Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:34]=[CH:33][C:6]([C:7]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:41]>C(N(CC)CC)C>[CH2:30]([O:29][CH2:28][CH2:27][CH:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([C:1](=[S:41])[NH2:2])=[CH:34][CH:33]=2)=[O:32])=[CH:13][CH:14]=1)[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH3:31]
Reactant: CCOCCC(Cc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1)C(=O)OC(C)(C)C
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOCCC(Cc1ccc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)cc1)C(=O)OC(C)(C)C

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (e) (600 mg), pyridine (42 ml), triethylamine (6 ml) and H2S gas were reacted to give t-butyl 2-(2-ethoxyethyl)-3-(4-[3-(4-thiocarbamoylbenzoyl)ureido]phenyl)propionate (585 mg) as a yellow solid: m.p. 199°-201° C.; NMR Spectrum (DMSO-d6) 1.10 (3H, t), 1.30 (9H, s), 1.70 (2H, m), 2.62 (1H, m), 2.72 (2H, m), 3.37 (4H, m), 7.15 (2H, d), 7.49 (2H, d), 7.95 (2H, d), 8.03 (2H, d), 9.67 (1H, br s), 10.06 (1H, br s), 10.72 (1H, s), 11.09 (1H, s); Mass Spectrum m/Z 522 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9]O)=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.CN(C)C=O.S(Cl)([Cl:23])=O>ClC(Cl)Cl>[Cl:23][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc(F)ccc1OCCCO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)ccc1OCCCCl
Reaction time: 1 h
Yield: 55 %

Procedure:
To a stirred mixture of 12.6 parts of 3-(4-fluoro-2-nitrophenoxy)propanol, 0.9 parts of N,N-dimethylformamide and 150 parts of trichloromethane were added dropwise 8.36 parts of thionyl chloride and stirring was continued for 1 hour at room temperature. The whole was further stirred and refluxed for 3 hours. The reaction mixture was evaporated under methylbenzene. The residue was stirred in petroleumether. The product was filtered off and dried, yielding 7.41 parts (55%) of 1-(3-chloropropoxy)-4-fluoro-2-nitrobenzene; mp. 143.3° C. (intermediate 25).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:29])([CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][C:16]=2[O:30]CC2C=CC=CC=2)([OH:14])[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:29][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:10]2([OH:14])[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[C:16]([OH:30])[CH:17]=1)([CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc(C2(O)CCCN(Cc3ccccc3)C2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(C2(O)CCCNC2)c(O)c1
Yield: 70 %

Procedure:
A mixture of 8.5 (17.03 mmols) of 1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-hydroxypiperidine, 2.0 g. of 10% palladium-on-carbon and 60 ml. of ethanol is stirred under one atmosphere of hydrogen for 2 hours. The reaction mixture is filtered through diatomaceous earth with ethyl acetate and evaporated. The residue is recrystallized from ethyl acetate to yield 3.8 g. (70%) of the title compound. A second crop of the title compound 0.396 g. (7%) is obtained from the mother liquor.
Reaction SMILES: [CH2:1]([CH2:4][NH:5][CH2:6][CH:7]([C:9]1([OH:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:8])[CH:2]=[CH2:3].[C:22](Cl)(=[O:24])[CH3:23]>>[C:22]([O:21][C:9]1([CH:7]([CH3:8])[CH2:6][NH:5][CH2:4][CH2:1][CH:2]=[CH2:3])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: C=CCCNCC(C)C1(O)CCCCC1c1ccccc1
Product: C=CCCNCC(C)C1(OC(C)=O)CCCCC1c1ccccc1

