Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:16])([CH3:15])[CH2:9]OS(C)(=O)=O)[C:5]([F:17])=[CH:4][CH:3]=1.[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+]>C(O)C.C(OCC)(=O)C>[N:20]([CH2:9][C:8]([C:6]1[C:5]([F:17])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)([OH:16])[CH3:15])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)(COS(C)(=O)=O)c1nc(Br)ccc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(O)(CN=[N+]=[N-])c1nc(Br)ccc1F
Temperature: 80 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
A mixture of methanesulfonic acid 2-(6-bromo-3-fluoro-pyridin-2-yl)-2-hydroxy-propyl ester (5 g, 15.24 mmol), ammonium chloride (4.08 g, 76 mmol) and sodium azide (2.476 g, 38.1 mmol) in ethanol (100 ml) was stirred at 80° C. for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. 3.1 g (74% yield). TLC (cyclohexane/ethyl acetate 9:1) Rf=0.35; LCMS RtH5=0.97 min. (ES+ 275, 277); 1H-NMR (360 MHz, CDCl3): 7.51 (dd, 1H), 7.36 (dd, 1H), 5.18 (s broad, 1H, OH), 3.68-3.60 (AB system, 2H), 1.59 (s, 3H, CH3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH2:14].C(N(CC)CC)C.[C:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:28][CH:29]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)OC)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 73 %

Procedure:
Into 200 mL methylene chloride was dissolved 10.45g (50 mmol) 2-aminoterephthalic acid dimethyl ester. The solution was cooled in an ice bath, and 7.73 mL (55 mmol) triethylamine was added, followed by 10.76 mL 4-tert-butylbenzoyl chloride in 50 mL methylene chloride dropwise. The mixture was allowed to come slowly to room temperature, and after 16 h the mixture was shaken with 200 mL cold dilute HCl and 200 mL satd NaHCO3. The organic layer was dried (MgSO4) and evaporated. The residue was redissolved in a minimum ether, giving 13.5 g (73%) of crystalline desired intermediate.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[CH:16]1([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[B][B][B][B][B][B][B][B][B][B]>CO>[CH:16]1([C:22]2[CH:23]=[CH:24][C:25]([NH:26][CH:2]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=4)[O:5][CH2:4][CH2:3]3)=[CH:27][CH:28]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: COC(=O)c1ccc2c(c1)OCCC2=O
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCCC2Nc1ccc(C2CCCCC2)cc1
Reaction time: 60 h

