Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:24]>CN(C)C=O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:6][CH2:5][C:1]([OH:24])([CH3:3])[CH3:2])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CCC(C)(C)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of Example 244A (75 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL) was treated with NaH 60% dispersion in oil (9.5 mg, 0.23 mmol) followed by Example 308A (60 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 18 hours, poured into water and extracted with ethyl acetate. The organic layer was washed with H2O (2×50 mL), dried over MgSO4, filtered, concentrated under reduced pressure and dried under vacuum (˜1 mm Hg) to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.17 (s, 6H), 1.32 (s, 9H), 1.76-1.91 (m, 2H), 3.79 (s, 3H), 4.14-4.31 (m, 2H), 4.43 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.31 (s, 1H), 7.44 (dd, J=9.0, 2.9 Hz, 1H), 7.76 (d, J=3.1 Hz, 1H); MS (ESI) m/z 411 (M+H)+. Anal. Calculated for C20H27ClN2O3S C, 58.45; H, 6.62; N, 6.82. Found C, 58.30; H, 6.51; N, 6.71.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([O:19]C)=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.O.[OH-].[Li+].O>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([OH:19])=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2c1cc(F)cc(F)c1
Yield: 52.4 %

Procedure:
The title compound was synthesized from methyl 4-(3,5-difluorophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.081 g, 0.29 mmol) and lithium hydroxide monohydrate (61 mg, 1.45 mmol), according to General Procedure 7. A 1:6 mixture of water and methanol (MeOH)(3.5 mL) was used. The resulting product was purified by chromatography over silica gel (gradient 0 to 100% EtOAc in heptane over 20 min) to give the title compound 40 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.21 (ddt, 1H), 2.70-2.88 (m, 2H), 2.89-2.99 (m, 1H), 4.20 (dd, J=7.61, 6.64 Hz, 1H), 6.55 (s, 1H), 6.68-6.80 (m, 3H). 19F NMR (376 MHz, METHANOL-d4) δ ppm −112.87 (t, J=8.58 Hz). LCMS m/e 262 (M−H). 100% pure by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[S:14][CH3:15])[CH:4]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[S:14]([CH3:15])=[O:24])[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc(-c2sccc2SC)c1
Solvent: CCOC(C)=O
Product: COc1ccnc(-c2sccc2S(C)=O)c1

Procedure:
The product of step (c) above was dissolved in ethyl acetate (100 ml) and cooled to -10°. m-Chloroperbenzoic acid (2.98 g) was added and after 1.5 hour the mixture was worked-up then chromatographed (ethyl acetate) to give the sub-title compound as a solid, mp 103°-105°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:8]1(=[O:24])=[O:23].[CH3:28][NH:29][CH3:30]>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][C:5]2[CH:4]=[C:3]([CH2:2][N:29]([CH3:30])[CH3:28])[CH:27]=[CH:26][CH:25]=2)[S:8]1(=[O:24])=[O:23]
Reactant: O=S1(=O)N(Cc2cccc(CBr)c2)c2ccccc2N1c1ccccc1F
Reactant: CNC
Product: CN(C)Cc1cccc(CN2c3ccccc3N(c3ccccc3F)S2(=O)=O)c1
Yield: 39 %

Procedure:
In an analogous manner to general procedure V, 1-[3-(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.07 g, 0.18 mmol) was treated with dimethylamine (10 mL) to provide 0.03 g (39%) of 1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]methyl}phenyl)-N,N-dimethylmethanamine. HRMS: calcd for C22H22FN3O2S+H+, 412.14895; found (ESI, [M+H]+), 412.1493; HPLC purity 96.3% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH2:10][Br:15])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1cc(C)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(CBr)ccc1[N+](=O)[O-]

