Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:41])([C:17]3[N:18]=[CH:19][N:20]([C:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[CH:14]([CH3:16])[CH3:15])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:42]([O:44]C)=O.CO.[CH3:48][NH2:49]>C1COCC1>[OH:41][C:13]([C:9]1[CH:10]=[CH:11][C:12]2[C:3]3[CH2:2][N:49]([CH3:48])[C:42](=[O:44])[C:4]=3[CH:5]=[CH:6][C:7]=2[CH:8]=1)([C:17]1[N:18]=[CH:19][N:20]([C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:21]=1)[CH:14]([CH3:15])[CH3:16]
Reactant: CN
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1CBr
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccc2c3c(ccc2c1)C(=O)N(C)C3)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methyl 1-bromomethyl-6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthoate (0.80 g) was dissolved in THF (8 ml) and 40% methylamine methanol solution (8 ml) was added. The reaction mixture was stirred at room temperature for 20 hrs. and the solvent was evaporated. The residue was suspended in ethyl acetate and filtrated to give 7-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one as a colorless solid (0.77 g). This solid was suspended in a mixed solution of THF and methanol (1:3, 20 ml) and pyridine hydrochloride (0.23 g) was added. The reaction mixture was stirred with heating at 60° C. for 6 hrs., and the solvent was evaporated. The residue was diluted with saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate-THF (1:1). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from THF-methanol to give the title compound as colorless crystals (0.28 g).
Reaction SMILES: CC1C2C(=O)CCCC=2N=CN=1.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[NH2:22][C:23]1[N:32]=[C:31]([CH3:33])[C:30]2[C:29](=[O:34])[CH2:28][CH:27]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3C3C=CC=CC=3)[CH2:26][C:25]=2[N:24]=1>>[NH2:22][C:23]1[N:32]=[C:31]([CH3:33])[C:30]2[C:29](=[O:34])[CH2:28][CH:27]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)[CH2:26][C:25]=2[N:24]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1ccccc1)C2
Reactant: OB(O)c1ccncc1
Agent: Cc1ncnc2c1C(=O)CCC2
Product: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1ccncc1)C2

Procedure:
The title compound was prepared from 2-amino-4-methyl-7-(2-bromo-phenyl), 4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/i) and pyridin-4-yl-boronic acid, following the procedure describing the synthesis of 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 5/a stage 1).
Reaction SMILES: [F:1][CH:2]([F:4])Cl.[NH2:5][C:6]1[N:11]=[C:10]([SH:12])[CH:9]=[C:8]([O:13][CH3:14])[N:7]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C>[NH2:5][C:6]1[N:11]=[C:10]([S:12][CH:2]([F:4])[F:1])[CH:9]=[C:8]([O:13][CH3:14])[N:7]=1
Reactant: COc1cc(S)nc(N)n1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(SC(F)F)nc(N)n1

Procedure:
Gaseous difluorochloromethane is introduced for 11/2 hours at 60° to 65° C. into a suspension of 7.8 g of 2-amino-4-mercapto-6-methoxy-pyrimidine and 30 ml of concentrated sodium hydroxide solution in 100 ml of dioxane. By the addition of water, extraction with ethyl acetate, concentration of the organic phase by evaporation and crystallisation from methanol at -78° C., there are obtained 6.4 g of 2-amino-4-difluoromethylthio-6-methoxy-pyrimidine, m.p. 83° to 84° C. (compound No. 1.13).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11](I)[CH:10]=2)[N:4]=1.ONC(=N)CC1C=CC([I:26])=CC=1>>[Cl:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([I:26])=[CH:11][CH:10]=2)[N:4]=1
Reactant: N=C(Cc1ccc(I)cc1)NO
Reactant: ClCc1nc(Cc2cccc(I)c2)no1
Product: ClCc1nc(Cc2ccc(I)cc2)no1

