Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:53])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:42])[C@@H:12]([NH:20][C:21](=[O:41])[C@@H:22]([NH:26][C:27](=[O:40])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]2[C:37](=[O:38])[CH:36]=[CH:35][C:34]2=[O:39])[CH:23]([CH3:25])[CH3:24])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[O:18])=[CH:6][CH:5]=1.[N:54]1([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.C(OCC)C>CS(C)=O>[O:39]=[C:34]1[CH:35]=[CH:36][C:37](=[O:38])[N:33]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]([NH:26][C@H:22]([C:21]([NH:20][C@H:12]([C:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][O:2][C:1]([N:57]2[CH2:56][CH2:55][N:54]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:59][CH2:58]2)=[O:53])=[CH:9][CH:8]=1)=[O:42])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:18])[NH2:19])=[O:41])[CH:23]([CH3:24])[CH3:25])=[O:40]
Reactant: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 1 h

Procedure:
Step 1 4-((S)-2-((S)-2-(6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl 4-nitrophenyl carbonate 58 (30 mg, 0.041 mmol) was reacted with tert-butyl piperazine-1-carboxylate (5.3 mg, 0.0287 mmol) in anhydrous DMSO under argon atmosphere at room temperature (FIG. 7d). The reaction mixture was stirred for 1 h, until disappearance of the starting material (HPLC-MS analysis). Diethyl ether (80 ml) was then added to the reaction mixture and the precipitate thus obtained was collected by filtration to give N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-{4-[({[4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl}oxy)methyl]phenyl}-N5-carbamoyl-L-omithinamide 59 as a yellow solid, 22.0 mg) was isolated and used without further purification in the next step. MS (ESI): 785 [M+H]+. Retention time=4.87 min (method 1).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([NH2:9])[CH2:7][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1)=[N+:2]=[N-:3].[Br:17][CH2:18][C:19]([F:26])([F:25])[CH2:20][CH2:21][C:22](O)=[O:23].C(N(CC)CC)C>C(OCC)(=O)C>[N:1]([C@H:4]1[CH2:5][N:6]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:7][C@@H:8]1[NH:9][C:22](=[O:23])[CH2:21][CH2:20][C:19]([F:26])([F:25])[CH2:18][Br:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H]1CN(Cc2ccccc2)C[C@@H]1N
Reactant: O=C(O)CCC(F)(F)CBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=N[C@H]1CN(Cc2ccccc2)C[C@@H]1NC(=O)CCC(F)(F)CBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
To a solution of the product from Step 5 (17.5 g, 80.6 mmol), 5-bromo-4,4-difluoropentanoic acid (17.5 g, 80.6 mmol) from Preparation 3 and triethylamine (32.6 g, 323 mmol) in ethyl acetate (250 mL) was added a 50% solution of propanephosphonic acid cyclic anhydride in ethyl acetate (48.0 mL, 80.6 mmol). The reaction was warmed to reflux and stirred for 16 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate and H2O. The organic phase washed with saturated sodium carbonate solution and saturated sodium chloride solution and then dried over sodium sulfate and concentrated to provide 22.0 g (65%) of the product as an oil. MS m/z 416. (MH+).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=2[N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:12]2=[O:26])[CH2:3][CH2:2]1.C(OC(=O)C)(=[O:29])C>>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([OH:29])[C:5]=2[N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:12]2=[O:26])[CH2:3][CH2:2]1
Reactant: O=C1N(c2ccnc(C(F)(F)F)c2)CCN1c1c[n+]([O-])ccc1C1CC1
Reactant: CC(=O)OC(C)=O
Product: O=C1N(c2ccnc(C(F)(F)F)c2)CCN1c1c(C2CC2)ccnc1O
Yield: 8 %

