Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([NH:22][CH:23]1[CH2:26][N:25]([S:27]([O-:30])(=[O:29])=[O:28])[C:24]1=[O:31])=[O:21])(OCC1C=CC=CC=1)=O.[Na+:32].C(O)(=O)C>CO.[H][H].[Pd]>[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([NH:22][CH:23]1[CH2:26][N:25]([S:27]([O-:30])(=[O:28])=[O:29])[C:24]1=[O:31])=[O:21].[Na+:32]
Reactant: [H][H]
Reactant: O=C(Cc1ccccc1CNC(=O)OCc1ccccc1)NC1CN(S(=O)(=O)[O-])C1=O
Agent: [Pd]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NCc1ccccc1CC(=O)NC1CN(S(=O)(=O)[O-])C1=O
Yield: 77.9 %

Procedure:
In 35 ml of 30% methanol is dissolved 0.30 g of the above sodium 3-[2-(2-carbobenzoxyaminomethylphenyl)acetamido]-2-oxoazetidine-1-sulfonate, followed by addition of 0.68 ml of 6% acetic acid and 76 mg of palladium black. The mixture is stirred in hydrogen gas streams at room temperature for 90 minutes. The catalyst is filtered off and the filtrate is purified on an Amberlite XAD-II column. The above procedure provides 0.167 g of sodium 3-[2-(2-aminomethylphenyl)acetamido]-2-oxoazetidine-1-sulfonate.acetate.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:17].ON1[C:23]2[CH:24]=[CH:25][CH:26]=C[C:22]=2[N:21]=N1.CCN=C=NCCCN(C)C.Cl>>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:25]1[CH2:26][OH:17])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: O=C(c1ccccc1Oc1ccccc1)N1CCC[C@H]1CO

Procedure:
2.14 g (10 mmol) of 2-phenoxybenzoic acid, 1.35 g (10 mmol) of 1-hydroxybenzotriazole hydrate, 2.0 ml (20 mmol) of A and 1.92 g (10 mmol) 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide HCl were reacted as described in Example 25, except that a water soluble carbodiimide was used in place of DCC. The title compound was obtained in pure form as a colorless gum without chromatographic purification and the yield was 2.90 g (98%). TLC (90:10/CH2Cl2 :MeOH):Rf =0.80. 1H NMR (CDCl3) δ: 6.80-7.45 (m,9H); 4.60-4.95(m,1H); 3.30-3.80(m,4H); 1.50-2.20(m,4H).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=[CH:28][C:21]=34)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].Cl.O1CCOCC1>C1COCC1.CO>[CH3:35][Si:33]([CH3:34])([CH3:36])[CH2:32][CH2:31][O:30][CH2:29][N:26]1[C:22]2=[N:23][CH:24]=[CH:25][C:20]([C:18]3[CH:17]=[N:16][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]4)[CH:19]=3)=[C:21]2[CH:28]=[CH:27]1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 126.8 %

Procedure:
A solution of tert-butyl 3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (341 mg, 0.67 mmol) in THF (5 mL) and methanol (5 mL) was added a 4.0 M solution of hydrogen chloride in 1,4-dioxane (5 mL, 20 mmol). The mixture was stirred at room temperature for 2 hours and concentrated to give 347 mg (100%) of {3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile.2[HCl] as a yellowish solid. LC/MS found: 409.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].CO[C:10](OC)([CH3:12])[CH3:11].O1CCCC1>C(N(CC)CC)C>[CH3:11][C:10]1([CH3:12])[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: OCC(CO)CO
Reactant: COC(C)(C)OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CO)CO1
Temperature: 20 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
