Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13]([OH:15])=O)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:63]1([CH2:68][C@H:69]2[NH:72][C:71](=[O:73])[C@H:70]2[NH2:74])[CH:67]=[N:66][CH:65]=[N:64]1>C(Cl)Cl.CN(C=O)C.O.C(Cl)Cl>[N:63]1([CH2:68][C@@H:69]2[C@H:70]([NH:74][C:13](=[O:15])/[C:12](=[N:11]\[O:10][C:7]([CH3:8])([CH3:9])[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:29])/[C:16]3[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=3)[C:71](=[O:73])[NH:72]2)[CH:67]=[N:66][CH:65]=[N:64]1
Reactant: N[C@@H]1C(=O)N[C@@H]1Cn1cncn1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2cncn2)cs1
Yield: 64.5 %

Procedure:
To a slurry of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (81 mg, 0.19 mmol) in DCM (800 μL) at 0° C. was added DIPEA (88 μL, 0.504 mmol) followed by HATU (72 mg, 0.190 mmol). A few drops of DMF were added to homogenize the mixture. To the resulting solution was added a solution of (3S,4R)-4-((1H-1,2,4-triazol-1-yl)methyl)-3-aminoazetidin-2-one (21 mg, 0.126 mmol) in DCM (1 mL). After 1.5 h of stirring it was diluted with water/DCM and the layers separated. The aqueous layer was extracted with DCM and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM) to afford the title compound (47 mg, 65%). LCMS: Rt=0.88 min, m/z=579.3 (M+1) Method 2m_acidic.
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][CH3:11])[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9])[CH3:2].[Cl-].[Li+].[CH2:14]1[O:17][CH:15]1[CH3:16].S(=O)(=O)(O)O>CN(C)C=O>[OH:17][CH:15]([CH3:14])[CH2:16][N:7]1[C:3]([CH2:1][CH3:2])([CH2:10][CH3:11])[C:4](=[O:9])[N:5]([CH2:14][CH:15]([OH:17])[CH3:16])[C:6]1=[O:8]
Reactant: CCC1(CC)NC(=O)NC1=O
Reactant: CC1CO1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC1(CC)C(=O)N(CC(C)O)C(=O)N1CC(C)O
Reaction time: 5 h

Procedure:
A solution of 125.0 g of 5,5-diethylhydantoin (0.8 mol), 300.0 g of dimethylformamide and 2.00 g of lithium chloride is stirred at 52° C. 128.0 g of propene oxide (2.2 mols) are added dropwise over the course of 21/2 hours. Stirring is then continued for 5 hours at 85°-90° C. The reaction mixture is adjusted to pH=7 with 2-3 drops of 25% strength sulphuric acid, and is filtered. The clear solution is concentrated on a rotational evaporator at 80° C. bath temperature, under a waterpump vacuum, and is subsequently treated under a high vacuum (0.1 mm Hg) at 80° C. until constant weight is reached.
Reaction SMILES: O1C2=CN=CC=C2C(=O)C1.C(OC([C:16]1[O:28][C:19]2=[N:20][C:21]([CH3:27])=[CH:22][C:23]([O:24][CH2:25][CH3:26])=[C:18]2[C:17]=1[OH:29])=O)C>>[CH2:25]([O:24][C:23]1[CH:22]=[C:21]([CH3:27])[N:20]=[C:19]2[O:28][CH2:16][C:17](=[O:29])[C:18]=12)[CH3:26]
Reactant: CCOC(=O)c1oc2nc(C)cc(OCC)c2c1O
Agent: O=C1COc2cnccc21
Product: CCOc1cc(C)nc2c1C(=O)CO2

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridin-3(2H)-one (A.2.4.3), 3-hydroxy-4-ethoxy-6-methylfuro[2,3-b]pyridine-2-carboxylic acid ethyl ester replacing 3-hydroxyfuro[2,3-c]pyridine-2-carboxylic acid ethyl ester;
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11](O)[CH2:10][CH2:9]2.C1(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCCC1.C(OCC)(=O)C>[N:30]([CH:11]1[C:12]2[C:8](=[CH:7][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)=[N+:31]=[N-:32]
Reactant: OC1CCc2cc(-c3cccs3)ccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: [N-]=[N+]=NC1CCc2cc(-c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.6 %

