Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:19]([O:21]C)=[O:20])=[C:8]2[C:13]=1[O:12][CH2:11][CH:10]([CH2:14][O:15]C(=O)C)[O:9]2)=[O:4].[OH-].[K+].O>C(O)C>[OH:15][CH2:14][CH:10]1[O:9][C:8]2=[C:7]([C:19]([OH:21])=[O:20])[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:13]2[O:12][CH2:11]1
Reactant: COC(=O)c1sc(C(=O)OC)c2c1OCC(COC(C)=O)O2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1sc(C(=O)O)c2c1OCC(CO)O2
Reaction time: 0.5 h

Procedure:
2-Acetoxymethyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine-5,7-dicarboxylic acid dimethyl ester (60 g, 0.18 mol) was dissolved in ethanol (680 mL). Potassium hydroxide (36 g) was added to this solution after which water (500 mL) was added upon continuous cooling. After addition of the water the reaction mixture was stirred for another 30 minutes after which the solvents were removed by distillation. To the remaining part of the reaction mixture, we dropwise added a mixture of ice (50 g) and concentrated hydrochloric acid (25 mL), and stirred. The mixture was then filtered and the residue was washed with water. Subsequent drying resulted in quantitative formation of pure 2-hydroxymethyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine-5,7-dicarboxylic acid as demonstrated by NMR and mass spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[Br:22][CH2:23]/[CH:24]=[CH:25]/[CH2:26]Br>O>[Br:22][CH2:23]/[CH:24]=[CH:25]/[CH2:26][NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6]
Reactant: BrC/C=C/CBr
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NC/C=C/CBr)c1Oc1ccccc1

Procedure:
A solution of 3-amino-4-phenoxy-5-sulfamylbenzoic acid (2 g) and 1,4-trans-dibromo-2-butene (3.2 g) in dioxame (35 ml) was heated to reflux overnight. The solvent was removed under reduced pressure and the dark, gummy residue was chromatographed on a silica gel column using chloroform/benzene/acetic acid/methanol (80:10:10:2.5) as the eluting solvent. The fractions containing the product were combined and concentrated leaving an acetic acid solution of it. This was diluted with water to give a cream colored powder which was filtered, dried and washed with pet. ether to remove unreacted dibromobutene. The resulting 3-(4-bromo-trans-2-butenylamino)-4-phenoxy-5-sulfamylbenzoic acid was an off-white solid 0.75 g (26%) with m.p. 191°-194°; ir (Nujol) 3350, 3200, 2600 (broad), 1690, 1605, 1585, and 1530 cm-1 ; nmr (CDCl3 /d6 -DMSO) 3.7-4.5 (m, 5H incl. NH), 5.73 (t, 2H, vinyl), 6.27 (s, SO2NH2), 6.8-7.4 (m, C6H5), 7.57 (d, J=2, CH), and 8.03 ppm (d, CH); mass spectrum is of decomposition products.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][O:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[Br:18]Br>O.CC(O)=O>[NH2:1][C:2]1[C:3]([C:8]([NH:10][O:11][CH3:12])=[O:9])=[N:4][C:5]([Br:18])=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CONC(=O)c1ncccc1N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CONC(=O)c1nc(Br)ccc1N
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
A suspension of 3-amino-N-methoxypyridine-2-carboxamide (Compound 46E, 0.275 g, 1.64 mmol) in H2O (4.5 mL) was treated with a drop of Sulfuric acid and 0.6 mL of AcOH. After about 10 min of vigorous stirring, a solution of Bromine (84.7 uL, 1.64 mmol) in 0.4 mL of AcOH was cautiously added. After an additional 15-20 min of stirring the texture of the reaction mixture/suspension changed to become a more coarse orange ppt. This material was collected by filtration and dried to afford 240 mg of the title compound as an orange solid (59%). 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 6.91 (br. s., 2H), 3.66 (s, 3H); MS (ESI): m/z=245.98, 247.98 [M+H]+; UPLC: tR=0.67 min (UPLC-TOF: polar—2 min)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1.[Br:24]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[Br:24][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:18])[CH3:19])[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccc3nc(NC(=O)C(C)(C)C)[nH]c(=O)c3c2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Nc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1

