Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]4[CH2:21][O:20]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([OH:20])[CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Brc1cnc2[nH]c(-c3ccc(OCC4CO4)cc3)nc2c1
Product: OC(COc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1)CN1CCOCC1

Procedure:
The title compound was prepared from 6-bromo-2-[4-(oxiran-2-ylmethoxy)phenyl]-3H-imidazo[4,5-b]pyridine and morpholine.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19]CC([O:23][CH2:24][CH3:25])=O.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C.C(O)(C)C>[ClH:19].[C:13]1([CH2:12][N:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:25][C:24]2=[O:23])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CCl
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCO
Product: O=C1CN(Cc2ccccc2)CCN1Cc1ccccc1

Procedure:
A mixture of N,N'-dibenzylethylenediamine (24.0 g., 0.1 mole), ethyl chloroacetate (V, 24.51 g., 0.2 mole), anhydrous sodium carbonate (10 g., 0.094 mole) in ethanol (250 ml.) is heated under reflux for 20 hours. The ethanol is removed under reduced pressure and the residue is partitioned between chloroform and water. Evaporation of the chloroform gives an oil which is dissolved in isopropanol (200 ml.) and acidified with ethereal hydrogen chloride. The precipitate of 1,4-bis(phenylmethyl)piperazinone hydrochloride is filtered off and recrystallized from isopropanol, m.p. 209°-212°.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[CH:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:27]>>[CH2:2]([N:3]1[C:9]2[C:8](=[CH:13][C:12]([F:14])=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:25][C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[O:27])[CH2:17][CH2:16]3)[CH:10]=2)[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:1]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(OC)cc4)CC3)cc21

Procedure:
1-Ethyl-6-fluoro-7-{4-[2-(4-methoxyphenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was prepared from norfloxacin (0.50 g, 1.56 mmole) [H. Koga et. al., J. Med. Chem. , 23, 1358 (1980).] and 2-bromo-4′-methoxyacetophenone (0.43 g, 1.86 mmole) by a method similar to that described for Example 4 (75% yield). Mp: 202° C. (dec). 1H NMR (DMSO-d6) δ 1.41 (t, 3H, J=7.0), 2.73 and 3.3 (two m, 8H), 3.85 (s, 3H), 3.88 (s, 2H), 4.58 (q, 2H, J=7.0), 7.02-7.2 (m, 3H), 7.87 (d, 1H, J=13.8), 8.01 (m, 2H), 8.94 (s, 1H), 15.33 (br s, 1H). Anal. Calcd. for C25H26FN3O5: C, 64.23; H, 5.61; N, 8.99. Found: C, 63.88; H, 5.61; N, 8.94.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([CH3:17])[N:11]=1.O>O1CCCC1>[Cl:9][C:10]1[N:15]=[C:14]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([CH3:17])[N:11]=1
Reactant: Oc1ccc(F)cc1
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2ccc(F)cc2)nc(Cl)n1
Temperature: 20 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
4-Fluorophenol (103 mg, 0.92 mmol) and potassium-tert-butylate (113 mg, 1.0 mmol) were dissolved in 7 mL of tetrahydrofurane. 2,4-dichloro-6-methylpyrimidine (150 mg, 0.92 mmol) was added and the mixture stirred at 20° C. overnight. Water was added and the mixture extracted with diethyl ether. Chromatography of the crude reaction product on silica gel using a heptane/ethyl acetate as an eluent gave the title compound (150 mg, 68%) as a slightly yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.50-7.40 (m, 2H), 7.28 (t, 1H), 7.14 (d, 2H), 6.57 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:7]([C:17](=[O:32])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:6]1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>CN(C)C=O>[CH3:3][O:4][C@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[C@@H:7]([C:17](=[O:32])[N:18]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:6]1
Reactant: COC(=O)CBr
Reactant: CO[C@@H]1C[C@H](C(=O)Nc2ccc(N3CCOCC3=O)cc2)N(C(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)[C@H]1C[C@@H](OC)CN1C(=O)OC(C)(C)C)c1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
61 mg (2.54 mmol) of sodium hydride are added to the solution of 1 g (2.31 mmol) of tert-butyl (2R,4R)-4-methoxy-2-[4-(3-oxomorpholin-4-yl)-phenylcarbamoyl]pyrrolidine-1-carboxylate (prepared analogously to Example 7.1) in 20 ml of dimethylformamide, and the mixture is stirred at room temperature for 30 minutes. 0.22 mg (2.31 mmol) of methyl bromoacetate is subsequently added to the reaction mixture, which is then left to stir at room temperature for 12 hours. The reaction mixture is then evaporated under reduced pressure, the residue is taken up in 20 ml of water, and the aqueous solution is extracted three times with 20 ml of methylene chloride each time. Drying of the combined organic phases over sodium sulfate and stripping-off of the solvent gives 1.1 g of tert-butyl (2R,4R)-4-methoxy-2-{methoxycarbonylmethyl-[4-(3-oxomorpholin-4-yl)phenyl]-carbamoyl}pyrrolidine-1-carboxylate as a yellow oil; ESI (M-BOC) 392.
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH2:17]([OH:19])[CH3:18]>>[CH2:17]([O:19][CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2)[CH3:18]
Reactant: CCO
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Product: CCOC1c2ccccc2-c2[nH]c(=O)c(=O)[nH]c21
Yield: 25 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (0.50 g, 2.13 mmol) was refluxed in 25 ml dry ethanol for 7 hours. The mixture was evaporated to few ml and the precipitate was filtered off, washed with ethanol and dried to give 0.229 g of the crude compound, which was recrystallized from acetic acid-water to yield 0.131 g (25%) of the title compound. M.p.>300° C. 1H-NMR (DMSO-d6, δ): 1.1 (t, 3H), 3.25 (dq, 1H), 3.43 (dq, 1H), 5.22 (s, 1H), 7.17 (t, 1H), 7.33 (t, 1H), 7.42 (d, 1H), 7.51 (d, 1H), 12.1 (s, 1H), 12,31 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:22]([O:23][CH3:24])=[CH:21][C:7]2[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:9][CH2:10][C:11](=[O:14])[N:12]([CH3:13])[C:6]=2[CH:5]=1)[CH3:2].[N+](C1C=CC=CC=1CBr)([O-])=O.Br[CH2:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[C:41]#[N:42]>>[CH2:1]([O:3][C:4]1[C:22]([O:23][CH3:24])=[CH:21][C:7]2[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:9][CH:10]([CH2:37][C:38]3[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=3)[C:41]#[N:42])[C:11](=[O:14])[N:12]([CH3:13])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CCOc1cc2c(cc1OC)C(c1ccccc1)=NCC(=O)N2C
Agent: O=[N+]([O-])c1ccccc1CBr
Product: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(Cc1cccc(C#N)c1)C(=O)N2C
Yield: 35 %

