Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][S:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[CH:6][CH:7]=1.[CH2:21]([N:28]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:29](=[O:32])[CH2:30]Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:21]([N:28]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:29](=[O:32])[CH2:30][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][S:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[CH:6][CH:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCCCN(Cc1ccccc1)C(=O)CBr
Reactant: COC(=O)c1ccccc1SCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCN(Cc1ccccc1)C(=O)COc1cccc(CCSc2ccccc2C(=O)OC)c1
Yield: 89.5 %

Procedure:
Methyl 2-{[2-(3-hydroxyphenyl)ethyl]thio}benzoate (129 mg, 0.447 mmol), N-benzyl-2-bromo-N-hexylacetamide (154 mg, 0.492 mmol) and potassium carbonate, anhydrous (93 mg, 0.671 mmol) were mixed in acetonitrile (10 ml). The mixture was heated to reflux overnight and then evaporated to dryness. Water and ethyl acetate were added into the residue. The two phases were separated. The organic phase was washed with brine and dried with magnesium sulphate and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using ethyl acetate/heptane (10:90, then 25:75) as eluant gave 208 mg the desired product, yield 89.5%.
Reaction SMILES: [Na].[N+:2]([NH:5][C:6]([NH2:8])=[NH:7])([O-:4])=[O:3].[CH:9]([CH:11]([CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:12](OCC)=O)=[O:10]>CO>[N+:2]([NH:5][C:6]1[NH:8][C:9](=[O:10])[C:11]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:12][N:7]=1)([O-:4])=[O:3]
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: CCOC(=O)C(C=O)Cc1cccnc1
Agent: [Na]
Solvent: CO
Product: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Yield: 38 %

Procedure:
(a)(i) Sodium (1.15 g) was dissolved in methanol (50 ml), and nitroguanidine (4.7 g) was added to the cooled solution. The mixture was refluxed for 45 minutes, ethyl 2-formyl-3-(3-pyridyl)propionate (9.3 g) was added portionwise and the mixture was refluxed for 45 hours and evaporated to dryness. Water was added to the residue and the mixture was extracted with chloroform. The aqueous phase was adjusted to pH 5 with acetic acid, and the solid which was precipitated was filtered off, washed and dried to give 2-nitroamino-5-(3-pyridylmethyl)-4-pyrimidone, m.p. 214.5°-216°, in 38% yield.
Reaction SMILES: [F:1][C:2]1[C:3]([N:18]2[C:22](=[O:23])[N:21]([CH:24]([F:26])[F:25])[C:20]([CH3:27])=[N:19]2)=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH2:8][CH:9]([Br:14])[C:10](OC)=[O:11])[CH:7]=1.O>C(O)(=O)C.[Fe]>[Br:14][CH:9]1[CH2:8][C:6]2[C:5](=[CH:4][C:3]([N:18]3[C:22](=[O:23])[N:21]([CH:24]([F:26])[F:25])[C:20]([CH3:27])=[N:19]3)=[C:2]([F:1])[CH:7]=2)[NH:15][C:10]1=[O:11]
Reactant: COC(=O)C(Br)Cc1cc(F)c(-n2nc(C)n(C(F)F)c2=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nn(-c2cc3c(cc2F)CC(Br)C(=O)N3)c(=O)n1C(F)F
Temperature: 40 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A solution of 9.0 g (0.020 mole) of methyl 3-[5- fluoro-4-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)-2-nitrophenyl]-2-bromopropionate in 100 mL of glacial acetic acid was stirred, and 9.0 mL of water was added. The reaction mixture was warmed to 40° C., and 9.0 g (0.16 mole) of iron powder was slowly added. Upon completion of addition the reaction mixture was allowed to cool to ambient temperature where it was stirred for 2 hours. The reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was diluted with water, and the mixture was extracted with 100 mL of ethyl acetate. The filtrate was concentrated under reduced pressure to yield 7.5 g of 1-(3-bromo-6-fluoro-3,4-dihydroquinolin-2(1H)-one-7-yl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[NH:12][C:11]=2[CH:21]=1)([O:3][CH2:4][CH3:5])=[O:2].[Br:22][CH:23]([CH3:27])[C:24](Cl)=[O:25].Cl>C1(C)C=CC=CC=1>[C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]([C:24](=[O:25])[CH:23]([Br:22])[CH3:27])[C:11]=2[CH:21]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CC(Br)C(=O)Cl
Reactant: CCOC(=O)Nc1ccc2c(c1)Nc1ccccc1CC2
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1ccc2c(c1)N(C(=O)C(C)Br)c1ccccc1CC2
Temperature: 25 °C
Yield: 93.5 %