Procedure:
To a hot solution of N-(1,2-dihydro-9-methyl-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.94 g, 3.0 mmol) in benzene (250 ml) under nitrogen were added N-bromosuccinimide (0.57 g, 3.2 mmol) (Kodak) and 2,2'-azobisisobutyronitrile (AIBN) (35 mg, 0.21 mmol) (Kodak). The solution was stirred at reflux for 1.5 hours and then concentrated in vacuo to give crude N-(9-bromomethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide. The pivalamide and N-(4-aminobenzoyl)-L-glutamic acid diethyl ester (2.5 g, 7.8 mmol)(Aldrich) in DMF (10 ml) were stirred under nitrogen at 105°-110° C. for 5 minutes and then allowed to cool. Triethylamine (0.5 ml, 3.6 mmol) was added and the solution was concentrated under high vacuum. The residue was purified by chromatography on silica gel (130 g) eluting with ethyl acetate:methylene chloride (1:19->2:3), followed by recrystallization of the solid from ethanol/diethyl ether. This was filtered and dried under high vacuum to give diethyl N-(4-(((1,2-dihydro-1-oxo-3-pivalamido-benzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamate (0.32 g) as a white solid. The filtrate was concentrated and the residue purified by chromatography and crystallization to give an additional 0.243 g. 1H NMR (DMSO-d6, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H, ester CH3), 1.16 (t, J=7 Hz, 3H, ester CH3), 1.28 (s, 9H, t-butyl), 1.87-2.13 (m, 2H, glu CH2), 2.39 (t, J=7 Hz, 2H, glu CH2), 4.03 (q, J=7 Hz, 2H, ester CH2), 4.07 (q, J=7 Hz, 2H, ester CH2), 4.30-4.40 (m, 1H, glu CH), 4.57 (d, J=6 Hz, 2H, C9 -CH2), 6.63 (d, J=9 Hz, 2H, Ar), 7.04 (t, J=6 Hz, 1H, ArNH), 7.63 (d, J=9 Hz, 1H, Ar), 7.61 (dd, J=8,2 Hz, 1H, Ar), 7.62 (d, J=9 Hz, 2H, Ar), 7.99 (d, J=8 Hz, 1H, Ar), 8.21 (d, J=8 Hz, 1H, glu NH), 8.22 (d, J=9 Hz, 1H, Ar), 9.75 (s, 1H, Ar), 11.25 (s, 1H, N2H), 12.30 (br s, 1H, NH). Mass spectrum (CI-CH4) 630 (M+1, 6.5%), 243 (100%). Anal. Calculated for C34H39N5O7 : C, 64.85; H, 6.24; N, 11.12. Found: C, 64.74; H, 6.25; N, 11.10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]=[C:6]2[CH2:12][CH2:13][OH:14].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl.C(OCC)C>N1C=CC=CC=1>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:8][CH:7]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)C(CCO)=CC2
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C(CCOS(=O)(=O)c1ccc(C)cc1)=CC2
Temperature: 25 °C
Yield: 84.1 %

Procedure:
1.27 g (0.0067 mol) of 5-methoxy-1H-indene-3-ethanol are dissolved in 11 ml of dry pyridine, the mixture is stirred, is cooled with an ice bath, 1.4 g (0.0073 mol) of 4-methylbenzenesulphonic acid chloride are added portionwise and stirring is maintained overnight while cold and then at room temperature for 4 h. The solution is poured onto a mixture of 16 ml of 10N hydrochloric acid and 48 g of ice, the mixture obtained is treated with diethyl ether, the organic phase is separated, is washed with water, in dried over magnesium sulphate and is filtered and the filtrate is evaporated under reduced pressure. 1.94 g of a colourless oily product are obtained, which product is used as is in the following stage.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[S:18](=[O:21])(=[O:20])[CH2:19][C:10]=3[C:9]([C:22](O)=[O:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C(Cl)Cl.CN(C=O)C.Cl>[N:31]1([C:22]([C:9]2[C:10]3[CH2:19][S:18](=[O:20])(=[O:21])[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]=3[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:23])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1ccccc1-2
Reactant: C1COCCN1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide (150.00 mg; 0.44 mmol; 1.00 Eq) is suspended in DCM (4.00 ml) and 2 drops of DMF and then Oxalyl chloride (3 mL) is added dropwise. The reaction mixture is stirred at room temperature for 30 min. The solution is evaporated to dryness. The residue is suspended in DCM (4.00 ml) and morpholine (350.00 μL; 4.02 mmol; 9.12 Eq) is added dropwise. The reaction mixture is stirred at rt for 30 min then diluted with aq. solution of HCl 0.05 M. The two layers are separated. The aqueous layer is extracted with DCM (2×). The organic layers are washed with a saturated solution of NaHCO3 and brine, dried over MgSO4 and evaporated to give foam. The foam is recrystallised in EtOH to the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.04-8.01 (m, 1H), 7.67-7.53 (m, 7H), 6.85-6.82 (m, 1H), 4.91 (s, 2H), 3.98-3.94 (m, 2H), 3.68-3.61 (m, 6H). UPLC/MS: (ES+): 410.1, (ES−): 408.1. HPLC (max plot) 100.0%; Rt 3.36 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[F:19][C:20]([F:25])([F:24])[CH2:21][NH:22][NH2:23]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:22]([CH2:21][C:20]([F:25])([F:24])[F:19])[N:23]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNCC(F)(F)F
Solvent: CCO
Product: Oc1ccccc1-c1nc(-c2ccccc2O)n(CC(F)(F)F)n1

