Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCC=O
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCCCCCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.711 g (5.0 mmol) of 1-nonanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 1.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=3/1) to yield 1.96 g (88.0%, yellow oily substance) of the desired product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:26]1([N:32]2[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccccc2)CC1
Temperature: 20 °C

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.5 g), triethylamine (4.2 cc) and N-phenylpiperazine (4.8 cc) in toluene (80 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (30 cc), 2-[3-(4-phenyl-l-piperazinyl)propyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (5.7 g) is obtained, m.p. 126° C.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1)=O.[CH:16]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)C.[BH4-].[Na+]>O>[CH:16]1([NH:23][CH2:1][C:3]2[CH:15]=[CH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6][C:5]=3[CH:4]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCCC1
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc2c(c1)Cc1cc(CNC3CCCCCC3)ccc1-2
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
2-Formylfluorene (2.27 g, 11.7 mmol) and cycloheptylamine (1.39 g, 12.3 mmol) were heated together at 120° C. for 14 hrs. After cooling, the reaction mixture was distilled under reduced pressure. Then, ethanol (30 ml) and sodium borohydride (0.44 g, 11.7 mmol) were added to the residue and the mixture was stirred for 0.5 hr. The mixture was then diluted with water (100 ml) and extracted with chloroform (80 ml×2 times). The organic layer was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to give 3.15 g of a pale yellow solid residue.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5]2[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:4]=2[N:3]=1.[Cl:20]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[Br:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3[O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:4]=3[N:3]=[C:2]2[Cl:20])=[CH:7][CH:8]=1
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Br)cc12
Product: Clc1nc2c3ccccc3oc2c2ccc(Br)cc12

Procedure:
The procedure was similar to step S19C, while the starting material was 20B in stead of 19B.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[C:12]([I:13])[C:5]=12.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[CH:11]=[C:12]([I:13])[C:5]=12
Reactant: Clc1ccnc2[nH]cc(I)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)ccnc32)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
Under an atmosphere of protective gas (argon), 63.5 g (1.59 mol) of sodium hydride are suspended in 1000 ml of abs. THF. With cooling, at a temperature of 0-5° C., a solution of 402 g (1.44 mol) of 4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine in 3000 ml of abs. THF is added dropwise, and the reaction mixture is, after the end of the addition, allowed to stir for 15 minutes. 358 g (1.88 mol) of p-toluenesulfonyl chloride are added a little at a time to the reaction mixture, so that the temperature is kept between 5 and 10° C. After the end of the addition, the mixture is allowed to warm to 20° C. and stirred at this temperature for another hour. After complete conversion (the conversion is monitored by TLC), 20 l of saturated sodium bicarbonate solution and 10 l of ethyl acetate are added to the reaction mixture, the mixture is extracted and the organic phase is separated off. The aqueous phase is reextracted two more times with in each case 10 l of ethyl acetate and the organic phases are combined, dried and, under water pump vacuum, freed from volatile components. For purification of the crystalline crude product, the product is taken up in dichloromethane and chromatographed on silica gel (dichloromethane:petroleum ether=3:7). The solvents are removed under reduced pressure and the crystal slurry is triturated with diethyl ether, filtered off with suction and dried at 20° C. under high vacuum. 372 g (60% of theory) of the title compound are isolated as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:12]([O:14][C:15](=[O:19])[CH2:16][CH2:17][NH2:18])[CH3:13].C(N(CC)CC)C>C(O)C>[CH2:12]([O:14][C:15](=[O:19])[CH2:16][CH2:17][NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:13]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.2 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (68.6 g, 0.434 mole), β-alanine ethyl ester hydrochloride (100 g, 0.651 mole), triethylamine (103.7 g, 1.03 mole) and 95% ethanol (675 ml) was refluxed for 5 hr and then stirred at room temperature overnight. The solvent was evaporated at reduced pressure and the residue was triturated in ethyl acetate (700 ml). The solid was filtered and washed with ethyl acetate. The filtrate was washed three times with water, dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to give 113.4 g of an oil. The oil was eluted through a silica gel column (400 g) with ethyl acetate. The eluent was evaporated at reduced pressure to give 106.2 g of an oil (100% yield). A small portion of the oil was crystallized from petroleum ether to give 0.7 g of yellow solid of the title compound, mp. 32.5°-33.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:22]=[C:23]([N:31]4[CH2:35][CH2:34][CH2:33][C@H:32]4[CH2:36][NH2:37])[C:24]4[S:29](=[O:30])[CH2:28][CH2:27][C:25]=4[N:26]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[N:22]=[C:23]([N:31]4[CH2:35][CH2:34][CH2:33][C@H:32]4[CH2:36][NH:37][C:45]([NH:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:46])[C:24]4[S:29](=[O:30])[CH2:28][CH2:27][C:25]=4[N:26]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC[C@@H]1CCCN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CCCN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg C—((S)-1-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl}-pyrrolidin-2-yl)-methylamine trifluoroacetate, Diastereomer 2 (Example 226) (see scheme 3, 3.17.2) are placed in 2 ml dichloromethane and 30 μl phenylisocyanate are added. The reaction mixture is stirred for 4 hours at ambient temperature and then evaporated to dryness. The product is purified by preparative HPLC (method A). 64 mg of the product are obtained as a powder. Analytical HPLC-MS (method D): RT=1.33 min.
Reaction SMILES: OS1C2C=CC=CC=2N=C1.C1(N=C=NC2CCCCC2)CCCCC1.N[CH:27]1[C:34](=[O:35])[N:33]2[CH:28]1[S:29][CH2:30][C:31](C1SC(NC3C=NC=CC=3)=NC=1)=[C:32]2C(OC(C1C=CC=CC=1)C1C=CC=CC=1)=O.CON=C(C1N=C(NC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)SC=1)C(O)=O>CN(C)C=O.C(O)(=O)C>[O:35]=[C:34]1[N:33]2[CH:28]([S:29][CH2:30][CH:31]=[CH:32]2)[CH2:27]1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4cccnc4)s3)CSC12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O[SH]1C=Nc2ccccc21
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1CC2SCC=CN12
Reaction time: 0.5 h
Yield: 517.2 %