Procedure:
5-Methyl-2-nitrobenzoic acid methyl ester (27.1 g, 138.8 mmol) was dissolved in carbon tetrachloride (500 mL), and N-bromosuccinimide (29.6 g, 166.6 mmol) was added, followed by benzoyl peroxide (6.72 g, 27.7 mmol). The mixture was illuminated and gently refluxed for 4 hours. Then, the mixture was cooled and concentrated, then purified by column chromatography silica gel 230-400 mesh; 10% ethyl acetate in hexanes as eluent) to give 5-bromomethyl-2-nitrobenzoic acid methyl ester. Yield: 17.9 g (47%).
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([CH:51]([C:67]2[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=2)[N:52]2[CH2:55][CH:54]([N:56]([CH2:60][CH:61]3[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]3)[SH:57](=[O:59])=[O:58])[CH2:53]2)=[CH:47][CH:46]=1.C(=O)([O-])O.[Na+]>ClCCl>[Cl:73][C:70]1[CH:69]=[CH:68][C:67]([CH:51]([C:48]2[CH:49]=[CH:50][C:45]([Cl:44])=[CH:46][CH:47]=2)[N:52]2[CH2:53][CH:54]([N:56]([CH2:60][CH:61]3[CH2:62][CH2:63][N:64]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:65][CH2:66]3)[SH:57](=[O:58])=[O:59])[CH2:55]2)=[CH:72][CH:71]=1
Reactant: CC(C)C=O
Reactant: O=[SH](=O)N(CC1CCNCC1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)CN1CCC(CN(C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)[SH](=O)=O)CC1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
N-{1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(1-isobutylpiperiod-4yl)methylsulfonamide may be prepared by carrying out the procedure in the following manner: 0.11 cm3 of isobutyraldehyde, 0.057 cm3 of 100% acetic acide and 320 mg of sodium triacetoxyborohydride are added to a solution of 0.47 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(piperid-4-yl)methylsulfonamide in 20 cm3 of dichloromethane. After stirring for 20 hours at 20° C., the reaction mixture is supplemented with 50 cm3 of a saturated aqueous sodium hydrogen carbonate solution and separated after settling. The organic phase is dried over mangesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on a silica gel column (particle size 0.063-0.200 mm, height 20 cm, diameter 2 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (40/60 by volume) and collecting 30-cm3 fractions. Fractions 3 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.22 g of N-{1-[bis(4-chloro-phenyl)methyl]azetidin-3-yl}-N-(1-isobutylpiperid-4 -yl)methylsulfonamide is obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 0.87 (d, J=7 Hz:6H); from 1.60 to 1.90 (mt:5H); 1.93 (broad t, J=11.5 Hz:2H); 2.03 (d, J=7.5 Hz:2H); 2.84 (s, 3H); 2.89 (broad d, J=11.5 Hz:2H); 3,38 (broad t, J=7 Hz:2H); 3.47 (broad t, J=7 Hz:2H); 3.62 (mt:1H); 4.08 (mt:1H); 4.43 (s:1H); from 7.20 to 7.40 (mt:8H)].
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[NH:22]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+]>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.O>[NH:22]1[CH:26]=[C:25]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)[CH:24]=[N:23]1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Reactant: OB(O)c1cn[nH]c1
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: [K+]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3cn[nH]c3)CCC2)CCN(C)C1
Temperature: 90 °C

