Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[CH2:6][CH2:5][C:4]([P:17]([O:23]C(C)C)(=[O:22])[O:18]C(C)C)([P:7]([O:13]C(C)C)(=[O:12])[O:8]C(C)C)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:47]>>[Cl:47][CH:2]1[CH2:6][CH2:5][C:4]([P:17]([OH:23])(=[O:22])[OH:18])([P:7]([OH:13])(=[O:12])[OH:8])[CH2:3]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)OP(=O)(OC(C)C)C1(P(=O)(OC(C)C)OC(C)C)CCC(O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=P(O)(O)C1(P(=O)(O)O)CCC(Cl)C1
Yield: 69 %

Procedure:
Tetraisopropyl 3-hydroxycyclopentane-1,1-diphosphonate (3.00 g, 7.24 mmol) was dissolved in 50 mL dry CCl4. Triphenylphosphine (3.80 g, 14.5 mmol) was added and the mixture was refluxed for 72 h. The mixture was filtered, concentrated, and the residue chromatographed (3:2 hexane:THF) on silica gel to afford 2.15 g (69%) of the desired product as a clear, viscous oil: 1H NMR (CDCl3) chemical shift 4.97-4.68 (m, 4H, OCHMe2), 4.24 (m, 1H, J=7 Hz, CHOH), 2.65-1.87 (m, 6H, ring CH2), 1.36 (d, 24H, J=6 Hz, CH3); 31P NMR (CDCl3) 25.3, 24.9, 24.4, 24.0; ammonia Cl mass spectrum m/e 433, 435 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([OH:14])[C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[OH:6].S(=O)(=O)(O)O>CCC(=O)CC>[CH3:1][O:2][C:3]([C@@H:4]1[C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[O:6][C:5]([CH2:7][CH3:8])([CH2:4][CH3:3])[O:14]1)=[O:15]
Reactant: COC(=O)[C@@H](O)[C@H](O)c1ccccc1Cl
Agent: O=S(=O)(O)O
Solvent: CCC(=O)CC
Product: CCC1(CC)O[C@H](C(=O)OC)[C@@H](c2ccccc2Cl)O1
Temperature: 25 °C
Yield: 60 %

Procedure:
3-pentanone was added to (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate at room temperature. Sulfuric acid (H2SO4) was added and stirred at room temperature. The reaction mixture was quenched with H2O, extracted with EA, washed with H2O, dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (1.6 g, 60˜85%).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C(O)C>[NH2:1][C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=3)=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cn1cnc2c([N+](=O)[O-])cccc21)Nc1cccc(C(F)(F)F)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc2c1ncn2CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 19.9 %

Procedure:
2-(4-Nitro-1H-benzimidazol-1-yl)-N-[3-(trifluoromethyl)phenyl]acetamide (60 mg, 0.17 mmol) (see Example 105) was dissolved in ethanol (1.44 mL) and tin(II) chloride (192 mg, is 0.85 mmol) was added. The reaction mixture was stirred at 70° C. for 16 h and then poured onto a mixture of ice and saturated aqueous NaHCO3 (20 mL). The basic solution was extracted with ethyl acetate (3×10 mL), washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated. The purification of the crude product was performed by preparative HPLC (XTerra C8 column 19×300 mm, 0.1 M NH4OAc/CH3CN). Product-containing fractions were pooled and lyophilised affording the title compound (11.3 mg, 20%). Calculated for C16H13F3N4O m/z: 334.10, found 335.09 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.07 (s, 2H), 5.24 (s, 2H), 6.37 (dd, J=7.6, 0.8 Hz, 1H), 6.64 (dd, J=8.0, 0.63 Hz, 1H), 6.90 (t, J=7.8 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.77 (m, 1H), 7.99 (s, 1H), 8.06 (s, 1H), 10.74 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([NH:14][NH:15]OC(C)(C)C)=[S:11]=C=O)[CH:5]=1.C1(OC)C=CC=CC=1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([NH:14][NH2:15])=[S:11])[CH:5]=1
Reactant: COC(=O)c1cccc(C(NNOC(C)(C)C)=S=C=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)c1cccc(C(=S)NN)c1

