Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[I-].[Na+].C(N(CC)CC)C.C(Br)[CH:24]=[CH:25][C:26]1[CH:31]=CC=C[CH:27]=1>CS(C)=O>[CH3:27][C:26]([CH3:31])=[CH:25][CH2:24][C:11]1[C:10](=[O:12])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3](=[O:13])[C:2]=1[OH:1]
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: BrCC=Cc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)=CCC1=C(O)C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a solution of 20 gram (0.11 moles) of 2-hydroxy-1,4-naphthoquinone in 200 ml of DMSO, 16.5 grams (0.11 moles) of sodium iodide, 15.3 ml (0.11 moles) of triethylamine and 23.8 grams (0.12 moles) of cinnamyl bromide were added. The mixture was vigorously stirred at 50° C. overnight, and then cooled by addition of 400 ml of ice water, and the resulting mixture was extracted with 300 ml of toluene twice. The combined organic phase was washed successively with 500 ml of water, and 400 ml of 2N sodium hydroxide twice, and 500 ml of water. The organic phase was dried with sodium sulfate and evaporated to dryness. The crude product 2-2 (R1=H, R4=H, R7=C6H5) residue was dissolved in 200 ml of anhydrous ethanol and refluxed for 3 hours. After evaporation, the residue was dissolved in 200 ml of toluene, and extracted with 200 ml of 2N sodium hydroxide twice. The combined extract was neutralized by addition of concentrated hydrochloric acid to pH 3-5, and extracted with 300 ml of dichloromethane. The dichloromethane solution was washed with equal volume of water, and dried with sodium sulfate, and then evaporated to yield crude lapachol analog 2-3 (R1=H, R4=H, R7=C6H5). To 2 grams of crude 2-3 (R1=H, R4=H, R7=C6H5), 20 ml of sulfuric acid was added, and the resulting mixture was placed at room temperature for 1 hour. The sulfuric acid mixture was poured into 200 ml of water and extracted with 200 ml of dichloromethane twice to give crude dunione analog 2-4 (R1=H, R4=H, R7=C6H5) which was then purified with silica gel chromatograph. Treatment of 2-4 (R1=H, R4=H, R7=C6H5) with N-bromosuccinimide and lead (IV) acetate was performed according to the procedure described in example 9 to give crude 2-5 (R1=H, R4=H, R7=C6H5). Without silica gel chromatograph, the crude 2-5 (R1=H, R4=H, R7=C6H5) was directly dissolved in 200 ml ethanol/concentrated HCl (1:1) and refluxed for 1 hour to give crude 2-6 (R1=H, R4=H, R7=C6H5) which was purified with silica gel chromatograph. Overall yield 10%. 2-methyl-3-phenyl-4H,9H-naphtho[2,3-b]furan-4,9-dione 2-6 (R1=H, R4=H, R7=C6H5) 1H NMR (in CDCl3) δ 2.51 (s, 3H), 7.42-7.50 (m, 5H), 7.71-7.74 (m, 2H), 8.10-8.13 (m, 1H), 8.21-8.23 (m, 1H).
Reaction SMILES: [I-].[N:2]1([C:12]([N:14]2[CH:18]=[CH:17][N+](C)=[CH:15]2)=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.ClCCl.N1CC[CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25]C1>C(N(CC)CC)C>[N:2]1([C:12]([N:14]2[CH2:15][CH2:25][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:17][CH2:18]2)=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)N2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
16.5 g of 1-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)-3-methyl-1H-imidazol-3-ium iodide, 224 ml of dichloromethane and 8.45 g of ethyl isonipecotate, followed by 31.22 ml of triethylamine, are introduced into a 500 ml round-bottomed flask. The reaction medium is stirred at ambient temperature for 20 hours. The solvent is evaporated under reduced pressure and the residue is taken up in ethyl acetate and then washed with water. The organic phase is dried over sodium sulfate and the solvent is evaporated under reduced pressure to result in 15.2 g of ethyl 1-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)piperidine-4-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:14]([S:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[CH:23][S:24][C:17]=34)=[CH:13][N:12]=[C:11]([NH:25][C:26]3[S:27][CH:28]=[C:29]([CH:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)[N:30]=3)[CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:44]>ClCCl>[ClH:44].[ClH:44].[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:14]([S:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[CH:23][S:24][C:17]=34)=[CH:13][N:12]=[C:11]([NH:25][C:26]3[S:27][CH:28]=[C:29]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[N:30]=3)[CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1Oc1cc(Nc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)cs2)ncc1Sc1ccnc2ccsc12
Agent: Cl
Solvent: ClCCl
Product: Cc1ncccc1Oc1cc(Nc2nc(C3CCNCC3)cs2)ncc1Sc1ccnc2ccsc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
tert-Butyl 4-(2-(4-(2-methylpyridin-3-yloxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate (0.14 g, 0.22 mmol was dissolved in dichloromethane (2 mL) and charged with HCl (2N in diethyl ether, 3 mL). After stirring at ambient temperature for 2 hours, the solution was concentrated and dried under high vacuum to give the title compound (0.10 g, 75% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)[CH2:38][O:37][CH2:36]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1.Br[C:60]1N=C(C(=O)NCC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(O)OCC)=CC=3OC)N=2)=CC=1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH2:10][CH3:60])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:21])([F:20])[F:22])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:50])([CH3:51])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)[CH2:38][O:37][CH2:36]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Reactant: CCNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CP(=O)(O)OCC)cc2OC)ncc1C(F)(F)F
Product: CCNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CP(=O)(OCC)OCC3(Cn4cc(B5OC(C)(C)C(C)(C)O5)cn4)COC3)cc2OC)ncc1C(F)(F)F
Yield: 34 %

