Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][CH2:6][CH:5]=1.[C:16](Cl)(=[O:20])[C:17](Cl)=[O:18]>CCOCC>[O:3]1[C:17](=[O:18])[C:16](=[O:20])[C:5]2[CH2:6][S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:4]1=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[Si](C)(C)OC1=CCSc2ccccc21
Solvent: CCOCC
Product: O=C1OC2=C(CSc3ccccc32)C1=O
Yield: 82.3 %

Procedure:
To a stirred mixture of 4-[trimethyl[silyl]oxy]-2H-benzothiopyran (380.5 g,1.609 mol), prepared according to the method of L. Hellberg et al, Tet. Letters, 3553-3554 (1974), and one liter of diethyl ether, were added 103.8 g (0.818 mol) of oxalyl chloride in a dropwise manner over a period of 50 minutes at room temperature under nitrogen. The mixture was stirred at room temperature for 17 hours after which time the ether was removed under reduced pressure. The residue was triturated with isopropyl ether/hexane to give 146.9 g (82.3%) of a brown crystalline solid, mp 156° C. (dec).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)=O.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27].C([BH3-])#N.[Na+]>CO.O.[Cl-].[Zn+2].[Cl-]>[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH:27][CH2:1][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCC(C=O)CC2)cc1
Reactant: CN(C)CCN
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)CCNCC1CCN(c2ccc(NC(=O)OC(C)(C)C)cc2)CC1
Reaction time: 0.17 h
Yield: 106.2 %

Procedure:
To a suspension of tert-butyl [4-(4-formyl-piperidin-1-yl)-phenyl]carbamate (0.30 g, 1.0 mmol) in methanol (5 mL) is added N,N-dimethylethylenediamine (0.18 g, 2.0 mmol). The reaction mixture is stirred for 10 minutes and then a mixture of zinc chloride (82 mg, 0.6 mmol) and sodium cyanoborohydride (75 mg, 1.2 mmol) in methanol (2 mL) is added in a dropwise fashion. After stirring for two hours at room temperature, the reaction mixture is diluted with water and extracted 3× with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give tert-butyl {4-[4-({[2-(dimethylamino)ethyl]amino}methyl)piperidin-1-yl]phenyl}carbamate as a white foam (0.4 g, 100%).
Reaction SMILES: Cl.[C:2]([NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:5])([CH3:4])[CH3:3].[N:13]([O-])=[O:14].[Na+]>O>[N:13]([N:6]([C:2]([CH3:5])([CH3:3])[CH3:4])[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:14]
Reactant: CC(C)(C)NC1CCCCC1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)N(N=O)C1CCCCC1
Temperature: 90 °C

Procedure:
A mixture consisting of 13.2 ml of 10N hydrochloric acid, 50 ml of water, 18.8 g of tert.-butyl-cyclohexyl-amine and 17.9 g of sodium nitrite is heated at 90° C. for 3 hours. On cooling, a solid precipitates and is filtered off with suction. Yield: 16.3 g melting point: 87° C.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].O.NN>CO.[Ni]>[NH:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc(N)cc1

Procedure:
1.688 g (9.38 mmol) p-acetamino nitrobenzene is dissolved in 10 ml of anhydrous methanol. Suitable amount, i.e., 0.1266 g Raney-Ni and 0.83 g (14.1 mmol, 85%) hydrazine hydrate is added to the solution. The mixture is reacted for 6 hours, and then suction filtered. The filtrate is concentrated to give a product, p-acetamino aniline. The yield reaches the theoretical value.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([Cl:20])[C:5]2[O:15][C:9]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:8][C:7](=[O:16])[C:6]=2[C:17]=1[O:18]C.B(Cl)(Cl)Cl.ClCCl.C(OCC)C>CCCCCC>[Cl:1][C:2]1[C:3]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([Cl:20])[C:5]2[O:15][C:9]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:8][C:7](=[O:16])[C:6]=2[C:17]=1[OH:18]
Reactant: CCOC(=O)COc1c(Cl)c(OC)c2c(c1Cl)OC1(CCCCC1)CC2=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)COc1c(Cl)c(O)c2c(c1Cl)OC1(CCCCC1)CC2=O

