Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH2:19][CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C>[Cl:18][CH2:19][CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(OCCCl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-hydroxybenzoate (10.0 g, 65.7 mmol) in DMF (100 mL) was added potassium carbonate (18.17 g, 131.4 mmol) and 2-chloroethyl-p-toluenesulfonate (15.7 g, 67.0 mmol). After stirring at 60° C. overnight the reaction mixture was poured into H2O, extracted with ethyl acetate (three times), dried over MgSO4 and concentrated under vacuum. Purification by silica gel chromatography (10% EtOAc/hexanes) afforded the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]2[N:24]=[C:23]([O:25][C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[C:28](=[O:36])[N:29]([CH3:35])[CH2:30]4)[C:22]([Cl:37])=[CH:21][N:20]=2)[C:15]([O:38][CH3:39])=[CH:14][C:3]=1[C:4]([O:6]CC1C=CC=CC=1)=[O:5]>C1COCC1.C(#N)C.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]2[N:24]=[C:23]([O:25][C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[C:28](=[O:36])[N:29]([CH3:35])[CH2:30]4)[C:22]([Cl:37])=[CH:21][N:20]=2)[C:15]([O:38][CH3:39])=[CH:14][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1cc(C(=O)OCc2ccccc2)c(Cl)cc1Nc1ncc(Cl)c(Oc2cccc3c2C(=O)N(C)C3)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)c(Cl)cc1Nc1ncc(Cl)c(Oc2cccc3c2C(=O)N(C)C3)n1
Reaction time: 2 h

Procedure:
Benzyl 2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yloxy)-pyrimidin-2-ylamino]-5-methoxy-benzoate (75 mg) is dissolved in THF (150 mL), Pd(OH)2 (0.01 g) is added and the mixture is stirred for 2 h under H2 gas. For working up the mixture is diluted with ACN (20 mL) and Isolute is added. The solvent is filtered off from the catalyst and the solvent is eliminated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH:13]([OH:17])[C:14]([OH:16])=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1O>C1(C)C(C)=CC=CC=1>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:14]1[CH:13]([C:3]1[CH:4]=[C:5]([O:8][C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:7][C:2]=1[F:1])[OH:17]
Reactant: O=C(O)C(O)c1cc(OC(F)(F)F)ccc1F
Reactant: Nc1ccccc1O
Solvent: Cc1ccccc1C
Product: OC(c1nc2ccccc2o1)c1cc(OC(F)(F)F)ccc1F

Procedure:
A mixture of (2-fluoro-5-trifluoromethoxyphenyl)hydroxyacetic acid (prepared according to 72C) (2.4 g), ortho-aminophenol (1.03 g) in xylene (25 mL) is refluxed for 4 h with a Dean-Stark apparatus and concentrated under reduced pressure. Purification by chromatography on silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0 to 98/2/0.5) to afford the pure benzoxazol-2-yl(2-fluoro-5-trifluoromethoxyphenyl)methanol.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O:50][C:51](=O)[C@H:52]([O:54][C:55]1[CH:60]=[C:59](Cl)[N:58]=[C:57]([S:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[C:65]=2[F:71])[N:56]=1)[CH3:53])C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:71][C:65]1[C:66]([F:70])=[CH:67][CH:68]=[CH:69][C:64]=1[CH2:63][S:62][C:57]1[N:58]=[C:59]([NH:7][S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:5])[CH:60]=[C:55]([O:54][C@H:52]([CH3:53])[CH2:51][OH:50])[N:56]=1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: NS(=O)(=O)C1CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)C2CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1, step iv) using a mixture of cyclopropanesulfonamide (prepared according to patent WO 2003/099274, 0.14 g), tris(dibenzylideneacetone)dipalladium (0) (71 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (52 mg), cesium carbonate (0.38 g), 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of Example 23 step i) (0.30 g) and dioxane (10 mL). Purification was by column chromatography on silica gel using EtOAc/isohexane (1:1) as eluent to give the subtitle compound as an oil. Yield: 0.30 g
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:10])[CH3:9].[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1.[Cl-].[NH4+]>[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:19]=[O:20])([CH3:10])[CH3:9]
Reactant: CN(C)C=O
Reactant: CC(C)c1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1ccccc1C=O