Procedure:
Racemic Compound 45A was prepared analogously to Compound 44A using ethyl hydrogen (4-{[4-{[6-bromo-2-(ethylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 45B, 78.1 mg, 0.123 mmol) to afford 37.7 mg of the title compound (34%). MS (ESI): m/z=909.40/991.51 [M+H]+. UPLC: tR=1.60 min (UPLC-TOF: polar—2 min).
Reaction SMILES: CS[CH2:3][N:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]#[C:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[N:12]=[C:11]2[CH3:24])=[CH:6][C:5]1=[O:25].S([O-])(O[O-])(=O)=O.[K+].[K+]>CO>[CH3:3][N:4]([CH3:9])[C:5](=[O:25])[CH2:3][N:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]#[C:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[N:12]=[C:11]2[CH3:24])=[CH:6][C:5]1=[O:25]
Reactant: CSCn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cccc(C#Cc2cn(-c3ccn(CC(=O)N(C)C)c(=O)c3)c(C)n2)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 152.6 %

Procedure:
To a solution of 15 mg (0.042 mmol) of 1-methylsulfanylmethyl-4-(2-methyl-4-m-tolylethynyl-imidazol-1-yl)-1H-pyridin-2-one in 0.6 ml of methanol were added 53 mg (0.09 mmol) of potassium peroxymonosulfate (Oxone). The mixture was then stirred for 3 h at 40° C. The solution was evaporated to dryness and worked up with methylene chloride/water. The crude material was purified by flash chromatography (SiO2, gradient ethyl acetate to ethyl acetate:methanol 90:10 v/v) to yield 12 mg of the title compound as a white solid, MS: 382.2 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([F:28])[CH:22]=1)=[O:17]>>[CH:11]1([CH2:10][S:9][C:4]2[C:3]([CH2:2][O:27][C:24]3[CH:25]=[CH:26][C:21]([CH:19]4[CH2:20][CH:18]4[C:16]([OH:17])=[O:15])=[CH:22][C:23]=3[F:28])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12]1
Reactant: ClCc1cccnc1SCC1CC1
Reactant: COC(=O)C1CC1c1ccc(O)c(F)c1
Product: O=C(O)C1CC1c1ccc(OCc2cccnc2SCC2CC2)c(F)c1
Yield: 95 %

Procedure:
3-Chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (0.026 g, 0.12 mmol) obtained in Step C of Preparation Example 18 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.025 g, 0.12 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.042 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.CN([CH:13]=[O:14])C.C([Li])CCC.C(NC(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:13]=[O:14])=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(F)cc(Br)cc1F
Yield: 58.9 %

