Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.Cl.[NH2:23][C@@H:24]([CH3:30])[C:25]([CH3:29])([CH3:28])[C:26]#[N:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:26]([C:25]([CH3:29])([CH3:28])[C@@H:24]([NH:23][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1)=[O:13])[CH3:30])#[N:27]
Reactant: C[C@H](N)C(C)(C)C#N
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(C)(C)C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
In a flask were combined 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1.10 g, 2.95 mmol), (S)-3-amino-2,2-dimethyl-butyronitrile hydrochloride (439 mg, 2.95 mmol), EDC (1.3 g, 6.8 mmol) and HOBt (1.15 g, 6.8 mmol). DMF (27 mL) was added followed by i-Pr2NEt (3.6 mL, 20.7 mmol). The reaction mixture was stirred at room temperature for 18 h and then quenched with water and extracted with EtOAc. The organics were washed with 10% citric acid, sat'd NaHCO3, sat'd LiCl, and sat'd NaCl then dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (50-100% EtOAc/hexane) to give 1.32 g (96%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-cyano-1,2,2-trimethyl-ethyl)-amide as an off-white powder.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[OH:22])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].CN(C)C.[C:27]([O:34][CH:35]([CH3:39])[C:36](Cl)=[O:37])(=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:36](=[O:37])[CH:35]([O:34][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:39])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CCCCCC(=O)OC(C)C(=O)Cl
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1O
Agent: CN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCC(=O)OC(C)C(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C

Procedure:
In 15 ml of dichloromethane are dissolved 0.75 g of 16β-ethyl-17β-hydroxy-4-estren-3-one and 0.5 ml of trimethylamine, and 0.5 ml of 2-(n-hexanoyloxy)propionyl chloride is added to the solution. The mixture is refluxed for 2 hours. After cooling, the reaction mixture is poured into a mixture of 100 ml of ethyl acetate and 30 ml of saturated aqueous sodium hydrogen carbonate solution. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue dissolved in a small amount of diisopropyl ether. The solution is subjected to silica gel column chromatography. After serial passage of diisopropyl ether-n-hexane mixtures (2:8, 100 ml and 1:6, 300 ml), elution is carried out with 500 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 0.48 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=1[C:36]([F:39])([F:38])[F:37]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[C:36]([F:38])([F:37])[F:39])[N:8]=1)=[O:5]
Reactant: FC(F)(F)c1cc(I)ccc1CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2ccc(I)cc2C(F)(F)F)n1)c1c(F)cccc1F
Reaction time: 0.25 h

Procedure:
To a solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(2.65 g, 11.9 mmol) in THF (20 ml) was added 1.0 lithium bis(trimethylsilyl)amide in THF (7.3 ml, 7.30 mmol, Aldrich) and stirred for 15 min. To the solution was added a solution of 1-(bromomethyl)-4-iodo-2-(trifluoromethyl)benzene (1.62 g, 4.44 mmol) in THF (10 ml). The resulting orange solution was stirred at ambient temperature under nitrogen overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate (150 ml). The phases were separated and the aqueous phase washed with ethyl acetate (50 ml). The combined organic phases were dried (MgSO4), filtered and the solvent removed in vacuo. The residue was loaded in dichloromethane and purified on silica 100 g×2 using 0-50% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white foam (1.3 g). LCMS: (System 4) MH+=508, tRET=3.22 min.
Reaction SMILES: FC(F)(F)C(O)=[O:4].O=S1(=O)CCNCC1.Cl[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:49]=[CH:48][C:24]([C:25]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:47])=[C:32]([NH:34][C:35](=[O:46])[C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=3)[CH:33]=2)=[O:26])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CC(N(C)C)=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[OH:4][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:49]=[CH:48][C:24]([C:25]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:47])=[C:32]([NH:34][C:35](=[O:46])[C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=3)[CH:33]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(OCCCCl)cc3)ccc2C)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S1(=O)CCNCC1
Agent: [I-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(OCCCO)cc3)ccc2C)cc1OC
Temperature: 100 °C

