Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[NH:20]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:29])[C:23]=2[CH2:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:29][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[CH2:22][CH2:21][N:20]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Oc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)N2CCc3c(O)cccc32)nc(N2CCOCC2)cc1=O
Yield: 23 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 270 mg of indolin-4-ol and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 85 mg of 2-[2-(4-hydroxy-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:16][C:17]#N.[OH-:19].[K+].[OH2:21]>C(O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:16][C:17]([OH:21])=[O:19]
Reactant: [OH-]
Reactant: COc1c(CC#N)cccc1Oc1ccccc1
Reactant: O
Agent: [K+]
Solvent: CCO
Product: COc1c(CC(=O)O)cccc1Oc1ccccc1

Procedure:
A mixture of 2-(2-methoxy-3-phenoxyphenyl)acetonitrile (2.5 g) and potassium hydroxide (2.3 g) in water (20 ml) and ethanol (40 ml) was treated in a similar manner to that of Example 17-(1) to give oily 2-(2-methoxy-3-phenoxyphenyl)acetic acid (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)C(O)=O)[C:5]([Cl:18])=[CH:4][N:3]=1.Cl.CN(C)CCCN=C=NCC.[OH:31][C:32]1C2N=NNC=2C=CC=1.Cl.[O:42]([NH2:44])[CH3:43].C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:11][C:10]=2[C:32]([NH:44][O:42][CH3:43])=[O:31])[C:5]([Cl:18])=[CH:4][N:3]=1
Reactant: O=C(O)c1cccc(Nc2cc(Cl)ncc2Cl)c1
Reactant: CON
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
A vessel was charged with 3-[(2,5-dichloro-4-pyridinyl)amino]benzoic acid (1.0 g, 3.53 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (677 mg, 3.53 mmol) and hydroxybenzotriazole (HOBT) (541 mg, 3.53 mmol) in N,N-dimethylformamide (DMF, 7.0 mL) and was stirred at room temperature for 30 min. To this solution methoxylamine hydrochloride (0.3 g, 3.53 mmol) was added and reaction mixture was stirred for another 10 min. The reaction mixture was cooled to 0° C. by using an ice bath. To this reaction mixture diisopropylethylamine (1.2 mL, 7.06 mmol) was added and the mixture was stirred at room temperature overnight. After concentrating under vacuum, the residue was worked up by using a saturated aqueous solution of NaHCO3 and CH2Cl2. The organic phase was washed with brine then dried over MgSO4 and filtered. The CH2Cl2 was removed by rotary evaporation. The crude material was loaded on silica gel column and eluted by MeOH in CH2Cl2 with NH4OH 0.1%, which gave the desired product 2-[(2,5-dichloro-4-pyridinyl)amino]-N-(methyloxy)benzamide (850 mg, 2.72 mmol, 77% yield) MS: M(C13H11C12N3O2)=312.15, (M+H)+=312, 314; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.57 (br. s., 1 H) 8.72 (s, 1 H) 8.22 (s, 1 H) 7.51-7.67 (m, 3 H) 7.25 (s, 1 H) 7.07-7.21 (m, 1 H) 3.92 (s, 3 H).
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[CH:27]=[CH:26][C:21]([C:22]([NH:24][CH3:25])=[O:23])=[CH:20][CH:19]=4)[S:17][C:10]=23)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]2([C:41](F)=[O:42])[CH2:40][CH2:39]2)=[O:37])=[CH:31][CH:30]=1.CC#[N:46]>>[F:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]([C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]4[CH:15]=[C:16]([C:18]5[CH:27]=[CH:26][C:21]([C:22](=[O:23])[NH:24][CH3:25])=[CH:20][CH:19]=5)[S:17][C:10]=34)=[CH:6][N:7]=2)[C:36]([C:38]2([C:41]([NH2:46])=[O:42])[CH2:40][CH2:39]2)=[O:37])=[CH:31][CH:30]=1
Reactant: O=C(F)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: CC#N
Reactant: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)nc4)c3s2)cc1
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)nc4)c3s2)cc1
Temperature: 25 °C
Yield: 11 %