Procedure:
A solution of 3-(N′-tert-butoxy-carbonyl-hydrazinocarbothioyl)-benzoic acid methyl ester (0.93 g) in TFA (9 mL)/anisole (2 mL) was stirred at 0° C. for 1 h. The solvents were evaporated in vacuum to give crude 3-hydrazinothiocarbonyl-benzoic acid methyl ester trifluoroacetate (0.98 g) as a crystallizing oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])([CH3:13])[CH2:9][C:10]([NH2:12])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])([CH3:13])[CH2:9][C:10]([NH2:12])=[S:37])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[SH](CC(N)=O)(c1ccc(F)cc1)(c1ccc(F)cc1)c1ccccc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C[SH](CC(N)=S)(c1ccc(F)cc1)(c1ccc(F)cc1)c1ccccc1F
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-[bis-(4-fluoro-phenyl)-(2-fluoro-phenyl)-methylsulfanyl]-acetamide (0.5 g) in toluene (20 ml) was treated with Lawesson's reagent (0.26 g) at room temperature under Argon and stirred for 1.5 hours at 80° C. After pouring into saturated brine the organics were extracted with dichloromethane (3×). Drying of the combined organic extracts (Na2SO4), filtration, concentration and flash-chromatography of the residue gave the title compound (42%; Isolated as an oil).
Reaction SMILES: C[O:2][CH:3]1[CH:8]2[C:9](=[O:14])[CH:10]=[CH:11][C:12](=[O:13])[CH:7]2[CH2:6][CH:5]([C:15]([CH3:17])=[O:16])[O:4]1.C(O[CH:22]=[CH:23][CH:24]=[CH2:25])(=O)C>C1C=CC=CC=1>[OH:2][CH:3]1[C:8]2[C:9](=[O:14])[C:10]3[C:11]([C:12](=[O:13])[C:7]=2[CH2:6][CH:5]([C:15]([CH3:17])=[O:16])[O:4]1)=[CH:25][CH:24]=[CH:23][CH:22]=3
Reactant: C=CC=COC(C)=O
Reactant: COC1OC(C(C)=O)CC2C(=O)C=CC(=O)C12
Solvent: c1ccccc1
Product: CC(=O)C1CC2=C(C(=O)c3ccccc3C2=O)C(O)O1
Temperature: 60 °C
Yield: 30.2 %

Procedure:
A mixture of methyl (1-methoxy-5,8 dioxo-tetrahydrobenzo [2,3-C] pyran-3-yl) ketone (100 mg, 0.450 mmol) and acetoxy butadiene (80 μg, 0.675 mmol) in dry benzene (5 mL) was heated for 3 hours at 60° C. under argon atmosphere. The solvent was then removed in vacuo and the resulting adduct was dissolved in 10 mL of toluene and then aromatized on silica gel by flash chromatography (toluene:ethyl acetate; 90%:10% followed by 70%:30%). Evaporation of the solvents gave 37 mg (31% yield) of pure titled compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[C:22]([C:24]4[N:25]=[C:26]([NH:29]C(OC(CC)(C)C)=O)[S:27][CH:28]=4)=[O:23])[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1>C(O)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[C:22]([C:24]4[N:25]=[C:26]([NH2:29])[S:27][CH:28]=4)=[O:23])[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: CCC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)cs1
Agent: CCC(C)(C)OC(=O)N=c1[nH]c(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)cs1
Solvent: O=CO
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)[C@H]2SC1
Reaction time: 5 h

