Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:4]([C:19](=[O:21])[CH3:20])[N:3]=1.[CH3:22][N:23](C)C=O>[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>[C:19]([C:4]1[N:3]=[C:2]([C:22]#[N:23])[C:11]2[C:6]([C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2)(=[O:21])[CH3:20]
Reactant: CN(C)C=O
Reactant: CC(=O)c1nc(Cl)c2ccccc2c1-c1cccc(F)c1
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]
Product: CC(=O)c1nc(C#N)c2ccccc2c1-c1cccc(F)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
A mixture of 1-[1-chloro-4-(3-fluorophenyl)isoquinolin-3-yl]ethanone (100 mg, 0.334 mmol), zinc cyanide (78 mg, 0.66 mmol) and tetrakis(triphenylphosphine)palladium(0) (77 mg, 0.067 mmol) in dry N,N-dimethylformamide (1.1 mL) was stirred at 130° C. overnight. The mixture was filtered, diluted with water, extracted with dichloromethane. The combined extracts were dried over MgSO4, concentrated and purified on silica gel (0-60% ethyl acetate in hexane) to give the desired product (6 mg, 6%). LCMS calculated for C18H12FN2O (M+H)+: m/z=291.1; Found: 291.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C:5](=[N:8][OH:9])[CH2:6]Br)[CH3:2].[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:10])[C:5](=[N:8][OH:9])[CH2:6][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([Br:11])[CH:13]=2)[NH:17][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)C(CBr)=NO
Reactant: Brc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(Cc1c[nH]c2ccc(Br)cc12)=NO
Reaction time: 20 h
Yield: 99.3 %

Procedure:
A solution of 3-bromo-2-hydroxyimino-propionic acid ethyl ester (3.21 g, 15.3 mmol) in CH2Cl2 (20 mL) was slowly added dropwise to a stirring mixture of 5-bromoindole (3.0 g, 15.3 mmol) and Na2CO3 (8.92 g, 84.2 mmol) in CH2Cl2 (30 mL) at room temperature. The mixture was stirred for 20 hours, filtered through CELITE® and concentrated to give 4.94 g of the title compound as a crude material. LCMS m/z (ESI) [M+H]+ calcd for C1-3H14BrN2O3 (Br79) 325.2, found 325.2.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[NH2:24][CH:25]1[CH2:30][NH:29][C:28](=[O:31])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>>[CH3:22][C:3]1[C:2]([NH:24][CH:25]2[CH2:26][CH2:27][C:28](=[O:31])[NH:29][CH2:30]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: NC1CCC(=O)NC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCC(=O)NC1
Temperature: 100 °C
Yield: 33 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48 mg, 0.162 mmol), rac-5-aminopiperidin-2-one hydrochloride (48.8 mg, 0.324 mmol, Advanced ChemBlocks, Inc., Burlingame, Calif.), and DIPEA (141 μl, 0.810 mmol), heating at 100° C. for 1.5 h. Purification by silica gel (100% DCM to 20% MeOH/DCM) provided rac-2-(2-methyl-3-((6-oxopiperidin-3-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (33% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.93-2.07 (m, 1H) 2.14-2.23 (m, 1H) 2.31-2.41 (m, 1H) 2.58 (s, 3H) 2.83-2.90 (m, 2H) 3.23-3.29 (m, 1H) 3.44 (td, J=6.85, 2.15 Hz, 2H) 3.51-3.59 (m, 1H) 4.39-4.51 (m, 1H) 6.94 (br. s., 1H) 7.00 (d, J=6.65 Hz, 1H) 7.13 (s, 1H) 7.37 (t, J=7.82 Hz, 1H) 7.50 (d, J=2.15 Hz, 1H) 7.61 (d, J=7.04 Hz, 1H) 7.89 (d, J=7.63 Hz, 1H) 11.90 (br. s., 1H). MS (ESI, pos. ion) m/z: 391.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=3.Cl[C:31]([O:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:32]>>[CH3:36][C:35]([CH3:38])([CH3:37])[CH2:34][O:33][C:31]([N:22]1[CH:23]=[CH:24][C:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:25])[C:12]2[N:26]([CH3:29])[C:27](=[O:28])[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:10][C:11]3=2)=[N:21]1)=[O:32]
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Reactant: CC(C)(C)COC(=O)Cl
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(C(=O)OCC(C)(C)C)n4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 99 above, with the compound from Ex 39, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydro-pyrido[2,3-b]indol-2-one and neopentyl chloroformate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([NH2:22])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[F:13][C:14]1[CH:15]=[C:16]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(N)cc1F
Reactant: Cc1nc(Cl)c2ccccc2n1
Product: COc1ccc(Nc2nc(C)nc3ccccc23)cc1F