Procedure:
S,S-Dioxothiamorpholine trifluoroacetic acid salt (0.22 g) was added to a stirred mixture of N-{5-[4-(3-chloropropoxy)benzamido]-2-methylphenyl}-3,4-dimethoxybenzamide (0.5 g), tetra-n-butylammonium iodide (0.096 g), di-isopropylethylamine (0.29 g) and DMA (4 ml) and the mixture was stirred and heated to 100° C. for 1 week. The reaction mixture was allowed to cool to ambient temperature and poured into water (100 ml). The resultant precipitate was isolated and washed with water and with diethyl ether. The solid so obtained was purified by column chromatography on silica gel using increasingly polar mixtures of methylene chloride and methanol as eluent. There were thus obtained in turn:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[Br:12]Br.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2
Reactant: Cc1ccc2ncccc2c1
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc2ncc(Br)cc2c1
Temperature: 80 °C

Procedure:
6-Methylquinoline (1.9906 g, 13.903 mmol) was dissolved in 20 mL of carbon tetrachloride. Bromine (0.72 mL, 14 mmol) was added dropwise to the reaction solution and the suspension was heated to reflux (80° C.). Pyridine (1.15 mL, 13.9 mmol) was added while reaction was heating to 80° C. and the reaction was allowed to stir at reflux for 1.5 hours. The reaction was cooled to room temperature and diluted with dichloromethane. The reaction was washed with water and the organic was dried over sodium sulfate, filtered and concentrated to give a thick brown oil that solidified upon standing. The crude solid was purified on an 80 g silica gel ISCO column eluting with a very slow gradient: 0% to 15% to 20% ethyl acetate in heptanes to give the desired 3-bromo-6-methylquinoline. 1H NMR (400 MHz, CDCl3) δ ppm 2.52 (s, 3 H) 7.47 (s, 1 H) 7.54 (dd, J=8.59, 1.95 Hz, 1 H) 7.95 (d, J=8.59 Hz, 1 H) 8.19 (d, J=2.15 Hz, 1 H) 8.81 (d, J=2.34 Hz, 1 H). GCMS=221 at 2.93 minutes.
Reaction SMILES: [CH2:1]([N:8]1CC=C[CH:10]([CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:19]CC1.[C:23]([OH:27])([CH3:26])(C)[CH3:24].S(=O)(O)[O-].[Na+]>O.CC(C)=O.[Os](=O)(=O)(=O)=O>[CH2:1]([N:8]1[CH2:9][CH:10]([CH3:14])[CH:24]([OH:19])[CH:23]([OH:27])[CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1C=CCN(Cc2ccccc2)C1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1CN(Cc2ccccc2)CC(O)C1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
37 (570 mg, 3 mmol) is dissolved in 10 ml of a 1:1 mixture of water and acetone. After addition of N-methyl-morpholine-N-oxide (529 mg, 4.5 mmol), a 2.5% solution of osmium tetroxide in tert. Butanol (527 ul, 52 umol) is added. The mixture is stirred at room temperature for 24 h. Then 10 ml of a saturated sodium bisulfite solution is added. After 15 min stirring at room temperature, the reaction mixture is extracted with ethyl acetate. The organic layers are washed subsequently with 1N NaOH and brine, dried over sodium sulphate and evaporated. The crude product, 460 mg of a dark brown oil, is purified by Flash-chromatography (silica gel, dichloromethane/methanol/ammonia 95:5:0.5).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[C:10](Cl)(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C(C)=CC=CC=1C.BrC1C=C(NC(=O)/C=C/C2C=CC=CC=2)C=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:19])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1cc(F)cc(F)c1
Agent: O=C(/C=C/c1ccccc1)Nc1cccc(Br)c1
Solvent: Cc1cccc(C)n1
Product: O=C(/C=C/c1ccccc1)Nc1cc(F)cc(F)c1

