Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:3]=1[NH2:4]>CO.[Pd]>[CH3:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(N)c1N

Procedure:
A solution of 4.56 (30 m mol) of 2-methyl-6-nitroaniline in 150 ml of methanol was hydrogenated at atmospheric pressure over 0.9 g of 5% Pd/C with Ishii's Catalytic Hydrogenation Apparatus with Magnetic Stirrer Model CHA-M. The catalyst was filtered off. The solvent was evaporated, and the residue was crystallized from petroleum ether to give 3.25 g (88.67%) as gray crystals.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[CH:29])=[N:26][CH:27]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[C:29][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]4)=[N:6][CH:7]=3)=[N:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: CN1CCN(c2ccc(I)cn2)CC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: CN1CCN(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn2)CC1

Procedure:
Prepared according to general working method I from 1-(5-iodo-pyridin-2-yl)-4-methyl-piperazine (235 mg, 0.78 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (167 mg, 0.78 mmol).
Reaction SMILES: [CH:1]([N:4]([C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2OS(C(F)(F)F)(=O)=O)[O:10][CH2:9]1)[CH2:5][CH2:6][CH3:7])([CH3:3])[CH3:2].[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+].[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH:1]([N:4]([C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:10][CH2:9]1)[CH2:5][CH2:6][CH3:7])([CH3:3])[CH3:2]
Reactant: CCCN(C(C)C)[C@H]1COc2cccc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCN(C(C)C)[C@H]1COc2cccc(-c3ccccc3)c2C1
Temperature: 90 °C
Reaction time: 7 h
Yield: 86 %

Procedure:
(R)-3-(N-Isopropyl,N-n-propylamino)-5-trifluoromethanesulfonyloxychroman (1 g, 2.6 mmol) was dissolved in toluene (25 mL) under a nitrogen atmosphere. Ethanol (11.5 mL), LiCl (0.22 g, 5.2 mmol), Na2CO3 (2M, 3.8 mL), Pd(PPh3)4 (0.054 g, 0.047 mmol) and phenylboronic acid (0.38 g, 3.1 mmol) were added and the reaction mixture was stirred at 90° C. for 7 h. The solvent removed in vacuo until 15 mL was left. The residue was diluted with diethyl ether, washed with NH3 (2M) twice and dried (MgSO4). Removal of the solvent in vacuo gave a yellow-brownish oily residue which was purified by flash chromatography )SiO2, CH2Cl2) to give the title compound in 86% yield (0.7 g). α=-50.7° (MeOH, 0.1M, 22° C.). The HCl-salt was precipitated from ether by the slow addition of HCl in ether to an ice-cold solution of the base. The crude salt was recrystallized from EtOAc/diethyl ether to give 650 mg of needle-like crystals. Mp. 141°-142° C.
Reaction SMILES: [O:1]=[C:2]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:12][N:11]=1)[CH2:3][CH2:4][C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>O1CCCC1.CO>[O:1]=[C:2]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)=[CH:12][N:11]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: COC(=O)CCC(=O)Nc1ccc(COCc2ccc(-c3ccccc3)cc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC(=O)Nc1ccc(COCc2ccc(-c3ccccc3)cc2)cn1
Reaction time: 1 h
Yield: 92.5 %

Procedure:
Methyl 4-oxo-4-({5-[(4-phenylphenyl)methoxymethyl]-2-pyridyl}amino)butanoate (0.168 g) was dissolved in a mixed solvent of tetrahydrofuran (3 mL) and methanol (1 mL). To the solution, an aqueous sodium hydroxide solution (1 M, 0.830 mL) was added at room temperature, and the mixture was stirred for 1 hour. Hydrochloric acid (1 M, 0.830 mL) was added to the reaction solution, and the mixture was stirred at 0° C. The resulting suspension was filtered, and the product collected by filtration was washed with water and dried under reduced pressure to obtain the title compound (0.150 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)(C)OC(=O)N1CCC(CNCc2cccc(-c3ccnc(Cl)n3)c2)C1

Procedure:
Intermediate 1 was coupled with 3-Aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 403.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38]Br)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][NH:41][CH3:42]>C1COCC1>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38][N:41]([CH3:42])[CH3:40])[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCBr)c2)cc1
Solvent: C1CCOC1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCN(C)C)c2)cc1
Temperature: 70 °C

