Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(Cl)Cl>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)=[N:13][C:14]([S:17]([CH3:18])=[O:38])=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)NCc2ccccc2)cc1Cl
Solvent: ClCCl
Product: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ccccc2)cc1Cl
Reaction time: 5 h

Procedure:
In DCM (20 mL) was dissolved N-benzyl-4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-formamide (201 mg, 0.47 mmol). Then was added m-CPBA (80 mg, 0.47 mmol). The reaction was conducted at ambient temperature for 5 h. After the reaction was completed, the reaction mixture was washed with water and extracted with DCM. The organic phase was dried, and the solvent was removed by rotary evaporation. The obtained solid was used in the subsequent procedure without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:41])([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:20]=[N:21][C:22]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:40])[F:41])=[CH:35][CH:34]=3)=[CH:23][CH:24]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(Cl)nn2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(-c3ccc(OC(F)(F)F)cc3)nn2)cs1
Yield: 79.8 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(6-chloropyridazin-3-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (500 mg) synthesized in Example 213-1 and 4-trifluoromethoxyphenylboric acid (300 mg) were dissolved in dioxane (6 mL) and 2 mol/L sodium carbonate (3 mL), tetrakis(triphenylphosphine)palladium (70 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:2) to give the title compound (520 mg).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH2:11]/[CH:12]=[CH:13]/[CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21](=[O:24])[CH2:22][CH3:23])C2)C1)(=[O:4])[CH2:2][CH3:3].N1C=CC=CC=1.C(O)(=O)CC(O)=O>CO>[C:1]([NH:5][CH2:10][CH2:9][CH2:8][NH:7][CH2:11]/[CH:12]=[CH:13]/[CH2:14][NH:15][CH2:20][CH2:19][CH2:18][NH:17][C:21](=[O:24])[CH2:22][CH3:23])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)N1CCCN(C/C=C/CN2CCCN(C(=O)CC)C2)C1
Agent: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: CO
Product: CCC(=O)NCCCNC/C=C/CNCCCNC(=O)CC

