Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C:12]2[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]3[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(C2=Nc3cc(N4CCOCC4)c(C(F)(F)F)cc3NC(=O)C2)ccn1

Procedure:
The title compound was prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-morpholin-4-yl-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M2) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (11 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[NH:14][C:13](=[O:15])[CH:6]3[CH2:7][C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[H-].[Na+].I[CH3:19]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[NH:14][C:13](=[O:15])[C:6]3([CH3:19])[CH2:7][C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C1CC2C(=O)Nc3cc(F)cc(c32)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC12CC(=O)Nc3cc(F)cc(c31)NC2=O
Reaction time: 0.25 h

Procedure:
To a stirred solution of (±)-7-fluoro-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione from Step E (608 mg, 2.95 mmol) in degassed DMF (10 mL) at 0° C. was added sodium hydride (142 mg of a 60% dispersion in mineral oil, 3.54 mmol). The mixture was stirred for 15 min, then iodomethane (0.184 mL, 2.95 mmol) was added and stirring was continued for 1 h. The reaction mixture was poured onto H2O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with H2O (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=221 (M+1).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1.ClCC1C(C(F)(F)F)=NC=CC=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@:24]2([C:42]3[C:33](=[CH:34][C:35]4[O:40][CH2:39][CH2:38][O:37][C:36]=4[CH:41]=3)[O:32][CH2:31]2)[C:23]1=[O:43].N1C2C(=CC=CC=2)C2(C3C(=CC4OCCOC=4C=3)OC2)C1=O>>[N:5]1[CH:6]=[CH:7][CH:8]=[N:9][C:4]=1[CH2:3][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@:24]2([C:42]3[C:33](=[CH:34][C:35]4[O:40][CH2:39][CH2:38][O:37][C:36]=4[CH:41]=3)[O:32][CH2:31]2)[C:23]1=[O:43]
Reactant: ClCc1ncccn1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: Cl
Agent: FC(F)(F)c1ncccc1CCl
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Product: O=C1N(Cc2ncccn2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in Example 5.9, making non-critical variations using 2-(chloromethyl)pyrimidine hydrochloride to replace 3-(chloromethyl)-2-(trifluoromethyl)pyridine, and (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, (8S)-1′-(pyrimidin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (59%) as a colorless solid: mp 210-212° C.; 1H NMR (300 MHz, CDCl3) δ 8.72-8.68 (m, 2H), 7.23-7.14 (m, 3H), 7.06-6.99 (m, 1H), 6.74-6.69 (m, 1H), 6.56 (s, 1H), 6.50 (s, 1H), 5.21 (ABq, J=82.1, 17.0 Hz, 2H), 4.86 (ABq, J=81.2, 8.9 Hz, 2H), 4.22-4.10 (m, 4H); 13C NMR (300 MHz, CDCl3) δ 177.8, 164.6, 157.5, 155.1, 144.5, 142.2, 138.2, 132.6, 128.6, 123.8, 123.3, 121.5, 119.8, 112.3, 108.7, 99.1, 80.0, 64.5, 63.9, 58.1, 45.7; MS (ES+) m/z 387.9 (M+1); Anal. Calcd for C22H17N3O4: C, 68.21; H, 4.42; N, 10.85. Found: C, 68.17; H, 4.41; N, 10.76.
Reaction SMILES: C([O:3][C:4]1(OCC)[CH2:10][CH:9]2[CH:5]1[CH2:6][CH2:7][C:8]2=[O:11])C.[BH4-].[Na+]>O1CCOCC1.OP([O-])(O)=O.[K+].Cl>[OH:11][CH:8]1[CH2:7][CH2:6][CH:5]2[CH:9]1[CH2:10][C:4]2=[O:3]
Reactant: CCOC1(OCC)CC2C(=O)CCC21
Agent: Cl
Agent: O=P([O-])(O)O
Agent: [BH4-]
Solvent: C1COCCO1
Product: O=C1CC2C(O)CCC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of compound 1F in dioxane (50 mL) and 2M KH2PO4 (50 mL) was added NaBH4 (1.0 g, 26.4 mmol) over a 10 min-period, and the stirring was continued at RT for 1 hr. The reaction mixture was diluted with 2M HCl to adjust pH to 1, and stirred at RT for another 1 hr. The reaction was concentrated, dissolved in EtOAc, washed with water, dried over Na2SO4, and concentrated. Purification by silica gel chromatography (50% EtOAc in hexanes) provided the title compound (1.9 g) as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:11]1[CH:13]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:12]1.Cl>CS(C)=O.O1CCCC1>[CH2:3]([O:10][CH2:12][CH:13]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)[OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C(CCCCCCC1CCCCC1)CCCCCOCC1CO1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: OC(COCCCCCCCCCCCCC1CCCCC1)COCc1ccccc1
Temperature: 60 °C
Yield: 78.9 %

