Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39]C1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH:26]2[CH2:39][CH2:40][C:41]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:37]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCc2ccccc2C1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC4CCc5ccccc5C4)c(C)c3C)c2cc1OC
Yield: 71.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1,2,3,4-tetrahydro-2-naphthalenol (34 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (55 mg, yield 69%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH:22]([F:43])[CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[C:33]3[CH2:35][NH:36][CH2:37][CH2:38][C:32]3=[N:31][C:30]=2[NH:39][CH:40]([CH3:42])[CH3:41])[CH2:25][CH2:24]1.C(N(CC)CC)C>C(Cl)Cl>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH:22]([F:43])[CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[C:33]3[CH2:35][N:36]([C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH2:37][CH2:38][C:32]3=[N:31][C:30]=2[NH:39][CH:40]([CH3:41])[CH3:42])[CH2:25][CH2:24]1.[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CNCC2
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CN(C(=O)N(C)C)CC2
Reaction time: 1 h

Procedure:
Dimethylcarbamic chloride (8.4 mg, 0.078 mmol) was added to a solution of 3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (20.8 mg, 0.039 mmol) and triethylamine (16 μL, 0.117 mmol) in DCM (390 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (20.8 mg, 88%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.31 (dd, J=6.6, 1.8 Hz, 6H), 1.40-1.48 (m, 1H), 1.58-1.78 (m, 2H), 1.95-2.03 (m, 1H), 2.03-2.18 (m, 1H), 2.71-2.88 (m, 4H), 2.90 (s, 6H), 3.42-3.52 (m, 2H), 3.54 (t, J=5.7 Hz, 2H), 4.07-4.16 (m, 1H), 4.22-4.27 (m, 2H), 5.53 (dd, J=46.5, 7.3 Hz, 1H), 6.97-7.08 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]+ 491.4.
Reaction SMILES: C([C:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=CC=1)#N.[H-].[Na+].C[N:19]1[C:23](=O)[CH2:22][CH2:21][CH2:20]1.[CH3:25]I>O>[C:23]([C:22]1[C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]([CH3:3])([CH3:25])[C:7]=2[CH:6]=[CH:20][CH:21]=1)#[N:19]
Reactant: CI
Reactant: CN1CCCC1=O
Reactant: N#Cc1cccc2c1-c1ccccc1C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC1(C)c2ccccc2-c2c(C#N)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4.25 g of 4-cyanofluorene, 2.6 g of sodium hydride (60% in oil) and 50 ml of NMP are stirred at room temperature for 2 hours. Then, 9.3 g of methyl iodide are added to the reaction mixture drop-wisely and stirred for an additional 2 hours at room temperature. The reaction mixture is poured into 100 ml of water and filtered. The crude product is purified by column chromatography, giving 3.9 g (80%) of 4-cyano-9,9-dimethylfluorene.
Reaction SMILES: [O:1]1[CH2:10][CH:2]1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O-][C:12]#[N:13].[K+].[OH2:15]>CN(C=O)C>[CH2:3]([CH:2]1[O:1][C:10](=[O:15])[NH:13][CH2:12]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#C[O-]
Reactant: c1ccc(CC2CO2)cc1
Reactant: O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NCC(Cc2ccccc2)O1
Yield: 36 %

Procedure:
2,3-Epoxypropylbenzene (60 g, 448 mmol) and potassium cyanate (70 g, 364 mmol) were refluxed in DMF (600 ml) and water (300 ml) for 4 hours. The solvent was evaporated in vacuo and water added. The aqueous was then extracted with ethyl acetate, dried (Mg SO4) and evaporated. Recrystallization from ethyl acetate gave the product (28.2 g, 36%) Mpt 106°-107° C. MS (EI) 177 (M+), 133, 86.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([CH2:21][O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])C1C=CC=CC=1.[H][H].C(Cl)Cl.CO>C(O)C.CO.Cl.[Pd]>[Si:23]([O:22][CH2:21][C@@H:10]([O:11][CH2:12][P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])[CH2:9][OH:8])([C:36]([CH3:38])([CH3:39])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOP(=O)(CO[C@@H](COCc1ccccc1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CCOP(=O)(CO[C@@H](CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Temperature: 25 °C
Yield: 85.1 %