Procedure:
A mixture of 1.84 g (0.005468mmol) of (E)-1,4-bis(3-propionylhexahydro-pyrimidin-1-yl)but-2-ene (Example 17b), 44 ml of methanol, 2.74 ml (0.03405 mol) of pyridine and 4.11 g (0.03949 mol) of malonic acid is heated for 2 h under reflux and is then concentrated by evaporation in vacuo. 10 ml of 30% sodium hydroxide solution are added to the oily residue, the mixture is extracted thoroughly with ethyl acetate, the combined ethyl acetate extracts are dried over anhydrous sodium sulfate, and the resulting product is concentrated by evaporation in vacuo to a volume of about 25 ml. The crystalline precipitate that forms is filtered off and, for purification purposes, is recrystallised from acetonitrile. The resulting title compound melts at 82°-84° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:8]3[C:9]=2[C:4](=[CH:5][CH:6]=[CH:7]3)[N:3]1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].S(Cl)([Cl:23])(=O)=O.[Cl-]>C(O)(=O)C>[Cl:23][C:7]1[C:8]2[C:9]3[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2](=[O:1])[C:10]=3[CH:11]=[CH:12][CH:13]=2
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CN1C(=O)c2cccc3cccc1c23
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCOC(=O)CN1C(=O)c2cccc3c(Cl)ccc1c23
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-oxo-benz[cd]indole-1(2H)acetic acid, ethyl ester (17 g, 0.067 mole, described in Example 3) in glacial acetic acid (67 mL) was added sulfuryl chloride (9 g, 5.4 ml, 0.067 mol) dropwise at room temperature over a period of 50 min with mechanical stirring. The solid initially disappeared after a few milliliters of the chloride were added. Towards the end of additon, the product started to precipitate. The reaction mixture was stirred at room temperature for an additional 30 min and then at 94° C. for 2 hr. After cooling to room temperature the mixture was poured into water (200 mL). The precipitate was filtered, dried (18.3 g), and crystallized from boiling ethanol (360 mL) to give the title compound: mp 138°-140° C.; Anal. Calcd for C15H12ClNO3 : C, 62.19% H, 4.18% N, 4.83% and Found: C, 61.98% H, 4.08% N, 4.82%; IR (CHCl3) 1745 and 1710 cm-1 ; UV max (methanol) 339 (ε3690), 322 (2530), 279 (6030), 258 (18,680) and 214 nm (32,760); NMR (CDCl3)δ 1.25 (t, 3H), 4.2 (q, 2H), 4.65 (s, 2H), and 7.5 (m, 5H).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[C:6]([C:10]1[CH:11]=[C:12]([OH:24])[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=2)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(OCC)C>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:24][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([C:20]([CH3:22])([CH3:21])[CH3:23])[CH:14]=2)[CH:19]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(O)c2cc(C(C)(C)C)ccc2c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(OP(=O)(Cl)Cl)c2cc(C(C)(C)C)ccc2c1
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (0.145 mL, 1 equiv) and 3,7-di-tert-butylnaphthalen-1-ol (J. Org. Chem. 1995, 60, 2909-2911, 0.4 g, 1 equiv) were stirred in anhydrous diethyl ether (10 mL). Anhydrous triethylamine was added (0.217 mL, 1 equiv) at −78° C. and stirred for 30 min. The dichloridate is very unstable at room temperature. The progress of the reaction was monitored by 31P NMR. This crude mixture was considered to be a 100% conversion to dichloridate and was used directly.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]([CH2:25][C:26](=[O:32])[O:27]C(C)(C)C)[C:9](=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]([N:8]([CH2:25][C:26]([OH:32])=[O:27])[CH2:7][C:6]([OH:33])=[O:5])=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)CCCCC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN(CC(=O)O)C(=O)CCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of benzyl 6-[bis(2-tert-butoxy-2-oxoethyl)amino]-6-oxohexanoate (5.9 g, 12.73 mmol) in CH2Cl2 (30 mL) at room temperature was added TFA (30 mL, 12.73 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated. The residue was purified by flash chromatography on C18 reverse phase silica gel to give the title compound. LC-MS Method A: m/e=486 [M+1]; Rt=2.53 min. 1H NMR (CD3OD) δ 7.30 (m, 5H), 5.06 (s, 2H), 4.81 (s, 4H), 4.19 (s, 2H), 4.07 (s, 2H), 2.34 (q, 4H, J=7.03).
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][CH:8]([CH2:21][OH:22])[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]([CH:21]=[O:22])[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)=[CH:23][CH:24]=1)#[N:2]
Reactant: COC(=O)c1ccc(CCC(CO)Cc2ccc(C#N)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCC(C=O)Cc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 400 mg (1.24 mmol) of methyl 4-[3-(4-cyanobenzyl)-4-hydroxybutyl]benzoate in 7 ml of dichloromethane is mixed with 320 mg (1.48 mmol) of pyridinium chlorochromate (PCC) and stirred at room temperature for 5 hours. After conversion is complete, about 1 g of silica gel is added, and the solvent is removed to dryness in vacuo. The residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). 302 mg (90% purity, 69% of theory) of a colorless solid are obtained.
Reaction SMILES: Cl[Si](C)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C=C[C@@H]1[C@@H]2C[C@H]([C@@H](O)C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.N1C=CC=CC=1.[CH3:41][NH:42][C:43]([C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[C:50]([C:55]([C:57]3[N:58]=[CH:59][N:60]([C:62]([C:75]4[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=4)([C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=4)[C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[CH:61]=3)=[O:56])[CH:51]=2)[CH:46]=1)=[O:44].Cl>C1COCC1.C(OCC)(=O)C.[Zn]>[OH:56][C@@:55]([C:50]1[CH:49]=[CH:48][C:47]2[C:52](=[CH:53][CH:54]=[C:45]([C:43]([NH:42][CH3:41])=[O:44])[CH:46]=2)[CH:51]=1)([C:57]1[N:58]=[CH:59][N:60]([C:62]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:75]2[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=2)[C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:61]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CBr
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccccc12
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@](O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
Under argon atmosphere, 10 liters of THF and 253 mL (2 mol) of chlorotrimethylsilane were added to 2616 g (40 mol) of zinc powders. The mixture was stirred at 25° C. for 30 minutes. A solution of 2212 mL (20 mol) of ethyl bromoacetate in 25 L of THF was added dropwise at 25˜35° C. 21.2 g (72 mmol, 1.25 eq) of (+)-cinchonine was added to 431 mL (0.23 mol) of the above Reformatsky reagent at 0˜5° C. 18.6 mL (230 mmol, 4 eq) of pyridine was added dropwise at 0˜5° C. over 7 minutes. The mixture was stirred at 0˜5° C. for 20 minutes. A solution of 30 g (57.5 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 300 mL of THF was added dropwise at −42˜−40° C. over 30 minutes. The mixture was stirred at −45˜−40° C. for 1 hour. 430 mL of 1N hydrochloric acid was added dropwise, diluted with 430 mL of ethyl acetate, and stirred at 20˜25° C. for 30 minutes. After the layers were separated, the organic layer was washed successively with 290 mL of 1N hydrochloric acid, 290 mL of water and 290 mL of an aqueous saturated sodium bicarbonate solution two times, and 290 mL of an aqueous saturated sodium chloride solution. After concentrated under reduced pressure, 90 mL of ethyl acetate was added to the concentration residue, and the mixture was warmed to 50° C. to dissolve it. The solution was stirred at 20˜25° C. for 1 hour. 90 mL of IPE was added, followed by stirring at 0˜5° C. for 2 hours. Crystals were filtered, and washed with 30 mL of IPE. Vacuum drying (50° C.) to a constant weight afforded 29.2 g of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 83%, enantiomer excess 93.5% ee).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:2][CH3:3].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrCC=CC1C=C(C=CC=1)C([O-])=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:3][CH:2]=[CH:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC=Cc1cccc(C(=O)OCC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])c1cccc(C=CCBr)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(C=CCBr)c1