Procedure:
To a solution of 5-(2-thienyl)-2,3-dihydro-1H-inden-1-ol (0.30 g, 1.39 mmol) in tetrahydrofuran (6 mL ) was added diphenylphosphoryl azide (0.58 g, 2.10 mmol) at 0° C. The reaction was stirred for 5 min prior to the addition of 1,8-diazabicyclo{5.4.0]undec-7-ene (DBU, 0.32 g, 2.10 mmol). The reaction was further stirred for 15 min at 0° C. before the reaction was allowed to warm to room temperature. The reaction was stopped after 1 h when the reaction was completed as monitored by thin layer chromatography. Diluted with ethyl acetate (200 mL), washed with water, saturated aqueous sodium chloride (brine), and dried over anhydrous magnesium sulfate. Filtration, concentration and column chromatography on silica (7:3 hexanes/ethyl acetate) gave 2-(1-azido-2,3-dihydro-1H-indene-5-yl)thiophene (0.24g, 72% yield) as oil. 1H NMR (400 MHz, CDCl3) 7.54 (m, 2H), 7.40 (m, 2H), 7.24 (m, 1H), 7.08 (m, 1H), 5.85 (t, 1H), 3.12 (m, 1H), 2.90 (m, 1H), 2.45 (m, 1H), 2.19 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:15][C@@:9]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:10](=[O:25])[CH:11]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].O.CO.C(OCC)(=O)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:17])=[O:18])[CH2:15][C@@:9]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:10](=[O:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=C[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CC[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
10% Palladium on carbon (1 g) was added as a slurry in water (2 ml) to a solution of (1R*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]oct-3-ene-2-one (Description 2; 11 g, 25.6 mmol) in methanol (50 ml) and ethyl acetate (50 ml). The mixture was hydrogenated at 30psi for one hour. The reaction mixture was filtered through a pad of Celite™. The filter cake was washed with dichloromethane (1L) and the combined filtrates concentrated in vacuo to give the title compound (10.8 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[N:35]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:37][C:38]=1[CH3:39])[CH2:6][N:7]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([O:20][C@@H:21]([CH2:27][CH3:28])[C:22]([O:24]CC)=[O:23])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[N:35]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:37][C:38]=1[CH3:39])[CH2:6][N:7]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([O:20][C@@H:21]([CH2:27][CH3:28])[C:22]([OH:24])=[O:23])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: CCOC(=O)[C@H](CC)Oc1cccc2c1c1ccccc1n2Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC[C@H](Oc1cccc2c1c1ccccc1n2Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
440 mg of ethyl (S)-(+)-2-{9-[3-methoxy-4-(5-methyl-2-phenyl-oxazole-4-ylmethoxy)-benzyl]-9H-carbazole-4-yloxy}butyrate was suspended in ethanol (4.4 mL), 175 μL of 5 N sodium hydroxide solution was added thereto, and stirred at room temperature for 4 hours. The reaction mixture was diluted with water, and adjusted to pH3 with 1 N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, and 420 mg of the subject compound was prepared as white solid. Optical purity 95% ee (HPLC).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[C:15]1=[O:33].C([O-])([O-])=O.[Na+].[Na+].CS(C)=O>O>[Cl:8][C:7]1[C:2]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:24][CH2:25]3)[C:15]2=[O:33])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](N)C2=O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Nc3ncc(C(F)(F)F)cc3Cl)C2=O)CC1
Temperature: 130 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A flask was charged with 2,3-dichloro-5-(trifluoromethyl)pyridine (0.2919 mL, 2.093 mmol), (S)-tert-butyl 3-amino-2-oxo-1,4′-bipiperidine-1′-carboxylate (0.415 g, 1.395 mmol), Na2CO3 (0.2958 g, 2.791 mmol), and DMSO (5 mL). The reaction mixture was stirred at 130° C. overnight. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layers were combined, dried, filtered, concentrated. The residue was purified using silica gel column chromatography with 30% ethyl acetate in hexanes to provide (S)-tert-butyl 3-(3-chloro-5-(trifluoromethyl)pyridin-2-ylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (0.51 g, 76.63% yield). Mass spectrum (apci) m/z=377.2 (M+H-Boc).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:14]1.[Cl-].[NH4+].C1C[O:29]CC1>CCOC(C)=O>[OH:29][CH:17]([C:16]([CH:13]1[CH2:15][CH2:14]1)([CH3:23])[CH3:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CC(C)(C)C1CC1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C(O)C(C)(C)C1CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisopropylamine (4.9 mL, 35 mmol) in dry THF (100 mL) at 0° C. under inert atmosphere was added n-butyllithium (14 mL, 35 mmol) dropwise over a period of 5 min. The solution was cooled to −78 ° C. and methyl 3-cyclopropyl-3-methylbutanoate (5.0 g, 32) was added dropwise over a period of 5 min. The solution was stirred at −78 ° C. for 1 h at which time (+)-camphorsulfonyloxaziridine (9.0 g, 39 mmol) was added all at once. The resulting suspension was stirred at −78 ° C. for 30 min and then allowed to warm to ambient temperature over 30 min. EtOAc (100 mL) and saturated aqueous ammonium chloride (50 mL) were added and the organic layer was separated and washed with water (50 mL), dried (MgSO4), and filtered. The solvents were removed under reduced pressure and the resulting oily solid was stirred in ether (50 mL) for 30 min. The solid was removed by filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by flash column chromatography using a gradient elution of 10% to 14% EtOAc in hexanes to give methyl 2-hydroxy-3-cyclopropyl-3-methylbutanoate as a colorless liquid. TLC Rf=0.4 (12% EtOAc-hexanes); HPLC RT=2.72 min (Method A); 1H NMR 400 MHz, CDCl3, 3.92 ppm ((d, J=7.9 Hz, 1H), 3.79 ppm (s, 3H), 2.79 ppm (d, J=7.9 Hz, 1H), 0.84 ppm (s, 3H), 0.83 ppm (m, 1H), 0.80 ppm (s, 3H), 0.32 ppm (m, 2H), 0.20 ppm (m, 2H)
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:21][C:14]=23)=[C:8]([F:30])[CH:7]=1)=[O:4].[Br:33]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.O.ClCCl>[Br:33][C:21]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][C:13]=2[CH2:12][C:9]2[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:31])[F:32])=[CH:7][C:8]=2[F:30])[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cc3ccc(NC(=O)C(F)(F)F)cc3F)ccnc21
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(Br)c2c(Cc3ccc(NC(=O)C(F)(F)F)cc3F)ccnc21

