Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14](CC)([NH:17][N:18]3[CH:22]=[CH:21][CH:20]=[CH:19]3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[N:30]#[C:31]Br.[Cl:33]CCl>>[ClH:33].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([N:17]([N:18]3[CH:22]=[CH:21][CH:20]=[CH:19]3)[C:31]#[N:30])[CH2:15][CH2:16]2)=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: N#CBr
Reactant: CCC1(Nn2cccc2)CCN(CCc2ccc(OC)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(CCN2CCC(N(C#N)n3cccc3)CC2)cc1
Product: Cl
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 1-[2-(4-methoxyphenyl)ethyl]-4-ethyl-4-(1H-pyrrol-1-yl)aminopiperidine of Example 12a (4 g, 13.4 mmole) in 150 ml dichloromethane containing sodium bicarbonate (3.4 g, 40 mmole) was added a solution of cyanogen bromide (1.6 g, 14.7 mmole) in 25 ml dichloromethane. After stirring twenty hours at ambient temperature, the reaction mixture was evaporated, stirred with water and extracted with ether. The organic extract was washed with water and saturated NaCl and was dried (anhydrous MgSO4), filtered and evaporated to 5 g of an oil. The oil was converted to the hydrochloride salt as in Example 2 and was recrystallized from isopropanol-ether to give 2.8 g (58%) of N-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)cyanamide hydrochloride, d 227°-229° C.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]#N)=[CH:26][CH:25]=3)=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:32].[OH-:33].[K+]>C(O)C>[CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:33])=[O:32])=[CH:30][CH:31]=3)=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [OH-]
Reactant: N#Cc1ccc(Cc2cc(-c3ccc(OC(F)(F)F)cc3)n(C3CCCCC3)n2)cc1
Reactant: O
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc(Cc2cc(-c3ccc(OC(F)(F)F)cc3)n(C3CCCCC3)n2)cc1

Procedure:
To a warm solution of 0.45 g 4-({1-cyclohexyl-5-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-3-yl}methyl)benzonitrile from Step D above in 10 mL ethanol and 2.5 mL water was added 0.70 g potassium hydroxide pellets. The resulting solution was refluxed under nitrogen over night. Ethanol was removed under reduced pressure. The product was precipitated by adding 11.5 mL 1 N HCl to the residue. The title compound was collected by filtrated, washed with water several times, and dried to give a slightly yellowish solid. 1H NMR (CD3OD, 500 MHz) δ 7.94˜7.96 (m, 2H), 7.47˜7.49 (m, 2H), 7.37˜7.41 (m, 4H), 6.09 (s, 1H), 4.06 (s, 2H), 4.05 (tt, J=3.8 & 11.9 Hz, 1H), 1.97˜2.05 (m, 2H), 1.85˜1.93 (m, 4H), 1.67˜1.71 (m, 1H), 1.26˜1.36 (m, 3H). LC-MS: 2.38 min. (M+H=445.2).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:58][CH3:59])[C@H:42]([NH:46][C:47]([N:49]([CH3:57])[CH2:50][C:51]1[N:52]=[C:53]([CH3:56])[S:54][CH:55]=1)=[O:48])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:21])[NH:19][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:4][C@H:3]([OH:32])[C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:43](=[O:44])[C@H:42]([CH:41]([CH2:58][CH3:59])[CH3:40])[NH:46][C:47](=[O:48])[N:49]([CH3:57])[CH2:50][C:51]1[N:52]=[C:53]([CH3:56])[S:54][CH:55]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)N(C)Cc1csc(C)n1)C(=O)O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)[C@H](NC(=O)N(C)Cc1csc(C)n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 109E (0.018 g, 0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-10% methanol in ethyl acetate, to give the title compound (0.030 g, 78% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.78 (m, 16 H), 1.01 (m, 1 H), 1.36 (m, 1 H), 1.50 (m, 2 H), 1.70 (m, 1 H), 2.61 (s, 3 H), 2.73 (m, 3 H), 2.86 (s, 3 H), 3.49 (s, 3 H), 3.62 (m, 1 H), 3.83 (d, J=9.93 Hz, 1 H), 3.98 (t, J=7.91 Hz, 1 H), 4.11 (m, 2 H), 4.43 (m, 2 H), 4.86 (d, J=5.88 Hz, 1 H), 6.19 (d, J=8.09 Hz, 1 H), 6.62 (d, J=9.56 Hz, 1 H), 7.16 (m, 8 H), 7.31 (m, 1 H), 7.42 (d, J=9.19 Hz, 1 H), 7.77 (d, J=8.09 Hz, 1 H), 7.85 (m, 4 H), 8.63 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [NH2:1][N:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[C:3]1=O.C(O[C:17](=[NH:30])[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)C>C(OCC)C>[C:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:19][C:18]([C:17]2[N:30]=[C:3]3[C:4]4[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=4[CH2:6][CH2:7][CH2:8][N:2]3[N:1]=2)=[CH:23][CH:22]=1
Reactant: NN1CCCc2ccccc2C1=O
Reactant: CCOC(=N)c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Product: c1ccc(-c2ccc(-c3nc4n(n3)CCCc3ccccc3-4)cc2)cc1
Yield: 63 %

