Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:34])([F:33])[C:22](B1OC(C)(C)C(C)(C)O1)=[CH2:23].C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:21]([F:34])([F:33])[C:22]([C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH2:23]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: C=C(B1OC(C)(C)C(C)(C)O1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2)C(F)(F)F
Temperature: 85 °C
Reaction time: 12 h
Yield: 87.4 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (328 mg, 1.00 mmol), 1-(trifluoromethyl)vinylboronic acid pinacol ester (222 mg, 1.00 mmol), saturated aqueous sodium carbonate solution (6 ml) and tetrakis(triphenylphosphine)palladium(0) (32.6 mg, 0.0282 mmol) in dimethoxyethane (10 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the desired product (300 mg, 87.5%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[O:4].Cl.CN(C)CCCN=C=NCC.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>ClCCl.CN(C1C=CN=CC=1)C>[C:3]([O:2][CH3:1])(=[O:4])/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][C:11]([N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)=[O:13])=[O:8]
Reactant: COC(=O)/C=C/C(=O)OCC(=O)O
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)/C=C/C(=O)OCC(=O)N1CCN(C)CC1
Yield: 12.6 %

Procedure:
Following general procedure B2,2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetic acid (23) (0.50 g, 2.65 mmol) was activated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) (0.60 g, 3.18 mmol) in 10 mL of dichloromethane (DCM) at ca. 0° C. N-Methyl piperazine (0.353 mL, 0.31 g, 3.18 mmol) and 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3.18 mmol) were added to the activated carboxylic acid. After work-up and isolation, and purification by mass-guided preparative HPLC afforded 0.09 g (13% yield) of the title compound (25) as a white solid after lyophilization. 1H NMR (CDCl3, 400 MHz): δ 6.93-6.78 (m, 2H), 4.77 (s, 2H), 3.73 (s, 3H), 3.56-3.54 (m, 2H), 3.35-3.25 (m, 2H), 2.37-2.33 (m, 4H), 2.31 (s, 3H). MS (ESI): m/z 271.13 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]C(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH3:16][C@@H:17]([C@@H:29]1[C@@:33]2([CH3:50])[C@@H:34](O)[CH2:35][C@@H:36]3[C@@:41]4([CH3:47])[CH2:42][CH2:43][C@@H:44]([OH:46])[CH2:45][C@H:40]4[CH2:39][C@@H:38](O)[C@H:37]3[C@@H:32]2[CH2:31][CH2:30]1)[CH2:18][CH2:19][C:20](NCCS([O-])(=O)=O)=O.[Na+].[Na]>>[CH3:1][CH:2]([CH2:20][CH2:19][CH2:18][C@H:17]([C@@H:29]1[C@:33]2([CH3:50])[C@H:32]([C@H:37]3[C@H:36]([CH2:35][CH2:34]2)[C@:41]2([CH3:47])[C:40]([CH2:45][C@H:44]([CH2:43][CH2:42]2)[OH:46])=[CH:39][CH2:38]3)[CH2:31][CH2:30]1)[CH3:16])[CH3:3]
Reactant: C[C@H](CCC(=O)NCCS(=O)(=O)[O-])[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: CCCC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [Na]
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The assay substrate contained p-Nitrophenyl butyrate (Sigma Cat. No. N9876) MW 209.2. Density 1.2 and Taurocholic acid, sodium salt (Sigma Cat. No. T 4009) MW 537.7 The assay substrate was prepared by dissolving 43 mg Taurocholic acid (6 mM final concentration)+87 μl p-Nitrophenyl butyrate (40 μM final concentration)+50 μl 20% Triton X-100 (0.08% final concentration) in 10 ml of 100 mM MOPS 2 mM CaCl2 pH 7.3. The substrate was shaken to dissolve the ingredients and centrifuged to clarify.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[F:9][C:10]([F:27])([F:26])[O:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=1.CCOCC>C[N+]([O-])=O>[N+:7]([C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:12]=1[O:11][C:10]([F:9])([F:26])[F:27])[CH2:16][NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:22])[CH3:20])([O-:8])=[O:6]
Reactant: CC(C)(C)C(=O)NCc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: CC(C)(C)C(=O)NCc1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Nitronium tetrafluoroborate (3.97 g, 29.9 mmol) was added in portions over 5 min to N-(4-trifluoromethoxy-benzyl)-2,2-dimethyl-propionamide (4.1 g, 15 mmol) in MeNO2 (35 mL) and the mixture was stirred at rt for 1 h. The mixture was treated with ice and Et2O was added. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was treated with PE and the sub-title compound was filtered off.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([N:13]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[N:24]=[C:23]([C:25]([O:27]C)=O)[CH:22]=[CH:21][CH:20]=2)[C:14]1=[O:29])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][Mg]Br>O1CCCC1.C(OCCCC)CCC>[C:25]([C:23]1[N:24]=[C:19]([CH2:18][N:15]2[CH2:16][CH2:17][N:13]([C@@H:8]([C:9]([CH3:10])([CH3:12])[CH3:11])[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:14]2=[O:29])[CH:20]=[CH:21][CH:22]=1)(=[O:27])[CH3:30]
Reactant: COC(=O)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Reactant: C[Mg]Br
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Product: CC(=O)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of the product from Example 17D (1.95 g, 4.815 mmol) in tetrahydrofuran (50 mL) at −78° C. was treated methylmagnesium bromide in butyl ether (5.7 mL, 1 M). The mixture was stirred 0.5 hours at −78° C., quenched with acetone (3 mL) and 10% citric acid. The reaction mixture was partitioned between ethyl acetate and 1 N NaHCO3, and the organic phase layer was decanted and concentrated. The residue was purified by flash chromatography on silica gel eluting with 25%-50% ethyl acetate in hexane give the title compound (1.6 g, 85% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Sn](C)(C)C>CN1CCCC1=O.C(OCC)(=O)C.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH3:19])=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Cu]I
Agent: C[Sn](C)(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc2c(cc1Cl)CN(C(=O)OC(C)(C)C)C2
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Lit. Tetrahedron Lett. 1999, 40, 2719-2722. To a stirred suspension of 1.58 mmol 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) in 3 ml N-methylpyrolidone were added 0.05 mmol tris(dibenzylideneacetone)dipalladium chloroform complex and 0.32 mmol triphenylphosphine and the mixture was stirred at 50° C. for 10 min. 0.16 mmol copper(I) iodide was then added and the mixture stirred at 50° C. for a further 10 min. Finally, 3.48 mmol tetramethyl tin was added and the reaction mixture was stirred at 80° C. for 16 h. The mixture was then cooled to room temperature, diluted with ethyl acetate and washed twice with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a yellow solid. MS (m/e): 214.1 ({37Cl}[M+H− Me2C═CH2]+, 35%), 212.0 ({35Cl}[M+H− Me2C═CH2]+, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C[C:38]([N:40](C)C)=O>[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:38]#[N:40])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(Br)cc4c3=O)cc2)CCC1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(C#N)cc4c3=O)cc2)CCC1
Temperature: 150 °C
Yield: 54 %

