Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:37])[CH2:14][CH2:15][N:16]([CH2:21][CH2:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[C:30]([O:32]C(C)(C)C)=[O:31])=[O:24])[CH2:17][CH2:18][O:19][CH3:20])=[O:7])(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl.O>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[C:30]([C@H:26]1[CH2:27][CH2:28][CH2:29][N:25]1[C:23](=[O:24])[CH2:22][CH2:21][N:16]([CH2:17][CH2:18][O:19][CH3:20])[CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:37])([OH:32])=[O:31]
Reactant: COCCN(CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN(CCC(=O)N1CCC[C@@H]1C(=O)O)CCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 16 h
Yield: 67 %

Procedure:
To a stirred solution of 150 mg (0.29 mmol) (R)-1-[3-[[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-(2-methoxy-ethyl)-amino]-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml dichloromethane at 0° C. was added dropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded, after resuspension in water and subsequent lyophilisation, 100 mg (67%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:6].C([C:28]1[C:29]([N:34]=[CH:35][N:36]([CH3:38])C)=[N:30][CH:31]=[CH:32][CH:33]=1)#N>>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][C:17]([S:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[C:2]([NH:1][C:38]3[C:28]4[CH:33]=[CH:32][CH:31]=[N:30][C:29]=4[N:34]=[CH:35][N:36]=3)[CH:3]=2)=[CH:9][CH:10]=1
Reactant: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Reactant: CN(C)C=Nc1ncccc1C#N
Product: O=C(Nc1ccc(Br)cc1)c1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3ncccc23)c1
Yield: 24 %

Procedure:
The product of Example 28A was reacted with the product of Example 29A using the procedure of Example 22C substituting the product of Example 28A for the product of Example 22B and substituting the product of Example 29A for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (11 mg, 24%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 6.85 (d, J=8.82 Hz, 2 H) 6.88-7.01 (br m, 1 H) 7.31 (d, J=8.46 Hz, 2 H) 7.52 (d, J=8.82 Hz, 2 H) 7.61-7.87 (br m, 2 H) 7.73 (d, J=9.19 Hz, 2 H) 7.92-8.09 (br m, 1 H) 8.54-8.72 (br m, 1 H) 8.87-9.04 (br m, 1 H) 9.03-9.19 (br m, 1 H) 9.96 (br s, 1 H) 10.31 (br d, J=9.56 Hz, 2 H); MS (ESI+) m/z 544/546 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:48])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C@H:14]([NH:28][C:29](=[O:45])[CH2:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([NH:37]C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)[B:15]2[O:23][CH:22]3[C:17]([CH3:27])([CH:18]4[CH2:24][CH:20]([CH2:21]3)[C:19]4([CH3:26])[CH3:25])[O:16]2)[C:8]=1[O:46][CH3:47])(C)(C)C.Cl.C(OCC)C>O1CCOCC1>[NH2:37][C@H:34]1[CH2:35][CH2:36][C@H:31]([CH2:30][C:29]([NH:28][C@H:14]([B:15]2[O:23][CH:22]3[C:17]([CH3:27])([CH:18]4[CH2:24][CH:20]([CH2:21]3)[C:19]4([CH3:26])[CH3:25])[O:16]2)[CH2:13][C:9]2[C:8]([O:46][CH3:47])=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:48])=[O:5])=[O:45])[CH2:32][CH2:33]1
Reactant: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@H](N)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 3-((2R)-2-(2-(tran-4-(tert-butoxycarbonylamino)cyclohexyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate from Step 1 of Example 6 (640 mg) was added 4 N HCl in dioxane (4 mL). The resultant reaction mixture was stirred at RT for 1 hr. Diethyl ether was added to precipitate out the product as while solid (500 mg) which was used directly to the next step.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:37])=[N:4][C:5]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:20]3[CH2:23][N:22](C(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:21]3)[C:9]=2[CH:8]=1)=[O:6]>[OH-].[Pd+2].[OH-].C(O)C>[NH:22]1[CH2:23][CH:20]([N:10]2[C:9]3[CH:8]=[C:7]([C:5]([N:4]=[C:3]([NH2:37])[NH2:2])=[O:6])[CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:21]1
Reactant: NC(N)=NC(=O)c1ccc2c3ccccc3n(C3CN(C(c4ccccc4)c4ccccc4)C3)c2c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: NC(N)=NC(=O)c1ccc2c3ccccc3n(C3CNC3)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 45.7 %

Procedure:
A 1.26 ml portion of 1 M hydrochloric acid and 30 mg of 20% palladium hydroxide were added to 9 ml ethanol solution of 300 mg N-(diaminomethylene)-9-[1-(diphenylmethyl)-azetidin-3-yl]-9H-carbazole-2-carboxamide, followed by stirring at room temperature for 4 days under an atmosphere of hydrogen gas. After carrying out celite filtration after adding 1 M sodium hydroxide aqueous solution, the solvent was evaporated, followed by purification by Chromatorex (methanol/chloroform) to obtain 89 mg of 9-azetidin-3-yl-N-(diaminomethylene)-9H-carbazole-2-carboxamide.