Procedure:
A stirred mixture of 4-(7-(6-aminopyridin-3-yloxy)thieno[3,2-b]pyridin-2-yl)-N-methyl-benzamide (11 mg, 0.029 mmol) and 1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonyl fluoride (9.9 mg, 0.044 mmol), in CH3CN (0.5 mL) was heated at 100° C. for 3 hours. After cooling to room temperature, the mixture was partitioned between EtOAc (5 mL) and 1:1 saturated aqueous NaHCO3/water (5 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (2×5 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO4), filtered, and concentrated. The crude was purified by preparative TLC (0.5 mm thickness, Rf=0.30), eluting with 10% MeOH/CHCl3. The product was obtained as a beige solid (2 mg, 11%). HPLC: 100% purity (220 nm); LRMS (ESI+): 94% purity, 220 nm, m/z 582 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.53 (d, J=5 Hz, 1H), 8.29 (m, 2H), 7.85 (m, 5H), 7.55 (m, 3H), 7.04 (t, J=9 Hz, 2H), 6.56 (d, J=5 Hz, 1H), 6.19 (m, 1H), 3.06 (d, J=5 Hz, 3H), 1.82 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.COC(C)(C)C.CC(C)([O-])C.[Na+].[N:32]1([C:38](=[O:40])[CH3:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.O1CCOCC1>[C:38]([N:32]1[CH2:37][CH2:36][N:35]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH2:34][CH2:33]1)(=[O:40])[CH3:39]
Reactant: CC(=O)N1CCNCC1
Reactant: O=S(=O)(Cc1ccccc1)NCc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: CC(=O)N1CCN(c2ccc(CNS(=O)(=O)Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.8 %

Procedure:
In a flask, N-[(4-bromophenyl)methyl]-1-phenyl-methanesulfonamide (2.79 g, 8.20 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2 aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (60 mg, 0.082 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (39 mg, 0.0820 mmol) and sodium tert-butoxide (1.22 g, 12.3 mmol) were combined and purged with nitrogen. 1,4-Dioxane (40 mL) and 1-piperazin-1-ylethanone (1.58 g, 12.3 mmol) were then added and the reaction was stirred at ambient temperature for 16 hours. The precipitate was collected by filtration, washed with DCM and then with water and dried under vacuum overnight to give N-[[4-(4-acetylpiperazin-1-yl)phenyl]methyl]-1-phenyl-methanesulfonamide (1.52 g, 48% yield). LCMS (m/z) ES+ 388.2 [M+1]+.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH2:6][C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][CH2:9][S:10][CH3:11].S(O)(O)(=O)=O.[CH2:20]([S:27]SCC[C@H](N)C(O)=O)C[C@H](N)C(O)=O.S([O-])([O-])(=O)=O>>[NH2:6][C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][CH2:9][S:10][CH3:11].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[CH3:20][SH2+:27].[CH3:9][SH2+:10]
Reactant: O=S(=O)(O)O
Reactant: N[C@@H](CCSSCC[C@H](N)C(=O)O)C(=O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: O=S(=O)([O-])[O-]
Product: C[SH2+]

Procedure:
The analysis of the above-mentioned reaction solution 1 by liquid chromatography showed that 2.6 g (0.01 mole) of L-methionine sulfate, 112.5 g (0.31 mole) of L-homocystine sulfate, 12.4 g (0.03 mole) of mesohomocystine sulfate and 52.7 g (0.17 mole) of L-methionine-S-methylsulfonium sulfate were produced. The conversion rate was 99%, and the selection rate was 61%.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1.O>[CH2:22]([O:21][C:19]([N:8]1[CH2:9][CH2:10][C:4]2[CH:3]=[CH:2][S:1][C:5]=2[CH2:6][CH2:7]1)=[O:20])[CH3:23]
Reactant: c1cc2c(s1)CCNCC2
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)N1CCc2ccsc2CC1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (951 mg, 5.03 mmol) in THF (20 ml) at 0° C. was added triethylamine (1526 mg, 15.09 mmol) and ethyl chloroformate (573 mg, 5.3 mmol). The reaction mixture was warmed to ambient temperature for 4 hours and then diluted with water (100 ml) and extracted with EtOAc (3×75 ml). The combined organic phases were washed with brine (100 ml), dried (MgSO4), and concentrated in vacuo to give the crude product as an oil. Purification by flash chromatography (gradient elution: 0 to 40% EtOAc in hexane) afforded the subtitled compound as an oil; yield 77%. 1H NMR (300 MHz, CDCl3) 6.96 (d, J=5 Hz, 1 H), 6.76 (d, J=5 Hz, 1 H), 4.18 (q, J=7 Hz, 2 H), 3.52-3.78 (m, 4 H), 2.78-3.08 (m, 4 H), 1.28 (t, J=7 Hz, 3 H); MS: ESI (positive): 226 (M+H).
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9].[F:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1>>[F:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9]
Reactant: FC[C@@H]1CCCN1
Reactant: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@H]1CO
Product: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@H]1CN1CCC[C@H]1CF