Procedure:
A solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4, 3-b]indole (100 mg, 0.29 mmol), 1H-pyrazole-4-boronic acid (75 mg, 0.580 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-DME (4 mL)-water (2 mL) was purged with nitrogen. Pd(PPh3)4 (16 mg, 0.0147 mmol) was added and the reaction mixture was heated at 90° C. for 45 min. The reaction mixture concentrated under vacuum, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under vacuum to obtain crude which was purified by reverse phase HPLC to yield 5-(2-(1H-pyrazol-4-yl)cyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.38 (s, 1H), 7.0 (m, 2H), 6.4 (m, 2H), 4.7 (m, 1H), 4.4 (m, 1H), 3.78 (m, 1H), 3.42 (m, 1H), 3.11 (m, 4H), 2.6-3.0 (m, 5H), 2.4 (s, 3H), 2.2 (m, 2H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C@H:36]([C:40]([N:42]2[CH2:59][CH2:58][CH2:57][C@H:43]2[C:44]([NH:46][CH:47]([CH:54]([CH3:56])[CH3:55])[C:48](=[O:53])[C:49]([F:52])([F:51])[F:50])=[O:45])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])=[CH:29][CH:28]=1)(O)=[O:25].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:12]([O:19][C:20]([CH2:21][NH:22][C:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C@H:36]([C:40]([N:42]2[CH2:59][CH2:58][CH2:57][C@H:43]2[C:44]([NH:46][CH:47]([CH:54]([CH3:55])[CH3:56])[C:48](=[O:53])[C:49]([F:50])([F:51])[F:52])=[O:45])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])=[CH:29][CH:28]=1)=[O:25])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)O)cc1)C(C)C)C(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)NCC(=O)OCc2ccccc2)cc1)C(C)C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
To a mixture of glycine benzyl ester p-toluene-sulfonate (66 mg) and 3(RS)-[(4-carboxyphenylcarbonyl)-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (100 mg) in DMF (6 ml) were added HOBT (26 mg) and WSCD (30 mg) under ice-bath cooling. After being stirred at room temperature for 4 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 ml) and washed with 5% aqueous citric acid (20 ml), water (20 ml), 5% aqueous sodium bicarbonate (20 ml) and brine (20 ml). The solution was dried over magnesium sulfate and evaporated under reduced pressure to give 3(RS)-[[4-[(benzyloxycarbonyl)methylaminocarbonyl]-phenylcarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (125 mg).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:15]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C)C1C=CC=CC=1>>[Cl:14][C:7]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH:27][C:26]2[CH:25]=[CH:24][C:23]([O:22][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:29][CH:28]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: Nc1ccc(OCc2ccccc2)cc1
Solvent: CN(C)c1ccccc1
Product: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Nc1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of 50.0 g of 2,6-dichloro-3-nitrobenzoic acid, 85.7 g of 4-benzyloxyaniline, and 115 ml of N,N-dimethylaniline was heated on a steam bath for 24 hours. The cooled mixture was triturated with 600 ml of chloroform and filtered. The precipitate was stirred in a mixture of 350 ml of chloroform and 350 ml of 1N aq NaOH. The red sodium salt was collected and stirred with a mixture of 300 ml of 1N hydrochloric acid and 1.5 l of chloroform. The chloroform layer was concentrated to provide the title compound as red crystals, mp 172°-174° C.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:17])[NH:13][N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][CH:5]=1.Cl.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](NN)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:13]2[C:12](=[O:17])[C:11]3[O:10][C:9]4[C:4]([O:3][CH:2]([F:1])[F:23])=[CH:5][CH:6]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]=4[C:16]=3[CH:15]=[N:14]2)=[CH:28][CH:27]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(OC(F)F)c2oc3c(=O)[nH]ncc3c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(OC(F)F)c2oc3c(=O)n(-c4ccc(Cl)cc4)ncc3c12
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of ethyl 6-difluoromethoxy-4-oxo-3,4-dihydrobenzo[4,5]furo[2,3-d]pyridazine-9-carboxylate (from step 6 of example 4) (168 mg, 0.4 mmol) in ethanol (20 ml), p-chloro phenylhydrazine hydrochloride (72 mg, 0.4 mol) and sodium carbonate (43 mg, 0.4 mmol) was added at room temp. The reaction mixture was stirred at room temp. for 4 hrs. Ethanol was distilled out under vacuum. The concentrated mass was heated to reflux temperature in acetic acid. Progress of reaction was monitored by TLC. At the end, water was added, the solid obtained was filtered and suck dried. The solid was dried in oven. White colored solid (160 mg) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([SH:16])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Cl)=[CH:30][CH:29]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][S:16][C:13]2[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:17])=[C:7]3[C:12]=2[O:11][CH2:10][CH2:9][CH2:8]3)=[CH:32][CH:33]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCCO2
Reactant: ClCc1ccc(OCc2cc(Cl)ccc2Cl)cc1
Product: O=C(O)COc1ccc(SCc2ccc(OCc3cc(Cl)ccc3Cl)cc2)c2c1CCCO2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester and 1,4-Dichloro-2-(4-chloromethyl-phenoxymethyl)-benzene prepared in the manner analagous to Example 71A. m/z 519 (M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:25][O:24][C:23]3[CH:26]=[C:27]4[C:31](=[CH:32][C:22]1=3)[CH2:30][CH2:29][O:28]4)[C:5](=[O:21])[N:6]2[CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1.BrC1C=CC=C2C=1[C:36]1([C:52]3=CC4OCOC=4C=[C:51]3[O:50][CH2:49]1)C(=O)N2CCCCC.O1C=CC(B(O)O)=C1.CN(C)C1N=CC(B(O)O)=CC=1>>[O:50]1[CH:51]=[CH:52][C:36]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([CH2:25][O:24][C:23]4[CH:26]=[C:27]5[C:31](=[CH:32][C:22]2=4)[CH2:30][CH2:29][O:28]5)[C:5](=[O:21])[N:6]3[CH2:11][C:12]2[O:13][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][CH:16]=2)=[CH:49]1
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: OB(O)c1ccoc1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(-c3ccoc3)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-furylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (27%) as a colorless solid: mp 167-169° C.; 1H NMR (300 MHz, CDCl3) δ 7.34-7.29 (m, 2H), 7.01 (dd, 1H), 6.95 (dd, 1H), 6.77 (dd, 1H), 6.74 (dd, 1H), 6.51 (s, 1H), 6.41 (d, 1H), 6.34 (s, 1H), 6.00 (dd, 1H), 4.97 (ABq, 2H), 4.67 (ABq, 2H), 4.56 (t, 2H), 3.01 (t, 2H); MS (ES+) m/z 494.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([CH:20]=[CH:21][C:22]([O:24]C)=O)[N:12]=2)[CH:8]=[N:9][CH:10]=1)=[O:4].CC(O)=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]3[NH:17][C:22](=[O:24])[CH2:21][CH2:20][C:13]=3[N:12]=2)[CH:8]=[N:9][CH:10]=1
Reactant: COC(=O)C=Cc1nc(-c2cncc(C(=O)OC)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cncc(-c2ccc3c(n2)CCC(=O)N3)c1
Temperature: 50 °C
Reaction time: 13 h
Yield: 65.4 %

