Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9]/[C:8](=[CH:11]/[C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=O)/[CH:7]=[C:6]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH3:3].C1CCC(N=C=NC2CCCCC2)CC1.O[CH:45]1[CH2:50][C:49](=O)[NH:48][C:46]1=O.C(NCC)C.[Cl-].[Na+]>CN(C)C=O>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9]/[C:8](=[CH:11]/[C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([N:48]([CH2:49][CH3:50])[CH2:46][CH3:45])=[O:17])/[CH:7]=[C:6]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH3:1]
Reactant: COc1cccc(C2=C/C(=C\c3cccc(C(=O)O)c3)CCC2CN(C)C)c1
Reactant: O=C1CC(O)C(=O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cccc(/C=C2\C=C(c3cccc(OC)c3)C(CN(C)C)CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
1.8 g of the Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid base prepared according to example 4 were dissolved in 50 ml analytical grade dimethylformamide, and 2 g DCC and 1.1 g hydroxysuccinimide were added at 0° C. to 15° C. The mixture was stirred at 0° C. for one hour and 2 ml diethylamine were then added dropwise at this temperature. The mixture was stirred at 0° C. for an additional hour and then at room temperature for four days. The reaction mixture was poured on to 300 ml saturated sodium chloride solution and the mixture was then extracted 3 times with 250 ml ethyl acetate each time. The organic phases were washed with 50 ml saturated sodium chloride solution and then dried over magnesium sulfate. The solvent was removed in vacuo. The residue was chromatographed on silica gel with ethyl acetate/methanol=6/5. 0.87 g Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-N,N-diethyl-benzamide base was obtained in this way in the form of an orange-yellow oil. To liberate the hydrochloride, the oil was dissolved in 5 ml acetone, and an equimolar amount of trimethylchlorosilane and water was added. 0.52 g (22.1% of theory) of the title compound 34 was obtained in this way in the form of white crystals.
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[C:11]1[C:12]2[N:13]([CH:25]=[N:26][N:27]=2)[C:14](SC)=[N:15][C:16]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[CH2:28]([C@H:35]1[CH2:40][NH:39][CH2:38][CH2:37][NH:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH2:28]([C@@H:35]1[NH:36][CH2:37][CH2:38][N:39]([C:14]2[N:13]3[CH:25]=[N:26][N:27]=[C:12]3[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[N:15]=2)[CH2:40]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c2nncn12
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Solvent: CN(C)C=O
Product: c1ccc(C[C@H]2CN(c3nc(-c4ccncc4)c(-c4ccc5ccccc5c4)c4nncn34)CCN2)cc1
Temperature: 100 °C

Procedure:
8-(2-naphthyl)-5-methylthio-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidine (200 mg, 0.54 mmol), K3CO3 (100 mg) and (S)-2-benzylpiperazine (170 mg, 0.97 mmol) were combined in dry DMF (ca. 4 mL) and the mixture was heated at 100° C. for 48 h. The reaction was cooled to RT, and partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4 and then concentrated in vacuo. The residue was purified by flash chromatography (2-8% MeOH/NH3:CH2Cl2) to provide the product as a tan solid; MS (m/z) 498.3 (M+H)+; C31H27N7 requir. 497.59.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17]P(OC)(OC)=O)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25](C)[C:26](=N)[N:27]([CH3:29])C.N1C=CN=C1C=O>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:26]1[NH:25][CH:24]=[CH:29][N:27]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(CP(=O)(OC)OC)NC(=O)OCc1ccccc1
Reactant: CN(C)C(=N)N(C)C
Agent: O=Cc1ncc[nH]1
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1ncc[nH]1)NC(=O)OCc1ccccc1
Temperature: -40 °C
Yield: 40 %