Reaction SMILES: [C:1]1([C:7](=[N:15][OH:16])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:25](OCC)(=[O:27])[CH3:26].Cl>C1COCC1.O>[OH:27][C:25]1([CH3:26])[O:16][N:15]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ON=C(Cc1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(O)ON=C(c2ccccc2)C1c1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
The deoxybenzoin oxime (Step 1) was dissolved in anhydrous THF (565 mL) under a nitrogen atmosphere. The solution was cooled to −20° C. The solution was treated with lithium diisopropylamide (2 M, 800 mL, 1.60 mol) while allowing the reaction temperature to warm to 10-15° C. The reaction mixture to was cooled to −10° C. to −20° C. and anhydrous ethyl acetate (218 mL) was added to the solution while allowing the reaction temperature to rise to a maximum of 25° C. and held for 30 minutes at 25° C. The reaction mixture was cooled to about 0° C. Water was added to a quench flask and cooled to 0-5° C. The pre-cooled reaction mixture was transferred from the reaction flask to the quench flask while maintaining the temperature of the quench mixture below 25° C. The quenched mixture was cooled to 0-5° C. Hydrochloric acid (12 M) was added to the mixture, keeping the temperature below 25° C. during the addition by controlling the addition rate and stirred until all the solids dissolve (˜5 minutes). The pH of the stirred mixture was measured to be pH 3-4. The layers were separated and the organic layer was removed. Heptane was added to the organic layer with stirring. The organic layer was distilled until the pot temperature reached 90-91° C. The solution was cooled to 5° C. and filtered. The solid was washed with two 300 mL portions of ethyl acetate-heptane (20/80), cooled to 5° C. The solid product was dried on the funnel for several hours then dried at ambient under vacuum with a nitrogen sweep over the weekend to yield the isoxazoline (108.75 g, 57.7%).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][C:4](C1C=C2C(=CC=1)NC(C(O)=O)=C2)=[O:5].[CH2:19]([O:21][C:22]([C:24]1[NH:25][C:26]2[C:31]([C:32]=1[Br:33])=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH3:20].[Al+3].[Cl-].[Cl-].[Cl-].C(Cl)(=O)CC(C)C>[N+](C)([O-])=O>[CH2:19]([O:21][C:22]([C:24]1[NH:25][C:26]2[C:31]([C:32]=1[Br:33])=[CH:30][C:29]([C:4](=[O:5])[CH2:3][CH:2]([CH3:18])[CH3:1])=[CH:28][CH:27]=2)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Reactant: CC(C)CC(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Agent: CC(C)CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)c1[nH]c2ccc(C(=O)CC(C)C)cc2c1Br
Temperature: 0 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
Preparation of 5-(3-Methyl-butyryl)-1H-indole-2-carboxylic acid (Froshauer, S. A.; Goldstein, S. W.; Stirtan, W. G. U.S. Pat. No. 5,981,762): 3-Bromo-1H-indole-2-carboxylic acid ethyl ester (536 mg, 2.0 mmol), prepared as previously described (Elliott, J. D.; Leber, J. D.; Thompson, S. K.; Halbert, S. M. U.S. Pat. No. 5,684,032) was dissolved in nitromethane (10 mL) and cooled to 0° C. AlCl3 was added to the flask. Then a solution of isovaleryl chloride (0.295 mL, 2.4 mmol) in nitromethane (2 mL) was added dropwise to the flask. The mixture was allowed to come to room temperature and stirred for 18 hours. The mixture was then cooled to 0° C. 20 mL ice-water was added and extracted with CH2Cl2 (4×20 mL). The combined organic phase was washed with saturated brine (20 mL), 1N NaHCO3 (20 mL) and saturated brine (2×20 mL), Dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give yellow solid. It was then purified by flash column chromatography eluted with hexane:ethyl acetate (6:1) to give 3-Bromo-5-(3-methyl-butyryl)-1H-indole-2-carboxylic acid ethyl ester (468 mg, 67%) as light yellow solid.
