Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:10][O-:11].[Na+].[Na+]>O.C([O-])(=O)CCCCCCCCCCCCCCCCC.[Zn+2].C([O-])(=O)CCCCCCCCCCCCCCCCC>[C:1]([O:10][O:11][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: [O-][O-]
Agent: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Product: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
One liter of water in a glass vessel of a capacity of 5 liters is cooled to 4° C. with ice. 75 g of Na2O2 are dissolved in water with agitation and cooling. Subsequently, a mixture prepared in advance from 260 g benzoyl chloride and 200 g of a commercially available desensitizing agent on the basis of phthalic ester (Ultramoll TGN, from the firm Bayer A. G., Leverkusen) is added drop by drop to the sodium peroxide solution within 20 minutes. During the first 10 minutes the temperature is held at about 8° C. by means of the addition of ice. During the following 10 minutes ice is added so that the temperature can slowly rise to 15° C. Subsequently, the reaction mixture is for 1/2 hour allowed to continue reacting while being agitated, and 12 g of zinc stearate are stirred into the reaction mixture. The pasty constituents are separated from the excess liquid in a centrifuge with settling sump. After two washing cycles and dehydration by means of a centrifuge one obtains a homogeneous, stable benzoyl peroxide paste with about 50% peroxide, 43% desensitizing agent and a remainder of water and zinc stearate. The paste has a viscosity of 1800 poise.
Reaction SMILES: S1CCS[CH:2]1[CH2:6][C:7]1[C:8]([Cl:14])=[N:9][CH:10]=[N:11][C:12]=1[Cl:13].C(#N)C.C(=O)([O-])[O-:19].[Ca+2]>[Hg](Cl)Cl.O>[Cl:14][C:8]1[C:7]([CH2:6][CH:2]=[O:19])=[C:12]([Cl:13])[N:11]=[CH:10][N:9]=1
Reactant: Clc1ncnc(Cl)c1CC1SCCS1
Reactant: O=C([O-])[O-]
Agent: Cl[Hg]Cl
Agent: [Ca+2]
Solvent: CC#N
Solvent: O
Product: O=CCc1c(Cl)ncnc1Cl
Yield: 87 %

Procedure:
5-[(1,3-dithiolan-2-yl)methyl]-4,6-dichloropyrimidine (compound of the formula IV-1, 13.4 g, 0.05 mol) was added to 200 mL of a 4:1 mixture of acetonitrile and water, and mercury dichloride (27.1 g, 0.1 mol) and calcium carbonate (10 g, 0.1 mol) were then further added with stirring. After 6 hours of reaction at the room temperature, suction filtration was carried out. The solid was washed with acetonitrile and then the combined filtrate was subjected to solvent removal, followed by the addition of 200 mL of dichloromethane. The organic phase was then washed with an aqueous solution saturated with sodium bicarbonate, dried and subjected to solvent removal, resulting in a yellow solid. The solid was then recrystallized in ethyl acetate and petroleum ether (1:1) in order to obtain a yellowish solid of 8.3 g with a yield of 87%. 1HNMR (400 MHz, CDCl3) δ: 9.80 (s, 1H), 8.74 (s, 1H), 4.14 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O=S(Cl)[Cl:18].Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([Cl:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: O=C(Cl)c1ccc(-c2ccc(Cl)cc2)o1

Procedure:
A mixture of 56 g. (0.25 mole) of 5-(p-chlorophenyl)-2-furoic acid and 100 ml. of SOCl2 is refluxed for 31/2 hours so that HCl gas evolves and there is dissolution. The SOCl2 is removed on a rotary evaporator. Benzene is added to the solid residue and is then removed on the rotary evaporator to give 5-(p-chlorophenyl)-2-furoyl chloride.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)(=O)C>O.CC(C)=O>[C:10]1([NH:9][C:5]2[C:4]([NH:23][C:22]3[CH:24]=[CH:25][CH:19]=[CH:20][CH:21]=3)=[N:3][C:2](=[O:1])[C:7](=[O:8])[CH:6]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: Oc1cccnc1O
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1C=C(Nc2ccccc2)C(Nc2ccccc2)=NC1=O
Reaction time: 2 h
Yield: 23 %