Procedure:
A mixture of methyl 2-{[(benzyloxy)carbonyl]amino}-3-(dimethoxyphosphoryl)-propanoate (1 g, 30 mmol) in tetrahydrofuran (7 ml) was stirred at −40° C. and tetramethylguanidine (380 mg, 33 mmol) was added. The reaction mixture was stirred at −40° C. for 20 minutes and then imidazole-2-carboxaldehyde (317 mg, 33 mmol) was added. The reaction was then allowed to warm to room temperature and was stirred at room temperature for 18 h. The solvent was then removed by evaporation under reduced pressure and the residue dissolved in ethyl acetate and washed with water and then brine. The organic phase was then dried (MgSO4), filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of ethyl acetate:pentane (30:70 to 80:20), to give the title compound, 366 mg, 40% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4].[C:27]12[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=1)[NH:32]C(=O)O[C:28]2=[O:29].CCCCCC>C1(C)C(C)=CC=CC=1>[NH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:27]=1[C:28]([NH:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4])=[O:29]
Reactant: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: Nc1ccccc1C(=O)NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A mixture of (3aR*,l0aS*)-4-(aminoacetyl)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta [e][1,4]diazepin-10(1H)-one (420 mg, 1.2 mmol) and isatoic anhydride (196 mg, 1.2 mmol) was stirred for 30 minutes in xylene at 140° C. The reaction mixture was left standing for cooling at room temperature, to which was added hexane (5 mL). The resulting solid was collected by filtration, which was recrystallized from ethanol-hexane to give 345 mg (yield 58%) of the titled compound. This compound was in good agreement in
Reaction SMILES: [CH3:1][C:2]([N+:15]([O-:17])=[O:16])([CH3:14])[CH:3](O)[C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1.S(Cl)([Cl:20])=O.C>C1C=CC=CC=1>[CH3:1][C:2]([N+:15]([O-:17])=[O:16])([CH3:14])[CH:3]([Cl:20])[C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C(O)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Agent: C
Solvent: c1ccccc1
Product: CC(C)(C(Cl)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Yield: 69.4 %

Procedure:
A solution of 242.8 g (1.016 moles) of 1,1-dimethyl-2-hydroxy-2-(3,4-methylenedioxyphenyl)nitroethane in 500 ml of benzene was treated with 139 g (84 ml, 1.17 moles) of thionyl chloride, after which the mixture was refluxed for 4 hours, cooled slightly and concentrated to a dark yellow oil which crystallised on cooling and seeding. The resulting solid was broken up and dispersed in 150 ml of 2-propanol after which it was separated, washed twice with cold 2-propanol and dried to give crude 1,1-dimethyl-2-chloro-2-(3,4-methylenedioxyphenyl)nitroethane as a light yellow solid, m.p. 63°-66° C (Yield 230.9 g). A 201.3 g portion of the crude product was treated with "Darco" (Trade Mark) and recrystallised from 402 ml of SDA-30 to give 181.6 g (79.6%) of the pure product as a white solid, m.p. 65°-67° C.
Reaction SMILES: [I:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](Cl)=[O:8].CCN(C(C)C)C(C)C.[F:19][C:20]([F:24])([F:23])[CH2:21][NH2:22]>O1CCCC1>[I:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([NH:22][CH2:21][C:20]([F:24])([F:23])[F:19])=[O:8]
Reactant: NCC(F)(F)F
Reactant: O=C(Cl)c1ccoc1I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(F)(F)F)c1ccoc1I
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a stirred solution of 2-iodofuran-3-carbonyl chloride (6.69 g, 26.1 mmol) in anhydrous tetrahydrofuran (120 ml) was added DIPEA (9.11 ml, 52.2 mmol) followed by 2,2,2-trifluoroethanamine (2.08 ml, 26.1 mmol) and the solution stirred for 1 h. The mixture was concentrated in vacuo. The residue was partitioned between 2M hydrochloric acid (aq) solution (100 ml) and dichloromethane (100 ml). The aqueous layer was separated and extracted with dichloromethane (2×100 ml). The combined organic layers were dried (phase separator) and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (gradient 0-50% ethyl acetate in cyclohexane) to afford the title compound (4.38 g, 53%). LCMS RT=0.98 min, M+H+=319.9.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][NH2:37]>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][NH:37][CH2:36][CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CN(C)CCCN
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CNCCCN(C)C)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 75 step ii) using the product of Example 75 step i) and N1,N1-dimethyl-propane-1,3-diamine.
Reaction SMILES: CS[C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[S:4][CH3:5].[CH3:11][NH:12][NH2:13]>O>[NH2:8][C:7]1[C:6]([C:9]#[N:10])=[C:3]([S:4][CH3:5])[N:12]([CH3:11])[N:13]=1
Reactant: CSC(SC)=C(C#N)C#N
Reactant: CNN
Solvent: O
Product: CSc1c(C#N)c(N)nn1C
Reaction time: 1 h