Procedure:
The starting material can be synthesized as follows. 3-Carbethoxyamino-10,11-dihydro-5H-dibenz[b,f]azepine (28.2 g, 0.1 moles) is mixed with 300 ml toluene and 20 g (0.11 moles) of 2-bromopropionyl chloride and stirred for 4 hours on a boiling water bath, while HCl gas is escaping. The mixture is allowed to cool to room temperature and filtered and the filtrate is evaporated to dryness under reduced pressure. Upon addition of diethyl ether, the residue crystallizes, after temporarily going into solution. The crystalline deposit is filtered off with suction, washed with ether and dried. 3-Carbethoxyamino-5-(α-bromopropionyl)-10,11-dihydro-5H-dibenz[b,f]azepine (39 g) is obtained, which is purified by recrystallization from the 5-fold amount of isopropanol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20]3([CH2:26][NH:25][CH2:24]3)[O:19][CH2:18]4)=[N:12][CH2:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.[CH3:31][S:32]([CH2:35][C:36](O)=[O:37])(=[O:34])=[O:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:9][C:7]1[CH:6]=[C:5]([C:10]2([C:27]([F:29])([F:28])[F:30])[CH2:14][C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20]3([CH2:24][N:25]([C:36](=[O:37])[CH2:35][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:26]3)[O:19][CH2:18]4)=[N:12][CH2:11]2)[CH:4]=[C:3]([Cl:2])[CH:8]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CN=C(c2ccc3c(c2)COC32CNC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CS(=O)(=O)CC(=O)N1CC2(C1)OCc1cc(C3=NCC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
To the stirred solution of 5′-(3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]hydrochloride (Preparation 13, 0.46 g, 0.963 mmol) in DMF (10 mL) was added TEA (0.67 mL, 4.81 mmol), methane sulfonyl acetic acid (0.266 g, 1.93 mmol) followed by addition of HOBt (0.13 g, 0.96 mmol) and EDC.HCl (0.276 g, 1.44 mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete conversion of starting material, reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×20 mL). Combined organic layer was washed with LiCl solution (2×40 mL) and brine (2×50 mL), dried over sodium sulfate and concentrated to get brown semi solid (0.597 g, crude). Crude compound was purified by column chromatography using silica gel (230-400 mesh). Desired compound was eluted in 0.8% methanol in DCM to get off white solid (403 mg). Compound was triturated thrice with chloroform n-hexane to get pure compound as off white solid (0.24 g, 44.4%), 1H NMR (400 MHz, DMSO-d6) δ: 3.14 (s, 3H), 3.73 (d, J=18.2 Hz, 1H), 3.87 (d, J=18.12 Hz, 1H), 4.23 (d, J=10.48 Hz, 4H), 4.42 (d, J=16.88 Hz, 1H), 4.57 (s, 2H), 4.82 (d, J=17.2 Hz, 1H), 5.13 (s, 2H), 7.57 (s, 2H), 7.65 (d, J=7.92 Hz, 1H), 7.70 (s, 1H), 7.86 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), LC-MS (m/z): 561.0 (M+H),
Reaction SMILES: C(O[C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:16][C:17]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:34]=O>C(O)=O.O.[OH-].[Na+]>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:17]2[N:16]=[C:15]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[C:12]3[CH2:13][CH2:14][N:8]([CH3:6])[CH2:9][C:10](=[CH2:34])[C:11]=3[N:18]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cc3ccc(F)cc3)nc(-c3ccc(F)cc3)c2CC1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: C=C1CN(C)CCc2c1nc(Cc1ccc(F)cc1)nc2-c1ccc(F)cc1
Temperature: 80 °C

Procedure:
To a solution of 2-(4-fluoro-benzyl)-4-(4-fluoro-phenyl)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylic acid tert-butyl ester in formic acid was added paraformaldehyde (10 equiv.). The mixture was heated at 80° C. for 6 h. The mixture was diluted with water and basified to pH ˜10 with 1 M NaOH. The mixture was extracted with CH2Cl2, dried and concentrated. Chromatography on SiO2 (0-5% 2 M NH3 in MeOH/CH2Cl2) afforded the desired compound. 2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine was also obtained. MS (ESI): exact mass calcd. for C23H21F2N3, 377.17; m/z found, 378.4 [M+H]+. 1H NMR (CDCl3): 7.50-7.46 (m, 2H), 7.42-7.37 (m, 2H), 7.17-7.12 (m, 2H), 6.99-6.94 (m, 4H), 6.03-6.01 (m, 1H), 5.47-5.46 (m, 1H), 4.25 (s, 2H), 3.51 (s, 2H), 2.87-2.83 (m, 2H), 2.76-2.72 (m, 2H), 2.41 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12]O.O=S(Cl)Cl>C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(O)cc1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(O)cc1