Procedure:
A mixture of methyl 4-oxochromane-7-carboxylate (1.50 g, 7.27 mmol), 4-cyclohexylaniline (2.55 g, 14.55 mmol), decaborane (0.27 g, 2.18 mmol) in dry MeOH (15 mL) was stirred under nitrogen for 60 h. Solvent evaporation in vacuo and chromatography (8% EtOAc in Hexane) gave methyl 4-[(4-cyclohexylphenyl)amino]chromane-7-carboxylate as a slightly yellow solid. HPLC/MS: m/z=365.2 (M+1), Rt=2.56 min. 1H NMR (CDCl3): δ 7.59 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.56 (1H, d, J=2.0 Hz), 7.43 (1H, d, J=8.0 Hz), 7.12 (2H, d, J=8.5 Hz), 6.69 (2H, d, J=8.5 Hz), 4.68 (1H, t, J=4.5 Hz), 4.35-4.26 (2H, m), 3.95 (3H, s), 3.86 (1H, br s), 2.46 (1H, m), 2.20 (2H, dd, J=4.5 Hz, 10.5 Hz), 1.92-1.87 (4H, m), 1.80-1.77 (1H, m), 1.43 (4H, m), 1.29 (1H, m).
Reaction SMILES: C(OC1CCN([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)CC1)(=O)C.BrC1C=CC([CH:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=CC=1>CCOC(C)=O.O>[CH3:39][N:36]1[CH2:37][CH2:38][CH:33]([C:11]2[CH:12]=[CH:13][C:14]([B:17]3[O:18][C:19]([CH3:24])([CH3:25])[C:20]([CH3:22])([CH3:23])[O:21]3)=[CH:15][CH:16]=2)[CH2:34][CH2:35]1
Reactant: CN1CCC(c2ccc(Br)cc2)CC1
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate, except substituting 4-(4-bromophenyl)-1-methylpiperidine (236 mg, 0.93 mmol). The reaction was then allowed to cool to rt and was diluted with EtOAc and water was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated to give a viscous brown solid (236 mg, used without further purification). 1H NMR (400 MHz, MeOD) δ 7.70 (d, J=7.5 Hz, 2H), 7.25 (d, J=7.5 Jz, 2H), 3.26-3.23 (m, 2H), 2.69-2.64 (m, 1H), 2.60-2.54 (m, 5H), 1.92-1.91 (m, 4H), 1.33 (s, 12H); MS ESI 302.2 [M+Na]+, calcd for [C18H28BNO2+Na]+ 302.22.
Reaction SMILES: Br[CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[SH:8][C:9]1[C:10]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:11]=2[S:12][C:13]=1[C:14]([NH2:16])=[O:15].C([O-])(O)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[NH2:16][C:14]([C:13]1[S:12][C:11]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:10]=2[C:9]=1[S:8][CH2:7][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[O:15]
Reactant: COC(=O)C(C)Br
Reactant: COc1ccc2sc(C(N)=O)c(S)c2c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCSc1c(C(N)=O)sc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Methyl bromopropionate (75 μL, 0.69 mmol) is added to a room temperature solution of 3-mercapto-5-methoxybenzo[b]thiophene-2-carboxamide (150 mg, 0.63 mmol) in 7 mL of THF followed by NaHCO3 (334 mg, 3.15 mmol). Additional methyl bromopropionate (150 μL) and Na2CO3 (70 mg) are added and the reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate and washed with 1N HCl, water, 1N NaOH, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate: hexane followed by recrystallization from methanol: water gives methyl 3-[[2-(aminocarbonyl)-5-methoxybenzo[b]thien-3-yl]thio]propanoate in 46% yield; mp=142°-144° C.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC.O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([CH:12]=[CH2:13])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)cnc1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1ncc(F)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromo-5-fluoro-3-nitropyridine (20 g, 90.50 mmol) in 1, 4 dioxane (270 mL) was added tributyl vinyl tin (34.54 g, 108.60 mmol). The reaction mixture was degassed using nitrogen for 30 min. Bis-(triphenylphosphin)-palladium(II)-chloride (3.17 g, 4.5 mmol) was added to the reaction mixture. Reaction mass was stirred at 110° C. for 16 h. The reaction mixture was cooled to 25° C. Water was added to the reaction mass and extracted with EtOAc. Organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated in vacuo and purified by column chromatography on silica gel using 0-2% EtOAc in hexane to give 5-fluoro-3-nitro-2-vinylpyridine: 1H NMR (400 MHz, DMSO-d6): δ 5.742 (dd, 1H, J=2 Hz, 10.8 Hz), 6.45 (dd, 1H, J=2 Hz, J=16.8 Hz), 7.11-7.17 (m, 1H), 8.489-8.516 (m, 1H), 8.959 (d, 1H, J=2.4 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][CH2:21][C:22]#[N:23])=[CH:15][CH:14]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].C([Sn]([N:44]=[N+:45]=[N-:46])(CCCC)CCCC)CCC>C1COCC1.CCOCC.Cl>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][CH2:21][C:22]3[NH:46][N:45]=[N:44][N:23]=3)=[CH:15][CH:14]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)CCC#N)cc2)ccc(C(C)=O)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1c(OCCCSc2ccc(C(=O)CCc3nnn[nH]3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The nitrile from Example 40, Step E, (1.0 g, 2.35 mmole) and tri-n-butyltin azide (1.0 g, 3.0 mmole) in dry THF (20 ml) were stirred at 70° for 48 hours, and then heated at reflux for 24 hours. The reaction mixture was cooled to room temperature, diluted with ether (20 ml) and concentrated HCl was added. After 1 hour, the solution was filtered, the solid was washed with ether and dried to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[C:5](=O)[NH:6][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].O=P(Cl)(Cl)Cl>>[Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:12])=[C:4]([CH:3]=1)[C:9]#[N:10]
Reactant: N#Cc1cc(Br)c[nH]c1=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(Br)cnc1Cl
Temperature: 25 °C