Procedure:
In 100 ml of dimethylsulfoxide is suspended 1.4 g of sodium hydride, to which 9.73 g of benzyl alcohol is added dropwise at room temperature with stirring. After the addition is over, the mixture is gradually heated to 60° C. and stirred at that temperature for 40 minutes. Then, a solution of 9.7 g of 1,2-epoxy-3-(12-cyclohexyldodecyloxy)propane in 50 ml of tetrahydrofuran is added dropwise to the mixture and the resulting mixture is stirred at 60° C. for 2 hours. The thus obtaind reaction mixture is then neutralized with dilute hydrochloric acid and extracted with hexane-ethyl acetate (1:1). The extract layer is washed with water, dried and concentrated. The residue is purified by silica gel column chromatography to yield 10.2 g of the captioned compound as an oily substance.
Reaction SMILES: [CH3:1][N:2]([CH2:46][CH:47]([OH:56])[CH:48]([OH:55])[CH:49]([OH:54])[CH:50]([OH:53])[CH2:51][OH:52])[C:3](=[O:45])[CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:18]([CH2:19][CH2:20][CH:21]([O:29][Si](C(C)(C)C)(C)C)[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:17](=[O:37])[N:16]2[C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[CH:11][CH:10]=1.Cl.[OH-].[Na+]>CO>[CH3:1][N:2]([CH2:46][CH:47]([OH:56])[CH:48]([OH:55])[CH:49]([OH:54])[CH:50]([OH:53])[CH2:51][OH:52])[C:3](=[O:45])[CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH:18]([CH2:19][CH2:20][CH:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[OH:29])[C:17](=[O:37])[N:16]2[C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)=[CH:13][CH:14]=1
Reactant: CN(CC(O)C(O)C(O)C(O)CO)C(=O)CCCC=Cc1ccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CC(O)C(O)C(O)C(O)CO)C(=O)CCCC=Cc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
70 mg of N-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)-6-{4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenyl}hex-5-enamide are dissolved in 6 ml of methanol. 0.1 N HCl(aq) is then added, and the mixture is stirred at room temperature overnight. The mixture is then neutralized with 1 N aqueous sodium hydroxide solution and concentrated using a rotary evaporator. The residue is stirred with dichloromethane and filtered and the mother liquor is concentrated using a rotary evaporator. The product is obtained following purification by preparative HPLC: C31H44F2N2O8 (682) MS (ESI): M+-18
Reaction SMILES: Cl[C:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH2:4][C:3]=1[CH:9]=O.C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][CH3:22])(=[O:20])[CH2:18][SH:19]>CN(C=O)C>[CH3:22][O:21][C:17]([C:18]1[S:19][C:2]2[CH2:7][CH:6]([CH3:8])[CH2:5][CH2:4][C:3]=2[CH:9]=1)=[O:20]
Reactant: CC1CCC(C=O)=C(Cl)C1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(s1)CC(C)CC2
Temperature: 100 °C
Yield: 69.1 %

