, s), 2.62-2.58 (2H, m), 2.41-2.37 (2H, m), 1.80-1.72 (4H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>ClCCl>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[NH:25][C:26]([NH:13][C:12]1[CH:14]=[CH:15][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)=[O:27]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Cc1ccc(F)c(N=C=O)c1
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
A 0° C. mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.5 g, 2.28 mmol) and 1-fluoro-2-isocyanato-4-methylbenzene (0.297 mL, 2.28 mmol) in dichloromethane (15 mL) was allowed to gradually warm to room temperature and stirred overnight. The resulting suspension was diluted with hexanes resulting in the formation of more precipitate, which was collected by filtration to provide 0.68 g of the desired product. MS (ESI(+)) m/e 370.7 (M+H)+.