Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:16].[C:17](Cl)(=[O:19])[CH3:18].C(OCC)(=O)C.O>CN(C=O)C>[C:17]([N:7]1[C:6]2[CH:5]=[CH:4][C:3]([OH:16])=[C:2]([Cl:1])[C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:19])[CH3:18]
Reactant: Oc1ccc2c(c1Cl)Sc1ccccc1N2
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccccc2Sc2c1ccc(O)c2Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-3-hydroxyphenothiazine (2.2 g) in DMF (10 ml) was added 10 ml of acetyl chloride. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate was then added, followed by ice and H2O. The organic layer was separated, dried and evaporated. The resulting residue was purified by chromatography on silica gel to give 1.4 g of 10-acetyl-4-chloro-3-hydroxy-10H-phenothiazine (m.p. 214° C.).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH-].[K+]>C(Cl)(Cl)Cl>[CH3:11][C:10]1([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[C:2]1=[CH2:1]
Reactant: CCCCCCCCCCCCBr
Reactant: CC1=Nc2ccccc2C1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=C1N(CCCCCCCCCCCC)c2ccccc2C1(C)C
Temperature: 80 °C
Yield: 82 %

Procedure:
To a solution of 1.6 g of 2,3,3-trimethylindolenine in 10 ml of chloroform was added 2.8 g of 1-bromododecane and the mixture was heated in an autoclave at 80° C. for 20 hours. The resulting precipitate was recovered by filtration to give 3.7 g of 1-dodecyl-2,3,3-trimethylindolenium as white crystals. To the crystals thus obtained was added 40 ml of 10N aqueous potassium hydroxide solution in a nitrogen atmosphere and the mixture was heated at 50° C. for 3 hours. The reaction mixture was then extracted with ether and the extract was dried over magnesium sulfate and concentrated under reduced pressure to give 2.7 g of 3,3-dimethyl-1-dodecyl-2-methyleneindoline (Yield 82%).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[C:8]([C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].C(=O)([O-])O.[Na+]>C(OCC)C.O1CCCC1.N1C=CC=CC=1>[CH3:6][C:7]1[C:8]2[C:14]3[N:18]([CH:17]=[CH:16][N:15]=3)[C:3](=[O:4])[NH:10][C:9]=2[CH:11]=[CH:12][CH:13]=1.[CH3:6][C:7]1[C:8]2[C:14]3[N:18]([CH:17]=[CH:16][N:15]=3)[CH2:2][C:3](=[O:4])[NH:10][C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(N)c1-c1ncc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1cccc2[nH]c(=O)n3ccnc3c12
Product: Cc1cccc2c1-c1nccn1CC(=O)N2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7. A solution of 8.25 ml of chloroacetyl chloride in 25 ml of diethyl ether is added dropwise at 0° C. within 15 min. to a solution of 11.5 g of 3-methyl-2-(1H-2-imidazolyl)aniline in 0.35 l of tetrahydrofuran and 21 ml of pyridine. The reaction mixture is stirred at 0° C. for 1 h, and then poured into saturated aqueous sodium hydrogen carbonate solution. The mixture is extracted three times with chloroform. The organic extracts are evaporated in a vacuum. The residue (13 g) is dissolved in 300 ml of dioxan and treated with 200 ml of 1N aqueous sodium hydroxide solution. The mixture is stirred at room temperature for 16 h., then adjusted to pH 6 with hydrochloric acid and evaporated in a vacuum. The residue is suspended in absolute ethanol and the insoluble inorganic salt is filtered off. The filtrate is evaporated in a vacuum, the residue is dissolved in trifluoroacetic acid and stirred at room temperature for 16 h. The reaction mixture is evaporated in a vacuum and the residue is partitioned between chloroform and saturated aqueous sodium hydrogen carbonate solution. The organic phases are evaporated in a vacuum. The residue is chromatographed over a column of 500 g of silica gel. Elution with ethyl acetate gives in succession 1.4g of 10-methylimidazo[1,2-c]quinazolin-5(6H)-one (m.p. 308°-310° C.) and 9.0 g 11-methyl-5H-imidazo[1,2-d][1,4]benzodiazepin-6(7H)-one of m.p. 188°-189° C.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:24]1[CH2:26][O:25]1)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:27][NH:28][CH3:29]>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:24]([OH:25])[CH2:26][N:28]([CH3:29])[CH3:27])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CNC
Reactant: CCCC(=O)c1cnc2c(C3CO3)cccc2c1Nc1ccccc1C
Product: CCCC(=O)c1cnc2c(C(O)CN(C)C)cccc2c1Nc1ccccc1C
Yield: 28 %

