Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[N:19]#[C:20]Br.[OH-].[Na+]>CCO>[C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:20]1=[NH:19]
Reactant: Cc1ccccc1NCCNc1ccccc1C
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1N1CCN(c2ccccc2C)C1=N
Reaction time: 1 h
Yield: 92.6 %

Procedure:
N,N' Bistolyl ethylene diamine (105.8 mg, .44 mmol) was taken up in EtOH (3 mL) to provide a light purple solution. This solution was then placed in a one-necked round-bottom flask (25 mL) equipped with magnetic stirbar and reflux condenser. To this solution, cyanogen bromide (50 mg, 0.47 mmol) in ethanol (2 mL) was added in a single portion. The resultant reaction mixture was stirred for 1 h. It was noted that the solution turned clear. The solution was then brought to reflux and maintained at that temperature for 16 h. The reflux condenser was then removed, allowing the solvent to evaporate. The reaction mixture was then fused at 150° C. for 30 min to provide a brown solid. This solid was immediately taken up in ethanol (4 mL) and placed into a centrifuge tube. To this solution 1N NaOH was added (8 mL) to provide a "whispy" tan precipitate. After several failed attempts to pellet the precipitate, the solution was simply extracted with chloroform (20 mL). The chloroform was concentrated to dryness to provide a clear oil (108.1 mg, 92.6%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20]([OH:22])=O)=[CH:5][N:4]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH2:30].ON1C2C=CC=CC=2N=N1.Cl.ClCCCl>CN(C)C=O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20](=[O:22])[NH:30][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[CH:5][N:4]=1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)O)cc1Cl
Reactant: NCc1ccccn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(CNc2nc(SC)ncc2C(=O)NCc2ccccn2)cc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Methylthio-4-(3-chloro-4-methoxybenzylamino)-5-carboxypyrimidine (prepared in Example 79) 0.500 g, 2-pyridylmethylamine 0.1749 g, 1-hydroxybenzotriazole 0.1987 g, 1,2-dichloroethane hydrochloride 0.3102 g and anhydrous dimethylformamide 5 ml are mixed together and stirred at 0° C. overnight and triturated with ethyl acetate-isopropyl ether to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyridylmethyl)carbamoyl]pyrimidine as a colorless powder, 0.5966 g. mp 143-144.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:18][C:19]#[N:20])[CH2:15][CH3:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCCl
Reactant: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCN(CC#N)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a solution of 150 mg 1-t-butyloxycarbonyl-4-ethylamino-piperidine (from Step A) in 3 ml DCE were added 60 mg of chloroacetonitrile, 109 mg of potassium carbonate, and 11 mg of potassium iodide. The reaction was stirred at 60° C. overnight. Methylene chloride was added, and the solution was washed with 2×20 ml water, and 20 ml brine. The solvent was then evaporated under reduced pressure. The residue was purified by flash chromatography with 20% EtOAc in hexane to give 115 mg of the title compound.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][NH:39][C:40]([CH3:42])=[O:41])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:15][CH2:16][C:17](=[O:20])[O:18][CH3:19])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.N[C@H](C(N[C@@H](C(NCC(N[C@H](C(NNC(C)=O)=O)CC1C=CC=CC=1)=O)=O)CC1C=CC=CC=1)=O)CC1C=CC(O)=CC=1.Cl>CO>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][NH:39][C:40]([CH3:42])=[O:41])=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26])=[O:22])[CH2:15][CH2:16][C:17](=[O:20])[O:18][CH3:19])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: COC(=O)CC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NNC(C)=O
Agent: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)CC[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NNC(C)=O
Yield: 86.1 %

Procedure:
Using Z-Tyr-(D)-Glu(OMe)-Gly-Phe-NHNH-COCH3 (0.40 g), the desired compound (0.28 g) is obtained in a similar manner to (III) of Example 47, Rf2 =0.27, [α]D23 +17.5° (c=0.38, MeOH), Aminoacid analysis (hydrolized with HCl); Glu 0.95, Gly 1.00, Tyr 0.92, Phe 0.98.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][C:15]=1[C:24]([F:27])([F:26])[F:25]>>[CH3:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[N:2]2)=[C:15]([C:24]([F:25])([F:27])[F:26])[CH:16]=1)(=[O:22])=[O:21]
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Product: CS(=O)(=O)c1ccc(Cn2ncc3cc(C=O)ccc32)c(C(F)(F)F)c1

