Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19])[CH:5]=[CH:6][C:7]=1[C:8](=[O:17])[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1.[ClH:28].O1CCOCC1>CO>[NH2:20][C@H:18]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)=[O:17])=[C:2]([F:1])[CH:3]=1)[CH3:19].[ClH:28]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)N[C@H]2CC[C@H](O)CC2)c(F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H](N)c1ccc(C(=O)N[C@H]2CC[C@H](O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl (S)-1-(3-fluoro-4-(trans-4-hydroxycyclohexylcarbamoyl)phenyl)ethylcarbamate (33 mg, 0.087 mmol) was added, HCl 4M in Dioxane (2 mL, 8.00 mmol) and MeOH (0.2 ml). The reaction was stirred at room temperature for 1 hour, followed by LCMS. The solvent was concentrated off to residue to give 4-((S)-1-aminoethyl)-2-fluoro-N-(trans-4-hydroxycyclohexyl)benzamide in quantitative yield (0.087 mmol) as HCl salt. LCMS m/z 281.1 (M+H)+, Rt 0.33 min.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:3]=1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.[Li]C(C)(C)C.[CH2:32]([Sn:36](Cl)([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35].C(=O)([O-])O.[Na+]>C1COCC1>[C:15]1([C:5]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:2]([Sn:36]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:32][CH2:33][CH2:34][CH3:35])=[C:3]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[N:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C[Si](C)(C)CCOCn1c(-c2ccccc2)nc(-c2ccncc2)c1Br
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(-c2ccncc2)nc(-c2ccccc2)n1COCC[Si](C)(C)C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of the product of Step 2 (13.4 g, 31.2 mmol) in THF (200 ml) at −78° C. was added dropwise tBuLi (22 ml, 1.7M, 38 mmol). After 25 minutes tributyltin chloride (12.37 g, 10.3 ml, 38 mmol) was added dropwise and the mixture was then allowed to reach room temperature overnight. The reaction was then poured into a saturated solution of sodium hydrogen carbonate and washed several times with diethyl ether. The combined organic layers were dried (magnesium sulphate), concentrated in vacuo and the residue purified by silica gel chromatography, eluting with a 0.5:4.5:45:50 mixture of 0.88 ammonia solution:methanol:hexane:diethyl ether to give the title compound (18.5 g, 93%) as a brown viscous oil; MS(AP+) m/e 641/643/644[M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:11][C:7]=2[C:6]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(Oc2ccccc2)c2sc(N)nc12
Product: COc1ccc(Oc2ccccc2)c2sc(NC(=O)c3ccccc3)nc12

Procedure:
Using 4-Methoxy-7-phenoxy-benzothiazol-2-ylamine and benzoyl chloride the title compound was obtained crude, which was chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2/EtOAc (1:1), to afford the pure title compound as a white solid (72% yield), MS: m/e=376.1 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]O)[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:18]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCc1cccnc1
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1conc1-c1ccc(OCc2cccnc2)cc1
Temperature: 25 °C

Procedure:
To a solution of [3-(4-hydroxy-phenyl)-isoxazol-4-yl]-carbamic acid tert-butyl ester (100 mg, 0.362 mmol), 3-pyridylmethanol (40 μL, 0.42 mmol)) and triphenylphosphine (200 mg, 0.76 mmol) in THF (2.1 mL) at 0° C. was added diethylazodicarboxylate (155 μL, 0.85 mmol) over 1.5 h. The reaction mixture was warmed rt for 24 h. Volatiles were removed under reduced pressure and the crude product was dry-loaded onto silica gel. Chromatography (1-2.5% CH3OH in CH2Cl2) provided {3-[4-(pyridin-3-ylmethoxy)-phenyl]isoxazol-4-yl}-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:22]1[CH2:25][S:24](=[O:27])(=[O:26])[CH2:23]1>CN(C)C=O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:22]3[CH2:25][S:24](=[O:27])(=[O:26])[CH2:23]3)[CH:10]=2)[O:3]1
Reactant: O=S1(=O)CC(Br)C1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(C3CS(=O)(=O)C3)c2)OC1(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
A 100-mL round bottomed flask was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.942 g, 4.85 mmol), N,N-dimethylformamide (20 mL) and cesium carbonate (3.16 g, 9.71 mmol). 3-Bromothietane 1,1-dioxide (0.925 g, 5.00 mmol) was added, and the reaction stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with water and brine and concentrated to afford an oil. This material was purified via column chromatography on silica gel (eluting with 1:5 ethyl acetate-hexanes) to afford 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thietane 1,1-dioxide (0.172 g, 12% yield) as a white solid. MS (ESI, pos. ion) m/z 299 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19](Cl)=[O:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:19](=[O:20])[C:18]3[C:17]([Cl:16])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:26])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1c(Cl)cccc1Cl