Procedure:
769 mg of the crude 2-chloro-4-methyl-cyclohex-1-enecarbaldehyde obtained in step a) were dissolved in DMF (10 ml). Then 837 mg (6.06 mmol) of potassium carbonate and 440 μl (4.85 mmol) of methyl thioglycolate were added and the mixture was heated to 100° C. for 16 h. After cooling to RT, the solvent was removed in vacuo. Water was added to the remaining residue and the mixture was extracted with ethyl acetate. The organic extracts were then washed with 50% sodium chloride solution, dried (MgSO4) and concentrated to give 704 mg of 6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid methyl ester (containing 10% of 4-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid methyl ester) as dark brown oil. MS (ISP) 211.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:25])[CH:10]([NH:14]C(OCC1C=CC=CC=1)=O)[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([NH:8][C:9](=[O:25])[CH:10]([NH2:14])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC(NC(=O)OCc1ccccc1)C(=O)NCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCC(N)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 96 %

Procedure:
To a solution of 12 (122.8 mg, 0.36 mmol) in methanol (2.0 mL) was added 10% Pd—C (11 mg) and the mixture stirred at room temperature in the presence of H2 gas for 75 min. Celite was added to the reaction mixture and the catalyst was removed by filtration. The clear filtrate was evaporated in vacuo to give pure 13 as a clear viscous oil (72 mg, 97%): Rf 0.30 (5% MeOH/CHCl3).
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH2:6]([C:11]1[CH:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:13][S:14][CH:15]=1)[C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[CH:27]([OH:30])([CH3:29])[CH3:28]>>[CH:27]([O:30][C:12]1([C:16]([CH3:19])([CH3:18])[CH3:17])[C:11]([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:15][S:14][S:13]1)([CH3:29])[CH3:28]
Reactant: CC(C)O
Reactant: CC(C)(C)CC1=CSSC1C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCN(CC)CC
Product: CC(C)OC1(C(C)(C)C)SSC=C1CC(C)(C)C
Yield: 98 %

Procedure:
To a sample of 5 grams of Example 2B, i.e., 4-neopentyl-3-t-butyl 1,2 dithiole perchlorate, in 50 grams of isopropanol was added 2.5 grams of triethylamine. The excess of isopropanol was removed by distillation under diminished pressure. The residue was dissolved in ether and the ethereal solution was filtered. The ethereal solution was evaporated under diminished pressure to yield 4.3 grams (98% of theory) of 3-isopropoxy-3-t-butyl-4-neopentyl 1,2 dithiole; n.m.r. (CCl4) in ppm, 3.97, 1H singlet (vinyl); 6.18 1H multiplet (isopropoxy); 7.17, 1H doublet (diastereotopic, J=15 cps, neopentyl; 7.88, 1H doublet (diastereotopic, J=15 cps, neopentyl); 8.62, 9H singlet (t-butyl); 8.83, 6H doublet (isopropoxy); and 8.91, 9H singlet (t-butyl).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([NH2:21])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:31][CH2:32][C:33](Cl)=[O:34].C(OCC)(=O)C.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([NH:21][C:33](=[O:34])[CH2:32][Cl:31])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)c(N)c2)CC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)c(NC(=O)CCl)c2)CC1
Reaction time: 2 h

Procedure:
To a solution of 4-(3-amino-4-chloro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (500 mg) and N,N-diisopropylethylamine (0.8 ml) in tetrahydrofuran (20 ml) cooled to 0° C. was added 2-chloroacetyl chloride (0.2 ml). After 2 hrs, the reaction was poured into ethyl acetate/water. The organic layer was separated, washed with water, aqueous NaHCO3 and brine, dried (MgSO4) and concentrated. Purification of the residue by silica gel chromatography (eluting ethyl acetate/iso-hexane (1:3 to 1:2) gave the sub-title product (0.5 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:24])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].Cl.NO.C[O-].[Na+].CO.Cl>O1CCOCC1>[C:18]1([CH2:17][C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]3[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=3)[CH2:11][CH2:12]2)=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cnc(N2CCN(C(=O)Cc3ccccc3)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: NO
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1cnc(N2CCN(C(=O)Cc3ccccc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 22c (100 mg, 0.377 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (208 mg, 3.771 mmol) and a freshly prepared solution of sodium methoxide in methanol (103 mg, 4.471 mmol of sodium dissolved in 1.5 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 23c. HPLC: Rt=5.62 min.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N+:7]([CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)([O-])=O.O.[OH-].[Na+]>C(OCC)C>[C:20]1([CH2:19][O:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][NH2:7])=[CH:17][CH:16]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])C=Cc1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NCCc1ccc(OCc2ccccc2)cc1
Yield: 90 %