Procedure:
The product from Example 72D in anhydrous THF (1 mL) was treated with 2.0 M dimethylamine (1.0 mL, 1.97 mmoles) in THF and heated to 70° C. overnight. Reaction mixture concentrated under reduced pressure and the residue was purified by preparative HPLC (CH3CN:0.1% trifluoroacetic acid in H2O) on a YMC ODS Guardpak column to provide the title compound. 1H NMR (300 MHz, CDCl3) δ7.10-7.30 (m, 11 H), 6.86 (d, 2 H), 6.72 (s, 1 H), 6.50-6.70 (m, 2 H), 6.32 (t, 1 H), 4.39 (s, 2 H), 4.35 (s, 2 H), 3.98 (t, 2 H), 3.30 (m, 2 H), 2.91 (s, 3 H), 2.90 (s, 3 H), 2.83 (s, 3 H), 2.25 (m, 2 H), 2.13 (s, 3 H); MS (ESI+) m/z 574 (M+H)+.
Reaction SMILES: [OH-].[B+3].[Na+].[OH-].[OH-].[OH-].CN(C=O)C.[CH:12]12[CH2:18][CH:15]([CH:16]=[CH:17]1)[CH:14]1[C:19]([O:21][C:22](=O)[CH:13]21)=[O:20].S(=O)(=O)(O)O>O>[C:15]12[CH2:18][CH:12]([CH2:17][CH2:16]1)[CH:13]1[C:14]=2[C:19](=[O:20])[O:21][CH2:22]1
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Agent: O=S(=O)(O)O
Agent: [B+3]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OCC2C1=C1CCC2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
22.3 g (0.53 mol) of sodium boron hydroxide and 344.0 g of DMF were placed in a 3-L round flask equipped with an agitator, a thermometer and a dropping funnel, and the mixture was stirred at room temperature so as to dissolve sodium boron hydroxide. Thereafter, the internal temperature was cooled to 0° C. to 5° C. in an ice bath. Separately, 161.6 g (0.984 mol) of a white solid 5-norbornene-2,3-dicarboxylic anhydride (Wako Pure Chemical Industries, Ltd.) and 242.4 g of DMF were placed in a 500 ml beaker, and the mixture was fully stirred so that the solid was completely dissolved. Thereafter, the mixture was transferred to the above dropping funnel, and it was dropped, while paying attention so that the internal temperature of the flask was controlled within a range of 5° C. to 30° C. After completion of the dropping, stirring was further continued for 2 hours in an ice bath. Thereafter, 1.5 L of water was added thereto, while paying attention so that the internal temperature of the flask was controlled within a range of 5° C. to 30° C., and then concentrated sulfuric acid was added thereto until the pH became 0.5. The obtained mixture was extracted twice with MIBK. This time, the water layer was well separated from the organic layer. Thereafter, the combined organic layers were washed with water, and they were then concentrated with an evaporator. The obtained concentrate was analyzed by gas chromatography using a capillary column HP-5 (Hewlett-Packard). As a result, 133.2 g (0.887 mol) of 4-oxatricyclo[5.2.1.02,6]decen-3-one was obtained at a yield of 90%. Moreover, in the concentrate, MIBK represented 42% to the total mass.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1)C1C=CC=CC=1.C(OC1C=NC2C(C=1)=NC=C(Br)C=2)C1C=CC=CC=1.CCN(CC)CC>CCO.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1
Reactant: CCOC(=O)c1cnc2cc(OCc3ccccc3)cnc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Brc1cnc2cc(OCc3ccccc3)cnc2c1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: N#Cc1ccccc1
Product: CCOC(=O)c1cnc2cc(O)cnc2c1
Temperature: 140 °C
Yield: 67 %