Procedure:
According to the procedure of Preparation 66 employing ethyl 2-{(6,8-dichloro-5-methoxy-3,4-dihydro-4-oxospiro[2H-1-benzopyran-2,1'-cyclohexan]-7-yl)oxy}acetate (65-1, prepared in Preparation 65) (0.635 g, 1.52 mmol) and 2M boron trichloride solution in dichloromethane (1.7 ml, 3.4 mmol), the title compound is prepared as a crystalline solid (0.60 g, yield 98%). Recrystallizaton from a mixture of diethyl ether and hexane gives a product having a melting point of 134°-135° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)C1C=CC=CC=1.[CH2:30]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=1)[CH:31]=[CH2:32]>>[CH3:42][O:41][C:35]1[CH:34]=[C:33]([CH2:30][CH2:31][CH2:32][C:13]2[CH:12]=[CH:11][C:10]([N:16]3[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:29])[CH2:17]3)=[C:9]([OH:8])[CH:14]=2)[CH:38]=[CH:37][C:36]=1[O:39][CH3:40]
Reactant: C=CCc1ccc(OC)c(OC)c1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: COc1ccc(CCCc2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)cc1OC

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and 4-allyl-1,2-dimethoxybenzene analogous to Example 51: (M−1)−=405.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].Cl.O>C(OCC)(=O)C.Cl[Ti](Cl)(Cl)Cl>[OH:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc(OC)c(C(=O)O)cc1OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(O)c(C(=O)O)cc1OC
Reaction time: 5 h
Yield: 133.3 %

Procedure:
In 30 mL of ethyl acetate was suspended 10 g of the compound (1a) in a stream of argon, to which 6.2 mL of TiCl4 was then added dropwise at 10 to 15° C. under cooling with ice. The reaction mixture was heated to reflux, and stirred for 5 hours. This reaction mixture was cooled, to which 4.9 g of 35% hydrochloric acid was then added dropwise at 24° C. before adding 30 mL of water, followed by heat stirring at 55° C. for one hour. The precipitated crystal was collected by filtration and washed with water to provide 12.45 g of compound (2a) in the form of a wet crystal. The moiety (6.23 g) of the resultant wet crystal was suspended in 15 mL of water, to which 3.52 g of a 25% (w/w) sodium hydroxide aqueous solution was then added dropwise at 18° C., followed by heat stirring at 60° C. for one hour. To the reaction mixture was added 20 mL of ethyl acetate, which was then subjected to liquid-separating operation, followed by dropwise adding 2.19 g of 35% hydrochloric acid to the separated aqueous layer. The precipitated crystal was collected by filtration and washed with water. The resultant crystal was dried under reduced pressure at 60° C. to provide 4.13 g of compound (2a) at a yield of 88%.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[N:4]1.[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:9][C:8]([F:11])([F:10])[C:5]1[N:6]=[CH:7][N:3]([CH2:2][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])[N:4]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(F)(F)c1ncn(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cnc(C(F)(F)F)n1
Yield: 5.7 %

Procedure:
1.56 g of 1-(chloromethyl)-3-(trifluoromethyl)-1H-1,2,4-triazole and 1.38 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 25 ml of N,N-dimethylformamide. 2.35 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.15 g of {[3-(trifluoromethyl)-1H-1,2,4-triazole-1-yl]methyl}(3,3,3-trifluoropropyl)malononitrile (referred as the compound of the present invention (33), hereinafter) shown by below formula.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#N)=[CH:5][CH:4]=1>CO>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH3:7])=[CH:9][CH:10]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: Cc1ccc(C(F)(F)F)cc1
Yield: 91 %

Procedure:
To 4 ml of methanol (3.06 g) was added 0.71 g of p-trifluoromethylbenzonitrile. The solution was added to the reactor at 0.34 ml/min. The product, p-trifluoromethyltoluene, was isolated in a methanol solution in a 91% yield.
Reaction SMILES: O1[CH2:5][CH2:4][NH:3]C1=O.[ClH:7].[F:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].C(O)C>C(OCC)C>[ClH:7].[F:8][C:9]1[CH:10]=[C:11]([NH:12][CH2:5][CH2:4][NH2:3])[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C1NCCO1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: NCCNc1cccc(F)c1
Temperature: 165 °C
Reaction time: 18 h

Procedure:
Equimolar quantities (45.7 mmol) of 2-oxazolidinone and 3-fluoroaniline hydrochloride were combined, heated to 165° C., and stirred for 18 hours. The dark-colored mixture was allowed to cool to ambient temperature and treated with ethanol (125 mL). The suspension was heated to reflux for 1 hour, allowed to cool to ambient temperature, treated with diethyl ether (125 mL), and the suspension was cooled to 0° C. for 2 hours. Filtration provided 5.53 g of the desired product as colorless crystals which were used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:4][C:5]([CH3:20])=[C:6]([CH3:19])[C:7]=1[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[C:28](OCC)(OCC)(OCC)[CH3:29].Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:28][C:29]1[N:8]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:7]2[C:6]([CH3:19])=[C:5]([CH3:20])[N:4]=[C:3]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:2]=2[N:1]=1
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCNC(=O)OC(C)(C)C)c1C
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCNC(=O)OC(C)(C)C)c2c1C
Yield: 100 %

