Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]([CH2:14][F:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.O.[Cl-].[Na+].O>[N:16]([CH:6]([CH2:14][F:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+:17]=[N-:18]
Reactant: CS(=O)(=O)OC(CF)Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC(CF)Cc1ccccc1
Temperature: 80 °C
Yield: 82.5 %

Procedure:
To a stirred solution of 1-fluoromethyl-2-phenylethyl methanesulfonate (1.1 g) in anhydrous DMF (15 mL) under nitrogen was added sodium azide (0.53 g) followed by heating at 80° C. overnight. The cooled reaction mixture was diluted with equal parts of water and brine and extracted with EtOAc. The extracts were washed with water and brine, dried over Na2SO4, and concentrated to an oil which was chromatographed over silica gel with a mixture of EtOAc and hexane to give 0.70 g of the title compound. MS ES (M++H−N2) 151.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11](OCC)=[O:12])[N:10]=[C:6]2[C:5]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:4][CH:3]=1.O.[NH2:23][NH2:24]>CCO>[Br:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]([NH:23][NH2:24])=[O:12])[N:10]=[C:6]2[C:5]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:4][CH:3]=1
Reactant: CCOC(=O)c1cn2c(Br)cnc(N3CCOCC3)c2n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cn2c(Br)cnc(N3CCOCC3)c2n1

Procedure:
A mixture of compound 21a (1.6 g, 4.5 mmol) and hydrazine monohydrate (2.6 mL, 27 mmol) in EtOH (20 mL) was heated at reflux overnight. An off-white solid formed, the collected by filtration and dried under reduced pressure to give 5-bromo-8-morpholinoimidazo[1,2-a]pyrazine-2-carbohydrazide which was directly used in next step without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[NH:12][N:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH:15]=2)=[O:9])=[N:6][CH:7]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH:30]1[CH3:35]>CS(C)=O>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([CH2:17][O:16][C:14]2[CH:15]=[C:11]([NH:10][C:8]([C:5]3[CH:4]=[N:3][C:2]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH:30]([CH3:35])[CH2:31]4)=[CH:7][N:6]=3)=[O:9])[NH:12][N:13]=2)[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=1
Reactant: COc1cc(COc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: CC1CNCCN1C
Solvent: CS(C)=O
Product: COc1cc(COc2cc(NC(=O)c3cnc(N4CCN(C)C(C)C4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (390 mg, 1.00 mmol) was added in one portion to 1,2-dimethyl-piperazine (228 mg, 2.00 mmol) in anhydrous dimethylsulfoxide (2.00 ml) at 25° C. The resulting solution was stirred at ambient temperature for 2 h. The residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by silica column chromatography, eluting with a gradient of 0 to 10% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (392 mg, 84%) as a yellow solid.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH:32]=[N:31][CH:30]=[N:29]1>C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:38][C:37]3[CH:39]=[CH:40][C:34]([CH2:33][N:28]4[CH:32]=[N:31][CH:30]=[N:29]4)=[CH:35][CH:36]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(Cn2cncn2)cc1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Cn2cncn2)cc1)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 100 mg; 0.36 mmol) in DCM (4 ml) was treated with polymer-supported Mukaiyama reagent (400 mg) followed by triethylamine (100 mL; 0.73 mmol) and 4-((1H-1,2,4-triazol-1-yl)methyl)aniline (Maybridge, 63.2 mg; 0.36 mmol). After stirring at RT for 24 hours the mixture was filtered and washed with saturated sodium bicarbonate solution. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13]([Cl:25])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CC(=O)C2)C(=O)O)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CC(=O)C2)C(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclobutyl)-propionic acid (0.12 g, 0.36 mmol) in methylene chloride (10 ml) was cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 0.22 ml, 0.43 mmol) and N,N-dimethylfomamide (two drops) which produced gas evolution and then it was stirred at 0° C. for 20 minutes and 40 min at 25° C. After this time, the reaction was concentrated in vacuo and azeotroped with methylene chloride (10 ml). The reaction was redissolved in methylene chloride (10 ml) to afford the crude 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclobutyl)-propionyl chloride as a 0.012M solution which was used in the following step with no further purification.
Reaction SMILES: [CH3:1][C:2]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:6])=[O:5])[CH3:3].[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:23]([N:20]1[CH2:21][CH2:22][CH:17]([C:2]([CH3:1])([S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)(=[O:5])=[O:6])[CH3:3])[CH2:18][CH2:19]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C1CCNCC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C1CCN(C(=O)c2ccccc2)CC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 10 ml vial was added 4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine (33 mg, 0.098 mmol), benzoic acid (10 mg, 0.082 mmol), Bop reagent (43.5 mg, 0.098 mmol), diisopropylethyl amine (0.029 ml, 0.164 mmol) and 2 ml dimethylformamide. The resulting solution was stirred at room temperature for 10 minutes. LC-Mass showed clean desired product. The reaction mixture was diluted with 1 ml dimethyl sulfoxide, 1 ml water and 0.03 ml of trifluoroacetic acid. This mixture was loaded on a reverse phase column and purified on HPLC eluted with water/acetonitrile gradient solvent. Desired fraction was collected and lyophilized to give the title compound as a fluffy white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[O:32]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([S:18][CH2:19][C:20]4[CH:25]=[N:24][CH:23]=[CH:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1>C(O)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([S:18][CH2:19][C:20]4[CH:25]=[N:24][CH:23]=[CH:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4cnccn4)CS[C@H]23)cs1
Solvent: O=CO
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4cnccn4)CS[C@H]23)cs1
Yield: 13 %