A mixture of 2-Hydroxymethyl-1,3-propanediol (9.0 g, 61.6 mmol), 2,2-dimethoxypropane (11.7 ml, 95.2 mmol) 4-toluenesulphonic acid monohydrate (0.49 g, 2.58 mmol) and tetrahydrofuran (450 ml) was stirred at 20° C. for 1 hour. Triethylamine (5 ml) was then added and the solvent removed under reduced pressure. Chromatography on silica gel (eluted with chloroform ethanol, 10.1) afforded the title compound (9.62 g, 78%) as a colourless oil. 1R: υmax (film) 3431, 2993, 2943, 2874, 1482, 1456, 1373 cm-1. 1H NMR: δH [(CD3)2SO] 1.30(6H, s, 2×CH3), 1.69(1H,m,CH), 3.38(2H,dd, J=5.2, 6.6 Hz, CH2OH), 3.61(2H,dd, J=11.8, 7.1 Hz, 2×H(ax)), 3.82 (2H, dd, J=11.8, 4.4 Hz, 2×H(eq)), 4.53(1H, t, J=5.2 Hz, D2O exchangable, OH). Found: C, 56.73; H, 9.80%. C7H14O3.0.01H2O requires: C, 56.80; H, 9.69%.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][N:7]([C:10](=[O:20])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[CH3:21][NH:22][CH3:23].[CH2:24]=O>C(O)(=O)C>[CH3:21][N:22]([CH2:24][C:2]1[O:1][C:5]2[CH2:6][N:7]([C:10](=[O:20])[CH2:11][CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=1)[CH3:23]
Reactant: C=O
Reactant: O=C(CCCc1ccccc1)N1CCc2ccoc2C1
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)CCCc1ccccc1)CC2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.210 g (0.780 mmol) of 1-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-yl)-4-phenylbutan-1-one in 20 ml of acetic acid, 0.11 ml (1.2 mmol) of 50% aqueous dimethylamine and 0.095 ml (1.2 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate/methanol=9/1 to 5/1) to yield the desired product.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=O.[Cl:9]C[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[ClH:9].[ClH:9].[CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]
Reactant: O=CN1CCNCC1
Reactant: O=C(CCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cl
Product: O=C(CN1CCNCC1)c1ccccc1
Yield: 95 %

Procedure:
A mixture of N-formyl piperazine 35.5 g (310 mmol), 2-chloro-1-phenylethanone (57.6 g, 372 mmol) and anhydrous K2CO3 (64.3 g, 465 mmol) in 320 ml of acetone was treated according to general preparation 1 to give 49 g of N-phenacyl piperazine dihydrochloride, yield 57%, mp 246-8° C. (dec). M+ 204.
Reaction SMILES: [Cl:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH3:11])[CH2:9][NH:8][C:7](=S)[C:6]1=[O:13].[C:22]([NH:30][NH2:31])(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>C(O)CCC>[Cl:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]2[C:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:30][N:31]=[C:7]2[C:6]1=[O:13]
Reactant: NNC(=O)c1cccnc1
Reactant: C[C@H]1CNC(=S)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Solvent: CCCCO
Product: C[C@H]1Cn2c(nnc2-c2cccnc2)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of (S)-1-(2-chloro-3-(trifluoromethyl)benzyl)-6-methyl-3-thioxopiperazin-2-one (105 mg, 0.31 mmol) and nicotinohydrazide (47 mg, 0.34 mmol) in 1-butanol (3.1 mL) was heated at 130° C. for 16 h. After cooling to rt, the solvent was removed in vacuo. Purification by chromatography (SiO2; 0-20% IPA/EtOAc) afforded the desired product as a white solid (102 mg, 78%). MS (ESI): mass calcd. for C19H15ClF3N5O, 421.1; m/z found, 422.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.90 (d, J=1.8 Hz, 1H), 8.74 (dd, J=4.8, 1.4 Hz, 1H), 8.16-8.12 (m, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.48 (dd, J=7.9, 4.9 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 5.35 (d, J=15.6 Hz, 1H), 4.68 (dd, J=12.9, 4.5 Hz, 1H), 4.57 (d, J=15.6 Hz, 1H), 4.25 (dd, J=12.9, 1.8 Hz, 1H), 4.19-4.09 (m, 1H), 1.30 (d, J=6.7 Hz, 3H).