Reaction SMILES: ClC1C=CC(OC2C=CC(NC(=O)[NH:15][C@@H:16]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[O:18])=CC=2)=CC=1.Cl.O1CCOCC1.[F:46][C:47]1[CH:62]=[CH:61][C:50]([O:51][C:52]2[CH:57]=[CH:56][C:55]([N:58]=[C:59]=[S:60])=[CH:54][CH:53]=2)=[CH:49][CH:48]=1>C(Cl)Cl>[CH:26]([N:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][CH2:20][NH:19][C:17](=[O:18])[C@@H:16]([NH:15][C:59]([NH:58][C:55]1[CH:54]=[CH:53][C:52]([O:51][C:50]2[CH:61]=[CH:62][C:47]([F:46])=[CH:48][CH:49]=2)=[CH:57][CH:56]=1)=[S:60])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:27])[CH3:28]
Reactant: Fc1ccc(Oc2ccc(N=C=S)cc2)cc1
Reactant: CC(C)N(CCNC(=O)[C@H](Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)N(CCNC(=O)[C@H](Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccc(F)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To a solution of [(S)-1-(2-diisopropylamino-ethylcarbamoyl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester (Example 3, step B) (0.093 g, 0.24 mmol) in CH2Cl2 (2 mL) a 4 M solution of HCl in dioxane (0.6 mL, 2.4 mmol) was added, and the mixture was stirred for 3 h at rt. The solvents were removed, and the residue was treated with CH2Cl2. The solvents were removed again under reduced pressure. The residue was dissolved in MeOH and treated with strongly basic ion exchange resin. After 10 min of stirring, the resin was filtered off and the solvents were removed. The residue was dissolved in CH2Cl2 (2 mL), and 4-(4-fluoro-phenoxy)-phenylisothiocyanate (0.064 g, 0.26 mmol) was added. After the mixture was stirred for 4 h, a small amount of 4-(4-fluoro-phenoxy)-phenylisothiocyanate (0.02 g) was added, and the mixture was stirred for 12 h. The crude mixture was purified by flash column chromatography using 0–20% MeOH(1% NH4OH)/CH2Cl2 afforded 0.07 g (55%) of the desired product. MS (electrospray): mass calculated for C30H37FN4O2S, 536.26; m/z found, 537.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.26–6.89 (m, 13H), 5.17 (t, J=7 Hz, 1H), 3.17–2.96 (m, 6H), 2.44 (m, 2H), 1.02 (d, J=6.5 Hz, 12H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([CH:14]=[O:15])=[CH:4][N:3]=1.S(=O)(=O)(O)N.Cl([O-])=O.[Na+].C(Cl)(=O)C(Cl)=O.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>C1COCC1.O.C(Cl)Cl.CN(C=O)C>[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:14]([C:5]2[C:6]([NH:8][CH2:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=2)=[O:15])=[CH:35][CH:34]=1
Reactant: CC(C)(C)CNc1nc(Cl)ncc1C=O
Reactant: COc1ccc(CN)cc1
Agent: NS(=O)(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)c2cnc(Cl)nc2NCC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carbaldehyde (1.2 g, 5.27 mmol) in THF (20 ml) is added sulfamic acid (0.819 g, 8.4 mmol) at ambient temperature. To the mixture, sodium chlorite (1.43 g, 15.8 mmol) in water (10 ml) is added dropwise at 0° C. and the reaction mixture is allowed to warm to ambient temperature. After being stirred for 30 min. at ambient temperature, the reaction mixture is diluted with water and extracted with CH2Cl2. The combined extracts are washed with water, brine, dried over MgSO4 and concentrated under reduced pressure to afford crude acid (1.17 g). To a solution of the crude acid (0.5 g, 2.05 mmol) in CH2Cl2 (10 ml) are added oxalyl chloride (0.36 ml, 4.1 mmol) and catalytic amount of DMF successively at 0° C., and the mixture is allowed to warm to ambient temperature. After being stirred for 1 hour at ambient temperature, the mixture is transferred to a solution of p-methoxybenzylamine (2.25 g, 16.7 mmol) in THF (30 ml) at −10° C.–−20° C. and the reaction mixture is stirred for 1 hour. The reaction mixture is quenched with cold water and extracted with CH2Cl2. The combined extracts are washed with water, brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent:n-hexane:AcOEt=2:1) give 2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic acid 4-methoxy-benzylamide. Rf=0.38 (n-hexane:AcOEt=2:1). 1H NMR (400 MHz, DMSO-d6) δ 1.01 (s, 9H), 3.35 (d, 2H), 3.81 (s, 3H), 4.52 (d, 2H), 6.23 (brs, 1H), 6.90 (d, 2H), 7.25 (d, 2H), 8.15 (s, 1H), 9.09 (brs, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8]([CH2:10][CH2:11][NH2:12])=[O:9].[C:13](=[S:15])=[S:14]>>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8]([CH2:10][CH2:11][NH:12][C:13](=[S:14])[SH:15])=[O:9]
