Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH:12]1[C:16](=[O:17])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH:13]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C@H:12]2[C:16](=[O:17])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][C@H:13]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCCCCN1CC(C(=O)OCC)C(N)C1=O
Solvent: ClCCl
Product: CCCCCN1C[C@@H](C(=O)OCC)[C@@H](NC(=O)Nc2ccc(Cl)cc2)C1=O
Reaction time: 18 h
Yield: 72.3 %

Procedure:
To a solution of 4-chlorophenyl isocyanate (113 mg, 0.734 mmol) in CH2Cl2 (1 ml) was added the aminopyrrolidinone of Example R (178 mg, 0.734 mmol) in CH2Cl2 (1 ml). After stirring for 18 h, the solvent was removed in vacuo and the resulting mixture was chromatographed on silica gel (5% EtOH/CH2Cl2) to give the title compound (210 mg, 72%). 'H NMR (300 MHz, CDCl3) δ7.99 (1H, s), 7.42 (2H, d), 7.24 (2H, t), 6.21 (1H, d), 4.92 (1H, q), 4.21 (1H, m), 4.11 (1H, m), 3.55 (2H, q), 3.32 (2H, m), 1.55 (2H, q), 1.29 (4H, m), 1.21 (2H, t), 0.89 (3H, t).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH2:34][CH2:35][CH3:36])[CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH2:34][CH2:35][CH3:36])[CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=2)=[CH:9][CH:8]=1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: CCCC(CC(=O)OC)c1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CC(=O)OC)c1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 21 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged dry THF (5.0 mL) and (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.134 g, 0.5 mmol). To the above mixture methyl 3-(4-hydroxyphenyl)hexanoate (0.11 g, 0.5 mmol) was added and the resulting mixture stirred at 0° C. for 5 min. Triphenyl phosphine (0.17 g, 0.65 mmol) was added to the mixture and stirred at 0° C. for 15 min followed by the addition of diethylazadicarboxylate (0.13 g, 0.65 mmol). After stirring the resulting mixture at RT for 16 h, the RM was evaporated to remove the THF. The residue was diluted with water (15 mL) and extracted with ethyl acetate (15 mL×2). The organic layer was washed with saturated brine solution (15 mL) and dried over anhydrous Na2SO4. Concentration of the solvent and purification of the resulting residue by column chromatography on silica gel (100/200 mesh), using petroleum ether and ethyl acetate as eluent, gave the product (0.05 g, yield: 21.74%)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[S:8]([NH:11][CH3:12])(=[O:10])=[O:9].[C-:13]#[N:14].[K+].Cl>C(O)COCCOCCO>[C:13]([CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[S:8]([NH:11][CH3:12])(=[O:10])=[O:9])#[N:14]
Reactant: CNS(=O)(=O)c1sccc1CCl
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: OCCOCCOCCO
Product: CNS(=O)(=O)c1sccc1CC#N
Temperature: 0 °C

Procedure:
7.9 g (32.7 mmol) of 3-chloromethyl-2-N-methylthiophenesulfonamide and 4.7 g (72 mmol) of potassium cyanide are heated to 80° C. for 15 minutes in 40 ml of triethyleneglycol. Thereafter, the mixture is poured into 100 ml of 2-N hydrochloric acid and 50 g of ice and extracted with three 200 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate, stirred with 1 g of active carbon, filtered and evaporated to give a noncrystallizing oil. There is obtained 3-cyanomethyl-2-N-methylthiophenesulfonamide.
Reaction SMILES: CC(O[C:6]([N:8](C)[C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)C.Cl>O1CCOCC1>[CH3:6][NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@@H](C(=O)O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@H]1CC[C@@H](C(=O)O)CC1
Yield: 51.7 %