Procedure:
This compound was prepared according to the procedure of Example 3 starting from 2-amino-4,5-dihydro-2-benzazepine-1(2H,3H)-one and 4-phenyl-benzimidic acid ethyl ester. Yield 63%. M.p. 135°-37° C. (from diethyl ether).
Reaction SMILES: CS(O[CH:6]([CH2:14][F:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.O.[Cl-].[Na+].O>[N:16]([CH:6]([CH2:14][F:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+:17]=[N-:18]
Reactant: CS(=O)(=O)OC(CF)Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(CF)Cc1ccccc1
Temperature: 80 °C
Yield: 82.5 %

Procedure:
To a stirred solution of 1-fluoromethyl-2-phenylethyl methanesulfonate (1.1 g) in anhydrous DMF (15 mL) under nitrogen was added sodium azide (0.53 g) followed by heating at 80° C. overnight. The cooled reaction mixture was diluted with equal parts of water and brine and extracted with EtOAc. The extracts were washed with water and brine, dried over Na2SO4, and concentrated to an oil which was chromatographed over silica gel with a mixture of EtOAc and hexane to give 0.70 g of the title compound. MS ES (M++H−N2) 151.
Reaction SMILES: [OH-].[Na+].[O:3]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@@H:4]1[O:10][C@@H:9]([C@@H:11]([C:13]([O:15]CCCCCCCCCC)=[O:14])[OH:12])[C@H:7]([OH:8])[C@H:5]1[OH:6].C(OCC)C>C1COCC1>[O:3]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@@H:4]1[O:10][C@@H:9]([C@@H:11]([C:13]([OH:15])=[O:14])[OH:12])[C@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: CCCCCCCCCCOC(=O)[C@@H](O)[C@@H]1O[C@@H](OCCCCCCCCCC)[C@H](O)[C@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCO[C@@H]1O[C@@H]([C@H](O)C(=O)O)[C@H](O)[C@H]1O
Reaction time: 3 h
Yield: 82.1 %

Procedure:
20 ml of 2.5N sodium hydroxide are added to 240 mg (0.51 mmol) of n-decyl n-decyl β-D-galactofuranoside uronate solubilized in 5 ml of THF and the mixture is allowed to stand at room temperature for 3 hours. 30 ml of ethyl ether are added and then after decanting, the aqueous phase is washed with 30 ml of ethyl ether. The aqueous phase is acidified with 50% HCl at 0° C. to pH=2 and then extracted three times with 30 ml of ethyl acetate. The organic phases are pooled, washed with 30 ml of water, dried over magnesium sulphate (2 g) and evaporated. 140 mg of n-decyl β-D-galactofuranoside uronic acid are then obtained (82% yield) in the form of a gum. *Rf=0.67 (dichloromethane/methanol-1/1-v/v) *13C NMR in CD3OD
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[N:23]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH:27]=[CH:26][N:25]=[CH:24]1.C(N(C(C)C)CC)(C)C.C1COCC1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH:31][CH2:30][CH2:29][CH2:28][N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Reactant: NCCCn1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(NCCCn3ccnc3)c(Br)c2)c(SC)s1
Temperature: 80 °C