Procedure:
2,3-dihydroxypyridine (0.0027 mol), aniline (0.0027 mol), p-acetylaniline (0.0027 mol), and NaIO3 (0.0009 mol) were dissolved in 160 ml water/acetone (80:1, v/v) solvent. The reaction mixture was stirred for 2 hours, and maintained still overnight. The product mixture was filtered, and passed through a silica gel column (200-400 mesh). The final product was 5-p-acetylphenylamino-6-phenylamino-2,3-pyridindione in yellow powder. The yield was 23%-45%. 5,6-diphenylamino-2,3-pyridindione can also be obtained.
Reaction SMILES: [NH2-].[Na+].N.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH2:14][C:15]#N)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].ClC1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][CH:34]=[C:33]2Cl>>[CH2:14]([C:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1)[C:8]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:6]([O:5][CH3:4])[CH:7]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][CH:34]=[C:33]2[CH2:14][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:6]([O:5][CH3:4])[CH:7]=1
Reactant: Clc1ccnc2ccccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccc(CC#N)cc1OC
Agent: N
Agent: [NH2-]
Agent: [Na+]
Product: COc1ccc(Cc2ccnc3cc(OC)c(OC)cc23)cc1OC
Product: COc1ccc(Cc2ccnc3ccccc23)cc1OC

Procedure:
The process of this invention utilizing sodium amide in liquid ammonia is effective in promoting the condensation of 3,4-dimethoxyphenylacetonitrile with 4-chloroquinoline and 6,7-dimethoxy-4-chloroquinoline to furnish 4-veratrylquinoline and 6,7-dimethoxy-4-veratrylquinoline, respectively, after hydrolysis. The process of U.S. Pat. No. 2,568,778 issued Sept. 25, 1951, utilizing sodium amide in benzene is ineffective in promoting these condensations.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:8][CH3:9].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1(C)C=CC=CC=1>[CH3:9][C:8]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([CH3:16])[C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CCC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Clc1nccs1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CI
Product: CC(C)(C)OC(=O)C(C)(C)c1nccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
Toluene (30 mL) was placed in a nitrogen-flushed flask and degassed with nitrogen (20 min). 2-Chlorothiazole (900 mg, 7.53 mmol) and tert-butyl propionate (1.176 g, 9.03 mmol) were added, and the mixture was cooled to 0° C. NaHMDS (0.6 M in toluene, 30.1 mL, 18.06 mmol) was added. The reaction was stirred for 2 h at 0° C., allowed to warm to room temperature, and stirred for 18 h at room temperature. Methyl iodide (3.85 g, 27.1 mmol) was then added. After 1 h at room temperature, the orange reaction was quenched (under nitrogen) with aqueous saturated NH4Cl. The mixture was extracted with ethyl acetate (2×), and the combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (0-25% ethyl acetate in hexanes) afforded tert-butyl 2-methyl-2-(1,3-thiazol-2-yl)propanoate (1.06 g, 62%) as a pale yellow oil. MS ESI: [M+H]+ m/z 228.1.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=1)[CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]1.[NH:31]1[C:35]([CH2:36][NH2:37])=[N:34][N:33]=[N:32]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:37][CH2:36][C:35]2[NH:34][N:33]=[N:32][N:31]=2)=[O:28])=[CH:24][CH:23]=1)[CH:11]1[CH2:12][CH2:13][CH:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:15][CH2:16]1
Reactant: NCc1nnn[nH]1
Reactant: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)O)cc2)c2nc3ccccc3[nH]2)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)NCc3nnn[nH]3)cc2)c2nc3ccccc3[nH]2)CC1