Procedure:
A mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (1.8 g.) and 98 to 100% formic acid (40 ml.) was allowed to stand for 5 hours. After the reaction, the reaction mixture was post-treated in the similar manners as in Examples 16 to 17 to give 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (0.32 g.), mp. 147° to 160° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:12]([O-])=O.[Na+]>C(O)(=O)C.O>[N+:9]([C:8]1[CH:7]=[CH:6][CH:5]=[C:3]2[C:2]=1[CH:1]=[N:12][NH:4]2)([O-:11])=[O:10]
Reactant: O=N[O-]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cccc2[nH]ncc12
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, the deep red solution was poured onto ice/water and the resulting precipitate collected by filtration to yield 4-nitro-1H-indazole C (1.98 g, 81%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([N+:16]([O-])=O)[CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1>CO.[Pd]>[F:1][C:2]1[CH:15]=[C:14]([CH:13]=[C:4]([CH2:5][N:6]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[CH:3]=1)[NH2:16]
Reactant: CN1CCN(Cc2cc(F)cc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(Cc2cc(N)cc(F)c2)CC1
Yield: 100 %

Procedure:
A solution of 1-(3-fluoro-5-nitrobenzyl)-4-methylpiperazine (0.15 g, 0.592 mmol) in MeOH (5 mL) was treated with 10% Pd—C (dry) (0.063 g, 0.059 mmol) and hydrogenated (1 atm) for 3 h. The solids were removed via filtration, rinsed with MeOH and the filtrate concentrated to dryness to afford 3-fluoro-5-((4-methylpiperazin-1-yl)methyl)aniline (100% yield assumed). MS (ESI) m/z: 224.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([CH3:25])=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:12]=[C:13]([NH:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[C:14]([Cl:17])=[N:15][CH:16]=3)=[CH:9][N:10]=2)[CH:7]=1.Br[C:27]1[C:28](C)=[CH:29][C:30]2[N:31](C(I)=CN=2)[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:17][C:14]1[C:13]([NH:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:28]4[CH:27]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:3]([CH3:25])=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:16][N:15]=1
Reactant: Cc1cc2ncc(I)n2cc1Br
Reactant: Cc1cc2ncc(-c3cnc(Cl)c(NS(=O)(=O)N(C)C)c3)n2cc1Br
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc2ncc(-c3cnc(Cl)c(NS(=O)(=O)N(C)C)c3)n2cc1-c1ccncc1
Temperature: 110 °C