Procedure:
{1-[4-(6-Bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (92 mg, 0.17 mmol), zinc (II) cyanide (40 mg, 0.34 mmol) and tetrakis(triphenyphosphine)palladium(0) (20 mg, 0.017 mmol) were suspended in DMA (2 mL) in a microwave vial. The vial was sealed, evacuated and flushed twice with nitrogen. The mixture was heated in a microwave at 150° C. for 30 min. The resulting mixture was allowed to cool to RT, partitioned between ethyl acetate (40 mL) and water (20 mL) and the phases separated. The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, 20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (45 mg, 54%). LCMS (Method B): RT=4.76 min, [M+Na]+=515.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[C:4]([N+:14]([O-])=O)[CH:3]=1.[CH2:17]([OH:19])[CH3:18].[BH4-].[Na+]>C1COCC1>[C:17]([NH:14][C:4]1[CH:3]=[C:2]([F:1])[C:11]([CH3:12])=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2)(=[O:19])[CH3:18]
Reactant: CCO
Reactant: Cc1c(F)cc([N+](=O)[O-])c2c1C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(F)c(C)c2c1CCCC2
Temperature: 25 °C

Procedure:
The compound obtained in (4) above (1.35 gm) was dissolved into 5 ml of ethanol and 15 ml of THF. To the solution Was added 114 mg of sodium borohydride while stirring at room temperature. After stirring for 20 minutes, the reaction mixture was concentrated. To the concentrate were added 25 ml of toluene and 840 mg of p-TsOH, followed by heating under reflux for 30 minutes. Upon the addition of 100 ml of ethyl acetate, the reaction product was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved into 20 ml of ethyl acetate and catalytically hydrogenated with the addition of 400 mg of platinum oxide for 4 hours. The catalyst was removed, the filtrate was concentrated, and 10 ml of dichloromethane was added to the concentrate. After the further addition of 1.2 ml of triethylamine and 0.81 ml of acetic anhydride, the mixture was stirred for 40 minutes. The reaction product was diluted with 50 ml of chloroform, washed with dilute hydrochloric acid, saturated sodium bicarbonate and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 1.23 gm of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([NH:14][CH:15]3[CH2:24][CH2:23][C:18]4([CH2:22][NH:21][CH2:20][CH2:19]4)[CH2:17][CH2:16]3)[CH:11]=[CH:10][N:9]=2)[CH:4]=[N:3]1.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([NH:14][CH:15]3[CH2:24][CH2:23][C:18]4([CH2:22][N:21]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:20][CH2:19]4)[CH2:17][CH2:16]3)[CH:11]=[CH:10][N:9]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(Nc2nccc(NC3CCC4(CCNC4)CC3)n2)cn1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cc(Nc2nccc(NC3CCC4(CC3)CCN(C(=O)CC#N)C4)n2)cn1
Temperature: 45 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
To a solution of N2-(1-methyl-1H-pyrazol-4-yl)-N4-(2-azaspiro[4.5]decan-8-yl)pyrimidine-2,4-diamine (80 mg, 0.24 mmol) and 2-cyanoacetic acid (22 mg, 0.26 mmol) in DCM (3 mL) and DMF (2 mL) were added EDCI (49 mg, 0.26 mmol) and HOAT (17 mg, 0.12 mmol). The mixture was stirred at 45° C. for 1 h then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as a yellow solid (13 mg, 13%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])C.[CH3:21][NH2:22].CO.O>C(O)(=O)C>[CH2:18]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)[C:15]([OH:16])=[C:6]([C:4]([NH:22][CH3:21])=[O:5])[C:7]1=[O:20])[CH3:19]
