Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2]CCC.CCCCCC.[CH:12]([C:14]1[S:15][CH:16]=[C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:18]=1[CH3:19])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH:12]([C:14]1[S:15][CH:16]=[C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:18]=1[CH3:19])=[CH2:2]
Reactant: [Li]CCCC
Reactant: Cc1c(C2CCCCC2)csc1C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: CCOCC
Product: C=Cc1scc(C2CCCCC2)c1C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 50 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (4.983 g, 13.96 mmol) in ether at 0° C. was added dropwise 1.6 M n-BuLi solution in hexane (8.7 ml, 13.96 mmol). The solution was stirred at 0° C. for 40 min and then was warmed to room temperature. A solution of 2-formyl-3-methyl-4-cyclohexylthiophene dimer (2.7 g, 6.98 mmol) in a minimum of ether was added. The solution was stirred overnight. The reaction mixture was then diluted with ether and washed with water and brine, and dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by column chromatography using hexane as the eluant to afford 2-vinyl-3-methyl-4-cyclohexylthiophene dimer 1.32 g (50% yield) as a white solid. 1H NMR (CDCl3) δ 6.98 (s, 1H), 6.90 (dd, 1H), 5.52 (d, 1H), 1.15 (d, 1H), 2.22 (s, 1H), 2.19 (s, 1H), 2.11 (s, 1H), 2.10 (s, 1H), 2.09 (s, 1H), 2.08 (s, 1H). 13C NMR (CDCl3) δ 147.93, 146.37, 137.41, 136.09, 134.78, 129.97, 128.44, 127.57, 118.61, 112.7, 40.07, 38.86, 33.74, 31.37, 27.19, 26.91, 26.30, 26.12, 13.61, 13.33.
Reaction SMILES: [C:1]([C:3]1[CH:34]=[CH:33][C:6]2[NH:7][C:8]([C:10]([C:21]3[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)([O:15][CH2:16][C:17]([O:19]C)=[O:18])[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:3]1[CH:34]=[CH:33][C:6]2[NH:7][C:8]([C:10]([C:21]3[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)([O:15][CH2:16][C:17]([OH:19])=[O:18])[C:11]([F:13])([F:14])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)COC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2[nH]ccc12)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(OCC(=O)O)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
(+) or (−)-Methyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate (tr=2.4 min—from Example 35-B) (116 mg, 0.246 mmol) was dissolved in THF (1.2 mL) and MeOH (1.2 mL). A 3N aq. NaOH solution (0.45 mL, 1.35 mmol) was added. The reaction was stirred at 40° C. for 1 hour. At this point the reaction mixture was concentrated. The residue was dissolved in MeOH, and purified with RP-HPLC(HC-A) to provide (−)-2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetic acid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>C1COCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: OCc1cccc(CBr)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: BrCc1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3-(bromomethyl)phenyl)methanol (8.78 g) and 3,4-dihydro-2H-pyran (5.99 mL) in THF (60 mL) was added p-toluenesulfonic acid monohydrate (415 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added an aqueous solution of sodium hydrogen carbonate (367 mg), and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (11.9 g) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH2:38][C@@:39]1([C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:44][C@@H:43]([S:45][C:46]2[NH:50][CH:49]=[N:48][N:47]=2)[C@@H:42]2[C@H:40]1[C@H:41]2[C:51]([O:53][CH2:54][CH3:55])=[O:52].C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:38][C@@:39]1([C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:44][C@@H:43]([S:45][C:46]2[NH:50][CH:49]=[N:48][N:47]=2)[C@@H:42]2[C@H:40]1[C@H:41]2[C:51]([O:53][CH2:54][CH3:55])=[O:52])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](N)(C(=O)OCC)C[C@H]2Sc1nnc[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)CNC(=O)OC(C)(C)C)(C(=O)OCC)C[C@H]2Sc1nnc[nH]1
Reaction time: 0.33 h