Procedure:
N-(5-(6-bromo-7-methylimidazo[1,2-a]pyridin-3-yl)-2-chloropyridin-3-yl)dimethylaminosulfonamide. To a 5 mL microwave tube was added N-(2-chloro-5-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-N′,N′-dimethylsulfonamide (0.300 g, 0.830 mmol), 6-bromo-3-iodo-7-methylimidazo[1,2-a]pyridine (0.335 g, 0.995 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(ii) (0.061 g, 0.083 mmol), sodium carbonate (1.037 mL, 2.074 mmol), and dioxane (3 mL). The resulting mixture was sealed and underwent microwave heating at 110° C. for 20 min. The solvent was removed. The residue was partitioned between pH 7-buffer (1M TRIS-HCL) and DCM. The aqueous layer was extracted more with DCM (2×10 mL). The combined organic layer was dried over MgSO4 and concentrated. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, 80 g SiO2, DCM:EtOAc:MeOH=65%:32%:3%, Flow=65 mL/min). The solvent was removed in vacuo to afford the desired product as light yellow solid (160 mg). MS (ESI pos. ion) m/z: 443.8. Calcd exact mass for C15H15BrClN5O2S: 442.9. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.51 (s, 3H) 2.95 (s, 6H) 6.92 (br. s., 1H) 7.59 (s, 1H) 7.75 (s, 1H) 8.09 (s, 1H) 8.34 (s, 1H) 8.48 (s, 1H).
Reaction SMILES: [C:1]1(=[O:14])[C:10]2[C:5](=CC(C(O)=O)=C[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=O.C1(N=C=NC2CCCCC2)CCCCC1.[Cl-].[NH4+].C(N(CC)CC)C>C(Cl)Cl>[CH2:2]1[C:3]2[C:17](=[CH:18][C:19]([C:20]([NH2:16])=[O:21])=[CH:5][CH:4]=2)[CH2:9][CH2:10][C:1]1=[O:14]
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1ccc2c(c1)CCC(=O)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
Tetralone-6-carboxylic acid, ethylene ketal (395 mg, 2.07 mmol) was codissolved in CH2Cl2 (50 mL) with N-hydroxysuccinimide (260 mg, 2.76 mmol) at 0° C. and treated with a slight excess of 1,3-dicyclohexylcarbodiimide (502 mg, 2.50 mmol). The mixture was allowed to warm to ambient temperature over 30 minutes, during which time a fine white precipitate formed. Ammonium chloride (333 mg, 6.23 mmol) and triethylamine (1.58 mL, 12.5 mmol, d=0.797) were added. The solution was stirred at ambient temperature for 16 hours. The suspended urea and salts were filtered away and the solution concentrated in vacuo to a colorless oil. The oil was applied to a silica flash chromatography column and eluted with 50-100% EtOAc in hexanes to yield 250 mg (64%) of 2-tetralone-6-carboxamide, ethylene ketal as a white solid, clean by NMR, TLC.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:17])[N:10]([C@@H:18]3[O:35][C@H:34]([CH2:36][O:37]C(=O)C)[C@@H:29]([O:30]C(=O)C)[C@H:24]([O:25]C(=O)C)[C@H:19]3[O:20]C(=O)C)[CH:9]=2)=[CH:4][CH:3]=1.[F:41][C:42]1[N:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1>>[F:41][C:42]1[N:47]=[CH:46][C:45]([C:2]2[S:6][C:5]([CH2:7][C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][C:15]=4[CH3:17])[N:10]([C@@H:18]4[O:35][C@H:34]([CH2:36][OH:37])[C@@H:29]([OH:30])[C@H:24]([OH:25])[C@H:19]4[OH:20])[CH:9]=3)=[CH:4][CH:3]=2)=[CH:44][CH:43]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(Br)s3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OB(O)c1ccc(F)nc1
Product: Cc1cccc2c1c(Cc1ccc(-c3ccc(F)nc3)s1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
3-(5-Bromothiophen-2-yl-methyl)-4-methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 45-(3) and 6-fluoropyridine-3-boronic acid were treated in a manner similar to Example 45-(4) and 2-(7) to give the titled compound as a colorless powder. APCI-Mass m/Z 485 (M+H). 1H-NMR (DMSO-d6) δ 2.50 (s, 3H), 3.20-3.50 (m, 4H), 3.70 (m, 2H), 4.40 (s, 2H), 4.54 (t, J=5.4 Hz, 1H), 5.09 (d, J=5.3 Hz, 1H), 5.16 (d, J=5.7 Hz, 1H), 5.17 (d, J=5.7 Hz, 1H), 5.36 (d, J=9.0 Hz, 1H), 6.75 (d, J=7.1 Hz, 1H), 6.87 (d, J=3.4 Hz, 1H), 7.00 (t, J=7.7 Hz, 1H), 7.19 (dd, J=8.6, 2.7 Hz, 1H), 7.33 (s, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.44 (d, J=3.4 Hz, 1H), 8.16 (dt, J=8.2, 2.4 Hz, 1H), 8.45 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:11](=[O:13])[O:10][C:9](C)(C)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH2:2].C[O-].[Na+].CO>Cl>[CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:12]=1[C:11]([O:10][CH3:9])=[O:13])=[CH2:2]
Reactant: C=Cc1cccc2c1C(=O)OC(C)(C)O2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=Cc1cccc(O)c1C(=O)OC
Yield: 57.3 %

Procedure:
To 5-ethenyl-2,2-dimethyl-4H-1,3-benzodioxin-4-one (4.01 9, 19.6 mmol) was added 0.5 M sodium methoxide in methanol (85 mL, 42.5 mmol) at room temperature. Aqueous 1 N HCl (100 mL) was added to the solution after 15 minutes. The cloudy solution was extracted with ether (2×100 mL). The combined organic extracts were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to afford 2-ethenyl-6-hydroxybenzoic acid, methyl ester (2.0 g, 57%) as a yellow oil. This material was used without further purification in the next step: 1H NMR (CDCl3) δ 3.96 (s, 3H), 5.26 (dd, J=10.8, 1.5 Hz, 1H), 5.49 (dd, J=17.3, 1.5 Hz, 1H), 6.95 (m, 2H), 7.23-7.39 (m, 2H), 11.12 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[N:12]=[C:13]([CH2:15][C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[CH:14]=[C:4]2[NH:3]1>N.CO.[Ni]>[NH2:20][CH2:19][C:18]1[CH:17]=[C:16]([CH:23]=[CH:22][CH:21]=1)[CH2:15][C:13]1[CH:14]=[C:4]2[NH:3][C:2](=[O:1])[C:11]3[C:6]([N:5]2[N:12]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: N#Cc1cccc(Cc2cc3[nH]c(=O)c4ccccc4n3n2)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cccc(Cc2cc3[nH]c(=O)c4ccccc4n3n2)c1

