Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:22][S:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)(=[O:21])=[O:20])=[O:6]
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(Cl)cc1)c1ccc(Br)cc1Cl
Reaction time: 72 h

Procedure:
An 8 mL reaction vial is charged with 2-chloro-4-bromobenzoic acid (0.39 mmol, 1.5 eq) and 2.0 mL of dichloromethane. A stock solution (4.0 mL) containing 4-chlorophenylsulfonamide (0.26 mmol, 1 eq) and N,N-[dimethyl]-4-aminopyridine (48 mg, 0.39 mmol, 1.5 eq) in dichloromethane is added, followed by 0.261 g carbodiimide polystyrene resin (2.0 mmol/g, 0.52 mmol, 2.0 eq, Novabiochem) and the vial is capped and rotated. After 72 hr, 0.77 g sulphonated polystyrene resin (NP-TsOH) is added (1.53 mmol/g, 1.17 mmol, Argonaut). After about 18 hr the reaction mixture is filtered and concentrated under a stream of nitrogen. The residue is subjected to reverse phase HPLC; CombiPrep column, YMC ODS-A 20×50 mm column with 5 micron, C18, 120 Angstrom pore size, gradient: 5% to 95% CH3CN/0.01 HCl aqueous solution. Fractions containing product are combined and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C1C(=O)N([Br:28])C(=O)C1>CN(C=O)C>[Br:28][C:16]1[CH:17]=[CH:18][C:19]2[N:11]([S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:2])=[O:3])[CH:12]=[CH:13][C:14]=2[C:15]=1[NH2:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N)cccc32)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N)c(Br)ccc32)cc1
Temperature: -20 °C

Procedure:
To 1-tosyl-1H-indol-4-amine (9.1 g, 31.8 mmol) in DMF (300 mL) at −20° C. was added NBS (5.60 g, 31.5 mmol) and the mixture was stirred at −20° C. After 5 minutes the reaction was quenched with sat. aq. NaHCO3, then with sat. sodium thiosulfate, extracted with EtOAc (three times), dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 364.9, 366.9 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]([F:27])([F:26])/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O>[Cl:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][CH:19]([C:18]([F:17])([F:27])[F:26])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: Nc1ccc(Cl)cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)ccc2NC1C(F)(F)F
Temperature: 100 °C

Procedure:
The 2-amino-5-chlorobenzaldehyde from Step 1 (15.0 g, 96 mmol), anhydrous potassium carbonate (27.6 g, 200 mmol), and ethyl 4,4,4-trifluorocrotonate (34 mL, 200 mmol) were mixed in anhydrous dimethyformamide (60 mL) and heated at 100° C. for 7 hours. The contents were allowed to cool and partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (1×100 mL). The ethyl acetate extracts were combined and washed with brine (1×200 mL), dried over MgSO4, and concentrated in vacuo leaving a dark oil which solidified upon standing. The solid was purified-by flash chromatography (silica gel; ethyl acetate-hexanes, 1:9). Fractions containing the desired product were combined, concentrated in vacuo and the residue recrystallized from ethyl acetate-hexanes to afford the ethyl 6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid (16.36 g, 56%): mp 132.6–134.2° C. 1H NMR (CDCl3, 300 MHz) 7.61 (s, 1H), 7.10 (m, 2H), 6.55 (d, 1H, J=8.0 Hz), 5.10 (q, 1H, J=6.0 Hz), 4.55 (brs, 1H), 4.23 (m, 2H), 1.32 (t, 3H, J=7.0 Hz). FABHRMS m/z 306.0468 (M+H+, Calc'd 306.0509). Anal. Calc'd for C13H11NO2F3Cl: C, 51.08; H, 3.63; N, 4.58. Found: C, 50.81; H, 3.49; N, 4.72.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21]/[CH:22]=C(\C)/CCC(O)=O.CCCCCC.C(OCC)(=[O:38])C>>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21][CH:22]=[O:38]
Reactant: CCOC(C)=O
Reactant: COCCOCOc1c(C/C=C(\C)CCC(=O)O)c(OC)c(C)c2c1C(=O)OC2
Solvent: CCCCCC
Product: COCCOCOc1c(CC=O)c(OC)c(C)c2c1C(=O)OC2