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-dichlorobenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 2,6-dichlorobenzoyl chloride in a similar manner as described above to give a white solid (25% yield). 1H-NMR (DMSO-d6): δ 10.80 (s, 1H), 9.18 (d, 1H), 7.61 (d, 1H), 7.52 (d, 1H), 7.49 (d, 1H), 7.43 (dd, 1H), 7.36 (d, 1H), 7.19 (dd, 1H), 5.27 (m, 1H), 2.69 (m, 2H), 2.08-1.82 (m, 4H); MS m/z 437 (M−1).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]2=[O:23])[CH2:2]1.Br[CH2:25][CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:38][CH3:39])[C:33]=2[CH3:37])[CH:28]=1>>[CH3:37][C:33]1[C:32]([O:38][CH3:39])=[CH:31][CH:30]=[C:29]2[C:34]=1[CH:35]=[CH:36][C:27]([CH2:26][CH2:25][N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][N:9]3[CH2:18][CH2:17][C:16]4[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=4)[C:10]3=[O:23])[CH2:2]1)=[CH:28]2
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCCNC1)CC2
Reactant: COc1ccc2cc(CCBr)ccc2c1C
Product: COc1cc2c(cc1OC)C(=O)N(CC1CCCCN(CCc3ccc4c(C)c(OC)ccc4c3)C1)CC2

Procedure:
Prepared from 2-[(hexahydro-azepin-3-yl)-methyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 2-(2-bromoethyl)-5-methyl-6-methoxy-naphthalene analogously to Example 1.
Reaction SMILES: C(N(CC)CC)C.Br.[NH2:9][C:10]1[N:17]=[CH:16][C:15]([Br:18])=[CH:14][C:11]=1[CH:12]=O.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1.[BH4-].[Na+]>CO>[Br:18][C:15]1[CH:14]=[C:11]([CH2:12][NH:28][CH2:27][CH2:26][N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[C:10]([NH2:9])=[N:17][CH:16]=1
Reactant: CN1CCN(CCN)CC1
Reactant: Nc1ncc(Br)cc1C=O
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1CCN(CCNCc2cc(Br)cnc2N)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (1.0 mL, 7.09 mmol) was added to a solution of 2-amino-5-bromonicotinaldehyde hydrobromide (1.0 g, 3.54 mmol) in methanol (24 mL) at room temperature. The reaction mixture was stirred for 10 minutes prior to the addition of 2-(4-methylpiperazin-1-yl)ethanamine (558 mg, 3.90 mmol). The reaction mixture was then stirred overnight and cooled to 0° C. Sodium borohydride (201 mg, 5.32 mmol) was added portionwise at 0° C. and the reaction mixture was allowed to reach room temperature and stirred for 4 hours. After concentration to dryness, the residue was purified by chromatography on silica gel using dichloromethane/methanol/ammoniac (10:0:0.1 to 9:1:0.1) as eluent. The title product was obtained as a yellow solid (560 mg, 48%).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][C:4](OC)=[O:5].O.[NH2:11][NH2:12]>CCO>[CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][C:4]([NH:11][NH2:12])=[O:5]
Reactant: NN
Reactant: COC(=O)CC(C)(C)C
Solvent: CCO
Solvent: O
Product: CC(C)(C)CC(=O)NN
Temperature: 80 °C
Yield: 18 %

Procedure:
To a mixture of methyl 3,3-dimethylbutanoate (500 mg, 3.84 mmol) in EtOH (12 ml) was added hydrazine monohydrate (1.87 ml, 38.4 mmol). The mixture was heated to 80° C. under reflux for overnight. The reaction was cooled back down to room temperature and concentrated to dryness affording a crude residue. The residue was dried under high vacuum to afford the title compound as crystalline solid (90 mg, 18% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69-9.12 (s, 1H) 4.13 (br. s, 2H) 1.89 (s, 2H) 0.94 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.CCCCCC.C([Li])CCC.C(OC([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)=O)C.O>O1CCCC1>[O:8]1[C:5]2[CH:6]=[CH:7][C:2]([C:30]3([OH:33])[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]3)=[CH:3][C:4]=2[O:10][CH2:9]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2ccc3c(c2)OCO3)CCNCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
4-Bromo-1,2-(methylenedioxy)benzene (Tokyo Chemical Industry CO., LTD., 2.0 g) was dissolved in tetrahydrofuran (15 ml) and the mixture was cooled to −78° C. An n-butyllithium hexane solution (2.44 M, 5.7 ml) was added to the solution. The mixture was stirred at −78° C. for 1 hr, and 1-(ethoxycarbonyl)-4-piperidone (Aldrich Co., 1.7 g) was added. Then, the reaction temperature was raised to 0° C., and the mixture was further stirred for 1 hr. After completion of the reaction, water was added and the mixture was extracted three times with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (5:1-2:1)). Then, the residue was dissolved in ethylene glycol (20 ml), a 50% aqueous potassium hydroxide solution was added, and the mixture was stirred with heating at 120° C. for 6 hr. After completion of the reaction, the mixture was extracted three times with chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-(1,3-benzodioxol-5-yl)piperidin-4-ol (1.0 g, yield 43%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](Br)[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[N:19][CH:20]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:17]2[CH:18]=[N:19][CH:20]=[C:15]([F:14])[CH:16]=2)[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)cc(C)n1
Reactant: OB(O)c1cncc(F)c1
Product: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1

