Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Br:9])[C:3]=1[N:10]=[C:11]1[NH:15][CH2:14][CH2:13][NH:12]1.Cl[CH:17]([CH3:21])[C:18](=O)[CH3:19]>COCCO>[Br:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([Br:1])[C:3]=1[N:10]1[C:11]2=[N:12][CH2:13][CH2:14][N:15]2[C:18]([CH3:19])=[C:17]1[CH3:21]
Reactant: Cc1cc(Br)c(N=C2NCCN2)c(Br)c1
Reactant: CC(=O)C(C)Cl
Solvent: COCCO
Product: CC1=C(C)N(c2c(Br)cc(C)cc2Br)C2=NCCN21

Procedure:
5.0 gm (0.015 mol) of 2-(2,6-dibromo-4-methyl-phenylimino)-imidazolidine were refluxed for about 30 hours with 1.8 gm (110%) of 96% 3-chloro-2-butanone in 25 ml of glycol monomethyl ether. The reaction mixture was then evaporated to dryness in vacuo, and the oily residue was dissolved in 1 N hydrochloric acid. The hydrochloric acid solution was adjusted to a pH value of 7 with dilute NaOH and, starting from the pH value, was fractionally extracted with ether at increasing pH values (NaOH). The ether extracts which were uniform according to thin-layer chromatography were combined, dried over magnesium sulfate, and the ether was eliminated in vacuo. The residual oil crystallized out after a short time. Yield: 0.4 gm of the compound of the formula ##STR10## corresponding to 7% of theory. Melting point: 154°-156° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([SH:11])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[OH-].[Na+].[CH3:17]OS(OC)(=O)=O>O>[CH3:17][S:11][C:5]1[CH:6]=[C:7]([CH:8]([CH3:9])[CH3:10])[C:2]([Br:1])=[CH:3][C:4]=1[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)c1cc(Br)c(C(C)C)cc1S
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1cc(C(C)C)c(Br)cc1C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
A mixture of 78.4 g of 4-bromo-2,5-diisopropylbenzenethiol and 12.8 g of sodium hydroxide was stirred together in 200 ml of water while 50.4 g of dimethylsulfate was added at a rate to maintain the reaction temperature between 45°-55°C. After stirring for 3 hours at ambient temperature, the reaction mixture was extracted with ether. The ether solution, washed with half saturated sodium chloride solution and dried over sodium sulfate, was concentrated to an oil which was distilled to give 64 g of 4-bromo-2,5-diisopropylphenyl methyl sulfide, boiling at 91°-93°C at 0.15-0.1 mm Hg; ND23 1.5714.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[C:5]([CH3:16])[CH:4]=1)#[N:2].S(Cl)([Cl:20])(=O)=O.Cl>C(Cl)(Cl)(Cl)Cl>[Cl:20][CH2:16][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=1[NH:9][C:10](=[O:15])[C:11]([F:13])([F:12])[F:14]
Reactant: Cc1cc(C#N)ccc1NC(=O)C(F)(F)F
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(NC(=O)C(F)(F)F)c(CCl)c1
Temperature: 25 °C

Procedure:
In a round-bottomed flask N-(4-cyano-2-methylphenyl)-2,2,2-trifluoroacetamide (Intermediate 1, 19.37 g, 85 mmol), sulfuryl dichloride (27.6 mL, 340 mmol) and diphenylperoxyanhydride (1.028 g, 4.24 mmol) were heated in carbon tetrachloride (210 mL) at 100° C. for 3 h. The mixture was cooled to room temperature and then the reaction mixture was poured into 2M HCl (350 mL). The organic layer was then collected and the solvent was removed to give N-[2-(chloromethyl)-4-cyanophenyl]-2,2,2-trifluoroacetamide as an orange oil, (25.54 g) which was used in the next step without further purification. This oil was added to triphenylphosphine (26.2 g, 100 mmol) and the mixture was heated in toluene (300 mL) at 110° C. for 3 h. The mixture was cooled to room temperature overnight and the precipitate was filtered and washed with small amounts of toluene and diethyl ether to give the title compound as an off-white solid (29.91 g);
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8](COCC[Si](C)(C)C)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[C:3]2[C:10]([S:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reactant: COc1ccccc1S
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1Sc1c[nH]c2ncnc(Cl)c12
Temperature: 50 °C
Yield: 87.6 %