Procedure:
The title compound is prepared essentially as described for 5-chloromethyl-3-(3-iodo-benzyl)-[1,2,4]oxadiazole, employing N-hydroxy-2-(4-iodo-phenyl)-acetamidine. LC-MS (m/e): 335 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)#[N:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]([S:26]([C:23]2[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:25][CH:24]=2)(=[O:28])=[O:27])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)CCNCCc1ccc(OC)cc1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
To a solution of methyl 3-[(4-methoxy-phenethyl)amino]-propionate (3.0 g, 12.6 mmol) in anhydrous methylene chloride (35 mL) was added 4-cyanobenzenesulfonyl chloride (2.6 g, 12.6 mmol), followed by triethylamine (2.6 g, 25.3 mmol). After stirring for 18 h at room temperature, the mixture was quenched with 1 N HCl solution (150 mL) and extracted with methylene chloride (2×100 mL). Combined organic layers was washed successively with 1 N HCl solution (100 mL) and brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel flash chromatography (2/1: hexanes/EtOAc) to provide methyl 3-[(4-methoxyphenethyl)-(4-cyanobenzenesulfonyl)-amino]-propionate (3.14 g, 7.8 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:10])([CH3:9])[CH3:8])=[CH:3][CH:2]=1.C([Li])CCC.[C:16]12([C:26](Cl)=[O:27])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>C1COCC1.CCCCCC>[C:16]12([C:26]([O:10][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)([CH3:9])[CH3:8])=[O:27])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(O)c1ccncc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(OC(=O)C12CC3CC(CC(C3)C1)C2)c1ccncc1
Yield: 70.8 %

Procedure:
The method followed that described in Example 1, but using 2-(4-pyridyl)propan-2-ol (0.69 g, 5.0 mmol) in THF (20 ml), n-butyllithium (2.5 M; 2.0 ml, 5.0 mmol) in hexane, and 1-adamantanecarbonyl chloride (1.09 g, 5.5 mmol) in THF (6 ml). Chromatography, on elution with ether-petrol-triethylamine 50:50:1, gave the title compound (1.06 g, 71%) as an oil. IR νmax 1730 cm-1 ; 1H-NMR (CDCl3) δ1.71 (6H, s, CMe2), 1.71 and 1.90 (12H, 2s, adamantyl CH2), 2.02 (3H, s, adamantyl CH), 7.23 (2H, d, J 6.1 Hz, Py 3 and 5-H), 8.56 (2H, d, J 6.1 Hz, Py 2 and 6-H). Anal. Calcd: C, 76.22; H, 8.42; N, 4.68. Found: C, 76.17; H, 8.47; N, 4.64%.
Reaction SMILES: C=[O:2].S(=O)(=O)(O)O.O.[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=NO)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:2])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C=O
Reactant: CCOC(=O)C(CCCCCCl)=NO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(=O)CCCCCCl

Procedure:
The solution of ethyl 7-chloro-2-hydroxyiminoheptanoate [III-1] in toluene obtained in Example 9 (without being concentrated) is added dropwise into 36 % aqueous formalin solution, and thereto is added sulfuric acid. The mixture is warmed, and further thereto is added water. The organic layer is separated, neutralized, washed with water, and concentrated under reduced pressure to give ethyl 7-chloro-2-oxoheptanoate [I-1].
Reaction SMILES: [N:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:30]1[CH:35]=[C:34]([C:36](Cl)=[O:37])[CH:33]=[N:32][CH:31]=1.N>ClCCl>[N:30]1[CH:35]=[C:34]([C:36]([N:4]2[CH2:3][CH2:2][N:1]([C@H:7]3[CH2:12][CH2:11][C@H:10]([N:13]4[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[NH:15][C:14]4=[O:22])[CH2:9][CH2:8]3)[CH2:6][CH2:5]2)=[O:37])[CH:33]=[N:32][CH:31]=1
Reactant: O=C(Cl)c1cncnc1
Reactant: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](N2CCNCC2)CC1
Agent: N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cncnc1)N1CCN([C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 0.044 g of trans-1,3-dihydro-1-{4-(1-piperazinyl)-1-cyclohexyl}-2H-benzimidazol-2-one and 20 mL of triethylamine in 3 mL of dichloromethane was added 0.03 g of pyrimidine-5-carboxylic acid chloride. After 2 h, 5 mL of dilute aqueous ammonia was added and the mixture stirred for an additional 30 min. The organic layer was separated, the aqueous layer extracted with two additional 20 mL portions of chloroform and the combined organic extracts dried over MgSO4 and concentrated under reduced pressure. Chromatography over silica gel eluting with 90:10 EtOAc: MeOH gave 0.030 g of trans-1,3-dihydro-1-{4-[4-(5-pyrimidinecarbonyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: mp>250° C.; 1H NMR (400 MHz, CDCl3) 9.76 (bs 1H), 9.27 (s, 1H), 8.83 (s, 2H), 7.27-7.04 (m, 4H), 4.27 (br t, 1H), 3.84 (br s, 2H), 3.43 (br s, 2H), 2.73 (br s, 1H), 2.61 (br s, 2H), 2.54 (d, 1H), 2.34 (q, 2H), 2.02 (br t, 3H), 1.97 (br s, 1H), 1.52 (q, 2H). The dihydrochloride salt was recystallized from ethanol: Analysis calculated for C22H26N6 O2.2HCl.0.65 CHCl3C: 48.84, H: 5.18, N: 15.09; found C: 48.85, H: 5.36, N: 14.72.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:9][CH:10]=O)[CH2:3][C:4]([O:6]CC)=[O:5].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1.CCOCC>[CH3:12][C:2]1([CH3:1])[CH:9]=[CH:10][O:6][C:4](=[O:5])[CH2:3]1
Reactant: CCOC(=O)CC(C)(C)CC=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1(C)C=COC(=O)C1
Yield: 40.1 %

