Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](CCSCCC#N)#[N:2].[C:10]([NH:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[N:25]=[N:26][C:27]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][C:30]([N+:36]([O-:38])=[O:37])=[CH:29][C:28]=1Br)[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])(=[O:12])[CH3:11].[C-]#N.[Na+]>O>[C:10]([NH:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[N:25]=[N:26][C:27]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][C:30]([N+:36]([O-:38])=[O:37])=[CH:29][C:28]=1[C:1]#[N:2])[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])(=[O:12])[CH3:11]
Reactant: N#CCCSCCC#N
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 60 °C
Reaction time: 0.42 h

Procedure:
Into a reactor there are introduced 765 parts of bis (β-cyanoethyl) sulfide, followed by 14.35 parts of cuprous bromide. On heating to 60° C. with continuous stirring, a brownish-yellow solution of the copper complex is obtained. 95.8 parts of 3-acetamido-4-(2'bromo-4',6'-dinitrophenylazo)-N,N-diethylaniline are added, and the temperature is raised to 115° C. Raising the temperature to 115° C. causes the compound to completely dissolve. At ths temperature, a solution of 10.8 parts of sodium cyanide in 40 parts of water is introduced into the reactor during a period of 20 minutes, allowing the steam to escape. Stirring is continued for a further 20 to 30 minutes while verifying by thin layer chromatography that the starting organic bromo-derivative is absent. The reaction mass is cooled to 30°-35° C., which causes crystallization of the dyestuff. The resultant product is filtered off, washed with water to displace the solvent contained in the paste, and dried. 80.2 parts of 3 -acetamido-4-(2'cyano-4',6'-dinitro-phenylazo)-N,N-diethylaniline are obtained. The titre (purity) of this product is 98.5% and it contains a copper concentration of less than 3000 parts per million. The wash water is introduced into a decanter, and the organic solvent part is withdrawn and reunited with the fraction of solvent obtained during filtration. There are thus recovered 720 parts of bis(β-cyanoethyl) sulfide which contain 4.35 parts of the cyanoazo dyestuff (giving an overall balance of the reaction of 98%) and 5.75 parts of copper (which corresponds to a recovery of 91% of the initial copper complex.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][N:4]=1)=[O:2].C[O-].[Na+].S([CH2:26][N+:27]#[C-:28])(C1C=CC(C)=CC=1)(=O)=O>CO>[O:2]1[C:1]([C:3]2[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=2)=[CH:28][N:27]=[CH:26]1
Reactant: COC(=O)c1ccc(C=O)nc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc(-c2cnco2)nc1

Procedure:
To a suspension of methyl 6-formylnicotinate (60 mg, 0.363 mmol) in methanol (3 mL) was added sodium methoxide in methanol (0.5M, 2.91 mL, 1.45 mmol). Tosylmethyl isocyanide (85 mg, 0.436 mmol) was added to the reaction and the mixture was heated at reflux overnight. After cooling, the reaction mixture was concentrated. The residue was treated with 5% citric acid/50% brine (1:1) and extracted with ethyl acetate. The suspension was filtered, washed with water, and dried under vacuum to provide the title compound. MS (DCI/NH3) m/z: 191.0 (M+1)+.
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.[F:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[CH:32]([NH:34][C:35]1[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([NH2:45])[CH:41]=3)[N:36]=1)[CH2:31][CH2:30]2>>[F:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:1]([NH:45][C:40]2[CH:41]=[C:42]3[C:37](=[CH:38][CH:39]=2)[N:36]=[C:35]([NH:34][CH:32]2[C:33]4[C:29](=[CH:28][CH:27]=[CH:26][C:25]=4[O:24][CH3:23])[CH2:30][CH2:31]2)[CH:44]=[CH:43]3)=[O:2])[CH2:18][CH2:17]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: NC1CCN(CCF)CC1
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)NC4CCN(CCF)CC4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-(2-fluoroethyl)-piperidin-4-ylamine and rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172); MS: m/e=478.7 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(=O)CCCC1.[C-]#N.[K+].CN(C)[C:21]1([C:26]#[N:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.C#N>O>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:21]1([C:26]#[N:27])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CNCc1ccccc1
Reactant: CN(C)C1(C#N)CCCC1
Agent: C#N
Agent: [C-]#N
Agent: [K+]
Solvent: O=C1CCCC1
Solvent: O
Product: CN(Cc1ccccc1)C1(C#N)CCCC1
Yield: 84 %