Procedure:
The title compound, was prepared from 4-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester (example 1, step 4) and 5-Fluoropyridine-3-boronic acid in accordance with the general method of example 1, step 6 to yield the final compound as a light yellow oil, MS (ISP): m/e=261.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21](=S)[NH:22][CH2:23][CH3:24])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2].C(O)(=[O:30])C>C(OCC)(=O)C>[CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]([NH:22][CH2:23][CH3:24])=[O:30])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2]
Reactant: CC(=O)O
Reactant: CCNC(=S)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccccc1S2
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccccc1S2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of mercuric acetate (0.70 g) in acetic acid (11 cc) is added dropwise during a period of 10 minutes to a solution of 10-[(2RS)-1-diethylamino-2-propyl]-N-ethyl-2-phenothiazinecarbothioamide (0.87 g) in glacial acetic acid (11 cc). The reaction mixture is stirred for 90 minutes at 25° C. and then filtered on sintered glass covered with supercel. The celite is washed with acetic acid (2×2 cc) and the combined filtrates are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give a residue which is diluted in ethyl acetate (50 cc). The organic phase is washed with 1 N sodium hydroxide (20 cc) and distilled water (3×20 cc) and then with brine (1×20 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give a residue which is purified by chromatography on a column (height: 15.5 cm; diameter: 1.6 cm) of alumina (0.05-0.16 mm), eluting with mixtures of cyclohexane and ethyl acetate in proportions (by volume) of 80:20 (375 cc) and 75:25 (3 liters), collecting 25-cc fractions. The first three liters are discarded and fractions 3 to 12 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-[(2RS)-1-diethylamino-2-propyl]-N-ethyl-2-phenothiazinecarboxamide (0.54 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH2:16](O)[CH3:17]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:14])[C:11]([O:13][CH2:16][CH3:17])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])cc1

Procedure:
23.3 g of the crude 2-(4-nitrophenyl)propionic acid was dissolved in 100 ml of 22% hydrochloric acid-ethanol solution, and the solution was refluxed on an oil bath for two hours. After ethanol was distilled off under reduced pressure, the residue was neutralized with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off ethyl acetate under reduced pressure, the residue was subjected to silica gel chromatography with chloroform solvent to give 55 g of ethyl 2-(4-nitrophenyl)propionate.
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH2:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:20][C@@H:21]1[C@H:25]([O:26]C(=O)C2C=CC=CC=2)[C@@H:24]([CH2:35][O:36]C(=O)C2C=CC=CC=2)[O:23][C@H:22]1[N:45]1[CH:53]=[N:52][C:51]2[C:46]1=[N:47][C:48]([Cl:55])=[N:49][C:50]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C>O1CCOCC1>[Cl:55][C:48]1[N:49]=[C:50]([NH:11][C@H:9]([CH3:10])[CH2:8][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:51]2[N:52]=[CH:53][N:45]([C:46]=2[N:47]=1)[C@@H:22]1[O:23][C@H:24]([CH2:35][OH:36])[C@@H:25]([OH:26])[C@H:21]1[OH:20]
Reactant: C[C@@H](N)CSc1ccccc1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H](CSc1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.7 %