Procedure:
A mixture of 4-hydroxyphenylacetic acid (9.12 g, 0.06 mol), methanol (50 ml) and SOCl2 (2 mL, 0.028 mol) was refluxed for 3 hours. The residue was cooled, diluted with ethyl acetate (20 mL), washed first with aqueous 5% Na2CO3 solution and then twice with water (100 mL), then dried over anhydrous MgSO4, filtered and evaporated in vacuo to give methyl 4-hydroxyphenylacetate as an oil.
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]([C:26]23[CH2:33][CH2:32][C:29]([NH:34][S:35]([CH:38]4[CH2:40][CH2:39]4)(=[O:37])=[O:36])([CH2:30][CH2:31]2)[CH2:28][CH2:27]3)[N:7]2[C:12]3[CH:13]=[CH:14][N:15]([S:16]([C:19]4[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=4)(=[O:18])=[O:17])[C:11]=3[N:10]=[CH:9][C:8]=12)C=C.C[N+]1([O-])CCOCC1.C(Cl)Cl.[O:52]1[CH2:57][CH2:56][O:55]CC1>O.[Os](=O)(=O)(=O)=O>[OH:52][CH:57]([CH2:56][OH:55])[CH2:1][C:4]1[N:5]=[C:6]([C:26]23[CH2:31][CH2:30][C:29]([NH:34][S:35]([CH:38]4[CH2:40][CH2:39]4)(=[O:36])=[O:37])([CH2:28][CH2:27]2)[CH2:32][CH2:33]3)[N:7]2[C:12]3[CH:13]=[CH:14][N:15]([S:16]([C:19]4[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=4)(=[O:17])=[O:18])[C:11]=3[N:10]=[CH:9][C:8]=12
Reactant: C=CCc1nc(C23CCC(NS(=O)(=O)C4CC4)(CC2)CC3)n2c1cnc1c2ccn1S(=O)(=O)c1ccc(C)cc1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(CC(O)CO)nc(C45CCC(NS(=O)(=O)C6CC6)(CC4)CC5)n23)cc1
Reaction time: 15 h
Yield: 3 %

Procedure:
To a solution of N-(4-(3-allyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo-[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.27 g, 0.47 mmol, prepared using E with 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid [Prime Organics], K with cyclopropylsulfonyl chloride, H from Preparation #12, HATU and DIEA, Q with Lawesson's reagent and mercury (II) trifluoroacetate) in 1,4-dioxane (10 mL) and water (1 mL) was added N-methylmorpholine-N-oxide (0.22 g, 1.8 mmol) followed by osmium tetroxide (4 wt % in water, 0.36 mL, 0.047 mmol). The reaction mixture was stirred for about 15 h and then DCM (20 mL) and water (10 mL) were added to the reaction mixture. The organic layer was separated, concd in vacuo, and purified by chromatography on silica gel eluting with 10-50% MeCN in DCM, to provide N-(4-(3-(2,3-dihydroxypropyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.009 g, 3%): LC/MS (Table 1, Method a) Rt=1.90 min; MS m/z: 612 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]3[S:14][CH:15]=[C:16]([CH3:18])[N:17]=3)[N:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:19][O-:20].[Na+]>S1(CCCC1)(=O)=O.O>[CH3:19][O:20][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]3[S:14][CH:15]=[C:16]([CH3:18])[N:17]=3)[N:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: Cc1csc(Nc2nccc3ccc(Cl)nc23)n1
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: COc1ccc2ccnc(Nc3nc(C)cs3)c2n1
Temperature: 100 °C
Yield: 78.9 %