Procedure:
To a solution of diethyl (S)-[2-benzyloxy-1-(t-butyldiphenylsilyloxymethyl)ethoxy]methylphosphonate (1.90 g, 3.3 mmol) in ethanol (20 ml) containing a trace of methanol/HCl (10 drops), was added 10%Pd-C (1.2 g). The mixture was shaken under an atmosphere of hydrogen at ambient temperature and atmospheric pressure until hydrogen uptake was complete and t.l.c. (SiO2, CH2Cl2 -MeOH, 95:5) indicated no starting material remained. The reaction mixture was filtered, the filtrate evaporated and the residue obtained chromatographed on silica gel (dichloromethanemethanol, 95:5 as eluant) to give the title compound as a colourless oil (1.35 g, 84%).
Reaction SMILES: CNC([N:5]([S:14]([CH3:17])(=[O:16])=[O:15])[N:6]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][CH2:8]Cl)=O.[OH:18]CCNN.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[CH3:13][S:10]([N:6]([CH2:7][CH2:8][O:25][S:24]([CH3:23])(=[O:26])=[O:18])[NH:5][S:14]([CH3:17])(=[O:16])=[O:15])(=[O:12])=[O:11]
Reactant: CNC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O
Reactant: NNCCO
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NN(CCOS(C)(=O)=O)S(C)(=O)=O
Yield: 10 %

Procedure:
A three-step process with a total yield less than 10% has been previously reported published in the following patents and journal articles: U.S. Pat. No. 5,637,619 (Jun. 10, 1997 for VNP40101M); U.S. Pat. No. 4,684,747 (Aug. 4, 1987 for intermediate VNP4090CE); WO97/02029 (Jan. 23, 1997); Journal of Medicinal Chemistry, 1990, 33(8): 2259-2264; Journal of Medicinal Chemistry, 1996, 39(3): 796-801, as illustrated in FIG. 1. 2-Hydroxyethylhydrazine (HEH) was used a starting material and reacted with methanesulfonyl chloride to obtain 1,2-bis(methylsulfonyl)-1-[2-(methylsulfonyloxy)ethyl]hydrazine (BMH) at −20° C. for 18 hours, using pyridine as base. The crude intermediate BMH was treated with lithium chloride in acetone under reflux for 3 days to afford 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (VNP4090CE). After purification by flash column chromatography, an approximately 20% yield was reached for the two steps. VNP4090CE was condensed with methyl isocyanate at room temperature using triethylamine (TEA) as a base. After crystallization from ethanol, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylcarbamoyl)hydrazine (VNP40101M) with an approximately 42% yield. The total yield of this process was less than 10%. It is noted that the process used methyl isocyanate, which is extremely dangerous for manufacturing in scaleup kilogram amounts. For this reason, the present inventors investigated the synthesis and have developed new methods to prepare VNP40101M.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.N([O-])=O.[Na+].[BrH:17]>O.[Cu]Br>[Br:17][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: Br
Reactant: Nc1ccc2c(c1)CCCC2=O
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CCCc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-amino-3,4-dihydro-2H-naphthalen-1-one (20.5 g, 127 mmol) in 25% HBr (aq) (1017 ml) at 0° C. was added a solution of sodium nitrite (10.53 g, 153 mmol) in water (50 ml) dropwise at a rate as to maintain the temperature below 3°. The cooled reaction mixture was then added to a cooled solution of copper(I) bromide (18.79 g, 131 mmol) in HBr (98 ml, 865 mmol). When the addition was done, the reaction mixture was stirred at 0° C. for 1 h, then warmed to rt. Water (380 mL) was added and the product was extracted with a mixture of Et2O/EtOAc (8:2, 3×). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give a dark brown crude oil. The crude was purified by distillation (3 mm Hg) to give 16.415 g of 6-bromo-3,4-dihydro-2H-naphthalen-1-one.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)=[CH:25][CH:24]=1)[CH3:21]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: CCOc1ccc(-c2nc(Nc3cc[nH]n3)cc3cc(OC)ccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-ethoxy-phenylboronic acid to give [1-(4-ethoxy-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[N:15][CH:14]=2)=[N:8]1.O1CCCC1.CO.[OH-].[Na+]>C(OCC)(=O)C>[CH3:1][Si:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[N:15][CH:14]=2)=[N:8]1
Reactant: COC(=O)c1cncc(Nc2ccn(COCC[Si](C)(C)C)n2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc(Nc2cncc(C(=O)O)n2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of 52 mg of methyl 6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carboxylate, 0.5 ml of tetrahydrofuran and 1 ml of methanol was added an aqueous sodium hydroxide solution (1.0 M, 0.5 ml), followed by stirring at room temperature for 15 hours. The obtained reaction solution was diluted with ethyl acetate, and then washed with aqueous ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and filtrate was concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.B(F)(F)F.[CH2:23](O)CC>C(N(CC)CC)C>[CH2:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[CH:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])[CH2:1][CH3:23]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CCCO
Agent: FB(F)F
Solvent: CCN(CC)CC
Product: CCCOCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1