Procedure:
A solution of 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-[(pyrazin-2-yl)methylthio]-3-cephem-4-carboxylic acid (1.5 g, 2.04 m mol) in 90% formic acid aqueous solution was stirred at room temperature for 2 hours. Insoluble material in the reaction mixture was filtered off. The filtrate was adjusted to pH 3 and washed with ethyl acetate. The aqueous solution was chromatographed on HP-20 and eluted with 5-14% isopropanol aqueous solution. The eluent was lyophilized to give crude product (275 mg). The crude product was purified with preparative HPLC to give 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrazin-2-yl)methylthio]-3-cephem-4-carboxylic acid (131 mg, 0.265 m mol).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:14]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:13][C@@H:12]1[CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[O:39]1CCO[CH2:41][CH2:40]1>>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:14]([N:21]([C:40](=[O:39])[CH3:41])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:13][C@@H:12]1[CH3:29])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1C[C@@H](NCc2ccccc2)c2ccccc2N1C(=O)OCc1ccccc1
Reactant: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)N(C(=O)OCc2ccccc2)c2ccccc21

Procedure:
To a solution of Cis-2-Methyl-4-benzylamino-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (300 mg, 0.776 mmol), diisopropyl ethyl amine (0.135 mL, 0.776 mmol) in dioxane (1.5 mL), was added anhydride acetic (0.732 mL, 7.76 mmol) with stirring. The mixture was heated under reflux over night, cooled and directly chromatographed on silica gel utilizing 50% ethyl acetate/hexane to provide the title compound (300 mg) as an oil. 1H NMR [CDCl3]: δ 7.6–6.9 (m, 14H), 5.5 (d, 1H), 5.3 (d, 1H), 5.2 (t, 1H), 4.8 (m, 1H), 4.4 (m, 2H), 3.8 (d, 1H), 2.4 (s, 3H), 1.5 (m, 1H), 1.2 (m, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[CH:31]1[CH2:32][CH2:33][N:34]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:35][CH2:36]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: Fc1ccc(C2CCNCC2)c(F)c1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC(c2ccc(F)cc2F)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 4-(2,4-difluorophenyl)piperidine (1.2 equiv) to give 214 (11.8 mg, M+1 493.1)
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1.[CH2:14]([O:19][C:20]1[C:25]([C:26]2[C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=[C:28]([C:38]#[N:39])[CH:27]=2)=[CH:24][C:23]([C:40]#[N:41])=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH2:17][CH3:18].O>CS(C)=O>[C:40]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:25]([C:26]2[C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=[C:28]([C:38](=[NH:39])[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=3)[CH:27]=2)[CH:24]=1)#[N:41]
