Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:18]([C:20]([CH2:27][CH3:28])([C:24](Cl)=[O:25])[C:21](Cl)=[O:22])[CH3:19]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([N:8]2[C:21](=[O:22])[C:20]([CH2:27][CH3:28])([CH2:18][CH3:19])[C:24](=[O:25])[O:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NO)c1ccc(Cl)cc1
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1(CC)C(=O)ON(C(=O)c2ccc(Cl)cc2)C1=O
Yield: 16.4 %

Procedure:
A mixture consisting of 2.70 g (0.0157 mol) of 4-chlorobenzohydroxamic acid, mp 170-171° C. (dec). (lit. mp 168° C. dec., Bielstein Handbook of Organic Chemistry, series H, vol 9. p. 341), 5 ml of pyridine, and 100 ml of methylene chloride was prepared in a 250 ml round bottom flask. The mixture was cooled in an ice bath, and 3.097 g (0.0157 mol) of diethylmalonyl chloride was added dropwise over a 15 minutes period with stirring. The reaction mixture was stirred for 4 hours at room temperature after which time all the hydroxamic acid had dissolved. The solution was extracted two times with 50 ml portions of water, three times with 50 ml portions of 5% hydrochloric acid, and two times with 50 ml portions for 5% sodium carbonate. The methylene chloride was dried (MgSO4) and evaporated to dryness under reduced pressure to give 0.76 g (16.4%) of crude 2-(4-chlorobenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a solid residue. Recrystallization of the solid from methanol gave pure 2-(4-chlorobenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a white solid: mp 98-100° C.; IR (Nujol) 1812 (s, C=0) 1745 (s C=0) 1700 cm-1 (s, C=0); 1H NMR (400 MHz, CDCl3) 7.77-7.80 (m, 2H), 7.49-7.52 (m, 2H), 1.99 (q/ 4H), 1.04 (t, 6H); High resolution MS, calc'd for: C14H14NO4 -Cl: 295.0612. Found: 295.0615. Anal. Calc'd for: C14H14NO4Cl: C, 56.86; H, 4.77; N, 4.74; Cl, 11.99. Found: C, 57.04; H, 4.63; N, 4.58; Cl, 11.88.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:32]([CH2:36][C:37](Cl)=[O:38])([CH3:35])([CH3:34])[CH3:33].C1(C(N2CCC(OC3C=CC(NC4C5C=C(F)N=CC=5N=CN=4)=CC=3C)CC2)=O)CCCC1>>[CH3:33][C:32]([CH3:35])([CH3:34])[CH2:36][C:37]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:15][C:16]3[C:17]4[CH:25]=[C:24]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[N:23]=[CH:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:3][C:2]=2[CH3:1])[CH2:10][CH2:11]1)=[O:38]
Reactant: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1OC1CCNCC1
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)C2CCCC2)CC1
Product: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1OC1CCN(C(=O)CC(C)(C)C)CC1

Procedure:
The title compound was prepared from [3-Methyl-4-(piperidin-4-yloxy)-phenyl]-(6-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine and tert-butylacetyl chloride by a procedure analogous to the synthesis of Cyclopentyl-{4-[4-(6-fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-piperidin-1-y}-methanone above.
Reaction SMILES: C(Cl)[Cl:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])=[N:13][C:14]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=3)=[C:15]([CH:19]=2)[C:16]([OH:18])=O)=[CH:7][CH:6]=1.C(Cl)(=O)C(Cl)=O>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])=[N:13][C:14]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=3)=[C:15]([CH:19]=2)[C:16]([Cl:2])=[O:18])=[CH:9][CH:10]=1
Reactant: ClCCl
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Oc1ccc(F)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Oc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a dried round bottom flask was added methylene chloride (2 mL), the product of Example 86 (0.110 g; 0.217 mmol), oxalyl chloride (0.02 mL, 0.217 mmol), and DMF (1 drop; cat.). The reaction mixture was stirred for 1.5 hours at room temperature. Toluene (1 mL) was added to the reaction mixture and the volatiles were removed in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5](O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2].[Na].[CH2:33]([SH:35])[CH3:34]>>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([S:35][CH2:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCS
Reactant: CCCCCCCN(CCc1ccc(CC(O)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Agent: [Na]
Product: CCCCCCCN(CCc1ccc(CC(SCC)C(=O)OCC)cc1)C(=O)OC(C)(C)C