Procedure:
A mixture of ethyl 3-(1-propenyl)benzoate (14.0 g., 0.074 mole), N-bromosuccinimide (14.9 g., 0.084 mole), benzoyl peroxide (150 mg.), and carbon tetrachloride (75 ml.) is stirred and heated at reflux for 46 hours. The mixture is cooled. Solids are filtered off and the filtrate is washed with water and dried over magnesium sulfate. The solvent is evaporated and the residual oil distilled to yield 10.2 g. (51%) of ethyl (3-(3-bromo-1-propenyl)benzoate, b.p. 129°-131° C. (0.05 mm.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[N:5][CH:4]=1.[H-].[Na+].[CH2:16](I)[CH:17]=[CH2:18]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[N:10]2[CH2:18][CH:17]=[CH2:16])=[N:5][CH:4]=1
Reactant: C=CCI
Reactant: COc1cnc2ccc(=O)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)ccc2ncc(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
7-(Methoxy)-1,5-naphthyridin-2(1H)-one (5.958 g, 33.852 mmol) was suspended in dry DMF (100 ml) under argon at rt, and the stirred suspension was treated with sodium hydride (2.98 g, 60% suspension in oil, 74.48 mmol) and stirred at rt for 0.5 h. Allyl iodide (6.88 ml, 74.475 mmol) was then added. The reaction was stirred at rt for 0.5 h and then the mixture was diluted with water to 300 ml and extracted with DCM (3×300 ml). The DCM extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give a brown gum which was purified by chromatography on silica gel using a 0-10% MeOH/DCM gradient to provide the desired compound (4.096 g, 56%). Mixed fractions could be triturated with diethyl ether to provide further compound (0.95 g, 13%).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:33])=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[S:29]([CH3:32])(=[O:31])=[O:30])[CH:21]=1>>[F:33][C:19]1[CH:18]=[CH:17][C:16]([C:12]2[N:4]3[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]3=[N:14][CH:13]=2)=[CH:21][C:20]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[S:29]([CH3:32])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)c1cc(F)ccc1-c1cc(Br)ccc1F
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(F)cc4S(C)(=O)=O)c3)cnc2c1F
Yield: 33 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 5′-bromo-4,2′-difluoro-2-methanesulfonylbiphenyl as described in Example 6 to give 3-(2,4′-difluoro-2′-methanesulfonylbiphenyl-5-yl)-8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridine as an off-white solid (149 mg, 33%): δH (400 MHz, d6-DMSO) 1.57 (6H, s), 3.11 (3H, s), 5.54 (1H, s), 7.20 (1H, t, J 7), 7.49 (1H, t, J 9), 7.65-7.79 (5H, m), 7.96 (1H, dd, J 9 and 3), 8.40 (1H, d, J 7); m/z (ES+) 461 [MH+].
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:15]=1Cl.[H-].[Na+]>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:15]=1[S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: N#Cc1ccc2sc(S)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2sc(Sc3c(Cl)cc([N+](=O)[O-])cc3Cl)nc2c1
Yield: 99 %