Procedure:
A mixture of Example 62 (0.32 g, 1.066 mmol) and 3 g raney-nickel in methanol ammonia (30 mL) was stirred under a hydrogen atmosphere at 60 psi for 3.5 hr. The mixture was filtered then evaporated and purified by chromatography on silica gel with 10% MeOH/CH2Cl2 to provide the desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.17 (s, 1 H) 3.71 (s, 2 H) 3.97 (s, 2 H) 5.66 (s, 1 H) 7.14-7.20 (m, 2 H) 7.22-7.29 (m, 2 H) 7.42-7.47 (m, 1 H) 7.82-7.87 (m, 1 H) 8.03 (d, J=8.29 Hz, 1 H) 8.11 (dd, J=7.98, 1.53 Hz, 1 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4]3[C:5](=[CH:10][CH:11]=[CH:12][C:3]=3[C:2]1=[O:13])[CH:6]=[CH:7][CH:8]=2.S(OCC)(O[CH2:18][CH3:19])(=O)=O>[OH-].[K+]>[CH2:18]([N:1]1[C:9]2[C:4]3[C:5](=[CH:10][CH:11]=[CH:12][C:3]=3[C:2]1=[O:13])[CH:6]=[CH:7][CH:8]=2)[CH3:19]
Reactant: O=C1Nc2cccc3cccc1c23
Reactant: CCOS(=O)(=O)OCC
Agent: [K+]
Agent: [OH-]
Product: CCN1C(=O)c2cccc3cccc1c23
Reaction time: 16 h
Yield: 46 %

Procedure:
A mixture of benz[cd]indol-2(1H)-one (15.0 g, 88.8 mmole) in 20% aqueous potassium hydroxide (200 ml) was heated at 55°-60° C. while 60 ml of diethyl sulfate was added dropwise over a three hour period. After 16 hours at room temperaure and an additional hour at 55°-60° C., the mixture was partitioned between dichloromethane and water. The organic phase was concentrated and purified by chromatography on silicon dioxide with 5% acetone/dichloromethane to give the desired product (8.0 g, 46%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CO[C:9](=O)[NH:10][CH2:11][CH:12]1[CH2:16][C:15]2[CH:17]=[C:18]([Cl:27])[CH:19]=[C:20]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:14]=2[O:13]1.Cl>O1CCCC1>[Cl:27][C:18]1[CH:19]=[C:20]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:14]2[O:13][CH:12]([CH2:11][NH:10][CH3:9])[CH2:16][C:15]=2[CH:17]=1
Reactant: COC(=O)NCC1Cc2cc(Cl)cc(C3CCCCC3)c2O1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CNCC1Cc2cc(Cl)cc(C3CCCCC3)c2O1
Temperature: 25 °C
Reaction time: 30 h
Yield: 50 %