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure RR starting from (2-(S)-hydroxymethyl-pyrrolidin-1-yl)-(4′-trifluoromethyl-biphenyl-4-yl)-methanone and 2-(S)-Fluoromethyl-pyrrolidine (CAS 460748-85-0) MS (M+H) 435.2
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].FC(F)(F)C1C=CC(C(=O)C(C2C=CC(C(F)(F)F)=CC=2)O)=CC=1.CN1CCOCC1.[OH:37][CH:38]([C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=1)[C:39]([C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH3:48])=[CH:43][CH:42]=1)=[O:40]>ClCCl>[Br:1][CH2:2][C:3]([O:40][CH:39]([C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH3:48])=[CH:43][CH:42]=1)[C:38]([C:49]1[CH:50]=[CH:51][C:52]([CH2:55][CH3:56])=[CH:53][CH:54]=1)=[O:37])=[O:4]
Reactant: O=C(Cl)CBr
Reactant: CCc1ccc(C(=O)C(O)c2ccc(CC)cc2)cc1
Agent: O=C(c1ccc(C(F)(F)F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCc1ccc(C(=O)C(OC(=O)CBr)c2ccc(CC)cc2)cc1
Reaction time: 1 h
Yield: 65 %

Procedure:
A solution of bromoacetyl chloride (2.00 mL, 24.2 mmol) in anhydrous dichloromethane (20 mL) was added dropwise to a cold (0° C.) mixture of 2-hydroxy-1,2-di-(4-ethylphenyl)ethanone (IX; 6.5 g, 24.2 mmol) and N-methylmorpholine (NMM; 2.7 mL, 24.2 mmol) in anhydrous dichloromethane (180 mL). The mixture was stirred at 0° C. for 1 h and at ambient temperature for 2 h before additional 2-hydroxy-1,2-di-(4-ethylphenyl)ethanone (0.5 mL) and NMM (0.6 mL) were added to aid in completion. After 1 h, the mixture was washed with saturated sodium bicarbonate solution, 1N HCl and brine. Following drying and solvent evaporation, the residue was purified by flash chromatography on silica gel (gradient elution with 10% ethyl acetate in hexanes followed by 25% ethyl acetate in hexanes) and furnished 6.10 g (65%) of bromoacetoxy-1,2-di-(4-ethylphenyl)ethanone as a pale-yellow oil which was carried on directly. A portion of bromoacetoxy-1,2-di-(4-ethylphenyl)ethanone (3.15 g, 8.09 mmol) was treated with anhydrous sodium carbonate (0.86 g, 8.09 mmol), sodium iodide (0.12 g) and N-(2,6-dimethylphenyl)-1-piperazineacetamide (2.0 g, 8.09 mmol) in anhydrous acetonitrile (120 mL) and the resulting mixture was heated to 80° C. for 5 h before it was cooled and concentrated down in vacuo. Purification of the residue by flash chromatography on silica gel with absolute ethyl acetate gave 3.40 g (76%) of 2-oxo-1,2-di-(4-ethylphenyl)ethyl 4-[[[(2,6-dimethylphenyl) amino]carbonyl]-methyl]-1-piperazineacetate as pale-yellow foam. A portion of 2-oxo-1,2-di-(4-ethylphenyl)ethyl 4-[[[(2,6-dimethylphenyl)amino]carbonyl]-methyl]-1-piperazineacetate (2.50 g, 4.50 mmol) was dissolved in glacial acetic acid (75 mL) and ammonium acetate (1.65 g, 22.5 mmol) was added. The mixture was gently refluxed under nitrogen for 6 h before the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and 1N sodium hydroxide solution (until basic) and the organic phase was separated, washed with brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (gradient elution with ethyl acetate followed by 10% methanol in ethyl acetate) and yielded 0.61 g (22%) of the oxazole product I as a white solid and 0.85 g (30%) of the imidazole product I as a white solid after salt formation with ethereal hydrogen chloride.
Reaction SMILES: C[Li].[CH:3]1([C@:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([OH:13])[C:10]([OH:12])=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:20](O)(=O)C.O>CCOCC.C1COCC1>[CH:3]1([C@@:9]([OH:13])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10](=[O:12])[CH3:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCCC1