Procedure:
To a solution of (2-chloro-[1,7]naphthyridin-8-yl)-(4-methyl-thiazol-2-yl)-amine (0.055 g, 0.20 mmol) in 1.5 ml sulfolane was added g sodium methylate (0.55, 1.0 mmol). The reaction mixture was heated for 10 min at 100° C. under microwave irradiation. The reaction mixture was diluted with water and extracted with three portions of methyl-tert.-butyl ether. The combined organic layers were washed with two portions of water, dried over sodium sulfate and concentrated to dryness. Flash-chromatography gave the title compound (0.043 g, 79%) as an off-white solid, MS m/e (%): 273 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](\[O:27][CH3:28])/[C:25]#[N:26])=[CH:19][C:17]=2[CH:18]=1.Cl.C[OH:31]>[OH-].[Na+]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](\[O:27][CH3:28])/[C:25]([NH2:26])=[O:31])=[CH:19][C:17]=2[CH:18]=1
Reactant: CO
Reactant: CO/C(C#N)=C\c1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CO/C(=C\c1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1)C(N)=O

Procedure:
A solution of (Z)-3-[2-(5-methyl-2-phenyl-4-oxazolyl) methyl- 5-benzofuranyl]-2-methoxy-2-propenenitrile (0.10 g, 0.27 mmol) in methanol (10 ml) and sodium hydroxide (2 ml) was heated to reflux for 3 hours then cooled, acidified with 6N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated. The product was purified by flash chromatography (ethyl acetate/methanol/acetic acid, 75:1:1) and obtained as a solid (31 mg, m.p. 166°-169° C.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH2:14]>>[O:1]1[CH:5]=[CH:4][C:3]([C:10]2[CH:11]=[C:12]([CH2:13][NH2:14])[CH:15]=[CH:16][CH:17]=2)=[CH:2]1
Reactant: OB(O)c1ccoc1
Reactant: NCc1cccc(Br)c1
Product: NCc1cccc(-c2ccoc2)c1
Yield: 76 %

Procedure:
Using the same method as in Example 19-(ii), 3-furanboronic acid was reacted with the 3-bromobenzyl amine to give 1-[3-(furan-3-yl)phenyl]methanamine (yield: 76%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([C:14](O)=O)(O)[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[CH3:17].O[C:19]1[CH:20]=[C:21]([CH:25]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH:22]=[CH:23]C=1>C(O)(=O)C>[O:34]=[C:33]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:35])[C:25]1=[C:21]1[CH:22]=[CH:23][C:14]2=[C:9]([C:5]3[CH:4]=[C:3]([CH3:17])[C:2]([NH2:1])=[C:7]([CH3:8])[CH:6]=3)[C:10](=[O:11])[O:12][C:19]2=[CH:20]1
Reactant: Cc1cc(C(O)(C(=O)O)C(=O)O)cc(C)c1N
Reactant: O=C1c2ccccc2C(=O)C1c1cccc(O)c1
Solvent: CC(=O)O
Product: Cc1cc(C2=c3ccc(=C4C(=O)c5ccccc5C4=O)cc3OC2=O)cc(C)c1N
Temperature: 20 °C
Yield: 38 %

Procedure:
4-Amino-3,5-dimethylphenyltartronic acid (2.1 parts), 2-(3-hydroxyphenyl)-1,3-indandione (1.3 parts) and glacial acetic acid (125 parts) were stirred under reflux for 2 hours. The reaction mixture was cooled to 20° C. and the precipitated solid was recovered by filtration, washed with methanol and dried to give 6-(1,3-dioxoindan-2-ylidene)-2-oxo-3-(4-amino-3,5-dimethylphenyl)-2,6-dihydrobenzofuran (0.9 parts, 38%), m.pt. >250° C. λmax (CH2Cl2)=656 nm.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:3]1[CH3:30].[H-].[Na+].[CH3:33]I>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4]([CH2:20][CH2:21][N:22]([CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[C:3]1[CH3:30]
Reactant: Cc1c(CCNC(=O)OC(C)(C)C)c2cc(S(=O)(=O)c3ccccc3)ccc2n1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CCN(C)C(=O)OC(C)(C)C)c2cc(S(=O)(=O)c3ccccc3)ccc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A solution of tert-butyl 2-[1,2-dimethyl-5-(phenylsulfonyl)-1H-indol-3-yl]ethylcarbamate (2.99 g, 6.98 mmol) in DMF (20.0 mL) was added to a 0° C. suspension of 60% sodium hydride (0.75 g, 18.82 mmol) in DMF (5.0 mL) and stirred at room temperature for one hour. Methyl iodide (0.55 mL, 8.83 mmol) was added and the reaction was stirred at room temperature for 22 hours. The reaction was cooled to 0° C., quenched with water (10.0 mL) and filtered. The filtrate was concentrated in vacuo, combined with the previously filtered solid and partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo and recrystallized from EtOAc/hexane to give 2.56 g (83%) of colorless crystals as the title compound: mp 147.1-149.0° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.15-8.10 (m, 1H), 7.92 (d, J=7.1 Hz, 2H), 7.62-7.53 (m, 5H), 3.67 (s, 3H), 3.32 (m, 2H), 2.91-2.88 (m, 2H), 2.79 (br, 3H), 2.33 (br, 3H), 1.35-0.99 (2 br, 9H); 13C NMR (100 MHz, DMSO-d6) δ 154.4, 142.9, 138.0, 137.1, 132.7, 130.4, 129.3, 126.9, 126.7, 119.0, 117.7, 109.9, 109.4, 77.7, 48.8, 33.7, 29.7, 27.9, 27.4, 22.0, 9.8; IR (diffuse reflectance) 1692, 1482, 1446, 1364, 1303, 1219, 1192, 1164, 1152, 1140, 1095, 725, 689, 655, 609 cm−1; HRMS (FAB) calcd for C24H30N2O4S+H 443.2004, found 443.2025. Anal. Calcd for C24H30N2O4S: C, 65.13; H. 6.83; N, 6.33. Found: C, 65.06; H, 6.86; N, 6.33.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11].O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(N)cc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 73.6 %