Procedure:
9.63 g (56.6 mmol) [Bis(methylmercapto)methylene]-malononitrile was suspended in 50 ml water and treated with 3.7 ml (67.9 mmol) methylhydrazine. The mixture was heated at boiling for 1 hour, the reaction solution cooled, the precipitate suction filtered and recrystallised from ethanol.
Reaction SMILES: C([Li:5])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1>CCCCCC>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([Li:5])[CH:11]=[CH:12][CH:13]=1
Reactant: [Li]CCCC
Reactant: COc1cccc(Br)c1
Solvent: CCCCCC
Product: [Li]c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 159 ml. of n-butyllithium in 100 ml. of hexane containing 47.7 g. of 3-methoxybromobenzene was stirred at -25° C. for twenty minutes and then was warmed to room temperature and stirred for one hour to provide 3-methoxyphenyl lithium. The reaction mixture was chilled to 10° C. and stirred while a solution of 50 g. of 1-methyl-4-piperidone in 100 ml. of diethyl ether was added dropwise over thirty minutes. Following complete addition, the reaction mixture was stirred for two hours, and then was diluted with 50 ml. of saturated aqueous sodium chloride solution. The solution was extracted several times with diethyl ether, and the ethereal extracts were combined and concentrated to dryness to provide 38 g. of 1-methyl-4-hydroxy-4-(3-methoxyphenyl)piperidine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41]1([CH2:47][CH2:48][CH2:49][O:50][NH2:51])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:15])[NH:51][O:50][CH2:49][CH2:48][CH2:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NOCCCc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NOCCCc1ccccc1
Yield: 44.4 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and 3-phenylpropoxyamine (41 mg, 0.22 mmol) according to Method C with HPLC purification to give the title compound (53 mg). 1H-NMR (400 MHz, CD3OD) d 7.57 (s, 1H), 6.94 (d, J=8.3 Hz, 1H), 4.28 (m, 1H), 3.65 (m, 2H), 3.04 (dd, J=4.9 Hz, J=13.9 Hz, 1H), 2.97 (m, 1H), 2.73 (dd, J=9.6 Hz, J=13.8 Hz, 1H), 2.65 (t, J=7.7 Hz, 2H), 1.78 (m, 2H), 1.37 (s, 3H), 1.36 (s, 6H); IR (KBr) 3293, 2949, 1681, 1651 cm−1; HRMS m/z 663.2806 (calc. of monoisotopic mass for C35H41N3O10 gives 663.2792).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)([O-])=O.N1C=CC=CC=1>C(O)C>[NH2:8][C:11]1[CH:19]=[CH:18][C:14]([C:15]([N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH2:3]2)=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1cccnc1
Solvent: c1ccncc1
Solvent: CCO
Product: NC1=CC=CN(C(=O)c2ccc(N)cc2)C1