Reactant: S=C=S
Reactant: Cc1[nH]cnc1CS(=O)CCN
Product: Cc1[nH]cnc1CS(=O)CCNC(=S)S

Procedure:
Oxidation of 5-methyl-4-(2-aminoethylthio)methylimidazole with one equivalent of sodium metaperiodate yields 5-methyl-4-(2-aminoethylsulphinyl)methylimidazole and reaction of this compound with carbon disulphide gives N-[2-((5-methyl-4-imidazolyl)methylsulphinyl)ethyl]dithiocarbamic acid which, on treatment with methyl iodide may be converted into S-methyl-N-[2-((5-methyl-4-imidazolyl)methylsulphinyl)-ethyl]dithiocarbamate hydriodide.
Reaction SMILES: [Br-].[Cl:2][C:3]1[C:4]([C:10](=[O:22])[CH2:11][N+:12]23CN4CN(CN(C4)C2)C3)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1>C(O)C.Cl>[ClH:2].[NH2:12][CH2:11][C:10]([C:4]1[C:3]([Cl:2])=[CH:8][C:7]([Cl:9])=[CH:6][N:5]=1)=[O:22]
Reactant: O=C(C[N+]12CN3CN(CN(C3)C1)C2)c1ncc(Cl)cc1Cl
Agent: Cl
Agent: [Br-]
Solvent: CCO
Product: NCC(=O)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 179.1 %

Procedure:
To a suspension of 7.0 g of 1-[2-(3,5-dichloropyridin-2-yl)-2-oxoethyl]-1,3,5,7-tetraazatricyclo[3,3,1,13,7]decan-1-ium bromide in 70 ml of ethanol, 7 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the solid was collected by filtration and washed with 15 ml of ethanol to obtain 3.7 g of the desired product as white crystals.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:21]([OH:23])=O)[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]([C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1)[NH2:25].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:21]([NH:25][NH:24][C:26]2[N:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][N:27]=2)=[O:23])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CCC(CN(C=O)OCc2ccccc2)(C(=O)O)CC1
Reactant: NNc1nccc(C(F)(F)F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC1(C)CCC(CN(C=O)OCc2ccccc2)(C(=O)NNc2nccc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a mixture of 1-[(benzyloxy-formyl-amino)-methyl]-4,4-dimethyl-cyclohexanecarboxylic acid (0.10 g, 0.31 mmol), 2-hydrazino-4-(trifluoromethyl)pyrimidine (0.067 g, 0.37 mmol), NMM (0.095 g, 0.93 mmol) and HOAt (0.05 g, 0.37 mmol) in DMF (1 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.072 g, 0.37 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.11 g, 74%). MH+480.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:18]([CH3:19])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:20])[NH:4][CH2:3]1.C[C@H]1[C@H](C)OS(=O)(=O)N(C(OC(C)(C)C)=O)C1>>[CH3:1][C@H:2]1[C@@H:18]([CH3:19])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:20])[NH:4][CH2:3]1
Reactant: C[C@@H]1CNC(=O)c2cc3ccc(C(=O)O)cc3n2[C@H]1C
Agent: C[C@@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O[C@H]1C
Product: C[C@@H]1CNC(=O)c2cc3ccc(C(=O)O)cc3n2[C@@H]1C

Procedure:
This compound is synthesized using the similar procedure used to prepare trans-4,5-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate O), replacing the tert-butyl cis-5,6-dimethyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide with tert-butyl trans-5,6-dimethyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide in step 6.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].[CH2:18]([O:20][C:21]([CH:23]([S:25][CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:24])=[O:22])[CH3:19].C([BH3-])#N.[Na+]>C(O)C>[CH2:18]([O:20][C:21]([CH:23]([S:25][CH2:26][CH:27]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:24])=[O:22])[CH3:19]
Reactant: CCOC(=O)C(=O)CSC(C)C(=O)OCC