Procedure:
To a suspension of lithium aluminum hydride (0.114 g, 3.0 mmol) in tetrahydrofuran (30 mL) was added (±)-methyl(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (0.65 g, 2.0 mmol) and the reaction mixture was allowed to stir at room temperature for 30 h. The reaction mixture was quenched with saturated ammonium chloride (50 mL), diluted with tetrahydrofuran (70 mL), and the aqueous layer was extracted with tetrahydrofuran (2×50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (100 mL) and saturated aqueous sodium chloride (100 mL), were dried (sodium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, dichloromethane:methanol 97:3) gave a light brown oil. The oil was re-dissolved in tetrahydrofuran (50 mL) and aqueous hydrogen chloride (1 N, 3 mL) was added. The resulting precipitate was filtered and washed with diethyl ether to provide 0.28 g (44%) of (±)-N-[(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methyl]-N-methylamine as a white solid, hydrochloride salt. mp 125-128° C.; Anal. calcd. for C16H22ClNOHCl: C, 60.76; H, 7.33; N, 4.43. Found: C, 60.92; H, 7.46; N, 4.09.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].[C:25]([O:29][C:30](=[O:33])[CH2:31]Br)([CH3:28])([CH3:27])[CH3:26]>CC(C)=O>[C:25]([O:29][C:30](=[O:33])[CH2:31][O:14][C:12]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([C:3]([O:2][CH3:1])=[O:18])[CH:13]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCC(=O)OC(C)(C)C)cc(C(=O)OC)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To a solution of 2.55 g. of dimethyl-5-hydroxy-2-nitroisophthalate (prepared as in Example 15, Part B) in 25 ml. of acetone is added 0.69 g. of anhydrous potassium carbonate, followed by 1.95 g. of tert-butylbromoacetate. The mixture is stirred and refluxed for 20 hr. After this time, the cooled reaction mixture is poured with rapid stirring into 200 ml. of ice-cold 1% hydrochloric acid. The solid is collected and washed well with water. Yield 3.4 g.; m.p. 106°-108° C.
Reaction SMILES: [OH-].[Na+].C([NH:11][C:12]([NH:14][C:15]1[CH:20]=[C:19]([N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[CH:18]=[C:17]([Br:26])[CH:16]=1)=[S:13])(=O)C1C=CC=CC=1>O.C1COCC1>[Br:26][C:17]1[CH:16]=[C:15]([NH:14][C:12]([NH2:11])=[S:13])[CH:20]=[C:19]([N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[CH:18]=1
Reactant: O=C(NC(=S)Nc1cc(Br)cc(-n2cccn2)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)Nc1cc(Br)cc(-n2cccn2)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
A solution of NaOH (0.13 g, 3.35 mmol) dissolved in 1.0 mL of H2O was added to a solution of 1-Benzoyl-3-(3-bromo-5-pyrazol-1-yl-phenyl)-thiourea 3 (0.27 g, 0.67 mmol) in 5.0 mL of THF. The resulting reaction mixture was stirred at 70° C. for 12 hours. THF was distilled off and extracted with ethyl acetate (×3). The combined organic layer was dried over Na2SO4, filtered and distilled off to get the crude residue that was washed with 2% Ethyl acetate-hexane to obtain the desired compound (0.17 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.CCCCCC>C(Cl)(Cl)(Cl)Cl.N(C(C)(CC(OC)(C)C)C#N)=NC(C)(CC(C)(OC)C)C#N>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: Cc1ccc(I)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(I)ccc1CBr
Temperature: 55 °C
Reaction time: 3.5 h
Yield: 84.8 %

Procedure:
To a solution of 2-chloro-4-iodotoluene (7.59 g) in carbon tetrachloride (76 ml) were added N-bromosuccinimide (5.89 g) and 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (Wako V-70, 281 mg) at room temperature and the mixture was stirred at 55° C. for 3.5 hr. The reaction mixture was allowed to cool to room temperature and thereto was added hexane (76 ml). Insoluble matter was filtered off. The filtrate was concentrated and the residue was again dissolved in hexane. The mixture washed successively with water, 5% aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 2-chloro-4-iodobenzyl bromide (8.45 g) as an oil.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:11]([F:31])[CH:10]=1>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:12]3[CH:13]=[CH:14][C:9]([N:6]4[CH:2]([CH3:1])[CH2:3][CH2:4][C:5]4=[O:7])=[CH:10][C:11]=3[F:31])=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CC1CCC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3F)CC2)c(C)c1
Yield: 42 %

Procedure:
Using 5-methylpyrrolidin-2-one (54 mg) and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (240 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 1, the title compound (94 mg) was obtained.