Procedure:
Add thionyl chloride (2.5 mL, 34.32 mmol) to a stirred solution of ditert-butyl (1R,2S,4R,5R,6R)-2-(tert-butoxycarbonylamino)-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.1 g, 4.23 mmol) in ethanol (40 mL) at 0-5° C. dropwise over 5 minutes with caution (exothermic reaction). Remove the cooling bath and heat the reaction mixture at reflux temperature for 16 hours. Evaporate the volatiles and dry the residue under high vacuum for 7 hours to obtain a colorless foam of diethyl (1R,2S,4R,5R,6R)-2-amino-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate hydrochloride. Add then 2-(tert-butoxycarbonylamino)acetic acid (0.89 g, 5.07 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.93 g, 5.07 mmol) to a solution of diethyl (1R,2S,4R,5R,6R)-2-amino-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate hydrochloride in anhydrous N,N-dimethylformamide (20 mL) at room temperature then add diisopropylethylamine (2 mL, 11.47 mmol) and stir the resulting yellow solution under nitrogen for 18 hours. Concentrate the solvent and partition the residue between ethyl acetate (40 mL) and a saturated solution of sodium hydrogen carbonate in water (40 mL). Stir the mixture for 20 minutes, separate the layers and extract the aqueous layer with more ethyl acetate (40 mL). Combine the organics layers, dry on sodium sulfate and concentrate to dryness. Purify the residue by flash chromatography eluting with ethyl acetate: iso-hexane (80:20 to 100:0) to give the title compound as a colorless solid (2.42 g, 4.86 mmol). MS (m/z): 498 (M+1), 520 (M+23).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH:9](I)([CH3:11])[CH3:10]>>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH:9]([CH3:11])[CH3:10])[C:4](=[O:8])[CH:3]=1
Reactant: CC(C)I
Reactant: O=c1cc(I)cc[nH]1
Product: CC(C)n1ccc(I)cc1=O

Procedure:
4-iodo-1-isopropylpyridin-2(1H)-one was prepared from 4-iodopyridin-2(1H)-one and isopropyl iodide following a procedure analogous to that described in Example 628 Step 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH:9]1[CH:15](C(OC)=O)[C:16]([O:18]C)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[C:12]([CH3:13])([CH3:14])[CH2:11][CH2:10][CH:9]1[CH2:15][C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C(=O)OC)C1CCC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(CC(=O)O)CCC1(C)C
Temperature: 65 °C
Reaction time: 20 h
Yield: 72.2 %

Procedure:
Dimethyl 2-(1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)malonate (220 mg, 0.7 mmol) was placed in 1:1 THF:MeOH (3 mL). KOH (0.8 mL, 1.7 mmol) was then added, and the reaction heated to 65° C. for 6 hours. The reaction was then cooled to room temperature and concentrated to remove the THF and MeOH. The reaction was then acidified with 6M HCl and then heated to 85° C. overnight to achieve decarboxylation. The reaction was then cooled to room temperature and basicified with solid NaOH until a pH of 14. THF (10 mL) and Boc2O (5 equivalents) were then added. The reaction was stirred for 20 hours at 50° C. and then cooled to room temperature. The reaction was extracted with DCM, and the organic fraction was discarded. The aqueous fraction was then acidified to a pH of 2 with 10% aqueous citric acid and then extracted with DCM. The combined organic fractions were dried, filtered, and concentrated to give the product 2-(1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (130 mg, 75% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14])(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NCCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 97.4 %