Procedure:
By replacing 1-ethyl-7,8-dimethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIbd) in example IIbh by 8-ethoxy-7-methoxy-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIIda), and 2-nitrobenzyl bromide by 3-bromomethyl-benzonitrile, and proceeding in the same manner, the abovenamed product is obtained. Yield: 35%. M: 148–150° C. 1H-NMR (CDCl3, 200 MHz): d 1.53 (s, 3H, CH3), 3.40 (s, 3H, NCH3), 3.58–3.62 (m, 2H, 1H —CH2Ph+CH), 3.72 (s, 3H, OCH3), 3.75–3.80 (m, 1H CH2Ph), 4.17 (q, 2H, CH2), 6.66 (s, 1H Ar), 6.76 (s, 1H Ar), 7.35–7.67 (m, 9H Ar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([NH:8][NH2:9])=O.[C:16]([NH2:19])(=S)[CH3:17]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[NH:19][C:16]([CH3:17])=[N:9][N:8]=2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: COc1cc(C(=O)NN)ccc1[N+](=O)[O-]
Reactant: CC(N)=S
Solvent: c1ccncc1
Product: COc1cc(-c2nnc(C)[nH]2)ccc1[N+](=O)[O-]
Temperature: 95 °C

Procedure:
The mixture consisting of 590 mg g of 3-methoxy-4-nitrobenzoic hydrazide, 6 ml of pyridine and 210 mg of thioacetamide was heated to 95° C. for 2 hours. After cooling, the volatile fractions were removed under reduced pressure at 40° C. and the residue was subjected to column chromatography purification (silica gel, solvent: 95:5 dichloromethane:methanol)
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(Nc2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.5 %