Procedure:
200 mg (0.38 mmol) of 2,2,2-trifluoro-N-{3-fluoro-4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl]phenyl}acetamide and 68.5 mg (0.38 mmol) of N-bromo-succinimide in 8 ml of carbon tetrachloride are heated at reflux for 20 min. After cooling, the mixture is diluted with water and dichloromethane and extracted. The organic phase is separated off, dried over sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]1[O:20][C:19]2[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][NH2:16])=[CH:12][C:11]=2[O:10]1>ClCCl.C(N(CC)CC)C>[CH2:9]1[O:20][C:19]2[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][NH:16][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[CH:12][C:11]=2[O:10]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1ccc2c(c1)OCO2)c1ccco1

Procedure:
N-[2-(3,4-methylenedioxyphenyl)-ethyl]furan-2-carboxamide was prepared by condensation of 2-furoyl chloride and 3,4-methylenedioxyphenethylamine in dichloromethane with triethylamine as catalyst.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[C:6]([F:13])[CH:5]=[CH:4][C:3]=1[N:14]([CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[S:15]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[F:25])(=[O:17])=[O:16].[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][C:12]1[C:8]([C:7]2[C:2]([F:1])=[C:3]([N:14]([CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[S:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])(=[O:17])=[O:16])[CH:4]=[CH:5][C:6]=2[F:13])=[N:9][NH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCOCN(c1ccc(F)c(-c2cc[nH]n2)c1F)S(=O)(=O)c1cc(F)ccc1F
Solvent: ClCCl
Product: COCCOCN(c1ccc(F)c(-c2n[nH]cc2Br)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-[2,4-difluoro-3-(1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-N-(2-methoxyethoxy-methyl)-benzenesulfonamide (1.27 g, 2.76 mmol) was dissolved in dry DCM (10 mL). N-bromosuccinimide was then added (737 mg, 4.14 mmol, 1.5.eq) and the reaction was stirred at room temperature for 3 hours. The reaction mixture was then diluted with DCM and washed with 10% aqueous NaHSO3 and brine. The organic phase was dried over Na2SO4 and evaporated to dryness. The desired N-[3-(4-bromo-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-N-(2-methoxyethoxymethyl)-benzenesulfonamide was isolated from the crude mixture by chromatography on silica gel (DCM/MeOH 95:5) obtaining 584 mg (39%) of off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:26]([N:28]([CH2:32][CH3:33])[C:29](Cl)=[O:30])[CH3:27]>CN(C1C=CN=CC=1)C.O.C(O)(=O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][C:29](=[O:30])[N:28]([CH2:32][CH3:33])[CH2:26][CH3:27])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCN(CC)C(=O)Cl
Reactant: COc1ccc(-c2cc3ccc(O)cc3s2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)C(=O)Oc1ccc2cc(-c3ccc(OC)cc3)sc2c1
Temperature: 66 °C
Reaction time: 4 h