Procedure:
The compound was prepared from 3,5-difluoroaniline (5 g, 38.7 mmol) and cinnamoylchloride (6.45 g, 38.7 mmol) in the presence of 2,6-lutidine (6.8 mL, 58 mmol) as described for Intermediate 18 to give a colorless solid, 8.1 g (81%).
Reaction SMILES: N1(C2CCCCC=2)CC[O:4]CC1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>O>[C:14]1([CH:13]=[C:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]2=[O:4])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccccc1
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: O
Product: O=C1CCCCC1=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
According to the procedure of Birkofer, et al., Chem. Ber., 85, 1495 (1962), a mixture of 1-morpholinyl-1-cyclohexene (125.2 g. 0.75 mole), prepared as described above, benzaldehyde (53.1 g, 0.5 mole), and 200 ml of benzene was refluxed for 12 hours with azeotropic separation of 5.3 ml of water. The reaction mixture was cooled and treated with 300 ml of 6N aqueous hydrochloric acid and stirred at room temperature for one hour. The organic layer was separated, the aqueous layer was extracted with diethyl ether, and the combined organic layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. Distillation in vacuo (0.07 mm Hg) gave a fraction bp 124°-128° C., 61.1 g of the substitled product (96.2% pure by gas liquid chromatography (GLC) gas analysis). Crystallization from diethyl ether-petroleum ether (30°-60° C.) at -70° C. gave 47.7 g of the subtitled product, mp 48° -50° C. (100% pure by GLC; Birkhofer, et al., loc cit report mp 56° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)C=CC=CC=1.[OH-].[Na+].[ClH:22].C1(C2NC(C)=C(C([Cl:36])C)N=2)C=CC=CC=1>C(O)C.O>[ClH:36].[ClH:22].[ClH:36].[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Cc1[nH]c(-c2ccccc2)nc1C(C)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C1CNCCN1
Temperature: 25 °C
Yield: 55 %

Procedure:
14 Grams (0.052 mol) of N-(diphenylmethyl)piperazine and 6 grams (0.15 mol) of sodium hydroxide were dissolved in 180 ml of a mixture of ethanol :water 60:40. The mixture was heated to reflux, then 2-phenyl-4-(1-chloroethyl)-5-methylimidazole hydrochloride in 180 milliliters of ethanol:water 60:40 were added dropwise. After 4 to 5 hours under reflux, the reaction mixture was allowed to cool to room temperature. The oil that separated was washed twice with water, then dissolved in ether and hydrochloric acid was added. The precipitate was recrystallized from ethanol to give 1-diphenylmethyl-4- 1-(2-phenyl-5-methyl-1H-imidazol-4-yl)ethyl!piperazine trihydrochloride (55% yield), which melted at 215° C.
Reaction SMILES: CN(C)C=O.[CH2:6]([O:13][CH:14]1[CH2:19][CH2:18][C:17]([O:20][Si](C(C)(C)C)(C)C)=[CH:16][CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CCCCCC>[CH2:6]([O:13][CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]([F:29])[CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OC1=CCC(OCc2ccccc2)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C1CCC(OCc2ccccc2)CC1F
Yield: 62 %

Procedure:
A N,N-dimethylformamide (150 mL) solution of {[4-(Benzyloxy)cyclohex-1-en-1-yl]oxy}(tert-butyl)dimethylsilane (23.2 g, 73.0 mmol) was cooled in an ice bath under nitrogen and to this was added Selectfluor™ (51.6 g, 146 mmol) in several portions. After 1 h the contents of the reaction flask were poured into 5% sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (4×) and the combined organic extracts were washed successively with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Flash column chromatography (hexane:ethyl acetate, 80:20) gave 4-(Benzyloxy)-2-fluorocyclohexanone as a pale oil (10.0 g, 62% yield): 1H NMR (CDCl3) δ 7.39-7.30 (m, 5H), 5.36-5.19 (m, 1H), 4.61 (s, 2H), 4.02 (m, 1H), 2.81-2.73 (m, 2H), 2.45-2.41 (m, 1H), 2.36-2.30 (m, 1H), 2.05-1.88 (m, 1H), 1.85-1.77 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:8]2)([O-:3])=[O:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[C:7]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1cc2c([N+](=O)[O-])cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c([N+](=O)[O-])cccc2n1Cc1ccc(Cl)c(Cl)c1
Yield: 89 %