Procedure:
A rapidly stirred solution of tert-butyl 2-(2-hydroxyethoxy)ethylcarbamate (47.1 g, 0.230 mol) in 1 L of anhydrous CH2Cl2 was cooled to 0° C. under N2 and treated with triethylamine (48.0 mL, 0.345 mol). Methanesulfonyl chloride (19.6 mL, 0.253 mol) was then added dropwise over 30 min. The reaction mixture was then allowed to warm to room temperature and was stirred an additional 22 h. The reaction was quenched by addition of 500 mL saturated NaHCO3 solution and the organic layer was separated. The organic phase was then washed with H2O (3×500 mL) and brine. The organic portion was dried over Na2SO4 and concentrated to give 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate as a brown oil (63.5 g).
Reaction SMILES: [CH:1]1([N:6]2[CH2:14][C:11]3([CH2:13][CH2:12]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:74][CH:75]1[CH2:80][CH2:79][N:78]([CH3:81])[CH2:77][CH2:76]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:14][C:11]3([CH2:13][CH2:12]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:74][CH:75]5[CH2:80][CH2:79][N:78]([CH3:81])[CH2:77][CH2:76]5)=[O:28])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)cc2)CC1
Reaction time: 0.33 h
Yield: 76.5 %

Procedure:
To a suspension of 0.0275 g (0.0000675 mole) of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-benzoic acid (I-62a) in 3 mL of dimethylformamide was added 0.0157 g (0.000116 mole) of 1-hydroxybenzotriazole, 0.0396 g (0.000104 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate and 0.07 mL (0.000402 mole) of ethyldiisopropylamine. The mixture was stirred for 20 minutes and then 0.0125 g (0.00011 mole) of 4-amino-1-methylpiperidine was added. The mixture was stirred for an additional 2.5 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 1 M sodium hydroxide, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (98:2-80:20) to give 0.026 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-N-(1-methyl-4-piperidinyl)benzamide (I-62).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[C:12](O)[CH:13]=[CH:14][CH:15]=3)[C:10]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)=[C:9]2[C:27]([O:29]CC)=[O:28])=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:9]2[C:27]([OH:29])=[O:28])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2c(O)cccc2C1c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
Ethyl (RS)-1-(4-Fluorophenyl)-3-(3,4-methylene-dioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1-(4-fluorophenyl)-hydroxy-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (45 mg, 0.11 mmol) in CH2Cl2 (3 ml) at 0° C. was added triethylsilane (38 μl, 0.24 mmol), followed by boron trifluoride etherate (121 μl, 0.98 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 15 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (40 mg, 90%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:21])[N:4]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)=O>O>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:21][C:12]2[NH:13][C:14]3[C:19]([C:11]=2[C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1nc(OC)nc(C2C(=O)Nc3c(F)cccc32)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1nc(OC)nc(-c2c(OS(=O)(=O)c3ccc(C)cc3)[nH]c3c(F)cccc23)n1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 23.3 %

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-7-fluoro-1,3-dihydro-2H-indol-2-one (1.15 g), 4-methylbenzenesulfonyl chloride (1.06 g) and sodium carbonate (0.41 g) are introduced as initial charge in 5.5 ml of water and 11 ml of acetone and, with stirring, heated to 80° C. in a preheated oil bath. After 45 minutes, the hot solution is filtered, and the solid is washed with 20 ml of water/acetone (1:1) and methanol and dried in vacuo. This gives 0.76 g of product in an HPLC purity of 97% (42% of theory). Structure elucidation by NMR verifies that it is the O-sulfonylated product. A further 0.41 g of product in an HPLC purity of 89% can be isolated from the filtrate (21% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35]>C1COCC1>[CH3:32][N:33]([CH3:37])[C:34]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)=[O:35]
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2

Procedure:
1-(6-Aminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine, 2a (3 g) was dissolved in THF (50 ml) and triethylamine (2 g) was added. At 5° C. dimethylcarbamoylchloride (1 g) in THF (15 ml) was added dropwise. After completed addition the mixture was refluxed for 1.5 hours. THF was evaporated. Water was added and extraction with dichloromethane (2×50 ml) and work-up as above of the combined organic phases yielded crude title product, which was purified by column chromatography on silica gel (eluted with 4% triethylamine in a 1:1 mixture of ethyl acetate and heptane). The pure title compound 6a crystallized from diethyl ether. Yield: 1.4 g, mp: 141-144° C. 1H NMR (CDCl3): δ 1.65-2.55 (m, 10 H); 2.70 (dd, 1 H); 2.70-2.95 (m, 2 H); 2.95-3.05 (m, 1 H); 3.05 (s, 6 H); 3.15 (broad d, 1 H); 3.35 (qui, 1 H); 6.25 (s, 1 H); 6.95-7.25 (m, 6 H); 7.45 (s, 1 H)
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH:21]=O>>[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][NH:10][C@H:7]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[CH2:8][OH:9]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: NC(CO)c1ccccc1
Product: OC[C@H](NCc1ccc2ccccc2c1)c1ccccc1