Procedure:
The procedure of Example I(c) is followed using 4.8 g of 1-(2-Allylmethylamino-1-methylethyl)-2-phenylcyclohexanol and 13 ml acetyl chloride to give 3.2 g pure product.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=O.Cl.[NH2:25][CH2:26][CH2:27][N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30].C[O-].[Na+]>CCO>[CH3:32][S:29]([N:28]([CH3:33])[CH2:27][CH2:26][NH:25][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:2])(=[O:31])=[O:30]
Reactant: CN(CCN)S(C)(=O)=O
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O)S(C)(=O)=O
Temperature: 140 °C
Yield: 63.1 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.081 mmol), N-(2-amino-ethyl)-N-methyl-methanesulfonamide HCl salt (61 mg, 0.32 mmol), and NaOMe (17 mg, 0.32 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. The mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 22 mg of the title compound as an off-white solid. MS: (+) m/z 431.28 (M+1).
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:17])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:20][CH:21]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(NCC(F)F)CC2
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)F)CC3)ncc1Cl
Yield: 14.3 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide to yield 2-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide (15.43 mg, 14.3% yield) as a off white foam. 1H-NMR (CDCl3) δ 8.69 (s, 1H), 8.05 (s, 1H), 7.24 (m, 2H), 7.14 (s, 1H), 7.09 (d, J=8.1 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 6.83 (s, 1H), 6.05 (m, 1H), 5.83 (m, 1H), 5.83 (m, 1H), 3.01 (t, J=4.3 Hz, 1H), 2.90 (d, J=4.9 Hz, 1H), 2.77 (m, 2H), 2.60 (m, 3H), 2.02 (m, 2H), 1.25 (m, 2H). LC/MS (ESI+)=519 (M+H).
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[N:5]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.O>[CH2:12]([S:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[N:5]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cc(O)nc(S)n1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Oc1cc(O)nc(SCc2ccccc2)n1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of sodium hydroxide (3.30 g) in ethanol/H2O (60 ml/60 ml) was added to 2-mercaptopyrimidine-4,6-diol (10.00 g) and the mixture stirred for 10 min. Benzyl bromide (13.45 g) was then added dropwise and the mixture heated at 60° C. for 2 h. The reaction was cooled to 0° C. for 1 h before the precipitate was filtered and washed with H2O (100 ml) and then dried in vacuo to afford the subtitle compound as a cream solid. Yield: 15.0 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)=[CH:11][N:10]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1.[Na]>CN(C)C=O>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:10]2[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:39]([NH:38][C:35]4[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:41])[F:42])=[CH:37][CH:36]=4)=[O:40])[CH:7]=[CH:6][CH:5]=3)=[N:9]2)=[CH:27][CH:26]=1
Reactant: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(N)c2)ccn1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
250 mg (0.65 mmol) of 4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-methylpyridin-2-amine were dissolved in 10 ml of dry dimethylformamide and 92 μl of p-trifluoromethyl-phenylisocyanate were added. The reaction was stirred at room temperature overnight, poured into aqueous sodium hydrogenocarbonate and extracted with dichloromethane. The organic phase was then dried over sodium sulphate and evaporated. The residue was purified by flash-chromatography on a silica gel column CH2C12-CH3COCH3; from 9/1 to 8/2), giving 234 mg (63%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[C:5]([C:24](O)=[O:25])[CH:4]=[N:3]1.[NH:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1>>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][C:11]=1[CH2:10][CH2:9][NH:8][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[C:24]([N:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1)=[O:25])=[O:23]
Reactant: Cc1oc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)O)cnn1C
Reactant: C1CSCCN1
Product: Cc1oc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)N2CCSCC2)cnn1C

Procedure:
The product was obtained starting from 1-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethylcarbamoyl)-1H-pyrazole-4-carboxylic acid (40 mg, 113 μmol) and thiomorpholine (14.4 mg, 14.3 μL, 135 μmol) according to the method described in example 37, step 3 as colorless oil (41.7 mg, 94.9 μmol, 84.0%).
Reaction SMILES: [CH2:1]([NH:8]C(C1SC(N2C=C(C(O)=O)N=N2)=NC=1C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:32][C:33]([C:35]1[S:39][C:38]([N:40]2[C:44]([CH3:45])=[C:43]([C:46]([OH:48])=O)[N:42]=[N:41]2)=[N:37][C:36]=1[CH3:49])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N)C1C=CC=CC=1>>[CH2:25]([NH:32][C:33]([C:35]1[S:39][C:38]([N:40]2[C:44]([CH3:45])=[C:43]([C:46](=[O:48])[NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:42]=[N:41]2)=[N:37][C:36]=1[CH3:49])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1nc(-n2nnc(C(=O)O)c2C)sc1C(=O)NCc1ccccc1
Reactant: Cc1nc(-n2cc(C(=O)O)nn2)sc1C(=O)NCc1ccccc1
Solvent: NCc1ccccc1
Product: Cc1nc(-n2nnc(C(=O)NCc3ccccc3)c2C)sc1C(=O)NCc1ccccc1
Yield: 11 %