Procedure:
To a vial containing a stirbar was added 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example 2: step c), 3-imidazol-1-yl-propylamine (0.018 g, 0.146 mmol), diisopropylethylamine (0.073 g, 0.565 mmol), THF [0.50 mL], DMF [0.50 mL]. The reaction vessel was sealed and the solution was heated to 80° C. for 18 hours. Removal of the solvents in vacuo followed by chromatography (5% MeOH/DCM) yielded the title compound. 1H-NMR (CDCl3): δ 8.69 (d, 1H, J=2.1 Hz), 8.10 (d, 1H J=2.1 Hz), 8.03 (s, 1H), 8.02 (s, 1H), 7.57 (s, 1H), 7.10 (s, 1H), 6.97 (s 1H), 5.70 (t, 1H, J=5.8 Hz), 4.06 (t, 2H, J=6.8 Hz), 3.89 (s, 3H), 3.57 (m, 2H), 2.97 (s, 2H), 2.90 (s, 2H), 2.64 (s, 3H), 2.17 (m, 2H). ESI-MS (m/z): Calcd. For C18H19BrN4O4S3: 532.5 (M+H); found 530.9, 532.9.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=1)[CH3:2].[BH4-].[Na+].Cl>CO.O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=1)[CH3:2]
Reactant: CCc1cccc(CC)c1-c1cccc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1-c1cccc(CO)c1
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of 2′,6′-diethylbiphenyl-3-carbaldehyde (3.48 g, 14.6 mmol) in a mixture of methanol (35 mL) and tetrahydrofuran (35 mL) was added sodium borohydride (0.28 g, 7.3 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was adjusted to pH 3 with 1N hydrochloric acid, diluted with ethyl acetate, washed successively with water and saturated brine, dried (magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-2/1) to give the title compound (2.82 g, yield 80%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]2[CH:16]=[N:17][S:18][C:14]=2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:41][O:42][CH2:43][C@@H:44]([OH:46])[CH3:45].CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[OH:46][C@@H:44]([CH3:45])[CH2:43][O:42][NH:41][C:19]([C:11]1[CH:12]=[CH:13][C:14]2[S:18][N:17]=[CH:16][C:15]=2[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: C[C@H](O)CON
Reactant: O=C(O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](O)CONC(=O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
To a solution of 4-(2-fluoro-4-iodo-phenylamino)-benzo[d]iso-thiazole-5-carboxylic acid (150 mg, 0.362 mmol), diisopropylethylamine (0.25 mL, 1.45 mmol), HOBt (98 mg, 0.724 mmol) and (S)-1-aminooxy-propan-2-ol (92 mg, 0.724 mmol in DMF (2 mL) was added EDCI (139 mg, 0.724 mmol). The reaction mixture was stirred for 16 hours at room temperature, diluted with ethyl acetate, and washed with water, a saturated aqueous solution of sodium hydrogen carbonate, then brine before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 30% to 80%, EtOAc in cyclohexane) to afford the title compound as a solid (45 mg, 26%). LCMS (method A): RT=10.26 min, [M+H]+=488. 1H NMR (DMSO-d6, 400 MHz) 11.72 (1 H, s), 9.22 (1 H, s), 8.69 (1 H, s), 7.86-7.81 (1 H, m), 7.64-7.55 (2 H, m), 7.30 (1 H, dd, J=8.47, 1.83 Hz), 6.63 (1 H, t, J=8.72 Hz), 4.73 (1 H, s), 3.76-3.68 (1 H, m), 3.53 (2 H, d, J=5.78 Hz), 0.99 (3 H, d, J=6.33 Hz).
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH2:14]O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH2:14][Br:2]
Reactant: BrP(Br)Br
Reactant: OCc1cc(Cl)cc(Cl)c1Cl
Solvent: Cc1ccccc1
Product: Clc1cc(Cl)c(Cl)c(CBr)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 276 %

Procedure:
A solution of 7.6 grams (0.028 mole) of phosphorus tribromide in 200 mL of toluene was stirred, and 17.0 grams (0.080 mole) of 2,3,5-trichlorophenylmethanol was washed into the reaction vessel with about 5 mL of toluene. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 16 hours. The reaction mixture was then concentrated under reduced pressure to a residue. The residue was dissolved in ethyl acetate and washed with three portions of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 21.2 grams of 2,3,5-trichlorophenylmethyl bromide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20]([N:22]3[CH2:27][CH:26]([CH3:28])[O:25][CH:24]([CH3:29])[CH2:23]3)=[O:21])[C:12]2=[N:11][C:10]=1[C:30]1[S:31][C:32]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[S:43][CH3:44])=[CH:33][N:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.CC(O)=[O:49]>O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20]([N:22]3[CH2:27][CH:26]([CH3:28])[O:25][CH:24]([CH3:29])[CH2:23]3)=[O:21])[C:12]2=[N:11][C:10]=1[C:30]1[S:31][C:32]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[S:43]([CH3:44])=[O:49])=[CH:33][N:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CSc1cc(F)ccc1Cc1cnc(-c2nc3n(CC(=O)N4CC(C)OC(C)C4)ccn3c(=O)c2OCc2ccccc2)s1
Agent: OO
Solvent: O
Product: CC1CN(C(=O)Cn2ccn3c(=O)c(OCc4ccccc4)c(-c4ncc(Cc5ccc(F)cc5S(C)=O)s4)nc23)CC(C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
The mixture of the product of example 168 (160 mg, 0.25 mmol), H2O2 (30%, 1 ml) and HOAc (5 ml) was stirred at room temperature for 3 h. H2O (6 ml) was added and then extracted with ethyl acetate. The organic layer was washed with H2O, dried and concentrated. The residue was purified by column chromatography (ethyl acetate) to give the titled compound (170 mg, 100% yield)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@H:4]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[NH:5][C:6](=[O:29])[CH:7]([CH2:24][S:25][C:26](=[O:28])[CH3:27])[CH2:8][CH2:9][CH2:10][NH:11]C(OCC1C=CC(OC)=CC=1)=O.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>>[CH3:1][O:2][C:3](=[O:40])[C@H:4]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[NH:5][C:6](=[O:29])[CH:7]([CH2:24][S:25][C:26](=[O:28])[CH3:27])[CH2:8][CH2:9][CH2:10][NH2:11].[F:41][C:42]([F:47])([F:46])[C:43]([O-:45])=[O:44]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(CCCNC(=O)OCc1ccc(OC)cc1)CSC(C)=O
Reactant: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(CCCN)CSC(C)=O
Product: O=C([O-])C(F)(F)F