Procedure:
Synthesized from 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-hydroxy-propionic acid ethyl ester using a procedure analogous to that used for Example 50 and substituting the sodium salt of ethanethiol as the nucleophile to give an approximate 1:1 mixture of ethyl and methyl ester as a clear film (23 mg, 43%).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:9]=[C:8]2[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[CH:36]1([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:42]1([C:36]2[CH:37]=[CH:38][C:39]([C:2]3[CH:3]=[CH:4][C:5]([CH2:6][N:7]4[CH:11]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=5[Cl:19])[N:9]=[C:8]4[C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]5)=[CH:22][CH:21]=4)=[CH:34][CH:35]=3)=[CH:40][CH:41]=2)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: O=C1CN(c2ccc(-c3nc(-c4ccc(Cl)cc4Cl)cn3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Product: O=C1CN(c2ccc(-c3nc(-c4ccc(Cl)cc4Cl)cn3Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{-4-[1-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-cyclohexylphenylboronic acid (41 mg, 0.2 mmol) to give 5-{4-[1-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1H-imidazol-2-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: ClC(O[C:6](=[O:12])OC(Cl)(Cl)Cl)(Cl)Cl.[F:13][C:14]([F:23])([F:22])[C:15]1[N:20]=[C:19]([NH2:21])[CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.[Br:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][CH:36]=[C:35]2[NH2:42]>C(Cl)Cl>[Br:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][CH:36]=[C:35]2[NH:42][C:6]([NH:21][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:13])([F:22])[F:23])[N:20]=1)=[O:12]
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: Nc1ccnc2ccc(Br)cc12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)n1)Nc1ccnc2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 159.6 %

Procedure:
366 mg of bis(trichloromethyl)carbonate (1.234 mmol) were dissolved in 7 ml of DCM and cooled to 0° C. To this mixture the solution of 400 mg of 6-(trifluoromethyl)pyridin-2-amine (2.467 mmol) and 379 μl of triethylamine (5.43 mmol) in 9.7 ml DCM was slowly added over 60 minutes at 0° C., and stirring was continued for an additional 60 minutes at room temperature. 550 mg of 6-bromoquinolin-4-amine (2.467 mmol) and 379 μl of triethylamine (5.43 mmol) were suspended in 9.7 ml and subsequently slowly added to the reaction mixture at RT, which became a clear solution after 45 minutes. After stirring over night the reaction mixture was poured into ice water and stirred for 2 h. The precipitation formed was filtered off and dried in vacuum for 24 h. 810 mg of the desired product were obtained as an off white powder (yield: 80%). The quite pure raw material was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=2[NH2:20])=[C:6]([CH3:21])[CH:5]=1.[CH3:23][C:24]1[O:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1.C(OCC)(=O)C.O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=2[NH:20][S:29]([C:27]2[O:28][C:24]([CH3:23])=[CH:25][CH:26]=2)(=[O:31])=[O:30])=[C:6]([CH3:21])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)o1
Reactant: COC(=O)c1ccc(COc2cc(C)c(C)cc2N)c(C)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(COc2cc(C)c(C)cc2NS(=O)(=O)c2ccc(C)o2)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2-amino-4,5-dimethylphenoxymethyl)-3-methylbenzoic acid methyl ester prepared in Reference Example 2 (632 mg) in pyridine (4 ml) was cooled to 0° C., then 5-methylfuran-2-sulfonyl chloride (490 mg) was added dropwise thereto. After the solution was stirred for 1 hour at room temperature, the reaction mixture was diluted by ethyl acetate, and poured into water. The organic layer was washed, dried, concentrated under reduced pressure. The residue was washed by mixed solvent of diisopropylether and hexane to give the title compound (875 mg) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([OH:16])=O)[CH:5]=[CH:4][C:3]1=2.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:1])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[O:16])=[CH:21][CH:20]=1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21
Reactant: Nc1ccc(F)cc1
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(F)cc3)ccc21
Yield: 60.7 %

