Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][C:30]3[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=3)=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:40])[C:8]1=[O:41])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][C:30]3[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=3)=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:40])[C:8]1=[O:41]
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(C(F)(F)F)nc3)c(Oc3cccc(C(F)(F)F)c3)cnc21
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(C(F)(F)F)nc3)c(Oc3cccc(C(F)(F)F)c3)cnc21
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
To a solution of 3-(1-methyl-2,4-dioxo-6-(3-(trifluoromethyl)phenoxy)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (35 mg, 0.060 mmol) in THF (4 mL) and water (4 mL) was added LiOH.H2O (5.04 mg, 0.12 mmol). The reaction was stirred for 15 min then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethyl)phenoxy)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (13 mg, 39.0% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.63 (s, 1H), 8.51 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.51-7.49 (m, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.23 (d, J=9.2 Hz, 1H), 6.98 (s, 1H), 4.78 (s, 2H), 4.50-4.48 (m, 1H), 4.00-3.96 (m, 2H), 3.61 (s, 3H), 3.48-3.43 (m, 2H), 1.75-1.71 (m, 2H). LCMS: MH+ 555 and TR=3.087 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH2:25][CH2:26]SC)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)[N:13]=[C:12]([CH3:24])[N:11]=2.[S:29]([O-:34])(O[O-])(=O)=[O:30].[K+].[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].O1CCC[CH2:47]1>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH2:25][CH2:26][S:29]([CH3:47])(=[O:34])=[O:30])[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)[N:13]=[C:12]([CH3:24])[N:11]=2
Reactant: CSCCn1c(-c2ccccc2Cl)nc2c(N3CCN(C)CC3)nc(C)nc21
Reactant: C1CCOC1
Reactant: O=S(=O)([O-])O[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Cl)n(CCS(C)(=O)=O)c2n1
Reaction time: 0.5 h

Procedure:
Dissolve 8-(2-chlorophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)-9-(2-methylsulfanylethyl)purine (38.5 g, 92.3 mmol) in a solution of tetrahydrofuran (277 mL) and methanol (277 mL). Prepare a solution of potassium peroxymonosulfate (Oxone®) (79.5 g, 129.3 mmol) in water (554 mL). Add the potassium peroxymonosulfate solution (300 mL) over a 5 min period and stir for 30 min. Then add additional potassium peroxymonosulfate solution (150 mL, followed by 50 mL after 30 min). Stir the reaction mixture for 30 min following the final addition. Add solid sodium metabisulfite (49.1 g, 258.5 mmol) and stir the mixture at ambient temperature overnight. Add aqueous sodium bicarbonate solution (400 mL) and extract into ethyl acetate (3×1 L). Dry the combined organic layer over anhydrous sodium sulfate, filter, and concentrate to afford an orange residue. Purify the residue on a silica gel column using 5-50% ethanol in 1:1 dichloromethane-hexane as eluent. Combine and evaporate the appropriate fractions to provide a solid. Triturate the solid with ether and dry under vacuum to afford 8-(2-chlorophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)-9-(2-methylsulfonylethyl)purine (11.4 g). ES/MS m/z 449 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:28])[CH2:17][S:18][C:19]3[N:27]=[CH:26][N:25]=[C:24]4[C:20]=3[NH:21][CH:22]=[N:23]4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37].CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH:16]([O:28][C:36](=[O:38])[CH3:37])[CH2:17][S:18][C:19]3[N:27]=[CH:26][N:25]=[C:24]4[C:20]=3[NH:21][CH:22]=[N:23]4)[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: OC(CSc1ncnc2nc[nH]c12)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(CSc1ncnc2nc[nH]c12)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 70 h
Yield: 65 %

