Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:34][C@H:35]([C:56]1[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=1)[C@H:36]([NH:40][C:41](=[O:55])[C@@H:42]([NH:45][C:46](=[O:54])[CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[CH2:43][OH:44])[C:37](O)=[O:38].[NH2:64][C@@H:65]([CH2:72][C:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=1)[C:66]([C@@:68]1([CH3:71])[CH2:70][O:69]1)=[O:67]>CN(C=O)C>[C:73]1([CH2:72][C@H:65]([NH:64][C:37](=[O:38])[C@@H:36]([NH:40][C:41](=[O:55])[C@@H:42]([NH:45][C:46](=[O:54])[CH2:47][N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH2:43][OH:44])[C@H:35]([OH:34])[C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=2)[C:66]([C@@:68]2([CH3:71])[CH2:70][O:69]2)=[O:67])[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=1
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)CN2CCOCC2)C(=O)O)cc1
Reactant: C[C@]1(C(=O)[C@@H](N)CC2=CCCCC2)CO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)CN2CCOCC2)C(=O)N[C@@H](CC2=CCCCC2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
Sequentially HATU (537 mg, 1.41 mmol) and DIEA (1.02 mL, 5.88 mmol) were added to a 0° C. solution of (2S,3R)-3-hydroxy-2-((S)-3-hydroxy-2-(2-morpholinoacetamido)propanamido)-3-(4-methoxyphenyl)propanoic acid (500 mg, 1.18 mmol) and (S)-2-amino-3-(cyclohex-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)propan-1-one (TFA salt, 364 mg, 1.18 mmol) in DMF (10 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (DCM/MeOH=50:1 to 30:1) twice to afford (2S,3R)-N-((S)-3-(cyclohex-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-2-((S)-3-hydroxy-2-(2-morpholinoacetamido)propanamido)-3-(4-methoxyphenyl)propanamide (500 mg, 57% yield) as a colorless solid. 1H NMR (300 MHz, DMSO-d6): δ 7.97 (d, J=7.5 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.26 (d, J=8.7 Hz, 2H), 6.80 (d, J=8.7 Hz, 2H), 5.61 (d, J=4.5 Hz, 1H), 5.40-5.38 (m, 1H), 5.23-5.21 (m, 1H), 5.04-5.02 (m, 1H), 4.62-4.51 (m, 1H), 4.45-4.35 (m, 2H), 3.71 (s, 3H), 3.68-3.41 (m, 6H), 3.33 (s, 1H), 3.21 (d, J=5.1 Hz, 1H), 2.97-2.80 (m, 3H), 2.39-2.21 (m, 4H), 2.11-1.71 (m, 4H), 1.56-1.40 (m, 4H), 1.26 (s, 3H), 1.28-1.22 (m, 1H). MS(EI) for C31H44N4O9, found 617.4 (MH)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11]([NH2:13])=[S:12])=[CH:4][C:3]=2[O:2]1.BrBr.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[NH2:13][C:11]1[S:12][C:6]2[CH:7]=[C:8]3[O:9][CH2:1][O:2][C:3]3=[CH:4][C:5]=2[N:10]=1
Reactant: NC(=S)Nc1ccc2c(c1)OCO2
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc2cc3c(cc2s1)OCO3
Reaction time: 1 h

Procedure:
3,4-Methylenedioxyphenylthiourea (1.96 g; Lancaster Chemical Co) in chloroform (6 cm3) was stirred at ambient temperature and a solution of bromine (0.37 cm3) in chloroform (3 cm3) was added in portions. The mixture was cooled using a water bath and after 1 hr. was stored for 64 hr., diluted with water (100 cm3), basified with aqueous 2M sodium hydroxide and extracted with ethyl acetate (2×150 cm3). The combined organic phases were washed with water and dried (magnesium sulphate). The solution was evaporated under reduced pressure to give the required product as a pale pink solid; mp 200° C.; 1H NMR (CDCl3): δ7.06 (1H,s); 7.02(1H,s); 5.98(2H,s); 5.0(broad signal, 2H).