Reaction SMILES: ClC1C2SC=CC=2N[C:6](=[O:10])[C:7]=1[C:8]#[N:9].[CH3:14][O:15][C:16]([C:18]1[S:19][CH:20]=[CH:21][C:22]=1[NH2:23])=[O:17].COC(=O)CC#N>>[CH3:14][O:15][C:16]([C:18]1[S:19][CH:20]=[CH:21][C:22]=1[NH:23][C:6](=[O:10])[CH2:7][C:8]#[N:9])=[O:17]
Reactant: COC(=O)c1sccc1N
Reactant: N#Cc1c(Cl)c2sccc2[nH]c1=O
Agent: COC(=O)CC#N
Product: COC(=O)c1sccc1NC(=O)CC#N

Procedure:
To prepare compounds of structure (I) with R2 as carbonitrile, and R1 and R3 as defined above, 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carbonitrile, depicted by formula (12), was used as a key intermediate. To prepare this intermediate, methyl-3-amino-thiophene-2-carboxylate was reacted with methylcyanoacetate to yield intermediate 3-(2-cyano-acetylamino)-thiophene-2-carboxylic acid methyl ester, depicted by formula (10). This intermediate was converted to 7-hydroxy-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carbonitrile, depicted by formula (11), by reacting with sodium ethoxide, and was then converted into 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carbonitrile, depicted by formula (12), as shown in Scheme 5.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:17][C:4]=2[O:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[O:8].[C:25](Cl)(=[O:27])[CH3:26].[C:29](OCC)(=[O:31])[CH3:30].CCCCCC>ClC(Cl)C>[C:25]([N:1]([C:2]1[C:3]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:17][C:4]=2[O:5][C:6]=1[C:7](=[O:8])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])[C:29](=[O:31])[CH3:30])(=[O:27])[CH3:26]
Reactant: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc3c(cc12)CCCC3
Reactant: CC(=O)Cl
Reactant: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(Cl)Cl
Product: CC(=O)N(C(C)=O)c1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc3c(cc12)CCCC3
Temperature: 70 °C
Reaction time: 15 h

Procedure:
A mixture of (3-amino-5,6,7,8-tetrahydronaphtho[2,3-b]furan-2-yl)(2,4-dichlorophenyl)methanone (150 mg, 0.46 mmol) from Example 142, acetyl chloride (0.16 mL, 2.3 mmol, 5.0 eq), and diisopropylethylamine polystyrene resin (245 mg, 0.92 mmol, 2.0 eq, 3.77 mol/g loading) in dichloroethane (4.6 mL) was shaken at 70° C. for 15 h. The resin was filtered and washed with dichloromethane (2×10 mL), methanol (2×10 mL), and dichloromethane (2×10 mL). The filtrate was evaporated in vacuo. Crystallization from ether-hexane gave 73.2 mg (35.8%) as a white solid. 1H-NMR (DMSO-d6) δ 7.82 (s, 1H), 7.62 (d, J=0.6 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.46 (broad s, 2H), 2.84 (m, 4H), 2.20 (s, 6H), 1.73 (broad s, 4H); MS GC-MS (MH+=444/445); Rf=0.55 (25% ethyl acetate-hexane).