Procedure:
1-(4-Methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-indazole-5-carbaldehyde and 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene following General Procedure A.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].C([CH2:25][NH2:26])C1C=CC=CC=1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:25][NH:26][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17]
Reactant: NCCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
To a solution of N-(5-bromopentyl)phthalimide (5 g, 16.9 mmol) in ACN (50 mL) was added N-benzylmethylamine (2.04 g, 16.9 mmol), followed by DIPEA (2.93 mL, 16.9 mmol). The reaction mixture was stirred at 50° C. for 3 hours and then the solvent was removed in vacuo. The residue was dissolved in DCM (100 mL), washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in MeOH (100 mL) and hydrogenated to remove the benzyl group using palladium on activated carbon (1 g, 10 wt. % (dry basis)) as a catalyst under a hydrogen gas balloon at room temperature overnight. The mixture was filtered through Celite and the solvent was removed in vacuo to yield 4.2 g of the title intermediate as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](OC2C(F)=C(F)C=C(F)C=2F)=[O:29])([C:16]2[CH:21]=CC=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH3:41][O:42][C:43]([CH:45]1[CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[C:50]3[NH:56][CH:55]=[CH:54][C:51]3=2)[NH:46]1)=[O:44].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([N:56]2[C:50]3[C:51](=[C:52]4[C:47](=[CH:48][CH:49]=3)[NH:46][CH:45]([C:43]([O:42][CH3:41])=[O:44])[CH2:53]4)[CH:54]=[CH:55]2)=[O:29])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[CH2:21])[CH:17]=[CH2:18])=[CH:7][CH:8]=1
Reactant: COC(=O)C1Cc2c(ccc3[nH]ccc23)N1
Reactant: COc1ccc(C(NCCCCCC(=O)Oc2c(F)c(F)cc(F)c2F)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=C)C(NCCCCCC(=O)n1ccc2c3c(ccc21)NC(C(=O)OC)C3)(c1ccccc1)c1ccc(OC)cc1
Reaction time: 15 h
Yield: 80.3 %

Procedure:
A solution of 7 (0.6 g, 1.1 mmol) was combined with 0.24 g (1.2 mmol) methylpyrrolo[4,5-e]indoline-7-carboxylate (Boger et al, supra) and 0.1 ml triethylamine in 5 ml of anhydrous CH2Cl2. The mixture was kept at room temperature for 15 h and concentrated under vacuum. The resultant solid, which was the desired product, was washed with 50% ethyl acetate/50% hexane to remove unreacted starting materials and 2,3,5,6-tetrafluorophenol. Drying under vacuum afforded 0.51 g (77%) of the title compound as a pale-yellow, crystalline solid.
Reaction SMILES: Cl.CN(C)C.C(N(CC)CC)C.[F:13][C@H:14]1[C@@H:19]([CH2:20][CH2:21][OH:22])[CH2:18][CH2:17][O:16][CH2:15]1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.O>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:22][CH2:21][CH2:20][C@H:19]2[CH2:18][CH2:17][O:16][CH2:15][C@H:14]2[F:13])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: OCC[C@H]1CCOC[C@H]1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC[C@H]2CCOC[C@H]2F)cc1
Reaction time: 1 h

Procedure:
Trimethylamine hydrochloride (128 mg, 1.34 mmol) and triethylamine (0.39 mL, 2.81 mmol) were added to a solution of (±)-cis-2-(3-fluorotetrahydro-2 H-pyran-4-yl)ethanol obtained (198 mg, 1.34 mmol) in toluene (5 mL). Subsequently, p-toluenesulfonyl chloride (382 mg, 2.00 mmol) was added thereto while cooling in ice, and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane only→hexane:ethyl acetate=1:1) to afford the title compound (354 mg) as a colorless oil.
Reaction SMILES: [OH:1][OH:2].S(=O)(=O)(O)O.[CH3:8][C:9](O)([CH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])[CH3:10]>O>[CH3:14][C:13]([O:15][O:15][C:13]([CH3:16])([CH3:14])[CH3:12])([CH2:12][CH2:11][C:9]([CH3:10])([O:1][O:2][C:9]([CH3:11])([CH3:10])[CH3:8])[CH3:8])[CH3:16]
Reactant: OO
Reactant: CC(C)(O)CCC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)OOC(C)(C)CCC(C)(C)OOC(C)(C)C
Reaction time: 1 h
Yield: 90 %