Procedure:
In a manner analogous to Example 1, 2 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene-carboxylic acid and 1 g of 4-fluoroaniline were used to obtain 1.7 g of 4'-fluoro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxanilide in colorless crystals. m.p. 163° C.-165° C. (from ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH:18]=O)[CH:15]=[N:14]1.[Br-].[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:60](Br)(Br)([Br:62])[Br:61].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH:18]=[C:60]([Br:62])[Br:61])[CH:15]=[N:14]1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: FC(F)(F)c1cc(Cl)c(-n2ncc(C=C(Br)Br)n2)c(Cl)c1
Reaction time: 1 h

Procedure:
A solution of 2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxaldehyde (3.1 g), in dichloromethane (20 ml) was added to a solution of triphenylphosphonium dibromide at -20° (prepared by mixing a solution of carbon tetrabromide (31.2 g) in dichloromethane (30 ml) with a solution of triphenylphosphine (21 g) in dichloromethane (70 ml)) and the mixture stirred for 1 hour. Hexane was added and the mixture filtered. The filtrate was worked up to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2,2-dibromo-vinyl)-2H-1,2,3-triazole. 89°-91° . (Compound 24)
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH3:37])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH3:37])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: CCCc1cccc2sc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 69.9 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-propylbenzothiazole (97 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (6×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 116 mg (70%) of the title compound as an amorphous solid. mp 109°-111°. FDMS: m/e=436. α[D]589 =+45.00 (c=0.80, chloroform).
Reaction SMILES: CC(C)(S([NH:6][CH:7]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:25][CH3:26])[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=O)C.Cl.O1CCOCC1>CO>[NH2:6][CH:7]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:25][CH3:26])[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)ccc2ccccc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CCCC(N)c1c(OC)ccc2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) solution of methyl 5-(1,1-dimethylethylsulfinamido)-5-(2-methoxynaphthalen-1-yl)pentanoate (0.268 g; 0.68 mmol) in MeOH (5 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.35 ml; 1.40 mmol). The resulting mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the oily residue was further dried under HV to give the chlorhydrate salt of methyl 5-amino-5-(2-methoxynaphthalen-1-yl)pentanoate. LC-MS (conditions A): tR=0.55 min. and [M+H]+: 288.16 g/mol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.S([O-])(OC)(=O)=O>CN(C=O)C.O>[CH3:16][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)Cc1ccc(OC)c([N+](=O)[O-])c1
Yield: 82 %