Procedure:
5-Bromo-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (33 g, 166 mmol) was added to a suspension of PCl5 (96.6 g, 464 mmol) in POCl3 (20 ml, 216 mmol). The mixture was stirred at reflux for 3 hours, cooled to room temperature and then poured slowly into ice/water. The resulting solid was fitered, washed with water, and dried in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[S:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[Br:28]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[S:11][C:12]=1[Br:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2csc(-c3ccc4c(c3)OCO4)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1sc(-c2ccc3c(c2)OCO3)nc1Cc1ccccc1
Reaction time: 8 h

Procedure:
367 mg of 4-benzyl-2-(3,4-methylenedioxyphenyl)thiazole was dissolved in 2 ml of N,N-dimethylformamide 244 mg of N-bromosuccinimide was added thereto under ice-cooling, followed by stirring overnight. Then, ethyl acetate was added to the reaction solution, followed by washing with water. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 3% ethyl acetate/hexane as an eluent for separation and purification, to give 377 mg of the target compound.
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].[H-].[Na+].[CH2:19](I)[CH3:20]>C(OCC)(=O)C>[CH2:19]([O:13][C:10]1[CH:11]=[CH:12][C:7]([F:6])=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=1)[CH3:20]
Reactant: O=[N+]([O-])c1cc(O)ccc1F
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(F)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a DMF (10 mL) solution of 4-fluoro-3-nitro-phenol (628 mg), sodium hydride (purity: 55% or higher, 209 mg) was added in small portions at room temperature. After 30 minutes, ethyl iodide (0.38 mL) was added thereto at room temperature. After 2 hours, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and saturated brine, then dried over sodium sulfate, and then concentrated. The residue was purified by column chromatography (hexane/ethyl acetate) to obtain the title compound (685 mg, 93%) as a yellow solid.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(C(=N)N)ccc1NCc1nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)ccc2n1C
Yield: 71 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidino-2-methoxyphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 71% of theory, C27H28N6O4 (500.6); Rf value: 0.15 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=501; (M+Na)+=523; (M+2Na)++=273.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([C:7]([O:9]C2C=CC=CC=2)=O)[CH:6]=1.[ClH:16].Cl.[NH2:18][C@@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:16].[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[C@@H:19]([NH:18][C:7]([N:5]1[CH:6]=[C:2]([I:1])[CH:3]=[N:4]1)=[O:9])[CH2:20]2
Reactant: O=C(Oc1ccccc1)n1cc(I)cn1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)n1cc(I)cn1
Reaction time: 36 h
Yield: 83.4 %