Procedure:
Using analogous reaction condition and reagents as described in Example 20 for the preparation of I-20a above, 1-bromo-3,5-difluoro-benzene (2 g, 2.10.36 mmol) in THF was reacted with DMF (1.43 g, 19.68 mmol), n-butyl lithium (1.56 ml, 12.4 mmol) and diisopropyl amine (0.57 mL, 15.5 mmol) to afford crude product. Purification by column chromatography on silica gel (2% ethyl acetate in hexane) afforded 1.35 g of the product (61% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:16](OCC)(OCC)([O:19][CH2:20][CH3:21])[CH2:17][CH3:18]>>[CH2:20]([O:19][C:16]1([CH2:17][CH3:18])[NH:1][C:2]2[N:3]=[C:4]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:5][C:6]=2[C:7](=[O:8])[NH:9]1)[CH3:21]
Reactant: CCOC(CC)(OCC)OCC
Reactant: NC(=O)c1sc(N2CCOCC2)nc1N
Product: CCOC1(CC)NC(=O)c2sc(N3CCOCC3)nc2N1

Procedure:
The title compound was prepared from 4-amino-2-(morpholin-4-yl)-1,3-thiazole-5-carboxamide and triethyl orthopropionate according to Method G and was isolated as a white solid (39%) after purification by preparative HPLC. δH (DMSO-d6) 7.26 (1H, br. s), 7.06 (1H, br. s), 4.19 (2H, q, J 7.0 Hz), 3.74-3.66 (4H, m), 3.46-3.36 (4H, m), 2.55-2.47 (2H, m), 1.29 (3H, t, J 7.0 Hz), 1.10 (3H, t, J 7.5 Hz). LCMS (ES+) 313.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30](I)=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34](#[N:37])[CH:35]=[CH2:36]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30](/[CH:36]=[CH:35]\[C:34]#[N:37])=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC#N
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(/C=C\C#N)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Yield: 19 %

Procedure:
Using methods substantially equivalent to those described in Example 259-A, 2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-iodobenzamide was condensed with acrylonitrile. From the reaction mixture was isolated (Z)-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)benzamide (0.19 g, 19%), as well as the (E)-isomer (see prior example).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].CO>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Yield: 90.7 %

Procedure:
To a solution of p-bromobenzyl alcohol (5.0 g, 26.7 mmol) in DMF (10 mL) was added imidazole (4.54 g, 66.7 mmol) followed by addition of tert-butyldimethylsilyl chloride (6.01 g, 40 mmol). The progress of the reaction was monitored by TLC. When the reaction was complete (about 2 h), methanol was added and diluted by 20% ethyl acetate in hexane. The organic layer was washed several times with water and then with brine, dried, concentrated under reduced pressure to give 7.5 g of the crude product which was passed through a short column chromatography to give 7.3 g (91%) of the desired compound.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>CO>[C:4]1([CH:7]([C:8]([OH:10])=[O:9])[NH:11][C:21](=[O:22])[C:20]([F:27])([F:26])[F:19])[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC(C(=O)O)c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)C(NC(=O)C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42 %