Procedure:
To a solution of the title compound of Example 1 Step D (0.04 mmol, 16 mg), 1H-tetraazol-5-ylmethylamine (0.06 mmol, 8 mg), HOBt (0.1 mmol, 15 mg) and EDC (0.12 mmol, 23 mg) in 0.4 mL of DMF was added DIEA (0.2 mmol, 35 μL). After 3 h the reaction mixture was concentrated under reduced pressure. The product was purified by reverse-phase chromatography (Condition A) and lyophilized, affording the title compound as a white solid. MS (ESI): m/z 487 (M+H). HPLC A: 1.58 min.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:51])[N:20]([CH2:39][C:40]2[N:41]=[C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[S:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:51])[N:20]([CH2:39][C:40]2[N:41]=[C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[S:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2csc(-c3ccccc3)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(Cc2csc(-c3ccccc3)n2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A mixture of hydroxylammonium chloride (1.34 g), sodium hydrogen carbonate (1.90 g) and dimethyl sulfoxide (18 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-2-methyl-6-oxo-1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (1.20 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (0.42 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.38 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.80 g, 60%).
Reaction SMILES: [Pd:1](Cl)Cl.C([O-])(=O)C.[Na+].[CH:9](=[CH:16][C:17]([CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[CH:24]1[CH:23]=[CH:22][C:21](/[CH:20]=[CH:19]/[C:17](/[CH:16]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:18])=[CH:26][CH:25]=1.[CH:24]1[CH:23]=[CH:22][C:21](/[CH:20]=[CH:19]/[C:17](/[CH:16]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:18])=[CH:26][CH:25]=1.[CH:24]1[CH:23]=[CH:22][C:21](/[CH:20]=[CH:19]/[C:17](/[CH:16]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:18])=[CH:26][CH:25]=1.[Pd:1].[Pd:1]
Reactant: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Reactant: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: [Pd]
Temperature: 55 °C

Procedure:
1.05 g palladium chloride were added to a 100 mL methanol solution containing 3.9 g sodium acetate and 4.6 g dibenzylideneacetone. The reaction mixture was warmed to 55° C. and the temperature maintained for one hour so that a precipitate was formed. The precipitate was then filtered from the methanol and redissolved in chloroform to produce a dark purple solution. This solution was stripped under reduced pressure at 25°-30° C. to produce a dark purple or black solid of Pd2DBA3.CHCl3. 1.5 g of the solid was dissolved in 100 mL THF, and added to a solution of 140-150 g of 30-5 NBR in 1.1-1.2 L THF. After 22 hours at 75°-90° C. and 350 psi hydrogen, a sample was withdrawn and a cast film IR analysis indicated that 63 percent of the olefinic NBR unsaturation had been hydrogenated.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>CO>[CH:1]([N:14]1[CH2:18][CH:17]([OH:19])[CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CO
Product: OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.8 %

Procedure:
A mixture of benzhydrylamine (25.0 g, 136 mmol), epichlorohydrine (12.6 g, 136 mmol) in MeOH (55 mL) was stirred for 3 days at room temperature. Then the mixture was stirred under reflux for 2 days. After cooling, the solvent was evaporated in vacuo and the resulting solid was washed with acetone (30 mL). Then the solid was suspended in Et2O (500 mL) and washed with aqueous 6N NaOH (100 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to afford a product (13.6 g, 42%). This compound was used for the next reaction without further purification.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[Li]CCCC.[C:15](Cl)(=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[C:15]([N:5]1[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]1=[O:9])(=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: CCCCCCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C

Procedure:
The synthesis of Fragment B is comprised of the following steps: (a) a solution of 4-(S)-isopropyl-oxazolidin-2-one 2 in THF at a temperature of −78° C. is treated with a solution of n-BuLi in hexanes, or any suitable base; (b) heptanoyl chloride 3 is added to the mixture to yield 3-heptanoyl-4-(S)-isopropyl-oxazolidin-2-one 4; (c) treatment of a solution of 4 in THF with lithium diisopropylamide, or similar bases, followed by bromoacetic acid tert-butyl ester yield 3-(4-(S)-isopropyl-2-oxo-oxazolidine-3-(S)-carbonyl)octanoic acid tert-butyl ester 5; (d) treatment of a mixture of 5 in THF/water with hydrogen peroxide in water followed by lithium hydroxide in water at 0° C. to yield 2-(R)-pentylsuccinic acid 4-tert-butyl ester 6; (e) treatment of a mixture of 6 and hydroxysuccinimide 7 in dimethylformamide or any suitable solvent, such as dioxane, with dicyclohexylcarbodiimide, or similar imides, to afford 2-(R)-pentylsuccinic acid 4-tert-butyl ester (should this be 1, if it is 4-t-butyl ester?)4-(2,5-dioxo-pyrrolidin-1-yl) ester 8 (Scheme 2, FIG. 3A).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=[O:16])[NH:11][CH2:12][C:13](=O)[CH3:14])[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:9][C@@H:8]1[NH:7][CH:13]([CH3:14])[CH2:12][NH:11][C:10]1=[O:16]
Reactant: CC(=O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CNC(=O)[C@H](C)N1
Reaction time: 24 h