Procedure:
4-Cyclopropyl-3-(2-oxo-3-(2-(trifluoromethyl) pyridin-4-yl)imidazolidin-1-yl)pyridine 1-oxide (I-50b: 100 mg, 0.273 mmol) was heated with acetic anhydride (5 mL) at 120° C. for 3 hours. The resulting mixture was concentrated, basified with dilute sodium bicarbonate solution, and diluted with DCM. The organic layer was dried over sodium sulphate and concentrated to afford the crude product. Purification by column chromatography on silica gel (3% methanol in chloroform), followed by preparative HPLC afforded 8 mg of the product (8% yield).
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[O:44]=[C:45]1[CH2:49][CH2:48][CH2:47][N:46]1[C:50]1[CH:51]=[C:52]([CH:56]=[C:57]([N:59]2[CH2:63][CH2:62][CH2:61][C:60]2=[O:64])[CH:58]=1)[C:53](O)=[O:54].[CH:65]12[CH2:71][CH:68]([CH2:69][CH2:70]1)[CH2:67][CH:66]2[NH:72][C:73](=[O:92])[C@H:74]([CH2:87][CH2:88][CH:89]([CH3:91])[CH3:90])[CH2:75][C@H:76]([OH:86])[C@@H:77]([NH2:85])[CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1>>[CH2:78]([C@H:77]([NH:85][C:53](=[O:54])[C:52]1[CH:51]=[C:50]([N:46]2[CH2:47][CH2:48][CH2:49][C:45]2=[O:44])[CH:58]=[C:57]([N:59]2[CH2:63][CH2:62][CH2:61][C:60]2=[O:64])[CH:56]=1)[C@@H:76]([OH:86])[CH2:75][C@H:74]([C:73](=[O:92])[NH:72][CH:66]1[CH2:67][CH:68]2[CH2:71][CH:65]1[CH2:70][CH2:69]2)[CH2:87][CH2:88][CH:89]([CH3:91])[CH3:90])[C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1
Reactant: CC(C)CC[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Reactant: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: CC(C)CC[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E6 from 3,5-bis-(2-oxopyrrolidin-1-yl)benzoic acid (D8) and (2R,4S,5S)-5-amino-4-hydroxy-2-(3-methyl-butyl)-6-phenyl-hexanoic acid bicyclo[2.2.1]hept-2-ylamide (D33).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:16]=[C:8]2[C:9]3[C:14]([CH2:15][N:7]2[N:6]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OC(C)C)(C)C>C(COC)OC>[CH2:1]([NH:4][C:5]1[N:16]=[C:8]2[C:9]3[C:14]([CH2:15][N:7]2[N:6]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CC(=O)Nc1nc2n(n1)Cc1ccccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)OC(C)C
Solvent: COCCOC
Product: CCNc1nc2n(n1)Cc1ccccc1-2
Yield: 60 %

Procedure:
2-Acetamido-5H-s-triazolo[5,1-a]isoindole is reduced with lithium aluminum hydride at 0-10°C in dimethoxyethane. Yield 60%. M.p. 150-2°C (isopropyl ether).
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3=[CH:16][C:17]([C:19]([OH:21])=O)=[N:18][N:10]3[C:9](=[O:22])[C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1>CN(C=O)C>[CH2:1]([S:5][C:6]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3=[CH:16][C:17]([C:19]([NH:36][C:37]4[NH:41][N:40]=[N:39][N:38]=4)=[O:21])=[N:18][N:10]3[C:9](=[O:22])[C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1nnn[nH]1
Reactant: CCCCSc1ccc2[nH]c3cc(C(=O)O)nn3c(=O)c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCSc1ccc2[nH]c3cc(C(=O)Nc4nnn[nH]4)nn3c(=O)c2c1