Reactant: CN
Reactant: CCOC(=O)c1c(O)c2ccc(C)nc2n(CC)c1=O
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCn1c(=O)c(C(=O)NC)c(O)c2ccc(C)nc21

Procedure:
A stirred mixture of 4 g. of 1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (prepared as in Example 1) and 30 ml. of 40% aqueous methylamine in 20 ml. of methanol was heated under reflux for 5 hours. The solution was cooled, diluted with 100 ml. of water and was acidified with glacial acetic acid. The precipitate which formed was collected, air dried and was recrystallized from heptane to give 1.9 g. of the title compound, m.p. 150°-4° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([I:7])=[C:5]([CH3:8])[NH:4][N:3]=1.[CH2:9]([O:11][C:12]([C@H:14]1[CH2:19][CH2:18][C@@H:17](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:16][CH2:15]1)=[O:13])[CH3:10].C([O-])([O-])=O.[K+].[K+].O1CCOCCOCCOCCOCCOCC1.CN(C=O)C>>[I:7][C:6]1[C:2]([CH3:1])=[N:3][N:4]([C@H:17]2[CH2:18][CH2:19][C@H:14]([C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:15][CH2:16]2)[C:5]=1[CH3:8]
Reactant: CCOC(=O)[C@H]1CC[C@@H](OS(=O)(=O)c2ccc(C)cc2)CC1
Reactant: Cc1n[nH]c(C)c1I
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](n2nc(C)c(I)c2C)CC1
Temperature: 80 °C

Procedure:
A mixture of 3,5-dimethyl-4-iodopyrazole (300.0 mg, 1.351 mmol), cis-4-(toluene-4-sulfonyloxy)-cyclohexanecarboxylic acid ethyl ester (573.4 mg, 1.756 mmol), K2CO3 (373.5 mg, 2.702 mmol), 1,4,7,10,13,16-hexaoxacyclooctadecane (71.43 mg, 0.2702 mmol) and DMF (6 mL, 70 mmol) was heated to 80° C. overnight. The material was extracted with EtOAc, and washed with water (3×). The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 10-20% EtOAc in hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a clear oil. MS (ES+): m/z=377.03 (100) [MH+]. HPLC: tR=3.74 min (polar—5 min, ZQ3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([CH3:27])=[C:21]2[C:28]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[S:31](=[O:39])(=[O:38])[NH:30][N:29]=1.Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CC#N.O.C(Cl)Cl>[C:45]([O:44][C:42](=[O:43])[CH2:41][N:23]1[C:24]2[C:20](=[CH:19][C:18]([F:17])=[CH:26][CH:25]=2)[C:21]([C:28]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[S:31](=[O:38])(=[O:39])[N:30]([CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:29]=2)=[C:22]1[CH3:27])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COc1ccc(CN2N=C(c3c(C)n(CC(=O)OC(C)(C)C)c4ccc(F)cc34)c3ccccc3S2(=O)=O)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Methoxybenzyl chloride (10 μL, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[S:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3cc4ccccc4nc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate(56 mg, 0.5 mmol) and 1-(3,5-dimethoxyphenyl)piperazine(111 mg, 0.5 mmol) were dissolved in anhydrous tetrahydrofuran and DBU(117 mg, 0.75 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. The above solution was concentrated under the reduced pressure to remove tetrahydrofuran and concentrated was purified by column chromatography(Hexane:ether=5:1) to obtain the titled compound.
Reaction SMILES: C(S)C.[Na].[O:5]=[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18]C>CN(C=O)C>[O:5]=[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]
Reactant: COc1ccccc1-n1ccccc1=O
Agent: [Na]
Solvent: CCS
Solvent: CN(C)C=O
Product: O=c1ccccn1-c1ccccc1O
Temperature: 100 °C