Procedure:
(1S)-[1-(2-oxo-propylcarbamoyl)-ethyl]-carbamic acid tertbutyl ester (5.93 g, 24.3 mmol) is stirred in a solution of 30% trifluoroacetic acid in methylene chloride (100 mL) for three hours. The solvents are removed in vacuo. The residue is dissolved in 50 mL of MeOH and transferred to a par bottle. Palladium on carbon (10%, 1.0 g) is added, and the mixture is hydrogenated under pressure for 24 hours. The catalyst is filtered off; the MeOH is removed in vacuo to afford (3S, 5RS)-3,5-dimethyl-piperazin-2-one which is directly protected with a benzyl carbamate without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:31].CCOCC>CO>[IH:31].[IH:31].[N:11]1([C:15]2[N:19]([CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCn2cccn2)CC1
Agent: I
Solvent: CO
Solvent: CCOCC
Product: c1ccc2c(c1)nc(N1CCCNCC1)n2CCn1cccn1
Reaction time: 1 h

Procedure:
Reflux 4-[1-(2-pyrazol-1-yl-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.71 g, 1.73 mmol) in methanol (15 mL) with hydroiodic acid (57%, 0.5 mL) for 12 hours. Cool, add ether (80 mL) to afford a suspension and stir the suspension for one hour. Collect the solid by filtration and dry to provide 2-[1,4]diazepan-1-yl-1-(2-pyrazol-1-yl-ethyl)-1H-benzoimidazole dihydroiodide (0.81 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[CH3:2].[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH2:28])[CH3:24]>C(O)=O>[ClH:13].[CH2:1]([O:3][C:4]([C:5]1[N:28]([CH2:27][CH2:26][N:25]([CH2:29][CH3:30])[CH2:23][CH3:24])[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[C:7]=1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9]2)=[O:22])[CH3:2]
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)C(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: O=CO
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCN(CC)CC
Product: Cl

Procedure:
In a manner analogous to that described in Example 19, from 0.95 g. of o-benzoyl-p-chloro-phenylglyoxylic acid ethyl ester, 1.05 g. of 2-diethylaminoethylamine and 0.83 g. of formic acid, there is obtained 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride; melting point 248°-250° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:38]([C:41]1[N:42](C)[CH:43]([NH:46][C:47]([O:49]C2C=CC=CC=2)=O)[S:44][CH:45]=1)(=O)C.[C:57](OCC)(=[O:59])[CH3:58]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:47]([NH:46][C:43]2[S:44][C:45]([C:57](=[O:59])[CH3:58])=[C:41]([CH3:38])[N:42]=2)=[O:49])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)C1=CSC(NC(=O)Oc2ccccc2)N1C
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)c1sc(NC(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)nc1C
Temperature: 60 °C
Reaction time: 64 h
Yield: 57 %

Procedure:
In a dry flask (3R,4R)-4-Amino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (73 mg, 0.174 mmol) was dissolved in acetonitrile (2 mL) and triethylamine (25 μL, 0.179 mmol) and 4-acetyl-3-methyl-2-(phenoxycarbonylamino)-thiazole (58 mg, 0.21 mmol) were added. The reaction mixture was stirred for 64 hours while heating to 60° C. The reaction mixture was cooled, diluted with ethyl acetate, washed twice with water and once with brine. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (60 mg, 57%). 1H NMR (300 MHz, CDCl3), δ: 7.14 (m, 1H), 6.98 (m, 2H), 6.88 (t, 1H, J=10), 4.39 (d, 1H, J=13), 4.09 (bs, 2H), 3.94 (bm, 2H), 3.12 (t, 1H, J=11), 2.74 (bm, 5H), 2.62 (m, 3H), 2.52 (m, 1H), 2.47 (m, 3H), 2.36 (m, 2H), 2.03 (bm, 3H), 1.74 (bm, 2H), 1.48 (2s, 9H), 1.40 (m, 1H), 1.22 (m, 1H). HRMS (ESI), C30H41FN5O5S m+/z: calc.=602.2813, found=602.2811.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][O:9][C:10]1[C:11]([N:16]=[C:17](SC)[S:18][CH3:19])=[N:12][CH:13]=[CH:14][N:15]=1.O>C(#N)C>[CH3:8][O:9][C:10]1[C:11]2[N:12]([C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:17]([S:18][CH3:19])[N:16]=2)[CH:13]=[CH:14][N:15]=1
Reactant: COc1nccnc1N=C(SC)SC
Reactant: CCOC(=O)CBr
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1c(SC)nc2c(OC)nccn12
Temperature: 100 °C
Reaction time: 14 h