Procedure:
A mixture of 3-butyryl-4-(2-methylphenylamino)-8oxiranylquinoline (1.0 g, 2.89 mmol) and 33% w/w dimethylamine in methylated spirits (10 ml) was heated at 95° for 2 hours in a pressure vessel. After cooling and evaporation of the solvent, the residue was purified by flash chromatography (silica gel, methanolic ammonia/dichloromethane) and crystallistion from aqueous ethanol to give 3-butyryl-4-(2-methylphenylamino)-8-(1-hydroxy-2-dimethylaminoethyl)quinoline (0.32 g, 28%), m.p. 95°-96°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([CH2:18][OH:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C[N:23]=[C:24]=[S:25].O1CCC[CH2:27]1>[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[C@H:17]([CH:18]([CH3:27])[O:19][C:24](=[S:25])[NH2:23])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN=C=S
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1CO
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(OC(N)=S)[C@@H]1Cc2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To 50 mL dichloromethane solution containing (S)-3-hydroxymethy-1,2,3,4-tetrahydroisoquinoline (4.53 g, 27.75 mmol) was added di-tert-butyl dicarbonate (5.45 g, 25.0 mmol, 0.9 eq) and the reaction mixture was stirred for 2 hours until no gas bubbling was observed. The reaction mixture was washed with 0.5 N HCl (50 mL) followed by brine (50 mL) to remove the residual starting material. After drying wth MgSO4 and filtration the, dichloromethane mixture was evaporated to yield crude (S)-N-tert-Butyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline. The crude N-tert-Butyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline was redissolved in 100 mL tetrahydrofuran. NaH (60%, 1.22 g) was added portion by portion to the solution at 0° C. and after 30 min stirring at room temperature, MeNCS (2.23 g) was added and the mixture was stirred for 2 h at rt. Brine (50 mL) was added to the mixture to quench the reaction and after evaporation of volatile component in vacuo, it was extracted with dichloromethane (50 mL×2) and combined layer was dried (MgSO4), filtered, evaporated. The resulting material was chromatographed with hexane-EtOAc (4:1) mixture over SiO2 to provide 7.07 g (81.8%) of (S)-N-tert-butyloxycarbonyl-3-(-Methyl-thiocarbamoyloxymethyl)-1,2,3,4tetrahydroisoquinoline. This material was dissolved in THF(30 mL) and 10 mL conc. HCl was added to the solution. One hour later, 5 mL of conc. HCl was added and stirred another 1 h until the reaction was finished. The reaction mixture was diluted with 30 mL of water and volatile components were evaporated. During the evaporation, desired product was precipitated as white solid. The solid was filtered and dried to yield the product as the hydrochloride salt (4.8 g).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[C:7](=[O:17])[NH:6]1)[CH:2]([CH3:4])[CH3:3]>CO.[Pd]>[NH2:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[NH:6][C:7]2=[O:17]
Reactant: CC(C)Cn1[nH]c(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)Cn1[nH]c(=O)c2cc(N)ccc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of 1-isobutyl-5-nitro-1,2-dihydro-indazol-3-one (0.9 g) in MeOH (50 mL) was added Pd/C(10%) catalyst (0.3 g) and the reaction mixture was stirred for 1 hour at 40° C. under a hydrogen atmosphere using a balloon. After this time the reaction mixture was filtered through Celite® which was washed with more EtOAc. The combined organic solution was evaporated in vacuo for afford the desired 5-amino-1-isobutyl-1,2-dihydro-indazol-3-one (0.6 g) which was taken into the next reaction without further purification. MS (ESI+): 206.1 ([M+H]+).
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14]C)=[C:10]([N+:16]([O-])=O)[CH:9]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H].[CH2:21](O)C>[Ni]>[N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([NH:16][CH3:21])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [H][H]
Reactant: CNc1ccc(C(C)n2ccnc2)cc1[N+](=O)[O-]
Reactant: CCO
Agent: [Ni]
Product: CNc1cc(C(C)n2ccnc2)ccc1N
Yield: 100 %

