Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:14]1([O:20][CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:21][O:20][C:14]1[CH:19]=[CH:18][C:17]([C:9]([C:8]2[CH:12]=[CH:13][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)=[O:10])=[CH:16][CH:15]=1
Reactant: CC(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(NC(C)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
A round-bottomed flask was charged with 4-acetamidobenzoyl chloride (0.95 g, 4.57 mmol), anisole (0.60 mL, 5.48 mmoL) and CH2Cl2 (15 mL). Cooled in an ice bath, AlCl3 (0.93 g, 6.85 mmol) was added in portions. The mixture was stirred at 0° C. for 4 h. The resulting dark brown solution was poured into 1 N HCl (25 mL) with ice and the mixture was extracted with EtOAc (2×60 mL). The combined EtOAc extract was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give brown solid. The crude product was purified by chromatography on a silica gel column eluted with hexanes:EtOAc (1:1) to give 0.55 g (45%) of compound 56 as light brown solid. mp 160-162° C. 1H NMR (400 MHz, CDCl3): δ 2.22 (s, 3H), 3.88 (s, 3H), 6.96 (d, J=8.8 Hz, 2H), 7.34 (br s, 1H), 7.55-7.65 (m, 2H), 7.77 (d, J=8.6 Hz, 2H), 7.79 (d, J=8.8 Hz, 2H). LCMS (ESI): m/z 270 (M+H)+, 268 (M−H)−.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[O:29][C:28]([CH3:31])([CH3:30])[O:27][C:26](=[O:32])[C:25]=2[CH:33]=1>>[CH3:30][C:28]1([CH3:31])[O:29][C:24]2[CH:23]=[CH:22][C:21]([NH:20][CH2:16][C:15]3[CH:18]=[CH:19][C:12]([C:11]#[C:10][C:7]4[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=4)=[CH:13][CH:14]=3)=[CH:33][C:25]=2[C:26](=[O:32])[O:27]1
Reactant: CCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Product: CCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Yield: 25.2 %

Procedure:
The title compound was prepared following procedure described in Example 1, step c) from 4-[(4-propylphenyl)ethynyl]benzaldehyde (1.53 g; 6.16 mmol) and 6-amino-2,2-dimethyl-benzo[1,3]dioxin-4-one (1.19 g; 6.16 mmol). Purification of the yellow solid (2.4 g) obtained by flash chromatography using silica gel (EtOAc:c-Hex 10:90 to 20:80) gave 660 mg (25%) of the title compound as a yellow solid. HPLC, Rt: 5.48 min (purity: 72.4%), 1H NMR (CDCl3) δ: 7.47 (d, J=7.5 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H),: 7.31 (d, J=8.1 Hz, 2H), 7.08 (m, 3H), 6.70-6.79 (m, 2H), 4.25 (s, 2H), 2.57 (t, J=7.6 Hz, 2H), 1.62 (s, 6H), 1.55 (m, 2H), 0.86 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7](=[O:15])([O:12][CH2:13][CH3:14])[O:8][CH:9](Cl)[CH3:10].[OH-].[K+]>C(#N)C.O.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[C:7](=[O:15])([O:12][CH2:13][CH3:14])[O:8][CH:9]([O:5][C:1](=[O:6])[CH2:2][CH2:3][CH3:4])[CH3:10]
Reactant: CCOC(=O)OC(C)Cl
Reactant: CCCC(=O)O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCCC(=O)OC(C)OC(=O)OCC

Procedure:
To a solution of butyric acid (0.58 g., 6.55 mmol.) and 1-chloroethyl ethyl carbonate (1 g., 6.55 mmol.) in acetonitrile (15 ml.) is added water (2 drops), benzyltrimethylammonium hydroxide (2 drops of 40% aqueous solution) and potassium hydroxide (0.44 g., 7.86 mmol.). The reaction mixture is stirred under reflux for 4 hours, it is filtered, and ether is added to the filtrate. The combined organic phase is thrice washed with water, dried over magnesium sulfate and filtered. The filtrate is concentrated in vacuo and the residue is distilled at 75° C. in a Kugelrohr apparatus at 0.1 mm. Hg. Yield 0.57 g. (42.7%). VPC chromatography on a 4 m, 20% Carbowax 20M on Chromosorb WAW, temperature 110° C., flow rate 65 ml./min., gave a retention time of 66.6 minutes. 1H-NMR ppm (CDCl3): 6.77 (q. J=5 Hz, 1H), 4.22 (q. J= 7 Hz, 2H), 2.32 (t, J=7.5 Hz, 2H), 1.66 (sextet, J=7.5 Hz, 2H), 1.52 (d, J=5.5 Hz. 3H), 1.318 (t, J=7.5 Hz, 3H). 0.95 (t. J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]#[N:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#CCc1ccc(F)c(F)c1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(F)c(F)c2)CCCCC1
Reaction time: 0.08 h
Yield: 87.2 %