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of 2-bromoisopropyl benzene (2.0 g, 10.0 mmole) in dry THF (20 mL), nBuLi (1.6 M in hexane), (6.9 mL, 11.05 mmole) was added at −78° C. and the mixture was stirred at same temperature for one hour. DMF (0.9 g, 12.0 mmole) was added and the mixture was stirred at −78° C. for half an hour then allowed to stir at 0° C. for 15 min. The reaction mixture was diluted with saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (3×30 mL). The organic layers were combined and washed with brine, dried over sodium sulfate, and concentrated to yield 2-isopropyl benzaldehyde (1.4 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:19]([OH:23])[CH2:20][CH2:21][CH3:22].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:23][CH2:19][CH2:20][CH2:21][CH3:22])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CCCCO
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCCCOc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, butanol and DBU in DME. EI-MS m/e (%): 258 (M+, 20), 202 ([M—C4H8]+, 100).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6](C)[CH:7]=1.BrC1C(=O)[NH:15]C(=O)NC=1>>[Br:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:7])[N:15]=1
Reactant: Cn1cc(Br)c(=O)n(C)c1=O
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Product: Cn1nc(Br)c(=O)n(C)c1=O
Yield: 82 %

Procedure:
Synthesis of the intermediate 1c is achieved from 5-bromo-1H-pyrimidine-2,4-dione according to the operating procedure described for the synthesis of 1b (solid, yield 82%).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]4[N:17]=[C:18]([NH:20][C:21]5[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=5[Cl:28])[NH:19][C:9]=4[C:7]=3[N:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:4]2[O:5][C:6]3[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]4[N:17]=[C:18]([NH:20][C:21]5[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=5[Cl:28])[NH:19][C:9]=4[C:7]=3[N:8]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2nc(C3CC3)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2nc(C3CC3)oc12
Yield: 79.5 %

Procedure:
The title compound was prepared following the procedure described for Step-5 of Intermediate-55 using methyl 2-cyclopropyl-7-[(2,6-dichlorophenyl)amino]-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylate (0.100 g, 0.234 mmol), MeOH (3.0 mL) and sodium hydroxide (0.047 g, 1.17 mmol) to afford 0.075 g of the desired product. 1HNMR (DMSO-d6): δ 1.07 (s, 4H), 2.32 (s, 1H), 6.56 (m, 1H), 7.07 (m, 1H), 7.31 (s, 1H), 7.57 (s, 1H), 12.15 (s, 2H).
Reaction SMILES: [C:1]([O:3][CH2:4][CH3:5])#[CH:2].B.O1CCCC1.I[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3]/[CH:4]=[CH:5]/[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[CH:14]=1)[CH3:2]
Reactant: C#COCC
Reactant: C[C@H](Nc1cc(I)ccn1)c1ccccc1
Agent: [Pd+2]
Agent: B
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCO/C=C/c1ccnc(N[C@@H](C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.3 mL of ethyl ethynyl ether (50% v/v hexane solution) was dissolved in 10 mL of tetrahydrofuran, and in an ice bath, 2.04 mL of borane-tetrahydrofuran complex (1.0M tetrahydrofuran solution) was added dropwise over 30 minutes. Thereafter, the reaction mixture was heated to room temperature, and stirred for 3 hours. Thereto, 10 mL of tetrahydrofuran solution containing 330 mg of the 4-iodo-N-[(1S)-1-phenylethyl]-2-pyridinamine [58-1], 11.5 mg of palladium acetate, 40.2 mg of triphenylphosphine, and 1.28 mL of a 4N aqueous solution of sodium hydroxide, were added, and further stirred at room temperature for 5 hours. The reaction mixture was diluted with 150 mL of ethyl acetate, washed with water and saturated brine in the subsequent order, and the thus obtained organic layer was dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, to obtain 94 mg of 4-[(E)-2-ethoxyethenyl]-N-[(1S)-1-phenylethyl]-2-pyridinamine [58-2] as a brown oily product.