Procedure:
Following the procedure as described in Example 18, making variations as necessary to replace 1-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-1H-1,2,3-triazole-4-carboxylic acid with 1-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid to react with benzylamine, the title compound was obtained as a white solid in 11% yield (0.033 g): mp 183-186° C. (methanol); 1H NMR (300 MHz, DMSO-d6) δ 9.30 (t, J=6.0 Hz, 1H), 9.01 (t, J=6.0 Hz, 1H), 7.36-7.22 (m, 10H), 4.46 (d, J=6.0 Hz, 4H), 2.90 (s, 3H), 2.64 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 160.1, 159.9, 155.1, 152.4, 139.4, 139.2, 138.9, 137.5, 128.3, 128.2, 127.3, 127.2, 126.9, 126.7, 125.1, 42.8, 41.9, 17.2, 10.3; MS (ES+) m/z 447.4 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][C:17]#[N:18])=[C:11]([F:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][NH2:22]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([NH2:18])[NH:22][N:21]=2)=[C:11]([F:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCC(=O)c1ccc(OCc2ccccc2)cc1F
Reactant: NN
Solvent: CCO
Product: Nc1cc(-c2ccc(OCc3ccccc3)cc2F)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
3-(4-(Benzyloxy)-2-fluorophenyl)-3-oxopropanenitrile (1.7 g, 6.3 mmol) was dissolved in ethanol (21 mL), and then hydrazine (0.22 mL, 6.9 mmol) was added. The reaction mixture was stirred at room temperature for about one hour, and the progress of the reaction was followed by thin-layer chromatography. If no progress had been made, the temperature was gradually increased until the reaction began proceeding. As soon as the reaction appeared complete by thin-layer chromatography, the crude material was concentrated in vacuo and purified by chromatography to provide the title compound 97% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18]C)=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[NH2:21][NH2:22]>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([NH:21][NH2:22])=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NN
Reactant: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCO
Solvent: O
Product: NNC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 84 %

Procedure:
To a stirred solution of 4-fluoro nitrobenzene (1a, 3.1 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(4-nitrophenyl)-4-piperidinecarboxy-late (3a, 4.93 g, 85%). To a stirred solution of ester (3a, 4.75 g, 18 mmol) in ethanol, NH2NH2. H2O (2.25 g, 45 mmol) is added and refluxed for 24 h. After completion of the reaction ethanol is evaporated under vacuum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(4-nitrophenyl)-4-piperidinecarbohydrazide (4a, 3.99 g, 84%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4a, 3.17 g, 12 mmol) in pyridine at room temperature (27° C.) and followed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.39 g, 40%). Nitro compound (5a, 1.16 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7a, 884 mg, 85%). To a stirred solution of 5-nitro2-furanoic acid (0.16 g, 1 mmol) in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide)) (0.19 g, 1 mmol) and amine compound (7a, 0.26 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8a, 323 mg, 81%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:12]([NH:14][CH3:15])=[O:13].[C:26](Cl)(=O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>C(Cl)(Cl)Cl>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][CH2:20][N:19]1[C:18]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[CH:10][C:9]=2[N:8]=[C:43]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CNC(=O)c1ccc(NCCCN(C)C)c(N)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCc1nc2cc(C(=O)NC)ccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
Triethylamine (0.77 ml) was added to a solution containing 3-amino-4-{[3-(dimethylamino)propyl]amino}-N-methylbenzamide (1.44 g) in chloroform (10 ml), and then a solution containing stearoyl chloride (1.51 g) in chloroform (5 ml) was added thereto while being cooled with ice. After being stirred for 1.5 hours at room temperature, the reaction mixture was diluted with chlorofonr, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (4.00 ml) was added to a solution containing the residue (2.78 g) in ethanol (25 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 4N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.77 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1-10:1), thereby yielding the entitled compound (2.11 g) as grayish yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=O)[CH:8]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][CH2:40][CH:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1>C(Cl)Cl>[CH2:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:51][CH2:52][N:43]1[CH2:42][CH:41]([OH:53])[CH2:40][NH:39][C:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)=[O:14]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: Cc1ccc2cc(C(=O)O)ccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2cc(C(=O)NCC(O)CN3CCc4ccccc4C3)ccc2n1
Temperature: 15 °C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
To a solution of 2-methylquinoline-6-carboxylic acid (100 mg, 0.535 mmol) in DCM (20 mL) was added HATU (244 mg, 0.642 mmol) and TEA (162 mg, 1.604 mmol). The mixture was stirred at 15° C. for 30 minutes before 1-amino-3-(3,4-dihydro isoquinolin-2(1H)-yl)propan-2-ol (110 mg, 0.535 mmol) was added. The resulting mixture was stirred for another 16 h at 15° C., at which point LCMS showed the completion of the reaction. The mixture was concentrated and the residue was purified by Preparation HPLC to give the desired title compound (106.2 mg, 53%). 1H NMR (400 MHz, METHANOL-d4) δ=8.32 (d, J=1.9 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.09 (dd, J=2.1, 8.8 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.16-7.08 (m, 3H), 7.08-7.03 (m, 1H), 4.18 (quin, J=6.1 Hz, 1H), 3.79 (s, 2H), 3.59 (d, J=5.8 Hz, 2H), 2.94-2.88 (m, 4H), 2.79-2.68 (m, 5H). LCMS (m/z): 376.0 (M+1).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([C:15]([NH2:17])=[O:16])[C:8]([NH2:14])=[N:9]3)=[CH:4][C:3]=2[O:2]1.C[O-].[Na+].[C:21](OCC)(=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]4[C:15](=[O:16])[NH:17][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:14][C:8]4=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: NC(=O)c1cc2cc3c(cc2nc1N)OCO3
Agent: C[O-]
Agent: [Na+]
Product: CCOC(=O)c1nc2nc3cc4c(cc3cc2c(=O)[nH]1)OCO4
Temperature: 150 °C