Procedure:
A mixture of tert-butyl 2-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]ethylcarbamate (43.7 g, 117 mmol), triethyl orthoacetate (22.6 mL, 123 mmol), pyridine hydrochloride (4.4 g) and toluene (440 mL) was heated at reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure to provide a brown oil. The oil was dissolved in ethyl acetate (1 L) and washed with water (2×500 mL). The aqueous washes were combined and extracted with ethyl acetate (2×500 mL). The combined organics were washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide 46.4 g of tert-butyl 2-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)ethylcarbamate as a white solid, m.p. 180-182° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:21])([F:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17].[CH3:22][P:23]([CH2:28][OH:29])(=[O:27])[O:24][CH2:25][CH3:26]>C1COCC1>[CH3:22][P:23]([CH2:28][O:29][S:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([F:8])([F:20])[F:21])(=[O:18])=[O:17])(=[O:27])[O:24][CH2:25][CH3:26]
Reactant: CCOP(C)(=O)CO
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)COS(=O)(=O)c1ccccc1C(F)(F)F
Reaction time: 8 h
Yield: 14.5 %

Procedure:
A solution of 8 ml of triethylamine diluted with 25 ml of THF was slowly added dropwise over two hours to a mixture of 11.2 g of 2-(trifluoromethyl)benzenesulfonyl chloride, 6.05 g of O-ethyl P-methyl(hydroxymethyl)phosphinate, (Example 22, Method B), and 60 ml of THF. A white precipitate began to form shortly after the addition of the triethylamine solution was begun. No significant exotherm occurred and the reaction was allowed to stir overnight. The reaction mixture was concentrated and the concentrate was partitioned between 220 ml of ethyl acetate and 50 ml of water. The organic phase was washed with an additional 50 ml of water, dried with magnesium sulfate, gravity filtered, and concentrated to yield an orange solid. The solid was flash chromatographed on silica gel using ethyl acetate to yield 2.2 g of the desired product, melting point 91°-92.5° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[N:4][N:3]=1.[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>N1C=CC=CC=1>[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:1][C:2]2[S:6][C:5]([S:7](=[O:9])(=[O:8])[NH2:10])=[N:4][N:3]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: Nc1nnc(S(N)(=O)=O)s1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1nnc(NC(=O)c2ccc(I)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
To a solution of 5-amino-1,3,4-thiadiazole-2-sulfonamide (0.133 g, 0.50 mmol) in pyridine (5.0 mL) was added 4-iodobenzoyl chloride (0.162 g, 0.75 mmol). The reaction mixture was stirred at room temperature for overnight under nitrogen. Solvent was concentrated and water (60 mL) was added the mixture. The precipitated sulfonamide was filtered and dried over vacuum to give desired compound (27.3 mg, 13%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].O=C1N[C:27]2[CH:29]=[C:30](C)[CH:31]=[CH:32][C:26]=2NCC1NC(OC(C)(C)C)=O>>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:32]2[CH2:31][CH2:30][CH2:29][CH:27]=[CH:26]2)[CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Product: CC(C)(C)OC(=O)NC1CN(C2C=CCCC2)c2ccccc2NC1=O

Procedure:
Step 1 of Referential Example 10 was repeated except that 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine obtained from Referential Example 1 was used instead of 2-oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine, to thereby obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Br[C:17]1[C:18](=[O:25])[N:19]([CH3:24])[CH:20]=[C:21]([Br:23])[CH:22]=1>>[Br:23][C:21]1[CH:22]=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:18](=[O:25])[N:19]([CH3:24])[CH:20]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cn1
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: Cn1cc(Br)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Yield: 21 %

