Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([CH2:6][F:7])[C:3](Cl)=[O:4].[F:8][C:9]([F:18])([CH:12]([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:10][OH:11].N1C=CC=CC=1.O>ClC(Cl)(Cl)Cl>[F:1][CH:2]([CH2:6][F:7])[C:3]([O:11][CH2:10][C:9]([F:8])([F:18])[CH:12]([F:17])[C:13]([F:15])([F:16])[F:14])=[O:4]
Reactant: O=C(Cl)C(F)CF
Reactant: OCC(F)(F)C(F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=C(OCC(F)(F)C(F)C(F)(F)F)C(F)CF
Reaction time: 1 h
Yield: 75.7 %

Procedure:
34.6 g (0.27 mole) of 2,3-difluoropropanoyl chloride were added dropwise to a solution of 50 g (0.27 mole) of 2,2,3,4,4,4-hexafluoro-1-butanol and 21.6 g (0.27 mole) of pyridine in 200 ml of dry tetrachloromethane. Stirring was continued for a further 1 hour and then the mixture was poured into water, extracted, dried and distilled. In this manner, 56 g of 2,2,3,4,4,4-hexafluorobutyl 2,3-difluoropropionate were obtained having a melting point of 84° to 86° C. at 20 mbar. The purity of the product prepared was 95% (determined by gas chromatography).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH2:5][N:6]=1.[SH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1>>[CH3:1][C:2]([NH:6][CH2:5][CH2:4][S:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:3]
Reactant: CC1=NCCO1
Reactant: Oc1ccc(S)cc1
Product: CC(=O)NCCSc1ccc(O)cc1
Temperature: 130 °C
Yield: 87 %

Procedure:
A mixture of 2-methyl-2-oxazoline (16.9 mL, 0.197 mol) and 4-mercaptophenol (24.85 g, 0.197 mol) was heated under reflux (neat) for 2 h at about 130° C. under Ar (spontaneous heating occurred upon mixing). Upon cooling of the reaction mixture to 0° C., a white solid precipitated, which was collected and recrystallized from dilute EtOH to give a white product (36.2 g, 87%): mp 123°-125° C.; 1H NMR [(CD3)2 =O]δ6.99 (d,d, 4 H) , 3.50-2.60 (m, 5 H), 1.87 (s, 3 H); mass spectrum (EI) , m/e 211 (M+), (CI) m/e 212 (M+1). Anal. (C10H13NO2S) C,H,N.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[N:27]1[O:28][N:29]=[C:30]2[CH:35]=[C:34]([CH2:36][N:37]3[CH2:41][CH2:40][N:39]([C:42]4[S:43][C:44]([C:48]([OH:50])=O)=[C:45]([CH3:47])[N:46]=4)[C:38]3=[O:51])[CH:33]=[CH:32][C:31]=12.[NH2:52][CH2:53][C:54]1[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=1>>[N:27]1[O:28][N:29]=[C:30]2[CH:35]=[C:34]([CH2:36][N:37]3[CH2:41][CH2:40][N:39]([C:42]4[S:43][C:44]([C:48]([NH:52][CH2:53][C:54]5[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=5)=[O:50])=[C:45]([CH3:47])[N:46]=4)[C:38]3=[O:51])[CH:33]=[CH:32][C:31]=12
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccc4nonc4c3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc4nonc4c3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 34 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 34% yield: mp 110-112° C. (dichloromethane/hexanes): 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.54-8.52 (m, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.72-7.69 (m, 2H), 7.39-7.35 (m, 1H), 7.30-7.28 (m, 1H), 6.14 (br s, 1H), 4.60 (d, J=6.0 Hz, 2H), 4.57 (s, 2H), 4.15 (t, J=6.0 Hz, 2H), 3.56 (t, J=6.0 Hz, 2H), 2.62 (s, 3H): MS (ES+) m/z 450.2 (M+1).