Procedure:
A mixture of 6,7-methylenedioxy-2-aminoquinoline-3-carboxamide (1.50 g., 6.5 millimoles), sodium methoxide (0.05 g., 1.25 millimoles) and diethyl oxalate (150 ml.) is heated to 150° C. for 3.5 hours. The mixture is then cooled to room temperature to precipitate the product which is recovered by filtration (1.0 g.). It is purified by chromatography on silica gel using chloroform:methanol (99:1) as eluant. The product is recovered by evaporation of the eluate and recrystallization of the residue from ethanol. Yield = 0.414 g. (20.4%) of the cyclized product. M.P. 267° C. (dec.).
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH2:10][C@@H:9]([C:12]([CH3:14])=[CH2:13])[CH2:8][C:7]1=[CH:6][C:5](=[O:15])[CH2:4][CH2:3]2.S(=O)(=O)(O)[OH:17].C([O-])([O-])=O.[K+].[K+]>C(O)=O>[CH3:1][C:2]12[CH2:11][CH2:10][C@@H:9]([C:12]([OH:17])([CH3:14])[CH3:13])[CH2:8][C:7]1=[CH:6][C:5](=[O:15])[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CCC2(C)CCC(=O)C=C2C1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Product: CC12CCC(=O)C=C1C[C@H](C(C)(C)O)CC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 39 %

Procedure:
1.2 g (5.87 mmol) of (6R/S,9R)6-Methyl-9-(1-methylvinyl)-bicyclo[4.4.0]dec-1-ene-3-one from step C of preparation A was dissolved in 20 mL of formic acid and added to 4 mL of 5% sulfuric acid solution. The reaction mixture was stirred at room temperature for 2 days, in refrigerator for 3 days, then neutralized with K2CO3 with cooling, and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 5/1) to give 500 mg of product as oil and 620 mg of recovered starting material, yield 39%.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.Cl.N[C@H](C([NH:14][CH:15]1[C:21](=[O:22])[N:20]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[N:17]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:16]1=[O:35])=O)C>>[CH:1]1([CH2:4][C:5]([NH:14][C@H:15]([C:21]([C:15]2([NH2:14])[C:21](=[O:22])[N:20]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:16]2=[O:35])=[O:22])[CH3:16])=[O:7])[CH2:2][CH2:3]1
Reactant: CC(C)CN1C(=O)C(NC(=O)[C@H](C)N)C(=O)N(CC(C)C)c2ccccc21
Reactant: O=C(O)CC1CC1
Agent: Cl
Product: CC(C)CN1C(=O)C(N)(C(=O)[C@H](C)NC(=O)CC2CC2)C(=O)N(CC(C)C)c2ccccc21

Procedure:
Following General Procedure I above using cyclopropylacetic acid (Lancaster) and 3-(L-alaninyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-S), the title compound was prepared as a white solid (melting point=190-191° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1 gradient to 3:4) and a second flash chromatography eluting with EtOAc/Toluene (7:3). Rf=0.28 (EtOAc/Toluene, 7:3).