Procedure:
Phenyl 4-iodo-1H-pyrazole-1-carboxylate (1.6 g, 5.2 mmol) and (R)-(+)-3-aminoquinuclidine dihydrochloride (1.0 g, 5.2 mmol) are suspended in 10 mL DMF. DIEA (2.7 mL, 15.5 mmol) is added dropwise. After 36 h, the solvent is removed and the residue is taken up in 1N NaOH and CHCl3. The aqueous layer is extracted with CHCl3, dried (MgSO4), filtered and concentrated. The residue is purified by chromatography (Biotage 40S, 90:9:1 CHCl3/MeOH/NH4OH) to provide 1.66 g (93%) of the product as a white solid. A portion of the material is converted into the hydrochloride salt and recrystallized from MeOH/EtOAc. HRMS (FAB) calcd for C11H15IN4O+H 347.0370, found 347.0357.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[C:7]([N:11]=[N:12][C:13]1([N:19]=[C:20]=[S:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:10])([CH3:9])[CH3:8].O>CCCCC>[C:7]([N:11]=[N:12][C:13]1([NH:19][C:20]([O:4][CH:1]([CH3:3])[CH3:2])=[S:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)O
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: O
Product: CC(C)OC(=S)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 50 ml of isopropanol in a 125 ml erlenmeyer flask stirred with a magnetic stirrer, was slowly added 2.1 grams (0.05 moles) of 57% sodium hydride. The reaction mixture was cooled back to 25° C. and 11.2 grams (0.05 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane was added dropwise over 5 minutes. The reaction mixture was stirred for 2 hours at room temperature and then allowed to stand overnight. The next morning the reaction mixture was poured into 200 ml of water and the product extracted with 50 ml pentane. The pentane extract was washed twice with water, once with 10% NaHCO3, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave a semi-solid. The semi-solid was slurried in cold pentane and filtered. The filter cake was air dried and weighed 4.0 grams (20% crude yield) and melted at 62°-64° C. The product had a strong band at 1525 cm-1 and a sharp NH band at 3300 cm-1 in its infrared spectrum.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13][C:14]1[CH:15]=[C:16]2[C:25](=[CH:26][CH:27]=1)[C:24](Cl)=[C:23]1[C:18]([CH:19]=[CH:20][C:21]([O:29][CH3:30])=[CH:22]1)=[N:17]2.C1(C)C=CC=CC=1>C(O)C.C(=O)([O-])[O-].[K+].[K+]>[Cl:13][C:14]1[CH:15]=[C:16]2[C:25](=[CH:26][CH:27]=1)[C:24]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[C:23]1[C:18]([CH:19]=[CH:20][C:21]([O:29][CH3:30])=[CH:22]1)=[N:17]2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1c2ccc(Cl)cc2nc2ccc(OC)cc12

Procedure:
To a solution of sodium (1.3 g, 52 mmol) in ethanol (50 mL) was added diethyl malonate (8.8 g 55 mmol) followed by 6,9-dichloro-2-methoxyacridine (9.68 g, 35 mmol) and toluene (5 mL). The mixture was heated to reflux for 24 h, diluted with aqueous potassium carbonate, extracted with ethyl acetate, dried, and concentrated in vacuo to give solid which was purified by flash column chromatography (silica gel, 5-12% methanol:dichloromethane) to give the title compound. MS(ES) m/e 402.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]2[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:19][C:12]=12)C(=O)OC(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][NH:2][CH2:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]2[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[CH:18]=[CH:19][C:12]=12
Reactant: CN(Cc1cncc2c1ccn2COCC[Si](C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cncc2c1ccn2COCC[Si](C)(C)C
Yield: 76.4 %

Procedure:
A solution of tert-butyl methyl((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)methyl)carbamate (232 mg, 0.593 mmol) in DCM (20 mL) and TFA (10 mL) was stirred at RT for 3 h. The reaction mixture was quenched with water (100 mL) and extracted with DCM (50 mL×3). The combined extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to afford 132 mg (76.4%) of N-methyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)methanamine as a yellow solid. MS (ESI): m/z=292.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.[Na].[S:14]1[CH2:18][C:17](=[O:19])[NH:16][C:15]1=[O:20].[I-].[Na+].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][N:16]2[C:17](=[O:19])[CH2:18][S:14][C:15]2=[O:20])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1OCCCCl
Reactant: O=C1CSC(=O)N1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncccc1OCCCN1C(=O)CSC1=O
Temperature: 80 °C

Procedure:
To a suspension of 9.33 g (50 mmol) of 2-amino-3-(3-chloropropyloxy)pyridine and 6.97 g (50 mmol) of thiazolidine-2,4-dione sodium salt in 200 ml of N,N-dimethylformamide, 7.49 g (50 mmol) of sodium iodide was added, followed by refluxing at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→ethyl acetate) to yield 8.14 g (60.9%, yellow solid) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Reaction time: 144 h
Yield: 107.8 %