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (150 mg, 0.84 mmol), 3-fluoro-4-methoxy-phenylamine (1 18.5 mg, 0.84 mmol) by a procedure similar to Example 78. 1H NMR (CDCl3): 7.89-7.75 (m, 4H), 7.53-7.48 (m, 1H)), 7.38-7.34 (m, 2H), 7.0 (t, J=8.7 Hz, 1H), 3.92 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([OH:6])=[O:5].[C:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Li+].[Li+]>C(O)CC>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:2]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[C:3]=2[C:4]([OH:6])=[O:5])=[CH:24][CH:25]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CCCO
Product: CC(C)(C)c1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1
Reaction time: 20 h

Procedure:
A mixture of 2,6-dichloro-3-nitrobenzoic acid (4.72 g, 0.02 mol), 4-tertbutylaniline (4.47 g, 0.03 mol), lithium carbonate (1.48 g, 0.02 mol), and 1-propanol (10 mL) was refluxed with stirring for 20 h. The solvent was evaporated and to the residue, water (30 mL) and benzene (50 mL) were added. The mixture was made strongly basic with sodium hydroxide and stirred for 1h. Orange precipitate was collected by filtration and washed with benzene and ether. Dry precipitate was dissolved in water and acidified with diluted hydrochloric acid. Resulting precipitate was collected and crystallized from acetone-water to give 4.55 (65%) of the desired product, mp 201°-204° C. Anal. (C31H27N7O6) C, H, N.
Reaction SMILES: C(OC([NH:8][CH:9]([CH3:40])[C:10]([NH:12][CH:13]([C:36]([O:38][CH3:39])=[O:37])[CH2:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][C:20]2[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1)=[O:11])=O)(C)(C)C.[ClH:41]>ClCCl>[ClH:41].[NH2:8][CH:9]([CH3:40])[C:10]([NH:12][CH:13]([C:36]([O:38][CH3:39])=[O:37])[CH2:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][C:20]2[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1)=[O:11]
Reactant: COC(=O)C(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)NC(=O)C(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)NC(=O)C(C)N
Yield: 66.3 %

Procedure:
A solution of 5-[4-(4-(2-(2-t-butoxycarbonylaminopropanamido)-2-methoxycarbonyl ethyl)phenoxy)benzyl]thiazolidin-2,4-dione (1 g, 1.75 mmol) in dichloromethane (10 ml) was bubbled with HCl gas at −10° C. for 50 minutes. The excess HCl gas was removed by N2 bubbling and concentrated to dryness to afford the title compound (0.59 g, yield 66.3%).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:8]([C:20]2[S:21][CH:22]=[C:23]([CH2:25][C:26](O)=[O:27])[N:24]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31][CH2:30]1>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[C:8]([C:20]2[S:21][CH:22]=[C:23]([CH2:25][C:26]([NH:36][CH2:35][CH:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)=[O:27])[N:24]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCc2c(-c3nc(CC(=O)O)cs3)cnn2C(C)(C)C)cc1
Reactant: NCC1CCOCC1
Product: COc1ccc(CCc2c(-c3nc(CC(=O)NCC4CCOCC4)cs3)cnn2C(C)(C)C)cc1

Procedure:
Using the compound obtained in step 5 and (tetrahydro-2H-pyran-4-yl)methanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:13]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:12](=[O:31])[C:6]3=[CH:7][CH2:8][CH2:9][C:10]([CH:11]=1)=[C:5]23.C(Cl)Cl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CO>[CH:2]([C:3]1[N:4]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:13]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:12](=[O:31])[C:6]3=[CH:7][CH2:8][CH2:9][C:10]([CH:11]=1)=[C:5]23)=[O:1]
Reactant: O=C(NN1C=C(c2ccccc2)n2c(CO)cc3c2C(=CCC3)C1=O)c1ccncc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: O=Cc1cc2c3n1C(c1ccccc1)=CN(NC(=O)c1ccncc1)C(=O)C3=CCC2