Procedure:
A mixture of the 4-fluoro-3-nitroaniline (5.00 g, 32.03 mmol), phenylboronic acid (7.81 g, 64.05 mmol), copper(II) acetate (5.82 g, 32.03 mmol) and 4 Å molecular sieves (5.00 g) in dichloromethane (200.0 mL) and triethylamine (22.3 mL, 160 mmol) was placed in a round bottomed flask. The resulting suspension was stirred at room temperature under a dry ambient atmosphere for 48 h. The mixture was filtered through diatomaceous earth and the solvent was removed via rotary evaporation. The resulting residue was re-dissolved in EtOAc, adsorbed on silica gel and flash chromatographed (15% EtOAc/hexanes) to give 4-fluoro-3-nitro-N-phenylaniline as an orange solid (5.24 g, 70.5 % yield). M−, 231.
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])=[CH:18][C:17]=1[CH3:26])[CH3:14].CN(CC1OC(CSC[CH2:39][NH:40][C:41]2[C:45](OC)=[N:44][S:43](=[O:49])(=[O:48])[N:42]=2)=CC=1C)C.CN>CO>[CH3:14][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH:25][C:45]2[C:41]([NH:40][CH3:39])=[N:42][S:43](=[O:49])(=[O:48])[N:44]=2)=[CH:18][C:17]=1[CH3:26])[CH3:12]
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1cc(C)c(CN(C)C)o1
Reactant: Cc1cc(CSCCN)oc1CN(C)C
Agent: CN
Agent: COC1=NS(=O)(=O)N=C1OC
Solvent: CO
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1cc(C)c(CN(C)C)o1

Procedure:
When a methanol suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with an equimolar amount of 2-[(5-dimethylaminomethyl-4-methyl-2-furyl)methylthio]ethylamine [prepared in Step C] and the resultant 3-{2-[(5-dimethylaminomethyl-4-methyl-2-furyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is treated with an excess of methylamine, the title compound is produced.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([NH:8][C:9](=O)[O:10]C2C=CC=CC=2)[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1)[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][N:30]=[C:29]2[O:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CS(C)=O.C(OCC)(=O)C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][N:30]=[C:29]2[O:38][C:39]1[CH:40]=[C:41]([NH:42][C:9]([NH:8][C:6]2[N:5]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=2)=[O:10])[CH:43]=[CH:44][CH:45]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CCc1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)n(-c2ccccc2)n1
Temperature: 70 °C
Yield: 31.3 %

Procedure:
A stirred mixture of phenyl 3-ethyl-1-phenyl-1H-pyrazol-5-ylcarbamate (0.15 g, 0.50 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (0.15 g, 0.50 mmol) in DMSO (2 mL) was heated at 70° C. for 15 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×20 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to afford an oil. Purification via preparative silica gel thin-layer chromatography (eluting with a mixture of 8% methanol in dichloromethane containing 0.5% ammonia) followed by recrystallization from diethyl ether afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-ethyl-1-phenyl-1H-pyrazol-5-yl)urea (80 mg, 32%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) 89.21 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 7.52-7.55 (m, 6H), 7.34-7.42 (m, 3H), 7.18 (m, 1H), 6.92 (m, 1H), 6.30 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 2.56 (m, 2H), 1.19 (m, 3H); LC-MS (ESI) m/z 511 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(CCCCCO)nnc1-c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(CCCCCOS(C)(=O)=O)nnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 116 %