Reactant: CC(=O)O
Agent: [Li]C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(=O)[C@](O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a mixture of 315 ml of 1.4M CH3Li (0.44 mole) in ether and 750 ml of THF at room temperature was added a solution of 26 g (0.11 mole) of (R)-cyclohexylmandelic acid, prepared by the method of R. B. Barlow, F. M. Franks, and J. D. M. Pearson, J. Med. Chem., 16, 439 (1973), in THF. Following the addition, the mixture was stirred at room temperature for 3.5 hours and then brought to reflux for 3 hours. The mixture was cooled and then added dropwise to a mixture of 300 ml of glacial acetic acid and 700 ml of water. This mixture was extracted with ether, the organic layer was separated, washed with water and saturated aqueous sodium bicarbonate, dried, and the solvent removed. The mixture was distilled to give 20 g of clear oil (bp 120° C., 0.1 mm Hg), NMR (chloroform-d) δ7.5(m, 5H), 4.5(S, 1H), 2.4(t, 1H), 2.0(s, 3H), 1.9-1.0(m, 10H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([NH:1][CH:2]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[OH:4])=[O:35])=[CH:26][CH:25]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (412 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (221 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (573 mg, 82%).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH:13]1([CH2:18][CH2:19][C:20](OCC)=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(=O)C.O1CCCC1.C(OCC)C>[CH:13]1([CH2:18][CH2:19][C:20](=[O:21])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)CCC1CCCC1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: COP(=O)(CC(=O)CCC1CCCC1)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
125 g. of dimethyl methylphosphonate were dissolved in 720 ml. of tetrahydrofuran and the solution cooled to -65°C. To this solution a solution of butyllithium [prepared from 150 g. of butyl bromide and 14.5 g. of lithium] in 550 ml. of diethyl ether was added dropwise. To the mixture a solution of 52.5 g. of ethyl 3-cyclopentylpropionate in 280 ml. of tetrahydrofuran was added drop-wise and the reaction mixture was stirred at the same temperature for 2 hours and afterwards at 0°C. overnight. The reaction mixture was then neutralised with acetic acid, concentrated under reduced pressure and the resulting residue after the addition of water was extracted with diethyl ether. The ethereal extract was dried over sodium sulphate, the solvent distilled off and the residue distilled under reduced pressure to obtain 47 g. (yield 61.2%) of the title compound as a colourless oil, b.p. 142°- 144°C./0.4 - 0.5 mm.Hg. NMR spectrum (tetrachloromethane): δ = 3.84 (6H, doublet), 3.19 (2H, doublet), 2.42 (2H, triplet), 2.0 - 1.09 (11H, multiplet).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][C:16]#[N:17])=[CH:3][CH:2]=1.CCCCC.[H-].[Na+].Br[CH2:26][C:27]1[C:31]2[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=2[S:29][CH:28]=1>CN(C=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]2[S:29][CH:28]=[C:27]([CH2:26][N:12]3[C:13]4[CH:1]=[CH:2][CH:3]=[C:4]([O:14][CH2:15][C:16]#[N:17])[C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:31]=2[CH:32]=1
Reactant: N#CCOc1cccc2[nH]c3ccccc3c12
Reactant: Clc1ccc2scc(CBr)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: N#CCOc1cccc2c1c1ccccc1n2Cc1csc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.7 %