Procedure:
By following the procedure of part A and substituting methyl (E)-6-(4-t-butyldimethylsilyloxy-1,3-dihydro -6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate with (E)-6-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl -3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, there was obtained 2-(1,3-dihydro-6-methoxy -4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-acetaldehyde, m.p. 61°-63° C. (hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:36])=[C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Li+]>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:36])=[C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(Cl)nc3c2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(5-chloro-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (332 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N lithium hydroxide aqueous solution (3.00 mL), and the mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (3.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (278 mg, 89%) as a pale-yellow solid.
Reaction SMILES: C(Cl)(Cl)Cl.[OH:5][CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[CH3:18][C:19](OC(C)=O)=[O:20].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.CCN(CC)CC>[C:19]([O:5][CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1)(=[O:20])[CH3:18]
Reactant: O=C1CCc2ccc(CO)cc2N1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a CHCl3 (30.0 mL) solution, the compound (670 mg) obtained in Step 52-1, Ac2O (536 μL), DMAP (20.0 mg) and Et3N (1.05 mL) were added under ice cooling and the mixture was stirred at room temperature for 45 minutes. To the reaction mixture, a saturated aqueous NaHCO3 solution was added and the solution was extracted three times with CHCl3. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60 N, mobile phase: MeOH/CHCl3=0/100 to 10/90; v/v) to obtain (2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl acetate (767 mg, a light yellow solid).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Br:24]>>[Br:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1sccc1Cc1ccccc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2sccc2Cc2ccccc2)c1Br
Yield: 24 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-benzylthiophene-2-sulfonamide was prepared in the same manner as described in Example 2 by reacting 2-chlorosulfonyl-3-benzylthiophene with 5-amino-4-bromo-3-methylisoxazole resulting in a 24% yield, m.p. 180°-183° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([CH3:30])[N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:10]([F:31])[CH:9]=1>>[F:31][C:10]1[CH:9]=[C:8]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH:13]=[CH:12][C:11]=1[C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([CH3:30])[N:23]=2)[CH2:20][CH2:21]1)=[O:15]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Reactant: O=C1CCCN1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3F)CC2)nc1C
Yield: 89.7 %

Procedure:
Using pyrrolidin-2-one (94 mg) and (4-bromo-2-fluorophenyl) [4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (406 mg) described in Preparation Example 128 and by the reaction and treatment in the same manner as in Example 1, the title compound (368 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:6](C)[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)[C:3]=1[CH:19]=[O:20].O1CCCC1.[CH3:26][S-:27].[Na+]>O>[CH:19]([C:3]1[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)=[N:5][NH:6][C:2]=1[S:27][CH3:26])=[O:20]
Reactant: C[S-]
Reactant: Cc1cc(-c2nn(C)c(Cl)c2C=O)ccc1OC(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1[nH]nc(-c2ccc(OC(C)C)c(C)c2)c1C=O
Reaction time: 8 h
Yield: 104.9 %

Procedure:
At room temperature, to a mixture of 5-chloro-4-formyl-3-(4-isopropoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole (described in Reference Preparation example 96) 10 g and tetrahydrofuran 100 ml was added sodium thiomethoxide 2.9 g and the resulting mixture was stirred for eight hours. To the reaction mixture was added water 50 mL and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 4-formyl-3-(4-isopropoxy-3-methyl-phenyl)-5-methylthio-1H-pyrazole 10.4 g.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:11][C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(OCC)(=O)C>[F:10][C:9]1[C:2]([N:14]2[CH2:15][CH2:16][CH:12]([F:11])[CH2:13]2)=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: O=Cc1cccc(F)c1F
Reactant: F[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=Cc1cccc(F)c1N1CCC(F)C1
Yield: 26.9 %