Reaction SMILES: [CH2:1]=O.Cl.[CH3:4][NH:5][CH3:6].[CH3:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[OH-].[Na+]>CCOCC>[CH3:4][N:5]([CH2:1][C:9]1[N:8]([CH3:7])[CH:12]=[CH:11][CH:10]=1)[CH3:6]
Reactant: C=O
Reactant: Cn1cccc1
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CN(C)Cc1cccn1C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
A mixture of 35% aqueous formaldehyde solution (20.8 mL, 264 mmol) and dimethylamine hydrochloride (22.7 g, 278 mmol) was added to 1-methylpyrrole (21.4 g, 264 mmol) under ice-cooling with stirring over 1 hour and 30 minutes and the mixture was stirred at room temperature for 6 hours. A 10% aqueous sodium hydroxide solution (150 mL) and ether were added to the reaction mixture to separate it. The thus obtained organic phase was separated, washed with a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (methylene chloride:methanol, 10:1) to obtain 2-(N,N-dimethylaminomethyl)-1-methylpyrrol (31.5 g, yield: 86%). Methyl iodide (16.2 mL, 260 mmol) was added to a solution of 2-(N,N-dimethylaminomethyl)-1-methylpyrrol (30.0 g, 217 mmol) in ethanol (220 mL) under ice-cooling and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (220 mL) was added to the reaction mixture, the precipitated crystal was collected by filtration, washed with ethyl acetate and dried to obtain (1-methylpyrrol-2-yl)methyltrimethylammonium iodide (55.3 g, yield: 91%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH2:7]O)=[N:3]1.S(Cl)(Cl)=O.[I:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[N+:23]([O-:25])=[O:24])[NH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[I:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[N+:23]([O-:25])=[O:24])[N:16]([CH2:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[N:15]=1
Reactant: Cn1ccc(CO)n1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
To (1-methyl-1H-pyrazol-3-yl)methanol (2.01 g, 17.93 mmol) in DCM (80 mL) at 0° C. was cautiously added thionyl chloride (10.43 mL, 143.4 mmol). The cold bath was removed and the reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residual yellow solid was diluted with DMF (30 mL). 3-Iodo-4-nitro-1H-indazole (5.181 g, 17.93 mmol) and K2CO3 (7.432 g, 53.78 mmol) were added to the DMF solution. The reaction mixture was stirred for 20 hours, and concentrated under reduced pressure to remove most of the DMF. The residue was diluted with DCM (100 mL) and washed with H2O. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/Hexane 1:3) to provide the product (5.11 g).
Reaction SMILES: CS(C)=O.Cl.Cl.[NH2:7][CH:8]1[CH2:11][NH:10][CH2:9]1.[NH2:12][C:13]1[CH:14]=[C:15]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27](F)[C:28]=3[Cl:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH:16]=[N:17][C:18]=1[Cl:19]>C(N(CC)CC)C>[NH2:7][CH:8]1[CH2:11][N:10]([C:27]2[C:28]([Cl:30])=[C:29]3[C:24]([C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21][N:20]3[C:15]3[CH:16]=[N:17][C:18]([Cl:19])=[C:13]([NH2:12])[CH:14]=3)=[CH:25][C:26]=2[F:32])[CH2:9]1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)cnc1Cl
Reactant: NC1CNC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)cnc1Cl
Yield: 49.6 %

Procedure:
To dimethylsulfoxide solution 1 ml of 53 mg of 3-aminoazetidine dihydrochloride and 146 mg of triethylamine at 80° C. was added 80 mg of 1-(5-amino-6-chloropyridine-3-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with stirring, and the mixture was stirred at 80° C. for 1 hour. The reaction solution was allowed to cool and decanted with diethylether. Ethanol was added to the residue to disperse the solid content, and the solid content was collected by filtration, washed with ethanol, and dried to obtain 45 mg of the title compound as a pale yellow powder.
Reaction SMILES: O1CCOCC1.[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CN(C)P(N(C)C)(N(C)C)=O.[C:26]1([NH:32]O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:26]1([NH:32][CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ONc1ccccc1
Reactant: C=CCCCCCC
Solvent: C1COCCO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CCCCC/C=C/CNc1ccccc1
Yield: 95 %

Procedure:
A stirred mixture containing dioxane (12 mL), 3 mL of 1-octene, 1 g of 4A Molecular Sieves, and 0.051 g (0.11 mmol) of (2,6-dipicolinato)MoO2 (hexamethyl phosphoramide) is heated at reflux (ca. 100° C.) under a nitrogen atomosphere while a toluene solution (50 mL) of N-phenyl hydroxylamine (1.26 g, 11.6 mmol) is added dropwise over a 24 hr period. After heating an additional 6-12 hr, the mixture was allowed to cool and the volatiles were removed by evaporation at reduced pressure and the residue chromatographed over silica gel. Elution with pentane afforded phenyl trans-2-octenyl amine (>95% one isomer by NMR, GC/MS) in 20-30% yield based on the hydroxylamine. Later fractions contained aniline, azobenzene and azoxybenzene.
