Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:21]([CH3:22])=[C:20]([C:23]#[N:24])[C:11]3[N:12]=[C:13]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[O:14][C:10]=3[C:9]=2F)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:33][NH:34][C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:21]([CH3:22])=[C:20]([C:23]#[N:24])[C:11]3[N:12]=[C:13]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[O:14][C:10]=3[C:9]=2[N:37]2[CH2:38][CH2:39][C@H:35]([NH:34][CH3:33])[CH2:36]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2cccc(Cl)c2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CN[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN[C@H]1CCN(c2c(-c3cccc(Cl)c3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
6-(3-Chlorophenyl)-4-cyano-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (I-311) (500 mg, 1.40 mmol) was dissolved in dimethyl sulfoxide (20 ml), and at room temperature, triethylamine (215 μl, 1.54 mmol) was added. The solution was gradually heated from room temperature up to 150° C., and a solution of (3S)-3-(methylamino)pyrrolidine (164 μl, 1.54 mmol) dissolved in dimethyl sulfoxide (3 ml) was added all at a time. After stirred at the same temperature for 30 minutes, this was cooled to room temperature. The solvent was evaporated away under reduced pressure, and the resulting residue was fractionated with chloroform and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was first roughly purified by middle-pressure liquid chromatography using an eluent of chloroform:methanol=95:5 (v/v), and then the roughly-purified product was purified by preparative TLC (eluent, chloroform:7 N ammonia/methanol solution=95:5, v/v), and further the obtained solid was purified in slurry with diisopropyl ether to obtain the entitled compound (250 mg, 41%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][N:18]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[C:19]3=[O:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4ccc(Cl)c(Cl)c4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
3,4-Dichlorophenyl isocyanate (0.5 g, 2.7 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.9 mmol) in THF (30 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL). The mixture was filtered, and the solid was slurried with hot methanol (20 mL) to give 1-(3,4-dichloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.6 g, 67%) as a white solid: mp 253-255° C.; 1H NMR (DMSO-d6) δ 2.00-2.05 (m, 1H), 2.37-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.36-4.58 (m, 4H, 2CH2), 5.11-5.18 (dd, J=4.9 and 13.1 Hz, 1H, CH), 6.89 (t, J=5.6 Hz, 1H, NH), 7.24-7.84 (m, 6H, Ar), 8.96 (s, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.56, 31.17, 39.69, 46.19, 51.58, 117.86, 118.83, 121.58, 122.37, 128.29, 130.38, 130.86, 131.64, 135.27, 139.91, 140.56, 154.87, 168.05, 170.98, 172.81; Anal. calcd. for C21H18N4O4Cl2: C, 54.68; H, 3.93; N, 12.15; Cl, 15.37. Found: C, 54.52; H, 3.78; N, 11.89; Cl, 15.28.