Procedure:
0.100 g (0.24 mmol) of N-(9-hydroxymethyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)-isonicotinamide and 20 ml of CH2Cl2 are introduced successively into a 50-ml one-necked flask. The mixture is stirred and 0.200 g (0.93 mmol) of pyridinium chlorochromate are added. The suspension is stirred for 1 h at 20-25° C. The purification is carried out directly on the reaction mixture by rapid chromatography on a silica column, eluting with CH2Cl2 enriched with MeOH. The residue obtained after removal of the solvent is concreted in a few millilitres of ether. 0.022 g (0.054 mmol) of a beige powder is obtained.—TLC (CH2Cl2/MeOH 95/5 v/v): Rf=0.50.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([C:14]1[C:20]([C:21]#[N:22])=[C:19]([OH:23])[CH:18]=[CH:17][C:15]=1[OH:16])#[N:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:23][C:19]2[CH:18]=[CH:17][C:15]([O:16][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])=[C:14]([C:12]#[N:13])[C:20]=2[C:21]#[N:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1c(O)ccc(O)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)Oc2ccc(OS(=O)(=O)c3ccc(C)cc3)c(C#N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
p-Toluenesulfonyl chloride (25.80 g, 135 mmol) was added to a suspension of 2,3-dicyanohydroquinone (10.00 g, 62.5 mmol) and potassium carbonate (34.50 g, 250 mmol) in acetone (75 mL). The temperature of the flask rose rapidly, which stabilised after 2 minutes. The mixture was then heated to reflux and stirred for 2 hours. TLC (eluting: CH2Cl2) indicated that all the starting 2,3-dicyanohydroquinone had been consumed. The mixture was allowed to cool to room temperature, and was poured into water (200 mL), and the mixture stirred for 1 hour. Filtration gave the title compound (Product A) as a colourless solid, which was washed with more water (˜30 mL) and pulled dry. The solid was then dried in an oven (28.36 g, 97%). This material was used without further purification. [Found: C, 55.8%; H, 3.3%; N, 6.0%; S, 13.5%; C22H16O6N2S2 requires C, 56.4%; H, 3.4%; N, 6.0%; S, 13.7%]; MS (EI+) 468 (M+, 80%), 155 (CH3C6H4SO2, 100%), 91 (CH3C6H4, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][NH:11][C:10]2=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].[Cl:18][C:19]([Cl:23])([Cl:22])[S:20]Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10](=[O:15])[N:11]([S:20][C:19]([Cl:23])([Cl:22])[Cl:18])[N:12]([S:20][C:19]([Cl:23])([Cl:22])[Cl:18])[C:13]2=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: O=c1[nH][nH]c(=O)n1-c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1n(-c2ccc(Cl)c(Cl)c2)c(=O)n(SC(Cl)(Cl)Cl)n1SC(Cl)(Cl)Cl

Procedure:
To a solution of 24.6g (0.1 mole) 4-(3,4-dichlorophenyl)urazole in 100 ml water was added a solution of 8g (0.2 mole) sodium hydroxide in 10 ml water. A mixture of 37.2g (0.2 mole) trichloromethylsulfenyl chloride and 1.5g of an emulsifier solution (as in example 1) in 25 ml water was added dropwise to the above basic solution while keeping the reaction mixture at 0° C. The precipitate that formed was filtered and the filter cake was washed with water. After drying and recrystallizing from benzene there was obtained 48g (87%) of 4-(3,4-dichlorophenyl)-1,2-bis(trichloromethylthio)urazole having a melting point of 167° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[N:25][C:26]=3[NH2:28])[N:21]([CH:29]3[CH2:34][CH2:33][N:32]([CH2:35][C:36]4[NH:37][CH:38]=[CH:39][N:40]=4)[CH2:31][CH2:30]3)[N:20]=2)=[CH:15][C:14]=1[O:41][CH3:42]>N1C=CC=CC=1>[NH2:28][C:26]1[N:25]=[CH:24][N:23]=[C:22]2[N:21]([CH:29]3[CH2:34][CH2:33][N:32]([CH2:35][C:36]4[NH:37][CH:38]=[CH:39][N:40]=4)[CH2:31][CH2:30]3)[N:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:9](=[O:10])[CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[C:14]([O:41][CH3:42])[CH:15]=3)[C:27]=12
Reactant: COc1cc(-c2nn(C3CCN(Cc4ncc[nH]4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(Cc4ncc[nH]4)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Reaction time: 2 h
Yield: 50.7 %

