Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1CCC(C(NN[C:18]([C:20]2[CH:34]=[CH:33][C:23]([O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:22]([O:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:21]=2)=[O:19])=O)CC1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[CH3:87][N:88]([NH2:99])[C:89]([O:91][CH2:92][C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1)=[O:90]>CN(C=O)C.C(OCC)(=O)C>[CH3:87][N:88]([NH:99][C:18](=[O:19])[C:20]1[CH:34]=[CH:33][C:23]([O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:22]([O:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:21]=1)[C:89]([O:91][CH2:92][C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1)=[O:90]
Reactant: CN(N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)NNC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1OCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(NC(=O)c1ccc(OCC(=O)OC(C)(C)C)c(OCC(=O)OC(C)(C)C)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of the product of Example 2, starting material step (c) (470 mg), HBTU (460 mg) and HOBT (190 mg) in DMF (3 ml) under argon was added diisopropylethylamine (0.63 ml). After 2-3 minutes the resultant pale yellow reaction mixture was added to benzyl 2-methylcarbazate (Dutta, A. S. et al (1975), J. Chem. Soc. Perkin Trans. I, 1712-20) (200 mg). The reaction mixture was stirred at ambient temperature under argon for 3.5 hours then diluted with ethyl acetate (50 ml) and washed with water, dilute KHSO4 (aq.) and dilute NaOH (aq.) and water, dried (MgSO4) and evaporated to give benzyl 2-methyl-3-(3,4-di-t-butoxycarbonylmethoxybenzoyl)carbazate (0.61 g) as a glass; NMR Spectrum (DMSO-d6) 1.43 (18H, s), 3.13 (3H, br s), 4.70 (2H, s), 4.75 (2H, s), 5.02-5.20 (2H, br), 6.99 (1H, m), 7.20-7.50 (7H, m), 10.68 (1H, br); Mass Spectrum m/Z 544 (M+). In the ambient temperature NMR spectrum, ancillary signals attributable to rotamers were observed.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][S:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.C[S:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=CC=1.[N-]=[C:27]=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:27][C:22]1[CH:21]=[C:20]([NH:23][C:24](=[O:25])[O:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])[CH:7]=2)[S:16][CH:17]=1
Reactant: [N-]=C=O
Reactant: COC(CSc1cccc(O)c1)OC
Reactant: CSc1ccc(N=C=O)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(CSc1cccc(OC(=O)Nc2cc(C)cs2)c1)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(2,2-Dimethoxyethylthio)phenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. 4-Methylthiophenyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[3-(2,2-dimethoxyethylthio)-phenyl] N-4-methylthiophenylcarbamate as the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].S(Cl)(Cl)=O.C(Cl)Cl.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:13])[S:10][C:3]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: C1CCNC1
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Yield: 57.4 %