Procedure:
1.38 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one boiled under reflux for 0.5 h with 1.6 of 2,2,2-trifluorethylhydrazine in 20 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from methanol/water. After drying, 3,5-bis(2-hydroxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 154-156° C.
Reaction SMILES: CS(O[C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:7]1)(=O)=O.[CH3:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=4)[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:7]1
Reactant: CS(=O)(=O)O[C@H]1CCN(c2nc3ccc(-c4ccc(C#N)cc4)cc3s2)C1
Reactant: C[C@@H]1CCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCCN1[C@@H]1CCN(c2nc3ccc(-c4ccc(C#N)cc4)cc3s2)C1
Temperature: 25 °C

Procedure:
A stirred solution of (S)-1-(6-(4-cyanophenyl)benzo[d]thiazol-2-yl)pyrrolidin-3-yl methanesulfonate (Reference Example 13c, 32 mg, 0.080 mmol), (R)-2-methylpyrrolidine (27.3 mg, 0.320 mmol), and N,N-diisopropylethylamine (0.17 mL, 0.961 mmol) in acetonitrile (2 mL) was heated to 150° C. under microwave irradiation for 20 minutes. The reaction mixture was cooled to room temperature then purified by silica gel chromatography (98:2:0 to 98:2:1 dichloromethane/methanol/aqueous NH4OH). Fractions containing product were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give to give 4-(2-((2R,3′R)-2-methyl-1,3′-bipyrrolidin-1′-yl)benzo[d]thiazol-6-yl)benzonitrile. 1H NMR (300 MHz, CD3OD) δ ppm 1.17 (d, J=6 Hz, 3H), 1.45-1.57 (m, 1H), 1.73-1.90 (m, 2H), 1.98-2.20 (m, 2H), 2.24-2.35 (m, 1H), 2.62 (q, J=8 Hz, 1H), 2.83-2.96 (m, 1H), 2.99-3.08 (m, 1H), 3.36-3.62 (m, 3H), 3.69-3.78 (m, 1H), 3.86-3.93 (m, 1H), 7.57 (d, J=8 Hz, 1H), 7.65 (dd, J=2, 9 Hz, 1H), 7.80 (q, J=9 Hz, 4H), 8.03 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 389 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][CH2:14][C:15]12[CH2:22][CH2:21][CH2:20][N:19]1[CH2:18][CH2:17][CH2:16]2>>[N:19]12[CH2:20][CH2:21][CH2:22][C:15]1([CH2:14][CH2:13][NH:12][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH2:16][CH2:17][CH2:18]2
Reactant: NCCC12CCCN1CCC2
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Product: O=[N+]([O-])c1cc(F)ccc1NCCC12CCCN1CCC2

Procedure:
The procedures described in Example 1 were repeated except that 2,5-difluoronitrobenzene (1.00 g, 6.29 mmol) and 5-(2-aminoethyl)-1-azabicyclo[3.3.0]octane (2.42 g, 15.7 mmol) were employed. In this case, the desired compound was obtained as a colorless liquid (2.00 g, quantitative).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc(Cl)nc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(Cl)nc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 6-chloropyridine-3-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(6-chloropyridin-3-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[CH:6]=[C:5]([C:9]([O:11]C)=[O:10])[CH:4]=1)=[O:2].[CH3:13]O.[OH-].[Na+]>O>[CH3:13][C:6]1[N:7]([CH3:8])[C:3]([CH:1]=[O:2])=[CH:4][C:5]=1[C:9]([OH:11])=[O:10]
Reactant: CO
Reactant: COC(=O)c1cc(C=O)n(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)cc(C=O)n1C
Temperature: 40 °C
Yield: 85 %