Procedure:
Charge a vessel with 2-(4-methoxy-phenyl)-benzo[b]thiophen-6-ol (1.000 mol, 256.3 g), 99% DMAP (0.100 mol, 12.34 g), and THF (10.0 L/kg, 2.56 L). Add 99% triethylamine (1.050 mol, 107.3 g) and 97% diethylcarbamyl chloride (DEC-Cl) (1.050 mol, 146.8 g). Heat the contents of the reactor to reflux/66° C. Stir 4 hours or until reaction is complete as determined by HPLC. Begin to cool to 50° C. and add acetic acid solution made up of DI water (3.0 L/kg, 769 mL) and glacial acetic acid (0.300 mol, 18.02 g). Separate the layers at 50° C., and remove the bottom aqueous layer. Cool the organic layer to −5 to 0° C. (−20° C. to ambient is acceptable). The organic layer contains a solution of diethyl-carbamic acid 2-(4-methoxy-phenyl)-benzo[b]thiophen-6-yl ester which is most conveniently carried directly to the next step, the bromination step.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23](=[N:29]O)[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[F:14][C:2]([F:1])([F:15])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[O:13][N:29]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:22]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc(Cc2ccc(OC(F)(F)F)cc2)n1
Yield: 10.4 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(4-(trifluoromethoxy)phenyl)acetic acid (0.833 g; 3.78 mmol) and oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (6 mL); (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.124 g (10%) of ethyl 5-(4-(trifluoromethoxy)benzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: [S:1]=[C:2]1[NH:6][C:5]2=[C:7]([C:11]([O:13]C)=[O:12])[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1.O.[OH-].[Li+:17]>C1COCC1.O>[S:1]=[C:2]1[NH:6][C:5]2=[C:7]([C:11]([O-:13])=[O:12])[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1.[Li+:17]
Reactant: COC(=O)c1cccc2oc(=S)[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cccc2oc(=S)[nH]c12
Temperature: 75 °C
Reaction time: 72 h
Yield: 93.2 %

Procedure:
To a solution of methyl 2-thioxo-2,3-dihydrobenzoxazole-4-carboxylate (150 mg, 0.72 mmol) in THF (6 mL) was added a solution of lithium hydroxide monohydrate (45.1 mg, 1.08 mmol) in H2O (3 mL). The reaction mixture was heated to 75° C. with stirring for 3 days, cooled down to room temperature and concentrated under reduced pressure to afford the lithium 2-thioxo-2,3-dihydrobenzoxazole-4-carboxylate (135 mg, 96.5%) as a yellow solid. MS consistent
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[NH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.CNC1CCCCC1NC>[Cu]I.CN(C=O)C>[CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Fc1ccc(I)cc1
Reactant: CCCCNc1ncc2[nH]ccc2n1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCCCNc1ncc2c(ccn2-c2ccc(F)cc2)n1
Temperature: 110 °C
Yield: 98.6 %