Procedure:
6-(2-Methoxycarbonyl-vinyl)-5-nitro-[2,3′]bipyridinyl-5′-carboxylic acid methyl ester (926 mg, 2.7 mmol), 10% Pd/C (300 mg) and AcOH (1.3 mL) were suspended in methanol (300 mL) and the reaction mixture was stirred at 50° C. under 50 psi H2 pressure for 13 hours. After filtration, the reaction mixture was concentrated in vacuo to give a crude product of 5-(6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridin-2-yl)-nicotinic acid methyl ester (500 mg, 65.4%) as a light yellow solid. MS: 284.1 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]2[C:8]([O:14]C(=O)C)=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[C:4]=1[C:18](=[O:31])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CNC>C1COCC1>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:2][C:3]2[O:7][C:6]3[C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=3[C:4]=2[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH2:35][CH2:34]1
Reactant: COc1cc(C(=O)c2c(CBr)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: CN1CCNCC1
Agent: CNC
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(CN3CCN(C)CC3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 2 h
Yield: 46.8 %

Procedure:
To a stirred solution of 2-bromomethyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-acetoxybenzo[b]furan (Example 33) (50 mg, 0.10 mmol) in dry THF (2 mL) at room temperature was added N-methylpiprazine (24 μL, 0.22 mmol) and the mixture was stirred for 2 hours and then added solution of dimethylamine (0.2 mL, 2M solution in THF, excess) and stirred for 4 hours. The solvent was distilled and the crude was purified over silica gel column and the product was crystallized from acetonitrile to afford the title compound as a light yellow crystalline solid (22 mg, 46%). 1H NMR (300 MHz, CDCl3) δ 7.12 (s, 2H, benzoyl Hs), 6.89 (d, J=8.58 Hz, 1H), 6.85 (d, J=8.58 Hz, 1H), 3.93 (s, 6H, 2×OMe), 3.82 (s, 6H, 2×OMe), 2.57 (b, 4H), 2.39 (b, 4H), 2.23 (s, 3H, NMe).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH2:15]1[O:23][C@H:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:23])[CH2:11][CH2:10]1
Reactant: c1ccc([C@H]2CO2)cc1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CC#N
Product: COc1ccccc1N1CCN(C[C@@H](O)c2ccccc2)CC1
Yield: 99.3 %