Procedure:
To a solution of methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate (90.0 g, 0.540 mol), MeOH (1000 mL) and water (500 mL) was added sodium hydroxide solution (1000 mL, 1.0 M in water). The mixture was heated at 40° C. overnight. Solvent was then evaporated, and the aqueous residue was neutralized with 1 N HCl and extracted with EtOAc (3×500 mL) to give methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylic acid (70.0 g, 85%). 1H NMR (CDCl3, 400 MHz) δ 9.54 (s, 1H), 7.45 (s, 1H), 7.32 (s, 1H), 3.93 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:13]Br>C(O)(=O)C>[Br:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([CH3:1])[C:3]=1[OH:12]
Reactant: Cc1cc2ccccc2cc1O
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc2ccccc2c(Br)c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.3 %

Procedure:
3-Methylnaphthalen-2-ol (4A) (2.09 g, 13.2 mmol) was taken in acetic acid (50 mL) and bromine (2.11 g) was added to it. The mixture was stirred at room temperature for 20 minutes, concentrated and purified by flash chromatography (silica gel, ethyl acetate/hexanes) to give the desired product (2.7 g, 80%). 1H-NMR: 300 MHz, (CDCl3) δ 7.98 (d, 1 H), 7.60 (d, 1 H), 7.58 (s, 1 H), 7.53 (dd, 1 H), 7.38 (dd, 1 H), 6.05 (s, 1 H), 2.48 (s, 3 H).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[N:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:17]2[CH:18]=[N:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ncc(Br)cc2[N+](=O)[O-])cn1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
A stirred mixture of 2,5-dibromo-3-nitropyridine (1.57 g, 5.57 mmol), 6-methoxypyridin-3-ylboronic acid (1.03 g, 6.73 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.2 g, 0.28 mmol), and 2.0M sodium carbonate (8.4 mL, 16.8 mmol) in 1,4-dioxane (27 mL) was heated to 90° C. After 19 h, the reaction was cooled to rt then diluted with water. After extraction with EtOAc, the organic extraction was dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified on silica gel (0-20% EtOAc in hexanes) to afford a light yellow solid as 5-bromo-6′-methoxy-3-nitro-2,3′-bipyridine. 1H NMR (400 MHz, CDCl3) δ ppm 8.92 (1H, d, J=2.2 Hz), 8.40 (1H, dd, J=2.5, 0.6 Hz), 8.32 (1H, d, J=2.2 Hz), 7.78 (1H, dd, J=8.6, 2.5 Hz), 6.85 (1H, dd, J=8.7, 0.7 Hz), 4.02 (3H, s).
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[Na].[CH:9]1([N:15]2[C:20](=[O:21])[N:19]=[C:18]([S:22][CH3:23])[NH:17][C:16]2=[O:24])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.S(OC)(OC)(=O)=O.[OH-].[Na+]>O>[CH3:1][N:19]1[C:18]([S:22][CH3:23])=[N:17][C:16](=[O:24])[N:15]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[C:20]1=[O:21]
Reactant: CSc1nc(=O)n(C2CCCCC2)c(=O)[nH]1
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CSc1nc(=O)n(C2CCCCC2)c(=O)n1C

Procedure:
This toluene slurry of 3-cyclohexyl-6-methylthio-s-triazine-2,4(1H,3H)-dione sodium salt is then agitated with 650 parts of water for 0.15 hrs. The aqueous layer is separated and reacted at 25°-30° during 0.25 hrs with 57 parts of dimethyl sulfate. After the dimethyl sulfate is added, the pH of the reaction is maintained at pH 9-9.5 by addition of a total of 7.5 parts of 50% aqueous sodium hydroxide. The total reaction time is 1.8 hrs at which time filtration and drying gives 70 parts of white 1-methyl-3-cyclohexyl-6-methylthio-s-triazine-2,4(1H,3H)-dione, m.p. 137°-139°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:37][CH:38]([CH3:40])[CH3:39]>CCOC(C)=O>[CH3:37][CH:38]([CH3:40])[CH2:39][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2c(c1)c(-c1ccc(O)cc1)nn2C1CCCCO1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
A mixture of 3-(4-hydroxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (219 mg, 0.686 mmol), potassium carbonate (K2CO3, 568 mg, 4.12 mmol, 6.00 equiv.), 2.00 mL of dimethylformamide (DMF), and 1-bromo-2-methylpropane (Aldrich, 300 mg, 2.18 mmol, 3.20 equiv.) were stirred at room temperature for 2 h, and then heated at 40° C. for 22 h. Additional potassium carbonate (568 mg, 4.12 mmol, 6.00 equiv.), and 1-bromo-2-methylpropane (Aldrich, 300 mg, 2.18 mmol, 3.20 equiv.) were added, and heating continued for another 28 h. The mixture was diluted with EtOAc, washed with 2× sat. aq. NaHCO3, 2× sat. aq. NaCl, and dried (Na2SO4). Purification by silica gel chromatography using 20% EtOAc in hexanes afforded the title compound (190 mg, 73.6% yield): ES-MS (m/z) 376 [M+1]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:42]>C(#N)C.C(OCC)(=O)C>[CH2:14]([O:13][C:12](=[O:21])[NH:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][Br:42])=[CH:4][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(NCCc1ccc(CO)cc1)OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccc(CBr)cc1)OCc1ccccc1
Yield: 78.7 %