Procedure:
A reactor corresponding to FIG. 1 was initially charged with a mixture of 550 kg of 70% by weight hydrogen peroxide and 366 kg of 80% by weight sulphuric acid. With stirring and cooling of the reactor through the jacket, 250 kg of 2,5-dimethyl-2,5-hexanediol were metered in within 60 min, in the course of which the temperature rose from 20° C. to 30-32° C. The reaction mixture was stirred at 30° C. for another 90 min and then admixed with 200 kg of water. The stirrer was then switched off and the suspension formed was filtered within 10 min by applying reduced pressure to the filtration devices (5), in the course of which the liquid phase was sucked into the collecting vessel (7) and the precipitated 2,5-dimethylhexane-2,5-dihydroperoxide was retained in the vessel (2). The solid product retained in the reactor was washed by adding 500 kg of water, stirring the suspension for 3 min and filtering again by applying reduced pressure to the filtration devices (5). This washing operation was repeated once more. Thereafter, 481 kg of tert-butanol were added and the solid was dissolved therein by stirring and heating. 500 kg of 80% by weight sulphuric acid were metered into the resulting solution within 60 min with stirring and cooling of the reactor through the jacket, in the course of which the temperature rose to from 40 to 45° C. The reaction mixture was stirred at this temperature for a further 60 min and then admixed with 50 kg of water. The lower aqueous phase was removed and the liquid product was washed successively with 150 kg of water, 150 kg of 1% by weight sodium hydroxide solution and 150 kg of water, by stirring the phases and then removing the lower aqueous phase. After removal of residual water and volatile by-products by stripping under reduced pressure in a stripping column, 405 kg (90%) of 2,5-dimethyl-2,5-di(tert-butylperoxy)hexane were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:23][O:24][C:25](=[O:46])[C@H:26]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]2[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=2[Cl:45])=[O:37])=[CH:31][CH:30]=1)[NH2:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:23][O:24][C:25](=[O:46])[C@H:26]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:36]([C:38]2[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=2[Cl:45])=[O:37])=[CH:33][CH:34]=1)[NH:27][C:4]([C:3]1[CH:7]=[CH:8][C:9]([S:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:13])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6]
Reactant: O=C(O)c1ccc(S(=O)(=O)NCc2cccc(O)c2)cc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(S(=O)(=O)NCc2cccc(O)c2)cc1Cl
Yield: 54.5 %

Procedure:
A solution of 2-chloro-4-[(3-hydroxybenzylamino)sulfonyl]benzoic acid (50 mg; 0.146 mmol), 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester (60 mg; 0.1486 mmol), HBTU (5 mg; 0.15 mmol) and DIPEA (0.102 mL; 0.585 mmol) in dimethylformamide (3 mL) was stirred for 17 hr under argon at room temperature, then was concentrated to dryness under reduced pressure. The residue was partitioned between dichloromethane (25 mL) and 0.5 N HCl (25 mL). The separated aqueous phase was re-extracted with dichloromethane (10 mL), then the organic extacts were washed in turn with water (2×25 mL). The combined dichloromethane layers were dried (Na2SO4) and evaporated to give 90 mg of the crude product as a dark oil. Chromatography of the oil over silica gel (9 g; 4:1 ethyl acetate-hexane) yielded 55 mg of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]sulfonyl]phenyl]carbonyl]-L-phenylalanine methyl ester, as a colorless solid. FAB HRMS: (C31H26Cl3N3O7S) Obs. Mass 690.0639 Calcd. Mass 690.0635 (M+H).
Reaction SMILES: C([O:4][CH2:5][C:6]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:7][S:8]([NH2:11])(=[O:10])=[O:9])(=O)C.CO.C[O-].[Na+]>CO>[OH:4][CH2:5][C:6]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:7][S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: CCC(CC)(COC(C)=O)CS(N)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(CO)CS(N)(=O)=O
Yield: 61.7 %