Procedure:
A mixture of DL-phenylglycine (15.1 g, 0.10 mol) in methanol is treated with triethylamine (10.1 g, 0.10 mol) and ethyl trifluoroacetate (17.8 g, 0.125 mol), stirred at room temperature for 72 hours, diluted with methanol and treated with Dowex 50× acidic resin. The reaction mixture is stirred for 10 minutes and filtered. The filtrate is concentrated in vacuo to give a pale yellow solid which is recrystallized from 1,2-dichloroethane to give the title product as white needles, 10.5 g (42% yield), mp 155-157° C.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]2C(O)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:46]([O:52][CH2:53][CH3:54])(=[O:51])[CH2:47][C:48]([O-])=[O:49].[K+].[Cl-].[Mg+2].[Cl-]>O1CCCC1.C(#N)C.C(N(CC)CC)C>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]2[C:48](=[O:49])[CH2:47][C:46]([O:52][CH2:53][CH3:54])=[O:51])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1-c1cccc2c1cc(C(=O)O)n2CCCOc1cccc2ccccc12
Reactant: CCOC(=O)CC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1-(3-(naphthalen-1-yloxy)propyl)-4-o-tolyl-1H-indole-2-carboxylic acid (EXAMPLE 103) (536 mg) and 1,1′-carbonyldiimidazole (200 mg) in tetrahydrofuran (10 ml) was stirred at room temperature. overnight. To a suspension of potassium ethyl malonate (419 mg) in acetonitrile (10 ml) and triethylamine (0.515 ml) was added magnesium chloride (300 mg) and the mixture was stirred at room temperature for 4 hours then cooled in an ice bath. The above-prepared solution was added dropwise to the first solution, and the resultant suspension was stirred at room temperature for three days. After this time the solvent was removed in vacuo, the residue was taken up in toluene (50 ml), cooled (ice bath), and aqueousHCl (12%) was slowly added. The mixture was warmed to room temperature and extracted twice with ethyl acetate. The combined layers were washed with aqueous NaHCO3, and brine and dried over Na2SO4. After concentration of the solvent, the residue was loaded on a column and eluted with 5% ethyl acetate in hexane to give the title compound.
Reaction SMILES: CO[N:3]([CH3:21])[C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[C:19]#[N:20])=O.[CH3:22]NC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:22][N:3]([CH2:4][CH:6]1[CH2:8][CH:7]1[CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[C:19]#[N:20])[CH3:21]
Reactant: CON(C)C(=O)C1CC1Cc1ccc2[nH]cc(C#N)c2c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN(C)CC1CC1Cc1ccc2[nH]cc(C#N)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A solution of 2-(3-cyano-1H-indol-5-ylmethyl)-cyclopropanecarboxylic acid methoxy-methyl-amide (0.029 g, 0.13 mmol), dimethylamine (0.7 ml, 1.4 mmol, 2M/THF), and methyl alcohol (5 ml) was treated with sodium triacetoxyborohydride (0.28 g, 1.13 mmol) and stirred at ambient temperature for 1 h. The solution was concentrated in vacuo and the residue applied directly to a silica gel column and eluted with chloroform, methyl alcohol, triethylamine 95:5:0.1 to afford 5-(2-Dimethylaminomethyl-cyclopropylmethyl)-1H-indol-3-carbonitrile (23 mg, 69%) as a light salmon colored solid. 1H-NMR (400 MHz, CDCl3) 8.88 (1H, br s), 7.66 (2H, dd, J=19.4, 2.3 Hz), 7.33 (1H, d, J=8.4 Hz), 7.18 (1H, dd, J=8.4, 1.5 Hz), 2.72 (2H, m), 2.25 (6H, s), 2.24 (2H, m), 0.88 (2H, m), 0.53 (1H, m), 0.45 (1H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:19][CH2:20][C@H:21]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:39]([O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][CH2:54]Br)=[CH:49][CH:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C)C=O>[CH2:39]([O:46][C:47]1[CH:48]=[CH:49][C:50]([CH2:53][CH2:54][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:19][CH2:20][C@H:21]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[CH:51][CH:52]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: BrCCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(CCc1ccc(OCc2ccccc2)cc1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
To a solution of 1.11 g di-tert-butyl (5S)-2-(benzyloxycarbonyl)-5-[(tert-butoxycarbonyl)-amino]hexanedioate (2.19 mmol; see example 12f) in N,N-dimethyl formamide (30 mL) was added under argon atmosphere 96 mg of sodium hydride (60% in oil, 2.40 mmol), and the mixture was stirred for 30 min at room temperature. Subsequently, a solution of 700 mg of 1-(benzyloxy)-4-(2-bromoethyl)benzene (2.40 mmol) in N,N-dimethyl formamide (15 mL) was added, an the mixture was stirred at 60° C. for 3 hours. The mixture was concentrated in vacuo, partitioned between water and ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by preparative HPLC (Method A) to give 413 mg of the target compound in approx. 90% purity (26% purity adjusted yield).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCBr
Reactant: O=C(O)c1ccc(-c2ccc(O)c(F)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1F
Yield: 86.2 %

Procedure:
To 75 ml of an aqueous solution of 13% potassium hydroxide were added 120 ml of ethanol and 10 g (43.1 mmol) of the above 3'-fluoro-4'-hydroxybiphenyl-4-carboxylic acid, which were refluxed for 30 minutes and added with 25.0 g (129 mmol) of 1-bromooctane and then refluxed for 15 hours. After the air cooling, the precipitated crystal was filtered and recrystallized with acetic acid containing 5% hydrochloric acid and further with acetic acid to obtain 12.8 g (yield: 86.4%) of 3'-fluoro-4'-octyloxybiphenyl-4-carboxylic acid. This compound had the following properties:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9]N1C(=O)CCC1=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][Cl:9])=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=C1CCC(=O)N1Cl
Product: Fc1ccc(SCl)cc1
Yield: 75.7 %