Procedure:
Ethyl 7-(benzyloxy)-1,5-naphthyridine-3-carboxylate. A mixture of 3-(benzyloxy)-7-bromo-1,5-naphthyridine (30.0 g, 95.5 mmol), Et3N (19.47 g, 193 mmol), Pd(PhCN)2Cl2 (1.2 g, 3.13 mmol) and dppf (5.28 g, 9.5 mmol) in EtOH (500 mL) was pressurized to 15 bars with CO gas. Then the mixture was heated at 140° C. for 24 h. After cooling to ambient temperature, the solvent was removed under reduced pressure. Purification (FCC, SiO2, DCM/EtOAc, 1:1) afforded the title compound as a yellow solid (14 g, 67%). [M+H]=309.3.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[C:34]([NH:37][CH2:38][C:39](O)=[O:40])(=[O:36])[CH3:35].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:34]([NH:37][CH2:38][C:39]([N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:40])(=[O:36])[CH3:35]
Reactant: CC(=O)NCC(=O)O
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)NCC(=O)N(CC(C)C)NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
A solution of 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 4 ml of dimethylformamide was cooled to 0° C. and treated with 0.351 g of N-acetyl-glycine and 690 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride. The mixture was stirred at room temperature for 16 hours and evaporated. The residue in ethyl acetate was washed with 5% sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulphate and evaporated. The resulting solid was triturated with diethyl ether and filtered off to give 0.436 g of (E)-2′-(2-acetamidoacetyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([N:15]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([O:21]CC)=[O:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CCO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([N:15]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([OH:21])=[O:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccc(N(Cc2cccnc2)c2ccc(OC)c(OC3CCCC3)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(N(Cc2cccnc2)c2cccc(C(=O)O)c2)cc1OC1CCCC1
Reaction time: 6 h
Yield: 78.8 %

Procedure:
A solution of 6.5 g of ethyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoate in 50 mL of EtOH was treated with 10 mL of 6N NaOH. The mixture was allowed to stand for 6 hours, concentrated, and diluted with 50 mL of H2O. The aqueous mixture was extracted with 2×50 mL of ether, acidified with AcOH to pH 3, and extracted with 2×50 mL of EtOAc. The combined EtOAc fractions were washed with 25 mL of H2O and 25 mL of brine, dried (MgSO4), and concentrated. The residue was purified by chromatography over SiO2 (35 g RediSep® column) using a linear gradient of EtOAc and hexanes as eluant (50% EtOAc to 70% EtOAc over 20 minutes) to provide 4.8 g of a yellow solid product after drying in vacuo for 12 h at 60° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[N:2]1.[Br:10]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:10][C:3]1[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[NH:1][N:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cc2[nH]ncc2cn1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1n[nH]c2ccncc12
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a solution of 3.85 g of 1H-pyrazolo[4,3-c]pyridine in 50 mL of N,N-dimethylformamide was added 6.04 g of N-bromosuccinimide at room temperature and stirred at this temperature for 2 hours. Adding 10 mL of 10% sodium thiosulfate aqueous solution, the solution was diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated, to afford 4.69 g of the title compound as pale red-brown crystals.
Reaction SMILES: [CH:1]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][SiH:9]([Cl:11])[Cl:10]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:8][Si:9]([Cl:11])([Cl:10])[C:2]([CH2:3][CH2:4][CH2:5][CH:6]([Si:9]([Cl:11])([Cl:10])[Cl:8])[CH3:7])=[CH2:1]
Reactant: C1=CCCCC=C1
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: C=C(CCCC(C)[Si](Cl)(Cl)Cl)[Si](Cl)(Cl)Cl
Temperature: 180 °C
Yield: 24.8 %

Procedure:
As in Example 1, 1,3-cycloheptadiene (1.00 g, 10.62 mmol), trichlorosilane (5.76 g, 42.52 mmol) and tetrabutylphosphonium chloride (0.31 g, 1.05 mmol) were added in a 25 mL stainless steel tube under nitrogen atmosphere. After sealing the cylinder with a cap, the reactor was maintained at 180° C. for 18 hours. The resulting mixture was distilled to yield 0.96 g (yield: 25%) of 2,6-bis(trichlorosilyl)-1-heptene.
Reaction SMILES: [CH2:1]([O:9][CH2:10][CH2:11][OH:12])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[C:13](OC)(=[O:17])[C:14]([CH3:16])=[CH2:15]>>[CH3:16][C:14](=[CH2:15])[C:13]([O:12][CH2:11][CH2:10][O:9][CH2:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8])=[O:17]
Reactant: C=C(C)C(=O)OC
Reactant: C=CCCCC=CCOCCO
Product: C=CCCC/C=C/COCCOC(=O)C(=C)C