Procedure:
A solution of benzyl {2-[4-(hydroxymethyl)phenyl]ethyl}carbamate (1 g), triphenylphosphine (0.97 g) and carbon tetrabromide (1.2 g) in acetonitrile (1 ml) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography [developing solvent:ethyl acetate-hexane (1:5, volume ratio)] and crystallized from hexane to give the title compound (0.96 g) as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([CH2:17][OH:18])[C@@H:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:14]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.OP(O)(O)=O.O>CS(C)=O>[CH2:1]([O:8][C@@H:9]1[C@@H:16]([CH:17]=[O:18])[C@@H:15]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@H:14]([CH2:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](CO)[C@H]1OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=P(O)(O)O
Solvent: CS(C)=O
Solvent: O
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](C=O)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of methyl 2,4,6-tri-O-benzyl-3-deoxy-3-C-(hydroxymethyl)-α-D-galacto-hexopyranoside (5.13 g, 10.72 mmol) in 25 ml of dry DMSO, 5.0 g of DCC and 0.5 ml H3PO4 were added. The mixture was stirred overnight at room temperature. The reaction mixture was treated with water (100 ml), and extracted several times with ethyl acetate. The combined organic extracts were washed with a saturated sodium hydrogen carbonate solution, dried with MgSO4 and concentrated in vacua. Purification of the crude product by flash chromatography with petroleum ether/ethyl acetate (4:1) gave 4.9 g (94%) methyl 2,4,6-tri-O-benzyl-3-deoxy-3-C-(formyl)-α-D-galacto-hexopyranoside as a colorless oil. —TLC (petroleum ether/ethyl acetate, 4:1): Rf=0.36.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20](=[O:23])[CH2:21][NH3+:22])[CH:14]=[CH:13]2.[Cl-].[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](Cl)=[O:36])=[CH:27]1>C(Cl)Cl>[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([NH:22][CH2:21][C:20]([C:15]2[CH:14]=[CH:13][C:12]3[C:17](=[CH:18][CH:19]=[C:10]([O:9][CH3:8])[CH:11]=3)[CH:16]=2)=[O:23])=[O:36])=[CH:27]1
Reactant: COc1ccc2cc(C(=O)C[NH3+])ccc2c1
Reactant: Cn1cc(C(=O)Cl)c2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2cc(C(=O)CNC(=O)c3cn(C)c4ccccc34)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Triethylamine (3.2 mL, 22.8 mmol) in 30 mL of methylene chloride was added dropwise over 2 h to a mixture of 2-(6-methoxy-naphthalen-2-yl)-2-oxo-ethyl-ammonium; chloride (2.47 g, 11.4 mmol), prepared in step 3 of Example 1, and 1-methyl-1H-indole-3-carbonyl chloride (2.21 g, 11.4 mmol), prepared in the previous step, in 100 mL of methylene chloride at room temperature. After the addition of the reaction was stirred at room temperature for 16 h (overnight). The reaction was diluted with methylene chloride, extracted twice with 1N HCl, dried (MgSO4), filtered and the solvent removed under reduced pressure to give 1-methyl-N-[2-(6-methoxy-2-naphthyl)-2-oxoethyl]-1H-indole-3-carboxamide (3.86 g, 91%) as a yellow solid, mp 177-180° C. Elemental Analysis for C23H20N2O3 Calc'd: C, 74.18; H, 5.41; N, 7.52. Found: C, 72.68; H, 5.34; N, 7.29