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][C:13]3=[O:20])=[CH:8]2)=[N:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:19][CH2:18][C:15]1[CH:16]=[CH:17][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=3)[CH:8]=2)[C:13](=[O:20])[CH:14]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c2cc(-n3ccc(CO)cc3=O)ccc2nn1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c2cc(-n3ccc(COS(C)(=O)=O)cc3=O)ccc2nn1C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-(hydroxymethyl)pyridin-2(1H)-one (100 mg) in dichloromethane (5 ml) was added triethylamine (0.153 ml) at 0° C., and the mixture was stirred at the same temperature for 30 min. To the obtained reaction mixture was added methanesulfonyl chloride (0.057 ml) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([OH:21])=O)=[C:11]2[CH3:22])[CH3:9])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([NH:51][CH2:52][C:53]3[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=3[CH3:59])=[O:21])=[C:11]2[CH3:22])[CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)O)c2ccccc2n1C(C)c1ccc(Cl)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)c3ccc(Cl)cc3)c3ccccc23)c(O)n1
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
To a solution of 1-(1-(4-chlorophenyl)ethyl)-2-methyl-1H-indole-3-carboxylic acid (200 mg, 0.64 mmol) in anhydrous DCM (5 mL) was added HOBt (130 mg, 0.96 mmol), EDCI (184 mg, 0.96 mmol) and Et3N (194 mg, 1.92 mmol) at room temperature under N2. The reaction was stirred for 30 min and then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (107 mg, 0.7 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was diluted with water and adjusted to pH 7 and extracted with DCM. The crude product was purified by silica gel chromatography (Eluent: DCM:MeOH=30:1) to afford the title compound a yellow solid. (120 mg, yield 41.9%) 1H NMR (DMSO-d6, 400 MHz) δ 11.6 (s, 1H), 7.74-7.68 (m, 2H), 7.39 (dd, J1=2.0 Hz, J2=6.8 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 7.06-6.93 (m, 3H), 5.92 (t, J=7.2 Hz, 2H), 4.33 (d, J=5.6 Hz, 2H), 2.59 (s, 3H), 2.26 (s, 3H), 2.11 (s, 3H), 1.87 (d, J=7.2 Hz, 3H); ESI-MS: m/z 447.8 [M+H]+.
Reaction SMILES: Cl.C([N:9]1[C:13]([CH2:14][CH2:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][N:11]=[CH:10]1)C1C=CC=CC=1.Cl.[H][H]>[Pd].C(O)C>[C:24]1([CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][CH2:15][CH2:14][C:13]2[N:9]=[CH:10][NH:11][CH:12]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(Cn2cncc2CCCC(c2ccccc2)c2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(C(CCCc2c[nH]cn2)c2ccccc2)cc1

Procedure:
1-benzyl-5-(4,4-diphenylbutyl)-1H-imidazole hydrochloride (0,6 g) is hydrogenated in the mixture of 20 ml of 2N hydrochloric acid and 10 ml of ethanol at 80° C. Pd/C (10%) as catalyst. When the uptake of the hydrogen ceases, the reaction mixture is cooled, filtered and evaporated to dryness. Water is added and the mixture is made alkaline with sodium hydroxide. The product is then extracted to methylene chloride which is washed with water, dried with sodium sulphate and evaporated to dryness. The residue is the product as base and it is made to its hydrochloride in ethyl acetate using dry hydrochloric acid. Yield 0,2 g. M.p. 204°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([F:12])[C:3]=1F.[CH2:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([F:12])[C:3]=1[N:19]1[CH2:20][CH2:21][N:16]([CH2:14][CH3:15])[CH2:17][CH2:18]1
Reactant: CCN1CCNCC1
Reactant: Nc1c([N+](=O)[O-])cc(Cl)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCN1CCN(c2c(Cl)cc([N+](=O)[O-])c(N)c2F)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
To a solution of 768 mg of 4-chloro-2,3-difluoro-6-nitroaniline (which was prepared by the method described in WO 98/56761 or WO 98/35977) and 629 mg of 1-ethylpiperazine in 5 ml of dimethylsulfoxide, 1.00 g of potassium carbonate was added, followed by 2 hours' stirring at 50° C. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried on anhydrous magnesium sulfate, and the solvent was distilled off. The residue was separated and purified on silica gel column chromatography (chloroform/methanol=50/1) to provide 704 mg of the title compounds.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][C:28]#[N:29].[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[CH2:21]([C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[C:31]([F:30])([F:40])[F:41])[C:12]=1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([Br:1])=[C:3]([O:26][CH2:27][C:28]#[N:29])[CH:4]=[CH:5]2)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)[nH]c2ccccc12
Reactant: FC(F)(F)c1ccccc1CBr
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)n(Cc2ccccc2C(F)(F)F)c2ccccc12