Reaction SMILES: C(O)C.C(O)(=O)C.[CH3:8][N:9]([CH2:11][C:12]1[CH:13]=[C:14]([CH:43]=[CH:44][CH:45]=1)[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][C:20]([N+:39]([O-])=O)=[C:21]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH3:38])[CH2:28][CH2:27]3)[CH:22]=2)[C:17]1=[O:42])[CH3:10]>[Fe]>[NH2:39][C:20]1[CH:19]=[C:18]2[C:23]([CH2:24][CH2:25][N:16]([CH2:15][C:14]3[CH:43]=[CH:44][CH:45]=[C:12]([CH2:11][N:9]([CH3:10])[CH3:8])[CH:13]=3)[C:17]2=[O:42])=[CH:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH2:30][CH2:31]1
Reactant: Cc1ccccc1N1CCN(c2cc3c(cc2[N+](=O)[O-])C(=O)N(Cc2cccc(CN(C)C)c2)CC3)CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccccc1N1CCN(c2cc3c(cc2N)C(=O)N(Cc2cccc(CN(C)C)c2)CC3)CC1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
In a 100 ml round bottom flask equipped with a magnetic stir bar and fitted with a septum with a nitrogen inlet, the iron powder (382.70 mg, 6.85 mmol) was suspended in clean, dry, reagent-grade ethanol (30.00 ml, 513.81 mmol) under nitrogen and at room temperature. To the stirred reaction was added the acetic acid (3.00 ml, 52.40 mmol) and the mixture was stirred to ensure homogeneity. The 2-(3-dimethylaminomethyl-benzyl)-7-nitro-6-(4-o-tolyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one 11a (140.80 mg, 0.27 mmol) was then added in one portion and the reaction was warmed to 75° C. and allowed to stir under nitrogen for 4 h. After 4 h, the reaction was cooled to room temperature and the reaction solution was filtered through Celite, eluting heavily with methanol. The collected solution was then concentrated under reduced pressure and the solvent was removed under reduced pressure. The resultant red oil was taken up in 50 ml of ethyl acetate and washed with 50 ml of saturated NaHCO3 (aq) solution. The product was then extracted from the aqueous using ethyl acetate (3×30 ml) and the organic phases were combined and washed with brine (1×100 ml). The solution was then dried over Na2SO4; the solution was decanted and the solvent was removed under reduced pressure. The resultant brown solid was then purified using silica gel column chromatography, eluting a gradient of 100% dichloromethane to 10% MeOH in dichloromethane. 7-amino-2-(3-dimethylaminomethyl-benzyl)-6-(4-o-tolyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one 1 b (73.70 mg, 0.15 mmol) was isolated as a tan solid and was carried on without further purifications. LCMS (m/e)=483 (M+H).
Reaction SMILES: [S:1]([CH2:11][N:12]=[C:13]=[O:14])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH:15](=O)[CH2:16][CH3:17].[C-]#N.[Na+].O1CCN=C1>C(O)C>[CH2:16]([CH:17]1[O:14][CH:13]=[N:12][CH:11]1[S:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2])[CH3:15]
Reactant: CCC=O
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Agent: C1=NCCO1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CCC1OC=NC1S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a stirred suspension of tosylmethylisocyanate (TosMIC, 3.90 g, 20 mmol) and propionaldehyde (1.5 mL 20.4 mmol) in 60 mL dry ethanol, finely powdered sodium cyanide (0.098 g, 2 mmol) was added. The reaction mixture became clear and white crystals of oxazoline began to precipitate in 15 min. The reaction was continuously stirred for an additional 30 min. The mixture was filtered and the crystals were washed with ether-hexane (1:1) before drying. Compound 15 was attained in 81% yield (4.1 g). The structure was confirmed by 1H NMR in CDCl3. LC-MS: [M+1]=254. Purity was >98%.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CCN(CC)CC.[CH3:17][O:18][C:19]([C:21]1[S:25][C:24]2[C:26]([NH2:30])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)=[O:20]>C(Cl)Cl>[CH3:17][O:18][C:19]([C:21]1[S:25][C:24]2[C:26]([NH:30][C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[O:9])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)=[O:20]