Procedure:
The title compound (15 g; 84%) was prepared from N-methylbenzylamine (10.08 g; 83 mmol), cyclopentanone (7 g; 83 mmol) and potassium cyanide (5.41 g; 83 mmol) in water (45 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 1.90 (6H, m), 2.20 (3H, s), 2.3 (2H, m), 3.62 (2H, s), 7.25 (1H, m), 7.32 (4H, m); Mass Spectrum (Electrospray LC/MS): Found 188 (MH+−HCN). C14H18N2 requires 214. Ret. time 1.21 min.
Reaction SMILES: [I-].[K+].II.[CH3:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]([SH:21])=[N:19][N:18]=[N:17]2)[CH:13]=[CH:14][CH:15]=1)=[S:8]>O.C(O)C>[CH3:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]([S:21][S:21][C:20]3[N:16]([C:12]4[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:7](=[S:8])[CH2:6][CH3:5])[CH:11]=4)[N:17]=[N:18][N:19]=3)=[N:19][N:18]=[N:17]2)[CH:13]=[CH:14][CH:15]=1)=[S:8]
Reactant: CCC(=S)Nc1cccc(-n2nnnc2S)c1
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCC(=S)Nc1cccc(-n2nnnc2SSc2nnnn2-c2cccc(NC(=S)CC)c2)c1

Procedure:
A solution of 3.0 g of potassium iodide and 3.2 g of iodine in 50 ml of water and 25 ml of ethanol was added dropwise with stirring and at room temperature to 7 g of 1-[m-(methylthioacetylamino)-phenyl]-5-mercaptotetrazole. The precipitate was purified by recrystallization from methanol.
Reaction SMILES: Cl.CC[O:4]CCO.[Cl:8][C:9]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:10]=1[C:11]([C:13]1[C:22]([OH:23])=[CH:21][C:16]2[C:17]([C:19]#[N:20])=[CH:18][C:15]=2[CH:14]=1)=[O:12]>O>[Cl:8][C:9]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:10]=1[C:11]([C:13]1[C:22]([OH:23])=[CH:21][C:16]2[C:17]([C:19]([NH2:20])=[O:4])=[CH:18][C:15]=2[CH:14]=1)=[O:12]
Reactant: N#CC1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Reactant: CCOCCO
Agent: Cl
Solvent: O
Product: NC(=O)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Reaction time: 48 h

Procedure:
20 ml of concentrated hydrochloric acid and 10 ml of Cellosolve are added to 2 g of 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carbonitrile and stirring is carried out for 2 days at room temperature. 100 ml of water are added with stirring and the whole is filtered with suction and recrystallised from ether/hexane. 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxamide is obtained having a melting point of 174°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[C:20]([CH:32]([F:34])[F:33])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[C].[Pd]>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:32]([F:34])[F:33])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C#Cc2ccc(OCc3ccccc3)c(C(F)F)c2)COC(C)(C)OC1
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(CCc2ccc(O)c(C(F)F)c2)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 89.4 %