Procedure:
(R)-1-Phenylthio-2-propylamine (0.4 g, 1.96 mmol) was reacted with 9-(2,3.5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.2 g, 1.9 mmol) in dioxan (15 ml) in the presence of triethylamine (0.4 g, 4 mmol). The reaction mixture was stirred at room temperature for 72 h, heated at 50° C. for 24 h, cooled, filtered and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the title 2-chloro- N-[(R)-1-phenylthio-2-propyl]adenosine (after column chromatography) as a foam (0.47 g, 52%), 1H NMR (DMSO-d6)δ 1.34 (3H, d, --CH3), 3.01 (1H, dd, --C--H), 3.52-3.60 (1H, m, H-5'a), 3.62-3.72 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.13 (1H, m, H-3'), 4.30-4.45 (1H, m, --C--H), 4.53 (1H, m, H-2'), 5.09, 5.22, 5.50 (3H, 3 br, 2', 3' and 5'-OH), 5.84 (1H, d, H-1'), 7.19 (1H, t, Ar--H), 7.30 (2H, t, Ar--H), 7.45 (2H, d, Ar--H), 8.29-8.45 (2H, s & m, H-8 and N--H).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][CH:13]([N:16]([C:20]4[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1.[NH2:29][C@@H:30]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])[C:31]([O:33]CC)=[O:32]>>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][CH:13]([N:16]([C:20]4[CH:21]=[CH:22][C:23]([C:24]([NH:29][C@@H:30]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[C:31]([OH:33])=[O:32])=[O:25])=[CH:27][CH:28]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1
Reactant: C#CCN(c1ccc(C(=O)O)cc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Reactant: CCOC(=O)CCCC[C@H](N)C(=O)OCC
Product: C#CCN(c1ccc(C(=O)N[C@@H](CCCCC(=O)O)C(=O)O)cc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Yield: 25 %

Procedure:
Using an analogous procedure to that described in Example 3, p-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoic acid was coupled to diethyl (2S)-2-aminopimelate (J. Med. Chem., 1983, 26, 1719) and the resultant product was hydrolysed to give (2S)-2-{p-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzamido)pimelic acid in 25% yield, m.p. 165° C.;
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3][C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH2:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[C:12](=[O:13])[C:6]=2[CH:5]=1.[OH:21]O>C(O)(=O)C>[F:20][C:2]([F:1])([F:19])[S:3]([C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH2:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[C:12](=[O:13])[C:6]=2[CH:5]=1)=[O:21]
Reactant: OO
Reactant: O=C1c2cc(SC(F)(F)F)ccc2CCn2cccc21
Solvent: CC(=O)O
Product: O=C1c2cc(S(=O)C(F)(F)F)ccc2CCn2cccc21

Procedure:
A solution of 3 gm. of 9-trifluoromethylthio- 6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one in 25 ml. of acetic acid containing 3 ml. of 50% hydrogen peroxide is stirred at 25° C. for 6 hr. The solvent is evaporated and the residue dissolved in 100 ml. of methylene chloride. The solution is washed with 2 × 25 ml. of 5% Na2CO3 solution, dried and evaporated. Chromatography of the residue on silica gel yields 9-trifluoromethylsulfinyl-6,11- dihydro-5H-pyrrolo [2,1-b][3]benzazepin-11-one.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([N:43]=[C:44]=[O:45])=[CH:39][N:38]=1)=[O:36]>ClCCl>[CH3:33][O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:45])=[CH:39][N:38]=1)=[O:36]
Reactant: COC(=O)c1ccc(N=C=O)cn1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (67.8 mg, 0.67 mmol) (Aldrich), followed by the addition of solution of 5-isocyanato-pyridine-2-carboxylic acid methyl ester in toluene (from Example 83c supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-5-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-pyridine-2-carboxylic acid methyl ester as a white solid. (Yield 83 mg, 56.1%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH2:7][CH2:6][CH2:5]2.FC1(F)OC2C=C(C)C(C3N=C[C:26]([NH:29][C:30](=O)[C:31]4[CH:36]=[CH:35]C=CC=4F)=[N:27]C=3)=CC=2O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(#N)C.O.ClCCl>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][CH2:7]2)=[CH:3][C:2]=1[C:31]1[CH:36]=[CH:35][C:26]([NH2:27])=[N:29][CH:30]=1
Reactant: COc1cc2c(cc1Br)CCC2
Reactant: Cc1cc2c(cc1-c1cnc(NC(=O)c3ccccc3F)cn1)OC(F)(F)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc2c(cc1-c1ccc(N)nc1)CCC2
Temperature: 90 °C
Reaction time: 48 h

Procedure:
Palladium tetrakis-triphenylphosphine (25 mg, 20 μmol) was added to a degassed solution of bromide 125 (100 mg, 0.4 mmol) and boronate 11 (174 mg, 0.8 mmol) in dioxane:acetonitrile:water (9:9:2, 2.2 mL) and potassium carbonate (139 mg, 0.7 mmol). The resulting mixture was heated under argon at 90° C. with stirring for 2 days. The mixture was then cooled, diluted with dichloromethane (5 mL), dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 126 as an impure oil: LRESIMS m/z 241.1 [M+H]+, calcd. for C15H17N2O1 241.1.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](=[S:21])[NH:18][C:17]3=[O:22])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.I[CH2:34][CH3:35]>>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([S:21][CH2:34][CH3:35])=[N:18][C:17]3=[O:22])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1NC(=S)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Reactant: CCI
Product: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one and iodoethane following General Procedure C.