Procedure:
From 4,9-dihydro-7-butylthio-9-oxo-pyrazolo-[5,1-b]quinazoline-2-carboxylic acid (1.9 g; 6 mmole), DMF (25 ml), 1,1'-carbonyl-diimidazole (2.19 g; 13.5 mmole) and 5-amino-1H-tetrazole, monohydrate (0.70 g; 6.8 mmole), following the procedure of Example 3, there is obtained 4,9-dihydro-7-butylthio-9-oxo-N-1H-tetrazol-5-yl-pyrazolo[5,1-b]quinazoline-2-carboxamide, with 1H-imidazole (3:1) (0.4 g); mp 285° (d).
Reaction SMILES: S(=O)(=O)(O)O.[N:6]([O-:8])=O.[Na+].[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]>O>[OH:8][N:6]=[C:12]([C:10]#[N:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC#N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C#N)=NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
62.5% sulfuric acid (603.7 g) were added dropwise to sodium nitrite (507.2 g) and ethyl cyanoacetate (791.0 g) in water (2,540 ml) at 30° to 40° C. over 2.2 hrs. under cooling. After completion of the addition, the mixture was stirred at a room temperature for 2 hrs, and the nitrogen oxide (NO2) was removed under reduced pressure, and the residue was cooled to 15° C. to separate crystals, which were filtered off and washed twice with water (150 ml) and twice with toluene (200 ml), and dried at 50° C. to give ethyl 2-hydroxyiminocyanoacetate (932.9 g, yield: 93.9%).
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH:16](O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O.O>ClCCl>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH:16]([Cl:26])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1OC(Cc2ccccc2)CN1CCC(O)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C1OC(Cc2ccccc2)CN1CCC(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
5-Benzyl-3-(3-hydroxy-3-phenylpropyl)-1,3-oxazolidine-2-one (0.31 g, 1 mmol) prepared in the above (2) was dissolved in dichloromethane (3 ml). To the solution, thionyl chloride (0.08 ml, 1.1 mmol) was added and stirred at room temperature for 30 minutes. After water was added, the obtained solution was extracted with ethyl acetate. The organic portion was sequentially washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and then dried over sodium sulfate. The solvent was then removed by distillation under reduced pressure to obtain 0.34 g of the titled compound as a colorless oil (yield: 100%).
Reaction SMILES: [O:1]=[C:2]1[N:11]2[CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH:13]3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:3]1.[H-].[Na+].[CH3:30]I>CN(C=O)C.O>[CH3:30][CH:3]1[C:2](=[O:1])[N:11]2[CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH:13]3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CI
Reactant: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(=O)CN3C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(=O)C(C)N3C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
To a solution of diethyl 1-oxo-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (360 mg, 0.97 mmol) in DMF (20 mL) at 0° C. was added NaH (193 mg, 4.8 mmol), MeI (0.3 mL, 4.8 mmol) and stirred at rt for 16 hours. The solution was diluted with water (20 mL), and extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate, concentrated to afford diethyl 2-methyl-1-oxo-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (300 mg, 80%) as a crude oil. MS [M+H]+ 388.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([OH:35])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:45]=1[O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:45]=3[O:58][CH2:59][C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OCc2ccccc2)c1
Reactant: BrCCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Yield: 76.7 %