Procedure:
2-(4-(Phenylmethoxy)phenyl)ethylamlne. Lithium aluminum hydride (8.48 g, 223 mmol) was suspended in dry diethyl ether (600 mL). 1-(2-Nitroethenyl)-4-(phenylmethoxy)benzene (13.9 g, 55 mmol) was extracted into this mixture using a Soxhlet apparatus. The mixture was boiled under reflux for 16 h. Water (7.38 mL) was added, followed by aqueous sodium hydroxide (20%; 5.53 mL) and water (27.8 mL). The suspension was filtered. The solvent was evaporated from the filtrate under reduced pressure to give 2-(4-(phenylmethoxy)phenyl)ethylamine (11.25 g, 91%).
Reaction SMILES: BrC1C=CC(CCC(C2C=CC=CC=2)=O)=CC=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26]/[C:27](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26]/[C:27](/[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:28]\[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:24]=1
Reactant: CCOC(=O)/C=C(/CCc1ccc(Br)cc1)c1ccccc1
Agent: O=C(CCc1ccc(Br)cc1)c1ccccc1
Product: CCOC(=O)/C=C(\CCc1ccc(Br)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 3-(4-bromophenyl)-1-phenylpropan-1-one, (Z)-ethyl 5-(4-bromophenyl)-3-phenylpent-2-enoate and (E)-ethyl 5-(4-bromophenyl)-3-phenylpent-2-enoate were obtained as colourless oils.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[O:11]=[C:12]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:15]([C:24]([O:26][CH3:27])=[O:25])[CH2:14][CH2:13]1.CI.[CH3:30]C(O)=O>C1COCC1>[CH3:30][C@H:13]1[C:12](=[O:11])[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:15]([C:24]([O:26][CH3:27])=[O:25])[CH2:14]1
Reactant: CC(=O)O
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)[C@@H]1C[C@@H](C)C(=O)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
This compound is prepared as described by Gu et al, Tetrahedron Lett., 2003, 44, 3203-3205. Lithium hexamethyldisilazide in THF (1.0 M; 8.47 mL, 8.47 mmol) was added dropwise over 30 min. to a solution of 1-tert-butyl 2-methyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (2.0 g, 8.2 mmol) in THF (20 mL) at −78° C. The resulting mixture was stirred at −78° C. for 1 h. Methyl iodide (1.30 mL, 20.9 mmol) was then added dropwise over 10 min. After stirring at −78° C. for 2 h, the reaction mixture was allowed to warm to room temperature and stirred for 14 h. The reaction was then quenched with AcOH (1.00 mL, 17.6 mmol), and the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-50% EtOAc in hexanes) to give the sub-title compound (0.47 g, 22%). LCMS calc. for C12H19NNaO5 (M+Na)+: m/z=280.1. found 280.1. 1H NMR (CDCl3, 400 MHz) δ 4.57 (1H, dd, J=1.6 and 9.6 Hz), 3.77 (3H, s), 2.68 (1H, m), 2.27 (1H, m), 1.93 (1H, m), 1.49 (9H, s), 1.21 (3H, d, J=6.8 Hz) ppm.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20](=[S:22])[NH2:21])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:24][C:25](=O)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:22][CH:24]=[C:25]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:21]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC(C)(C)c1csc(-c2cc3cc(CC(N)=S)ccc3o2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1csc(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)n1
Yield: 62.7 %

Procedure:
A mixture of crude 4-tert-butyl-2-[5-(thiocarbamoylmethyl)benzofuran-2-yl]thiazole (0.73 g) and ethyl 4-chloroacetoacetate (0.92 g) in ethyl acetate (30 ml) was stirred under reflux for 18 hours. After being cooled, the resulting mixture was poured into aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate. The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-{5-{[4-(ethoxycarbonylmethyl)thiazol-2-yl]methyl}benzofuran-2-yl}thiazole (0.61 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][N:18]1[CH:26]([OH:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C(N(CC)CC)C.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>C1(C)C=CC=CC=1.C(Cl)Cl.C(C(C)=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[OH:27][CH:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:28])[N:18]1[CH2:17][CH2:16][CH2:15][N:11]1[CH2:10][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: O=C1c2ccccc2C(O)N1CCCBr
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCC(C)=O
Product: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccc(F)cc2)CC1
Yield: 59.2 %