Procedure:
To a solution of 2-(3,4-difluorophenyl)acetonitrile (2 g, 13.06 mmol) in 20 mL of DMF at 0° C. was added 60% sodium hydride (1.149 g, 28 7 mmol), and the mixture was stirred at the same temperature for 5 mins. Then a solution of 1,5-dibromopentane (1.779 mL, 13.06 mmol) in 20 mL of DMF was added dropwise and the mixture was stirred at a temperature in the range of 0° C. to room temperature for 5 hrs. The reaction was quenched with water, and extracted with EtOAc. The mixture was washed with water and brine. The combined aqueous layers were back extracted with EtOAc once and washed with brine. The combined extracts were dried over Na2SO4 and evaporated to give an oily residue. It was purified by Combiflash (120 g silica gel) eluting with 1:9 EtOAc-hexane to give 1-(3,4-difluorophenyl)cyclohexanecarbonitrile (Int. 3-A, 2.52 g, 11.39 mmol, 87% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.12-7.35 (3 H, m), 2.14 (2 H, d, J=11.86 Hz), 1.75-1.95 (6 H, m), 1.64-1.75 (2 H, m).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[C:8]([C:3]1([CH2:2][O:1][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC1(CO)CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C#N)CCCC2)cc1
Reaction time: 3 h

Procedure:
At 0° C., to a solution of 1-hydroxymethyl-cyclopentanecarbonitrile (10 g, 79.9 mmol) in CH2Cl2 (100 mL) was added pyridine (6.3 g, 79.9 mmol) and p-toluenesulfonyl chloride (12.18 g, 63.9 mmol). After stirred for 3 h, the solution was concentrated and the residue was used for next step reaction without further purification.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH2:12]Cl)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:14][C:15]([NH2:17])=[S:16].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CO.O>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:14]=[C:15]([NH2:17])[S:16][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(=NOC)c1csc(N)n1
Reaction time: 0.58 h
Yield: 68.5 %

Procedure:
Ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (50 g.) was added over 3 minutes with stirring at ambient temperature to a solution of thiourea (18.4 g.) and sodium acetate (19.8 g.) in a mixture of methanol (250 ml.) and water (250 ml.). After stirring for 35 minutes at 40° to 45° C., the reaction mixture was cooled with ice and adjusted to pH 6.3 with a saturated aqueous solution of sodium bicarbonate. After stirring for 30 minutes at the same temperature, precipitates were collected by filtration, washed with water (200 ml.) and then with diisopropyl ether (100 ml.), and dried to give colorless crystals of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (37.8 g.), mp 161° to 162° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:20][C:21]#[C:22][CH3:23])([CH2:16][C:17]#[C:18][CH3:19])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:25][OH:26]>>[OH:26][NH:25][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:20][C:21]#[C:22][CH3:23])[CH2:16][C:17]#[C:18][CH3:19]
Reactant: CC#CCC(CC#CC)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Product: CC#CCC(CC#CC)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 89 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid hydroxyamide was prepared according to the method as outlined in example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid (0.27 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.23 g of the product was isolated. Yield 89%; white solid; mp 135-137° C.; MS: 349.9 (M+H)+1; 1H NMR (300 Mz, DMSO-d6) δ1.67 (s, 6H), 2.70-3.10 (mn, 4H), 3.88 (s, 3H), 7.15 (d, J=10.0 Hz, 2H), 7.71 (d, J=10.0 Hz, 2H), 9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm−1): 3301s, 3161m, 2922m, 1640m, 1595s, 1500m.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10](Cl)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:17]([O:21][CH3:22])(=[O:20])[CH2:18][SH:19].O.[OH-].[Li+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[C:4]([OH:6])=[C:18]([C:17]([O:21][CH3:22])=[O:20])[S:19][C:8]=2[CH:9]=[CH:10][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(Cl)c(C(=O)OC)c1Cl
Reactant: COC(=O)CS
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2sc(C(=O)OC)c(O)c2c1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.4 %

Procedure:
Dimethyl 2,4-dichloroisophthaloate (11.95 g) and methyl thioglycolate (7.23 g) was dissolved in N,N-dimethylformamide, and lithium hydroxide monohydrate (3.81 g) added. The mixture was stirred at ambient temperature for 2 days, diluted with water and brought to pH 1 with hydrochloric acid. The solid was filtered, washed with boiling cyclohexane and dried by azeotropic removal of toluene to give dimethyl 4-chloro-3-hydroxybenzo[b]thiophene-2,5-dicarboxylate (13.44 g) as a beige solid, m.p. 127°-131° C.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[O:19])[CH2:14][CH2:13]2)[CH2:6][CH2:5]1.[N:27]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C@H:7]3[CH2:8][CH2:9][C@H:4]([NH:3][C:37](=[O:38])[C:36]4[CH:35]=[CH:34][C:33]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[CH:41][CH:40]=4)[CH2:5][CH2:6]3)[CH2:17][CH2:16]2)=[O:19])=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)cc3)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)cc3)CC2)CC1)c1ccc(N2CCOCC2)cc1