Procedure:
2,3-Difluorobenzaldehyde (1.0 g, 7.037 mmol) was taken up in dry dioxane (20 ml) in a tube and (S)-3-fluoropyrrolidine (627.1 mg, 7.037 mmol) and K2CO3 (676.4 mg, 10.56 mmol) were added and the mixture refluxed overnight. The reaction mixture was diluted with ethyl acetate, filtered, concentrated to dryness and purified on an ISCO system eluting with Hexane/ethyl acetate (10-100) to give 400 mg of 3-fluoro-2-(3-fluoropyrrolidin-1-yl) benzaldehyde.
Reaction SMILES: [F:1][C:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([F:4])[CH3:3].C1C(=O)N([I:36])C(=O)C1.C(O)(C(F)(F)F)=O>CC#N>[F:1][C:2]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([I:36])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([F:4])[CH3:3]
Reactant: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2I)CC1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
(R)-4-(6-(trans-4-(1,1-difluoroethyl)cyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (865 mg, 2.22 mmol) and NIS (550 mg, 2.45 mmol, 1.1 eq.) were dissolved in CH3CN (5 mL). Then CF3COOH (76 mg, 0.67 mmol, 0.3 eq.) was added to the mixture dropwise at 0° C. The mixture was warmed to 15° C. and stirred for another 1 h. Then the mixture was extracted with EtOAc and the organic layer was concentrated and purified by silica gel chromatography using PE/EA (1/1) as eluent to give the title compound as a slight red solid (1.02 g, 90%). EDI-MS (M+1): 515.8. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, 1H), 7.73 (d, 2H), 7.48 (dd, 1H), 7.18 (d, 1H), 6.49 (s, 1H), 4.45-4.40 (m, 2H), 4.33-4.30 (m, 1H), 2.27-2.25 (m, 2H), 2.03-2.01 (m, 2H), 1.84 (s, 3H), 1.65-1.24 (m, 8H).
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([OH:8])[CH:6]=[CH2:7].C([O:11][C:12]([CH2:14][C:15]1[N:16]2[CH:22]=[N:21][CH:20]=[C:17]2[S:18][CH:19]=1)=O)C>>[CH2:5]([O:8][C:12]([CH2:14][C:15]1[N:16]2[CH:22]=[N:21][CH:20]=[C:17]2[S:18][CH:19]=1)=[O:11])[CH:6]=[CH2:7]
Reactant: CCOC(=O)Cc1csc2cncn12
Reactant: C=CCO
Agent: CC[O-]
Agent: [Na+]
Product: C=CCOC(=O)Cc1csc2cncn12

Procedure:
A 30 mg potion of a sodium ethoxide powder was added to 6.2 ml of an allyl alcohol solution containing 314.2 mg of 3-ethoxycarbonylmethylimidazo[5,1-b]thiazole, and the mixture was then was then heated under reflux for 7 hours. After cooled, the reaction solution was concentrated under reduced pressure, and the organic layer extracted with dichloromethane (10 ml×4) was dried over anhydrous magnesium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by a silica gel column chromatograph to obtain 240.4 mg of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:19][O:20][CH2:21][CH2:22][OH:23].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:23][CH2:22][CH2:21][O:20][CH3:19])[N:3]=1
Reactant: COCCO
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: COCCOc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, 2-methoxyethanol and DBU in DME. ES-MS m/e (%): 283 (M+Na+, 15), 261 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:17].C(=O)([O-])[O-].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].CN(C=O)C>O>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:17][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: O=c1c2ccccc2oc2c(Cl)c(O)ccc12
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc2c(=O)c3ccccc3oc2c1Cl
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A mixture of 1.2 g of 4-chloro-3-hydroxy-9-oxo-9H-xanthene, 1.7 g of postassium carbonate, 2.1 g of ethyl bromoacetate and 30 ml of DMF was stirred at 60°-70° C. for 3 hours. After cooling the mixture, water was added and the resulting crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.1 g of ethyl 4-chloro-9-oxo-9H-xanthene-3-yloxyacetate. m.p. 183°-185° C.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:7][C:6]23[CH2:17][CH:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH:5]2[CH2:4]1)[C:9]1[CH:18]=[CH:19][CH:20]=[CH:21][C:8]3=1.[N+:22]([O-])([O-:24])=[O:23].[K+]>F>[ClH:1].[N+:22]([CH:4]1[CH:5]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH:10]3[CH2:17][C:6]2([C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]3=2)[CH2:7][N:3]1[CH3:2])([O-:24])=[O:23]
Reactant: CN1CC2c3ccccc3C3CC2(C1)c1ccccc13
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: F
Agent: [K+]
Product: CN1CC23CC(c4ccccc4C2C1[N+](=O)[O-])c1ccccc13
Temperature: 25 °C
Yield: 57.6 %