Procedure:
3-Phenylpropanoyl chloride (0.011 mL, 0.0715 mmol) was added to a solution of 3-(4-amino-3-methoxyphenyl)-1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.0715 mmol) in pyridine (1.2 mL) at 0° C. After 2 hours, the solvent was evaporated and the residue was purified by flash column chromatography to give N1-(4-{4-amino-1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide (20 mg, 51%). 1H NMR (CDCl3) δ 2.27(m, 2H), 2.61 (m, 2H), 2.76 (m, 4H), 3.09 (m, 2H), 3.93 (s, 3H), 4.07 (s, 2H), 4.96 (m, 1H), 5.61 (bs, 2H), 7.06-7.33 (m, 10H), 7.78 (s, 1H), 8.35 (s, 1H), 8.55 (d, J=8.15 Hz, 1H). LCMS (Finigan-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.0 mL/min.): MH+=552.5, Rt=1.83 min.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([NH:22][CH:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24](O)=[O:25])=[O:21])=[CH:14]2>>[CH2:27]([CH:23]([NH:22][C:20]([C:15]1[NH:16][C:17]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:10])=[CH:19][CH:18]=2)=[O:21])[C:24]([N:6]1[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]1)=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Product: CN(C)C1CCN(C(=O)C(Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1

Procedure:
4-Dimethylaminopiperidine (1.0 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (1.0 mmol) were coupled according to Procedure A. The residue was purified by chromatography on silica gel eluted with 5-30% ethanol in dichloromethane containing 0.5% ammonium hydroxide, followed by trituration with ether: Yield 21 mg, 5%; PBMS 453/455 (MH+, 100%);
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=2)=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][N:10](C(=O)C(F)(F)F)[CH2:9][CH2:8]2)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:1]([C:3]1[C:4]([NH:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([C:29]([F:30])([F:32])[F:31])[CH:22]=2)=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2)[CH3:2]
Reactant: CCc1c(NC(=O)c2ccc(OC)c(C(F)(F)F)c2)ccc2c1CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCc1c(NC(=O)c2ccc(OC)c(C(F)(F)F)c2)ccc2c1CNCC2
Reaction time: 8 h
Yield: 774.6 %

Procedure:
N-(8-Ethyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4methoxy-3-trifluoromethylbenzamide (0.157 g) was dissolved in methanol/water (5:1 6 ml), potassium carbonate (0.228 g) added and the mixture stirred overnight. The mixture was partitioned between dichloromethane and water the organic phase separated and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, ammonia/methanol/dichloromethane mixtures as eluant) to give the title compound (0.97 g)
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>C(#N)C>[N:13]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C1CCNCC1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc(N2CCCCC2)cc1

Procedure:
Reaction of ethyl 4-fluorobenzoate with piperidine (3 equivalents) in acetonitrile was carried out at reflux for 4 days. Dilution of the cooled reaction mixture with several volumes of water provided a precipitate, which was filtered to provide ethyl 4-(piperidin-1-yl)benzoate. Reduction of the ester with lithium aluminum hydride (2 equivalents) in tetrahydrofuran gave the corresponding alcohol (Examples 71, 72).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:25][C@H:24]([CH2:26][O:27][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:14]([O:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:12]2[OH:13])=[C:4]([NH2:36])[N:3]=1.N1C=CC=CC=1.[O:43](S(C(F)(F)F)(=O)=O)[S:44]([C:47]([F:50])([F:49])[F:48])(=O)=[O:45]>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:25][C@H:24]([CH2:26][O:27][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:14]([O:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:12]2[O:13][S:44]([C:47]([F:50])([F:49])[F:48])(=[O:45])=[O:43])=[C:4]([NH2:36])[N:3]=1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OS(=O)(=O)C(F)(F)F
Temperature: 10 °C
Yield: 95 %