Reactant: CCCCCOc1ccc(C#N)cc1-c1cc(C#N)ccc1OCCCCC
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCOc1ccc(C#N)cc1-c1cc(C(=N)Nc2cccc(C(F)(F)F)c2)ccc1OCCCCC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A slurry of sodium hydride (50% in oil, 1.76 g), m-aminobenzotrifluoride (5.91 g) and 6,6'-dipentyloxy[1,1'-biphenyl]-3,3'-dicarbonitrile (6.9 g; additional material is added to the batch of part A) in 50 ml of anhydrous dimethylsulfoxide is stirred at room temperature for 3 days. The reaction mixture is poured into water and the resultant precipitate collected by filtration. The dried material is chromatographed on 1 liter of silica gel eluting with (1) dichloromethane and (2) 1% methanol/dichloromethane to yield 5'-cyano-2',6-bis(pentyloxy)-N-[3-(trifluoromethyl)-phenyl][1,1'-biphenyl]-3-carboximidamide (melting point 74°-75° C after two recrystallizations from cyclohexane). The column is next eluted with 2% methanol/dichloromethane to yield 1.3 g of the desired product. Two recrystallizations of this material from 1% hydrochloric acid/methanol yields 900 mg of the title compound, melting point 207°-2l0° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][C:18]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]([O:13]CC)=[O:12])[C:5]2[CH:26]=[CH:27][NH:28][C:4]=2[C:3]1=[O:29].[OH-].[Na+].O.Cl>O1CCOCC1>[CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][C:18]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]([OH:13])=[O:12])[C:5]2[CH:26]=[CH:27][NH:28][C:4]=2[C:3]1=[O:29]
Reactant: CCOC(=O)c1ccc(Oc2ccccc2)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc(C(=O)O)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Temperature: 25 °C
Yield: 98.8 %

Procedure:
A mixture of Example 9b (0.23 g, 0.59 mmol) and sodium hydroxide (0.89 mL of 2.0 M aqueous solution) in dioxane (10 mL) was heated at 60° C. for 2 hours. The reaction mixture was cooled to room temperature and poured into water (100 mL). After addition of concentrated HCl (5 mL), the mixture was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to afford 0.21 g (98%) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ 3.55 (s, 3H), 6.24-6.25 (m, 1H), 6.94 (d, J=8.54 Hz, 1H), 7.05 (d, J=7.63 Hz, 2H), 7.16 (t, J=7.32 Hz, 1H), 7.27 (t, J=2.9 Hz, 1H), 7.35-7.40 (m, 3H), 7.92 (dd, J=8.7, 2.29 Hz, 1H), 8.04 (d, J=2.14 Hz, 1H), 12.03 (s, 1H). MS (ESI+) m/z 361.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=2)(C#N)[CH2:5][CH2:4][CH2:3]1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1.CCCCCC>[N:11]1[CH:10]=[C:9]([CH:6]2[CH2:5][CH2:4][CH2:3][N:2]2[CH3:1])[CH:14]=[CH:13][CH:12]=1
Reactant: CN1CCCC1(C#N)c1cccnc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CN1CCCC1c1cccnc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 4 %