Procedure:
4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (110 mg, 0.27 mmol) was treated with 2-methoxybenzenethiol (49 μl, 0.40 mmol), copper(I) iodide (77 mg, 0.40 mmol) and potassium carbonate (74 mg, 0.54 mmol) in 2.2 mL dimethylformamide according to the method described in Preparation 86 but heating the reaction mixture at 50° C. overnight. The residue was purified using SP1® Purification System (0% to 15%, hexane-ethyl acetate) to give 69 mg (60% yield) of the title compound.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.[NH2:19][C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:1][NH:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cnccn1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(CNc2cnccn2)CC1
Reaction time: 1 h

Procedure:
Benzyl 4-formyl-1-piperidinecarboxylate (P. E. Maligres, Tetrahedron, 53(32):10983–10992(1997)) (100 mg, 0.40 mmol) and aminopyrazine (46 mg, 0.48 mmol) were dissolved in toluene under N2 and was heated to reflux under Dean Stark conditions for 18 h. The volatiles were removed in vacuo and the residue taken up in ethanol and treated with solid NaBH4 (76 mg, 2.00 mmol) in small portions. The reaction aged at 20° C. for 1 h then was quenched with 2N HCl. The reaction was basified with 1M NaOH and was extracted with ethyl acetate (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to give the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:23]([NH:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:24])[C@H:19]([CH2:21][CH3:22])[CH3:20])=[O:16])[CH3:14])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39]([NH:41][C@H:42]([C:48](OC2C=CC([N+]([O-])=O)=CC=2)=[O:49])[CH2:43][CH2:44][C:45]([NH2:47])=[O:46])=[O:40])=[CH:33][CH:32]=1>CN(C)C=O.CCOCC>[NH:41]([C:39]([O:38][CH2:37][C:34]1[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=1)=[O:40])[C@H:42]([C:48]([NH:1][C@H:2]([C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:23]([NH:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:24])[C@H:19]([CH2:21][CH3:22])[CH3:20])=[O:16])[CH3:14])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:6])([CH3:8])[CH3:7])=[O:49])[CH2:43][CH2:44][C:45](=[O:46])[NH2:47]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)[C@@H](C)OC(C)(C)C)C(=O)NCC(=O)OC
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C)C(=O)NCC(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.6 g of the H-Thr(tBu)-Ala-Ile-Gly-OMe described under 28) in 30 ml of dimethylformamide, are mixed with 3.5 g of Z-Gln-ONP and stirred at room temperature until the mixture becomes solid. After allowing to stand overnight the mixture is diluted with ether and the precipitate is filtered off and washed with ether until free of nitrophenol. The protected pentapeptide shows Rf = 0.14 in the system chloroform-methanol (95:5) in a thin layer chromatogram on silica gel. Melting point: > 250° C.
Reaction SMILES: [NH2:1][OH:2].[NH:3]1[C:11]2[C:6](=[C:7]([C:12]3[N:13]=[C:14]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[C:15]4[S:20][C:19]([CH2:21][N:22]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=O)=[CH:18][C:16]=4[N:17]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1>>[NH:3]1[C:11]2[C:6](=[C:7]([C:12]3[N:13]=[C:14]([N:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)[C:15]4[S:20][C:19]([CH2:21][N:22]([CH2:23][CH2:24][CH2:25][C:26]([NH:1][OH:2])=[O:28])[C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[CH:18][C:16]=4[N:17]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: NO
Reactant: CCOC(=O)CCCN(Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N(CCCC(=O)NO)Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Yield: 91 %