Procedure:
Employing the procedure of Example 13, p-fluorothiophenol (5.0 g., 39 mmoles) and N-chlorosuccinimide (5.2 g., 39 mmoles) were reacted to form p-fluorobenzenesulfenyl chloride (4.8 g., oil).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:8](=[O:14])[CH2:7][CH2:6]2.C([O:19][N:20]=O)CCC.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:8](=[O:14])[C:7](=[N:20][OH:19])[CH2:6]2
Reactant: COc1cc2c(c(OC)c1)C(=O)CC2
Reactant: CCCCON=O
Agent: Cl
Solvent: CO
Product: COc1cc2c(c(OC)c1)C(=O)C(=NO)C2
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 5,7-Dimethoxy-indan-1-one (8.7 g, 45.26 mmol) in the methanol (80 ml) was added n-butylnitrite (6.13 ml, 49.78 mmol) followed by concentrated HCl (4.4 ml). The solution was stirred at 40° C. for one hour during which time a precipitate was formed. The precipitate was collected and dried to yield product as a yellow solid (10 g, 99%). LC-MS: m/e 222 (MH+).
Reaction SMILES: [H-].[Li+].[N:3]1[CH:8]=C[CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].ClC1N=C(Cl)C(C)=C[N:14]=1.O>C1COCC1>[N:11]1[CH:10]=[CH:9][C:4]([CH2:5][C:6]#[N:14])=[N:3][CH:8]=1
Reactant: N#CCc1ccccn1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCc1ccncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of LiH (404 mg, 50.79 mmol) in anhydrous THF (10 mL), was added dropwise a solution of 2-pyridylacetonitrile (3 g, 25.39 mmol) in anhydrous THF (10 mL). The reaction mixture was stirred at zero degree for 1 hour. A solution of 2,4-dichloro-5-methyl-pyrimidine (4.55 g, 27.93 mmol), dissolved in anhydrous THF (5 ml), was added dropwise at zero degree. The reaction mixture was stirred and heated to reflux for 14 hours. The reaction mixture was allowed to warm to r.t. and water was added (20 mL). THF was evaporated under vacuum and a solution of 1N HCl (20 mL) was added. The precipitate was filtered and washed with water (10 mL) and cyclohexanes (10 mL) to give a yellow solid which was dried under vacuum at 40 degrees. The yellow crystalline product 4-pyrimidineacetonitrile, 2-chloro-5-methyl-alpha-2(1H)-pyridinylidene was isolated. (5.5 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:16](OCC)(=[O:22])[C:17](OCC)=[O:18]>>[Cl:15][C:13]1[CH:14]=[C:2]2[C:3](=[CH:11][CH:12]=1)[N:4]([CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)[C:17](=[O:18])[C:16](=[O:22])[NH:1]2
Reactant: Nc1cc(Cl)ccc1NC1CCCCC1
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cc(Cl)ccc2n(C2CCCCC2)c1=O
Yield: 63 %

Procedure:
34.5 g (0.15 mol) of 2-amino-4-chloro-N-cyclohexylaniline were refluxed in 500 ml of diethyl oxalate for 4 h. After cooling, the precipitate was filtered off with suction, washed with n-pentane and dried to yield 26.8 g (63%) of the product. Melting point 265°-266° C.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[C:7]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1.[Li+].[OH-]>>[C:17]1([S:16][C:7]2[C:6]([CH:5]=[CH:4][C:3]([OH:23])=[O:2])=[CH:11][CH:10]=[C:9]([C:12]([F:14])([F:15])[F:13])[N:8]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C=Cc1ccc(C(F)(F)F)nc1Sc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Sc1ccccc1
Yield: 82.1 %

Procedure:
3-(2-phenylthio-6-trifluoromethyl-pyridin-3-yl)-acrylic acid methyl ester (80 mg) was hydrolyzed with 1 M LiOH solution (3 mmol) at room temperature to yield the title compound (63 mg)