Procedure:
Ethyl 4-nitroindole-2-carboxylate (26 g) [prepared according to S. M. Parameter et al. J. Amer. Chem. Soc., 1958, 80, 4621], 3,4-dichlorobenzyl chloride (16 ml), potassium carbonate (17 g) and potassium iodide (2 g) in DMF (250 ml) were stirred at 60° C. for 2 hours. The reaction was concentrated in vacuo and the residue partitioned between water and dichloromethane. Iso-hexane was added to the combined organic extracts resulting in crystallisation of the product as yellow needles (39 g, 89%) NMR d (CD3SOCD3) 1.30 (t, 3H), 4.32 (q, 2H), 5.93 (s, 2H), 6.88 (dd, 1H), 7.18 (d, 1H), 7.52 (d, 1H), 7.56 (dd, 1H), 7.78 (s, 1H), 8.17 (m, 2H); M/Z (+)1395 (MH+), 393.
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4].[CH:14]1([N:20]=[C:21]=[N:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1.O1CCOCC1>[OH:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4].[CH:23]1([NH:22][C:21]([NH:20][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:1])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The N-hydroxy-5-norbornene-2,3-dicarboximide active ester of N-benzyloxycarbonyl DL-2-hydroxy-4-aminoburyric acid was prepared according to the procedure of M. Fujino, et al [Chem. Pharm. Bull. Japan, 22, 1857 (1974)]. To an ice cold solution of 0.40 g. of N-benzyloxycarbonyl-DL-2-hydroxy-4-aminoburyric acid and 0.32 g. of N-hydroxy-5-norbornene-2,3-dicarboximide in 3 ml. of tetrahydrofuran-dioxane (1:1 v/v), there was added, with stirring, 0.36 g. of N,N'-dicyclohexylcarbodiimide and 1 ml. of the above solvent mixture. The solution was stirred in the cold for 30 minutes and then at room temperature for 2 hours. The N,N'-dicyclohexylurea which formed in the above reaction was collected on a filter and washed with three 1-ml. portions of tetrahydrofuran-dioxane (1:1 v/v).
Reaction SMILES: [C:1]([N:4]([CH3:24])[N:5]([C:13]1[CH:18]=[CH:17][C:16]([C:19](OCC)=[O:20])=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[BH4-].[Li+].C(O)C.CC(C)=O>C1COCC1>[C:1]([N:4]([CH3:24])[N:5]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(N(C(=O)OC(C)(C)C)N(C)C(C)=O)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(=O)N(C)N(C(=O)OC(C)(C)C)c1ccc(CO)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
tert-Butyl 2-acetyl-1-[4-(ethoxycarbonyl)phenyl]-2-methylhydrazinecarboxylate (2.06 g) was dissolved in THF (60 ml), lithium borohydride (90%, 0.74 g) was added, and ethanol (15 ml) was slowly added dropwise. The obtained mixture was stirred at 80° C. for 3 hr. Acetone (6.0 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water and then saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 (volume ratio)→1:2 (volume ratio)), and further recrystallized from ethyl acetate to give the title compound (1.22 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([S:17]([N:20](CC4C=CC(OC)=CC=4OC)[C:21]4[S:25][N:24]=[CH:23][N:22]=4)(=[O:19])=[O:18])=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[C:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH:3]=1.Cl.[CH3:44]O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([S:17]([NH:20][C:21]4[S:25][N:24]=[CH:23][N:22]=4)(=[O:18])=[O:19])=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[C:4]([C:37]2[CH:38]=[CH:39][N:40]([CH3:44])[N:41]=2)[CH:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([S:17]([NH:20][C:21]4[S:25][N:24]=[CH:23][N:22]=4)(=[O:19])=[O:18])=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[C:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH:3]=1
Reactant: CO
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4-c4ccnn4C)c[nH]c3c2)c(OC)c1
Agent: Cl
Solvent: ClCCl
Product: Cn1ccc(-c2cc(Cl)ccc2-c2c[nH]c3cc(S(=O)(=O)Nc4ncns4)ccc23)n1
Product: Cn1nccc1-c1cc(Cl)ccc1-c1c[nH]c2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A vial was charged with 3-(4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (Intermediate A) (28.44 mg, 0.046 mmol) in methanol (0.5 mL). Hydrogen chloride (4M in 1,4-dioxane) (114 μl, 0.458 mmol) was added, and the resulting mixture was stirred for 30 min. The mixture was diluted with DCM and concentrated in vacuo. The residue was suspended in MeOH, then filtered through Celite® (diatomaceous earth). The filtrate was concentrated, and the residue was dissolved in methanol and loaded onto a 500 mg SCX-2 ion exchange column. The column was eluted with methanol, then with a solution of 2N ammonia in methanol. The basic fractions were concentrated to give 3-(4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide 3-(4-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (19.36 mg, 0.041 mmol, 90% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=11.57 (br. s., 1 H), 8.05 (s, 1 H), 7.85 (dd, J=0.5, 1.6 Hz, 1 H), 7.71-7.58 (m, 2 H), 7.54 (d, J=8.5 Hz, 1 H), 7.49 (d, J=2.2 Hz, 1 H), 7.43-7.33 (m, 2 H), 7.23-7.04 (m, 1 H), 6.93 (d, J=2.6 Hz, 1 H), 6.30 (d, J=1.9 Hz, 1 H), 3.19 (br. s., 1 H). m/z (ESI) 471.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[N:6]([CH3:7])[C:5]3[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Cn1c(Cl)nc2ccccc21
Product: Cn1c(Nc2ccc(Br)cc2)nc2ccccc21
Temperature: 170 °C
Yield: 96.5 %