Procedure:
To a solution of 6-[1-[1-[bis(4-fluorophenyl)methyl]-piperazin-4-yl]-2-hydroxy-3-propanylthio]purine (1.0 g, 0.002 mol) in CH2Cl2 (7 mL), acetic anhydride (0.2 mL, 0.002 mol) in Et3N (0.2 mL, 0.002 mol) was added dropwise over 5 min at room temperature under nitrogen. After 70 h, CH2Cl2 (50 mL) was added and the solution was extracted with saturated NaHCO3 (2×100 mL), H2O (1×100 mL), and saturated brine (1×100 mL); the organic layer was dried over Na2SO4. Solvent removal of the dried organic layer gave a solid which was dried in vacuo at 40° C. to give pure product (0.7 g, 64.8%), mp 105°-109° C. (dec). DCI/MS (M+1) 539. 400 MHz 1H NMR (CDCl3) δ: 8.7 (s, 1H), 8.2 (s, 1H), 7.3 (m, 4H), 6.95 (m, 4H), 5.3 (m, 1H), 4.2 (s, 1H), 3.4 and 4.0 (m, 2 H), 2.65 (m, 2H), 2.6 (m, 4H), 2.4 (m, 4H), 2.0 (s, 3H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>CC#N.O>[C:1]([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)SCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(=O)SCCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
Referring to FIG. 40, to a solution of 6-(acetylthio)hexanoic acid (3 g, 15.8 mmol) in CH3CN (80 mL) were added K2CO3 (4.3 g, 31.6 mmol) and benzyl bromide (2.68 g, 15.8 mmol). The reaction mixture was stirred at room temperature overnight and ethyl acetate (200 mL) and water (100 mL) were added. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.2 g, 50% yield) as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]([CH:6]([C:14]([C:16]2[C:17]([S:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])C(OC(C)(C)C)=O)=[O:5])[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.O>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:5])[CH2:6][C:14]([C:16]2[C:17]([S:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])[CH2:3][CH2:2]1
Reactant: CSc1ncccc1C(=O)C(C(=O)OC(C)(C)C)C(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1ncccc1C(=O)CC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.4 %

Procedure:
A mixture of t-butyl 2-cyclopropanecarbonyl-3-(2-methylsulphenylpyridin-3-yl)-3-oxopropanoate (9.44 g) and 4-toluenesulphonic acid (0.4 g) in dry toluene was stirred at reflux for 5 hours then allowed to stand at room temperature overnight. The mixture was stirred at reflux for a further 5 hours, cooled to room temperature and taken up into ethyl acetate and water. The phases were separated and the aqueous phase was further extracted with ethyl acetate. The combined organic extracts were dried (anhydrous magnesium sulphate), filtered and evaporated to give 1-cyclopropyl-3-(2-methylsulphenylpyridin-3-yl)propan-1,3-dione (7.64 g) as a brown oil which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH:24]([N:38]([CH3:52])[S:39](C2C3C=CN=CC=3C=CC=2)(=[O:41])=[O:40])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH:12]=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.B(F)(F)F.C([O:59][CH2:60][CH3:61])C.C(=O)(O)[O-].[Na+].[CH2:67](S)[CH2:68]S>>[OH:8][C:9]1[CH:10]=[C:11]([CH2:23][CH:24]([N:38]([CH3:52])[S:39]([C:27]2[C:67]3[C:68](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:24]=[CH:25][N:26]=2)(=[O:41])=[O:40])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH:12]=[CH:61][C:60]=1[OH:59]
Reactant: CCOCC
Reactant: SCCS
Reactant: CN(C(Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)CN1CCN(c2ccccc2)CC1)S(=O)(=O)c1cccc2cnccc12
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C(Cc1ccc(O)c(O)c1)CN1CCN(c2ccccc2)CC1)S(=O)(=O)c1nccc2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
310 mg of the amorphous compound obtained in Example 6 was dissolved in 2 ml of 1,2-ethanedithiol, and to the solution were added 1 ml of boron trifluoride/ethyl ether, and after stirring at a room temperature for 18 hours, was added saturated sodium bicarbonate aqueous solution, and the reaction mixture was extracted twice with a mixture of chloroform and methanol (10:1). The extract was dried over magnesium sulfate, and concentrated under a reduced pressure to obtain a residue, which was applied to a silica gel column and eluted with chloroform/methanol (80:1 to 20:1) to obtain 148 mg of the title compound in a colorless amorphous form.
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:10]=1[C:35]([O:37]CC)=O)C1C=CC=CC=1.Cl.[CH2:41]([NH2:43])[CH3:42].[CH:44]([Mg]Cl)([CH3:46])[CH3:45]>C1COCC1>[CH2:45]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22]([N:23]([CH3:24])[CH3:25])=[O:26])[N:11]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:10]=1[C:35]([NH:43][CH2:41][CH3:42])=[O:37])[C:44]1[CH:46]=[CH:35][CH:10]=[CH:9][CH:13]=1
Reactant: CCN
Reactant: CC(C)[Mg]Cl
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCNC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 191.5 %