Procedure:
Compound 51-3 (11.1 g) was dissolved in 1,4-dioxane (250 ml), 10% palladium carbon (3.5 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3.5 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The residue was suspended in a mixed solution of diisopropyl ether and hexane and collected by filtration to give the object product (8.17 g) as a white powder.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([C:8]1[O:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1)([CH3:7])([CH3:6])[CH3:5].[OH-].[Na+]>CS(C)=O>[C:4]([C:8]1[O:9][CH:10]=[C:11]([CH2:13][C:1]#[N:2])[N:12]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: [C-]#N
Reactant: CC(C)(C)c1nc(CCl)co1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)c1nc(CC#N)co1
Temperature: 65 °C
Yield: 92.6 %

Procedure:
6.2 g of sodium cyanide was weighed, 50 ml of dimethylsulfoxide was added thereto, and a dimethylsulfoxide solution of 16.9 g of 2-tert-butyl-4-chloromethyloxazole was dropwise added thereto, and heated on an oil bath at 65° C. for 1 hour with stirring. After the resulting product was cooled to room temperature, 150 ml of a dilute aqueous solution of sodium hydroxide was added thereto, and extracted with toluene. The organic layer was fully washed with water, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 14.8 g of 2-tert-butyl-4-cyanomethyloxazole.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:11]([O:13][C:14]([CH:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:15])[CH3:12].Cl.[CH3:30]N(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1.CN(C1C=CC=CN=1)C>[CH2:11]([O:13][C:14]([CH:16]1[N:21]([C:6]([C:5]2[CH:4]=[N:3][CH:2]=[CH:10][C:9]=2[CH3:30])=[O:8])[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:17]1)=[O:15])[CH3:12]
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1cnccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 6-methylnicotinic acid (29 g) in dry dichloromethane (400 mL) was treated with piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (57.58 g, prepared according to the procedure described in WO 96/31478 Step B page 94), then with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40.7 g). After stirring at room temperature for a further 1 hour the reaction mixture was treated with 4-dimethylaminopyridine (3.00 g) and stirring continued overnight. The reaction mixture was then further treated with dimethylaminopyridine (1.00 g). After stirring for a further 7 hours the reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and then water. The organic phase was dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of ethyl acetate and pentane (2:1, v/v) to give the title compound (54.0 g) as a yellow oil, Rf 0.31 (ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[NH:10][C:9]1=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][CH2:20][O:21][CH3:22]>>[C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[N:10]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:9]1=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)NC2CCCC21
Reactant: COCCCBr
Product: COCCCN1C(=O)N(C(=O)OC(C)(C)C)C2CCCC21

Procedure:
The title compound was prepared in accordance with the general method of example 1, step 2 starting from (rac)-(3aSR,6aRS)-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butyl ester (Example 1, step 1) and using 1-bromo-3-methoxypropane instead of iodoethane to yield the desired product as a light yellow oil which was directly used in the next step without further characterisation.
Reaction SMILES: [C:1]([CH:8]([CH2:12][CH3:13])[C@@H:9](N)[OH:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC1(C)[N:20]([O])C(C)(C)CCC1.[Br-].[Na+].C(=O)([O-])O.[Na+]>ClCCl.O>[C:4]([O:3][C:1]([C@:8]([NH2:20])([CH2:12][CH3:13])[CH:9]=[O:10])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC1(C)CCCC(C)(C)N1[O]
Reactant: CCC(C(=O)OC(C)(C)C)[C@@H](N)O
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC[C@](N)(C=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 77 %