Reaction SMILES: CN1CCN(C)[C:4]2[CH:9]=NC=[CH:12][C:3]1=2.[C:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=O)[CH3:23])[C:18]2[CH:25]=[CH:26][N:27]=[CH:28][C:17]1=2)(=O)[CH3:14]>CCOC(C)=O.CO>[CH2:22]([N:19]1[CH:20]2[CH:21]([CH2:12][CH2:3][CH2:4][CH2:9]2)[N:16]([CH2:13][CH3:14])[C:17]2[CH:28]=[N:27][CH:26]=[CH:25][C:18]1=2)[CH3:23]
Reactant: CN1CCN(C)c2cnccc21
Reactant: CC(=O)N1CCN(C(C)=O)c2cnccc21
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN1c2ccncc2N(CC)C2CCCCC21

Procedure:
A suspension of 0.77 g (5.80 mmol) of AlCl3 in 30 ml of MTBE was stirred at room temperature for 45 minutes and subsequently cooled to 0° C. and 1.32 g (9.35 mmol) of LiAlH4 were then added in small portions. After the addition was complete and the mixture had been stirred for another 15 minutes, compound 14 (0.64 g, 2.23 mmol) was added and the mixture was stirred at 0° C. for 1 hour. It was subsequently refluxed for 8 hours and then cooled to room temperature and poured into ice water. The inorganic precipitate was filtered off with suction and washed twice with 30 ml of DCM. The aqueous phase was brought to a pH of 12 and extracted three times with 40 ml of DCM. The combined organic phases were dried over Na2SO4 and the solvent was distilled off on a rotary evaporator. The crude product obtained was purified by flash chromatography on silica gel (EtOAc/MeOH/NEt3, 10:2:1) and on basic aluminum oxide (EtOAc/MeOH, 10:1). This gave 0.30 g (1.22 mmol, 55%) of a colorless solid. Rf=0.32 (basic alumina, EtOAc/MeOH, 10:1). 1H NMR: (400 MHz, CDCl3): δ=1.11, 1.13 (t, 3J=7.2 Hz, H3C—CH2—N-5, 3J=7.2 Hz, H3C—CH2—N-10, 6-H), 1.37 (m, 2H, H-7,8), 1.56 (m, 3Jaa=6.8 Hz, 3Jee=3.2 Hz, 4H, H-6, H-9, H-7, H-8), 1.76 (m, 3Jae=3.2 Hz, 1H, H-9), 1.89 (m, 3Jae=3.2 Hz, 1H), 3.18 (dq, 3J=7.2 Hz, 2J=14.4 Hz, 2-H, H3C—CHAB—N-5, H3C—CHAB—N-10), 3.23 (ddd, 3Jae=2.8 Hz, 3Jae=3.2 Hz, 3Jaa=6.8 Hz, 1H, H-5a), 3.34 (ddd, 3Jae=2.8 Hz, 3Jae=3.2 Hz, 3Jae=3.2 Hz, H-1, H-9a), 3.43 (dq, 3J=7.2 Hz, 2J=14.4 Hz, H3C—CHAB—N-5, H3C—CHAB—N-10, 2H, H-1), 6.33 (d, 3J=5.6 Hz, 1H, H-4), 7.67 (s, 1H, H-1), 7.72 (d, 1H, H-3) ppm. 13C NMR (100 MHz, CDCl3): δ=10.8 (H3C—CH2—N-5), 11.8 (H3C—CH2—N-10), 21.7 (C-7), 22.9 (C-8), 27.3 (C-6), 27.8 (C-9), 40.4 (H3C—CH2—N-5), 41.7 (H3C—CH2—N-10), 52.8 (C-9a), 56.4 (C-5a), 104.3 (C-4), 130.6 (C-10a, C-1), 139.4 (C-3), 141.2 (C-4a) ppm. GC-MS (EI): RT 10.58 min, m/e (%) 246 (18), 245 (M+, 100), 231 (9), 230 (57), 217 (7), 216 (44), 207 (6), 186 (7), 174 (15), 162 (6), 160 (16), 158 (6), 148 (12), 146 (6), 132 (8); IR (neat): ν=3436 (s), 2970 (m), 2860 (vs), 2860 (s), 1628 (w), 1576 (vs), 1513 (vs), 1473 (w), 1447 (m), 1348 (s), 1317 (w), 1267 (s), 1211 (s), 1167 (w), 1125 (w), 1107 (w), 1077 (w), 1059 (w), 1040 (w), 920 (w), 798 (s) 777 (m), 746 (m) cm−1. HRMS (EI): calculated for C15H23N3 245.1892 [M+], found: 245.1889.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([NH2:35])[C:30]=1[CH:36]([CH3:38])[CH3:37]>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:23][CH2:24][N:25]([C:29]3[N:34]=[CH:33][N:32]=[C:31]([NH2:35])[C:30]=3[CH:36]([CH3:38])[CH3:37])[CH2:26][CH2:27]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)c1c(N)ncnc1Cl