Procedure:
(b-1) A mixture of 21 parts of 4-[1-(1H-imidazol-1-yl)ethyl]-N-methyl-2-nitrobenzenamine and 160 parts of ethanol was hydrogenated at room temperature in a Parr apparatus at 0.5 105Pa with 20 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, nitrogen was bubbled through the mixture and the catalyst was filtered off over diatomaceous earth. The filtrate was evaporated at <40° C., yielding 18.5 parts (100%) of 4-[1-(1H-imidazol-1-yl)ethyl]-N2 -methyl-1,2-benzenediamine as a residue (int. 97).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42])=[O:34]>C(#N)C>[CH3:42][O:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:33](=[O:34])[CH2:32][N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:16]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: COc1ccccc1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccccc1OC
Yield: 89 %

Procedure:
Using the procedure described in example 5, treatment of L-proline-L-isoleucine benzylamide (317 mg, 0.99 mmol), with sodium carbonate (211 mg, 1.99 mmol), and 2-bromo-2'-methoxyacetophenone (457 mg, 1.99 mmol, 2.0 eq) in acetonitrile (10 mL), provided 410 mg (88%) of L-isoleucine, N-[1-(2-(2-methoxyphenyl)-2-oxoethyl)-L-prolyl] benzylamide as a pale yellow oil.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]3[N:18]=[N:17][NH:16][N:15]=3)=[CH:12][C:11]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:10]([Cl:23])[CH:9]=2)[S:4][CH:5]=1.[CH2:24]=O.CO.CN([CH:31]=[O:32])C>C(Cl)Cl.C(Cl)Cl.CN(C=O)C>[Cl:23][C:10]1[CH:9]=[C:8]([NH:7][CH2:6][C:3]2[S:4][CH:5]=[CH:1][CH:2]=2)[C:13]([C:14]2[N:15]([CH2:24][O:32][CH3:31])[N:16]=[N:17][N:18]=2)=[CH:12][C:11]=1[S:19]([NH2:22])(=[O:21])=[O:20]
Reactant: CN(C)C=O
Reactant: C=O
Reactant: NS(=O)(=O)c1cc(-c2nn[nH]n2)c(NCc2cccs2)cc1Cl
Solvent: ClCCl
Solvent: CO
Product: COCn1nnnc1-c1cc(S(N)(=O)=O)c(Cl)cc1NCc1cccs1

Procedure:
Azosemide can be reacted with formaldehyde and methanol in methylene chloride, methylene chloride-DMF mixtures or DMF to yield 2-chloro-5-[1-(methoxymethyl)-1H-tetrazol-5-yl]-4-[(2-thienylmethyl)amino]benzenesulfonamide.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([NH2:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O>C(O)C>[CH2:26]([NH:31][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: CC(C)(C)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)CNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (200 mg, 0.774 mmol) in ethanol (5 mL) was added potassium carbonate (214 mg, 1.55 mmol) and neopentylamine (135 mg, 1.55 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (245 mg, 97% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([C:12]1[N:17]=[C:16]([Cl:18])[N:15]=[C:14]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)[CH:13]=1)[CH3:11]>CN(C)C=O>[ClH:18].[CH2:10]([C:12]1[N:17]=[C:16]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])[N:15]=[C:14]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)[CH:13]=1)[CH3:11]
Reactant: CCc1cc(N2CCc3ccccc3C2)nc(Cl)n1
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: CCc1cc(N2CCc3ccccc3C2)nc(Nc2ccc(F)cc2C)n1
Product: Cl
Yield: 53.9 %

Procedure:
After 2-methyl-4-fluoroaniline(0.57 ml, 5.13 mmol) was added to a mixture solution of 6-ethyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine(0.7 g, 2.56 mmol) and dimethylformamide(5 ml), 0.55 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:11]1[CH:16]=[C:15]([CH2:17][O:18][CH3:19])[N:14]=[CH:13][N:12]=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[CH:16]=[C:15]([CH2:17][O:18][CH3:19])[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: COCc1cc(Cl)ncn1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: C1COCCO1
Product: COCc1cc(Nc2ccc(Cl)c(Cl)c2)ncn1
Temperature: 100 °C
Yield: 56.7 %