Procedure:
To a solution of (S)-2-Boc-aminobutanol (50 g; 264 mmol) in dichloromethane (500 mL) and water (350 mL) were added at 20° C. TEMPO (0.01 eq), sodium bromide (1 eq) and sodium hydrogencarbonate (3 eq). The reaction mixture was stirred at 0° C. and diluted bleach (1.3 eq, 450 mL) was added over 40 min. The reaction mixture was stirred for 30 min. at 0° C. and then quenched with aq. thiosulfate. After decantation and extractions (dichloromethane), the organic phase was washed with brine, dried and concentrated in vacuo to dryness, giving (S)-2-(tert-butoxycarbonyl)-aminobutyraldehyde as a low-melting solid (38.1 g; yield: 77%).
Reaction SMILES: N[C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:11])[O-:10])[C@H:4]([C:12]2[O:16][N:15]=[C:14]([CH3:17])[N:13]=2)[CH2:3]1.[CH3:18][C:19]([CH3:21])=O.[C:22]([BH3-])#[N:23].[Na+].C=O>C(Cl)Cl>[CH:19]([N:23]([CH3:22])[C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:11])[O:10][CH2:12][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[C@H:4]([C:12]2[O:16][N:15]=[C:14]([CH3:17])[N:13]=2)[CH2:3]1)([CH3:21])[CH3:18]
Reactant: [BH3-]C#N
Reactant: Cc1noc([C@@H]2C[C@H](N)CC[C@@H]2NC(=O)[O-])n1
Reactant: CC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1noc([C@@H]2C[C@H](N(C)C(C)C)CC[C@@H]2NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The entirety of (1S,2R,4R)-4-amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexylcarbamate prepared in Step 1 (1 eq) was dissolved in CH2Cl2 (20 mL) The resultant solution was charged with acetone (10 eq) and stirred at RT for 10 min before sodium cyanoborohydride (2 eq) was added in one portion. The reaction was stirred at RT for 10 h and then charged successively with formaldehyde (10 eq in 37 wt % aq soln) and sodium cyanoborohydride (2 eq). The reaction was stirred for another 9 h at RT and then quenched with sat. NaHCO3. The aqueous mixture was extracted with EtOAc (40 mL, then 2×40 mL). The organic extracts were combined, washed with brine (30 mL), dried (MgSO4), filtered, and concentrated in vacuo. After the resulting oil stood, some paraformaldehyde-related products solidified; these were removed by dissolving the mixture in a minimal volume of EtOAc and filtering. Subsequent concentration provided 270 mg of benzyl (1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexylcarbamate. MS found: (M+H)+=387.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][O:7][C:8]2[C:33]([F:34])=[CH:32][C:11]([CH2:12][C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[N:15]([Si](C(C)C)(C(C)C)C(C)C)[CH:14]=3)=[C:10]([F:35])[CH:9]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[C:33]([F:34])=[CH:32][C:11]([CH2:12][C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)=[C:10]([F:35])[CH:9]=2)=[CH:36][CH:37]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2cc(F)c(OCc3ccc(Cl)cc3)cc2F)c2cccnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Fc1cc(OCc2ccc(Cl)cc2)c(F)cc1Cc1c[nH]c2ncccc12
Reaction time: 0.17 h
Yield: 28.6 %

Procedure:
To 3-[4-(4-chloro-benzyloxy)-2,5-difluoro-benzyl]-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (604, 0.150 g, 0.28 mmol) in tetrahydrofuran (10.0 mL) was added tetra-n-butylammonium fluoride (80.0 mg, 0.31 mmol). After 10 minutes, the reaction was concentrated and purified by silica gel column chromatography eluting with 50% ethyl acetate in hexane to give the compound as a white solid (P-1974, 30.8 mg, 28.9%). MS(ESI) [M+H+]+=385.3.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([O:27]C)=[O:26])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[NH:17][CH2:16][CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1.CO.[OH-].[Na+]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([OH:27])=[O:26])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[NH:17][CH2:16][CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNc1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNc1ccccc1-3
Yield: 76.7 %