Procedure:
Sodium ethanethiol (0.108 g, 1.29 mmol) was added to a solution of 2-(2-oxo-2H-pyridin-1-yl)-anisole (0.100 g, 0.497 mmol) in DMF (2 mL), and the reaction mixture was heated at 100° C. for 3 hr. The reaction mixture was partitioned between CHCl3 and saturated aqueous ammonium chloride and treated with 8N HCl (pH=1). The organic layer was separated, washed with H2O, brine, dried (Na2SO4), filtered, concentrated, and taken up in EtOAc, then extracted with 2% NaOH solution. The aqueous basic layer was acidified with 10% HCl solution, then extracted with EtOAc, the organic layer washed with brine, dried (Na2SO4), filtered, and concentrated to give the desired product.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([OH:31])[CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:32][C:33]([F:42])([F:41])[C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([O:31][C:37]3[CH:38]=[CH:39][C:34]([C:33]([F:42])([F:41])[F:32])=[CH:35][CH:36]=3)[CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc4c(c3)CCC4)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(C(F)(F)F)cc3)c3ccc4c(c3)CCC4)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-trifluoromethylphenol: ESMS m/e: 565.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[NH:30][N:29]=[N:28][N:27]=2)[CH:23]=[CH:24][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH:21]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)cc2)cc1
Yield: 79 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 4′-methoxy[1,1′-biphenyl]-4-sulfonyl chloride (15.6 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 79% yield (16 mg). MS (ESI+) calcd mass for C20H17N5O3S 407.105210, found 407.105280.
Reaction SMILES: [Cl:1]C(OCC)=O.[Cl:7][C:8]1[CH:35]=[CH:34][C:11]([CH2:12][NH:13][C:14]([C:16]2[C:17](=[O:33])[C:18]3[CH:25]=[C:24]([CH2:26]N4CCOCC4)[O:23][C:19]=3[N:20]([CH3:22])[CH:21]=2)=[O:15])=[CH:10][CH:9]=1.C(Cl)Cl.O>C(OCC)C>[Cl:7][C:8]1[CH:35]=[CH:34][C:11]([CH2:12][NH:13][C:14]([C:16]2[C:17](=[O:33])[C:18]3[CH:25]=[C:24]([CH2:26][Cl:1])[O:23][C:19]=3[N:20]([CH3:22])[CH:21]=2)=[O:15])=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cl
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)oc21
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Temperature: 39.5 °C
Reaction time: 2 h

Procedure:
Ethyl chloroformate (150.1 ml) was added to a suspension of N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 1, 262.0 g) and CH2Cl2 with very low water content (2.63 L). The slurry was warmed to 39-40° C. After 2 h, the reaction mixture was cooled to room temperature and ethyl ether (2.63 L) was added. The mixture was stirred overnight, filtered, was washed with ethyl ether (3×2 L), and dried in a vacuum oven (40° C.) to afford 221.8 g of the title compound as a colorless solid. Physical characteristics. 1H NMR (400 MHz, TFA-d) δ 11.50, 8.94, 7.23, 4.64, 4.27; 13C NMR (100 MHz, TFA-d) δ 167.3, 165.2, 155.8, 155.1, 140.4, 134.2, 132.7, 128.4, 128.3, 113.5, 110.6, 103.8, 43.4, 38.9, 33.8. Anal. Found: C, 55.89; H, 3.69; N, 7.60; Cl, 18.98.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:19](C)[C:20]2[CH:25]=[CH:24][CH:23]=[C:22](N)[CH:21]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][S:29](Cl)(=[O:31])=[O:30].[N:33]1C=CC=C[CH:34]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:34][NH:33][S:29]([CH3:28])(=[O:31])=[O:30])[CH:21]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: c1ccncc1
Reactant: CCOC(=O)C1(C(C)c2cccc(N)c2)CCN(C(=O)OC(C)(C)C)CC1
Product: CCOC(=O)C1(Cc2cccc(CNS(C)(=O)=O)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C

Procedure:
A mixture of ethyl N-tert-butoxycarbonyl-4-(3-amino-methylbenzyl)piperidine-4-carboxylate (400 mg, 0.106 mmol) and methanesulfonyl chloride (99 μL, 0.127 mmol) in anhydrous pyridine (4 mL) was heated at 70° C. for 4 h. The resultant mixture was concentrated, and the residue was subjected to column chromatography on silica gel eluting with 50% ethyl acetate in hexane. Collection and oncentration of appropriate fraction provided the title compound.