Procedure:
A solution of 11.16 g (0.065 mole) of ethyl 3,3-dimethyl-5-oxopentanoate and 11.2 g (0.073 mole) of phosphoryl chloride in 90 ml of toluene was heated under reflux for 14 hours. The mixture was diluted with ether, washed with an aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated to give, after distillation, 3.29 g (40% yield) of 3,4-dihydro-4,4-dimethyl-2H-pyran-2-one, bp 105°-110° C./2670 Pa (20 mm Hg).
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>C1COCC1>[C:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([NH:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:30])=[O:29])=[CH:26][CH:27]=1)(=[O:21])[CH3:20]
Reactant: NCc1cccc2ccccc12
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(=O)(=O)NCc2cccc3ccccc23)cc1
Reaction time: 0.17 h
Yield: 23.5 %

Procedure:
1-Napthalene-methylamine (1.118 g, 7.11 mmol) was dissolved in THF before pyridine (1.725 ml, 21.3 mmol) was added. 4-Acetyl-benzenesulfonyl chloride (1.554 g, 7.11 mmol) was then added as a solid, and the resulting dark solution was stirred for 10 minutes. The volatiles were then removed, and the resulting residue was suspended in THF. Excess Et3N was then added, and the mixture was stirred for several minutes before the solids were filtered. The mother liquor was then evaporated to a solid which was recrystalized in ethylacetate and hexanes to yield 0.5697 g (0.00167 mol, 23%) of desired compound that was pure enough for the next step. LC-MS (ES+): 340 [MH]+ m/e.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH2:14].C1COCC1>>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:14][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)NCCCBr
Solvent: C1CCOC1
Product: CNCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
(3-Bromo-propyl)-carbamic acid tert-butyl ester (11.2 g, 47.0 mmol) was combined with 2.0 M Methylamine in THF (100 mL, 200 mmol) and was stirred at room temperature for 4 h. After this period, a precipitate formed in the solution. The solution was filtered and concentrated under reduced pressure to yield 7.58 g (86%) of (3-methylamino-propyl)-carbamic acid tert-butyl ester as a clear oil. [M+H]+ 188.94.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=1)#[N:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCc1ccc(Cl)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 4-chlorobenzylamine (0.41 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from methanol-diethyl ether to give the title compound (0.65 g, 2.4 mmol, yield: 91%) as colorless powder.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>O1CCCC1>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20]([CH2:1][NH:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: CNCCC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCNCS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
A solution of 1.0 g (6.28 mmol) of tert.-butyl N-methyl-β-alaninate, 1.54 g (6.28 mmol) of 2,3-dichlorobenzenesulphonyl chloride and 0.70 g (6.92 mmol) of triethylamine in 30 ml of tetrahydrofuran was stirred at room temperature overnight and then evaporated to dryness. About 50 ml of water were added to the residue, and the mixture was extracted three times with in each case 20 ml of ethyl acetate. The organic extracts were washed with about 20 ml of saturated sodium chloride solution and then evaporated to dryness. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: dichloromethane).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([O:7][CH2:8][CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH3:6].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH2:5]([O:7][CH2:8][CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[NH:19][CH:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]#[N:4])[CH2:24][CH2:25]1)[CH3:6]
Reactant: N#CCCl
Reactant: CCOCCn1c(NC2CCNCC2)nc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1c(NC2CCN(CC#N)CC2)nc2cccnc21
Temperature: 25 °C
Yield: 21 %