Procedure:
A solution of methyl 13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-carboxylate (45.8 mg, 0.12 mmol) in THF/MeOH (1:2, 3 mL) and 1N aqueous NaOH (0.5 mL) was heated at 50° C. for 5 h. The reaction solution was concentrated to remove volatile organics, neutralized with TFA (0.04 mL) and purified by preparative HPLC (MeOH/H2O with TFA buffer) to yield 13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-carboxylic acid (33 mg, 0.092 mmol, 76%) as white solid. 1HNMR (500 MHz, MeOD) δ 8.25 (s, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.79 (dd, J=8.5, 1.2 Hz, 1H), 7.63–7.52 (m, 3H), 7.50–7.46 (m, 1H), 4.44 (br s, 2H), 3.92–3.86 (m, 2H), 3.03 (tt, J=12.4, 3.1 Hz, 1H), 2.21–2.10 (m, 2H), 1.97–1.80 (m, 5H), 1.54–1.36 (m, 2H). LCMS: m/e 361 (M+H)+, ret time 1.88 min, column C, 2 minute gradient, start at 0% B.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:25]=[O:26])C1C=CC=CC=1.Cl>C1COCC1.O>[CH:25]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=1[C:6]([NH:8][CH3:9])=[O:7])=[O:26]
Reactant: CN(C=O)c1ccccc1
Reactant: CNC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Cl)cc1C=O
Temperature: 0 °C
Yield: 59 %

Procedure:
To a solution of 4-chloro-N-methyl-benzamide (3.1 g) in THF (30 mL) was added n-butyl lithium (30.1 mL of 2.5M hexane solution) and the solution refluxed for 45 min. The solution was then cooled to 0° C. and N-methylformanilide (9.27 mL) added dropwise over 2 min. The solution was then refluxed for 2 h and then cooled to ambient temperature, water (80 mL) added and the solution acidified to pH 1 with 2M HCl. The solution was then extracted three times with ethyl acetate (3×50 mL), washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resulting brown oil was purified on silica by flash chromatography to afford the sub-titled product as a pale yellow solid (2.13 g; 59%); 1H NMR (400 MHz, CDC13) δ 2.90 (3H, s), 4.25 (1H, d) 5.60 (1H, d), 7.35 (2H, s), 7.60 (1H, s).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([OH:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1.OO.S(=O)(=O)(O)O.N=O.[OH2:22]>C(O)(C)(C)C>[OH:1][CH:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:3][C:4]([OH:22])([CH3:12])[CH3:11])[C:4]([CH3:12])([CH3:11])[CH2:3]1
Reactant: O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: N=O
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CC(C)(C)O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A solution of 17.2 g (100 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine dissolved in 40 mL of water and three-fourths of a solution of 25.0 g (0.37 mol) of 50% aqueous hydrogen peroxide are added simultaneously over 2.5 hours to 40° C. to a mixture of 1.46 g (4.1 mmol) of ferric acetylacetonate, 25 mL of water, 0.5 mL of 98% sulfuric acid and 200 mL of tert-butyl alcohol. At the conclusion of the nitroxyl addition, 0.18 g (0.5 mmol) of ferric acetylacetonate is added to the reaction mixture. The remaining one-fourth of the peroxide solution is added over one hour at 40° C. After heating for two hours, gas chromatography shows less than 10% nitroxyl compound remaining in the reaction mixture. Sulfuric acid (0.3 mL) and a solution of 4.9 g (72 mmol) of 50% aqueous hydrogen peroxide are added to the reaction mixture at 40° C., and the reaction mixture is stirred overnight at room temperature. Work-up as in Example 20 affords 18.1 g (74% yield) of the title compound as a white solid.
Reaction SMILES: CCCC[C@H]1C(=O)O[C@H](C)[C@H](NC(C2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26]C=O)[C:21]=2O)=O)C(=O)O[C@@H](C)[C@@H]1OC(C(CC)C)=O.ClCC[N:41]1CCCC1.[H-].[Na+].C[N:49]([CH:51]=[O:52])[CH3:50]>>[NH2:26][C:22]1[C:21]2[C:50](=[N:49][C:51](=[O:52])[N:41]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: ClCCN1CCCC1
Reactant: CCCC[C@H]1C(=O)O[C@H](C)[C@H](NC(=O)c2cccc(NC=O)c2O)C(=O)O[C@@H](C)[C@@H]1OC(=O)C(C)CC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Nc1cccc2c1=NC(=O)N=2