Procedure:
To a stirred suspension of ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (6) (200 mg, 0.38 mmol) and ethylamine hydrochloride (61.7 mg, 0.75 mmol) in THF (2 mL) was added isopropylmagnesium chloride (2 M in THF) (757 μL, 1.51 mmol) and the reaction stirred at RT for 2 h, further portions of ethylamine hydrochloride (120 mg, 1.5 mmol) and isopropylmagnesium chloride (2 M in THF) (1.5 mL, 3.0 mmol) were added and the reaction stirred for 16 h at RT. The reaction mixture was partitioned between sat. NH4Cl solution (aq.) (5 mL) and EtOAc (20 mL) the aqueous was further acidified with 1 M HCl (5 mL). The organic layer was separated and washed with brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo to afford crude product. The residue was purified by silica gel chromatography (25 g, 30-80% EtOAc in isohexane) to afford 3,4-bis(benzyloxy)-N2-ethyl-1-(4-methoxyphenyl)-N5,N5-dimethyl-1H-pyrrole-2,5-dicarboxamide (UL1-055) (192 mg, 95%) as a yellow oil: m/z 528 (M+H)+ (ES+). 1H NMR (400 MHz, CDCl3) δ: 7.44-7.30 (m, 10H), 7.20-7.09 (m, 2H), 7.06-6.97 (m, 1H), 6.89-6.80 (m, 2H), 5.20 (s, 2H), 5.07 (s, 2H), 3.79 (s, 3H), 3.25-3.14 (m, 2H), 2.79 (s, 3H), 2.72 (s, 3H), 0.97 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[C:17](Cl)=[CH:16][C:14]([NH2:15])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1.[OH-].[K+]>O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:17]1[C:11]([Cl:10])=[CH:12][C:13]([N+:19]([O-:21])=[O:20])=[C:14]([CH:16]=1)[NH2:15]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(Oc2cccc(Cl)c2Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A mixture of 171 g of 2,3-dichlorophenol and 186 g of 4,5-dichloro-2-nitroaniline is heated to 150° C. 101 g of a 50% potassium hydroxide solution are added dropwise to the dark-red liquid over a period of 1 hour. The water of reaction formed is distilled off with a small amount of phenol. The reaction mixture is stirred overnight at 150° C. and then, at that temperature, 450 ml of dimethylformamide are added. The solution is allowed to cool and is all poured onto a mixture of 3 1 of water and 150 ml of concentrated sodium hydroxide solution. The greenish suspension is stirred at room temperature for 1 hour, and the crystals that form are filtered off and washed neutral with water and then dried. The still moist yellowish crystals are used in crude form in the next reaction step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([N:13]1[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:15][CH2:14]1)[CH:7]=[CH:6]2.C=O.[C:26](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([N:13]1[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][N:21]([CH3:26])[CH2:20][CH2:19]3)[CH2:15][CH2:14]1)[CH:7]=[CH:6]2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccc2cc(N3CCC4(CCNCC4)CC3)ccc2c1
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc2cc(N3CCC4(CCN(C)CC4)CC3)ccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To an ice cooled solution of 3-(6-methoxy-naphthalen-2-yl)-3,9-diaza-spiro[5.5]-undecane (294 mg, 0.95 mmol) in dichloroethane (20 mL), formaldehyde (37% in water, 204 μL, 2.84 mmol) was added and stirred for 1 h at 0° C. Sodium triacetoxyborohydride (402 mg, 1.89 mmol) was added and stirred at room temperature over night. The reaction was quenched with aqueous sodium hydrogencarbonate (sat.) and evaporated. The remaining aqueous phase was extracted three times with dichloromethane and the combined organic phase was dried (sodium sulfate), filtered and evaporated to give 270 mg (80%) of 3-(6-methoxy-naphthalen-2-yl)-9-methyl-3,9-diaza-spiro[5.5]undecane. Mp. 122.2-124.9° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[C:7]([F:13])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[S:4][C:3]=1C(O)=O.[N+](=C1CCCCCCCCCC1C1CCCCCCCCCC1)=[N-]>CC(N(C)C)=O.C(OCC)C>[Cl:1][C:2]1[C:6]2[C:7]([F:13])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[S:4][CH:3]=1
Reactant: COc1ccc(F)c2c(Cl)c(C(=O)O)sc12
Agent: [N-]=[N+]=C1CCCCCCCCCC1C1CCCCCCCCCC1
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: COc1ccc(F)c2c(Cl)csc12
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A mixture of 3-chloro-4-fluoro-7-methoxy-1-benzothiophene-2-carboxylic acid (1.09 g, 4.19 mmol) and diazobicycloundecane (DBU) (2 mL) in dimethylacetamide (15 mL) was heated in a sealed vessel in a microwave (300W, 100%) for 1 h. After cooling to room temperature the mixture was diluted with diethyl ether (100 mL) and washed with brine (2×100 mL). The organic phase was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane:diethyl ether [10:1] to yield a white solid (520 mg, 57%); δH (300 MHz, CDCl3) 7.24 (1H, s, Ar), 7.05-6.92 (1H, m, Ar), 6.70-6.60 (1H, dd, Ar), 3.96 (3H, s, OCH3).
Reaction SMILES: [C:1](O)(=O)[CH3:2].[CH3:5][NH:6][CH3:7].[CH3:8][C:9]1[CH:10]=[C:11]([C:16]2[NH:17][C:18]3[C:23](C=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=[C:13]([CH3:15])[CH:14]=1>C(O)C>[CH3:8][C:9]1[CH:10]=[C:11]([C:16]2[NH:17][C:18]3[C:23]([C:1]=2[CH2:2][N:6]([CH3:7])[CH3:5])=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: CNC
Reactant: CC(=O)O
Reactant: Cc1cc(C)cc(-c2cc3ccccc3[nH]2)c1
Solvent: CCO
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CN(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.5 %