Procedure:
Using 1.00 g (7.29 mmol) of (R)-phenylglycinol ((R)-VIII-2) and β-naphthoaldehyde, a similar operation was carried out to obtain (R)-N-(β-naphthyl)methyl-2-phenylglycinol (2.01 g) ((R)-II-3) quantitatively. ##STR317##
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7]2.Br.OS([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][CH:12]=[C:4]([Cl:3])[CH:5]=2)[C:9]1=[O:13]
Reactant: BrBr
Reactant: O=C1CCc2cc(Cl)ccc21
Agent: Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccc(Cl)cc2CC1Br
Reaction time: 2 h

Procedure:
A solution of 37.9 g (0.237 mole) of bromine in 120 ml of glacial acetic acid is slowly added dropwise, whilst stirring, to a solution of 40.0 g (0.237 mole) of 5-chloro-1-indanone in 590 ml of glacial acetic acid, to which 0.2 ml of 48% strength aqueous hydrobromic acid has been added. The mixture is stirred for a further 2 hours and the reaction solution is poured into 1 l of water, to which 2.5 g of NaHSO3 have been added. The product, which initially precipitates in the viscous form, becomes crystalline after stirring for a relatively long time. The crude product is filtered off (melting point 69°-76° C.), washed with water and recrystallized from petroleum ether. The pure 2-bromo-5-chloro-1-indanone melts at 89°-90° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH2:17][CH2:18][Cl:19])[C:13]([O:20][CH3:21])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23].ClC1C2C(=CC3C=C(OC)C(OCCCl)=CC=3C=2)N=CC=1C#N.Cl.N1C=CC=CC=1.[Cl:54][C:55]1[CH:61]=[C:60]([Cl:62])[C:59]([O:63][CH3:64])=[CH:58][C:56]=1[NH2:57].C(OCCO)C>>[Cl:54][C:55]1[CH:61]=[C:60]([Cl:62])[C:59]([O:63][CH3:64])=[CH:58][C:56]=1[NH:57][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH2:17][CH2:18][Cl:19])[C:13]([O:20][CH3:21])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23]
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1OCCCl
Agent: COc1cc2cc3ncc(C#N)c(Cl)c3cc2cc1OCCCl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 135 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A mixture of 1.10 g (3.17 mmol) of 4-chloro-7-methoxy-8-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-chloro-8-methoxy-7-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture), 50 mg of pyridine hydrochloride, 742 mg (3.86 mmol) of 2,4-dichloro-5-methoxyaniline and 25 mL of 2-ethoxyethanol is stirred and heated to 135° C. After 1 hour, the reaction is cooled to room temperature, quenched with 1.0 mL of triethylamine and concentrated in vacuo. The residue is dissolved in 95:5 methylene chloride/methanol and chromatographed on silica gel, eluting with 1:1 hexane/ethyl acetate. The product is precipitated from ethyl acetate to provide 0.760 g (48%) of 4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-(chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-(2,4-dichloro-5-methoxy-anilino)-8-methoxy-7(chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture) as a dull yellow solid, m.p. 239–55° C. dec.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=2[F:21])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1.[NH2:39][O:40][CH2:41][CH2:42][OH:43]>C1COCC1>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:3]2[C:2]([F:1])=[C:10]([F:11])[CH:9]=[CH:8][C:4]=2[C:5]([NH:39][O:40][CH2:41][CH2:42][OH:43])=[O:7])=[C:14]([F:21])[CH:15]=1)#[CH:20]
Reactant: C#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reactant: NOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Product: C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
The product of Example 1, Step C, 3,4-difluoro-2-[(4-ethynyl-2-fluorophenyl)amino]benzoic acid (349 mg, 1.20 mmol) was dissolved in dry THF (15 mL), to which was added carbonyldiimidazole (CDI) (389 mg, 2.40 mmol). Within 10 minutes, a bright yellow solution was obtained and conversion to the imidazolide was confirmed by TLC (50% EtOAc/hexanes). A solution of 2-(aminooxy)ethanol (370 mg, 4.80 mmol) in THF (5 mL) was then added and the mixture stirred for 15 hours at room temperature. The reaction solvent was removed under reduced pressure and the residue partitioned between 1 M HCl (100 mL) and EtOAc (100 mL). The EtOAc layer was then washed with water (100 mL) and saturated NaCl solution (100 mL), dried (Na2SO4), and the solvent removed under reduced pressure to afford an oil which was purified by flash column chromatography on silica gel (50% EtOAc/hexanes) to give 2-[(4-ethynyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a pale yellow solid (232 mg, 55%); m.p. (EtOAc/hexanes) 158-161° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.84 (br s, 1 H), 7.43 (ddd, J=8.8, 5.9, 1.9 Hz, 1 H), 7.34 (dd, J=12.2, 1.9 Hz, 1 H), 7.25 (ddd, J=9.9, 9.0, 7.3 Hz, 1 H), 7.16 (ddd, J=8.3, 1.9, 0.9 Hz, 1 H), 6.79 (ddd, J=9.1, 8.3, 4.9 Hz, 1 H), 4.71 (br s, 1 H), 4.10 (s, 1 H), 3.84 (t, J=5.0 Hz, 2 H), 3.56 (t, J=5.0 Hz, 2 H). Anal. Calcd for C17H13F3N2O3: C, 58.5; H, 4.1; N, 8.0. Found: C, 58.3; H, 3.7; N, 8.0.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].[CH3:16][C:17]1[N:18]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=2)[CH:19]=[CH:20][N:21]=1>>[C:1]([C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:26][C:25]3[CH:24]=[CH:23][C:22]([N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH3:16])=[CH:29][CH:28]=3)[CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Reactant: N#CC1(c2cccc(O)c2)CCOCC1
Product: Cc1nccn1-c1ccc(COc2cccc(C3(C#N)CCOCC3)c2)cc1
Yield: 38 %