Procedure:
The title compound was prepared using the method of example 258, starting with 2-mercapto-benzothiazole-5-carbonitrile (243) (960 mg, 5.0 mmol), 1,2,3-trichloro-5-nitrobenzene (Acros, 1.13 g, 5.0 mmol) and NaH (Aldrich, 60% suspension, 200 mg, 5.0 mmol) in DMF (25 mL). Compound 262 (1.9 was 99%) was obtained as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)=[C:6]([S:13][CH3:14])[N:5]([NH2:15])[CH:4]([CH3:16])[N:3]=1.[CH3:17][O-:18].[Na+]>>[CH3:17][O:18][C:2]1[C:7]([C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)=[C:6]([S:13][CH3:14])[N:5]([NH2:15])[CH:4]([CH3:16])[N:3]=1
Reactant: CSC1=C(C2=NCCN2)C(Cl)=NC(C)N1N
Reactant: C[O-]
Agent: [Na+]
Product: COC1=NC(C)N(N)C(SC)=C1C1=NCCN1
Reaction time: 4 h

Procedure:
3 g 4-chloro-2-methyl-6-methylthio-5-(2-imidazolin-2-yl)-aminopyrimidine (Example 2) are mixed with 60 ml 15% methanolic sodium methylate solution and boiled for 4 hours under reflux. Then about 40 ml methanol are distilled off. The solution is mixed with water and cooled until it crystallizes. 1.5 g of 4-methoxy-2-methyl-6-methylthio-5-(2-imidazolin-2-yl)-aminopyrimidine is obtained, (Melting point 267° C.) after recrystallization from nitromethane.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH2:13][CH2:14][OH:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH2:13][CH:14]([Cl:18])[OH:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCCC1CCCN1CC1=CCCCC1
Solvent: ClC(Cl)Cl
Product: OC(Cl)CC1CCCN1CC1=CCCCC1

Procedure:
17.8 g of 2-[1-(1-cyclohexenylmethyl) 2-pyrrolidinyl]ethanol (0.085 mole) and 50 ml of chloroform are introduced into a 250 ml balloon flask provided with a stirrer, a thermometer, a condenser and a dropping funnel, then 15.3 ml of thionyl chloride is dropped in, the temperature being kept at about 25°-25° C. by cooling.
Reaction SMILES: [Br:1][C:2]1[C:15]2[S:14](=[O:17])(=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[CH:12]=3)[NH:7][C:6]=2[CH:5]=[C:4]([O:20][CH3:21])[C:3]=1[OH:22].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[Br:1][C:2]1[C:3](=[O:22])[C:4]([O:20][CH3:21])=[CH:5][C:6]2[C:15]=1[S:14](=[O:16])(=[O:17])[C:13]1[C:8](=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[CH:12]=1)[N:7]=2
Reactant: COc1ccc2c(c1)S(=O)(=O)c1c(cc(OC)c(O)c1Br)N2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: COC1=CC2=Nc3ccc(OC)cc3S(=O)(=O)C2=C(Br)C1=O
Reaction time: 0.25 h
Yield: 30.2 %