Procedure:
To 2.53 g glacial acetic acid was added 2.0 g dimethyl amine (40% aqueous solution) followed by 1.37 g fomalin (37% solution) then 4.0 g 2-(3,5-dimethylphenyl)-1H-indole and the mixture stirred at 0° C. After 15 minutes, 40 mL ethanol was added and the mixture allowed to warm to room temperature. After 1 hour at room temperature, the reaction was quenched by pouring into 50 mL of 1N sodium hydroxide. The resulting mixture was extracted with methylene chloride (4×10 mL) and the combined organics dried over potassium carbonate. Concentration in vacuo gave the crude title compound (4.15 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][OH:8])[NH:4][N:3]=1.CCO/[CH:12]=[C:13](/[CH:15]=O)\[CH3:14]>C(O)(=O)C>[CH3:15][C:13]1[CH:12]=[N:1][C:2]2[N:3]([N:4]=[C:5]([CH2:7][OH:8])[N:6]=2)[CH:14]=1
Reactant: CCO/C=C(\C)C=O
Reactant: Nc1n[nH]c(CO)n1
Solvent: CC(=O)O
Product: Cc1cnc2nc(CO)nn2c1
Temperature: 80 °C

Procedure:
To a solution of (3-amino-1H-1,2,4-triazol-5-yl)methanol (16.6 g, 87.6 mmol) in acetic cid was added 3-ethoxymethacrolein (10.0 g, 87.6 mmol), and the mixture was heated to 80° C. for 4 hours. Upon cooling of the reaction, the product crystallized out of solution. The collected product was a white solid (14.0 g, 92%). 1H NMR (300 MHz, DMSO-D6) δ: 2.38 (m, 3H) 4.63 (m, 2H) 5.52 (m, 1H) 8.75 (m, 1H) 9.21 (m, 1H). MS (APCI, M+H+): 163.1, 165.1.
Reaction SMILES: [OH2:1].[OH-].[K+].[CH3:4][C:5]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:6][C:7]#N.[CH2:20]([OH:22])C>>[CH3:4][C:5]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:6][CH2:7][C:20]([OH:22])=[O:1]
Reactant: CC(=CC#N)CCCC(C)CCCC(C)C
Reactant: CCO
Reactant: O
Agent: [K+]
Agent: [OH-]
Product: CC(=CCC(=O)O)CCCC(C)CCCC(C)C
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Water (130 mL) and 40 g (0.71 mol) of potassium hydroxide was added to a solution of 67.2 g (285 mmol) of 3,7,11-trimethyldodec-2-ene-1-nitrile in ethanol (470 mL). The solution was stirred for 18 hours at 80° C. After the reaction mixture was concentrated, and then neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate aqueous solution and saturated brine, successively, and dried over sodium sulfate. After filtration, the filtrate was concentrated to obtain 4,8,12-trimethyltridec-3-enoic acid as a crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][C@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@H:33]1[OH:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][C@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@H:33]1[OH:41])=[O:29]
Reactant: COc1cc2c(c(OC)c1)C(Cc1ccc(OC)c(OC)c1)NCC2
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: O=C(Br)CBr
Product: COc1cc2c(c(OC)c1)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)N[C@H]1c3ccccc3C[C@H]1O)CC2