Procedure:
12.3 g of p-anisidine were added in small fractions to a suspension of 18.6 g of 4-nitrobenzoic acid chloride in 100 ml of pyridine and the mixture was heated for 2 hours at reflux. After returning to ambient temperature, the solution was poured into 500 ml of iced water and the precipitate formed was separated and washed with water, then dried under reduced pressure at 80° C. to obtain 20 g of N-(4-methoxyphenyl)-4-nitrobenzamide melting at 200° C.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CCN=C=NCCCN(C)C>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:1][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:8])=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)ON2C(=O)CCC2=O)CC1
Temperature: 5 °C
Yield: 84.4 %

Procedure:
N-Hydroxysuccinimide (25.3 g) was added to a solution of 1-(t-butoxycarbonyl)piperidine-4-carboxylic acid (45.8 g) in DMF (250 ml) and the mixture stirred at 5° C. EDAC (42 g) was added and the mixture stirred for 4 hours at 5° C. A further portion of EDAC (5.73 g) was added and the mixture allowed to warm to ambient temperature and stirred overnight. The mixture was evaporated to half its original volume and the residue partitioned between ethyl acetate (1000 ml) and water (250 ml). The ethyl acetate phase was separated, washed with water (2×250 ml), brine (50 ml), dried (MgSO4) and evaporated to give a solid which was recrystallised from a mixture of ethyl acetate/hexane (250 ml/500 ml) to give 1-(1-(t-butoxycarbonyl)piperidin-4-ylcarbonyloxy)2,5-dioxopyrrolidine (55 g);
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[S:12]([NH:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[C:17]=1[CH3:22])(=[O:14])=[O:13].[CH3:23][C:24]([CH3:26])=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:23][CH:24]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[S:12]([NH:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[C:17]=1[CH3:22])(=[O:14])=[O:13])[CH3:26]
Reactant: CC(C)=O
Reactant: Cc1noc(NS(=O)(=O)c2cccc3c(N)cccc23)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2cccc3c(NC(C)C)cccc23)c1C
Reaction time: 0.75 h
Yield: 123.5 %

Procedure:
To a solution of Example 3 (0.150 g, 0.473 mmol) in 10 mL of methanol, was added acetone (0.035 g, 0.473 mmol). The resulting clear yellow solution was stirred for 45 minutes. Sodium cyanoborohydride (0.058 g, 0.95 mmol) and acetic acid (0.172 g, 2.85 mmol) were added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, taken up in 20 mL of water and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (1×35 mL), dried (magnesium sulfate) and concentrated in vacuo to give 0.21 g of a yellow solid. This material was chromatographed (50 g Merck silica gel) using ethyl acetate:hexanes (1:1) as the eluant to give 0.101 g (60%) of Example 18 as a yellow solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:30][CH2:31][N:32]([C:14]([C:13]4[CH:12]=[CH:11][C:10]([C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:19])([CH3:8])[CH3:9])=[CH:18][CH:17]=4)=[O:16])[CH2:33][CH2:34]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(c1ccc(C(=O)O)cc1)N1CCCS1(=O)=O
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(C(C)(C)N3CCCS3(=O)=O)cc2)CC1
Yield: 39.7 %

Procedure:
Using 4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1-methylethyl]benzoic acid (170 mg) described in Preparation Example 39 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (156 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (115 mg) was obtained.