Procedure:
To a solution of 4.2 g (19.8 mmol) of 4-hydroxy-N-methyl-3 -nitrobenzeneacetamide in 50 mL of DMF containing 5.5 g of anhydrous potassium carbonate was added 5.6 mL of dimethyl sulfate. The mixture was heated at 60°-70° C. for 45 min, treated with an additional 3.0 mL of methyl sulfate, and heated for another 30 min. The mixture was cooled, poured into 200 mL water, and extracted with dichloromethane. The extracts were washed with water, dried and evaporated to give a solid which was recrystallized from ethanol-water to afford 3.7 g of a yellowish solid (82%). 1H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.47 (d, 1H, J =9.0 Hz), 7.25 (d, 1H, J =8.4 Hz), 5.71 (brs, 1H), 3.90 (s, 3H) 3.47 (s, 2H), 2.75 (d, 3H, J=4.8 Hz).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][C:13]2[S:17][C:16]3=[CH:18][N:19]=[C:20]([Cl:21])[N:15]3[CH:14]=2)[CH2:10][C@@H:9]([O:22][Si](C(C)(C)C)(C)C)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].Cl>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][C:13]2[S:17][C:16]3=[CH:18][N:19]=[C:20]([Cl:21])[N:15]3[CH:14]=2)[CH2:10][C@@H:9]([OH:22])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cc1cn2c(Cl)ncc2s1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1cn2c(Cl)ncc2s1
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
A solution of 1.430 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-(5-chloroimidazo[5,1-b]thiazol-2-yl)methylpyrrolidine in 31.5 ml of dry acetonitrile is cooled to 3° C., 1.3 ml of concentrated hydrochloric acid is added dropwise thereto while maintaining the internal temperature at 4° C. or below, and the mixture is stirred in this state for 15 min. The reaction solution is diluted with 200 ml of ethyl acetate, washed with 40 ml of a 5% aqueous sodium hydrogencarbonate solution (aqueous layer pH 9) and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure to give a crude product which is then purified by column chromatography on silica gel (ethyl acetate) to give 1.020 g of (3R,5S)-allyloxycarbonyl-5-(5-chloroimidazo[5,1-b]thiazol-2-yl)methyl-3-hydroxypyrrolidine as a slightly yellow viscous material.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH2:17][S:18][CH3:19])[NH2:15].[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[C:30]1[O:34][C:33](=[O:35])[C:32]2([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[N:31]=1>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH2:17][S:18][CH3:19])[NH:15][C:33]([C:32]1([NH:31][C:30]([C:22]2[S:21][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:23]=2)=[O:34])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)=[O:35]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C1OC(c2cc3ccccc3s2)=NC12CCCCC2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CCSC)NC(=O)C1(NC(=O)c2cc3ccccc3s2)CCCCC1
Reaction time: 8 h
Yield: 86.4 %

Procedure:
679 mg (5.3 mmol) of diisopropylethylamine was added to a suspension of 419 mg (2 mmol) of L-methionine methyl ester hydrochloride and 500 mg (1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 10 ml of toluene, and the mixture was refluxed under heating overnight. After the solvent was distilled off under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with a 10% aqueous potassium hydrogensulfate solution and saturated brine and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, diethyl ether was added thereto, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 678 mg (86%) of the title compound.
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([O:17][CH3:18])[C@H:14]([CH2:19][NH2:20])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[Cl:21][C:22]1[S:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=1>>[C:5]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([O:17][CH3:18])[C@H:14]([CH2:19][NH:20][C:27]([C:25]2[S:26][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:28])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN
Reactant: O=C(O)c1ccc(Cl)s1
Solvent: CC(=O)O
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CNC(=O)c1ccc(Cl)s1

Procedure:
80.4 Using general procedure E, (3R,4S)-3-aminomethyl-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester acetate was coupled with 5-chlorothiophene-2-carboxylic acid to give (3R,4S)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester. Colorless foam. MS 318.9 ([M−isobutene+H]+)
Reaction SMILES: [C:1]1([C:7]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]3[CH:11]([CH2:12][N:13](C(OC=C)=O)[CH2:14]3)[C:10](=[O:21])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:28]>O1CCOCC1>[ClH:28].[C:22]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[C:10](=[O:21])[CH2:9][CH2:8]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=COC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
(3aRS,7aRS)-7,7-diphenyl-2-vinyloxycarbonyl-4-perhydroisoindolone (177 g) is treated with a 5.7N solution (1,000 cc) of hydrochloric acid in dry dioxane for 30 minutes at 20° C. The solution is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is taken up in ethanol (500 cc) and the reaction mixture is stirred at 60° C. for 30 minutes and then cooled to +5° C. The crystals obtained are drained, washed with ethanol (50 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (130 g) melting at 270° C. is obtained.
Reaction SMILES: Cl.Cl.[Cl:3][CH2:4][CH2:5][N:6]([CH2:14][CH2:15][Cl:16])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.C.O=C(Cl)[O:20][C:21](Cl)(Cl)Cl.[CH3:26][N:27]([CH3:57])[CH2:28][CH2:29][NH:30][C:31]([C:33]1[C:46]2[C:37](=[C:38]([NH:48][C:49]3[CH:54]=[C:53]([NH2:55])[CH:52]=[CH:51][C:50]=3[CH3:56])[C:39]3[C:44]([N:45]=2)=[C:43]([CH3:47])[CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][CH:34]=1)=[O:32]>O1CCOCC1.CN(C=O)C.N1C=CC=CC=1>[CH3:57][N:27]([CH3:26])[CH2:28][CH2:29][NH:30][C:31]([C:33]1[C:46]2[C:37](=[C:38]([NH:48][C:49]3[CH:54]=[C:53]([NH:55][C:21]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([N:6]([CH2:14][CH2:15][Cl:16])[CH2:5][CH2:4][Cl:3])=[CH:8][CH:9]=4)=[O:20])[CH:52]=[CH:51][C:50]=3[CH3:56])[C:39]3[C:44]([N:45]=2)=[C:43]([CH3:47])[CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][CH:34]=1)=[O:32]
Reactant: Cc1ccc(N)cc1Nc1c2cccc(C)c2nc2c(C(=O)NCCN(C)C)cccc12
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)cc1Nc1c2cccc(C)c2nc2c(C(=O)NCCN(C)C)cccc12
Temperature: 92.5 °C
Reaction time: 24 h