Procedure:
NMR(CDCl3)δ: 0.88(6H,t), 1.58(4H,q), 2.09(3H,s), 3.24(2H,s), 4.13(2H,s), 5.10(2H,bs). d) To a solution of 3-acetoxy-2,2-diethyl-1-propanesulfonamide (6.5 g) in methanol (60 ml) was added 28 W/W % sodium methoxide methanol solution (5.2 g) at room temperature with stirring. After stirring for 40 minutes, the reaction mixture was concentrated to dryness, and the residue was subjected to a silica gel column chromatography, eluting with n-hexane-ethyl acetate (1:3). The corresponding fractions were concentrated to obtain 3-hydroxy-2,2-diethyl-1-propanesulfonamide (3.3 g).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15](=[O:17])[CH3:16])[NH:12][C:9]2=[N:10][CH:11]=1)([O-:5])=[O:4].O.C(OCC)(=O)C>C1COCC1.CO>[N+:3]([C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([CH:15]([OH:17])[CH3:16])[NH:12][C:9]2=[N:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CC(=O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
Sodium tetrahydroborate (0.15 g, 4.10 mmol) was added to a solution of 1-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)ethanone (0.28 g, 1.37 mmol) in THF (8.7 mL) and methanol (0.90 mL) at 0° C., after which the reaction mixture was warmed up to room temperature and stirred for 1 hour. The reaction mixture was then treated with water and ethyl acetate, and the layers were separated. The aqueous layer was extracted once with ethyl acetate. The organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 1-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.12 g, 41%).
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:17])(=O)=O>C(Cl)(Cl)Cl>[CH2:1]([S:13][Cl:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCS
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCSCl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of dodecane thiol (1.00 mL, 4.17 mmol, Aldrich Chemical Company) in 20 mL CHCl3 was added sulfuryl chloride (0.74 mL, 9.18 mmol, Aldrich Chemical Company), and the resulting mixture was stirred at room temperature for 18 h. Removal of solvent (aspirator), afforded dodecansulfenyl chloride that was determined to be sufficiently pure by 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9](NC1CCN(C2SC=CN=2)CC1)=[O:10].Cl.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([CH:38]=[C:39]([Cl:41])[N:40]=2)[C:34]([O:36][CH3:37])=[O:35])[CH2:27][CH2:26]1>>[Cl:41][C:39]1[CH:38]=[C:33]([CH:32]=[C:31]([N:28]2[CH2:27][CH2:26][CH:25]([NH:24][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[CH2:30][CH2:29]2)[N:40]=1)[C:34]([O:36][CH3:37])=[O:35]
Reactant: COC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3nccs3)CC2)c(Cl)c1Cl
Agent: Cl
Product: COC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c1

Procedure:
The title compound was prepared in a manner analogous to Example 18 starting from 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3) and methyl 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinate hydrochloride salt (Intermediate 93).
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[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:35][C:36]1[C:37]([O:45][CH3:46])=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[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[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:38]5[CH:39]=[CH:40][CH:41]=[C:36]([F:35])[C:37]=5[O:45][CH3:46])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1c(F)cccc1B(O)O
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(F)c5OC)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-fluoro-2-methoxyphenylboronic acid.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][C:36]1[N:37]=[CH:38][NH:39][CH:40]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][C:36]1[N:37]=[CH:38][NH:39][CH:40]=1)[C:30]([N:32]([CH3:33])[CH3:34])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H](N)Cc1c[nH]cn1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](Cc2c[nH]cn2)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.48 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 77-2 (5.28 mmol, crude form) as starting materials, respectively 0.57 g (Isomer A, colorless powder) and 0.88 g (Isomer B, colorless powder) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C>CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: CN1CCC(N)CC1
Reactant: Nc1ccc(C(=O)O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of 1.0 g (5.9 mole) of 4-amino-3-chlorobenzoic acid, 0.8 g (7.0 mole) of 4-amino-1-methyl-piperidine and 4.14 mL (23 mmole) of ethyldiisopropyl amine in 20 mL of dimethylformamide was added a solution of 2.4 g (6.4 mole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate in 5 mL of dimethylformamide. The mixture was stirred at room temperature for 2 hours, then diluted with ice water and saturated sodium carbonate. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-60:40) gave 1.41 g of 4-amino-3-chloro-N-(1-methyl-piperidin-4-yl)-benzamide as a solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]3[C:22]([CH3:25])=[N:23][N:24]=[C:20]3[C@H:19]([CH3:26])[CH2:18][NH:17][C:16]=2[CH:27]=1.C([O-])(C)(C)C.[K+]>CS(C)=O.O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]3[C:22]([CH3:25])=[N:23][N:24]=[C:20]3[C@H:19]([CH3:26])[CH2:18][N:17]([C:2]3[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=3)[C:16]=2[CH:27]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1NC[C@H]2C
Reactant: O=[N+]([O-])c1ccc(F)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc([N+](=O)[O-])nc1)C[C@H]2C
Temperature: 120 °C
Yield: 77.1 %

Procedure:
To a solution of 5-fluoro-2-nitropyridine (284 mg, 2 mmol) and (R)-8-bromo-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (292 mg, 1 mmol) in dimethyl sulfoxide (5 mL) was added potassium tert-butanolate (223 mg, 2 mmol). The reaction mixture was heated at 120° C. for 1 hour under microwave (pressure: 3.2 bar, equipment power: 150 W). The mixture was diluted with water (50 mL), extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give (R)-8-bromo-1,4-dimethyl-6-(6-nitropyridin-3-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (320 mg, 77%) as a light yellow solid.