Procedure:
The freshly prepared hydroxylamine solution (6.00 mL) was placed in 50 mL flask. Compound 0405-41 (300 mg, 0.51 mmol) was added to this solution and degassed at room temperature for 30 minutes. The reaction process was monitored by TLC. The mixture was neutralized with dry ice, filtered, and the precipitation was washed with methanol and water to give tert-butyl (2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl(4-(hydroxyamino)-4-oxobutyl)carbamate (267 mg, 91%) as a white solid. LCMS: 568 [M+1]+; 1H NMR (400 MHz, DMSO-d6): δ1.45 (s, 9H), 1.74 (m, 2H), 1.96 (t, J=7.2 Hz, 2H), 3.23 (m, 2H), 3.83 (m, 4H), 4.00 (m, 4H), 7.47 (t, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.70 (s, 1H), 8.88 (s, 1H), 10.39 (s, 1H), 13.22 (s, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][C:29]([OH:31])=O)=[CH:23][C:22]=3[F:32])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CO.[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH2:49]>ClCCCl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][C:29](=[O:31])[NH:49][CH2:48][CH2:47][N:46]([CH3:50])[CH3:45])=[CH:23][C:22]=3[F:32])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CC(=O)O)cc3F)CC2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CO
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CC(=O)NCCN(C)C)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[1-(4-carboxymethyl-2,5-difluoro-phenyl)-piperidin-4-ylidene aminooxy]-piperidine-1-carboxylic acid isopropyl ester 75b (8 mg, 0.017 mmol) was dissolved in DCE (0.5 mL) and N,N-dimethylethylenediamine (0.01 mL). HOBt (4.5 mg, 0.034 mmol) and EDC(6.5 mg, 0.034 mmol) were added and the mixture was stirred at r.t. for 16 h. MeOH was added and the mixture purified by HPLC to give 4-(1-{4-[(2-dimethylamino-ethylcarbamoyl)-methyl]-2,5-difluoro-phenyl}-piperidin-4-ylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester 75-1. LC-MS 525.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:25][O:26][CH2:27][CH3:28])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:48][C@@H:49]2[O:51][CH2:50]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:48][C@H:49]5[CH2:50][O:51]5)=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:25][O:26][CH2:27][CH3:28])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOCc1nc(-c2ccc(O)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: CCOCc1nc(-c2ccc(OC[C@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenol (0.21 g, 0.5 mmol, 1.0 eq.) and Cs2CO3 (0.49 g, 1.5 mmol, 3.0 eq.) in DMF (2 mL) was stirred and preheated to 80° C. The reaction mixture was then treated with a solution of (2R)-(−)-glycidyl tosylate (0.17 g, 0.75 mmol, 1.5 eq.) in 1 mL of DMF dropwise, and further stirred at 80° C. for ˜30 min following completion of the addition. Analysis of the reaction by TLC and LC/MS showed that the starting phenol had been consumed and the desired alkylated-phenol was the major product. The reaction was then cooled and diluted with EtOAc and washed with brine. The organic phase was dried with Na2SO4 and evaporated in vacuo. The crude alkylated-phenol was then purified by flash column chromatography over silica gel (EtOAc/hexanes ˜1:3).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[I:8][C:9]1[C:14]2[O:15][CH2:16][O:17][C:13]=2[C:12]([NH2:18])=[CH:11][CH:10]=1.O>C(O)(=O)C>[I:8][C:9]1[C:14]2[O:15][CH2:16][O:17][C:13]=2[C:12]([NH:18][C:1](=[O:3])[CH3:2])=[CH:11][CH:10]=1
Reactant: Nc1ccc(I)c2c1OCO2
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(I)c2c1OCO2
Temperature: 25 °C
Yield: 92.6 %

