Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([O:53][C:54]([N:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=[C:57]1[C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([NH2:71])[CH:66]=1)=[O:55])([CH3:52])([CH3:51])[CH3:50]>CN(C=O)C>[C:49]([O:53][C:54]([N:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=[C:57]1[C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([NH:71][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:66]=1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: CC(C)(C)OC(=O)n1c(-c2cccc(N)c2)cc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc2ccccc21
Temperature: 25 °C
Yield: 62 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2-(3-Amino-phenyl)-indole-1-carboxylic acid tert-butyl ester (0.02 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.02 g of product in 64% yield: LCMS (ESI) m/z 497 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:28]1([CH2:34][CH2:35][C:36](=O)[CH2:37][CH3:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:36]([CH2:37][CH3:38])[CH2:35][CH2:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCC(=O)CCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(CC)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-phenyl-pentan-3-one.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=2)[CH:9]=[CH:8][CH:7]=1.[C:22]([C:24](=[CH2:28])[C:25](O)=[O:26])#[N:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:19][C:17]1[CH:18]=[C:13]([NH:12][C:10]2[N:11]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:25](=[O:26])[C:24]([C:22]#[N:23])=[CH2:28])[CH:7]=[CH:8][CH:9]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: C=C(C#N)C(=O)O
Reactant: Cn1cc(Br)cc(Nc2cccc(OCCN)n2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C#N)C(=O)NCCOc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
A mixture of 3-(6-(2-aminoethoxyl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one 103a (480 mg, 1.42 mmol), 2-cyanoacrylic acid (790 mg, 2.84 mmol), DIPEA (1.2 mL, 7.12 mmol) and HATU (810 mg, 2.13 mmol) in DCM (10 mL) was stirred at rt for 16 h. The reaction mixture was concentrated and purified by silica gel chromatography (PE/EA=1/2) to give N-(2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)ethyl)-2-cyanoacrylamide 117a (400 mg, 67%) as green solid. ESI-LCMS: m/z=420.0
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:18][Mg]Br.[NH4+].[Cl-]>CCOCC>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][C:14]([OH:17])([CH3:18])[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: C[Mg]Br
Reactant: O=C1CCN(c2cccc3c2OCCO3)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(O)CCN(c2cccc3c2OCCO3)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.5 g (15 mmol) of 1-(2,3-dihydro[1,4]benzodioxin-5-ylpiperid-4-one are dissolved in 30 ml of ether. The solution is cooled to 0° C. and, while that temperature is maintained, 10 ml of a 3M methylmagnesium bromide solution in ether are added. The whole is stirred for 1 hour at that temperature and then for 1/2 hour at room temperature, hydrolysed by pouring into 100 ml of a saturated aqueous NH4Cl solution, and extracted with 100 ml of ether. The extract is dried and evaporated to yield a residue of 3.3 g, which is purified by flash chromatography on silica (eluant CH2Cl2 /CH3COOC2H5 : 90/10). In that manner, 1.3 g of the expected product are isolated.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][C:10]([CH3:38])=[CH:11][C:12]=3[CH:14]([O:16][CH2:17][C:18]3([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH3:15])[CH:7]=[N:6]2)[CH2:3][CH2:2]1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][C:10]([CH3:38])=[CH:11][C:12]=3[CH:14]([O:16][CH2:17][C:18]3([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH3:15])[CH:7]=[N:6]2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C(=O)OC(C)(C)C)CC2)c2c(cnn2CC2CC2)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C)CC2)c2c(cnn2CC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-((1-(1-(cyclopropylmethyl)-5-methyl-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (7 mg, 0.01 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (4.2 mg, 0.07 mmol) and formalin (37 μL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by flash chromatography on silica gel (10% methanolic ammonia/methylene chloride) to afford 4 mg (68%). LC/MS (HPLC method 1): tR=2.49 min, 436.59(MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH2:13](O)[CH2:14][CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)C1(OCCCO1)C(=O)N2
Yield: 73.6 %

Procedure:
A mixture of 5-methylisatin (8.00 g, 49.6 mmol), 1,3 propanediol (10.89 mL, 149 mmol, 3 eq) and p-toluenesulfonic acid monohydrate (1.89 g, 9.92 mmol, 0.2 eq) in benzene (940 mL) was heated to reflux under a Dean Stark Trap for 17.5 hr. The reaction mixture was concentrated. The residue was taken up in EtOAc (300 mL) and washed with sat. aq. NaHCO3 (2×) and concentrated. The crude product was purified on Biotage KP silica gel eluting with 60/40 Pet ether/EtOAc to give the title compound as a yellow solid (8.0 g., 74% yield). NMR (300 Mz, DMSO-d6): consistent.
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][CH2:3]1.[CH2:13](I)[CH3:14]>>[CH2:13]([N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH2:3][C:2]1=[O:1])[CH3:14]
Reactant: O=C1CCNc2ccccc2N1
Reactant: CCI
Product: CCN1C(=O)CCNc2ccccc21