Procedure:
Ethyl bromoacetate (18.5 mL) and iso-dipropylethylamine (29 mL) were added to a solution of methyl N-(3-methoxy-2-pyrazinyl)-(methylsulfanyl)methaneimidothioate (19.1 g) in acetonitrile (42 mL), and the mixture was heated under stirring at 100° C. for 14 hours. After the reaction mixture was cooled to room temperature, water was added thereto, which was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and evaporated. The resulting residue was washed with n-hexane to give the title compound (10.7 g) as pale yellow crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([CH2:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[CH:6]=2)[CH2:3][CH2:2]1.C(O)C.[NH:28]1[CH2:34][C:32](=[O:33])[NH:31][C:29]1=[O:30].N1CCCCC1>O>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[C:34]4[C:32](=[O:33])[NH:31][C:29](=[O:30])[NH:28]4)=[C:9]3[N:8]=[C:7]([CH2:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[CH:6]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1cccc(Cc2cc(NC3CC3)n3ncc(C=O)c3n2)c1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(Cc2cc(NC3CC3)n3ncc(C=C4NC(=O)NC4=O)c3n2)c1
Temperature: 80 °C
Yield: 34 %

Procedure:
To the reaction flask, 3-((7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile (28 mg, 0.09 mmol) was added to ethanol (0.5 mL) along with hydantoin (9 mg, 0.09 mmol) and piperidine (9 μL, 0.09 mmol). The reaction was heated at 80° C. for 30 minutes in the microwave then cooled to room temperature and diluted with water. The solid was collected by filtration, washed with water, 50% ethanol/water, and then 100% ethanol. The material was dried under vacuum overnight. The product, 3-((7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile, was recovered as a solid in 34% yield. LCMS (M+1=400)
Reaction SMILES: [C:1]([NH-:5])([CH3:4])([CH3:3])[CH3:2].[Li+:6].C1COCC1.C1(C)C=CC=CC=1.[CH3:19][C:20]1[C:25]([CH3:26])=[C:24]([CH3:27])[C:22](=[CH2:23])[C:21]=1[CH3:28]>CCCCC>[C:1]([NH:5][CH2:23][C:22]1([Li:6])[C:24]([CH3:27])=[C:25]([CH3:26])[C:20]([CH3:19])=[C:21]1[CH3:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li+]
Reactant: C=C1C(C)=C(C)C(C)=C1C
Reactant: CC(C)(C)[NH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCC
Product: [Li]C1(CNC(C)(C)C)C(C)=C(C)C(C)=C1C
Reaction time: 8 h

Procedure:
200 mg (2.53 mmol) of lithium tert-butylamide are dissolved in 50 ml of pentane and 2 ml of THF and admixed with 2.5 g of a 9:1 mixture of toluene and 2,3,4,5-tetramethylfulvene. The reaction solution is stirred overnight, which results in precipitation of the product. The solvent is removed under reduced pressure, the residue is taken up in pure pentane and collected on a frit. After washing twice with 20 ml each time of pentane, the white, pulverulent product is dried under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:12].[K+].[OH-:17].[Na+]>>[C:1]([C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1)([OH:12])=[O:17]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: [OH-]
Reactant: Cc1ccc(B(O)O)cc1
Agent: [K+]
Agent: [Na+]
Product: O=C(O)c1ccc(B(O)O)cc1

Procedure:
To a solution of 4-methylphenylboronic acid (34 g, 0.25 mol) in aqueous sodium hydroxide (0.5 N, 1000 mL) was added potassium permanganate (83 g, 0.53 mol) while keeping the temperature at 35-40° C. After the addition the reaction was filtered and the filtrate acidified with concentrated hydrochloric acid (65 mL). The product was filtered off. A yield of 29.6 g was obtained. M.p. 228° C.