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:18][Mg]Cl.FC1C=C(F)C=CC=1/C=C1\CCC2NC(C(OC)=O)=CC\1=2>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:18][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: Fc1ccc(C[Mg]Cl)cc1Cl
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Agent: COC(=O)c1cc2c([nH]1)CC/C2=C\c1ccc(F)cc1F
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(F)c(Cl)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.50 g, 2.8 mmol) was reacted with 3-chloro-4-fluorobenzylmagnesium chloride (0.25 M in diethyl ether, 28 mL, 7 mmol) according to General Procedure 3. The resulting exo-olefin ((E)-methyl 4-(3-chloro-4-fluorobenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was then converted to the title compound by hydrogenation according to General Procedure 6 (with Pt2O). The crude product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-50% EtOAc/heptane to afford the title compound. 0.034 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.00-2.16 (m, 1H) 2.50-2.64 (m, 1H) 2.64-2.71 (m, 2H) 2.75 (d, J=7.37 Hz, 2H) 3.16-3.38 (m, 1H) 3.82 (s, 3H) 6.37 (d, J=1.66 Hz, 1H) 6.97-7.11 (m, 2H) 7.23 (dd, J=7.13, 2.00 Hz, 1H) 8.85 (br. s, 1H)).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH:23]=O)[N:13]=1>O.CO>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH:23]=[N:2][OH:3])[N:13]=1
Reactant: COc1cc(OC)nc(Oc2ccccc2C=O)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(OC)nc(Oc2ccccc2C=NO)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
3.5 g of hydroxylamine hydrochloride were added to 100 ml of a 1:1 mixed solution of water and methanol containing 3.5 g of potassium carbonate at 0° C. The solution was stirred at 0° C. for 10 minutes. At 0° C., 13.0 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldehyde were added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 hour and then warmed at 60° C. for 1 hour. After the reaction mixture was allowed to cool down, it was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate=5:1) to obtain 7.7 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:3]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(CC)C(C)C)(C)C.[Cl:41][C:42]1[CH:43]=[C:44]([N:62]2[C:67](=[O:68])[NH:66][C:65](=[O:69])[C:64]([C:70]#[N:71])=[N:63]2)[CH:45]=[C:46]([Cl:61])[C:47]=1[O:48][C:49]1[CH:54]=[C:53]([CH:55]([CH3:57])[CH3:56])[C:52](=[O:58])[N:51]([CH2:59]O)[N:50]=1>C(Cl)Cl>[Cl:61][C:46]1[CH:45]=[C:44]([N:62]2[C:67](=[O:68])[NH:66][C:65](=[O:69])[C:64]([C:70]#[N:71])=[N:63]2)[CH:43]=[C:42]([Cl:41])[C:47]=1[O:48][C:49]1[CH:54]=[C:53]([CH:55]([CH3:56])[CH3:57])[C:52](=[O:58])[N:51]([CH2:59][O:10][C:9](=[O:11])[CH2:8][C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)[N:50]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Reactant: O=C(O)Cc1cccnc1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(COC(=O)Cc2cccnc2)c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 22.4 %

Procedure:
A solution of pyridin-3-yl-acetic acid hydrochloride salt (57.3 mg, 0.33 mmol) in methylene chloride (1.84 mL) was treated with N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (119 mg, 0.39 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.99 mmol). The resulting solution was stirred at 25° C. for 2.5 h. At this time, 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (200 mg, 0.42 mmol) was added to the reaction. The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction mixture was diluted with methylene chloride (50 mL) and washed with water (3×150 mL). The organics were dried over sodium sulfate, filtered, rinsing with methylene chloride and concentrated in vacuo. Biotage flash chromatography (40S, 1-4% methanol/methylene chloride) followed by supercritical fluid chromatography (Daicel OD column, 60% methanol) afforded pyridin-3-yl-acetic acid 3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl ester (43.2 mg, 22%) as a yellow solid. ES+-HRMS m/e calcd for C25H19N7O6Cl2 (M+H+) 584.0847, found 584.0848.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[NH:10][C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24]C(C)(C)C)=[O:23])[CH:17]=3)=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[NH:10][C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=3)=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc(C(=O)O)c2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
At room temperature, tert-butyl 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)picolinate (1.4 g, 2.76 mmol) was dissolved in dichloromethane (20 mL). To the resulted solution, trifluoroacetic acid (20 mL) and triethylsilane (0.5 mL) were added. The resulted mixture was heated to 50° C. and stirred for 16 hours. The solvent was removed under reduced pressure, and water (50 mL) and ethyl acetate (70 mL) were added. The resulted mixture was separated and the organic phase was removed. The aqueous layer was filtered and the solid was washed with water (30 mL×2). The solid was dried under vacuum to give the title compound (1.1 g, purity 97%, yield 90%) as a light green solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[CH2:30]([O:32][CH2:33][CH2:34]O)[CH3:31].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH2:31][CH2:30][O:32][CH2:33][CH3:34])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CCOCCO