Procedure:
1-Hydroxybenzothiazole (3.24 g) and N,N'-dicyclohexylcarbodiimide (4.95 g) are added to a solution, cooled to 5° C., of 7-amino-2-benzhydryloxycarbonyl-3-[2-(pyridin-3-yl-amino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene (10.83 g) and the syn isomer of 2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetic acid (10.65 g) in dry N,N-dimethylformamide (200 cc). The mixture is stirred for 30 minutes at +5° C. and then for 4 hours at 20° C. Acetic acid (1 cc) is added to the reaction mixture and the precipitate is then filtered off. The filtrate is diluted with ethyl acetate (900 cc) and the organic phase is washed successively with distilled water (2×500 cc), a decinormal solution of hydrochloric acid (500 cc), a semi-saturated solution of sodium bicarbonate (500 cc), distilled water (2×500 cc) and a semi-saturated solution of sodium chloride (500 cc). After the organic phase has been dried over magnesium sulphate and filtered and the filtrate concentrated under reduced pressure (30 mm Hg; 4 kPa), a hard yellow foam is obtained which is purified by chromatography on a column (height 61 cm, diameter 4.8 cm) containing silica gel (0.06-0.20 mm), elution being carried out with a 25/75 (by volume) mixture of cyclohexane and ethyl acetate (2 liters) and ethyl acetate (500 cc) and 250 cc fractions being collected. Fractions 5 to 14 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. This gives the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-3-[2-pyridin-3-yl-amino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (14.6 g) in the form of a hard, bright yellow foam.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:14][C:15]1([CH3:32])[CH2:24][C:23](=O)[C:22]2[C:17](=[CH:18][C:19]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:20][CH:21]=2)[O:16]1>O1CCCC1>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:23]2[C:22]3[C:17](=[CH:18][C:19]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:20][CH:21]=3)[O:16][C:15]([CH3:32])([CH3:14])[CH:24]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)c2ccccc12
Reactant: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2=O
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2c(c1)OC(C)(C)C=C2c1ccc(F)c2ccccc12
Yield: 14 %