Procedure:
3-Aminopyridine, 60, is first reacted with 4-nitrobenzoyl chloride in the presence of pyridine at 80° C. (step 1) and the product, 62, is subsequently hydrogenated in the presence of ethanol (step 2) to give N-(p-aminobezoyl) -3-aminopyridine, 64. In a separate reaction, 2,5-dimethyl-1,4-phenylenediamine, 66, is converted to 2,5-dimethyl-1,4-dinitrobenzene in a "reverse" Sandmeyer reaction with isoamyl nitrite and acetic acid (step 3), and subsequently treated with copper sulfate in the presence of sodium nitrite (step 4) to produce the intermediate, 68. This intermediate, 68, is oxidized with CrO3 and chlorinated with SOCl2 (step 5) to give 2,5-dinitroterephthaloyl chloride 70. One equivalent of N-(p-aminobezoyl)-3-aminopyridine, 64, and 0.5 equivalent of 2,5-dinitroterephthaloyl chloride, 70, are reacted in pyridine (step 6) to produce a bis-anilide derivative of 2,5-dinitroterephthaloyl chloride 72, and the product is again hydrogenated and activated with isoamyl nitrite (step 7) to yield the final activated product 74.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:19]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[N:31]2[CH:35]=[C:34]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[N:33]=[CH:32]2)[NH:24][N:23]=1)([CH3:21])[CH3:20]>C(#N)C>[CH:19]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[N:31]2[CH:35]=[C:34]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[N:33]=[CH:32]2)[N:24]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[N:23]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1n[nH]c2cccc(-n3cnc(-c4cccnc4)c3)c12
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)c1nn(-c2ccc(C#N)cc2[N+](=O)[O-])c2cccc(-n3cnc(-c4cccnc4)c3)c12
Temperature: 70 °C
Yield: 63.4 %

Procedure:
4-Chloro-3-nitrobenzonitrile (331 mg) and cesium carbonate (700 mg) were added to a solution of compound (1a) (500 mg) in acetonitrile (5.5 mL), and the mixture was stirred under heating at 70° C. for 4 hours. After completion of the reaction, the reaction solution was allowed to standing still for cooling and partitioned between ethyl acetate and water. The organic layer was washed with saturated brine and dried by the addition of anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue was subjected to slurry washing (acetonitrile/methanol), thereby to obtain compound (10a) (470 mg, yield 64%) as a milky white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[CH:19]=[C:7]3[C:6]=2[CH:20]=1.C(=O)(O)[O-].[Na+].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>COCCOCCOC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:27])[CH2:9][N:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[CH:19]=[C:7]3[C:6]=2[CH:20]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1Cn2c(cc3ccccc32)-c2cc(Cl)ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: S=C1Cn2c(cc3ccccc32)-c2cc(Cl)ccc2N1
Yield: 40 %

Procedure:
A mixture of 3.74 g 2-chloroindolo[1,2-d][1,4]benzodiazepin-6(7H)-one, 2.58 g sodium bicarbonate, and 13.67 g P2S5 in 85 ml diglyme was heated at 105°-120° C. under nitrogen for one and a half hours. The cooled reaction mixtre was diluted with water to precipitate a solid. Recrystallization from toluene yielded 1.58 g solid, which decomposed at 265° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[S:36])([CH3:27])[CH3:26]>O1CCCC1>[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([NH:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:23])[F:24])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[S:36])([CH3:27])[CH3:26]
Reactant: NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(C)c1ccccc1N=C=S
Solvent: C1CCOC1
Product: CC(C)c1ccccc1NC(=S)NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
To a solution of (4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine (0.066 g, 0.20 mmol) in tetrahydrofuran (4.0 mL), 1-isopropyl-2-isothiocyanatobenzene (0.048 g, 0.27 mmol) was added. The reaction mixture was stirred in a pre-heated heating block at 80° C. for 4 hours. The reaction mixture was adsorbed onto Celite® and purified via reverse phase chromatography using 5-100% acetonitrile/water as eluent to afford the title compound as a white solid (0.070 g, 68%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.30 (s, 1H), 8.07 (dd, J=9.4, 7.3 Hz, 4H), 7.81 (s, 1H), 7.68-7.58 (m, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.36 (d, J=7.7 Hz, 1H), 7.29 (t, J=7.5 Hz, 1H), 7.21 (dd, J=13.2, 6.1 Hz, 2H), 4.78 (s, 2H), 3.11 (s, 1H), 1.15 (d, J=6.9 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 512 ([M+H]+).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[O:19][C:20](=[O:26])[NH:21][S:22](Cl)(=[O:24])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:27]([C:30]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([CH3:39])[CH3:38])[C:31]=1[NH2:32])([CH3:29])[CH3:28].C(N(CC)CC)C>O1CCCC1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[O:19][C:20](=[O:26])[NH:21][S:22]([NH:32][C:31]2[C:33]([CH:37]([CH3:38])[CH3:39])=[CH:34][CH:35]=[CH:36][C:30]=2[CH:27]([CH3:29])[CH3:28])(=[O:24])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(NS(=O)(=O)Cl)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1NS(=O)(=O)NC(=O)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of [1,1':3', 1"-terphenyl]-2'-yl(chlorosulfonyl)carbamate (5.0 g, 12.9 mmol) in 75 mL tetrahydrofuran was added dropwise to a solution of 2,6-diisopropyl aniline (2.29 g, 12.9 mmol) and triethylamine (1.3 g, 12.9 mmol) in 100 mL tetrahydrofuran at -15° C. under an atmosphere of nitrogen. The resulting mixture was warmed to room temperature and stirred for 16 hours. Concentrated in vacuo and partitioned the residue between water and ethyl acetate. Dried the organic layer over MgSO4 and evaporated to give an off-white solid. Chromatography on silica gel gave the title compound, mp 166°-168° C.
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].Cl[CH2:26][C:27]([N:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[O:28].[H-].[Na+]>>[CH:30]([N:29]([CH:33]([CH3:35])[CH3:34])[C:27](=[O:28])[CH2:26][N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])([CH3:32])[CH3:31]
Reactant: CC(C)N(C(=O)CCl)C(C)C
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CC(=O)N(C(C)C)C(C)C)C2=O)CC1
Yield: 31 %