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOCCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords the product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:11][C:12]([OH:14])=[O:13]
Reactant: O=Cc1cccc(O)c1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C(O)C=Cc1cccc(O)c1
Yield: 76 %

Procedure:
A mixture of 3-hydroxybenzaldehyde (1 g, 0.008 mol), malonic acid (1.69 g, 0.016 mol), piperidine (1 to 3 mL) and acetic acid (10–20 mL) were taken in a 100 ml Erlenmeyer flask and irradiated under microwave for 2–8 minutes in parts. The cooled mixture was poured into ice cold water and extracted with ethyl acetate. The organic layer was washed with dil HCl., saturated sodium chloride and then organic layer dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain crude solid which was recrystallised with methanol, provided a white solid in 76% yield; 193° C. (lit mp 194° C.); 1H NMR (CDCl3) δ 6.73(1H, s, H-3 and H-5), 6.62 (1H, dd, H-7), 5.61(1H, d, J=10.9 Hz trans, H-8), 5.16(1H, d, J=17.6, cis-H-8).; 13C NMR (CDCl3) δ 147.4 (C-2 and C-6), 137.2 (C-1), 135.1 (C-7), 129.5 (C-4), 112.2 (C-8), 103.3 (C-3 and C-5), 56.0 (2 OMe). This experiment clearly indicates that utilization of microwave technique as well as presence of hydroxy at 4-position of phenylaldehydes is important for the preparation of 4-vinylphenols (Example I, II and III).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:23])[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47](=[O:50])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].[Cl-].[NH4+]>C1COCC1>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47]([C:2]2[CH:25]=[CH:24][C:5]([O:6][C:7]3[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:23])[C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)([OH:50])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: O=C(Nc1ccc(Oc2ccc(Br)cc2)cc1)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cc3)cc2)CC1
Reaction time: 0.33 h
Yield: 36.5 %

Procedure:
To a solution of N-[4-(4-bromophenoxy)phenyl]-3,4-dichlorobenzamide (4.94 g, 11.3 mmol) in THF (100 mL) was stirred at −85° C., and added a solution of 2.46 M n-butyl lithium hexane (9.65 mL, 23.7 mmol) dropwise over 10 minutes. Upon stirring for 20 minutes at the same temperature, crystals were precipitated. To this reaction solution was added a solution of 1-(t-butoxycarbonyl)-4-piperidone (2.48 g, 12.4 mmol) in THF (20 mL). The temperature of the solution was raised over 3 hours to −40° C., and then aqueous saturated ammonium chloride was added to the solution. The resulting reaction solution was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was then evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:3 to 1:1), to yield 2.30 g of a white powder. These crystals were washed with ether, to thereby yield 1.80 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C([Li])CCC.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17]>C(OCC)C>[CH3:15][Si:16]([CH3:18])([CH3:17])[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6]
Reactant: OCc1cccc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1cccc(CO)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromobenzylalcohol (9.35 g, 50 mmol) in diethyl ether (50 ml) at 0° C. was added dropwise 1.5M butyllithium (66.7 ml) and the mixture was stirred 30 min. Then trimethylsilylchloride (11.39 g, 105 mmol) in diethyl ether (50 ml) was added dropwise and the mixture was stirred at room temperature 18 hours. The reaction mixture was treated with ice water (100 ml) and the organic layer extracted, washed with water, brine, dried over MgSO4 and concentrated. The crude product was dissolved in 90% aqueous methanol (100 ml) and refluxed 1 hour. The solvents were removed and 3-trimethylsilylbenzylalcohol was purified by distillation.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:15]([OH:19])(=[O:18])[CH:16]=[CH2:17].Cl>C1COCC1>[C:1]1([S:7][CH2:17][CH2:16][C:15]([OH:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)O
Reactant: Sc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)CCSc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a solution of thiophenol (8.87 g, 80.6 mmol) in THF (20 ml) and triethylamine (8.6 g, 11.9 ml, 85 mmol) was added dropwise, with ice cooling, acrylic acid (5.8 g, 5.5 ml, 81 mmol). The reaction mixture was stirred at 0° C. for 1 h and then at RT overnight, acidified with 2N hydrochloric acid and extracted with diethyl ether (2×100 ml). The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The desired 3-phenylsulfanylpropionic acid product (13.67 g, 93% of theory) was obtained as a white solid (m.p. 51-54° C.)