Procedure:
To a solution of 1.5 g (5.06 mmoles) of 2-methyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole hydrochloride in 25 ml of anhydrous hydrofluoric acid cooled at -78° was added 562 mg (5.06 mmoles) of potassium nitrate. The reaction mixture was allowed to warm to room temperature and the hydrofluoric acid was evaporated under a stream of nitrogen. The residue was dissolved in methylene chloride, and the solution washed with 1N aqueous sodium hydroxide, with water, and dried over potassium carbonate. The solvent was removed under vacuum, the residue was dissolved in ether and insolubles were removed by filtration. The ethereal filtrate was treated with dry hydrogen chloride to give 1.0 g of nitro-2-methyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole hydrochloride as a colorless solid, m.p. 202°-207° (slight decomp.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][N:10]([CH3:19])[N:9]=2)=[CH:4][CH:3]=1.[Br:20]Br>C(O)(=O)C.CN(C=O)C>[Br:20][C:11]1[N:10]([CH3:19])[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: BrBr
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(F)cc2)n1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1Br
Temperature: 80 °C
Yield: 35 %

Procedure:
To a solution of 4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine (2.7 g, 10.67 mmol) (prepared in accordance with Example A-212) in acetic acid (30 mL) and DMF (13 mL) was added bromine (19.5 g, 122.0 mmol). The solution was heated at 80° C. overnight. TLC indicated that the reaction was complete. The mixture was quenched slowly with K2CO3 (25 g). When pH was about 5, a precipitate was formed. The precipitate was washed with water (50 mL×5) to give 4-[5-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine (1.24 g, 35%): mp 174.38° C.; Mass spectrum m/z=332, 334; 1H NMR was consistent with the proposed structure. Anal. Calc'd for C15H11N3FBr.0.2 H2O: C, 53.66; H, 3.42; N, 12.51. Found: C, 53.58; H, 3.12; N, 12.43.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][C:10]2[C:11]([N+:20]([O-])=O)=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([CH3:19])=[CH:13]3)[CH:5]=[CH:4][C:3]=1[CH2:23][C:24]([OH:26])=[O:25].O.O.[Sn](Cl)(Cl)(Cl)Cl.[CH3:34]O>C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[NH2:20][C:11]1[C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:23][C:24]([O:26][CH3:34])=[O:25])=[C:2]([CH3:1])[C:7]=2[CH3:8])=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([CH3:19])[NH:15]2
Reactant: Cc1cc2c([N+](=O)[O-])c(Oc3ccc(CC(=O)O)c(C)c3C)ccc2[nH]1
Reactant: CO
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2N)c(C)c1C
Temperature: 60 °C

Procedure:
Under an N2 atmosphere, 2-(2,3-dimethyl-4-(2-methyl-4-nitro-1H-indol-5-yloxy)phenyl)acetic acid (0.335 g, 0.946 mmol) was suspended in methanol and tin chloride dihydrate (1.71 g, 7.57 mmol) was added. The reaction was heated to 60° C. for 16 h. The reaction was diluted with ethyl acetate and 10% NaHCO3 (aq). The layers were separated and the organic layer was washed with water (3×), dried (Na2SO4), filtered and concentrated in vacuo. Flash column chromatography of the residue, eluting with 20% to 80% ethyl acetate in hexanes, afforded the title compound. LC-MS ESI (pos.) m/z: 339.2 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12](=[O:14])[CH3:13])=[CH:10][C:5]=2[N:4]([CH3:15])[C:3]1=[O:16].[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O.N1CCCCC1>C1(C)C=CC=CC=1>[C:12]([C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3](=[O:16])[N:4]([CH3:15])[C:5]=2[CH:10]=1)=[CH:17][C:18]1[CH:19]=[C:20]([CH3:21])[CH:23]=[CH:24][CH:25]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Cc1ccc2c(c1)n(C)c(=O)n2C
Reactant: Cc1cccc(C=O)c1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1cccc(C)c1)c1ccc2c(c1)n(C)c(=O)n2C
Reaction time: 18 h