Procedure:
A solution of 2′-cyanonicotine 3 (324 mg, 1.73 mmol) in toluene (12.4 mL) was treated at −78° C. with DIBALH (8.65 mL of a 1.0 M solution in hexane, 8.65 mmol). After the reaction mixture had been stirred for an additional 3 h at −78° C., it was quenched by slow addition of saturated aqueous solution of NH4Cl. The resulting mixture was allowed to warm to room temperature. The organic layer was separated and the aqueous layer was extracted with methylene chloride. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (CH2Cl2/CH3OH/NH4OH concd 95:5:0.1) to give (±)-2′-aminomethylnicotine 8 as a clear oil (195.1 mg, 1.02 mmol, 59%) as well as nicotine (11 mg, 0.07 mmol, 4%). 1H NMR (300 MHz, CDCl3): δ=8.60 (d, 1H, J=2.7 Hz, ArH), 8.48 (dd, 1H, J=1.8, 4.8 Hz, ArH), 7.64 (dt, 1H, J=8.1, 1.8 Hz, ArH), 7.28 (ddd, 1H, J=8.1, 4.8, 0.9 Hz, ArH), 3.21 (d, 1H, J=12.9 Hz), 3.03 (d, 1H, J=12.9 Hz), 3.00 (m, 1H), 2.74 (m, 1H), 2.18 (m, 2H), 2.17 (s, 3H, NCH3), 1.93 (m, 2H), 1.32 (bs, 2H, NH2). —13C NMR (75.3 MHz, CDCl3): δ=149.1 (CH), 148.0 (CH), 138.3 (C), 135.0 (CH), 123.2 (CH), 68.0 (C), 54.8 (CH2), 46.5 (CH2), 36.5 (CH2), 35.5 (CH3), 22.5 (CH2). HRMS (ESI) m/z: found for [M+H]+ 192.1490. Calcd for C11H17N3 192.1495.
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1)=[O:2].C1COCC1.[BH4-].[Na+].Cl>CO>[OH:2][CH2:1][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1
Reactant: COC(=O)c1csc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1csc(CO)c1
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a mixed liquid of 5.00 g of methyl 5-formylthiophene-3-carboxylate and 50 ml of THF was added 0.67 g of sodium borohydride under ice-cooling. To the reaction solution was added dropwise 5 ml of methanol, followed by stirring for 1 hour under ice-cooling. The reaction solution was added with 1 M hydrochloric acid, extracted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated to obtain 4.86 g of methyl 5-(hydroxymethyl)thiophene-3-carboxylate as a pale yellow oily substance.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[C:6]=1[OH:17].[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[C:6]=1[O:17][CH3:18]
Reactant: O=C([O-])[O-]
Reactant: COCOc1cc(OC)c(OC)c(OC)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCOc1cc(OC)c(OC)c(OC)c1OC
Temperature: 45 °C

Procedure:
11.5 g of 2-methoxymethyloxy-4,5,6-trimethoxyphenol prepared in Referential Example 12 and 23.0 g of potassium carbonate were suspended in 100 ml of DMF. The suspension was heated at 45° C. while stirring, and 5.2 ml of iodomethane was dropwise added thereto. After the completion of the dropwise addition, the mixture was heated for 30 min, cooled and separated by filtration. 1 l of water was added to the mother liquor, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=85:15) to prepare 6.2 g of the product compound as a colorless oleaginous substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13].[C:17]([NH:20][NH2:21])([NH2:19])=[NH:18].Cl.B(F)(F)F.CCOCC>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[C:9](=[N:21]/[NH:20][C:17](=[NH:18])[NH2:19])/[CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13]
Reactant: N=C(N)NN
Reactant: O=C(CCC(F)(F)F)c1cc(Cl)ccc1Br
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: CO
Product: N=C(N)N/N=C(\CCC(F)(F)F)c1cc(Cl)ccc1Br
Temperature: 100 °C

Procedure:
To a screw cap pressure vessel was added the intermediate from Step A (3.22 g, 10.2 mmol), aminoguanidine hydrochloride (1.69 g, 15.3 mmol), methanol (25 mL) and boron trifluoride diethyl etherate (2.6 mL, 20.4 mmol). The reaction solution was heated at 100° C. for 70 minutes. The solution was concentrated and the residue partitioned between EtOAc and aqueous 1N NaOH. The organic phase was washed twice with aqueous 1N NaOH and brine (1×). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give the indicated compound as a mixture of E, Z hydrazone isomers. 1H NMR (400 MHz, CD3CN): δ 7.54 (d, J=8.4 Hz, 1H); 7.24-7.17 (m, 1H); 7.10 (d, J=2.6 Hz, 1H); 2.68-2.51 (m, 4H). m/z 371 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]#[N:17])=[C:11]([O:18][CH3:19])[N:10]=1)([CH3:4])([CH3:3])[CH3:2]>CC(O)=O.C(O)C.[Ni]>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16][NH2:17])=[C:11]([O:18][CH3:19])[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1nc(CNC(=O)OC(C)(C)C)cc(C)c1C#N
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1nc(CNC(=O)OC(C)(C)C)cc(C)c1CN
Yield: 87.9 %