Procedure:
4-Cyano-4-(3-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran was reacted with 4-(2-methylimidazol-1-yl)benzylchloride to give the titled compound in 38% yield as colorless needles according to the procedure described in Example 2H.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:32](Br)(Br)([Br:34])[Br:33].C(C1SC(C2SC=CC=2)=CC=1)=O.ClCCl>ClCCl.CCCCCC>[Br:33][C:32]([Br:34])=[CH:1][C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccc(-c2cccs2)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: BrC(Br)=Cc1ccc(-c2cccs2)s1
Reaction time: 1 h

Procedure:
0.55 g of 5-formyl-2,2'-bithiophene was dissolved in 10 ml of dichloromethane. 1.95 g of PPh3 and 1.23 g of CBr4 were dissolved in 40 ml of dichloromethane and mixed with the 5-formyl-2,2'-bithiophene/dichloromethane solution under nitrogen gas atmosphere at 0° C. After the mixture was stirred for 1 hour and 10 ml of n-hexane was added to precipitate the triphenyl-phosphine oxide. And the reaction solution was filtered. Further, 100 ml of n-hexane was then added into the solution and the yellowish solid was obtained. The solid was further purified by column chromatography and crystallized with ethanol. The crystal product was thus obtained and the melting point thereof was 112°-113° C.