Procedure:
A mixture of 3,4-dichloroaniline (1.328 g, 8.20 mmol) and 4-chloro-6-(methoxymethyl)pyrimidine (0.65 g, 4.10 mmol) in dioxane (20.5 ml) was heated at 100° C. for 54 h, cooled to room temperature and concentrated onto Na2SO4. The residue was purified on silica gel using 50-100% ethyl acetate in hexanes, then 10-15% methanol in ethyl acetate. The desired fractions were concentrated to give a dark brown solid which was triturated with DCM to yield N-(3,4-dichlorophenyl)-6-(methoxymethyl)pyrimidin-4-amine as a brown solid (0.66 g, 57%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.67 (1H, d, J=1.00 Hz), 7.69 (1H, d, J=2.51 Hz), 7.44 (1H, d, J=8.53 Hz), 7.29 (1H, dd, J=8.53, 2.51 Hz), 6.95 (1H, br. s.), 6.81 (1H, d, J=1.00 Hz), 4.45 (1H, d, J=0.50 Hz), 3.50 (2H, s). LCMS: R.T.=0.77; [M+H]+=283.98.
Reaction SMILES: C[O-].[Na+].[O:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6]2[N:11]=[CH:12][CH:13]=[CH:14][C:5]1=2.[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O>CN(C=O)C>[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=[C:9]1[O:4][C:5]2[CH:14]=[CH:13][CH:12]=[N:11][C:6]=2[NH:7][C:8]1=[O:10]
Reactant: O=C1COc2cccnc2N1
Reactant: O=Cc1ccc[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ncccc2OC1=Cc1ccc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (0.65 g, 0.012 mol) was added in one portion to a mixture of 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (1.50 g, 0.01 mol) and pyrrole-2-carboxaldehyde (1.58 g, 0.016 mol) in dry DMF (10 ml). The reaction mixture was refluxed for 48 h, then cooled to room temperature, poured into crushed ice and left overnight at 4° C. The precipitated solid was filtered off, washed with water and dried. The dark solid was boiled with ethanol (150 ml) and filtered hot to remove impurities. The filtrate was evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatographed using (95:5) toluene:ethyl acetate as the mobile phase.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[O:20])=[CH:15][C:14]=2[O:29][CH3:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:39])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])(=[O:39])=[O:20])=[CH:15][C:14]=2[O:29][CH3:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(S(=O)c2ccccc2C#N)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc(S(=O)(=O)c2ccccc2C#N)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.2 %

Procedure:
To 3-[4-(2-cyano-benzenesulfinyl)-2-methoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.135 mg, 0.3165 mmol) dissolved in DCM (5 mL) was added m-CPBA (0.115 mg, 0.9495 mmol), and the mixture was stirred at room temperature for 6 hours. DCM was added and the resulting mixture was washed with sodium thiosulfate (10% aqueous solution), NaHCO3 (saturated aqueous solution), water, and brine. The organic phase was then dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (hexane/EtOAc, 1/1) to give 0.125 g (89% yield) of 3-[4-(2-cyano-benzenesulfonyl)-2-methoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClCc1ccc(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
2,4-Dibenzyloxybenzyl alcohol [VI] (19.8 g) was dissolved in anhydrous benzene (150 ml) and then, thereto was added thionyl chloride (40 g), followed by reflux under heating for 1 hour. This was concentrated to dryness under reduced pressure to obtain crude 2,4-dibenzyloxybenzyl chloride [VII]. This was used for the subsequent reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:14](=O)[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Br:21])[CH:16]=2)=[CH:10][C:11]=1[O:12][CH3:13])[C:6](O)=[O:7].O.[NH2:24][NH2:25]>C(O)C>[Br:21][C:17]1[CH:16]=[C:15]([C:14]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=3)[C:6](=[O:7])[NH:25][N:24]=2)[CH:20]=[CH:19][N:18]=1
Reactant: NN
Reactant: COc1cc(C(=O)O)c(C(=O)c2ccnc(Br)c2)cc1OC
Solvent: CCO
Solvent: O
Product: COc1cc2c(-c3ccnc(Br)c3)n[nH]c(=O)c2cc1OC