Procedure:
A solution of cis-4-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]cyclohexane carboxylic acid (2.5 g, 16 mmol, 1.0 equiv) and 1 M HCl in dioxane (15 mL) was heated to reflux for 4 h. The solvent was removed under reduced pressure to afford 1.3 g of the title compound. This material was used without purification.
Reaction SMILES: [Li].[CH3:2][CH2:3][C:4](=[O:10])[CH2:5][C:6](=[O:9])[CH2:7][CH3:8].CN(C)C(=O)N(C)C.[CH2:19]([C:21](=[CH:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1)[CH2:22][CH2:23]I)[CH3:20]>>[CH2:19]([C:21](=[CH:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1)[CH2:22][CH2:23][CH:5]([C:4](=[O:10])[CH2:3][CH3:2])[C:6](=[O:9])[CH2:7][CH3:8])[CH3:20]
Reactant: CCC(=O)CC(=O)CC
Reactant: CCC(=CCCc1ccc2c(c1)OCO2)CCI
Agent: [Li]
Solvent: CN(C)C(=O)N(C)C
Product: CCC(=O)C(CCC(=CCCc1ccc2c(c1)OCO2)CC)C(=O)CC

Procedure:
A solution of 15 g. of the lithium salt of 3,5-heptanedione (prepared as described in Example 8 below) in 100 ml. of tetramethylurea was stirred under nitrogen at room temperature, and 10 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide (Preparation D1) was added. The reaction mixture was stirred for forty-eight hours, then concentrated to remove the solvent, and the residue slurried in ether and treated with excess glacial acetic acid. Water was added, the ether layer separated, washed with water and concentrated. The residue was distilled in a molecular still to remove volatile material at 110° C. (0.001 mml.), and the non-volatile residue was chromatographed on 10 g. of activated magnesium silicate in benzene solution and eluted with ethyl acetate to give 4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione as a yellow oil.
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:23])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[C:26]([NH2:31])=[N:27][NH:28][C:29]=1[CH3:30]>Cl.CCO>[ClH:23].[C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])[N:14]=[CH:13][CH:12]=[C:11]2[NH:31][C:26]1[NH:27][N:28]=[C:29]([CH3:30])[C:25]=1[CH3:24])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOc1cc2nccc(Cl)c2cc1S(=O)(=O)C(C)(C)C
Reactant: Cc1[nH]nc(N)c1C
Agent: Cl
Solvent: CCO
Product: COCCOc1cc2nccc(Nc3[nH]nc(C)c3C)c2cc1S(=O)(=O)C(C)(C)C
Temperature: 25 °C
Yield: 48 %

Procedure:
6-(tert-Butylsulfonyl)-4-chloro-7-(2-methoxyethoxy)quinoline (0.461 g, 1.288 mmol), 4,5-dimethyl-1H-pyrazol-3-amine (0.175 g, 1.546 mmol), and 2 drops of aq HCl (0.161 ml, 0.322 mmol) in EtOH (3.06 ml) were heated at 80° C. overnight. The reaction was cooled to rt and the precipitate was filtered, washed with MeCN, and vacuum-dried to yield 6-(tert-butylsulfonyl)-N-(3,4-dimethyl-1H-pyrazol-5-yl)-7-(2-methoxyethoxy)quinolin-4-amine, hydrochloride (0.290 g, 0.618 mmol, 48.0% yield). m.p. 181-184° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.71 (s, 1H), 11.20 (br. s., 1H), 9.22 (br. s., 1H), 8.48 (d, J=7.07 Hz, 1H), 7.63 (s, 1H), 6.64 (d, J=7.07 Hz, 1H), 4.36 (t, J=4.29 Hz, 2H), 3.78 (t, J=4.29 Hz, 2H), 3.35 (s, 3H), 2.24 (s, 3H), 1.84 (s, 3H), 1.35 (s, 9H). MS: m/z: 433.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl[CH2:29][C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>>[N:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[NH:34][C:30]=1[CH2:29][O:16][C:9]1[CH:10]=[C:11]2[C:6]3=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:19][N:5]3[C:4]3[CH:3]=[C:2]([Br:1])[CH:15]=[CH:14][C:13]=3[S:12]2)[CH:8]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Product: O=c1c(Cc2cccnc2)cn2c3c(cc(OCc4nc5ccccc5[nH]4)cc13)Sc1ccc(Br)cc1-2
Yield: 1.5 %