Reactant: O=C(O)c1cccnc1
Reactant: COC(=O)c1cc2cccc(N)c2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2cccc(NC(=O)c3cccnc3)c2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
Nicotinic acid (401 mg, 3.26 mmol) was suspended in 20 mL CH2Cl2 and Et3N (330 mg, 3.26 mmol, 245 uL) was added to give a colorless solution. BopCl (829 mg, 3.26 mmol) was added and the reaction was stirred at room temperature for about 15 min, then a solution of 7-amino-benzo[b]thiophene-2-carboxylic acid methyl ester (450 mg, 2.17 mmol) in 2 mL CH2Cl2 was added. The yellow solution was stirred at room temperature for 12 h. After this time, room temperature, the solvent was removed from the reaction and the residue was partitioned between EtOAc (100 mL) and water (75 mL). The layers were separated and the organic portion was washed with water (2×75 mL), brine (75 mL), dried (MgSO4), filtered and the solvent was removed in vacuo to afford 7-[(pyridine-3-carbonyl)-amino]-benzo[b]thiophene-2-carboxylic acid methyl ester as a yellow solid (460 mg, 45%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].[C:22]1(=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CCCCCC>[C:16]([CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[C:22]1([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)#[N:17]
Reactant: N#CCc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Product: N#CC(c1ccc(OCc2ccccc2)cc1)C1(O)CCCCC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
p-Benzyloxyphenyl acetonitrile (100 g) and methanol (300 ml) was charged into flask Subsequently the reaction mixture was cooled to 0-5° C. and 10% aqueous solution of sodium hydroxide (180 g) and PEG-400 (10 ml) were added. The reaction mixture was then stirred for 30 min. and cyclohexanone (64 g) was added dropwise at 0-5° C. Subsequently, the reaction mass temperature was raised to 25-27° C. and stirred for 15 hours. After completion of the reaction hexane (600 ml) was added, the reaction mixture filtered, washed with hexane (100 ml) followed by DM water to obtain 120 g (83.9%) of the 1-[cyano(p-benzyloxyphenyl)methyl]cyclohexanol.
Reaction SMILES: [BH4-].[Na+].O1CCCC1.[CH2:8]([N:11]([CH2:27][CH2:28][CH3:29])[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[C:15]([CH:22]=[CH:23][N+:24]([O-])=O)[CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[CH2:9][CH3:10].Cl>C(O)(C)C.C(N(CC)CC)C>[CH2:27]([N:11]([CH2:8][CH2:9][CH3:10])[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[C:15]([CH2:22][CH2:23][NH2:24])[CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[CH2:28][CH3:29]
Reactant: CCCN(CCC)C1CCc2cccc(C=C[N+](=O)[O-])c2C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCCN(CCC)C1CCc2cccc(CCN)c2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
820 mg (20.4 mmol) of sodium borohydride were initially introduced into 30 ml of absolute tetrahydrofuran at 0° C. under nitrogen. 3.24 ml (25.8 mmol) of boron trifluoride diethyl ether complex were added dropwise at this temperature, and the mixture was subsequently stirred for 15 minutes at room temperature. A solution of 1.3 g (4.3 mmol) of 2-dipropylamino-8-(2-nitro-ethenyl)-1,2,3,4-tetrahydronaphthalene and 10 ml of absolute tetrahydrofuran was then added dropwise, and the mixture was then stirred for 5.5 h under reflux. After cooling to room temperature, 55 ml of ice water were carefully added dropwise, and the mixture was then acidified using 55 ml of 1N hydrochloric acid. The mixture was subsequently stirred for 2 h at +80°-+85° C. The cooled aqueous phase was washed twice with 35 ml of ether, then adjusted to pH 12 using 5 molar sodium hydroxide solution, and the product was extracted with methylene chloride. The extract was dried over sodium sulphate and evaporated. The product was obtained by subsequent chromatography over silica gel 60, 40-63 μm, using isopropanol/triethylamine, 95:5.