Procedure:
The title compound was prepared as a solid (0.053 g, 14%) from {[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using 2-trifluoromethyl benzyl bromide and the procedure from step 4 of Example 2; 1H NMR (DMSO-d6) δ 0.72 (t, J=7.0 Hz, 3H), 1.11-1.22 (m, 4H), 1.54-1.62 (m, 2H), 2.71 (t, J=7.4 Hz, 2H), 5.42 (s, 2H), 5.48 (s, 2H), 6.34 (d, J=7.9 Hz, 1H), 7.11-7.20 (m, 2H), 7.28 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.57 (dd, J=1.7, 8.9 Hz, 1H), 7.63-7.68 (m, 2H), 7.69 (d, J=7.2 Hz, 1H), 7.95 (d, J=1.2 Hz, 1H), 8.03 (d, J=9.2 Hz, 1H), 8.12 (d, J=8.7 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[C@H:15]([CH2:20][CH2:21][S:22][CH3:23])[NH:16][C:17](=[O:19])[CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:17]([NH:16][C@H:15]([C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:24])[CH2:20][CH2:21][S:22][CH3:23])(=[O:19])[CH3:18]
Reactant: CSCC[C@H](NC(C)=O)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCC[C@H](NC(C)=O)C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
To a solution of 8.6 g (0.024 mol) of 1-(t-butoxycarbonyl)-4-(N-acetyl-L-methionyl)piperazine in 60 ml of dichloromethane was added 10 ml of trifluoroacetic acid and the mixture was stirred at room temperature overnight. The solution was extracted with water and the resulting aqueous solution was made basic with sodium hydroxide. The product was extracted with dichloromethane, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 2.1 g of 1-(N-acetyl-L-methionyl)piperazine, as an oil: IR (film) 3304, 3051, 2917, 2861, 1645, 1546, 1448, 1377 cm−1; NMR (CDCl3) δ 1.95 m, 2 H), 2.02 (s, 3 H), 2.10 (s, 3 H), 2.54 (m, 2 H), 2.98 (m, 4 H), 3.74 (m, 4 H), 5.10 (m, 1 H), 6.40 (b, 0.5 H), 6.48 (b, 0.5 H).
Reaction SMILES: [OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[H-].[Na+].CN(C)C=O.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([O:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC(=O)CC1CCC(O)c2sccc21
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)CC1CCC(OCc2ccccc2)c2sccc21
Temperature: 25 °C

Procedure:
A sample (0.5 g) of 4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-ylacetamide is suspended in 20 ml of dry tetrahydrofuran under a nitrogen atmosphere and the mixture is cooled in an ice bath while 2.1 equivalents or 120 mg of 57% sodium hydride in an oil dispersion is added. The mixture is then stirred at room temperature for an hour and 5 ml of dry N,N-dimethylformamide is added to facilitate dissolution of the sodium hydride. After stirring for an hour, the mixture is cooled in an ice bath and 330 mg of benzyl chloride in 5 ml of dry tetrahydrofuran is added dropwise. The bath is removed and the mixture is stirred at room temperature for several hours. It is then warmed (below boiling point) for an overnight period. Water (25 ml) is carefully added to the reaction mixture and the solvents are stripped off on a rotary evaporator. The residue (yellowish semisolid) is dissolved in dichloromethane and water is added. The dichloromethane layer is collected and the aqueous portion is further extracted with dichloromethane. The combined dichloromethane solutions are washed with 2N hydrochloric acid, water, and dried (magnesium sulfate). The solution is then evaporated in vacuo and the residue is triturated with diethyl oxide. The title product is collected and washed with diethyl oxide to afford 320 mg, m.p. 139° C to 143° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7]O)=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:4][N:3]=1.CS([Cl:19])(=O)=O>ClCCl>[Cl:1][C:2]1[C:6]([CH2:7][Cl:19])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1c(Cl)nsc1-c1ccccc1
Solvent: ClCCl
Product: ClCc1c(Cl)nsc1-c1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Into a 25-mL round-bottom flask, was placed (3-chloro-5-phenyl-1,2-thiazol-4-yl)methanol (80 mg, 0.34 mmol, 1.00 equiv, 97%), MsCl (81.6 mg, 0.72 mmol, 2.00 equiv), TEA (107.7 mg, 1.06 mmol, 3.00 equiv), dichloromethane (1.5 mL). The resulting solution was stirred for 1 h at 20° C. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3×5 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 85 mg (96%) of 3-chloro-4-(chloromethyl)-5-phenyl-1,2-thiazole as yellow oil.