Procedure:
Reaction of 4-fluoro-1-naphthylmagnesium bromide with an equivalent amount of 2,2-dimethyl-7-(2-dimethylaminoethoxy)-4-chromanone in dry tetrahydrofuran, by an analogous method to that described in Example 1 gave the title compound (14%). The hydrochloride salt had m.p. 224.5°-226° C.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[CH3:30][O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>CCCCCC.C(OCC)(=O)C>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]([CH3:29])=[C:2]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH3:30])[CH:37]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:18])[CH3:19]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: COc1cccc(B(O)O)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)c1
Yield: 64 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (3-methoxyphenyl)boronic acid, the title compound was synthesized in the same manner as in Example 101. Yield: 64%. Melting point: 209-210° C. (hexane-ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:13])[CH:4]=1.[OH:14]C1C2C(=CC=CC=2)N=C(C)C=1.ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[N+:6]([O-:14])=[C:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2
Reactant: Cc1cc(O)c2ccccc2n1
Reactant: COc1cc(C)nc2ccccc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(C)[n+]([O-])c2ccccc12
Temperature: 40 °C

Procedure:
31 g of 4-methoxyquinaldine (prepared from 4-hydroxyquinaldine by the method of M. Maurin, A. Ch. 4 [11] (1935), 301 and 335) are taken up in 80 ml of chloroform at room temperature, and 42 g of 85% strength m-chloroperbenzoic acid are added a little at a time, with stirring. The mixture is heated at 40° C. for 2 hours and is then cooled to 20° C. and brought to pH 6-7 with about 9 g of NaOH in 50 ml of H2O. The organic phase is separated off, dried with Na2SO4, filtered and concentrated. 34 g of crude product remain, and are recrystallized from toluene with addition of a small amount of solid KOH. 12 g of pure 4-methoxyquinaldine-N-oxide are obtained. Melting point 131°-132° C.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(C(C)C)CC)(C)C.[Br:29][C@H:30]([CH3:34])[C:31](Cl)=[O:32]>ClCCl>[Br:29][C@H:30]([CH3:34])[C:31]([N:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:32]
Reactant: O=C(OCc1ccccc1)[C@@H]1CC2=C(CCCC2)N1
Reactant: C[C@@H](Br)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Br)C(=O)N1C2=C(CCCC2)C[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Introduce 200 g of benzyl (2S)-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate and 1.5 litres of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0° C. and add 201 ml of diisopropylethylamine followed by 132 g of (2R)-2-bromopropionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with a dilute acetic acid solution. The benzyl (2S)-1-[(2R)-2-bromopropionyl]-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate solution so obtained is used as it is in the following Step.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[C:21]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27])#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1)=[O:27])#[N:22]
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: N#Cc1cccc(C(=O)O)c1
Product: N#Cc1cccc(C(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1

Procedure:
Prepared as described in Example 1 from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.2 g) and 3-cyanobenzoic acid (0.092 g). Title compound obtained as white solid (0.050 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[S:19]1[CH:23]=[CH:22][N:21]2[CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=[C:20]12.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:27]([C:25]3[N:26]=[C:20]4[N:21]([CH:24]=3)[CH:22]=[CH:23][S:19]4)=[O:28])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cn2ccsc2n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn2ccsc2n1