Procedure:
A solution of lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate (0.50 g, 2.4 mmol), thionyl chloride (3.5 mmol, 1.8 ml), CH2Cl2 (20 ml), and DMF (0.2 ml) was heated to reflux. After 3 h the resulting yellow solution was concentrated under reduced pressure, and the residue was suspended in CH2Cl2 (20 mL). Pyrrolidine (2.35 mmol, 167 mg) was then added dropwise. After 12h the reaction mixture was concentrated onto silica gel (5 mL) and purified by flash chromatography on silica gel eluting with CH2Cl2/MeOH (97/3) to afford the title compound as a white solid (360 mg, 57%). MS: 266.9/268.9 (MH+); HPLC Rf: 4.51 min; HPLC purity: 98%.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Br[CH2:14][C:15]#[N:16].N#N>C(#N)C>[O:10]1[CH2:11][CH2:12][N:7]([CH2:14][C:15]#[N:16])[CH2:8][CH2:9]1
Reactant: N#CCBr
Reactant: C1COCCN1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a suspension of K2CO3 (6.50 g, 47 mmol) and morpholine (3.75 g, 43 mmol) in acetonitrile (30 mL) was added 2-bromoacetonitrile (5.16 g, 43 mmol) in one portion under the protection of N2 in an ice bath. The mixture was stirred at rt for 2 h, then filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (5.41 g, 100%).
Reaction SMILES: C([O:3][C:4](=[O:55])[CH:5]([O:7][P:8]([CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:54])[NH:33][C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([NH:41][C:42]4[N:47]=[C:46]([C:48]5[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=5)[CH:45]=[CH:44][N:43]=4)[CH:35]=3)=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)([O:10]C1C=CC=CC=1)=[O:9])[CH3:6])C.[OH-].[Na+].Cl>C(#N)C.O>[OH:10][P:8]([CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32](=[O:54])[NH:33][C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([NH:41][C:42]4[N:47]=[C:46]([C:48]5[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=5)[CH:45]=[CH:44][N:43]=4)[CH:35]=3)=[CH:30][CH:31]=2)[CH2:21][CH2:20]1)([O:7][CH:5]([CH3:6])[C:4]([OH:55])=[O:3])=[O:9]
Reactant: CCOC(=O)C(C)OP(=O)(CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(CCP(=O)(O)OC(C)C(=O)O)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
To a solution of 2-{[2-(4-{4-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-piperazin-1-yl)-ethyl]-phenoxy-phosphinoyloxy}-propionic acid ethyl ester (6 mg, 0.008 mmol) in 2:1 acetonitrile/water (0.3 mL) was added 1N NaOH (50 μL, 0.048 mmol). The solution was allowed to stir at room temperature for 1 hour when completion of the reaction was observed by LCMS. The reaction was acidified by 1N HCl (50 μL) solution and purified by RP HPLC using a C18 column with a gradient of H2O— Acetonitrile (5-100%) over 20 minutes to provide 2 mg (38%) of the product. 1H NMR (300 MHz, CD3OD) δ 1.51 (d, 3H, J=7 Hz), 2.04 (m, 2H), 2.33 (s, 3H), 2.96 (bs, 4H), 3.31 (m, 2H), 3.4 (bs, 4H), 3.89 (s, 2H), 4.88 (1H, possible overlap with solvent), 7.30 (m, 2H), 7.48-7.57 (m, 4H), 7.96-7.99 (m, 4H), 8.32 (s, 1H), 8.56 (d, 1H, J=5 Hz), 8.86 (d, 1H, J=2 Hz), 9.10 (dd, 1H, J=2, 5 Hz), 9.59 (s, 1H); 31P (121.4 MHz, CD3OD) δ 20.0; MS (m/z) 660 [M+H]+.
Reaction SMILES: Cl[CH:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:14].[CH:15]([Mg]Cl)=[CH2:16].CN1C(=O)N(C)CCC1.[Cl-].[NH4+]>C1COCC1>[CH:15]([C:4]12[O:14][CH:3]1[CH2:2][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[CH2:16]
Reactant: O=C1CCCCCCCCCCC1Cl
Reactant: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: C=CC12CCCCCCCCCCC1O2
Temperature: 50 °C
Yield: 82.6 %