Procedure:
According to Example 34, the compound (500 mg) produced in Example 37 was reacted with 2-chloromethylbenzimidazole (243 mg) to obtain the title compound (10 mg; 0.2%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:16][CH2:17][CH:18]=[O:19])([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxy-propyl)-1,3-oxazinan-2-one (500 mg, 1.15 mmol), PDC (870 mg, 2.30 mmol) and 3 Å molecular sieves (1.3 g) in methylene chloride was stirred at room temperature for 3 hours. The reaction mixture was chromatographed on silica gel directly to give 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanal (300 mg, 60%). 1H NMR: (400 MHz, CDCl3): 1.43 (d, 2H), 2.10 (m, 2H), 2.19 (m, 3H), 2.67 (m, 1H), 2.86 (m, 1H), 5.54 (q, 1H), 6.75 (d, 2H), 7.00 (t, 2H), 7.17 (m, 4H), 9.60 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]([C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4])[CH3:2].Cl[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][O:27]1.C(=O)(O)[O-].[Na+].[I-].[K+].[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40]>CN(C)C=O.O.CCOCC>[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].[CH2:1]([C:3]([C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:6][CH2:7][N:8]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][O:27]2)[CH2:9][CH2:10]1)=[O:4])[CH3:2]
Reactant: CCC(=O)C1(c2ccccc2Sc2ccccc2)CCNCC1
Reactant: ClCC1CCCO1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)C1(c2ccccc2Sc2ccccc2)CCN(CC2CCCO2)CC1
Reaction time: 16 h

Procedure:
A mixture of 1.8 g of 4-ethylcarbonyl-4-(2-phenylthiophenyl)piperidine, free base of Example 11, 0.93 g of 2-chloromethyltetrahydrofuran, 1.6 g of sodium bicarbonate and 1.6 g of potassium iodide in 20 ml of dimethylformamide is stirred at 80°-85° C. for 16 hours. Thereafter, the mixture is permitted to cool before being diluted with 50 ml of water. The diluted mixture is extracted four times with 30 ml portions of ether and the combined ether extracts are washed with 25 ml saturated sodium chloride solution and then dried. The resulting oil product is chromatographed (alumina column, 10% methyl alcohol in ether eluant) to provide a purified product which, in ether, is converted to its oxalic acid salt. The salt is washed well with ether, dried under vacuum, recrystallized from a methanol-acetone-ether mixture and washed with ether to provide 4-ethylcarbonyl-4-(2-phenylthiophenyl)-1-(2-tetrahydrofurylmethyl)piperidine oxalate.
Reaction SMILES: [CH:1]1([N:7]2[CH2:16][CH2:15][C:9]3([NH:13][CH2:12][C@H:11]([OH:14])[CH2:10]3)[C:8]2=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1)[CH3:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)S(=O)=O>>[Br:31][C:28]1[CH:29]=[CH:30][C:25]([CH:23]([N:13]2[C:9]3([CH2:15][CH2:16][N:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:8]3=[O:17])[CH2:10][C@@H:11]([OH:14])[CH2:12]2)[CH3:24])=[CH:26][CH:27]=1
Reactant: O=C1N(C2CCCCC2)CCC12C[C@@H](O)CN2
Reactant: CC(OS(C)(=O)=O)c1ccc(Br)cc1
Agent: CN(C)[SH](=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(c1ccc(Br)cc1)N1C[C@H](O)CC12CCN(C1CCCCC1)C2=O
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of (3R)-7-cyclohexyl-3-hydroxy-1,7-diazaspiro[4.4]nonan-6-one (0.030 g, 0.00012 mol; which was prepared by using procedures analogous to those described for the synthesis of Example 32, derived from peak 2 of step 2), 1-(4-bromophenyl)ethyl methanesulfonate (0.053 g, 0.00019 mol) and potassium carbonate (0.035 g, 0.00025 mol) in dimethylsulfonamide (DMSO) (1.0 mL, 0.014 mol) was stirred at 100° C. for 16 h. The crude reaction mixture was purified by prep. HPLC to afford the desired product. LC-MS: 421.0/423.0 (M+1H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[C:27]([C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br)#[N:28]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:31][C:30]5[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=5[C:27]#[N:28])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3ccccc3C#N)C2=O)CC1
Yield: 81 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-cyanobenzyl bromide, to give the desired product as a light yellow solid (81%).
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=1.[N:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[F:27])=[N+:15]=[N-:16]>CO>[Cl:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[N:16]=[N:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][C:18]=3[F:27])[C:10]=2[NH2:11])=[CH:7][CH:6]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1c(-c2ccc(Cl)cc2)nnn1-c1ccc(C(F)(F)F)cc1F
Reaction time: 8 h
Yield: 26.8 %