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH:17]([CH:19]1[CH2:23][CH2:22][N:21](C(OCC2C=CC=CC=2)=O)[CH2:20]1)=O.O>O1CCCC1>[NH:21]1[CH2:22][CH2:23][CH:19]([CH2:17][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:20]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCC1CCNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (15.9 g) in tetrahydrofuran (200 mL) was added sodium hydride (60% in oil, 2.88 g) at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added benzyl 3-formylpyrrolidine-1-carboxylate (15.0 g) and the mixture was stirred for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was dissolved in methanol (500 ml), palladium hydroxide/carbon (2.0 g) was added, and the mixture was stirred under a hydrogen atmosphere (3 atm) at 40° C. for 4 hr. The reaction solution was allowed to cool to room temperature, the reaction system was substituted by nitrogen, filtered, and the solvent was evaporated to give the title compound (8.0 g, yield 73%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH3:2].[H-].[Na+].[F:12][C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[C:25](F)[CH:24]=[C:23]([F:31])[C:22]=1[F:32].C(OCC)(=O)C>C1COCC1.CCCCCC>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:6][C:25]1[C:26]([N+:27]([O-:29])=[O:28])=[C:21]([C:22]([F:32])=[C:23]([F:31])[CH:24]=1)[NH:20][C:14]1[CH:15]=[CH:16][C:17]([I:19])=[CH:18][C:13]=1[F:12])[CH3:2]
Reactant: CCOC(CO)OCC
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-])OCC
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
2,2-Diethoxy-ethanol (0.209 g, 1.2135 mmol) was added to a cooled suspension of NaH (0.034 g, 1.456 mmol) in THF (5 mL) at 0° C. and the resulting mixture was stirred for 30 minutes at 20-40° C. 2-Fluoro-4-iodo-phenyl-(2,3,5-trifluoro-6-nitro-phenyl)-amine (0.5 g, 1.2135 mmol) in THF (10 mL) was added slowly to the reaction mass at 0° C. and stirring was continued for a further 15 minutes. The reaction mass was stirred overnight at room temperature. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mass was concentrated under reduced pressure and the concentrate was extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford the crude compound. Purification by column chromatography on silica gel (15% ethyl acetate in hexane) afforded 0.3 g of the product (47% yield). 1H NMR (CDCl3, 300 MHz): δ 7.42 (d, 1H), 7.35 (d, 1H), 6.90 (bs, 1H), 6.58-6.68 (m, 2H), 4.58 (t, 1H), 4.15 (d, 2H), 3.51-3.80 (m, 4H), 1.22 (t, 6H).
Reaction SMILES: C(=[C:4]([CH:6]([CH2:8][OH:9])[OH:7])[OH:5])(C)C.[Cl:10][C:11]([O:13]C(Cl)(Cl)Cl)=O.CN(C)[C:20]1[CH:25]=CC=C[CH:21]=1.Cl>C1(C)C=CC=CC=1>[Cl:10][C:11]([O:9][CH2:8][CH:6]1[CH2:4][O:5][C:20]([CH3:25])([CH3:21])[O:7]1)=[O:13]
Reactant: CC(C)=C(O)C(O)CO
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC1(C)OCC(COC(=O)Cl)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 178.1 %

Procedure:
To a mixture comprising 6.6 g (0.05 mol) of isopropylideneglycerol, 5.9 g (0.03 mol) of trichloromethyl chloroformate and 50 ml of toluene was slowly added dropwise 7.3 g (0.06 mol) of N,N-dimethylaniline dissolved in 20 ml of toluene. After stirring at room temperature for 4 hours, the reaction mixture was poured into diluted hydrochloric acid, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. After distilling off the solvent, 10.4 g of 2,2-dimethyl-1,3-dioxolan-4-ylmethyl chloroformate was obtained as a colorless liquid. This product showed a single spot in thin layer chromatography (silica gel, benzene: ethyl acetate=10:3) and was satisfactory in NMR data [(60 MHz, CDCl3) α; 1.25, 1.30 (s×2, 6H), 3.1-3.7 (m, 4H), 3.8-4.1 (m, 2H), 3.6 (s, 1H, disappeared by adding D2O)]. Thus it was not purified but directly used in the subsequent step.