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CSC(C)C(=O)OCC)N[C@@H](C)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1 g (4.17 m mols) of (2S)-1-[(S)-alanyl]-2-carboxyperhydroindole, prepared as described in Example 3, Step F, and 4.72 g (19 m mols) of ethyl [(1RS)-1-ethoxycarbonylethylthio]-pyruvate are dissolved in 50 ml of anhydrous ethanol in the presence of 15 g of molecular sieve 4 Å. After 45 minutes' stirring at room temperature, 0.25 g of sodium cyanoborohydride in solution in 2.25 ml of anhydrous ethanol are added within 6 hours.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][C@H:33]([NH2:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([NH:38][C@@H:33]([CH3:32])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:4]=[C:3]([C:2]([F:31])([F:1])[F:30])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: C[C@H](N)C(C)(C)C
Product: C[C@H](NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)C(C)(C)C
Yield: 11 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.200 g, 0.4 mmol) was stirred in (S)-1,2,2-trimethylpropylamine (0.2 ml) at 80° C. in a sealed flask for 20 h. Work up as described in Example 1, 2) gave 25 mg (11%) of the title compound as white crystals. 1H NMR (300 MHz, CDCl3): d=0.95 (s, 9H), 1.15 (d, 3H), 3.0 (m, 1H), 7.40 (s, 2H), 7.50 (d, 2H), 7.70 (s, 1H), 7.82 (d, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:30][CH:15]([CH2:16][CH:17]([N:19]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=[O:29])[CH2:18]2)[N:14](C)[CH2:13][CH:12]3[CH3:32])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].ClC(OC(Cl)C)=O>ClC(Cl)C.CO>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:30][CH:15]([CH2:16][CH:17]([N:19]4[C:20](=[O:29])[C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:27]4=[O:28])[CH2:18]2)[NH:14][CH2:13][CH:12]3[CH3:32])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(C23CC(CC(N4C(=O)c5ccccc5C4=O)C2)N(C)CC3C)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: CC(Cl)Cl
Product: CC(C)Oc1cccc(C23CC(CC(N4C(=O)c5ccccc5C4=O)C2)NCC3C)c1

Procedure:
2-[5-(3-Isopropoxyphenyl)-2,4-dimethyl-2-aza-bicyclo[3 .3.1 ]non-7-yl]-isoindole-1,3-dione (2.5) (1.50 g, 3.5 mmol) was dissolved in dichloroethane and heated to reflux followed by the addition of 1-chloroethyl chloroformate (0.410 ml, 3.8 mmol). This solution was allowed to reflux for 3.5 hrs. The reaction was cooled and the solvent removed under reduced pressure. The crude material was taken up in ethyl acetate and washed with a saturated sodium bicarbonate solution (3×30 ml). The organic layer was collected, dried (Na2SO4) and the solvent removed under reduced pressure yielding crude product. This material was dissolved in methanol and refluxed overnight. The methanol was removed and the crude product dissolved in 1 N NaOH. The aqueous was extracted with 3:1 CH2Cl2:THF. The combined organic layers were collected, dried (Na2SO4) and the solvent removed under reduced pressure yielding crude product. This product was used with out further purification.
Reaction SMILES: C([O:5][C:6](=[O:48])[CH:7]([NH:12][C:13](=[O:47])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[S:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[C:32](=[O:46])[NH:33][CH:34]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[C:39]([CH:34]([NH:33][C:32]([C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[S:23][S:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:48])=[O:5])=[O:47])=[O:46])[CH2:35][CH:36]([CH3:38])[CH3:37])([OH:41])=[O:40]
Reactant: COc1ccc(SSc2ccc(OC)cc2C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c(C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(SSc2ccc(OC)cc2C(=O)NC(CC(C)C)C(=O)O)c(C(=O)NC(CC(C)C)C(=O)O)c1
Yield: 34.7 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)]-2-[2-[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-4-methoxy-phenyldisulfanyl]-5-methoxy-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester(2.4 g, 3.4 mmol) from Example 31, 25 mL dichloromethane, 25 mL trifluoroacetic acid and 2.5 mL anisole. The crude product was recrystallized from methanol/water to afford 0.7 g of the title compound, mp 168°-169° C.