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[OH:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].N1C=CN=C1.C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C>[OH:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:2]([CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:9])[CH3:11])[CH3:1])=[O:17]
Reactant: O=C(Cl)c1ccccc1O
Reactant: CNCCNC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CN(CCNC(=O)OC(C)(C)C)C(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
To a mixture of tert-butyl 2-(methylamino)ethylcarbamate (0.348 g, 2 mmol), 2-hydroxybenzoyl chloride (0.276 g, 2 mmol) and imidazole (0.136 g, 2 mmol) in ethyl acetate (8 mL) at 0° C. was slowly added a solution of DCC (0.412 g, 2 mmol) in ethyl acetate (2 mL). The mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel, eluting with EtOAc/PE (20-50%) to afford tert-butyl 2-(2-hydroxy-N-methylbenzamido)ethylcarbamate (0.2 g, 34%) as a colorless oil. 1HNMR (CDCl3): δ 7.5 (m, 2H, CH), 7.0 (d, 1H, CH), 6.8 (d, 1H, CH), 3.7 (m, 2H, CH2), 3.48 (m, 2H, CH2), 3.2 (m, 3H, CH3), 1.5 (s, 9H, CH3).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([CH2:19][O:20][CH2:21][C:22]3([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.C(Cl)Cl>>[F:41][C:38]1[CH:37]=[CH:36][C:35]([C:22]2([CH2:21][O:20][CH2:19][C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=3)[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(-c2cc(COCC3(c4ccc(F)cc4)CCNCC3)cc(C(F)(F)F)c2)cc1

Procedure:
tert-Butyl 4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (47.0 mg, 0.09 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were removed in vacuo to afford 37.0 mg (92%). 1H-NMR (CDCl3, 500 MHz) δ 7.75 (s, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.58 (s, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.40 s, 1H), 7.30-7.33 (m, 2H), 6.96-7.00 (m, 2H), 4.46 (s, 2H), 3.44 (s, 2H), 2.87-2.91 (m, 2H), 2.70-2.75 (m, 2H), 2.11-2.14 (m, 2H), 1.87-1.90 (m, 2H). Mass spec.: 469.33 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:21](=[O:22])[CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C(O)Cc1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1ccccn1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask was placed a solution of methyl 2-amino-5-bromobenzoate (5 g, 21.73 mmol, 1.00 equivalent), 2-(pyridin-2-yl)acetic acid hydrochloride (4.5 g, 25.92 mmol, 1.20 equivalent), HATU (10 g, 26.30 mmol, 1.20 equivalents), and DIEA (8.5 g, 65.77 mmol, 3.00 equivalents) in N,N-dimethylformamide (100 mL). After stirring overnight at 20° C., the reaction was quenched with 100 mL of water and extracted with 3×100 mL of dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (1:50) to give the title compound as a red solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([O:11][C:12](=[O:27])[NH:13][C:14]1[C:15]([CH3:26])=[N:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH3:10].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:22]2[CH:23]=[CH:24][C:19]([C:18]3[O:17][N:16]=[C:15]([CH3:26])[C:14]=3[NH:13][C:12]([O:11][CH:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[CH3:10])=[O:27])=[CH:20][CH:21]=2)=[CH:35][CH:34]=1)[CH3:29]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1c(F)cccc1F
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3c(F)cccc3F)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2,6-difluoro-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (4′-{4-[1-(2,6-difluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:29][C:30]1([S:33]([NH2:36])(=[O:35])=[O:34])[CH2:32][CH2:31]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@:9]1([C:14](=[O:16])[NH:36][S:33]([C:30]2([CH3:29])[CH2:32][CH2:31]2)(=[O:35])=[O:34])[CH2:11][C@H:10]1[CH:12]=[CH2:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(S(N)(=O)=O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(C)CC1
Temperature: 85 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
To a solution of (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid (25 g, 110 mmol) in THF (300 mL) was added CDI (205 g, 127 mmol) and the reaction mass was heated at 85° C. for 1 h. The reaction mass was cooled to rt and to this reaction mass was added 1-methylcyclopropane-1-sulfonamide (17.7 g, 131 mmol) followed by DBU (33.2 mL, 33.5 mmol). The reaction mixture was stirred at rt for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH˜2 by using aq. 1.5 N HCl solution. The precipitated solid was isolated via filtration and washed with water to get desired compound (22 g, 58%) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.01-11.17 (m, 1H), 7.17-7.33 (m, 1H), 5.35-5.51 (m, 1H), 5.18-5.29 (m, 1H), 4.99-5.09 (m, 1H), 2.21 (s, 1H), 1.69 (dd, J=7.78, 5.27 Hz, 1H), 1.40 (d, J=3.01 Hz, 14H), 1.20 (dd, J=9.29, 5.27 Hz, 1H), 0.82-0.96 (m, 2H). MS: MS m/z 343 (M++1).