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13]([N:22]2[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]2)[C:14]2[N:20]=[CH:19][N:18]=[C:17](Cl)[C:15]=2[N:16]=1>O1CCOCC1.O>[CH2:1]([N:8]([CH3:9])[C:17]1[C:15]2[N:16]=[C:11]([Cl:10])[N:12]=[C:13]([N:22]3[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]3)[C:14]=2[N:20]=[CH:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1ccccc1
Reactant: O=S1CCN(c2nc(Cl)nc3c(Cl)ncnc23)CC1
Solvent: C1COCCO1
Solvent: O
Product: CN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12

Procedure:
A solution of 12.2 gm (0.1 mol) of N-benzyl-methylamine in 50 ml of dioxane was slowly poured, while stirring, into a suspension of 15.9 gm (0.05 mol) of 2,8-dichloro-4-(1-oxido-thiomorpholino)-pyrimido[5,4-d]-pyrimidine in about 250 ml of dioxane, and the resulting mixture was heated at 30°-40° C. for about 30 minutes. The reaction mixture was taken up in about 1 liter of water, whereby the reaction product was precipitated as a slightly yellow precipitate. After standing for a little while, the precipitate was filtered off, washed with water and dried at about 60° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(N(CC)CC)C.[CH2:15](Br)[CH:16]=[CH2:17].Cl.[CH2:20]1[CH2:24]OC[CH2:21]1>>[CH3:2][O:3][C:4](=[O:7])[CH2:5][N:6]([CH2:24][CH:20]=[CH2:21])[CH2:15][CH:16]=[CH2:17]
Reactant: C=CCBr
Reactant: COC(=O)CN
Reactant: C1CCOC1
Agent: Cl
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)CC(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
1.5 g (11.9 mmole) glycine methylester hydrochloride was added to 100 ml dry THF and subsequently, 3.61 g (35.8 mmole) triethylamine was added. After 15 minutes stirring at room temperature, 4.33 g (35.8 mmole) allyl bromide was added dropwise and the mixture was refluxed for 16 hours. 100 ml of 2N HCl was added and then extracted with 100 ml diethyl ether. The aqueous phase was alkalinised after, acid extraction, with K2CO3 and extracted with CH2Cl2 (100 ml three times). The organic layer was dried with MgSO4. The product was further purified, after filtration of MgSO4 and evaporation of the solvent, via column chromatography, providing with 100% selectivity 0.78 g (5.75 mmole, yield 49%) diallylglycine methyl ester. This product was further characterised by the following spectra:
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8](Cl)[CH:9]=[CH:10][C:11]=1[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[Mg].S(Cl)(Cl)=O.C[Si]([O:27][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])(C)C.[Cl-].[NH4+]>C1COCC1>[F:32][C:31]([F:34])([F:33])[S:28]([O-:30])(=[O:29])=[O:27].[C:1]([O:5][C:6]1[CH:7]=[C:8]([S+:28]([C:31]2[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=2)[C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:7]=2)[CH:9]=[CH:10][C:11]=1[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)Oc1ccc(Cl)cc1OC(C)(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc([S+](c2ccc(OC(C)(C)C)c(OC(C)(C)C)c2)c2ccc(OC(C)(C)C)c(OC(C)(C)C)c2)cc1OC(C)(C)C
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A Grignard reagent was conventionally prepared using 51.3 g (0.2 mol) of 3,4-di-tert-butoxyphenyl chloride, 4.9 g (0.2 mol) of magnesium, and 100 g of THF. The Grignard reagent solution was cooled in an ice water bath whereupon 5.8 g (0.049 mol) of thionyl chloride diluted with 10 g of THF was added dropwise at less 30° C. Reaction mixture was ripened for about 30 minutes. Thereafter, 26.7 g (0.12 mol) of trimethylsilyltrifluoromethane sulfonate was added dropwise at less 20° C. Reaction mixture was further ripened for 1 hour and thereafter, the reaction solution was allowed to stand overnight at room temperature. After the reaction solution was again cooled in an ice water bath, 200 g of 16.7% ammonium chloride aqueous solution was added thereto at less 30° C. After separation, 100 g of chloroform was added to the organic layer, which was washed three times using 100 g of water. Thereafter, the solvent was distilled off under reduced pressure by means of a rotary evaporator, obtaining an oily residue. The oily residue was recrystallized, isolating tris(3,4-di-tert-butoxyphenyl)sulfonium trifluoromethanesulfonate of 99% purity in an amount of 13.2 g (yield 32%).
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4]([Cl:6])=[O:5].[CH2:10]([N:12](CC)CC)[CH3:11].CC[O:19]CC>O>[ClH:6].[F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4]([O:19][CH2:11][CH2:10][NH2:12])=[O:5]
Reactant: O=C(Cl)CC(F)=C(F)F
Reactant: CCOCC
Reactant: CCN(CC)CC
Solvent: O
Product: Cl
Product: NCCOC(=O)CC(F)=C(F)F
Yield: 77 %

Procedure:
A solution of 3,4,4-trifluoro-3-butenoyl chloride (1.97 g, 0.0124 mole) and N-t-Boc-aminoethanol (1.61 g, 0.010 mole) in dry ether (20 mL) is treated with triethylamine (1.25 g, 0.0124 mole) at -78° C. with stirring. The mixture is stirred for 30 min and allowed to reach room temperature and poured in 20 mL of water. The ether layer is successively washed with 5% sodium bicarbonate and brine and dried. The ether solution is saturated with dry HCl gas and stirred at room temperature for 30 min. The precipitate is filtered and dried to give 1.6 g of the title compound as a white solid, a 77% yield. m.p. 94°-100° C.