Procedure:
The resulting 2-octa-2,7-dienyloxyethanol was subsequently reacted with methyl methacrylate to give 2-((2-E)octa-2,7-dienyloxy)ethyl 2-methylprop-2-enoate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[C:12](=[O:36])[N:13](CC4C=CC(OC)=CC=4)[C:14](=[O:26])[N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)[C:5]=3[C:4]=2[N:3]=1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[Ce]>C(#N)C.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[C:12](=[O:36])[NH:13][C:14](=[O:26])[N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=4)[C:5]=3[C:4]=2[N:3]=1
Reactant: COc1ccc(Cn2c(=O)c3cnc4ccc(Cl)nc4c3n(-c3cccc(C(F)(F)F)c3)c2=O)cc1
Agent: [Ce]
Solvent: O
Solvent: O=[N+]([O-])O
Solvent: CC#N
Product: O=c1[nH]c(=O)n(-c2cccc(C(F)(F)F)c2)c2c1cnc1ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
9-chloro-3-(4-methoxybenzyl)-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione (700 mg, 1.36 mmol) was dissolved in acetonitrile (40 mL) and water (10 mL). Ammonium ceric nitrate (2.9 g, 5.65 mmol) was added in batch at room temperature. The reaction mixture was stirred at room temperature for 18 hrs, and then rotary-evaporated to remove the solvent. The resulting crude product was separated by silicagel column chromatography (EtOAc/PE=0-1/4) to obtain a yellow solid (400 mg).
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[CH:11]=[CH:12][O:13][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:6]([O:5][P:4](/[CH:9]=[CH:10]/[CH:11]=[CH:12][OH:13])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(/C=C/C=CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(/C=C/C=CO)OCC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of E-4-t-butyldiphenylsilyloxy-1,3-butadienyl phosphonic diethyl ester (11 g, 26.4 mmol) and tetrabutylammonium fluoride trihydrate (10 g, 31 mmol) in tetrahydrofuran (100 ml) is stirred 2 hours at 20° C. The reaction mixture is concentrated in vacuo, diluted with ethyl acetate and washed with brine. The title product is obtained by flash chromatography on silica gel (4.6 g, 80%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:4]2[CH2:5][C:6]3[C:10]([CH:3]12)=[N:9][NH:8][C:7]=3[C:11]#[N:12].[N-:14]=[N+:15]=[N-:16].[Na+].Cl>O1CCOCC1.[Br-].[Br-].[Zn+2]>[CH3:1][C:2]1([CH3:13])[CH:4]2[CH2:5][C:6]3[C:10]([CH:3]12)=[N:9][NH:8][C:7]=3[C:11]1[N:14]=[N:15][NH:16][N:12]=1
Reactant: CC1(C)C2Cc3c(n[nH]c3C#N)C21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)C2Cc3c(n[nH]c3-c3nn[nH]n3)C21
Temperature: 200 °C