Procedure:
2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (1.246 g) was dissolved in methanol (20 ml)-tetrahydrofuran (10 ml), and then 10% palladium carbon (1.0 g) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring for 6 days. After replacing with nitrogen inside the system, the catalyst was filtered and washed with ethanol. The filtrate was concentrated under a reduced pressure to provide the titled compound (1.182 g, quantitative) as brown crystals.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)(=[O:4])=[O:3].[CH:16]1([C:19]2[CH:20]=[C:21]([CH3:31])[C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][CH:24]=2)[CH2:18][CH2:17]1>>[CH:16]1([C:19]2[CH:20]=[C:21]([CH3:31])[C:22]([N:25]3[CH2:26][CH2:27][N:28]([C:11]([C:10]4[CH:9]=[CH:8][C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:15][CH:14]=4)=[O:13])[CH2:29][CH2:30]3)=[N:23][CH:24]=2)[CH2:18][CH2:17]1
Reactant: CS(=O)(=O)NCc1ccc(C(=O)O)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CNS(C)(=O)=O)cc2)CC1
Yield: 38.8 %

Procedure:
Using 4-(methanesulfonylaminomethyl)benzoic acid (138 mg) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (156 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (100 mg) was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([O:14][CH:15]([CH2:17][CH3:18])[CH3:16])[CH:11]=[CH:10][C:9]=1[OH:19].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>CN(C)C=O>[CH:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]([O:19][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)=[C:8]([Cl:7])[CH:13]=1)([CH2:17][CH3:18])[CH3:16]
Reactant: CCC(C)Oc1ccc(O)c(Cl)c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCc2ccc(F)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.30 g of potassium carbonate, 0.40 g of 2-chloro-4-sec-butoxyphenol, 0.37 g of p-fluorobenzyl bromide and 15 ml of N,N-dimethylformamide is stirred at room temperature overnight. The reaction mixture is poured into ice-water and extracted twice with 100 ml of ethyl acetate. The extracts are combined together, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel chomatography to give 1-sec-butoxy-3-chloro-4-(4-fluorobenzyloxy)benzene.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([CH3:12])=[CH:8][CH:9]=[CH:10][CH:11]=1)=[NH:5])C.[CH3:13][N:14]([C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:15]>C(OCC)C>[CH3:13][N:14]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5][C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])=[N:15]1
Reactant: CN(N)C(=O)c1ccccc1
Reactant: CCOC(=N)c1ccccc1C
Solvent: CCOCC
Product: Cc1ccccc1-c1nc(-c2ccccc2)n(C)n1
Reaction time: 5 h
Yield: 32 %

Procedure:
A mixture of 1.14 g. of o-toluimidic acid ethyl ester, 1.14 g. of 1-methyl-1-benzoylhydrazine and 0.1 g. of o-toluimidic acid ester hydrochloride, as a catalyst, is heated at about 100° C for 3 hours under reduced pressure (about 200 mm Hg) and then at about 120° C for 5 hours. The raw material is taken up with diethyl ether and the organic solution is washed with aqueous sodium bicarbonate and then dried over Na2SO4. After evaporation of the solvent, the product is distilled at 170° C/0.1 mm Hg. Yield 32%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18][CH3:19])[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[NH:8][C:7]=1[CH3:26])=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[CH3:26][C:7]1[NH:8][C:9]([CH3:25])=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([CH3:19])=[O:35])[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1SC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1S(C)=O
Yield: 96.6 %

Procedure:
A solution of 1.092 g (2.91 mm) of diethyl-2,6-dimethyl-4-(2-methylthiophenyl)-1,4-dihydropyridine-3,5-dicarboxylate 33 in 35 mL of dry CH2Cl2 was stirred at -78° C. under Ar and treated with 650 mg (3.20 mm) of m-chloroperbenzoic acid. After 1 hour the reaction was diluted with CH2Cl2 (150 mL) and washed with 10% aqueous sodium thiosulfate, H2O, and brine, dried (anhydrous MgSO4), filtered and concentrated to give 1.10 g of crude sulfoxide 34 (100%) used without purification for the following step.