Procedure:
A four-neck flask equipped with a thermometer, stirrer and condenser tube was charged with 100 g (0.46 mol) of 2-chlorocyclododecanone and 122 g of tetrahydrofuran, and at −10 to 0° C., a THF solution of vinylmagnesium chloride (0.82 mol) was added dropwise. The mixture was allowed to stand for reaction for 30 minutes, and 420 g (3.27 mol) of N,N′-dimethylpropyleneurea (DMPU) was added. The mixture was heated to 50° C. and allowed to stand for reaction for 1 hour, and saturated ammonium chloride aqueous solution was added dropwise for inactivation. The reaction mixture was subjected to extraction with hexane, and the solvent was recovered. The residue was distilled to obtain 1-vinyl-13-oxabicyclo[10.1.0]tridecane (80 g, 0.38 mol, chemical purity 98%, cis form:trans form=88:12). The yield was 82%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[N:19][CH:18]=[CH:17][N:16]=1>O1CCCC1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:15]1[C:20]([C:21]#[N:22])=[N:19][CH:18]=[CH:17][N:16]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1nccnc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.8 g (80 mmol) of 3-trifluoromethylphenol are added to a suspension of 2.2 g (90 mmol) of sodium hydride in 40 ml of tetrahydrofuran. The reaction mixture is heated to the boil. After 1 hour, a solution of 11.2 g (80 mmol) of 2-chloro-3-cyanopyrazine in 40 ml of tetrahydrofuran is added and the mixture is heated at the boil for a further 4 hours. After the mixture has cooled to room temperature, the solvent is distilled off under reduced pressure. The residue is taken up in diethyl ether and the solution is extracted with 5% strength, aqueous sodium hydroxide solution, washed with distilled water, dried over magnesium sulfate, filtered and freed from the solvent under reduced pressure. The crude product is purified by chromatography (silica gel, cyclohexane/ethyl acetate 20/1 (v/v)). 4.6 g (51%) of a yellow, crystalline solid of melting point 68-70° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13](O)=[O:14])[C:5]2=[O:16].S(Cl)([Cl:19])=O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]([Cl:19])=[O:14])[C:5]2=[O:16]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1coc2cc(O)c(O)cc2c1=O
Product: O=C(Cl)c1coc2cc(O)c(O)cc2c1=O

Procedure:
6,7-Dihydroxychromone-3-carboxylic acid (888 mg) and 25 ml of thionyl chloride were refluxed for one hour. Then, the thionyl chloride was removed by distillation, and after benzene was added, further distillation was conducted. Dichloromethane was added into the residue for solidification, whereby the desired product (719 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:34])[C:21]2[CH:26]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:24]=[C:23]([F:33])[CH:22]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:34])[C:21]3[CH:26]=[C:25]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH:24]=[C:23]([F:33])[CH:22]=3)[CH:15]=[CH:16][C:17]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1N
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1NC(=O)c1ccc(Cl)nc1
Temperature: 100 °C
Yield: 74 %

Procedure:
Using an analogous procedure to that described in Example 2 except that the reaction mixture was heated to 100° C. for 4 hours, 6-chloropyridine-3-carbonyl chloride was reacted with N-(3-amino-4-methylphenyl)-3-fluoro-5-morpholinobenzamide to give the title compound in 74% yield; NMR Spectrum: (DMSOd6): 2.2 (s, 3H), 3.18-3.22 (t, 4H), 3.75-3.85 (t, 4H), 6.9-7.0 (m, 1H), 7.1-7.15 (d, 1H), 7.2-7.3 (m, 2H), 7.55-7.6 (m, 1H), 7.65-7.7 (d, 1H), 7.8 (s, 1H), 8.3-8.4 (m, 1H), 8.95 (d, 1H), 10.15 (s, 1H), 10.17 (s, 1H); Mass Spectrum M+H+ 469 and 471.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]([NH:9][NH2:10])=O)[S:5][CH:6]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1.[C:15](O)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:3]=[C:4]([C:7]2[N:14]([CH:11]3[CH2:13][CH2:12]3)[CH:15]=[N:10][N:9]=2)[S:5][CH:6]=1
Reactant: NC1CC1
Reactant: CC(=O)O
Reactant: NNC(=O)c1nc(Br)cs1
Solvent: Cc1ccccc1
Product: Brc1csc(-c2nncn2C2CC2)n1
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
The 4-bromothiazole-2-carbohydrazide (620 mg, 2.8 mmol) and toluene (9 mL) were added to a sealable vial, and N,N-dimethylformamide/N,N-dimethylacetamide complex (920 μL, 6.9 mmol) was added. The mixture was stirred for 5 minutes, then cyclopropyl amine (770 μL, 11 mmol), and acetic acid (160 μL, 2.8 mmol) were added, and the reaction was heated in a microwave reactor at 150° C. for 30 minutes. The solvent was removed under reduced pressure, and the residue purified by flash chromatography (1→7% methanol in methylene chloride) to afford 740 mg of 4-bromo-2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazole (contaminated with DMF•DMA, but used directly in next step).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[O:24])[C@H:4]([CH2:25][CH3:26])[CH2:3]1.[C:27](O)(=O)C.[CH3:31][C:32]([CH3:34])=O>ClCCCl>[CH2:25]([C@@H:4]1[CH2:3][C@H:2]([N:1]([CH:32]([CH3:34])[CH3:31])[CH3:27])[CH2:7][CH2:6][C@@H:5]1[N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:9]1=[O:24])[CH3:26]
Reactant: CC(=O)O
Reactant: CC(C)=O
Reactant: CC[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: ClCCCl
Product: CC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 50 °C