Reactant: FC(F)(F)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Product: CC(C)c1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(F)(F)F)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “4” by using 4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-trifluoromethyl-pyridine and 6-chloro-5-isopropyl-pyrimidin-4-ylamine as the starting materials. LC-MS (M+H=515, obsd.=515). 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.16-8.01 (m, 6H), 7.97 (d, J=5.2 Hz, 2H), 6.11 (s, 4H), 3.94 (t, J=6.2 Hz, 4H), 3.46-3.25 (m, 4H), 3.12 (t, J=7.0 Hz, 8H), 2.92 (qd, J=12.0, 4.3 Hz, 7H), 2.72 (t, J=6.1 Hz, 4H), 2.03-1.84 (m, 13H), 1.30 (d, J=7.2 Hz, 13H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7](=[O:13])[CH2:8][NH:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=[CH:3]1.[Br:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:14][CH2:15][CH2:16][CH2:17][N:9]1[CH2:8][C:7](=[O:13])[C:6]2[N:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[S:10]1(=[O:12])=[O:11]
Reactant: Cn1ccc2c1C(=O)CNS2(=O)=O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1ccc2c1C(=O)CN(CCCBr)S2(=O)=O
Yield: 34.1 %

Procedure:
A suspension of 500 mg (2.5 mmol) of Compound 13, 2.5 g (12.5 mmol) of 1,3-dibromopropane and 690 mg (5 mmol) of potassium carbonate in 25 ml of acetone was refluxed for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: ethyl acetate/methylene chloride =1/40), whereby 274 mg of the title compound were obtained (yield: 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.ClC[C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14](N)=[O:15])[C:12]=1[C:20]([NH2:22])=[O:21].[CH3:23]O>[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:3]=1)[CH2:23][N:22]1[C:20](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:11]=2)[C:14]1=[O:15]
Reactant: CO
Reactant: Oc1ccc(Cl)cc1
Reactant: NC(=O)c1cccc(CCl)c1C(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)ccc1O
Temperature: 90 °C
Reaction time: 48 h

Procedure:
To 4-chlorophenol (2.0 g, 15.5 mmol) and chloromethylphthalamide (2.62 g, 13.4 mmol) was added zinc chloride (3 mL, 0.5 M in tetrahydrofuran, 1.5 mmol). The reaction was stirred at 90° C. for 48 hours. After cooling the reaction was diluted with methanol (15 mL) and brought to reflux. After 30 minutes the hot suspension was filtered through a medium glass frit and concentrated to an off-white solid. Methanol (50 mL) was again added and the reaction brought to reflux. After 3 hours the hot suspension was filtered through a medium glass frit and concentrated to an off-white solid. The crude product was purified via chromatography on silica gel to give the title compound (3.86 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:12][C:13]([O:16][C:17]([N:19]1[CH2:25][C:24]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:23]=2[O:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].ClCCl.C(N(C(C)C)CC)(C)C>O1CCOCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:27]2[CH:28]=[CH:29][C:23]3[O:22][CH2:21][CH2:20][N:19]([C:17]([O:16][C:13]([CH3:14])([CH3:12])[CH3:15])=[O:18])[CH2:25][C:24]=3[CH:26]=2)=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c([N+](=O)[O-])c3)cc2C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