Procedure:
A mixture of 9.4 parts of 2-chloroacetonitrile, 30 parts of 3-(2-ethoxyethyl)-N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine, 11 parts of sodium carbonate and 658 parts of N,N-dimethylformamide was stirred over weekend at room temperature. The reaction mixture was poured into water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried in vacuo, yielding 7.2 parts (21.0%) of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidineacetonitrile; mp. 141.4° C. (compound 92).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:8]([CH2:27][CH2:28][CH2:29][OH:30])[N:9]2[C:14]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:10]2)=[O:5])[CH3:2].CI.[CH3:38]COCC.CCCCCC>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:8]([CH2:27][CH2:28][CH2:29][O:30][CH3:38])[N:9]2[C:14]=1[C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[N:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1CCCO
Reactant: CCOCC
Solvent: CI
Solvent: CCCCCC
Solvent: CC#N
Product: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1CCCOC

Procedure:
A solution of 41 (10.4 mg, 0.022 mmol), MeI (24 μL, 0.389 mmol), and Ag2O (25 mg, 0.108 mmol) in CH3CN (1 mL) was heated at 80° C. for 24 h. The reaction mixture was filtered through celite and washed with CH2Cl2. The filtrate was concentrated in vacuo and purified by TLC (silica gel, 35% EtOAc/hexane) to provide a yellow oil. The oil was sonicated in 2:1 Et2O/hexane to provide the title compound as an off-white solid. 1H NMR (DMSO-d6) δ 0.88 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H), 1.87 (m, 2H), 3.20 (m, 2H), 3.21 (s, 3H), 3.52 (m, 8H), 3.72 (m, 4H), 4.17 (q, J=7.1 Hz, 2H), 6.77 (s, 1H), 7.40 (m, 2H), 7.46 (m, 3H). Mass Spectrum (ESI+) m/e=496.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]2[N:6]=[C:7](S)[S:8][C:4]=2[CH:3]=1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH:15]=[CH:14]1.O[S:21](O)(=O)=O>>[Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]2[N:6]=[C:7]([CH:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13]([OH:19])=[S:21])[S:8][C:4]=2[CH:3]=1
Reactant: O=C1C=CC(=O)O1
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(Cl)cc2sc(S)nc12
Product: Cc1cc(Cl)cc2sc(C(CC(=O)O)C(O)=S)nc12

Procedure:
8.6 g of 6-chloro-2-mercapto-4-methylbenzothiazole are reacted with 4.4 g of maleic anhydride in 70% H2SO4 at 47°-50° as described in Example 1. The crude product is purified by reprecipitation from NaHCO3 solution. 6-Chloro-4-methylbenzothiazol-2-ylthiosuccinic acid of melting point 168°-171°, with decomposition, is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:30]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:30])[CH:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[CH:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc4c(N)ncnn34)cc2)CC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc(Br)c4c(N)ncnn34)cc2)CC1
Temperature: -20 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
To a cooled (−20° C.) solution of tert-butyl 4-[4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)phenyl]piperazine-1-carboxylate (1.20 g, 3.04 mmol) in tetrahydrofuran (15 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (435 mg, 1.21 mmol) in four portions over 15 min. The mixture was allowed to stir (−20° C.) for 3 h. The reaction was quenched with the addition saturated aqueous Na2SO3 (20 mL) and was allowed to warm to rt. The mixture was extracted with ethyl acetate (2×25 mL). The combined organics were dried (Na2SO4) and concentrated. The crude material was purified by ISCO® chromatography using a gradient of 25 to 75% ethyl acetate in hexanes. 1H-NMR indicated the presence of residual hydantoin side product, thus the material was partitioned between ethyl acetate (50 mL) and 5% aqueous K2CO3 (50 mL). The layers were separated and the organic layer was further washed with 5% aqueous K2CO3 (2×25 mL). The combined aqueous was back extracted with ethyl acetate (2×25 mL) and the combined organics were washed with brine, dried (Na2SO4) and concentrated to afford 340 mg (23%) of the desired product as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.91-7.83 (m, 3 H), 7.09 (s, 1 H), 7.00 (d, 2H), 3.50-3.42 (m, 4 H), 3.20-3.14 (m, 4 H), 1.42 (s, 9 H); ES-MS m/z 473.0 [M+H]+, HPLC RT (min) 3.25.
Reaction SMILES: [O-]CC.[Na+:4].O.[O:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][Na])[Na:7].O.O>C(O)C>[Na:4][Na:7].[CH2:13]([OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:6]
Reactant: [Na]OCCCCCCO[Na]
Reactant: [Na+]
Agent: CC[O-]
Solvent: CCO
Solvent: O
Product: OCCCCCCO
Product: [Na][Na]