Procedure:
A mixture of N-butyl-5H-pyrrolo[3,2-d]pyrimidin-2-amine (0.73 g, 3.85 mmol), CuI (0.074 g, 0.39 mmol), and K3PO4 (1.63 g, 7.7 mmol) was added DMF (10 mL), 4-fluoroiodobenzene (0.54 mL, 4.62 mmol), and N,N′-dimethylcyclohexane-1,2-diamine (0.24 mL, 1.54 mmol) under Argon atmosphere. The mixture was heated at 110° C. for 16 h, then was filtered through a plug of celite at room temperature and washed with MeOH. The filtrate was concentrated and purified by ISCO to provide desired product (1.079 g, 99%). MS m/z 285.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3]/[CH:4]=[CH:5]/[C:6]1([OH:12])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[S:15]1[C:19]2=[CH:20][CH:21]=[CH:22][C:23]([S:24]([NH:27][C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)(=[O:26])=[O:25])=[C:18]2[N:17]=[CH:16]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:12][C:6]1(/[CH:5]=[CH:4]/[CH2:3][C:2]([F:1])([F:13])[F:14])[CH2:7][CH2:8][N:9]([C:32]([C:31]2[CH:30]=[CH:29][C:28]([NH:27][S:24]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]4[S:15][CH:16]=[N:17][C:18]=34)(=[O:26])=[O:25])=[CH:36][CH:35]=2)=[O:33])[CH2:10][CH2:11]1
Reactant: OC1(/C=C/CC(F)(F)F)CCNCC1
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2cccc3scnc23)cc1
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: ClCCl
Product: O=C(c1ccc(NS(=O)(=O)c2cccc3scnc23)cc1)N1CCC(O)(/C=C/CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottom flask was added with (E)-4-(4,4,4-trifluorobut-1-enyl)piperidin-4-ol (50 mg 0.24 mmol), 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (80 mg, 0.24 mmol), DIPEA (155 mg, 1.2 mmol), HATU (110 mg, 0.29 mmol), and DCM (5 mL). The mixture was stirred at r.t. for 16 hours. After washing with brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Purification by a standard method gave the desired compound. 1H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (d, J=8.1 Hz, 1H), 8.10 (d, J=7.5 Hz, 1H), 7.99 (s, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.17-7.24 (m, J=8.3 Hz, 2H), 7.08-7.15 (m, J=8.1 Hz, 2H), 5.78-5.94 (m, 1H), 5.64-5.76 (m, 1H), 4.28-4.47 (m, 1H), 3.51 (s, 1H), 3.32-3.48 (m, 1H), 3.27 (br. s., 1H), 2.84 (dd, J=10.5, 7.0 Hz, 1H), 1.66 (br. s., 4H), 1.46 (d, J=9.7 Hz, 2H). LC-MS: m/z 526.7 (M+H)+
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH2:17][N:16]2[C:28](=[O:40])[C:29]([NH:32]C(=O)OC(C)(C)C)([CH3:31])[CH3:30])[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].O>ClCCl.CO>[Cl:26][C:24]1[CH:23]=[CH:22][C:21]([F:27])=[C:20]([C:18]2[CH2:17][N:16]([C:28](=[O:40])[C:29]([CH3:31])([CH3:30])[NH2:32])[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=3)[CH:19]=2)[CH:25]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O)c1
Reaction time: 2 h

Procedure:
A solution of tert-butyl 2-[2-(3{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-(5-chloro-2-fluorophenyl)-2,5-dihydro-1H-pyrrol-1-yl]-1,1-dimethyl-2-oxoethylcarbamate (3-3, 247 mg, 0.419 mmol, 1 equiv) and trifluoroacetic acid (4 mL) in dichloromethane (10 mL) was stirred under ambient conditions for 1 h. The reaction was concentrated at 23° C. and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to yield a yellow gum. A solution of the gum in methanol (5 mL) was treated with potassium carbonate (290 mg, 2.10 mmol, 5.00 equiv) and water (1 mL). The reaction mixture was stirred under ambient conditions for 2 h, then concentrated. The aqueous solution was acidified with aqueous 1 N HCl solution to pH 8 and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to provide 4-(5-chloro-2-fluorophenyl)-2-(3-hydroxyphenyl)-1-(2-methylalanyl)-2,5-dihydro-1H-pyrrole (3-4) as a cream-colored solid. 1H NMR (500 MHz, CDCl3) δ 7.30 (dd, 1H, J=6.6, 2.7 Hz), 7.30 (m, 1H), 7.18 (t, 1H, J=7.8 Hz), 7.05 (t, 1H, J=9.2 Hz), 6.83 (br d, 1H, J=7.6 Hz), 6.78 (br s, 1H), 6.70 (dd, 1H, J=8.1, 1.8 Hz), 6.38 (s, 1H), 5.92 (br s, 1H), 5.30 (m, 1H), 5.08 (m, 1H), 1.46 (s, 6H). LRMS m/z (M+H) 375.0 found, 375.0 required.