Procedure:
Following Example 136e, 170a and 3,5-dibromo-1-methylpyridin-2(1H)-one were reacted to give 170b in 21% yield. LCMS: (M+H)+ 394. 1H NMR (500 MHz, MeOD) δ 8.84 (d, J=2.5, 1H), 8.42 (d, J=2, 1H), 7.72 (m, 1H), 7.42 (d, J=2, 1H), 7.11 (d, J=8.5, 1H), 3.72 (m, 8H), 3.63 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:12]3[CH2:16][S:15](=[O:18])(=[O:17])[CH2:14][CH:13]3[CH:8]2[C:7]1=[O:19].Cl.[Cl:21][C:22]1[N:27]=[C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[N:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[ClH:21].[Cl:21][C:22]1[N:27]=[C:26]([N:28]2[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH:9]4[CH:12]5[CH2:16][S:15](=[O:18])(=[O:17])[CH2:14][CH:13]5[CH:8]4[C:7]3=[O:19])[CH2:32][CH2:33]2)[CH:25]=[N:24][CH:23]=1
Reactant: O=C1C2C3CS(=O)(=O)CC3C2C(=O)N1CCCCBr
Reactant: Clc1cncc(N2CCNCC2)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1C2C3CS(=O)(=O)CC3C2C(=O)N1CCCCN1CCN(c2cncc(Cl)n2)CC1
Reaction time: 8 h

Procedure:
A solution of 2.0 g of 5-(4-bromobutyl)tetrahydro-1H-thieno-[3',4':3,4]cyclobuta[1,2-c]pyrrole-4,6(3H,5H)dione 2,2-dioxide in 50 ml of dimethylformamide is added to a stirred solution 2.0 g (0.007 mol) of 1-(6-chloro-2-pyrazinyl)-piperazine hydrochloride and 4 ml of triethylamine. The reaction mixture is stirred overnight and the solvent is removed under vacuum. The residue is partitioned between water and methlene chloride. The methylene chloride extracts are combined, washed with brine and dried over anhydrous sodium sulfate. Filtration and roto-evaporation gives the crude free base. Preparative HPLC [silica gel; ethyl acetate:methylene chloride (9:1)] followed by evaporation of the appropriate fractions (TLC Rf=0.4), treatment with ethanolic hydrogen chloride and recrystallization from ethanol gives the title compound: m.p. 154°-157° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.C(N(CC)CC)C.[CH2:16]([N:20]1[C:25]([NH:26][N:27]=[CH:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)=[CH:24][C:23](=[O:39])[N:22]([CH3:40])[C:21]1=[O:41])[CH:17]([CH3:19])[CH3:18]>CN(C)C=O>[CH2:16]([N:20]1[C:25]2=[N:26][N:27]([CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[CH3:1])=[C:24]2[C:23](=[O:39])[N:22]([CH3:40])[C:21]1=[O:41])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)Cn1c(NN=Cc2cccc3ccccc23)cc(=O)n(C)c1=O
Reactant: Cc1ccsc1C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccsc1-c1c2c(=O)n(C)c(=O)n(CC(C)C)c2nn1Cc1cccc2ccccc12
Temperature: 90 °C
Yield: 62.9 %

Procedure:
3-methyl-2-thiophenecarbaldehyde (0.063 g) and triethylamine (0.1 ml) was added to a solution of 1-naphthaldehyde (3-isobutyl-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)hydrazone (0.0875 g) in dimethylformamide (1.5 ml). The solution was heated at 90° C. for 24 hours. Reaction cooled to room temperature and purified on preparative HPLC to give the title compound (0.072 g). Mass: 458.87 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[K+].[I-].[K+].Cl[CH2:11][CH:12]([OH:15])[CH2:13][OH:14]>CC#N>[OH:15][CH:12]([CH2:13][OH:14])[CH2:11][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCC(O)CCl
Reactant: c1c[nH]cn1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: OCC(O)Cn1ccnc1
Temperature: 25 °C
Yield: 96 %