Reaction SMILES: CN(C=O)C.Br[C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[CH:13][CH:14]=2)[N:9]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([S:31][CH3:32])[N:26]=2)[CH:8]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=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.O.C(OCC)(=O)C>[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=4)=[CH:13][CH:14]=3)[N:9]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([S:31][CH3:32])[N:26]=3)[CH:8]=2)=[CH:45][CH:44]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CSc1nccc(-n2cc(Br)c3ccc(-c4cccc([N+](=O)[O-])c4)cc32)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(-c3ccnc(SC)n3)c3cc(-c4cccc([N+](=O)[O-])c4)ccc23)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
DMF (2 mL) was added to a mixture of 3-bromo-1-(2-(methylthio)pyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (130 mg, 0.295 mmol), K3PO4 (188 mg, 0.885 mmol) and 4-methoxyphenylboronic acid (90 mg, 0.59 mmol) and then the dissolved gas was removed. After adding Pd(PPh3)4 (68 mg, 0.055 mmol), the mixture was stirred at 100° C. for 4 hours. After adding ethyl acetate and water and then filtering using a diatomite pad, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (silica gel, EA:Hx=1:4-1:1). The target compound (96 mg) was obtained as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)[C:8]1=[O:28].C(N(CC)CC)C.I.[C:44]([CH2:49][CH2:50][CH2:51][N:52]1[C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=2[N:54]=[C:53]1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)([O:46][CH2:47][CH3:48])=[O:45]>C(#N)C.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][CH2:14][N:65]2[CH2:66][CH2:67][CH:62]([NH:61][C:53]3[N:52]([CH2:51][CH2:50][CH2:49][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=4[N:54]=3)[CH2:63][CH2:64]2)([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:8]1=[O:28]
Reactant: COc1cc(CN2CCC(CCCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Reactant: CCOC(=O)CCCn1c(NC2CCNCC2)nc2ccccc21
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CCCn1c(NC2CCN(CCCC3(Cc4ccc(F)cc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-methanesulfonyloxypropyl)-2-oxopyrrolidine (0.37 g, 0.73 mmol), triethylamine (0.45 mL, 3.23 mmol), and (1-(3-carboethoxypropyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt (0.40 g, 0.68 mmol) in acetonitrile (10 mL). Heat at 80° C. After 18 hours, cool, dilute the reaction mixture with dichloromethane and extract with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane/methanol/concentrate aqueous ammonium hydroxide 95/5/0.05 to give the title compound: Rf=0.65 (silica gel, dichloromethane/methanol/concentrate aqueous ammonium hydroxide 95/5/0.1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](C(O)=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:13](=[O:16])([O-])[OH:14].[Na+].CI.[CH3:20]N(C=O)C>C(OCC)(=O)C.O>[NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:13]([O:14][CH3:20])=[O:16])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1cccc2[nH]ccc12
Yield: 99 %

Procedure:
To a 100 mL round bottomed flask was added, indole-5-carboxylic acid (3.57 g, 22.2 mmol), powdered sodium hydrogen carbonate (5.95 g, 70.83 mmol), methyl iodide (5.95 mL, 95.6 mmol) and DMF (25 mL). The mixture was stirred for 72 h under an atmosphere of nitrogen, whereupon water (20 mL) and ethyl acetate (40 mL) was added. The phases were then partitioned and the aqueous phase extracted with ethyl acetate (40 mL). The combined organics were washed with aqueous sodium hydrogen carbonate, dried (sodium sulfate) and concentrated to furnish a white solid (3.88 g, 99%). 1H NMR (400 MHz, Acetone d6, δ in ppm) 10.61 (br s, 1H), 8.38 (s, 1H), 7.81 (dd, J=8.6 and 1.5 Hz), 7.51 (1H, d, J=8.6 Hz), 7.46 (m, 1H), 6.65-6.63 (1H, m) and 3.87 (3H, s).