Procedure:
To a stirred and ice-cooled solution of sodium methoxide (0.296 g, 5.4848 mmol) in methanol (25 ml), commercial 4-chlorobenzyl cyanide (0.610 g, 4.0222 mmol) and 1-azido-2-fluoro-4-trifluoromethyl-benzene (0.750 g, 3.6565 mmol) are added portion wise. The reaction mixture is allowed to reach room temperature spontaneously overnight, concentrated in vacuo, added water, and extracted with ethylacetate (3×80 ml). The combined organic layers are dried over MgSO4, filtered and evaporated, to afford a red solid residue (1.200 g, 92% mass balance). This crude material is purified by column chromatography over silica gel (230-400 mesh) eluting with 10% ethylacetate in petroleum ether, to obtain the title compound as an off-white solid (0.350 g, 26% yield). M.p. 169.9-170.2° C. LC-ESI-HRMS of [M+H]+ shows 357.0516 Da. Calc. 357.053011 Da, dev. −4 ppm.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]([CH3:17])[C:6](=[O:16])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:9]=1)[CH3:3].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([O:28][CH3:29])[CH:20]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C)C=O.O>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][CH:2]([C:4]2[N:5]([CH3:17])[C:6](=[O:16])[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][N:11]=3)[N:9]=2)[CH3:3])=[O:24])=[C:21]([O:28][CH3:29])[CH:20]=1
Reactant: CC(N)c1nc(-c2ccncn2)cc(=O)n1C
Reactant: COc1cc(F)ccc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1C(=O)NC(C)c1nc(-c2ccncn2)cc(=O)n1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
To a solution of 0.112 g (0.48 mmol) of (+/−) 2-(1-amino-ethyl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one in 5 mL of dimethylformamide was added 0.082 g (0.48 mmol) of 4-fluoro-2-methoxy-benzoic acid and 90 μL (0.58 mmol) of diethyl phosphorocyanidate (DEPC). The resulting mixture was cooled at 0° C., 70 μL (0.53 mmol) of triethylamine was added and stirred at room temperature for 1 h. Water was added and the mixture extracted with diethyl acetate. The extracts were washed with a saturated aqueous solution of ammonium chloride, dried and evaporated. The residue was purified on preparative thin layer chromatography eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 95/5/0.5 to afford 0.12 g (66%) of the desired compound as a white powder.
Reaction SMILES: C([O:8][C:9]([C:15]1[O:19][C:18]([C:20]2[C:21]([NH2:34])=[N:22][C:23]([C:30]([F:33])([F:32])[F:31])=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=2)=[N:17][N:16]=1)([CH3:14])[C:10]([F:13])([F:12])[F:11])C1C=CC=CC=1>CCO.[Pd]>[NH2:34][C:21]1[C:20]([C:18]2[O:19][C:15]([C:9]([OH:8])([CH3:14])[C:10]([F:13])([F:12])[F:11])=[N:16][N:17]=2)=[N:25][C:24]([C:26]([F:27])([F:29])[F:28])=[C:23]([C:30]([F:33])([F:32])[F:31])[N:22]=1
Reactant: CC(OCc1ccccc1)(c1nnc(-c2nc(C(F)(F)F)c(C(F)(F)F)nc2N)o1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CC(O)(c1nnc(-c2nc(C(F)(F)F)c(C(F)(F)F)nc2N)o1)C(F)(F)F
Reaction time: 8 h

Procedure:
A solution of 3-(5-(2-(benzyloxy)-1,1,1-trifluoropropan-2-yl)-1,3,4-oxadiazol-2-yl)-5,6-bis(trifluoromethyl)pyrazin-2-amine (Step 2) (50 mg, 0.100 mmol) in EtOH (3 ml) under N2 was charged with Pd/C (1.061 mg, 9.97 μmol) and placed under a positive pressure of H2 (0.35 bar) at RT overnight. The reaction mixture was filtered through Celite® (Filter Material) and washed through with ethanol (30 ml), followed by DCM (10 ml). The filtrate was concentrated in vacuo and the resulting crude product was purified by UV directed LC-MS eluting with MeCN/Water/0.1% TFA. The clean fractions were poured into EtOAc (50 ml) and washed with saturated NaHCO3 (50 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound to give a pale orange solid. 1H NMR (400 MHz, DMSO-d6) δ 9.22 (1H, broad hump), 8.1 (1H, broad hump), 7.92 (1H, s), 1.4 (3H, s). 19F NMR (400 MHz, DMSO-d6) Peak 1 at −61 ppm, peak 2 at −64 ppm, peak 3 at −79.4 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+].Cl[CH2:15][C:16]#[N:17].O1CCOCCOCCOCCOCCOCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH2:15][C:16]#[N:17])=[O:5]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: N#CCCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#CCOC(=O)c1c(Cl)cccc1Cl
Yield: 61 %