Procedure:
Imidazole (3.40 g, 50.0 mmol), pulverized potassium hydroxide (5.61 g, 100 mmol), and potassium iodide (8.30 g, 50.0 mmol) were suspended in CH3CN (100 mL). 3-Chloro-1,2-propanediol (8.29 g, 75.0 mmol) was added, and the mixture was stirred at reflux for 24 h. After cooling to room temperature, additional CH3CN (150 mL) was added to the reaction, which was then filtered through Celite and concentrated. The crude product was then suspended in CH2Cl2 (250 mL), heated to reflux and stirred overnight, and then decanted. The product was still slightly impure by 1H NMR, so the CH2Cl2 wash process was repeated once, to afford a white solid (6.82 g, 96%) after drying in vacuo. 1H NMR (400 MHz, DMSO) δ 7.54 (t, J=1.0 Hz, 1H), 7.11 (t, J=1.2 Hz, 1H), 6.84 (t, J=1.0 Hz, 1H), 5.08 (s, 1H), 4.83 (s, 1H), 4.05 (dd, J=13.9, 3.6 Hz, 1H), 3.84 (dd, J=14.0, 7.2 Hz, 1H), 3.70-3.58 (m, 1H), 3.31 (dt, J=13.8, 9.0 Hz, 3H), 3.19 (dd, J=11.0, 6.5 Hz, 1H).
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4C(=O)CCCC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:55]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:54][C:53]4[C:52](=[O:62])[CH2:51][C:50]([CH3:64])([CH3:63])[CH2:49][C:48]=4[N:47]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[NH2:35][C:36]1([C:40]2[CH:41]=[CH:42][C:43]([C:46]3[C:55]([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)=[CH:54][C:53]4[C:52](=[O:62])[CH2:51][C:50]([CH3:64])([CH3:63])[CH2:49][C:48]=4[N:47]=3)=[CH:44][CH:45]=2)[CH2:37][CH2:38][CH2:39]1
Reactant: CC1(C)CC(=O)c2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2C1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Product: CC1(C)CC(=O)c2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2C1
Yield: 113.5 %

Procedure:
Following the procedure for 2-(4-(1-aminocyclobutyl)phenyl)-3-phenyl-7,8-dihydroquinolin-5(6H)-one, tert-butyl(1-(4-(7,7-dimethyl-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (30 mg, 0.06 mmol) was reacted to afford the title compound as a white solid (27 mg, 87%). LCMS (Method A): RT=4.48 min, M-NH2=380. 1H NMR (500 MHz, MeOD): 8.26 (1H, s), 7.50 (2H, d), 7.43 (2H, d), 7.31-7.29 (3H, m), 7.21-7.19 (2H, m), 3.15 (2H, s), 2.78-2.72 (2H, m), 2.66 (2H, s), 2.60-2.54 (2H, m), 2.27-2.18 (1H, m), 2.00-1.91 (1H, m), 1.17 (6H, s).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH:42]=[C:41]2[C:54]1[CH:59]=[N:58][CH:57]=[C:56]([N:60]2[CH2:65][CH2:64][CH:63]([NH:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:62][CH2:61]2)[N:55]=1>C(Cl)Cl>[C:70]([O:69][C:67]([NH:66][CH:63]1[CH2:62][CH2:61][N:60]([C:56]2[N:55]=[C:54]([C:41]3[C:40]4[C:44](=[CH:45][CH:46]=[C:38]([NH:37][C:1](=[O:4])[CH2:2][CH3:3])[CH:39]=4)[N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH:42]=3)[CH:59]=[N:58][CH:57]=2)[CH2:65][CH2:64]1)=[O:68])([CH3:73])([CH3:72])[CH3:71]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccc(N)cc34)n2)CC1
Reactant: CCC(=O)Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1ccc2c(c1)c(-c1cncc(N3CCC(NC(=O)OC(C)(C)C)CC3)n1)cn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
To solution of propionyl chloride (52.5 mg, 0.708 mmol) in DCM (7 mL) at 0° C. was added Et3N (0.2 mL, 1.47 mmol), HBTU (292 mg, 0.75 mmol), tert-butyl 5-amino-3-(6-(4-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-1H-indole-1-carboxylate (300 mg, 0.59 mmol) The resulting reaction mixture was stirred at RT for 3 h. The reaction mixture was extracted with DCM (14 mL), washed with brine, dried over Na2SO4, and concentrated to dryness. The crude product was purified by column chromatography to obtain the title compound (150 mg, 45%) as an off white solid. MS (ESI, pos. ion) m/z: 565.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]=[N:10][C:9](SC)=[CH:8][C:7]2=1)([O-])=O>CN1CCCC1=O.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]=[N:10][CH:9]=[CH:8][C:7]2=1
Reactant: CSc1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])cc12
Agent: [Ni]
Solvent: CN1CCCC1=O
Product: Nc1ccc2[nH]c3cnccc3c2c1
Yield: 68.6 %

Procedure:
660 mg of 6-nitro-3-methylthio-β-carboline are hydrogenated in 50 ml of N-methylpyrrolidone with 3 g of Raney nickel at 50 bar of H2 pressure and 60° C. for 2 hours. After filtering, it is evaporated and the residue chromatographed on silica gel with methylene chloride/ethanol=10:2 as eluant. 320 mg of 6-amino-β-carboline as oil are obtained.