Procedure:
Acetic anhydride (14.25 ml) was added dropwise to a mixture of intermediate (2-a) (36.6 g) in acetic acid (500 ml), stirred at room temperature. The reaction mixture was stirred for 15 minutes at room temperature. The reaction mixture was poured out into water (500 ml). The precipitate was filtered, washed with water, then dried, yielding 39.29 g (92.6%) of N-(7-iodo-1,3-benzodioxol-4-yl)acetamide (intermediate 2-b).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:4](=[O:16])[C:3]=1[C:17]([O:19]CC)=O.[C:22]([NH:35][NH2:36])(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[C:22]([NH:35][NH:36][C:17]([C:3]1[C:4](=[O:16])[N:5]([CH2:12][CH:13]([CH3:14])[CH3:15])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:19])(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCOC(=O)c1c(O)c2ccccc2n(CC(C)C)c1=O
Reactant: CCCCCCCCCCCC(=O)NN
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2ccccc2n(CC(C)C)c1=O

Procedure:
Reagents: Comp 30 (0.52 mmols, 0.15 g); dodecanoyl hydrazine (0.78 mmols, 0.17 g). Yield: 0.05 g (21%), white solid, m.p.=112° C.-113° C.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[C:32]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:41]4[CH2:42][CH2:43][CH:38]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:39][CH2:40]4)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N2CCC(c3ccccc3)CC2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 38.7 mg (0.24 mmol) 4-phenylpiperidine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 14 mg (19.7%) product as an orange powder. MS (ESI) m/z 592.25 (M+1).
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[OH:31])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](N)=[O:39]>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=5)=[CH:18]4)=[CH:13][C:12]=3[O:31][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[C:38]=[O:39])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: NC(=O)CCCCCBr
Reactant: COC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Product: COC(=O)c1ccc(-c2ccc3cc(OCCCCC=C=O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Yield: 66 %

Procedure:
Following the procedure of Example 12(a), but reacting 640 mg (1.55 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 450 mg (2.32 mmol) of 6-bromohexanamide, 520 mg (65%) of the expected compound were obtained, which compound had a melting point of 209°-10° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][OH:9])=[O:7])([CH3:4])[CH3:3].[H-].[Na+].[Br:12][C:13]1[C:14](Cl)=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=1>C1COCC1>[C:2]([O:5][C:6](=[O:7])[CH2:8][O:9][C:14]1[C:13]([Br:12])=[CH:18][C:17]([Cl:19])=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)CO
Reactant: Clc1cnc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1ncc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-tert-butyl glycolate (437 mg; 3.31 mmol) in anhydrous THF (5 mL) was treated with NaH (159 mg; 3.97 mmol) and stirred at RT for 10 minutes before treating with a solution of 3-bromo-2,5-dichloropyridine (Matrix; 500 mg; 2.20 mmol) in anhydrous THF (5 mL). The resulting reaction mixture was stirred for 22 hours. The reaction mixture was treated with a solution of 2-tert-butyl glycolate (437 mg; 3.31 mmol) in THF (2 ml), then with NaH (159 mg; 3.97 mmol) and the reaction mixture was stirred for 16 h. The reaction was quenched with tBuOH, the solvent removed under reduced pressure affording a brown solid, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc, affording the title compound as a yellow sticky solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:14])[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.O=S(Cl)Cl.Cl.[CH3:20][O:21][C:22](=[O:25])[CH2:23][NH2:24]>>[C:22]([CH2:23][NH:24][C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH3:14])[C:2]=1[Cl:1])=[O:13])([O:21][CH3:20])=[O:25]
Reactant: COC(=O)CN
Reactant: Cn1c(Cl)c(C(=O)O)c2ccccc21
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)CNC(=O)c1c(Cl)n(C)c2ccccc12
Yield: 78 %

Procedure:
Similar reaction of 2-chloro-1-methylindole-3-carboxylic acid [XXI] with SOCl2 and glycine methyl ester hydrochloride gave N-carbomethoxymethyl 2-chloro-1-methylindole-3-carboxamide [XXII: R6 =H, R7 =CH2COOMe] (78% yield); mp (CHCl3 /light petroleum) 102.5°-104° C.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[OH:36])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>ClCCl>[C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[O:36][C:43](=[O:45])[CH3:44])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 98.1 %