Procedure:
A mixture of 1.5 g (3 mmol) of 3-hydroxy-5-(octadecyloxy) benzoic acid phenylmethyl ester, 1.6 g (3.4 mmol) of 1-(6-bromo-hexyl)-2,3-bis(phenylmethoxy)benzene [M. Carson, R.-J. Han and R. A. LeMahieu, U.S. Pat. No. 5,025,036 (1991)], 0.45 g (3 mmol) of potassium iodide and 0.84 g (6 mmol) of potassium carbonate in 40 ml of acetone and 10 ml of DMF was stirred at reflux for 47 hours. The solvents were removed at reduced pressure and the residue was purified by HPLC using 5% ethyl acetate-hexane to give 2.0 g (77% yield) of 3-[[6-[2,3-bis(phenylmethoxy)phenyl]hexyl]oxy]-5-(octadecyloxy)benzoic acid phenylmethyl ester as an oil. The nmr spectrum served to confirm the structure.
Reaction SMILES: C[N:2]([CH:4]=[C:5]([C:9](=O)[CH3:10])[C:6](=[O:8])[CH3:7])[CH3:3].NC1[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=1>C(O)C>[CH3:18][C:16]1[CH:17]=[C:3]2[N:2]=[CH:4][C:5]([C:6](=[O:8])[CH3:7])=[C:9]([CH3:10])[N:14]2[N:15]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CC(=O)C(=CN(C)C)C(C)=O
Solvent: CCO
Product: CC(=O)c1cnc2cc(C)nn2c1C
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 3-dimethylaminomethylene-pentane-2,4-dione (4 g, 25.8 mmol) and 3-amino-5-methylpyrazole (2.45 g, 24.5 mmol) in ethanol (50 mL) was heated to reflux for 2 hrs, then cooled to ambient temperature and stirred over night. The solid precipitate was collected by filtration and washed with cold ethanol (50 mL). The solid was dried under vacuum to provided 3.8 g of the title compound. 1H NMR (300 MHz, CD3OD) δ 2.52 (s, 3 H), 2.68 (s, 3 H), 3.07 (s, 3 H), 6.55 (s, 1 H), 6.87 (s, 1 H); MS (DCl/NH3) m/z 190 (M+H)+.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[C:26]([O:35][C:36]2[CH:37]=[C:38]([CH:41]=[C:42]([O:44][CH3:45])[CH:43]=2)[C:39]#[N:40])=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:40]=[C:39]([C:38]2[CH:41]=[C:42]([O:44][CH3:45])[CH:43]=[C:36]([O:35][C:26]3[C:25]([Cl:24])=[CH:30][C:29]([C:31]([F:33])([F:34])[F:32])=[CH:28][N:27]=3)[CH:37]=2)[N:2]([CH3:1])[N:3]=1
Reactant: COc1cc(C#N)cc(Oc2ncc(C(F)(F)F)cc2Cl)c1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(Oc2ncc(C(F)(F)F)cc2Cl)cc(-c2nc(-c3c(F)cccc3Cl)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (0.90 g), 3-(3-chloro-5-trifluoromethylpyridine-2-yloxy)-5-methoxybenzonitrile (0.80 g), anhydrous iron (III) chloride (0.80 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.60 g of desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]([N+:23]([O-])=O)=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[C:13]3[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=[CH:21][C:22]=3[NH:23][C:5]=2[CH:6]=[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=12
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1-c1ccc2c(c1OC)CCCC2
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Product: COC(=O)c1cccc2[nH]c3cc4c(c(OC)c3c12)CCCC4
Temperature: 25 °C
Yield: 44.1 %

Procedure:
A solution of 2-(1-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-3-nitrobenzoic acid, methyl ester, (0.5 g, 1.46 mM) in triphenyl phosphite (2.26 g, 1.91 mL, 7.29 mM) was heated at 160° C. for 48 h under a nitrogen atmosphere. The mixture was cooled to room temperature and dried azeotropically in vacuo with toluene, then purified by column chromatography on silica gel (elution with 10% ethyl acetate/hexane) to afford 0.2 g (44%) of the title compound 11-methoxy-7,8,9,10-tetrahydro-5H-benzo[b]carbazole-1-carboxylic acid, methyl ester as a tan solid (MP 194–196° C., MW 309.37).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH:18]([CH3:20])[CH3:19])=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[O:10][C:6]([CH2:4][OH:3])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1oc(-c2ccc(Br)cc2)nc1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(Br)cc2)oc1CO
Reaction time: 1.5 h
Yield: 99.2 %