Procedure:
To a stirred suspension of 4-bromo-3-hydroxy-2,7-dimethoxy-10H-phenothiazin-5,5-dioxide (from Step 4) (1 g) in THF (10 ml) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.17 g). After 15 minutes, the mixture was filtered, the solid washed with ether and air dried. The solid was filtered through a silica gel pad with CH2Cl2 :EtOAc, 1:1, to afford the title compound (300 mg), m.p. 228°-230° C. (dec), m/e 383.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([SH:34])[NH:25][C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:18][CH:17]=1.[H-].[Na+]>CN(C)C=O>[CH3:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]2[N:25]=[C:24]([S:34][C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[NH:23][C:22]=2[C:19]2[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=2)=[CH:32][CH:31]=1
Reactant: Cc1ccc(-c2nc(S)[nH]c2-c2ccc(C)cc2)cc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(Sc3ccc(C(F)(F)F)cc3[N+](=O)[O-])[nH]c2-c2ccc(C)cc2)cc1
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
Under agitation and covering with argon, a solution of 4.52 g of 4-chloro-3-nitrotrifluoromethylbenzene in 25 ml of dimethylformamide is added dropwise to a solution of 5.61 g of 4,5-bis(4-methylphenyl)-2-mercaptoimidazole and 0.6 g of sodium hydride (80% strength in white oil) in 200 ml of dimethylformamide. The solution is further stirred for 30 minutes, concentrated under vacuum, and the residue distributed between water and ethyl acetate. The organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized from ethanol, thus producing 8.26 g of 4,5-bis(4-methylphenyl)-2-(2-nitro-4-trifluoromethylphenylthio)imidazole in fine yellow needles having a decomposition point of 252°.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:34]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)(=[O:36])[CH3:35].O>ClCCl>[C:34]([C:37]1[CH:38]=[CH:39][C:40]([S:43]([N:12]2[C:6]3[CH:7]=[N:8][C:9]4[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][C:4]=4[C:5]=3[N:14]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:19][CH:20]=3)[C:13]2=[O:26])(=[O:45])=[O:44])=[CH:41][CH:42]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc2ncc3[nH]c(=O)n(-c4ccc(C(C)(C)C#N)cc4)c3c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(C)ccc4ncc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 3, 100 mg, 0.29 mmol) and triethylamine (60 mg, 0.58 mmol) in dichloromethane (6 ml) was added 4-acetylbenzene-1-sulfonyl chloride (103.75 mg, 0.44 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 50 mg (33%); 1H NMR (DMSO-d6, 300 MHz): δ 9.347 (s, 1H), 8.299-8.325 (d, 2H, J=7.8 Hz), 8.175-8.202 (d, 2H, J=8.1 Hz), 7.940-7.969 (d, 1H, J=8.7 Hz), 7.778-7.803 (d, 2H, J=7.5 Hz), 7.665-7.691 (d, 1H, J=7.8), 7.466-7.495 (d, 2H, J=8.7 Hz), 6.427 (s, 1H), 2.624 (s, 3H), 2.110 (s, 3H), 1.776 (s, 6H); MS: m/z 525 (M+).
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[CH3:30][C:31]([CH3:37])([CH3:36])[CH2:32][CH2:33]C=O>>[CH3:30][C:31]([CH3:37])([CH3:36])[CH2:32][CH2:33][C:21]1[C:20]2[C:19]([F:22])=[CH:18][C:17]([F:23])=[CH:16][C:15]=2[N:14]=[C:13]2[C:24]3[N:10]([CH2:11][C:12]=12)[C:9](=[O:27])[C:8]1[CH2:7][O:6][C:5](=[O:28])[CH2:4][C@@:3]([CH2:1][CH3:2])([OH:29])[C:26]=1[CH:25]=3
Reactant: CC(C)(C)CCC=O
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)cc(F)c1c2CCC(C)(C)C

Procedure:
The product of Example 100 is treated with 4,4-dimethylpentanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[S:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1)(=[O:15])(=[O:14])[NH2:13]>>[S:12]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][N:23]=[CH:4][C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])=[CH:20][CH:21]=1)(=[O:15])(=[O:14])[NH2:13]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=Cc2ccc(Cl)cc2Cl)cc1
Yield: 59 %

Procedure:
A solution of 2,4-dichlorobenzaldehyde (5 mmol) and 4-sulfamylphenylhydrazine hydrochloride was subjected to the General Procedure. The title compound, melting point 219–221° C., was obtained in 59% yield.