Procedure:
2-Oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (1.95 g, 11.96 mmol) was reacted with ethyl iodide (1.4 ml, 17.5 mmol) according to the procedure in Example 18A. The product was purified by flash chromatography on silica (eluant EtOAc); yield 1.70 g (75%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH2:28]([O:30][C:31](=[O:38])[C@@:32]([F:37])([CH3:36])[C:33](O)=[O:34])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:38])[C@@:32]([F:37])([CH3:36])[C:33]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2)=[O:34])[CH3:29]
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)[C@](C)(F)C(=O)O
Product: CCOC(=O)[C@](C)(F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and (R)-2-fluoro-2-methyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Light yellow oil (96%). MS: m/e=505(M+H+).
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])(=[O:5])[C:2]([O-:4])=O.[CH2:12]([NH2:15])[CH2:13][NH2:14]>FC(F)(F)CO>[F:9][C:8]([F:11])([F:10])[CH2:7][O:6][C:1](=[O:5])[C:2]([NH:14][CH2:13][CH2:12][NH:15][C:2](=[O:4])[C:1]([OH:6])=[O:5])=[O:4]
Reactant: O=C([O-])C(=O)OCC(F)(F)F
Reactant: NCCN
Solvent: OCC(F)(F)F
Product: O=C(O)C(=O)NCCNC(=O)C(=O)OCC(F)(F)F
Reaction time: 18 h