Procedure:
To a heterogeneous mixture of crystallized 2-chloro-9-(3′,5′-di-O-benzoyl-β-D-ribofuranosyl)-adenine (F) (65 g, purity: 94.7% by A % HPLC, 120.7 mmol) in DCM (650 mL) and pyridine (65 mL) at about 0 to 20° C. under an atmosphere of N2(g) was added Tf2O (85.1 g, 301.6 mmol) dropwise whilst maintaining the temperature within the range of 0 to 20° C. The mixture turned clear and the reaction was deemed complete when the HPLC purity of F was not more than 1%. The mixture was washed with saturated NaHCO3 (325 mL) and the organic phase was washed with 2 N H2SO4 (325 mL) at room temperature The organic phase was dried using 3 Å molecule sieves until the Karl Fischer titration value was <=1000 ppm. The organic phase was evaporated in vacuo at 40° C. until about 290 g of residue (including about 130 mL of DCM) remained. The residue was directly used in the next step. The typical purity of 2-chloro-9-(3′,5′-di-O-benzoyl-2′-O-trifluoromethylsulfonyl-β-D-ribofuranosyl)-adenine (G) was >=95% and the yield was >=95%. 1H NMR (300 MHz, CDCl3) δ 8.11 (dd, J=8.3, 1.2 Hz, 2H), 7.98 (dd, J=8.3, 1.2 Hz, 2H), 7.87 (s, 1H), 7.70-7.60 (m, 1H), 7.59-7.46 (m, 3H), 7.41 (t, J=7.7 Hz, 2H), 6.34-6.23 (m, 2H), 6.16 (dd, J=5.3, 3.2 Hz, 1H), 6.07 (bs, 2H), 4.86 (dd, J=12.2, 3.3 Hz, 1H), 4.81-4.74 (m, 1H), 4.65 (dd, J=12.2, 4.2 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:12]1([CH3:15])[CH2:14][CH2:13]1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28](O)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([NH:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:2]([CH3:1])[C:3]([C:12]4([CH3:15])[CH2:13][CH2:14]4)=[CH:4]5)=[O:29])[CH2:26][CH2:27]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Cn1c(C2(C)CC2)cc2cc(N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(C2(C)CC2)cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc21
Temperature: 80 °C
Reaction time: 6 h

Procedure:
1-Methyl-2-(1-methylcyclopropyl)-1H-indol-5-amine (20.0 mg, 0.100 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (42.1 μL, 0.300 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 6 h at 80° C. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(1-methyl-2-(1-methylcyclopropyl)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 388.2, found 389.2 (M+1)+. Retention time of 3.05 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH:17](OCC)(OCC)OCC.C(O)C.[BH4-].[Na+]>C(OCC)(=O)C>[CH3:17][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc2ccn3cccc3c(=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1ccc2ccn3cccc3c(=O)c2c1
Reaction time: 2 h

Procedure:
A solution of 9-amino-11H-pyrrolo[2,1-b][3]benzazepin-11-one in triethyl orthoformate (2.17 g., 10 mmoles in 80 ml.) is refluxed for 5 hrs. The volatiles are removed under vacuum and the residue, dissolved in 100 ml. absolute ethanol is stirred in an ice bath as sodium borohydride (0.88 g., 0.024 moles) is added over a period of 10 minutes. The mixture is stirred for a period of 2 hrs. After concentration of the ethanol, the residue is dissolved in ethyl acetate, washed with water, dried over Na2SO4 and concentrated to dryness to yield 9-methylamino-11H-pyrrolo[2,1-b][3]benzazepin-11-one as a brown amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=O)[CH2:8]2)=[CH:4][CH:3]=1.Cl.[NH2:16][CH2:17][C:18]#[C:19][CH3:20].O1CCCC1>C(N(CC)CC)C>[Cl:1][C:2]1[S:6][C:5]([CH:7]2[CH2:8][C:9]3[N:16]=[CH:17][CH:18]=[C:19]([CH3:20])[C:10]=3[C:11](=[O:13])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC#CCN
Reactant: O=C1CC(=O)CC(c2ccc(Cl)s2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccnc2c1C(=O)CC(c1ccc(Cl)s1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a mixture of 5-(5-chloro-2-thienyl)cyclohexane-1,3-dione (2.2 g), 1-amino-2-butyne hydrochloride (1.0 g) and tetrahydrofuran (40 ml) was added triethylamine (0.96 g), and the mixture was stirred at room temperature for 1 hour, refluxed for 12 hours and cooled. Insoluble materials were filtered off, and under reduced pressure, the solvent was evaporated. The residue was stirred at 250° C. for 3.5 hours, cooled and purified with silica gel column chromatography (EtOAc/hexane) to give oil of 7-(5-chloro-2-thienyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.79 g).