Procedure:
From {1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yl}-(4-chloro-phenyl)-methanone dihydrochloride (100 mg) and 4-morpholin-4-yl-benzoic acid. Yield: 56 mg (40%). MS (m/z): 538.5([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:20])[NH:15][C@H:16]([CH3:19])[CH2:17]O)([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1(C)C=CC=CC=1>[C:9]([O:13][C:14](=[O:20])[NH:15][C@H:16]([CH3:17])[CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Oc1ccc(Br)cc1
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H](COc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Bromophenol (0.2 g, 1.14 mmol), ((R)-2-hydroxy-1-methyl-ethyl)-carbamic acid tert-butyl ester (0.2 g, 1.14 mmol) and triphenylphosphine (0.45 g, 1.71 mmol) were dissolved in anhydrous toluene (10 ml) under an atmosphere of nitrogen. A solution of di-tert-butyl azodicarboxylate (0.39 g, 1.71 mmol) in toluene (5 ml) was added slowly ensuring that the temperature did not exceed 35° C. The reaction mixture was heated to 80° C. and stirred overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and subsequently washed with 1M HCl, water, brine then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by Flash Chromatography using 10% ethyl acetate/cyclohexane as the elutant gave the final product. Yield 80 mg, 21%. LCMS method: 2, RT: 6.17 min; MI: 330-332 [M+1].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][F:22].O>C(#N)C>[F:22][CH2:21][CH2:20][N:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[N:9]=[N:10]1
Reactant: Cc1ccc(-c2nn[nH]n2)cc1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(-c2nnn(CCF)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 5.0 grams (0.031 mole) 4-(4-methylphenyl)-1,2,3,5-(1H)-tetrazole and 4.8 grams (0.035 mole) of potassium carbonate in 150 mL of acetonitrile was heated to reflux and then cooled to ambient temperature. To this was slowly added 10.0 grams (0.078 mole) of 1-bromo-2-fluoroethane. Upon completion of the addition the reaction mixture was placed in a water bath and cooled to 0° C., where it stirred for one hour. After this time the reaction mixture was heated to reflux, where it stirred for three hours, and then cooled to 0° C., where it stirred for about 18 hours. At the conclusion of this period the reaction mixture was poured into 50 mL of water. The resulting solution was extracted with three 50 mL portions of ethyl acetate. The combined extracts were concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel. Elution was accomplished with methylene chloride and acetone. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.8 grams 1-(2-fluoroethyl)-(4-methylphenyl)-1,2,3,5-(1H)-tetrazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14].[Br:17]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([CH2:10][Br:17])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCC(=O)Nc1ccc(C)cc1C(=O)OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCC(=O)Nc1ccc(CBr)cc1C(=O)OC
Yield: 106.6 %

Procedure:
The radical bromination was performed as described by Patil et al. 1989: 5-Methyl-2-propionylamino-benzoic acid methyl ester (8.85 g, 40 mmol) and 1,3-dibromo-5,5-dimethyl hydantoin (DDH) (5,72 g, 20 mmol) in a mixture of CHCl3 (500 mL) and CCl4 (500 mL) was heated to reflux. Every 60 minutes 50 mg of dibenzoyl peroxide was added for six hours and then the reaction mixture was left at reflux over night. It was then allowed to reach room temperature and the solvents were removed by evaporation. Chromatography using silica gel 60 and heptane/ethyl acetate (18:2 ->17:3 ->16:4) as eluent afforded the pure title compound (6.40 g, 53%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[K+].[C:30]([C:32]1[N:33]=[C:34]([C:45]([O-])=[O:46])[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=1)#[N:31].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:45]([C:34]3[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=[C:32]([C:30]#[N:31])[N:33]=3)=[O:46])=[C:16]([C:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=3)[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)CC=C(c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CC=C(c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 87.1 %

Procedure:
A solution of 150 mg (0.389 mmol) 5-amino-6-(4,4-dimethyl-cyclohex-1-enyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (as prepared in the previous step) in 15 mL of CH2Cl2 was treated with 131 mg (0.428 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 3, step (b)), 272 mg (0.584 mmol) PyBroP, and 203 μL (1.17 mmol) DIEA at room temperature for 3 h. The mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo. Chromatography of the residue on a 50-g silica Varian MegaBond Elut column with 50% EtOAc-hexanes afforded 215 mg (87%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C34H50N6O4Si, 635.4 (M+H). found 635.3.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=2)[CH2:4][C@H:3]1[O:17][CH3:18].[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=3)[CH2:4][C@H:3]2[O:17][CH3:18])=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1ccc(N2CC[C@H](N)[C@H](OC)C2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(C(=O)OC)s3)C[C@H]2OC)nc1Cl
Yield: 50.2 %