Procedure:
To a solution of 5-(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-1-pentanol (127 mg, 0.52 mmol) in DCM (5 ml) was added trietylamine (0.62 mmol) and methansulfonyl chloride (0.57 mmol). The solution was stirred at r.t. for 2 h and quenched with saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated to give the title compound as light yellow oil (195 mg). MS (m/z): 324[MH]+.
Reaction SMILES: C([N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1(N)C)(OC(C)(C)C)=O.C([Li])CCC.[CH3:21][N:22](OC)[C:23]([CH:25]1[CH2:27][CH2:26]1)=O.Cl>C1COCC1>[CH:25]1([C:23]2[NH:22][C:21]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=2)[CH2:27][CH2:26]1
Reactant: CON(C)C(=O)C1CC1
Reactant: CC(C)(C)OC(=O)N1C=CC=CC1(C)N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1cnc2[nH]c(C3CC3)cc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
To a stirred mixture of N-boc-2-aminopicoline (10.4 g) in dry THF (70 ml) in an ice/salt bath was added, under an atmosphere of nitrogen, n-butyl lithium (2M solution in cyclohexane, 50 ml), keeping the temperature below 0° C. The reaction was stirred below 0° C. for 1 h before the addition of a solution of N-methyl-N-(methyloxy)cyclopropanecarboxamide (7.5 g) (available from Pfaltz-Bauer) in dry THF (20 ml). The reaction mixture was stirred at 0° C. for 2 h then warmed to 10° C. and poured into 5M hydrochloric acid (130 ml). The mixture was heated at 60° C. for 2 h, cooled and the aqueous layer separated. The aqueous layer was basified by the addition of 10M sodium hydroxide, with ice/water cooling, until the pH was 10-12. The resulting mixture was extracted with DCM (2×100 ml) and the combined organic extracts were washed with water (50 ml), dried using a hydrophobic frit and evaporated to give the title compound (7.89 g).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(#N)C>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCC(c3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a suspension of 4-phenylpiperidine (5.0 g) in acetonitrile (100 ml) was added triethylamine (8.64 ml) and then was added dropwise at 0° C. a solution of p-toluenesulfonyl chloride (6.50 g) in acetonitrile (30 ml). The mixture was stirred at 0° C. for 2 hours. Under reduced pressure, the solvent was evaporated, and to the residue was water. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the resulting crystals were collected by filtration, which were washed with hexane to give colorless crystals of 1-(4-methylphenylsulfonyl)-4-phenylpiperidine (8.93 g).
Reaction SMILES: CO.N1CC[CH2:6][CH2:5][CH2:4]1.[ClH:9].Cl.C[O:12][C:13]([C:15]1[CH:38]=[CH:37][C:18]([CH2:19][NH:20][C:21]([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[NH:25])=[NH:22])=[CH:17][CH:16]=1)=[O:14]>CC(C)=O>[ClH:9].[CH3:4][C:5]1([CH3:6])[N:22]=[C:21]([NH:20][CH2:19][C:18]2[CH:37]=[CH:38][C:15]([C:13]([OH:12])=[O:14])=[CH:16][CH:17]=2)[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[N:25]1
Reactant: CCCCCCCCCCNC(=N)NC(=N)NCc1ccc(C(=O)OC)cc1
Reactant: C1CCNCC1
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Product: CCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(C(=O)O)cc2)N1

Procedure:
50 ml of methanol, 100 ml of acetone and 1.6 ml of piperidine were added to 5.0 g (10.8 mmol) of N1-(4-methoxycarbonylbenzyl)-N5-decyl-biguanide dihydrochloride. The mixture was refluxed for 24 hours, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution with a mixture of chloroform/methanol/acetic acid (8:0.7:0.7→8:1:1)). 4.0 g of the purified product was dissolved in 60 ml of ethanol, and to the solution were added 60 ml of water and 2.4 ml of 5N aqueous sodium hydroxide. The mixture was refluxed for 2 hours, and 5 ml of concentrated hydrochloric acid was added thereto. The mixture was concentrated under reduced pressure, and extracted with chloroform. The aqueous layer was separated, and the solvent was distilled off under reduced pressure. The residue was dried well under reduced pressure, heated and extracted with methanol. The extract was filtered, and cooled. The resulting precipitates were filtered, and the solvent of the filtrate was distilled off under reduced pressure. The residue was extracted with ethanol under heating, and filtered. The solvent of the filtrate was distilled off under reduced pressure, and ether was added to the residue to obtain 3.4 g of a white yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([O:13]CC)=O)=[N:6][CH:7]=1.C(O)C.O.[NH2:21][NH2:22]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:13])[NH:21][N:22]=2)=[N:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)CCC(=O)c1ccc(Cl)cn1
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(Cl)cn2)=NN1
Yield: 81.1 %