Procedure:
A solution of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (12.3 g) in toluene (20 cc) is added to a solution of 2-(3-bromopropyl)-3-hydroxy-1-isoindolinone (18.9 g) in toluene (200 cc), at a temperature close to 20° C. and in the course of 10 minutes, followed by a solution of triethylamine (9.8 cc) in toluene (20 cc). The mixture is agitated at a temperature close to 111° C. for 3 hours. After cooling to a temperature close to 20° C, the precipitate formed is separated by filtration and washed with toluene (3×50 cc). The organic phases are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 60° C. The residue obtained is dissolved in methylene chloride (50 cc) and the solution poured onto silica (1 kg) contained in a column of 8 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (98-2 by volume). The first 4000 cc are eliminated and the next 4000 cc are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The oil obtained is dissolved in methyl ethyl ketone (70 cc). A solution of oxalic acid (1.6 g) in methyl ethyl ketone (20 cc) is added, and agitation is maintained for about 1 hour. The precipitate formed is separated by filtration, washed with methyl ethyl ketone (20 cc), and then recrystallized from a boiling mixture of isopropanol and isopropyl ether (75-25 by volume,150 cc). 4.8 g of 3-hydroxy-2-[3-(4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are obtained, melting at 93° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11].Cl[C:20](=[O:26])[C:21]([O:23]CC)=[O:22].[OH-].[Na+].Cl>ClCCl.O>[OH:11][CH2:10][C@H:9]([NH:8][C:20](=[O:26])[C:21]([OH:23])=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: N[C@@H](CO)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C(=O)N[C@@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Triethylamine (0.703 mL; 5.01 mmol) was added to the mixture of (R)-2-amino-3-phenylpropan-1-ol (0.515 g; 3.34 mmol) and ethyl 2-chloro-2-oxoacetate (0.400 mL; 3.50 mmol) in dichloromethane (15 mL) at 0° C. After addition, the mixture was stirred at room temperature for 30 minutes, diluted with 40 mL of dichloromethane, and washed successively with an aqueous solution of sodium carbonate, and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Water (5 mL) and a 2M solution of sodium hydroxide (5 mL; 10 mmol) were added to the resulting residue and the mixture was stirred at room temperature for 10 minutes. Water (10 mL) was added and the pH of the solution was adjusted to 1 by addition of a 6N hydrochloric acid. The formed precipitate was filtered off, and the filtrate was extracted with ethyl acetate (5×20 mL). The combined organic layers were dried over magnesium sulfate and evaporated to dryness to give 0.671 g (91%) of (R)-2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoacetic acid as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:17]1[S:21][C:20]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:24])=[N:19][CH:18]=1)[CH2:5][O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:2][CH2:3][CH:4]([C:17]1[S:21][C:20]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[O:24])=[N:19][CH:18]=1)[CH2:5][O:6][Si:7]([CH:14]([CH3:15])[CH3:16])([CH:11]([CH3:12])[CH3:13])[CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)C(CO[Si](C(C)C)(C(C)C)C(C)C)c1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[Si](OCC(CO)c1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
To a solution of compound 73.2 (0.275 mmol) in THF (2.5 mL) was added LAH (0.275 mL of a 1.0 M solution in THF) dropwise at 0° C. The reaction is allowed to warmed to room temperature and stirred until the starting material was consumed. The reaction is quenched by the dropwise addition of water and the reaction mixture was extracted with EtOAc. The combined organic layers were combined, dried and concentrated to give a residue that was purified by flash column chromatography (20 to 100% EtOAc in hexanes) to provide 1-[5-(2-hydroxy-1-triisopropylsilanyloxymethyl-ethyl)-thiazol-2-yl]-3-(3-trifluoromethyl-phenyl)-urea (compound 73.3).