Procedure:
The same operation as in Example (221c) was performed using methyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)thiophene-2-carboxylate obtained in Example (244c) (76 mg, 0.28 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (54 mg, 0.31 mmol), WSC hydrochloride (162 mg, 0.84 mmol), 1-hydroxybenzotriazole (38 mg, 0.28 mmol) and N-methylmorpholine (0.06 mL, 0.56 mmol), to obtain 60 mg of the title compound as a pale brown solid (50%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[N:12]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrochloride with 0.44 g of 4-methoxybenzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 50 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 40 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 40 ml of 50% ethanol yielded 0.31 g of 4-methoxy-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as yellowish crystals.
Reaction SMILES: C([O:5][C:6](=[O:23])[C@@H:7]([NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:8]([CH3:11])[CH2:9][CH3:10])(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([NH:12][C@@H:7]([CH:8]([CH3:11])[CH2:9][CH3:10])[C:6]([OH:23])=[O:5])=[O:22]
Reactant: CCC(C)[C@H](NC(=O)c1ccccc1OC)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)[C@H](NC(=O)c1ccccc1OC)C(=O)O
Yield: 85.8 %

Procedure:
(2S)-2-(2-Methoxybenzoylamino)-3-methylpentanoic acid tertbutyl ester (341 mg, 1.06 mmol) was dissolved in trifluoroacetic acid/CH2Cl2 (1:1, 10 ml). After 2 h at room temperature the solvent was removed in vacuo and the residue was purified by flash chromatography (eluant: 1% acetic acid, 2% methanol, 97% chloroform) to give a colourless oil identified as the title compound (242 mg, 0.91 mmol, 86%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][CH2:16][OH:17])([CH3:14])[CH2:6][CH2:5]2.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][CH2:16][OH:17])([CH3:14])[CH2:6][CH2:5]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCO)O2
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CCO)O2

Procedure:
Following the procedure described in Preparation 1, 2-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)ethanol was reacted with benzyl bromide and treated and purified to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][NH:15][CH:16]=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[CH:12].C(N(CC)CC)C.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[C:37]1([CH2:43][CH2:44][CH:45]=[O:46])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:46][CH:45]([CH2:44][CH2:43][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:16]([NH:15][CH2:14][CH2:13][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]#[CH:12])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: C#CCOc1ccc(CCNC=O)cc1OC
Reactant: O=CCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCOc1ccc(CCNC(=O)C(O)CCc2ccccc2)cc1OC
Temperature: -78 °C
Reaction time: 4 h

Procedure:
N-[2-(3-Methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-formamide (8.0 g, 34 mmol) and triethylamine (8.3 g, 82 mmol) are dissolved in dichloromethane (80 ml). Bis(trichloromethyl) carbonate (triphosgene, 4.0 g, 14 mmol) in dichloromethane (40 ml) is added at +5° C. The mixture is stirred for 4 hours at +5° C. and then cooled to −78° C. A solution of titanium tetrachloride (7.0 g, 38 mmol) in dichloromethane (70 ml) is added and the mixture is stirred for 2 hours at −40° C. 3-Phenylpropionaldehyde (4.8 g, 36 mmol) in dichloromethane (50 ml) is added dropwise and the mixture is stirred for 17 hours at room temperature. The mixture is hydrolysed with 5N HCl (25 ml), stirred 30 minutes at room temperature and washed with water. After evaporation of the organic layer the residue is submitted to flash-chromatography (ethyl acetate/hexane 6:3) to give 2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-4-phenyl-butyramide (Compound E1.01).
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH3:12])[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=2)[CH2:3][CH2:2]1.[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:9]([C:7]3[N:8]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:5]([CH3:12])[CH:6]=3)=[O:11])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: Cn1cc(C(=O)O)nc1C1CC1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(C)c(C2CC2)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-cyclopropyl-1-methyl-1H-imidazole-4-carboxylic acid (0.160 g, 0.96 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro benzonitrile (0.251 g, 0.96 mmol). The product was purified with flash chromatography. Yield 166 mg. 1H-NMR (400 MHz; DMSO-d6): δ 0.80-0.92 (m, 4H), 1.07 (d, 3H), 1.94-1.98 (m, 1H), 3.65 (s, 3H), 4.26-4.38 (m, 3H), 6.95 (s, 1H), 7.47 (s, 1H), 7.75 (d, 1H), 7.81 (s, 1H); 7.96 (s, 2H), 8.08 (s, 1H). LC-MS: [M+1]=409.28.