Procedure:
1,3-Dimethyl-5-(2-oxo-propyl)-1,3-dihydro-benzoimidazol-2-one was diluted with toluene (30 mL) and treated with 3-methylbenzaldehyde (0.82 mL) and piperidine (0.3 mL). The mixture was placed in an oil bath set to a temperature of 145° C. and the flask was fitted with a pressure equalizing funnel containing 4 Å molecular sieves and equipped with a condenser. After 18 hours the mixture was allowed to cool and was concentrated. Chromatography on silica gel afforded 5-(1-Acetyl-2-m-tolyl-vinyl)-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (1.077 g).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[C:25]([C:27](=[O:35])[NH:28][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][O:31]2)[CH:24]=[CH:23][C:5]=1[CH2:6][N:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:26]=[C:25]([C:27](=[O:35])[NH:28][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][O:31]2)[CH:24]=[CH:23][C:5]=1[CH2:6][N:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11]
Reactant: CC(C)(C)OC(=O)N(CCc1ccccn1)Cc1ccc(C(=O)NCC2CCCO2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCc1ccccn1)Cc1ccc(C(=O)NCC2CCCO2)cc1N
Temperature: 50 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-nitro-4-((tetrahydrofuran-2-yl)methylcarbamoyl)benzyl(2-(pyridin-2-yl)ethyl)carbamate, from above, (238 mg, 0.492 mmol) and SnCl2.2H2O (279 mg, 1.23 mmol) were suspended in ethanol (1.6 mL) and stirred at 50° C. for 1 hour. The reaction mixture was concentrated to dryness, re-suspended in ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4, concentrated onto silica gel and purified by flash chromatography (20 methanol:1 triethylamine:79 dichloromethane isocratic) to afford the desired intermediate, tert-butyl 2-amino-4-((tetrahydrofuran-2-yl)methylcarbamoyl)benzyl(2-(pyridin-2-yl)ethyl)carbamate (103 mg). LC/MS: Calc. C25H34N4O4 454.25 amu; Obs. [M+H]+=455.5 amu.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]=[C:31]=[O:32])[CH:25]=1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:31]([NH:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=3)=[O:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCCNCC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: C1CCOC1
Product: COCCN(CC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1)C(=O)Nc1cccc(Cl)c1

Procedure:
A mixture of 3-(3-Chloro-2-methyl-phenyl)-1-[2-(2-methoxy-ethylamino)-acetyl]-imidazolidin-4-one (100 mg, 0.3 mmol, 1 eq), 1-Chloro-3-isocyanato-benzene (56 mg, 0.36 mmol, 1.2 eq), in THF (2 ml) was stirred at room temperature overnight. It was concentrated, dissolved in acetonitrile and purified with HPLC to give the desired product. LCMS observed for (M+H)+: 479.3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][S:12](=[O:15])(=[O:14])[N:11]=[C:10](SC)[NH:9]2)=[CH:4][CH:3]=1.[OH-:18].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][S:12](=[O:15])(=[O:14])[NH:11][C:10](=[O:18])[NH:9]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CSC1=NS(=O)(=O)CC(c2ccc(Cl)cc2)N1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1NC(c2ccc(Cl)cc2)CS(=O)(=O)N1

Procedure:
Using a method similar to that described by K. Hasegawa and S. Hirooka (Bull. Chem. Soc. Jap., 1972, 45, 1893), 5-(4-chlorophenyl)-3-methylsulfanyl-5,6-dihydro-4H-[1,2,4]thiadiazine 1,1-dioxide DE2 in acetone is treated with 1N NaOH and the mixture is refluxed for 2 h. The acetone is evaporated and the mixture is acidified with conc. HCl to afford the title compound DE3.