Procedure:
To a suspension of 3-hydroxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (2) in dichloromethane (13 parts) at 0° C. are added pyridine (6 equivalents) and acetic anhydride (6 equivalents). After 14 hours at 0° to 5° C., the mixture is diluted with ice-water. The organic layer is taken, washed with hydrochloric acid, aqueous sodium hydrogen carbonate, and water, dried, and concentrated. The reaction is crystallized from a mixture of dichloromethane and hexane to give 3-acetoxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (3a). Yield: 98.1%. mp. 187°-188° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])[CH2:13][CH2:14]1)[CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCC(=O)O)CC1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCN(CC)C(=O)CCCC[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 0 °C

Procedure:
To 1 g (3.19 mmol) trans-5-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-pentanoic acid in 37 ml CH2Cl2 was added 0.5 ml (4.8 mmol, 1.5 eq) diethylamine and 0.53 ml (4.79 mmol, 1.5 eq) NMM. The solution was cooled to 0° C. and 795 mg (4.15 mmol, 1.3 eq) EDCI and 98 mg (6.4 mmol) HOBT were added. The mixture was stirred at RT over night, partitioned between CH2Cl2 and a saturated aqueous solution of NaHCO3. The organic phase was washed with KHSO4 and brine, dried over Na2SO4 and evaporated. Column chromatography with EtOAc/hexane 1:1 gave 1.05 g (86%) trans-[4-(4-Diethylcarbamoyl-butyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester as colorless liquid MS: 369 (MH+).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[OH:31][C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1>>[N:25]1([C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:10]4[O:9][C:8]([CH2:7][CH2:6][N:34]5[CH2:35][CH2:36][C@@H:32]([OH:31])[CH2:33]5)=[CH:12][C:11]=4[CH:13]=3)=[N:18][CH:19]=2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: O[C@@H]1CCNC1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CC[C@@H](O)C4)cc3c2)nc1)N1CCOCC1

Procedure:
The product from Example 44E and 3-(R)-hydroxypyrrolidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 4.55 (m, 1H), 3.3-3.8 (m, 16H), 2.0-2.4 (m, 2H); MS (DCI) m/z 422 (M+H)+;
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1.[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25]>CO>[S:8]1[C:4]2[CH:3]=[C:2]([CH:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:11][N:12]([CH3:21])[CH2:13]3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1.[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25].[S:8]1[C:4]2[CH:3]=[C:2]([CH:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:11][N:12]([CH3:21])[CH2:13]3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: Brc1ccc2ncsc2c1
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: CN1Cc2ccccc2C(c2ccc3ncsc3c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Racemic 4-benzothiazol-6-yl-2-methyl-1,2,3,4-tetrahydroisoquinoline was prepared from 6-bromo-benzothiazole by a method similar to the one described in Example 129 (Steps B to C). The desired tetrahydroisoquinoline (20.5 mg) was dissolved in methanol and treated with a solution of maleic acid in methanol (1 mL) at 0° C. The solution was stirred at room temperature overnight, then concentrated, and the solid was washed with diethyl ether providing (+/−)-4-benzothiazol-6-yl-2-methyl-1,2,3,4-tetrahydroisoquinoline, maleate salt (30 mg, 98%, >99% AUC HPLC): 1H NMR (CD3OD, 500 MHz) δ 9.28 (d, J=3.9 Hz, 1H), 8.09-8.08 (m, 1H), 8.00-7.9 g (m, 1H), 7.44-7.42 (m, 1H), 7.36-7.25 (m, 3H), 6.93-6.92 (m, 1H), 6.26-6.25 (s, 2H), 4.80-4.78 (m, 1H), 4.64-4.56 (m, 2H), 3.93-3.8 g (m, 1H), 3.63-3.61 (m, 1H), 3.08 (s, 3H); ESI-MS m/z=281 [M+H]+.