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.31 g, 1.19 mmol), imidazo[2,1-b]thiazole-6-carboxylic acid (0.2 g, 1.19 mmol), HOBt (0.24 g, 1.78 mmol), DIPEA (0.62 mL, 3.57 mmol) and EDCI (0.34 g, 1.78 mmol) using DMF (10 mL) as solvent using the method of Example 34(d) affording 232 mg of the product. 1H NMR (400 MHz; MeOD): δ 1.24 (d, 3H), 4.38 (m, 2H), 4.55 (m, 1H), 6.76 (d, 1H), 7.21 (d, 1H), 7.75 (m, 3H), 7.90 (dd, 1H), 8.06 (m, 1H), 8.09 (s, 1H).
Reaction SMILES: [C:1]([N:18]([CH2:24][CH3:25])[C@H:19]([C:21]([OH:23])=[O:22])[CH3:20])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:32](O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.CN(C)C=O.[Ag]C#N>[CH2:32]([O:22][C:21](=[O:23])[C@H:19]([CH3:20])[N:18]([C:1]([O:3][CH2:4][CH:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2])[CH2:24][CH3:25])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OCc1ccccc1
Reactant: CCN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)C(=O)O
Agent: N#C[Ag]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 377.2 %

Procedure:
A suspension of 848 mg (2.5 mmol) of (S)-N-Fmoc-N-ethylalanine in 10 mL of dichloromethane was treated with 436 μL (5.0 mmol) of oxalyl chloride followed by a catalytic amount (1 drop) of dimethylformamide. The mixture was stirred for one hour, then concentrated in vacuo. The yellow, oily residue was treated with 10 mL of toluene followed by 517 mg (0.5 mmol) of benzyl alcohol and 669 mg (5.0 mmol) of silver cyanide. The mixture was heated in an 80° C. oil bath with vigorous stirring for 20 minutes, then cooled and filtered through a pad of diatomaceous earth. The filtrate was concentrated, and the residue was purified by silica gel column chromatography, using 10% acetone in hexane as eluant. Ester (23) (810 mg) was obtained as a colorless oil; TLC: Rf =0.28, 15% acetone/hexane; 1H NMR (300 MHz) consistent with structure.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH3:25])[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:13]([O:17][C:18](=[O:19])[NH:20][C@H:21]([C:22](=[O:23])[NH:12][C:6]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=1[NH:4][CH:1]1[CH2:3][CH2:2]1)[CH3:25])([CH3:14])([CH3:15])[CH3:16]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1NC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
A mixture of N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.724 g, 4.4 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.91 g, 4.8 mmol), HOAt (0.65 g, 4.8 mmol), 4-methylmorpholine (1.1 mL, 9.7 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.92 g, 4.8 mmol) in DCM (15 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(S)-1-(2-cyclopropylamino-4-fluorophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester as a brown oil (1.07 g, 72%). LCMS (Method B): RT 3.40 min [M+H]+ 338.2. 110180243
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[NH2:15]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:15][C:14]1[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=[C:12]([F:11])[CH:13]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Product: Fc1cc(Nc2nc3ccccc3[nH]2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3-fluoro-5-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 263-265° C.). MS(ES+) m/z 296 ([M+1]+, 100).
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[NH:43]=[N+:44]=[N-:45]>C1C=CC=CC=1>[N:43]([CH2:2][C@@H:3]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1)=[N+:44]=[N-:45]
Reactant: [N-]=[N+]=N
Reactant: COC(=O)[C@H]1CC[C@@H](CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(=O)[C@H]1CC[C@@H](CN=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
To a mixture of methyl cis-3-hydroxymethylcyclopentancarboxylate (4.74 g, 30 mmol) in dry benzene (about 250 mL) was added triphenyl phosphine (7.86 g, 30 mmol), diethyl azodicarboxylate (5.22 g, 30 mmol) and hydrazoic acid (2.5 M in toluene, 14.0 mL, 35 mmol). The mixture was stirred at room temperature for about 16 h. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and hexane was added. A precipitate formed on standing in about 2 h and was removed by filtration. The filtrate was concentrated and the residue was passed through a column of silica gel using chloroform as eluent. The appropriate fractions were combined and concentrated to give 2.6 g (47%) of methyl cis-3-azidomethyl-cyclopentancarboxylate.