Procedure:
3,4-Dimethoxy-6-(2-bromoisonicotinoyl)benzoic acid (15.2 g) and hydrazine monohydrate (15 ml) are added to ethanol (30 ml), and the mixture is heated under reflux for one hour. The reaction mixture is cooled with ice, and the precipitates are collected by filtration to give 2-bromo-4-(6,7-dimethoxyphthalazin-1(2H)-on-4-yl)pyridine (14.1 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6](C)=[N:7][C:8]=1S)#[N:2].O.[NH2:14][NH2:15]>C(O)C>[C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6]([NH:14][NH2:15])=[N:7][CH:8]=1)#[N:2]
Reactant: CNc1nc(C)nc(S)c1C#N
Reactant: NN
Solvent: O
Solvent: CCO
Product: CNc1nc(NN)ncc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-cyano-4-methylamino-2-methyl-sulfanyl-pyrimidine (25.86 g) from Example 3 and hydrazine hydrate (52 mL) in ethanol (250 mL) was heated at reflux with stirring for 3 hours. The reaction mixture was cooled to room temperature and the insoluble product was collected by filtration, washed with cold aqueous ethanol (1:1) to give 23 g of the title compound. Crystallization from ethanol afforded an analytically pure sample of 5-cyano-2-hydrazino-4-methylamino-pyrimidine, mp 247°-249° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]([F:37])([F:36])[C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.FC(F)(F)[C:40]1[CH:41]=[C:42](S(N2C[C@H]3[C@H](N)CC[C@H]3C2)(=O)=O)C=[CH:44][CH:45]=1>>[CH:11]1([CH2:10][C@H:9]([N:8]([CH3:12])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13](=[O:15])[NH:35][C@@H:32]2[C@@H:30]3[C@@H:29]([CH2:28][N:27]([S:24]([C:21]4[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:36])[F:37])=[CH:23][CH:22]=4)(=[O:25])=[O:26])[CH2:31]3)[CH2:34][CH2:33]2)[CH2:42][CH2:41][CH2:40][CH2:45][CH2:44]1
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CN(C(=O)OC(C)(C)C)[C@@H](CC1CCCCC1)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
tert-Butyl(S)-3-cyclohexyl-1-oxo-1-((3aR,4S,6aS)-2-(4-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-ylamino)propan-2-yl(methyl)carbamate was prepared by substituting (S)-2-(tert-butoxycarbonyl(methyl)amino)-3-cyclohexylpropanoic acid for (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid and (3aR,4S,6aS)-2-(4-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 256 Step A for (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 266: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.51 (d, J=6.9, 1H), 8.13 (d, J=8.2, 2H), 7.90 (d, J=8.3, 2H), 5.23-5.14 (m, 0.4H), 4.89-4.79 (m, 0.6H), 4.28-4.15 (m, 1H), 3.83 (d, J=10.6, 1H), 3.17-3.01 (m, 5H), 2.94 (dd, J=9.4, 7.2, 1H), 2.57-2.48 (m, 2H), 1.99-1.74 (m, 5H), 1.67 (d, J=13.1, 1H), 1.62-1.48 (m, 4H), 1.45 (s, 9H), 1.34-1.20 (m, 2H), 1.18-1.00 (m, 3H), 0.98-0.85 (m, 1H), 0.81-0.66 (m, 1H); MS (ESI+) m/z 602 (M+H)+.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19](=[O:31])[CH2:20][C:21]1([NH2:30])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:16]([O:18][C:19](=[O:31])[CH2:20][C:21]1([NH:30][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)[CH3:17]
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Reactant: CCOC(=O)CC1(N)Cc2ccccc2C1
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: CCOC(=O)CC1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 2-cyclobutyloxy-3-methylbenzoic acid (210 mg-1.02 mmol), 2-aminoindan-2-acetic acid ethyl ester (A6) (260 mg-1.02 mmol) and HATU (470 mg-1.224 mmol-1.2 eq) in dry DMF (10 mL) is added diisopropylethylamine (0.36 mL-2.24 mmol-2.2 eq) and the resulting solution is stirred at RT overnight. After the removal of the DMF in vacuo, the residue is dissolved in EtOAc (60 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic layer is dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (120 g silica gel, 15% EtOAc in heptane) to give the pure product as colorless oil (400 mg, 96%).