Reaction SMILES: [CH2:1]([O:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[B-](F)(F)(F)F.CN(C(ON1C(=O)C2C([C@H]3C=C[C@@H]2C3)C1=O)=[N+](C)C)C.[NH2:43][C@H:44]([C:51]([OH:53])=[O:52])[CH2:45][C:46]1[N:50]=[CH:49][NH:48][CH:47]=1.[OH-].[Na+].Cl>CN(C)C=O.O.CC(C)=O.C(N(CC)CC)C>[CH2:1]([O:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([NH:43][C@H:44]([C:51]([OH:53])=[O:52])[CH2:45][C:46]1[N:50]=[CH:49][NH:48][CH:47]=1)=[O:17])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOC(=O)NCCC(=O)O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: CN(C)C(ON1C(=O)C2C(C1=O)[C@H]1C=C[C@@H]2C1)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCOC(=O)NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Temperature: 250 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
30 g of N-octyloxycarbonyl-β-alanine were dissolved in 300 ml of dimethylformamide and 1 molar equivalent of triethylamine. Next, 1 molar equivalent of 2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate was added. The mixture was then stirred for 1 hour at a temperature of 250° C. Next, a solution containing 1.2 molar equivalents of histidine and 1.2 molar equivalents of sodium hydroxide in 100 ml of water were added dropwise, while keeping the temperature below 30° C. After stirring for 6 hours, the mixture was neutralized with 1 molar equivalent of 5N hydrochloric acid, followed by 100 ml of water. After stirring for 30 minutes, the mixture was poured into 2 liters of acetone. The white precipitate formed was filtered off and dried. The crude product was dissolved in 10 ml/g of refluxing 96% ethanol. The solution was filtered while hot and the product then crystallized at room temperature. After processing the precipitate, 29.4 g of a white crystalline product were obtained (63% yield).
Reaction SMILES: [CH3:1][C:2]12[C:9](=[O:10])[C:6]([CH3:11])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2.[CH3:12][Li].O>COC.C(OCC)C>[CH3:11][C:6]12[C:9]([CH3:12])([OH:10])[C:2]([CH3:1])([CH2:8][CH2:7]1)[CH2:3][CH2:4][CH2:5]2
Reactant: CC12CCCC(C)(CC1)C2=O
Reactant: [Li]C
Agent: COC
Solvent: O
Solvent: CCOCC
Product: CC12CCCC(C)(CC1)C2(C)O
Yield: 73.3 %

Procedure:
To a solution of 45,8 g (0,3 mole) of 1,5-dimethyl-bicyclo[3.2.1]octane-8-one in 150 ml dried dimethylether at boiling temperature 250 ml (178 g) of a 5% solution of methyl lithium (4 mole) in diethylether were dropwise added under stirring. After 1 h of stirring at boiling temperature about 50 ml water were dripped in followed by extraction with diethylether. The combined organic phases were dried over Na2SO4, evaporated under vacuum and distilled which resulted in 37 g (73%) of 8 in form of a colorless oil having a boiling point (1 mm) of 74° C. IR (as oil film): 3500 cm-1 (O--H).--NMR (CCl4): δ=0,87, s, 6H (1,5-CH3), 1,05, s, 3H (8-CH3) 1.5 ppm, br.s, 4H (6,7-CH2).--MS: m/e (%)=168 (33, M+), 153 (28), 150 (29). 135 (46), 125 (30), 124 (18), 123 (31, 122 (20), 121 (42), 111 (11), 110 (10), 109 (16), 108 (19), 107 (85), . . . , 43 (100).C11H20O (M=168,27).