Procedure:
A mixture of 2-chloro-1-methyl-benzimidazole (0.639 g, 3.84 mmol) and 4-bromoaniline (0.710 g, 4.12 mmol) was heated at 170° C. for 21 h. The resulting brown solid was cooled to room temperature, washed with three 5-mL portions of heptane, and then triturated with toluene to afford N2-(4-bromophenyl)-1-methyl-1H-benzo[d]imidazol-2-amine (1.120 g, 90%) as a brown powder. RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=10.85 min, 96%; m/z 302 (MH+).
Reaction SMILES: O.NN.[C:4]([O:8][C:9]([N:11]1[C:24]2[C:16](=[CH:17][C:18]3[CH2:19][O:20][CH2:21][C:22]=3[CH:23]=2)[C@@H:15]([N:25]([CH2:44][C:45]2[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[C:47]([C:55]([F:58])([F:57])[F:56])[CH:46]=2)[C:26]2[N:27]=[N:28][N:29]([CH2:31][CH2:32][N:33]3C(=O)C4C(=CC=CC=4)C3=O)[N:30]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].CO.ClCCl>CO>[C:4]([O:8][C:9]([N:11]1[C:24]2[C:16](=[CH:17][C:18]3[CH2:19][O:20][CH2:21][C:22]=3[CH:23]=2)[C@@H:15]([N:25]([C:26]2[N:27]=[N:28][N:29]([CH2:31][CH2:32][NH2:33])[N:30]=2)[CH2:44][C:45]2[CH:46]=[C:47]([C:55]([F:57])([F:58])[F:56])[CH:48]=[C:49]([C:51]([F:52])([F:53])[F:54])[CH:50]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCN3C(=O)c4ccccc4C3=O)n2)c2cc3c(cc21)COC3
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCN)n2)c2cc3c(cc21)COC3
Temperature: 60 °C
Reaction time: 14 h

Procedure:
Add hydrazine monohydrate (1.94 mmol) to a solution of (S)-9-((3,5-Bis-trifluoromethyl-benzyl)-{2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-2H-tetrazol-5-yl}-amino)-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (0.13 mmol) in methanol (5 mL). After heating the mixture at 60° C. for 4 h cool to room temperature and stir for 14 h. Remove solvent under vacuum. Chromatograph over silica gel eluting with methanol/dichloromethane (0-5%) to provide the title compound as a colorless foam. MS (ES+): 642 (M+H).