Procedure:
N-[2-Acetylthiomethyl-5-(p-methoxybenzyloxycarbonylamino)pentanoyl]-L-tryptophane methyl ester (1 g) is dissolved in trifluoroacetic acid (10 ml), the solution is stored at room temperature for fifteen minutes, and then evaporated in vacuo to yield N-(2-acetylthiomethyl-5-aminopentanoyl)-L-tryptophane methyl ester, trifluoroacetate.
Reaction SMILES: F[C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][N:3]=1.[F:13][C:14]([F:18])([F:17])[CH2:15][NH2:16].Cl>CN1CCCC1=O.CO.[OH-].[Na+]>[CH3:12][C:11]1[C:2]([NH:16][CH2:15][C:14]([F:18])([F:17])[F:13])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cnc(F)c(C)c1
Reactant: NCC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1cc(C(=O)O)cnc1NCC(F)(F)F
Temperature: 220 °C
Reaction time: 2.5 h
Yield: 32 %

Procedure:
A mixture of methyl 6-fluoro-5-methylnicotinate (2.00 g, 11.8 mmol, Step-1 of Amine-36) and 2,2,2-trifluoroethanamine (9.37 g, 95 mmol) in N-methylpyrrolidone (24 mL) is stirred at 220° C. for 2.5 hours under microwave irradiation. The mixture is diluted with MeOH (30 mL), and 2 M aqueous sodium hydroxide solution (15 mL) is added to the mixture. After stirring at 50° C. for 1 hour, the mixture is acidified by 2 M hydrochloric acid, and extracted with EtOAc/hexane (100 mL×3). The combined organic layer is washed with water (100 mL), and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is crystallized from diisopropyl ether to give 884 mg (32%) of the title compound as a pale pink solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][N:12]1[CH2:20][CH2:19][C:15]([NH:21][C:22]2C=CC=CC=2)([C:16]([NH2:18])=[O:17])[CH2:14][CH2:13]1.C(OCC)(OCC)OCC.C1(C)C=CC=CC=1.[OH-].[NH4+]>C(O)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][N:12]1[CH2:13][CH2:14][C:15]2([NH:21][CH:22]=[N:18][C:16]2=[O:17])[CH2:19][CH2:20]1
Reactant: NC(=O)C1(Nc2ccccc2)CCN(CC2=Cc3ccccc3CC2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(OCC)OCC
Product: O=C1N=CNC12CCN(CC1=Cc3ccccc3CC1)CC2

Procedure:
A mixture of 1-[(3,4-dihydro-2-naphthalenyl)methyl]-4-anilino isonipecotamide (6.0 g), triethyl orthoformate (3.0 g), toluene (30 ml), and glacial acetic acid (1.5 ml) is refluxed under nitrogen for 38 hours. The reaction mixture is cooled and poured into aqueous ammonium hydroxide. The organic layer is separated, dried, and concentrated to give the crude product. Digestion of this material with benzene followed by filtration and concentration of the organic solution yields the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[C:7](OC)[C:6]([CH3:12])=[CH:5][N:4]=1.P(Br)(Br)[Br:14].CN(C=O)C.[NH4+].[OH-]>>[Br:14][C:7]1[C:6]([CH3:12])=[CH:5][N:4]=[C:3]([CH2:2][Cl:1])[C:8]=1[CH3:9]
Reactant: BrP(Br)Br
Reactant: COc1c(C)cnc(CCl)c1C
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cnc(CCl)c(C)c1Br
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 44.1 %