Procedure:
To a dry 200 mL flask equipped with magnetic stirrer, and reflux condenser was charged 3.7 g ethyl 4-(5-chloropyridin-2-yl)-4-oxobutanoate (0.0153 mol), 75 mL ethanol, and 0.8 g of hydrazine hydrate (0.0168 mol). The reaction was heated at reflux for about 2 hours. An aliquot was analyzed by GC which indicated no remaining starting material, and one major product. The reaction was cooled and poured into about 200 mL of water to afford a tan solid which was collected by vacuum filtration, washed with water, hexane, and dried overnight in vacuo at 40° C. Isolated 2.6 g of a tan solid. The NMR data is as follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 2.65 (t, 2H); 3.22 (t, 2H), 7.75 (d, 1H); 8.00 (d, 1H); 8.60 (s, 1H); 8.70 (bs, 1H). The sample was stored in the refrigerator and had 81% isolated yield.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([NH2:13])(=[O:12])=[O:11])[C:4]=2[CH2:3][S:2]1.C(N=[C:19]=[O:20])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([N:13]=[C:19]=[O:20])(=[O:11])=[O:12])[C:4]=2[CH2:3][S:2]1
Reactant: CCCCN=C=O
Reactant: NS(=O)(=O)c1cccc2c1CSC2
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1cccc2c1CSC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 5.5 g of 1,3-dihydrobenzo[c]thiophene-4-sulfonamide, 2.5 g of butyl isocyanate and 0.05 g of DABCO® in 50 ml of xylene was heated to 135° and 2.2 ml of liquid phosgene was added in small portions at approximately 135°. When the addition of phosgene was complete, heating was continued for 5 minutes before the dark brown suspension was cooled to ambient temperature under a slow stream of nitrogen. The reaction mixture was filtered under nitrogen and the filtrate was concentrated in vacuo to give 1,3-dihydrobenzo[c]thiophene-4-sulfonyl isocyanate as a dark red-brown oil. The crude sulfonyl isocyanate was dissolved in methylene chloride (total volume=26 ml) for reaction with aminoheterocycles.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[CH2:20][CH2:21]Br>>[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[CH2:20][CH2:21][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: Fc1ccc(CCBr)c(F)c1
Reactant: Brc1ccc2c(c1)N(C1CCNCC1)CC2
Product: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)c(F)c1
Yield: 60.1 %

Procedure:
1-(Piperidin-4-yl)-6-bromoindoline (3.0 g) and 2,4-difluorophenethyl bromide (3.1 g) were treated as in Example 2 to give the title compound (2.7 g) as a white powder (yield: 60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](F)[CH:18]=3)=[C:11]3[N:12]=[N:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O.[C:30](=O)(O)[O-:31].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([O:31][CH3:30])[CH:18]=3)=[C:11]3[N:12]=[N:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: Fc1ccc(-c2nn3ccnnc3c2-c2ccnc(F)c2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(-c2c(-c3ccc(F)cc3)nn3ccnnc23)ccn1

Procedure:
To a suspension of 7-(4-fluorophenyl)-8-(2-fluoropyridin-4-yl)pyrazolo[5,1-c][1,2,4]triazine (350 mg) in methanol (2 ml) was added conc. sulfuric acid (0.32 ml) dropwise. The mixture was refluxed for 1 hour, cooled and poured into cold water. The aqueous solution was neutralized with an aqueous saturated sodium bicarbonate solution and the separated oil was extracted with dichloromethane. The extract was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from methanol to give 7-(4-fluorophenyl)-8-(2-methoxypyridin-4-yl)pyrazolo[5,1-c][1,2,4]triazine (220 mg).
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][Mg]Br.C(OCC)C.O.Cl>C(OCC)C>[F:11][C:10]1[C:2]([CH3:14])=[C:3]([C:7]([F:13])=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: C[Mg]Br
Reactant: O=C(O)c1c(F)cc(F)c(F)c1F
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: Cc1c(F)c(F)cc(F)c1C(=O)O
Temperature: -10 °C
Reaction time: 17 h
Yield: 92 %

Procedure:
200 mg of 2,3,4,6-tetrafluorobenzoic acid was dissolved in 10 ml of diethyl ether and cooled to −10° C. in an argon atmosphere. Then 1.72 ml of a methyl magnesium bromide-diethyl ether solution (3 moles/liter) was added dropwise. After completion of dropwise addition, the reaction mixture was heated to room temperature and stirred at room temperature for 17 hours. The reaction mixture was added to about 50 ml of cold water and adjusted to pH 1 with concentrated hydrochloric acid. The reaction mixture was extracted with ethyl acetate and separated into liquids. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to give 181 mg of 3,4,6-trifluoro-2-methylbenzoic acid (yield: 92%).