Procedure:
The disodium salt of 1,6-hexane diol was prepared by an alkoxide exchange reaction with sodium ethoxide in the following manner. The diol was treated with two equivalents of sodium ethoxide in a 40/60 volume ratio mixture of water and ethanol. The water and ethanol were removed by heating and a quantity of benzene was added to further remove water by azeotroping. The product, NaO(CH2)6ONa.2H2O (13.1 g, 0.066 mole) had the following analysis:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)([O-])=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)([Cl:25])=O>O1CCCC1.C(N(CC)CC)C.CO.[Pd]>[ClH:25].[C:17]1([NH:16][C:13]([CH2:12][CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1
Reactant: O=S(Cl)Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: Cl
Product: Nc1ccc(CCCC(=O)Nc2ccccc2)cc1
Reaction time: 18 h

Procedure:
A stirred solution of 4-(4-nitrophenyl)butyric acid (5.0 g; 0.023 moles) in 20 ml of thionyl chloride was refluxed for 4 hours. The solvent was evaporated and the crude acid chloride, 2.5 g, was added dropwise to a stirred solution of aniline (2.0 g; 0.02 moles) in 30 ml of tetrahydrofuran and 10 ml of triethylamine and the reaction was then stirred 18 hours. The triethylamine hydrochloride was removed by filtration and 50 ml of ethyl acetate was added to the organic phase. The organic phase was washed with 1×100 ml of 1N hydrochloric acid and the dried over magnesium sulfate. The solvent evaporated to yield a yellow solid. The solid was dissolved in 100 ml of methanol and 250 mg of 10% palladium on carbon was added, the reaction was hydrogenated over a 4 hour period. The catalyst was removed by filtration and the solvent evaporated. To the residue was added 100 ml of ethyl acetate and hydrochloric acid-gas was added. Upon cooling 4(3-(((phenyl)amino)carbonyl)propyl)aniline hydrochloride, a white solid, crystallized and was collected by filtration to yield 1.7 g.
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[C:6]([Cl:14])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1Cl)([O-:3])=[O:2].[CH3:16][CH2:17][O-:18].[Na+].[CH2:20]([OH:22])[CH3:21]>>[N+:1]([C:4]1[C:5]([O:22][CH2:20][CH3:21])=[C:6]([Cl:14])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[O:18][CH2:17][CH3:16])([O-:3])=[O:2]
Reactant: CC[O-]
Reactant: CCO
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c([N+](=O)[O-])c1Cl
Agent: [Na+]
Product: CCOc1c(Cl)cc([N+](=O)[O-])c(OCC)c1[N+](=O)[O-]
Temperature: 75 °C

Procedure:
0.1 mole (27.15 g) of 3,5-dinitro-1,2,4-trichlorobenzene was heated to 75° C. in 110 ml of absolute ethanol. 0.2 mole of a 15% solution of sodium ethylate was added in absolute ethanol. Upon completion of the addition, the reaction mixture was heated for 30 minutes at 75° C. and then diluted with 300 g of an ice/water mixture. The expected product precipitated. After drying under vacuum and recrystallization from isopropyl ether, it melted at 78° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.ClC(Cl)(Cl)[CH:16]=[O:17]>C(OCCCC)CCC>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:16]=[O:17])[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: CCCCOCCCC
Product: Cc1ccccc1N1CCN(C=O)CC1
Temperature: 80 °C

Procedure:
With vigorous stirring, 437 mmol (77 g) of 2-methylphenylpiperazine are added to a solution of 415 mmol (61.3 g) of trichloroacetaldehyde in 400 ml of dibutyl ether. The reaction mixture is heated at 80° C. for 1 hour and, after cooling, concentrated to yield the expected product.