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[N:19][C:4]1=2.[CH3:22]C(C)([O-])C.[K+].CI>CS(C)=O.C(OCC)(=O)C>[CH3:22][C:3]1([S:2][CH3:1])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[N:19][C:4]1=2
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c(n1)C(SC)c1ncccc1C(=O)N2C
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccc2c(n1)C(C)(SC)c1ncccc1C(=O)N2C
Reaction time: 0.02 h

Procedure:
To a solution of 5,11-dihydro-11-methylthio-2-methoxy-5-methyl-dipyrido[3,2-b:2',3'-e]azepine-6-one (0.031 g) in DMSO (0.5 mL) stirred under argon was added potassium tert-butoxide (1M in tetrahydrofuran, 0.012 mL). After 1 minute, methyl iodide (0.05 mL) was added. After 5 minutes the mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Fractionation of the residue by preparative layer chromatography (developer, ethyl acetate/hexane) gave 5,11-dihydro-11-methyl-11-methylthio-2-methoxy-5-methyl-dipyrido[3,2-b:2',3'-e]azepine-6-one (0.029).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].B.C1COCC1.Cl.C(O)(=O)C(O)=O>O1CCCC1.CO.C(OCC)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][NH2:13]
Reactant: N#CCc1ccc2ccccc2c1
Agent: B
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: NCCc1ccc2ccccc2c1
Yield: 85 %

Procedure:
Arylethylamines that were not commercially available were made by the following procedure. 2-Naphthylacetonitrile Compound 3-2 (16.7 g, 0.10 mol) in anhydrous tetrahydrofuran (50 mL) was added to 1M solution of BH3-THF (250 mL, 0.25 mol) over 10 min at room temperature. The reaction proceeds with an induction period of 2-4 min. Following the addition, the mixture was heated under reflux and under argon for one hour (TLC of a quenched aliquot showed no starting material). The reaction was cooled in an ice bath and 10% aqueous HCl (150 mL) was added with caution over a 30 min period (vigorous reaction with the first few drops). Following the addition concentrated hydrochloric acid (100 mL) was added and the mixture brought up to reflux for 30 min. The reaction was cooled in an ice bath and extracted once with ethyl ether. The aqueous layer was carefully brought to pH 12 with 40% sodium hydroxide solution (use of concentrated base allows for smaller volumes of the aqueous layer and simplifies the extraction of the amine) and extracted with diethyl ether (4×250 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, and evaporated at reduced pressure below 40° C. The solvent was not completely removed to avoid loss of product. TLC (85:15 CHCl3/MeOH, Rf=0.1) shows that the amine is essentially pure. Oxalic acid (9.0 g, 0.10 mole) was dissolved in methanol (10 mL) and added to the crude amine diluted with diethyl ether to a 300 mL volume. The white precipitate was collected by filtration, washed with ether, and dried in vacuo to provide Compound 3-3 (22.3 g, 85%) as the oxalate salt (mp=191-193° C.). Anal Calcd. for C12H13N-0.85 C2O4H2: C, 66.42; H, 5.98. Found: C, 66.67; H, 6.05. Compound 3-3 freebase: 1H NMR (300 MHz, CDCl3) δ 7.83-7.77 (m, 3H), 7.65 (s, 1H), 7.49-7.40 (m, 2H), 7.34 (d of d, J=8.5 and 1.6 Hz, 1H), 3.06 (t, J=7 Hz, 2H), 2.92 (t, J=7 Hz, 2H).
Reaction SMILES: CN(C(/N=N/C(N(C)C)=O)=O)C.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32]CCO)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[C:36]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:37]=1.[OH:55][C:56]1[CH:57]=[C:58]([C:62]([F:65])([F:64])[F:63])[CH:59]=[CH:60][CH:61]=1>C1COCC1>[N:23]1([C:26]2[C:27](=[O:32])[N:28]([CH2:36][CH2:37][O:55][C:56]3[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:63])([F:64])[F:65])[CH:57]=3)[CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Solvent: C1CCOC1
Product: O=c1c(N2CCNCC2)nccn1CCOc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
(TMAD; 129 mg, 0.75 mmol) was added to a mixture of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-pyrazinyloxy]ethanol (200 mg, 0.62 mmol), triphenylphosphine (323 mg, 1.23 mmol), 3-hydroxybenzotrifluoride (199 mg, 1.23 mmol) in THF (1.5 mL). After being stirred at room temperature for 1 h, the reaction mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel using toluene/EtOAc (7:3) as eluent. The product-containing fractions were concentrated and the resulting N-t-BOC derivative was treated with dichloromethane/TFA/H2O (50:45:5) for 30 min with stirring. The mixture was concentrated in a speed vac overnight and the residue purified by chromatography on silica gel using CHCl3/MeOH (9:1) as eluent to afford 109 mg (49%) of the title compound. HRMS m/z calcd for C17H19F3N4O2 (M)+ 368.1460, found 368.1465.