Procedure:
A solution of 2-(4-bromo-phenyl)-4-isopropyl-oxazole-5-carboxylic acid ethyl ester (20.6 g, 60.9 mmol) in THF (300 mL) is cooled in an ice-water bath and treated portionwise with LiAlH4 (2.8 g, 73 mmol). The reaction is complete after 1.5 h. Ice chips (˜10 g) are added to quench the excess hydride reagent, and anhydrous Na2SO4 (˜50 g) is added. The thick suspension is stirred 30 min, filtered through celite, and washed with ThF (600 mL). The filtrate is dried (Na2SO4) and concentrated. The crude product is purified by silica gel flash chromatography using hexanes:ethyl acetate (3:1) to give a white solid (17.9 g, 99%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([NH:26][C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[N:8][C:9]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:5]=2[CH2:4][NH:3]1.[I:34]N1C(=O)CCC1=O>C(Cl)Cl>[I:34][C:10]1[C:5]2[CH2:4][NH:3][C:2](=[O:1])[C:6]=2[C:7]([NH:26][C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[N:8][C:9]=1[NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)c1
Solvent: ClCCl
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(I)c3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a screw-top vial was added tert-butyl (1S,2R)-2-(3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (73 mg, 0.162 mmol) and 1-iodopyrrolidine-2,5-dione (36.4 mg, 0.162 mmol) in DCM (1.6 mL) to give a yellow solution. The reaction was stirred 0.5 h at RT. The reaction mixture was diluted with DCM (10 mL) and washed with saturated aq NaHCO3 (10 mL), water (10 mL), and brine (10 mL). The collected organic layers were dried with sodium sulfate and concentrated to give the title compound as a brown solid, which was used without further purification (85.7 mg, 92%). [M+H] calc'd for C25H32IN5O3, 578. found, 578.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:25][CH2:26][CH2:27][CH2:28]Cl>CS(C)=O.O>[CH2:7]([NH:14][CH2:28][CH2:27][CH2:26][O:25][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: ClCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CNCCCOc2ccc3ccccc3c2)cc1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and benzyl amine (0.36 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 6 hrs. and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-benzyl-[3-(naphthalen-2-yloxy)-propyl]amine, solid, m.p. 109° C., (yield 0.62 gm, 93.6%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:20]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22])([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)NC(C)C)s1
Yield: 59 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (55 mg, 59%) which was obtained as an off white solid after recrystallization from heptane/ethyl acetate. MS: m/e=373.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26](Cl)=[N:25][S:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26]([O:37][CH2:36][CH:33]4[CH2:34][CH2:35][NH:30][CH2:31][CH2:32]4)=[N:25][S:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2Cl)CC1
Reactant: OCC1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2OCC2CCNCC2)CC1
Temperature: 50 °C
Yield: 15.2 %

Procedure:
4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)amide (50 mg, 0.11 mmol, prepared in Example 10b) was dissolved in 330 μL of t-butanol along with 4-piperadine methanol (38 mg, 0.33 mmol). Then, 330 μL of 1.0 M potassium t-butoxide in t-butanol was added. The reaction mixture was heated to 50° C. overnight. The reaction was quenched with the addition of a few drops of trifluoroacetic acid and the solution was diluted to 2 mL in volume with methanol. The reaction mixture was purified by reverse phase HPLC to give 9 mg of the product as a white solid. 1H NMR DMSO-d6) δ 9.37 (s, 1H), 8.25 (s, 2H), 7.62 (s, 1H), 4.28 (d, 2H), 3.63 (m, 4H), 3.54 (m, 4H), 3.08 (d, 2H), 2.59 (t, 2H), 1.93 (m, 1H), 1.71 (d, 2H), 1.29 (qd, 2H) ppm.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([OH:3])=[O:2].Br[CH:13](C(OCC)=O)[C:14]([O:16]CC)=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:1]1([C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:13]([C:14]([OH:16])=[O:15])[O:3]1)=[O:2]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=Cc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(O)c1cc2ccccc2c(=O)o1
Reaction time: 5 h

Procedure:
A mixture of 2- carboxybenzaldehyde (20.0g), diethyl bromomalonate (20.0g) and anhydrous potassium carbonate (20.0g) in ethyl methylketone (200ml.) was heated under reflux, with stirring, for 5 hours. The cooled mixture was evaporated to dryness and water (300ml.) added to the residue. After extraction with a mixture of ether-chloroform, the organic extracts were washed with water, dried and evaporated to dryness. The residual solid was heated under reflux with a mixture of concentrated hydrochloric acid (360ml.) -- acetic acid (240ml.) for 2 hours. After cooling, the mixture was poured into iced water (1,200ml.). Filtration gave the product as a white solid, m.p. 241°-2° (lit mp. 239-240°), (Found: C, 62.87; H, 3.39. C10H6O4 requires C, 63.16; H 3.18).