Procedure:
2-Methoxyphenylpiperazine (17.4 g, 0.0906 m) in dry acetonitrile (150 ml) was refluxed 24 hrs with (S)-styrene oxide (10.84 g, 0.09 m). The residue on evaporation was treated by acid-base extraction to remove unreacted styrene oxide to leave 28 g of the crude alcohol as a mixture of regioisomers which was purified by chromatography on silica, using 1:1 hexane ethylacetate, to give 16.5 g of the pure isomer, [α]23D +56° C.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][CH3:17])[O:11][C:10]1=[O:18])[CH2:7][CH3:8])[CH:2]=[CH2:3].C[OH:20]>CC(C)=O.O>[CH2:1]([O:4][NH:5][C:6]([CH:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][CH3:17])[O:11][C:10]1=[O:18])([OH:20])[CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCONC(CC)=C1C(=O)C=C(CC)OC1=O
Reactant: CO
Solvent: O
Solvent: CC(C)=O
Product: C=CCONC(O)(CC)C1C(=O)C=C(CC)OC1=O

Procedure:
1.0 g of 3-(1-allyloxyaminopropylidene)-6-ethyl-3,4-dihydro-2H-pyrane-2,4-dione (ND26.5 :1.5389) was dissolved in 50ml of acetone containing 5% of water. After it was poured shallowly into the vessel having an area of (30×35)cm2, it was allowed to stand for a day in the sunlight. 630mg of the crude product was obtained by the distillation of methanol after the precipitated crystal on the container was recovered by washing with methanol. The crude product was recrystallized three times from the mixture of ethanol and water and 300mg of 3-(1-allyloxyamino-1-hydroxypropyl)-6-ethyl-3,4-dihydro-2H-pyrane-2,4-dione having a melting point of 62.5° to 64°C as a white crystal was obtained.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][C:13](=[O:16])[CH:12]=[CH:11]1>C(O)(=O)C.C1COCC1.O>[OH:7][CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][C:13](=[O:16])[CH:12]=[CH:11]1
Reactant: O=c1ccn(CCOC2CCCCO2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=c1ccn(CCO)cc1
Yield: 71.2 %

Procedure:
A solution of 1-[2-(tetrahydropyran-2-yloxy)ethyl]-1,4-dihydro-4-pyridone (500 mg, 2.23 mmol) in acetic acid (4 ml), THF (2 ml) and water (1 ml) was heated at 45° C. for 4 hours. The volatiles were removed by evaporation to give 1-(2-hydroxyethyl)-1,4-dihydro-4-pyridone (221 mg, 71%) as an off-white solid. 1H NMR Spectrum: (DMSOd6) 3.70(t, 2H); 4.06(t, 2H); 6.95(d, 2H); 8.37(d, 2H)
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(N(CC)CC)C>C(#N)C.O.C(O)(=O)C>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:11]=1[CH3:12]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(N2CCC[C@H]2C(=O)OC(C)(C)C)nc2cc(F)cc(F)c2c1Cl
Temperature: 140 °C

Procedure:
The 2,4-dichloro-5,7-difluoro-3-methylquinoline (300 mg, 1.20 mmol), (S)-tert-butyl pyrrolidine-2-carboxylate (620 mg, 3.60 mmol) and triethylamine (50 μL, 3.60 mmol) were combined in acetonitrile (7.6 mL). The mixture was then heated in a microwave reactor at 140° C. for 90 min. The reaction mixture was then cond to dryness and the residue was diluted with water (˜25 mL) and acetic acid (2 mL). This mixture was extracted with DCM (2×75 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and dried over magnesium sulfate. The filtrate was cond to obtain (S)-tert-butyl 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyrrolidine-2-carboxylate. Mass Spectrum (ESI) m/e=383.2 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][C:19](=O)[NH:18][C:17](=O)[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2CC(=O)NC(=O)C2)cc1CC1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C2CCNCC2)cc1CC1CCCC1

Procedure:
Following the procedure of Nacci et al, Vide Supra, reaction of 4-(3-cyclopentylmethyl-4-methoxyphenyl)-2,6-piperidinedione (20.0 mmol, 6.0 g) and lithium aluminum hydride (209 mmol, 7.94 g) in dry THF (130 mL) afforded the title compound as a white, waxy solid (4.85 g, 89%) of sufficient purity for subsequent transformations.