Procedure:
A clear solution of tert-butyl((5-cyano-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (0.65 g, 2.344 mmol) in HOAc (5 mL) and Ethanol (20 mL) was treated on an H-Cube apparatus (50 psi, 40° C., 1 mL/min., Raney Nickel cartridge) for 18 hr overnight. LCMS showed that the reaction was complete. The reaction was evaporated to dryness under vacuum. Purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 10% (5% NH4OH/MeOH) in CH2Cl2). The pure fractions were combined and evaporated to dryness under vacuum to give the product tert-butyl((5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (0.58 g, 2.061 mmol, 88% yield) as a clear thick oil. 1H NMR (400 MHz, DMSO-d6) δ 7.31 (t, J=6.1 Hz, 1H), 6.63 (s, 1H), 4.06 (d, J=6.3 Hz, 2H), 3.84 (s, 3H), 3.61 (s, 2H), 2.29 (s, 3H), 1.53 (br. s., 2H), 1.41 (s, 9H). MS(ES)+m/e 282.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[C:20](OCC)(OCC)(OCC)[CH3:21]>CN(C=O)C>[CH3:20][C:21]1[N:6]([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])[C:4](=[O:5])[C:3]2[C:2](=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:19])[N:1]=1
Reactant: Cc1cccc(N)c1C(=O)NC1CCC(=O)NC1=O
Reactant: CCOC(C)(OCC)OCC
Solvent: CN(C)C=O
Product: Cc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 25 °C
Yield: 42.4 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide (1.00 g, 3.8 mmol) and triethyl orthoacetate (0.9 mL, 4.9 mmol) in DMF (10 mL) was heated to reflux for 1 hour. The mixture was cooled to room temperature. To the solution, Celite (40 mL) was added, and the solvent was removed in vacuo. The solid was loaded on a SIM and purified with ISCO flash gel chromatography (silica gel, CH3OH/CH2Cl2) to give 3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (0.46 g, 43% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 2.95 min (96%); mp: 292-294° C.; 1H NMR (DMSO-d6) δ 2.11-2.18 (m, 1H, CHH), 2.55-2.65 (m, 2H, CH2), 2.60 (s, 3H, CH3), 2.69 (s, 3H, CH3), 2.78-2.85 (m, 1H, CHH), 5.19 (dd, J=6, 11 Hz, 1H, NCH), 7.25 (d, J=8 Hz, 1H, Ar), 7.43 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.82, 22.43, 23.32, 30.55, 56.33, 118.69, 124.73, 128.82, 133.72, 139.82, 148.34, 154.58, 161.03, 169.61, 172.60; LCMS: MH=286; Anal. Calcd. for C15H15N3O3+1H2O: C, 59.26; H, 5.68; N, 13.66. Found: C, 59.26; H, 5.68; N, 13.66.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][N:18]([OH:20])[C:17](=[O:21])[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][N:18]([O:20][CH3:24])[C:17](=[O:21])[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccc(OCc3ccccc3)cc2)CN1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CN1CCCC1=O
Product: CON1CC(c2ccc(OCc3ccccc3)cc2)CC1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture containing 0.7 g 4-(4-benzyloxyphenyl)1-hydroxy2-pyrrolidone (Example 2), 5.0 ml methyl iodide and 2.0 g potassium carbonate in 5.0 ml N-methylpyrrolidone was stirred for 2 h at 50° C. 20 ml 1N sodium hydroxide solution was then added and the solution was extracted with a mixture of 20 ml cyclohexane and 10 ml of ether. The extract was washed with water and concentrated in vacuo whereupon the product crystallized. yield 0.31 g (41%), mp 92°-97° C.