Procedure:
Using the procedure of Step A of Example 8, 27.2 g of 7-amino-cephalosporanic acid, 170 ml of the etherate of of boron trifluoride, 131 ml of propanol and 128 ml of triethylamine were reacted to obtain 17.4 g of raw product which was purified with hot hydrochloric acid and ammonium hydroxide to obtain 7.45 g of 3-propoxymethyl-7-amino-ceph-3-eme-4-carboxy-lic acid.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:14]2[NH:13][C:12](=[O:15])[N:11](C(OC(C)(C)C)=O)[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].O>CN(C)C=O>[CH2:27]([N:13]1[C:14]2[C:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[CH:7][CH:8]=[CH:9][C:10]=2[NH:11][C:12]1=[O:15])[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: CCC(CC)c1cccc2c1[nH]c(=O)n2C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)[nH]c2cccc(C(CC)CC)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a solution of tert-butyl 4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (Reference Example 7; 30.4 g, 100 mmol) in N,N-dimethylformamide (300 mL) was added sodium hydride (60% dispersion in mineral oil, 4.80 g, 120 mmol) portionwise at 0° C. After stirring for 30 min, allyl bromide (10.4 mL, 120 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 16 hours. Water was added to the mixture, which was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in ethyl acetate (300 mL) and 4N hydrogen chloride solution in ethyl acetate (300 mL) was added. After stirring for 70 hr, the mixture was concentrated in vacuo to give a solid which was washed with n-hexane to afford the title compound (22.2 g, 90.6 mmol, 91%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][C:3]=1[CH2:4][C:5]1[NH:13][C:12]2[C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:9](=[O:24])[N:8]([CH3:25])[C:7]=2[N:6]=1.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][N:13]2[C:12]3[C:11](=[O:14])[N:10]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[C:9](=[O:24])[N:8]([CH3:25])[C:7]=3[N:6]=[C:5]2[CH2:4][C:3]2[CH:26]=[C:27]([O:30][C:31]([F:32])([F:34])[F:33])[CH:28]=[CH:29][C:2]=2[F:1])=[CH:38][CH:39]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COc1ccc(Cn2c(=O)c3[nH]c(Cc4cc(OC(F)(F)F)ccc4F)nc3n(C)c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3c(nc(Cc4cc(OC(F)(F)F)ccc4F)n3Cc3ccc(Cl)cc3)n(C)c2=O)cc1
Temperature: 60 °C
Yield: 84.3 %

Procedure:
To a solution of 8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (67 mg, 0.14 mmol) in DMF (3 mL) was added 1-(bromomethyl)-4-chlorobenzene (43.2 mg, 0.21 mmol) followed by potassium carbonate (38.7 mg, 0.28 mmol). The reaction was heated to 60° C. for 3 h. The reaction was partitioned between ethyl acetate and brine. The organic phase was dried and concentrated to give a crude product, which was purified by silica gel chromatography eluting with DCM/methanol (60:1) to give 7-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (71.2 mg, 84.3% yield) as a white solid. LCMS retention time 2.375 min; LCMS MH+ 603.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[CH2:26]Br>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[CH2:26][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Clc1cc(Cl)cc(CBr)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(Cl)cc(Cl)c2)c1
Yield: 63.6 %

Procedure:
5-isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-dichlorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (283 mg, yield: 63.6%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=[C:11]([CH3:21])[C:10]=2C(O)=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[NH2:39][C:10]1[C:11]([CH3:21])=[N:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(-c2ccccc2)cc(-c2cccc(C#N)c2)c1C(=O)O
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccccc2)cc(-c2cccc(C#N)c2)c1N
Temperature: 80 °C
Reaction time: 7.5 h
Yield: 38.7 %