Procedure:
This compound was prepared in the manner of Example 1, using 10.0 grams (0.052 mole) of 2,6-dichlorobenzoic acid, 2.9 grams (0.052 mole) of potassium hydroxide, 3.9 grams (0.052 mole) of chloroacetonitrile, and 1.4 grams of 1,4,7,10,13,16-hexaoxacyclooctadecane in 160 ml of dry toluene. The crude product was distilled to give 7.3 grams of cyanomethyl 2,6-dichlorobenzoate; bp 107°/0.006 mm. The ir and the nmr spectra were consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[N:15][CH2:14][CH:13]([O:16][CH3:17])[O:12][CH3:11]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: COC(CN)OC
Solvent: Cc1ccccc1
Product: COC(CN=Cc1cc(Br)ccc1F)OC

Procedure:
A mixture of 5-bromo-2-fluorobenzaldehyde (15 g, 74 mmol) and 2,2-dimethoxy-ethylamine (7.77 g, 74 mmol) in toluene (142 mL) was heated to reflux for 30 minutes using a Dean-Stark trap to remove water. The solution was then concentrated under vacuum to provide 5-bromo-2-fluorobenzylidene-2,2-dimethoxyethylamine. 5-Bromo-2-fluorobenzylidene-2,2-dimethoxyethylamine and cold concentrated sulfuric acid (28 mL) were added separately, dropwise, over a period of 20 minutes to concentrated sulfuric acid (83 mL) at 140° C. The mixture was stirred at 135° C. for 30 minutes, allowed to cool, and carefully poured onto ice. Filtered to remove solids and the mixture was washed with dichloromethane. The aqueous layer was made basic by cautious addition of 50% sodium hydroxide solution, and extracted with diethyl ether. Combined ether layers were dried (MgSO4), filtered and concentrated under vacuum to provide 310 mg (2%) of the desired product. MS (ESI) m/e 226 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:14]([CH3:16])[CH3:15])[C:6](=[O:13])[NH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH:24]=[CH2:25]>CN(C)C=O>[CH2:25]([O:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:14]([CH3:16])[CH3:15])[C:6](=[O:13])[NH:7]2)[CH:24]=[CH2:23]
Reactant: C=CCI
Reactant: Cc1ccc(O)c2cc(C(C)C)c(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C)c2[nH]c(=O)c(C(C)C)cc12
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
5-Hydroxy-3-isopropyl-8-methylcarbostyril (1.60 g, 7.37 mmol) was dissolved in dimethylformamide (30 ml), to which potassium carbonate (2.50 g, 18.1 mmol) and allyl iodide (0.71 ml, 7.76 mmol) were added. The mixture was stirred at 70° C. for 90 minutes. The reaction mixture was condensed under reduced pressure. The resultant residue was extracted from chloroform-water. The organic phase was washed with saturated aqueous NaCl solution, dried, and condensed under reduced pressure. The residue was recrystallized from chloroform-ether to obtain 1.85 g of the title compound as pale yellow powdery crystals (97.9%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:26][CH3:27])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1.O.NN>[Ni].CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:26][CH3:27])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1
Reactant: COc1ccc(C(=O)Nc2cccnc2)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)Nc2cccnc2)c2c1oc1ccc(N)cc12
Yield: 65.4 %

Procedure:
N1-(pyrid-3-yl)-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (500 mg) (from step1) was reduced using raney nickel (150 mg) (30% w/w aqueous suspension) in methanol (10 ml) in the presence of hydrazine hydrate (0.32 ml) under gentle reflux for 4 h. The reaction mixture was flitered through celite and the filterate was concentrated in vaccuo. The residue was triturated with water, to obtain a solid which was filtered dried to give the product as white solid (300 mg).