Procedure:
The benzyl (S)-1-((1S,2R,4R)-4-amino-2-ethylcyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (assumed 2.2 mmol) was dissolved in 1,2-dichloroethane (27 mL) and the resulting solution was charged successively with acetic acid (0.27 mL), acetone, and NaHB(OAc)3 (1.15 g) before being heated to 50° C. for 18 h. The reaction was concentrated in vacuo and the residue was dissolved in acetonitrile. The resulting solution was charged successively with formaldehyde and sodium cyanoborohydride. The reaction was concentrated in vacuo and purified via flash chromatography to afford benzyl (S)-1-((1S,2R,4R)-2-ethyl-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (607 mg). MS found: (M+H)+=416.3.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([OH:13])([C:9]([F:12])([F:11])[F:10])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[C:16]1([S+:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:35]12([CH2:45][C:46](Cl)=[O:47])[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)[CH2:36]1)[CH2:42]2.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:35]12([CH2:45][C:46]([O:13][C:3]([C:2]([F:1])([F:14])[F:15])([C:9]([F:12])([F:10])[F:11])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6])=[O:47])[CH2:42][CH:41]3[CH2:40][CH:39]([CH2:38][CH:37]([CH2:43]3)[CH2:36]1)[CH2:44]2.[C:29]1([S+:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: O=S(=O)([O-])CC(O)(C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CC12CC3CC(CC(C3)C1)C2)OC(CS(=O)(=O)[O-])(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 120 h
Yield: 48.5 %

Procedure:
Into a mixture solution of 2.6 g (5 mmoles) of triphenylsulfonium 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropane-1-sulfonate prepared in Synthesis Example 1-9, 1.3 g (6 mmoles) of 1-adamantaneacetyl chloride, and 15 g of methylene chloride was added a mixture solution of 0.63 g (6 mmoles) of triethylamine, 0.12 g (1 mmole) of 4-dimethylaminopyridine, and 5 g of methylene chloride, and they were stirred at room temperature for 5 days. Thereafter, the reaction was terminated by adding 7 g of 5% hydrochloric acid, and then the organic layer was separated, washed by water, and concentrated under reduced pressure. Into the concentrated solution was added methyl isobutyl ketone, and the resulted mixture was concentrated again under reduced pressure to distil the remaining water out. The obtained residue was recrystallized by adding diisopropyl ether, and then the crystals were recovered and dried to obtain the intended triphenylsulfonium 2-(2-adamantane-1-yl-acetoxy)-3,3,3-trifluoro-2-trifluoromethylpropane-1-sulfonate (1.7 g of white crystals (yield 48%)). The structure of the intended product is shown below.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]([Br:13])[C:3]=1[NH:4][N+:5]([O-:7])=[O:6].[OH-].[Na+].CO.Br[CH2:19][C:20]#[CH:21]>O>[Br:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]([Br:13])[C:3]=1[N:4]([N+:5]([O-:7])=[O:6])[CH2:21][C:20]#[CH:19]
Reactant: O=[N+]([O-])Nc1c(Br)cc(Br)cc1Br
Reactant: C#CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CCN(c1c(Br)cc(Br)cc1Br)[N+](=O)[O-]
Reaction time: 16 h