Procedure:
As a typical example of this convergent solution-phase method, Compound 1 may be synthesized as described in Scheme AA. Thus, treatment of 5-nitrobenzimidazolone AA1 with 2,6-diCl-Bn-Br in the presence of NaH in DMF afforded two regioisomers AA2a and AA3a (ca. 1:1 ratio), which were then separated by flash column. A small amount of bis-alkylated product was also obtained. The isolated AA3a was further alkylated with 2-chloroethylpyrrolidine by using NaH as a base in DMF to give the di-alkylated product, which was then subjected to nitro reduction with Me2NNH2/FeCl3 to provide aminobenzimidazolone intermediate AA4. Coupling of N-α-Fmoc-N-γ-Boc-diaminobutyric acid (AA5) with benzyl amine in the presence of DCC and HOBt was followed by de-protection of the Fmoc group with diethylamine. The resulting intermediate was coupled with Fmoc-3,4-diF-Phe-OH using DIC/HOBt and treated with diethylamine to give dipeptide amine AA6. Urea formation between the dipeptide amine AA6 and aminobenzimidazolone intermediate AA4 in the presence of 4-nitrophenylchloroformate was followed by de-protection of the Boc group with TFA to afford the target compound 1.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:2]=[CH2:3].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[CH2:23]=O>C(O)C>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:23][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]([OH:16])=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(O)c2c1NC(=O)CC2
Reactant: C1CCNCC1
Reactant: C=O
Solvent: CCO
Product: C=CCOc1cc(CN2CCCCC2)c(O)c2c1NC(=O)CC2
Temperature: 70 °C
Reaction time: 4 h

Procedure:
41 Grams of 8-allyloxy-3,4-dihydro-5-hydroxy-2(1H)-quinolinone was dissolved in 500 ml of ethanol, under stirring 30 ml of piperidine and 30 ml of 37%-formalin were added to this solution, this mixture was stirred at 70° C. for 4 hours. After cooled, the reaction mixture was concentrated to dryness, extracted with 1 liter of methylene chloride, the extract was washed with water and dried, again concentrated to dryness. The residue was purified by a silica gel column chromatography (eluent: methylene chloride: ethyl acetate=20:1). The purified product was recrystallized from ethyl acetate, there was obtained 61g of 8-allyloxy-3,4-dihydro-5-hydroxy-6-(1-piperidinyl)methyl-2(1H)-quinolinone.
Reaction SMILES: [S:1]([O-])([O-:4])(=[O:3])=[O:2].[NH4+:6].[NH4+].N>>[S:1]([O-:4])([O-:3])=[O:2].[NH4+:6].[NH4+:6].[S:1](=[O:2])([OH:4])[O-:3].[NH4+:6]
Reactant: O=S(=O)([O-])[O-]
Agent: N
Agent: [NH4+]
Product: O=S([O-])O
Product: O=S([O-])[O-]

Procedure:
In contrast, ammonia-based scrubbing processes have been used to produce a more valuable ammonium sulfate fertilizer, as taught by U.S. Pat. Nos. 4,690,807 and 5,362,458, each of which are assigned to the assignee of the present invention and incorporated herein by reference. In these processes (also known as ammonium sulfate flue gas desulfurization, or AS FGD), the scrubbing solution is accumulated in a tank where the absorbed sulfur dioxide reacts with dissolved ammonia (NH3) to form ammonium sulfite ((NH4)2SO3) and ammonium bisulfite (NH4HSO3), which are oxidized in the presence of sufficient oxygen to form ammonium sulfate ((NH4)2SO4) and ammonium bisulfate (NH4HSO4), the latter of which reacts with ammonia to form additional ammonium sulfate. A portion of the ammonium sulfate solution and/or ammonium sulfate crystals that form in the solution can then be drawn off to yield the desired byproduct of this reaction.