Procedure:
2-(9H-Carbazol-4-yloxy)acetonitrile (0.146 g, 0.66 mmol)) is added to a slurry of pentane-washed NaH (0.0441 g, 0.0011 mol) in DMF (1 mL) and allowed to stir for 20 min at room temperature. 3-(Bromomethyl)-5-chlorobenzothiophene (0.229 g, 0.88 mmol) is added and after stirring for 1 h the mixture is partitioned between ethyl acetate and water. The combined organic layers are dried over magnesium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (75 mL) using ethyl acetate/hexane (20/80) and solids are precipitated using dichloromethane/hexane to give 0.148 g (56%) of the title compound; MS (ESI+) for C23H15ClN2OS m/z 425.2 (M+Na); IR (drift) 1581, 1460, 1439, 1332, 1279, 1232, 1221, 1155, 1148, 1115, 1079, 833, 780, 752, 717 cm−1; 1H NMR (CDCl3) δ5.10, 5.70, 6.72, 6.80, 7.12, 7.28-7.47, 7.80, 7.87, 8.36. Anal. Calcd for C23H15ClN2OS: C, 68.57; H, 3.75; N, 6.95. Found: C, 68.87; H, 4.22; N, 6.56.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]([NH:11][SH:12](=[O:14])=[O:13])([CH3:10])([CH3:9])[CH3:8].C([Li])CCC.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C.Cl>C1COCC1.CCCCCC>[C:7]([NH:11][S:12]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[B:24]([OH:25])[OH:23])(=[O:14])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)N[SH](=O)=O
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Temperature: 10 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of 206.5 g (0.968 mol) of benzene-(N-t-butyl)sulfonamide in 2500 mL of THF under N2 was added 790 mL (1.98 mol) of 2.5M n-butyllithium in hexane over 35 minutes, keeping the temperature between 0-5° C. The reaction mixture was allowed to warm to 10° C., at which time a thick precipitate formed. Triisopropylborate (305 mL, 1.32 mol) was added keeping the temperature below 35° C. After 1 hour, the reaction mixture was cooled, 1N HCl (1570 mL) was added, and the mixture was stirred overnight. The mixture was extracted with 400 mL of ether three times, and the combined organic extracts were extracted with 500 mL of 1N NaOH three times. The aqueous extracts were acidified to pH 1 with 6N HCl and then extracted with 500 mL ether three times. The combined ether extracts were dried over MgSO4, and the solvents evaporated in vacuo until the volume was 700 mL. Hexane (150 mL) was added and overnight, a white precipitate formed. The solid was collected and washed with 10% ether/hexane (250 mL), then dried in vacuo to give 216.3 g (87%) of the desired compound as white crystals. m.p. 118-119° C.; 1H NMR (CDCl3): δ8.00 (d, 1H); 7.82 (d, 1H); 7.53 (m, 2H); 6.29 (br s, 2H); 5.13 (s, 1H); 1.18 (s, 9H).
Reaction SMILES: C(S[C:4](=[O:25])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[O:14])[CH2:8][CH2:7]1)C.C.C([SiH](CC)CC)C.CCCCCCC.C([O-])(=O)C>CC(C)=O.C(Cl)Cl.[Pd]>[O:25]=[CH:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[O:14])[CH2:8][CH2:7]1
Reactant: CCSC(=O)C[C@H]1CC[C@H](NC(=O)c2ccnc3ccccc23)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: CC(C)=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=CC[C@H]1CC[C@H](NC(=O)c2ccnc3ccccc23)CC1
Reaction time: 0.5 h

Procedure:
Trans-{4-[(Quinoline-4-carbonyl)-amino]-cyclohexyl}-thioacetic acid S— ethyl ester (1.87 g, 5 mmol) was solved in acetone/methylene chloride (40/40 mL), 0.8 g of molecular sieves were added to the mixture and the solution was stirred for 0.5 h. Then 0.558 g (1 mmol) of palladium on active charcoal 10% was added followed by 1.25 mL (8 mmol) of triethyl-silane. The reaction was stirred for 1.5 hours at room temperature and additional 0.558 g (1 mmol) of palladium on active charcoal 10% and 1.25 mL (8 mmol) of triethyl-silane were added and the stirring was continued for another hour. The mixture was filtrated through celite and the mother liquid was concentrated to obtain after chromatography using heptane/acetate 1:1 1.1 (37.1 mmol, 70.8% yield) of the final compound. MS (m/e): 297.3 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([I:13])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH2:14](O)[CH2:15][CH2:16][OH:17].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[O:17][CH2:16][CH2:15][CH2:14][O:7]2)[CH:8]=[C:9]([I:13])[C:10]=1[O:11][CH3:12]
Reactant: OCCCO
Reactant: COc1cc(C=O)cc(I)c1OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1cc(C2OCCCO2)cc(I)c1OC

Procedure:
3,4-dimethoxy-5-iodobenzaldehyde (41) (FIG. 22) (5.814 g,19.9 mmole), 1,3-propanediol (6.13 g, 79.6 mmole), pyridinium para-toluenesulfonate (2.0 g, 7.96 mmole) and 100 ml dry benzene were refluxed with Dean-Stark removal of the benzene-water azeotrope overnight. The benzene was removed in vacuo and the remaining oil redissolved in diethyl ether and was washed with 10% NaHCO3 and H2O. The organic layer was washed over MgSO4, and concentrated to a white solid in vacuo. (6.823 g, 98%). The solid can be recrystallized from hexane/ethyl acetate.