Procedure:
A 500 mL 3-neck round bottom flask equipped with a magnetic stirbar, thermocouple, and argon inlet was charged with 2,2,2-trifluoroethyl oxalate (from Preparatory Example P7) (152.5 grams) and 2,2,2-trifluoroethanol (150 grams). The contents were cooled in an ice bath, and a mixture of ethylene diamine (EDA) (3.606 grans) in 2,2,2-trifluoroethanol (40 grams) was added dropwise over a period of 75 minutes. The cooling bath was removed, and the contents were stirred for 18 hours, after which time methyl tert-butyl ether (100 mL) was added, and the solids were then collected via filtration. The resulting 10.2 grams of solids was recrystallized from boiling 2,2,2-trifluoroethanol (416 grams) to obtain 9.23 grams of ethylene-bis-oxamic acid trifluoroethyl ester as white crystals having a melting point of 223° C. 1H NMR (300 MHz, d6-DMSO) δ 9.18 (brs, 2H), 4.92 (q, J=8.9 Hz, 4H), 3.31-3.29 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[CH:4][C:3]=1[CH:16]([CH3:35])[C:17]([OH:34])([C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][C:28](=[O:31])[N:27]([CH3:32])[C:26]=2[CH:33]=1)[C:18]([F:21])([F:20])[F:19].[C:36]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)([OH:38])=[O:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:43]2[CH:42]=[CH:41][CH:40]=[C:39]([C:36]([OH:38])=[O:37])[CH:44]=2)=[CH:4][C:3]=1[CH:16]([CH3:35])[C:17]([OH:34])([C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][C:28](=[O:31])[N:27]([CH3:32])[C:26]=2[CH:33]=1)[C:18]([F:21])([F:20])[F:19]
Reactant: CC(c1cc(OS(=O)(=O)C(F)(F)F)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: CC(c1cc(-c2cccc(C(=O)O)c2)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, trifluoromethanesulfonic acid 4-chloro-3-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-phenyl ester (Example 17, step 1) was reacted with 3-carboxyphenylboronic acid to give the title compound as a light brown solid. MS (m/e, ISP neg. ion)=518.2 [M−H+].
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Br:5][C:6]([Br:10])([CH3:9])[CH2:7][OH:8].N1C=CC=CC=1>C(Cl)Cl>[Br:5][C:6]([Br:10])([CH3:9])[CH2:7][O:8][C:1]([Cl:4])=[O:2]
Reactant: CC(Br)(Br)CO
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Br)(Br)COC(=O)Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
16 ml (0.22 mol) of liquid phosgene are condensed into 33 g (0.15 mol) of 2,2-dibromopropanol in 150 ml of CH2Cl2, at -20° C, and 12 ml (0.15 mol) of pyridine in 15 ml of CH2Cl2 are then added slowly dropwise at -20° C to -5° C and the mixture is stirred for a further 2 hours at 20° C. The solution is washed, at 0° C, with water, 5% strength sulphuric acid and H2O and dried (Na2SO4) and the solvent is stripped off (46.1 g of crude product). Vacuum distillation gives 36.3 g (86%) of 2,2-dibromopropoxycarbonyl chloride as a colorless liquid. Boiling point12 = 81°-86° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@H:16]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:21][CH2:20]1)=[O:18])C)(C)(C)C>ClCCl>[CH3:27][N:26]([CH2:25][CH:22]1[CH2:23][CH2:24][N:19]([C:17](=[O:18])[C@H:16]([NH:14][CH3:13])[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:20][CH2:21]1)[CH3:28]
Reactant: CN(C)CC1CCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccccc1)C(=O)N1CCC(CN(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
At 0° C., trifluoroacetic acid (20 ml) was added to a solution of N-[(1R)-1-benzyl-2-(4-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamic acid tert-butyl ester (1.22 g, 3.02 mmol) in dichloromethane (20 ml). The reaction mixture was stirred for 1 h at 0° C. The solvents were removed in vacuo. The residue was dissolved in dichloromethane (70 ml) and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (100 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1), to give 659 mg of (2R)-1-(4-((dimethylamino)methyl)piperidin-1-yl)-2-(methylamino)-3-phenylpropan-1-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([CH2:23][OH:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([CH2:23][O:24][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCC1CC1
Reactant: Cc1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [H-]
Agent: [Na+]
Product: Cc1nc2c(cc1COCC1CC1)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 1 intermediate d) from (4R,9aR)-7-hydroxymethyl-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 15, intermediate b), sodium hydride and (bromomethyl)cyclopropane.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH2:21]([NH:28][CH2:29][C:30]1[N:31]=[N:32][N:33]([CH3:35])[N:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:28]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][C:30]3[N:31]=[N:32][N:33]([CH3:35])[N:34]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: Cn1nnc(CNCc2ccccc2)n1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2ccccc2)Cc2nnn(C)n2)[C@H]1O
Yield: 48 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using epoxide compound (200 mg, 0.71 mmol) obtained in step 1 of example 2 and N-benzyl-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (145 mg, 0.71 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:2), to give desired compound (165 mg, yield: 48%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][NH:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17]Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Si:1]([O:8][CH2:9][C@@H:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)CCCCCl)CO[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CN1CCCCC1=O
Reaction time: 4 h

Procedure:
Upon cooling a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-(5-chloropentanamido)propan-2-ylcarbamate (500 mg, 1.18 mmol) in DMF (10 mL) to 0° C., NaH (52 mg, 1.30 mmol) was added. The reaction mixture was stirred for 4 h. The mixture was taken up in EtOAc, washed with saturated NaCl solution, dried over Na2SO4, concentrated under reduced pressure and the crude (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-(2-oxopiperidin-1-yl)propan-2-ylcarbamate was used in next step without purification (370 mg, 81%). 1H NMR (CDCl3, 300 MHz) δ 5.25 (d, 1H), 4.04-3.81 (m, 2H), 3.67-3.20 (m, 4H), 2.36 (m, 2H), 1.78 (m, 4H), 1.41 (s, 9H), 0.88 (s, 9H), 0.0 (s, 6H).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[F:18][C:19]([F:38])([F:37])[C:20]1[CH:21]=[C:22]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=1>>[O:17]=[C:6]1[C:5](=[CH:4][NH:36][C:33]2[CH:34]=[CH:35][C:30]([S:27]([NH:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:38])([F:18])[F:37])[CH:21]=3)(=[O:29])=[O:28])=[CH:31][CH:32]=2)[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7]1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: Nc1ccc(S(=O)(=O)Nc2cccc(C(F)(F)F)c2)cc1
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)Nc2cccc(C(F)(F)F)c2)cc1
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and N-(3-trifluoromethylphenyl)-4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ11.2 (d, 1H), 10.9 (s, 1H), 10.7 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 (m, 3H), 7.5 (m, 4H), 7.1 (d, 1H); APCI−MS m/z 515 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH:30]=O)[CH2:10][N:11]2[C:17](=[O:18])[C:16]3[C:19]4[C:24]([CH:25]=[C:26]([C:27]#[N:28])[C:15]=3[S:14][CH2:13][CH2:12]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:33][O:34][NH2:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH2:30][NH:35][O:34][CH3:33])[CH2:10][N:11]2[C:17](=[O:18])[C:16]3[C:19]4[C:24]([CH:25]=[C:26]([C:27]#[N:28])[C:15]=3[S:14][CH2:13][CH2:12]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CON
Reactant: N#Cc1cc2ccccc2c2c1SCCN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C2=O
Agent: Cl
Product: CONCC[C@H](CN1CCSc2c(C#N)cc3ccccc3c2C1=O)c1ccc(Cl)c(Cl)c1
Yield: 65.8 %