Procedure:
A suspension of 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (3.24 g, 14.6 mmol) in PBr3 (8.0 ml, 85.1 mmol, 5.8 equiv.) was heated to 80° C. under nitrogen. A catalytic amount of DMF (0.50 ml, 6.4 mmol, 0.44 equiv.) was added, whereupon the suspension rapidly turned into an orange solution. After 40 min., the reaction was still incomplete as judged by HPLC. The temperature was raised to 110° C. and the reaction was prolonged for 30 min, at which point it was complete. The mixture was poured over ice, made basic with conc. aq. NH4OH and extracted into EtOAc. Washing with water, drying (brine, MgSO4) and concentration gave the title compound as a pink solid (1.51 g, 44%) containing 10% of an impurity by 1H-NMR. The crude was used without further purification. 1H-NMR (CDCl3) δ 8.19 (s, 1H), 4.59 (s, 2H), 2.48 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]#[C:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15].N1C=CC=CC=1.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]#[C:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])(=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)C(C)(C)C#Cc1cc([N+](=O)[O-])ccc1N
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1ccc([N+](=O)[O-])cc1C#CC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.1 %

Procedure:
To a solution of methyl 4-(2-amino-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (260 mg, 1.0 mmol) and pyridine (160 mg, 2.0 mol) in CH2Cl2 (20 mL) was added butyryl chloride (140 mg, 1.3 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 3 h before the mixture was poured into ice-water. The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain methyl 4-(2-butyramido-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (150 mg, 45%), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 8.79 (brs, 1H), 8.71 (d, J=9.2 Hz, 1H), 8.24 (d, J=2.8 Hz, 1H), 8.17 (dd, J=2.8, 9.2 Hz, 1H), 3.82 (s, 3H), 2.55 (t, J=7.2 Hz, 2H), 1.85-1.75 (m, 2H), 1.63 (s, 6H), 1.06 (t, J=6.8 Hz, 3H).
Reaction SMILES: [H-].[Na+:2].NC1C=CC=CC=1.[CH3:10][C:11]1[CH2:15][C:14]([CH3:16])=[C:13]([CH3:17])[C:12]=1[CH3:18]>O1CCCC1>[CH3:10][C:11]1[CH:15]([Na:2])[C:14]([CH3:16])=[C:13]([CH3:17])[C:12]=1[CH3:18]
Reactant: [Na+]
Reactant: CC1=C(C)C(C)=C(C)C1
Agent: [H-]
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: CC1=C(C)C([Na])C(C)=C1C
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Sodium hydride (containing mineral oil; the content of sodium hydride: 60%) (3.30 g) and aniline (0.237 g) were added to the solution of tetramethylcyclopentadiene (5.01 g) dissolved in tetrahydrofuran (45 ml), and stirred at 40° C. for 4 hours. Thus, tetramethylcyclopentadienylsodium was obtained in the form of a solution in tetrahydrofuran.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[S:6][C:7]([C:11]([OH:13])=O)=[C:8]([CH3:10])[N:9]=2)[CH2:3][CH2:2]1.C1(NC2SC(C(Cl)=O)=C(C)N=2)CC1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:34][CH:35]([C:38]1[CH:42]=[CH:41][S:40][CH:39]=1)[C:36]#[N:37]>C(N(CC)CC)C>[C:36]([CH:35]([NH:34][C:11]([C:7]1[S:6][C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[N:9][C:8]=1[CH3:10])=[O:13])[C:38]1[CH:42]=[CH:41][S:40][CH:39]=1)#[N:37]
Reactant: Cc1nc(NC2CC2)sc1C(=O)O
Reactant: N#CC(N)c1ccsc1
Agent: Cc1nc(NC2CC2)sc1C(=O)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(NC2CC2)sc1C(=O)NC(C#N)c1ccsc1
Yield: 32.5 %

Procedure:
1.4g of 2-cyclopropylamino-4-methyl-thiazole-5-carboxylic acid was converted into 2-cyclopropylamino-4-methyl-thiazole-5-carboxylic acid chloride using 1.6g of phosphorus pentachloride according to the same procedure as EXAMPLE 1. Then 1.4g of amino-thiophen-3-yl-acetonitrile hydrochloride and 3.2ml of triethylamine were added thereto and the reaction mixture was treated according to the same procedure as EXAMPLE 1 to obtain 0.73g (Yield 35%) of the title compound.