Procedure:
A mixture of 4-(3-cyanophenyl)-2-methyl-6-phenyl-3-pyridinecarboxylic acid (3.7 g), diphenylphosphoryl azide (3.24 g), triethylamine (1.19 g) and t-butanol (35 ml) was refluxed for 5 hours. After the organic solvent was evaporated, chloroform (40 ml) and a saturated aqueous solution of sodium bicarbonate (40 ml) were added to the residue. The separated organic layer was washed with water and brine, dried and concentrated in vacuo. The residue containing 3-(t-butoxycarbonylamino)-4-(3-cyanophenyl)-2-methyl-6-phenylpyridine was dissolved with ethanol (35 ml). After conc. hydrochloric acid (2 ml) was added to the solution at 0° C., the mixture was stirred at 0° C. for 1.5 hours and further at 80° C. for 7.5 hours. The mixture was concentrated, dissolved with chloroform (40 ml) and water (40 ml) and adjusted to pH 9 with 5N sodium hydroxide. The organic layer was separated, washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel (70 g) eluting with a mixture of chloroform and methanol (100:1 V/V). The fractions containing the desired compound were combined and concentrated in vacuo. The residue was triturated with diethyl ether to give 3-amino-4-(3-cyanophenyl)-2-methyl-6-phenylpyridine (1.30 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C@H:12]1[CH2:31][N:15]2[C:16](=[O:30])[N:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH2:18][C@@H:14]2[CH2:13]1.CCN(C(C)C)C(C)C.O>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C@H:12]1[CH2:31][N:15]2[C:16](=[O:30])[N:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=3)[CH2:18][C@@H:14]2[CH2:13]1)=[O:5]
Reactant: N[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
2-Chloro-benzoyl chloride (40.5 mg, 0.23 mmol) was dropped into a solution of (6R,7aS)-6-Amino-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (70 mg, 0.23 mmol) and DIPEA (23 mg, 0.23 mmol) in anhydrous dichloromethane (3 mL), the mixture was stirred at room temperature for 4 hours. Then the mixture was poured into water (10 mL) extracted with ethyl acetate (3×10 mL), the organic layers was combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to give 85 mg (83%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.70-7.67 (m, 1H), 7.60 (d, 2H, J=9.3 Hz), 7.43-7.32 (m, 3H), 7.20 (d, 2H, J=9.0 Hz), 6.49 (d, 1H, J=6.6 Hz), 4.76-4.68 (m, 1H), 4.26 (dd, 1H, J1=12.6 Hz, J2=7.2 Hz), 4.18-4.02 (m, 2H), 3.76 (dd, 1H, J1=9 Hz, J2=2.1 Hz), 3.13 (dd, 1H, J1=12.9 Hz, J2=3.3 Hz), 2.35-2.28 (m, 1H), 1.93-1.83 (m, 1H); LC-MS: 440.1 [M+1]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[CH3:28]>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:21][C:20]=1[CH3:28]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: Cc1cc(B(O)O)ccc1F
Product: Cc1cc(-c2cc(C#N)cc3cc4n(c23)CCNC4=O)ccc1F

Procedure:
The title compound, off-white solid (69 mg, 86%), MS (ISN) m/z=320.4 [(M+H)+], mp 290° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: [OH-].[Na+].O.[NH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1.C(Cl)(=O)OCC.[C:22](=S)=[S:23]>>[N:4]([CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10]1)=[C:22]=[S:23]
Reactant: S=C=S
Reactant: CCOC(=O)N1CCC(N)CC1
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)N1CCC(N=C=S)CC1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred and cooled mixture of 4 parts of sodium hydroxide in 60 parts of water were added successively 7.9 parts of carbon disulfide and 17.2 parts of ethyl 4-amino-1-piperidinecarboxylate at a temperature below 10° C. Stirring was continued for 30 minutes at this temperature. Then there were added dropwise 10.9 parts of ethyl carbonochloridate (exothermic reaction: temp. rises to about 35° C.). Upon completion, stirring was continued for 2 hours at 60° C. The reaction mixture was cooled and the product was extracted with methylbenzene. The extract was dried, filtered and evaporated, yielding 22 parts (100%) of ethyl 4-isothiocyanato-1-piperidine-carboxylate as a residue (intermediate 26).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[OH2:25].Cl>N1C=CC=CC=1>[S:20]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][O:13][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:21])=[O:25])([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCOCCOCCO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
To a solution of 1.64 g (8.44 mmol) of tetraethylene glycol in dry pyridine (30 ml) was added 3.55 g (18.6 mmol) of p-toluenesulfonyl chloride in an atmosphere of argon, and the mixture was allowed to react at room temperature for 15 hours. To the solution was added water followed by addition of conc. hydrochloric acid to adjust the pH to 4, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane-methanol (100:1) yielded 3.78 g (7.52 mmol) of O,O'-ditosyl-3,6,9-trioxaundecane-1,11-diol.