A mixture of 2-amino-5-bromo-3-nitropyridine (0.70 g, 3.2 mmol), (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 1, step 2) (1.0 g, 3.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.15 mg, 0.2 mmol), diisopropylethylamine (1.8 g, 14 mmol) in 50% aqueous 1,4-dioxane (40 mL) was degassed with nitrogen for 5 minutes and then stirred at 90° C. for one hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (80 mL) then filtered over celite. The filtrate was washed twice with brine (50 mL), filtered and the filtrate dried over sodium sulfate, filtered again and concentrated. The residue was purified by silica gel chromatography (25% to 95% ethyl acetate in hexanes gradient) to give 1,1-dimethylethyl 7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.58 g, 48% yield); MS (EI) for C19H22N4O5: 389 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH3:23])[N:5]([P@@:13]([CH2:21][CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])CC1C=CC=CC=1.[NH2:25][O:26][K].Cl>>[OH:26][NH:25][C:3](=[O:2])[C@H:4]([NH:5][P@@:13]([CH2:21][CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH3:23]
Reactant: NO[K]
Reactant: CC[P@@](=O)(c1ccccc1)N(Cc1ccccc1)[C@H](C)C(=O)OC
Agent: Cl
Product: CC[P@](=O)(N[C@H](C)C(=O)NO)c1ccccc1
Reaction time: 16 h
Yield: 33 %

Procedure:
N-((R)-Ethylphenylphosphinyl)-N-benzyl-D-alanine methyl ester (333 mg, 0.96 mmol) is treated with a solution of NH2OK (3.3 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478. The reaction is stirred for 16 hours at which time TLC indicates completion. The reaction mixture is neutralized with 1M aqueous HCl and the volatiles are removed. The residue is purified by silica gel flash chromatography (95:5 ethyl acetate:methanol) to give 110 mg (33%) of N-hydroxy-2(R)-[[(R)-ethylphenyl-phosphinyl]amino]-propionamide as colorless solid: MS-IS m/z 347 [M+H]+, 369 [M+Na]+. (R1 =benzyl, R2 =methyl, R3 =ethyl, R4 =phenyl).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]([CH3:36])[C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([S:28](=[O:35])(=[O:34])[NH:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:24][CH:23]=4)[N:16]=3)=[CH:13][N:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CCOC(C)=O>C(O)C.[Pd]>[CH2:9]([C:10]1[N:11]([CH3:36])[C:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:35])(=[O:34])[NH:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:24][CH:23]=3)[N:16]=2)=[CH:13][N:14]=1)[CH2:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: COCCNS(=O)(=O)c1ccc(Nc2nccc(-c3cnc(CCc4ccc(Cl)cc4)n3C)n2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCNS(=O)(=O)c1ccc(Nc2nccc(-c3cnc(CCc4ccccc4)n3C)n2)cc1
Reaction time: 72 h
Yield: 62.1 %

Procedure:
4-{2-[2-(4-Chlorophenyl)ethyl]-1-(methyl)imidazol-5-yl}-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine (Method 117; 115 mg, 0.219 mmol) and triethylamine (34 μl, 0.241 mmol) was dissolved in ethanol (20 ml) and EtOAc (10 ml) and 30% palladium on charcoal catalyst (30 mg) added. The mixture was stirred for 3 days under an atmosphere of hydrogen. The catalyst was removed by filtration and filtrate evaporated. The residue was dissolved in DCM (20 ml), washed with water (2×5 ml), dried and the solvent removed by evaporation to give the title compound (67 mg, 63%) as a white solid. NMR: 2.88 (q, 2H) 3.05 (s, 4H) 3.16 (s, 3H) 3.28 (t, 3H) 3.90 (s, 3H) 7.21 (d, 1H) 7.28 (m, 5H) 7.69 (s, 1H) 7.70 (d, 2H) 8.44 (d, 1H) 9.94 (s, 1H); m/z 493.