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1S,2R)-1-amino-2-indanol
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:30])=[C:13]([C:25](OCC)=[O:26])[C:14](=[O:24])[N:15]2[CH2:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:30])=[C:13]([C:25]([NH:35][CH2:34][CH2:33][O:32][CH3:31])=[O:26])[C:14](=[O:24])[N:15]2[CH2:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2nccs2)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2nccs2)c1=O

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-2-oxo-1-(1,3-thiazol-2-ylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 5 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.21 (1H, t, J=5 Hz), 8.56 (1H, s), 8.12 (1H, s), 7.69 (1H, d, J=3.2 Hz), 7.67 (1H, d, J=3.2 Hz) 7.28-7.22 (4H, m), 7.18 (1H, t, J=7 Hz), 5.78 (2H, s), 4.09 (2H, s), 3.56-3.48 (4H, m), 3.28 (3H, s); HRMS calcd for C23H22N4O4S+H+: 451.1440. Found: 451.1428.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:12](Cl)=[O:13])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.O.[NH2:16][NH2:17]>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:12]([NH:16][NH2:17])=[O:13])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: O=C(Cl)C1(c2cccs2)CCOCC1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: NNC(=O)C1(c2cccs2)CCOCC1

Procedure:
4-(2-Thienyl)tetrahydropyran-4-carboxylic acid was reacted with thionyl chloride and a catalytic amount of DMF in methylene chloride under heating to obtain 4-(2-thienyl)tetrahydropyran-4-carbonyl chloride. A THF solution of 4-(2-thienyl)tetrahydropyran-4-carbonyl chloride was added dropwise to a THF solution of hydrazine monohydrate and the whole was reacted at 0° C. to obtain 4-(2-thienyl)tetrahydropyran-4-carbohydrazide.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:9]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1F)[CH:14]=[O:15])#[N:10]>CN(C=O)C.[Cl-].[Na+].O.C(OCC)(=O)C>[CH:1]1([O:6][C:18]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=2[C:9]#[N:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: OC1CCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C=O)ccc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32.3 %

Procedure:
A solution of cyclopentanol (1.15 g, 0.013 mol), in DMF (50 ml) was cooled to 0° C. Sodium hydride (1.54 g, 0.016 mol) was added portionwise to the solution and the mixture stirred at 0° C. for 10 minutes after complete addition. 3-Cyano-4-fluorobenzaldehyde (commercial) (2.0 g, 0.013 mol) was then added and the mixture allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to 0° C. and brine was added, the mixture was diluted with ethyl acetate (˜25 ml) and partitioned, the organic layer was washed with water (˜30 ml) and passed through a phase separating cartridge to dry. The solution was concentrated in vacuo and the residue purified by Biotage SP4, 40M with 20-60% ethylacetate/hexane as eluant. The product containing fractions were concentrated in vacuo to yield the title compound (1.02 g, 4.2 mmol) as a yellow liquid. MS (ES): requires C13H13NO2 215; found 216 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[C:7]1([NH:6][CH2:2][C:3]([OH:5])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)CCl
Reactant: Nc1ccccc1
Solvent: O
Product: O=C(O)CNc1ccccc1

Procedure:
475 g (5 mols) of chloroacetic acid are heated at 100° C. with 930 g (10 mols) of aniline in 2 l. of water for 1.5 hours. After the mixture has been cooled, the N-phenylglycine formed is filtered off with suction and washed with water. Yield: 468 g (=62%, relative to the chloroacetic acid).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:7][CH2:8][C:9](=O)[NH:10][N:11]=1.Cl[C:14]1[N:15]=[N:16]C(C2OC=CC=2)=C[CH:19]=1.C(NN)(=O)C>C(O)CCC>[CH3:19][C:14]1[N:10]2[N:11]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH:7]=[CH:8][C:9]2=[N:16][N:15]=1
Reactant: O=C1CCC(c2ccco2)=NN1
Reactant: Clc1ccc(-c2ccco2)nn1
Agent: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccco3)nn12

Procedure:
As for Example 5, 4,5-dihydro-6-(2-furyl)-3(2H)-pyridazinone is converted to 3-chloro-6-(2-furyl)pyridazine. A 1.5 g. sample of the preceding compound, 1.2 g. of acethydrazide in 50 ml. of n-butyl alcohol is refluxed for 48 hours. The solvent is removed under reduced pressure and the residue is partitioned between dichloromethane and dilute sodium hydroxide. The dichloromethane layer is washed with water, dried over magnesium sulfate, filtered and concentrated. The residue is purified by conventional means to give the product of the Example.