Procedure:
By the method described in Example 79, Intermediate 78a (40 mg, 0.085 mmol) and methoxyamine hydrochloride (13 mg, 0.154 mmol) were converted to 28 mg of the title compound.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH2:11]>C(Cl)Cl>[NH:4]1[C@H:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]2[NH:11][C:1]1=[S:3]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: S=C=S
Solvent: ClCCl
Product: S=C1N[C@H]2CCCC[C@H]2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of carbon disulfide (1.1 mL, 17.9 mmol) and CH2Cl2 (10 mL) was treated dropwise with cis-1,2-diaminocyclohexane 20-1 (Aldrich) (2.0 g, 17.5 mmol) while maintaining the reaction mixture temperature below 20° C. with an ice bath. The reaction mixture was stirred at ambient temperature for 2.0 h after the addition was complete. Concentration followed by refluxing the resulting solid in H2O (20 mL) for 20 h gave a yellow solution. The cooled solution was extracted with CH2Cl2 and the CH2Cl2 portion was dried (MgSO4) and concentrated. The pale yellow solid was recrystallized from CH2Cl2 /ether to give 20-2 as a pale yellow solid. mp=164°-166° C.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[S:8])[CH2:6][CH:5]=[CH:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[OH-].[Na+].Br[CH:16]([CH3:20])[C:17]([OH:19])=[O:18]>O>[C:17]([CH2:16][CH2:20][S:8][C:7]1[C:2]([CH3:1])=[C:3]([CH:4]=[CH:5][CH:6]=1)[C:9]([O:11][CH3:12])=[O:10])([OH:19])=[O:18]
Reactant: COC(=O)C1=C(C)C(=S)CC=C1
Reactant: CC(Br)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cccc(SCCC(=O)O)c1C

Procedure:
70 g (0.38 mol) of methyl 3-thio-2-methylbenzoate are dissolved in 400 ml of water and refluxed for 7 hours together with 30.8 g (0.77 mol) of sodium hydroxide solution and 58.8 g (0.45 mol) of bromopropionic acid. After cooling, the aqueous phase is washed using methyl tert-butyl ether. The aqueous phase is subsequently acidified using 2N HCl, the precipitate which has formed is filtered off with suction and washed with water, and the product is dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([F:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[N:30]=[C:29]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]3[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:13]=[CH:12][CH:11]=3)[CH:5]=[CH:6][CH:7]=2)[C:28]([F:32])=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cccc(N)c2)n1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)n1
Yield: 76 %

Procedure:
To a solution of tert-butyl {6-[2-(3-aminophenyl)ethyl]pyridin-2-yl}carbamate (200 mg, 0.64 mmol) (prepared in Example C17, step B) and 2,4-dichloro-5-fluoropyrimidine (112 mg, 0.67 mmol) in N,N-dimethylformamide (2.9 mL) was added potassium carbonate (264 mg, 1.91 mmol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered first to remove K2CO3. The filtrate was concentrated to give the residue, which was purified by silica gel column chromatography to give the desired product as a light yellow gum (216 mg, 76%). LCMS for C22H24ClFN5O2 (M+H)+: m/z=444.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15]CC)=O)=[CH:9]2)([O-:3])=[O:2].[NH3:18]>>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH2:18])=[O:15])=[CH:9]2)([O-:3])=[O:2]
Reactant: N
Reactant: CCOC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Product: NC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Temperature: 50 °C

Procedure:
A suspension of 133 mg (0.57 mmol) of ethyl 7-nitroindole-2-carboxylate in 3.84 ml of 28% aqueous ammonia is heated at 50° C. for 18 h in a stoppered glass tube. The reaction medium is filtered over sintered glass. The yellow solid obtained is washed with water and with cyclohexane and then dried under vacuum. 70 mg of 7-nitro-1H-indole-2-carboxamide are obtained in the form of a yellow solid.