Reaction SMILES: C(O)C.[N:4]1[CH:5]=[CH:6][N:7]2[CH:12]=[C:11]([C:13]3[C:17]4[CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][CH2:21][C:16]=4[NH:15][N:14]=3)[CH:10]=[CH:9][C:8]=12.Cl>O1CCOCC1>[N:4]1[CH:5]=[CH:6][N:7]2[CH:12]=[C:11]([C:13]3[C:17]4[CH2:18][NH:19][CH2:20][CH2:21][C:16]=4[NH:15][N:14]=3)[CH:10]=[CH:9][C:8]=12
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc4nccn4c3)c2C1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: c1cn2cc(-c3n[nH]c4c3CNCC4)ccc2n1
Reaction time: 0.5 h

Procedure:
In a flask, ethanol (1 mL) was added to tert-butyl 3-(imidazo[1,2-a]pyridin-6-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (0.750 g, 0.0022 mol). Hydrochloric acid in dioxane (4 M, 8 mL) was added to the reaction and was stirred for 30 minutes. Ethanol (5 mL) was added to the reaction, and the resulting solution was concentrated in vacuo. The crude product was progressed to the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 13.9 g 4-(5-bromo-2-chloro-benzyl)-phenol in 140 ml dichloromethane is cooled in the ice bath. Then 7.54 g tert-butyldimethylsilylchlorid in 20 ml dichloromethane are added followed by 9.8 ml triethylamine and 0.5 g dimethylaminopyridine. The solution is stirred for 16 h at ambient temperature and then diluted with 100 ml dichloromethane. The organic phase is washed twice with aqueous 1 M hydrochloric acid and once with aqueous sodium hydrogen carbonate solution and then dried over sodium sulphate. After the solvent has been eliminated the residue is filtered through silica gel (cyclohexane/ethyl acetate 100:1).
Reaction SMILES: [CH3:1][C:2]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:11][CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[CH2:24]1[O:26][CH2:25]1>C(O)CCCCCCC>[OH:26][CH2:25][CH2:24][N:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][C:2]1([CH3:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C1CO1
Reactant: CCCCCCC1CC(C)(CCCCCC)NC2CCCCC12
Solvent: CCCCCCCCO
Product: CCCCCCC1CC(C)(CCCCCC)N(CCO)C2CCCCC12

Procedure:
Following the above procedures, 25 grams of 2-methyl-2,4-dihexyl decahydroquinoline in 50 milliliters of 1-octanol was reacted with ethylene oxide at 200° C. for 8 hours to yield 1-(2'-hydroxyethyl)-2-methyl-2,4-dihexyl decahydroquinoline which had a boiling point at 192° C. at 0.7 mm Hg. The products NMR and infrared spectra were consistent with the desired product.
Reaction SMILES: [CH3:1][C:2]([S:7][CH2:8][CH2:9][C@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1)([CH3:6])[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.[CH3:30][C:31]([C:42]1[CH:46]=[C:45]([NH2:47])[O:44][N:43]=1)([C@@H:33]([O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)[CH3:34])[CH3:32]>C(Cl)Cl.CN(C=O)C>[CH3:6][C:2]([S:7][CH2:8][CH2:9][C@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1)([CH3:1])[C:3]([NH:47][C:45]1[O:44][N:43]=[C:42]([C:31]([CH3:30])([C@@H:33]([O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH3:34])[CH3:32])[CH:46]=1)=[O:5]
Reactant: CC(C)(SCC[C@H]1CCOC1)C(=O)O
Reactant: C[C@H](OC1CCCCO1)C(C)(C)c1cc(N)on1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](OC1CCCCO1)C(C)(C)c1cc(NC(=O)C(C)(C)SCC[C@H]2CCOC2)on1
Temperature: 60 °C
Yield: 44.3 %

Procedure:
Activation of 0.35 g (1.61 mmol) of 2-methyl-2-({2-[(3R)-oxolan-3-yl]ethyl}sulfanyl)propanoic acid as the corresponding acid chloride is achieved by treatment with oxalyl chloride (0.28 mL, 3.22 mmol) and DMF (cat., 0.01 mL) in DCM (15 mL) at room temperature for 3 h. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in THF (5 mL) and concentrated under reduced pressure. This process is repeated. Then the crude acid chloride is dissolved in anhydrous THF (10 mL) and 0.32 mL (1.81 mmol) of N,N-diisopropylethylamine are added followed by 0.17 g (0.66 mmol) of 3-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-amine. After complete addition the reaction is heated to 60° C. for 17 h. The reaction is cooled to room temperature and the solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate (20 mL) and washed with saturated aqueous NaHCO3 solution (2×5 mL) and 1M aqueous HCl solution (2×5 mL). The organic layer is dried (Na2SO4) and filtered. The filtrate is concentrated under reduced pressure and the residue purified by column chromatography (silica, eluent heptanes, 30% ethyl acetate) to yield 133 mg of 2-methyl-N-{3-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-yl}-2-({2-[(3R)-oxolan-3-yl]ethyl}sulfanyl)propanamide. Yield: 55%; ES-MS: m/z 453 [M−H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm approx 1:1 mixture of diastereoisomers: 1.00 (4H, d, J=6.24 Hz), 1.14-1.20 (4H, m), 1.22-1.39 (11H, m), 1.41-1.91 (27H, m), 1.94-2.13 (2H, m), 2.20-2.36 (2H, m), 2.48-2.67 (4H, m), 3.26-3.38 (2 H, m), 3.41-3.55 (2H, m), 3.63-3.98 (12H, m), 4.53-4.59 (1H, m), 4.74 (1H, t, J=3.12 Hz), 6.31 (1H, s), 6.35 (1H, s), 9.50 (2H, s)
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1>C(=S)=S>[Br:1][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: COc1ccc(O)cc1
Reactant: BrBr
Solvent: S=C=S
Product: COc1ccc(O)c(Br)c1
Yield: 57.1 %

Procedure:
A solution of 2.6 mL (100 mmol) bromine in 10 mL carbon disulfide was added dropwise over 30 minutes to a solution of 12.4 gm (100 mMol) 4-methoxyphenol in 20 mL carbon disulfide at 0° C. After 30 minutes an additional 1 mL of bromine in 10 mL carbon disulfide are added dropwise. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in diethyl ether. This solution was washed sequentially with 100 mL water and 100 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0 to 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 11.6 gm (57%) of the desired compound as a crystalline solid.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=O.C([S:17](=S)OCC)C.C(N([CH2:27][CH3:28])CC)C>C(Cl)(Cl)Cl>[CH2:27]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([SH:17])=[S:1])[CH3:28]
Reactant: CCN(CC)CC
Reactant: O=C(O)CCCCCCCCCCS
Reactant: CCOS(=S)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCC(=S)S
Temperature: 25 °C
Reaction time: 24 h
Yield: 111.6 %

Procedure:
A mixture of 11-mercaptoundecanoic acid (1.40 g, 6.42 mmol), ethyl ethanethiosulfinate (1.18 g, 8.55 mmol) and triethylamine (0.72 mL, 5.2 mmol) in 16 mL of chloroform was stirred at room temperature for 24 hours. Evaporation of solvent under reduced pressure followed by chromatographic purification of the residue on a silica gel column (2.5×40 cm), eluting first with CHCl3 and then solvent A, furnished 1.43 g (80%) of 11-ethyldithioundecanoic acid; Rf =0.52 (5% CH3OH in CHCl3); IR(nujol) νC=O 1700 cm-1 ; 1H NMR(CDCl3) 1.3 (br s and t, 19H, CH2 and CH3CH2S), 2.33 (t, 2H, CH2CO), 2.45-2.9 (m, 4H, CH2S), 11.7 (s, 1H, CO2H).
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15](NCC(O)=O)=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1.C(N(C(C)C)C(C)C)C.[NH2:44][CH2:45][CH2:46][OH:47].F[P-](F)(F)(F)(F)F.C([C:57](=[N:63]O[C+](N(C)C)N1CCOCC1)[C:58](OCC)=[O:59])#N>CN(C=O)C.O>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:44][CH2:45][C:46]([NH:63][CH2:57][CH2:58][OH:59])=[O:47])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1
Reactant: NCCO
Reactant: O=C(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)NCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
To a solution of N-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]glycine hydrochloride (500 mg), N-ethyl-N-(1-methylethyl)propan-2-amine (0.49 mL) and 2-aminoethanol (172 mg) in DMF (5 mL) was added (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (403 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and the solid was recrystallized from diisopropyl ether/heptane to give the title compound (20 mg).