Procedure:
2,4,6-tribromo-N-nitroaniline (5.0 g; 0.01334 mol) is reacted with a methanolic solution of sodium hydroxide (0.53 g; 0.01324 mol) in the presence of methanol (60 ml). The solvent is then removed, and the residue dried. The thus obtained sodium salt is dissolved in dimethyl sulfoxide (DMSO) and reacted with 3-bromopropyne (1.52 g; 0.0147 mol) at 25° C. The reaction mixture is stirred 16 hours and then poured into water. The title product is extracted with ether (3×125 ml), the combined extract washed with water, dilute sodium hydroxide, water and brine. The ethereal solution is then dried over magnesium sulfate and the solution concentrated to afford the product, mp. 58°-58.5° C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17].[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH2:29]2.N1CCCCC1>C(O)C>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])/[C:29]/2=[CH:15]\[C:12]1[NH:11][C:7]2[CH2:8][CH2:9][CH2:10][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:18][N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:5](=[O:17])[C:6]=2[C:13]=1[CH3:14].[OH:1][CH:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][CH:12]=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CCC2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CCC2
Product: Cc1c[nH]c2c1C(=O)N(CC(O)CN1CCOCC1)CCC2
Temperature: 45 °C
Reaction time: 16 h
Yield: 249.4 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexa hydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (40 mg, 0.12 mmol 1) and 5-chloro-1,3-dihydro-indol-2-one (20 mg, 0.12 mmol) were dissolved in 1.5 ml of ethanol, and added with 6 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at 45° C. for 16 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (1 ml×2) and dried to obtain the title compound (S,Z)-2-(5-chloro-2-oxoindolin-3-ylidene)methyl)-5-(2-hydroxy-3-morpholinoprop yl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 79 (46 mg, yield 79%) as a yellow solid
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13](O)=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[Cl:16]C1C=CC(OS([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=O)=CC=1.CN(C)C=O>N1C=CC=CC=1>[ClH:16].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:26][C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Reactant: O=S(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N=C(N)N1CCC(CCC(=O)Oc2ccc(Cl)cc2)CC1
Yield: 79.4 %

Procedure:
A mixture of 1.5 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 7.7 g of bis-(p-chlorophenyl)sulfite was stirred at room temperature for 30 minutes in a solution of 12 ml of dry dimethylformamide and 6 ml of dry pyridine. The solvent was removed under reduced pressure, and ether was added to the residue to give crystals. The crystals were washed with ether twice and then with ethyl acetate and recrystallized from methanol-ether to obtain 1.75 g (yield: 79.5%) of p-chlorophenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 173° to 176° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:10]([CH2:11][CH2:12][OH:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[CH3:15][N:16](C=O)C>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[OH:13][CH2:12][CH2:11][CH:10]1[C:5]2[CH:4]=[CH:3][C:2]([C:15]#[N:16])=[CH:14][C:6]=2[CH2:7][CH2:8][O:9]1
Reactant: OCCC1OCCc2cc(Br)ccc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)CCOC2CCO

Procedure:
2-(6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (1.3 g, 5.1 mmol), zinc cyanide (0.36 g, 3 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.23 g, 0.20 mmol) were stirred in degassed DMF (20 mL) under nitrogen at reflux for 9 h. The reaction mixture was diluted with toluene and washed with 2M aqueous ammonia, the aqueous layer further extracted with ethyl acetate, then the combined organic extracts washed with brine. The organic extracts were dried (MgSO4), filtered and evaporated in vacuo. Purification by flash chromatography on silica, eluting with ethyl acetate/hexane (30:70 to 0:100), yielded the title compound as a light brown oil.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O.C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][N:24]([CH2:40][CH2:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:23][CH2:22]2)=[CH:10][CH:9]=1
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(CCCc2ccccc2)CC1
Temperature: 67.5 °C
Reaction time: 1.5 h

Procedure:
To 1.25 mL of an N,N-dimethylformamide solution containing 70 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 57 mg of potassium carbonate and 0.25 mL of an N,N-dimethylformamide solution containing 31 μL of (3-bromopropyl)benzene were added at room temperature, and stirred at 60-75° C. for 1.5 hours. After the reaction mixture was cooled to the room temperature, ethyl acetate and water were added. The organic layer was separated, and the mixture was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 81 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-(3-phenylpropyl)piperidine-4-carboxylate as a yellow oil.