Procedure:
(±)-1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonitrile (0.184 g, 1.06 mmol) was taken up in 1,4-dioxane (10 mL) with zinc dibromide (0.500 g, 2.22 mmol) and sodium azide (0.300 g, 4.62 mmol) in a heavy walled glass tube. The resulting solution was heated under microwave irradiation to 200° C. for 1 hour. The solution was poured into 1M aqueous hydrochloric acid (10 mL) and extracted into ethyl acetate (50 mL). Solvent was removed under reduced pressure and the resulting oil purified by preparative HPLC to give (±)-1,1-dimethyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene as a white solid. m/z (ES+): 217 [M+H]+, 189 [M−N2+H]+; 1H NMR (CD3OD): δ 2.87 (dd, 1H, J1=16.5, J2=5.6), 2.67 (dd, 1H, J1=16.5, J2=0.8), 2.1-2.0 (m, 2H), 1.08 (s, 3H), 0.69 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])=[C:8]([C:14]3[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=3)[CH:9]=2)=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccc(F)c(Cl)c2)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (57.3 mg, 0.209 mmol) in CH2Cl2 (2 mL) was added 3-chloro-4-fluorophenyl isocyanate (0.30 μL, 0.241 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 135 as a colorless solid (66.2 mg, 71%). LCMS m/z (%)=446 (M+H35Cl, 100), 448 (M+H37Cl, 35), 1H NMR (400 MHz, DMSO-d6) δ: 8.87 (bs, 1H), 8.69 (bs, 1H), 7.81-7.77 (m, 1H), 7.47-7.42 (m, 2H), 7.37 (d, J=2.71 Hz, 1H), 7.35-7.26 (m, 2H), 7.09 (d, J=8.98 Hz, 1H), 6.24 (d, J=1.83 Hz, 1H), 3.98 (t, J=6.36 Hz, 2H), 3.65 (s, 3H), 2.19 (t, J=7.04 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: [SH:1][C:2](=[C:4]([C:7]#[N:8])[C:5]#[N:6])[SH:3].[Na].[Na].Cl[C:12]1[C:17](Cl)=[N:16][C:15]([C:19]#[N:20])=[C:14]([C:21]#[N:22])[N:13]=1.O>CN(C)C=O>[C:5]([C:4]([C:7]#[N:8])=[C:2]1[S:3][C:12]2=[N:13][C:14]([C:21]#[N:22])=[C:15]([C:19]#[N:20])[N:16]=[C:17]2[S:1]1)#[N:6]
Reactant: N#CC(C#N)=C(S)S
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)=C1Sc2nc(C#N)c(C#N)nc2S1
Temperature: 40 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a stirred solution of 9.3 g (0.05 mol) of disodium dimercaptomethylenemalononitrile in 100 ml of dimethylformamide was gradually added 10 g (0.05 mol) of 2,3-dichloro-5,6-dicyanopyrazine in 70 ml of dimethylformamide. The reaction mixture was stirred at 40° C for 8 hours and poured into 700 ml of water. The resulting solid was collected by suction filtration, washed with water, and dried. The crude product was dissolved in acetone-CHCl3, decolorized with charcoal and dried over MgSO4. Recrystallization from CHCl3 yields 5.0 g (37%) of yellow crystals. M.p. ~280° C (dec.). νCN (cm31 1): 2220.
Reaction SMILES: C([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:17](=[O:32])[CH2:16]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C(O)C.[Pd]>[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:17](=[O:32])[CH2:16]1
Reactant: COc1ccc(CN2CCC(NC(c3ccccc3)c3ccccc3)CC2=O)c(OC)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(CN2CCC(N)CC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 74.2 %

Procedure:
A mixture of racemic 4-(benzhydryl-amino)-1-(2,4-dimethoxy-benzyl)-piperidin-2-one (3.30 g, 7.80 mmol), 10% Pd on carbon (410 mg, 0.39 mmol) and 2M aqueous HCl (4 mL, 8.15 mmol) in ethanol (150 mL) was stirred at ambient temperature under an atmosphere of hydrogen for 23 hours. The reaction mixture was filtered through Celite® which was washed with ethanol, and the filtrate concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel (gradient: 2M NH3 in methanol solution in DCM) to afford 1.53 g (75%) of 4-amino-1-(2,4-dimethoxy-benzyl)-piperidin-2-one as an oil. LCMS (Method I, ESI): RT=1.57 min, m+H=265.3; 1H NMR (400 MHz, CDCl3) δ: 7.15 (d, 1H), 6.46-6.42 (m, 2H), 4.56 (m, 2H), 3.80 (m, 6H), 3.33 (dt, 1H), 3.22 (m, 2H), 2.69 (ddd, 1H), 2.21 (dd, 1H), 1.94 (m, 1H), 1.59 (dtd, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[C:7](=O)[CH:8]=O.[CH2:12]([NH2:15])[CH2:13][NH2:14].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[CH:7]1[CH2:8][NH:15][CH2:12][CH2:13][NH:14]1
Reactant: NCCN
Reactant: O=CC(=O)c1cc(Cl)sc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Clc1cc(C2CNCCN2)c(Cl)s1
Reaction time: 3 h

Procedure:
A 10.45 g portion of the above aldehyde was suspended in 200 ml of ethanol, cooled to 0°-5° C. and a solution of 3.3 g of ethylenediamine in 20 ml of ethanol added dropwise with stirring. The mixture was allowed to come to room temperature over 3 hours, then 3.8 g of sodium borohydride was added and the mixture was evaporated to dryness. The residue was dissolved in dichloromethane, water washed, filtered, dried and evaporated. The resulting gum was triturated with ether producing an oil. The oil was purified by chromatography, eluting with chloroform:methanol (9:1), giving an oil which crystallized, giving 3.3 g of 2-(2,5-dichloro-3-thienyl)piperazine.