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), 2-chloro-N,N-diisopropyl-acetamide and sodium hydride, to give the desired product as a white solid (31%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH2:10])[CH3:9])=[N:6][CH:7]=1.Cl[C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][N:13]=1.CCN(C(C)C)C(C)C>CCCCO>[F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH:10][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)[C:15]([C:25]([F:26])([F:28])[F:27])=[CH:14][N:13]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: Cc1cc(Nc2nc(Cl)ncc2C(F)(F)F)n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2C(F)(F)F)n[nH]1
Temperature: 180 °C
Yield: 20.8 %

Procedure:
A microwave reaction vessel was charged with (S)-1-(5-fluoropyrimidin-2-yl)ethanamine (Method 7, 111 mg, 0.63 mmol), 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine (Method 23, 0.50 g, 1.77 mmol), and DIPEA (0.225 mL, 1.26 mmol). Anhydrous n-BuOH (2.1 ml) was added, and the tube was sealed and heated in a microwave reactor at 180° C. for 4 hours.) The solvent was removed under reduced pressure and the residue was purified by Gilson (5-95% MeCN/H2O, 15 minutes) to give the titled compound as solid (50 mg) 1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 2H) 8.16 (s, 1H) 8.08 (s, 1H) 5.77 (s, 1H) 5.13 (m, 1H) 2.12 (s, 3H) 1.43 (d, 3H); m/z 383.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1.B1([O-])OO1.[OH2:15].[OH2:16].O.O.[Na+].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]12[O:15][CH:7]1[CH2:6][CH:5]([C:8]1([CH3:10])[O:16][CH2:9]1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@H]1CC=C(C)CC1
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C2CCC3(C)OC3C2)CO1
Temperature: 60 °C
Reaction time: 12 h
Yield: 96.9 %

Procedure:
Limonene (1.36 g, 10 mmol) was dissolved in toluene (25 ml), and a composition containing sodium perborate tetrahydrate (15.4 g, 100 mmol) and acetic anhydride (10.2 g, 100 mmol) was added thereto. The mixture was stirred at 60° C. After 12 hours, the reaction solution was washed with water to thereby completely remove acetic acid and sodium acetate, which were generated as by-products, and the remaining H2O2. Toluene was distilled off from the organic phase by distillation, and as a result, 1.63 g (97% yields) of limonene diepoxide with a GC purity of 98% was obtained.