Procedure:
To a suspension of N,N-bis(2-chloroethyl)benzene-1,4-diamine hydrochloride (37) (0.918 g, 3 mmol) and charcoal (20 mg) in dry dioxane (30 mL) was added diphosgene (0.494 g, 2.5 mmol). The reaction mixture was heated at 90-95° C. for 5 h. After cooling, the reaction mixture was filtered through a pad of Celite and the filtrate containing crude mustard isocyanate 39 was added dropwise into the solution of 9-(5-amino-2-methyl-phenylamino)-5-methylacridine-4-carboxylic acid (2-dimethylaminoethyl)amide (0.732 g, 1.7 mmol)33 in dry DMF (25 mL) containing pyridine (2 mL) at −10° C. and then stirred at room temperature for 24 h. The solvent removed under reduced pressure to dryness and the residue was dissolved in a mixture of CHCl3/MeOH containing silica gel (10 gm) and evaporated in vacuo to dryness. The residue was put on the top of a silica gel column (4×30 cm) and chromatographed using CHCl3/MeOH (100:5 v/v) as eluent. The fractions containing the main product were combined and evaporated in vacuo to dryness. The residue was recrystallized from EtOH/hexane to give 9-[5-(3-{4-[bis(2-chloroethyl)amino]phenyl}ureido)-2-methyl-phenylamino]-5-methyl-acridine-4-carboxylic acid (2-dimethylaminoethyl)amide (19, BO-1053); 0.385 g (32%); mp 286-289° C.; 1H NMR (DMSO-d6) δ 2.19 (3H, s, Me), 2.67 (6H, m, NMe2), 2.85 (3H, s, Me), 3.14 (2H, brs, CH2), 3.63-3.69 (8H, m, 4×CH2), 3.85 (2H, brs, CH2), 6.41 (1H, m, ArH,), 6.65 (2H, d, J=9.0 Hz, ArH), 6.97 (1H, m, ArH), 7.24 (2H, d, J=9.0 Hz, ArH), 7.36-7.44 (1H, m, ArH), 7.51 (1H, m, ArH), 7.74 (2H, m, ArH), 7.93 (1H, m, ArH), 8.09 (1H, m, ArH), 8.41 (1H, m, ArH), 8.67 (1H, m, ArH), 9.04 (1H, brs, exchangeable, NH), 9.45 (1H, brs, exchangeable, NH), 12.18 (1H, brs, exchangeable, NH). Anal. Calcld. for (C37H41Cl2N7O2.6H2O): C, 54.91; H, 5.20; N, 12.34. Found: C, 55.08; H, 5.32; N, 12.44.