Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[CH2:26]([O:33][C:34]1[C:41]([O:42][CH3:43])=[CH:40][C:37]([CH:38]=[O:39])=[C:36]([F:44])[CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>O1CCCC1>[CH2:26]([O:33][C:34]1[C:41]([O:42][CH3:43])=[CH:40][C:37]([CH:38]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)[OH:39])=[C:36]([F:44])[CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1cc(C=O)c(F)cc1OCc1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)c(F)cc1OCc1ccccc1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (635, 620 mg, 1.5 mmol, prepared as described in Example 45) was dissolved in tetrahydrofuran (15 mL) at −20° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 840 μL) was added to the reaction. The reaction was stirred for 1.5 hours, during which the temperature rose to 5° C. The reaction was cooled to −20° C. 4-Benzyloxy-2-fluoro-5-methoxy-benzaldehyde (654, 250 mg, 0.9606 mmol) in tetrahydrofuran (5.0 mL) was added to the reaction. The reaction was stirred for 2.5 hours during which time the temperature rose to 5° C. The reaction was poured into water. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2-25% ethyl acetate in hexane to provide compound as a white solid (655, 501 mg, 63%). MS (ESI) [M+H+]+=535.4.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C1([Li:18])C=CC=CC=1>>[Li:18][CH:5]1[C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1.[Li:18][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: [Li]c1ccccc1
Reactant: Cc1ccc2c(n1)CCCC2
Product: [Li]C1CCCc2ccc(C)nc21
Product: [Li]Cc1ccc2c(n1)CCCC2

Procedure:
Reaction of 2-methyl-5,6,7,8-tetrahydroquinoline with phenyl lithium following the method of Example 1 gave 8-lithio-2-methyl-5,6,7,8-tetrahydroquinoline and 2-lithiomethyl-5,6,7,8-tetrahydroquinoline which were treated in situ with carbon dioxide followed by esterification of the product by refluxing in methanol saturated with dry HCl gas according to the general method described in our copending U.S. Ser. No. 460,265.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]=2[S:9][C:8]=1[CH2:16][CH3:17])=[O:6].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1.[C:35]([O-])(=O)[C:36]([O-])=[O:37]>>[C:36]([N:12]1[CH2:13][CH2:14][C:15]2[C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:30]3[CH2:29][CH2:28][CH:27]([C:24]4[C:23]5[CH:33]=[CH:34][C:20]([F:19])=[CH:21][C:22]=5[O:26][N:25]=4)[CH2:32][CH2:31]3)=[C:8]([CH2:16][CH3:17])[S:9][C:10]=2[CH2:11]1)(=[O:37])[CH3:35]
Reactant: O=C([O-])C(=O)[O-]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CCc1sc2c(c1C(=O)CCCCl)CCNC2
Agent: Cl
Product: CCc1sc2c(c1C(=O)CCCN1CCC(c3noc4cc(F)ccc34)CC1)CCN(C(C)=O)C2

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.5 g of 6-acetyl-3-(4-chlorobutyryl-4,5,6,7-tetrahydro-2-ethylthieno[2,3-c]pyridine and 1.2 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.7 g of 6-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-2-ethylthieno[2,3-c]pyridine as an oil, m.p. 93°-95° C. as oxalate 1/4 hydrate thereof.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[O:10][CH2:11][C:12]#CCO)[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.C(Cl)([Cl:24])=O>C(Cl)CCl.C1C=CC=CC=1>[CH:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([NH:8][C:9]([O:10][C:11]#[C:12][Cl:24])=[O:16])[CH:5]=1
Reactant: O=C(Cl)Cl
Reactant: O=C(Nc1cccc(Cl)c1)OCC#CCO
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Nc1cccc(Cl)c1)OC#CCl
Reaction time: 2 h

Procedure:
To a warm (50°) stirred solution of 4-hydroxy-2-butynyl N-(3-chlorophenyl)carbamate (59.9 g., 0.500 mole) and dimethylformamide (0.6 g) in 150 ml of EDC was added 250 ml of 12.5% phosgene in benzene over a period of about 30 minutes. The reaction mixture was heated at 50° for 4.5 more hours, then at 60° for 2 hours. Evaporation of solvent afforded a quantitative yield of technical barban.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=CC=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].CO[C:36]1[CH:41]=CC(CCO)=C[CH:37]=1.[CH3:45][O:46]C(C1(SC2SC(N)=NC=2)CCCCC1)=O.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:45][O:46][C:26]1[CH:25]=[CH:24][C:19]([CH2:18][CH2:17][N:16]([C@H:27]2[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]3([C:3]([OH:5])=[O:4])[CH2:6][CH2:41][CH2:36][CH2:37][CH2:1]3)=[CH:9][N:10]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)C1(Sc2cnc(N)s2)CCCCC1
Reactant: COc1ccc(CCO)cc1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: COc1ccc(CCN(C(=O)Nc2ncc(SC3(C(=O)O)CCCCC3)s2)[C@H]2CC[C@H](C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl) -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 2-(4-methoxyphenyl)-ethanol and 1-(2-amino-thiazol-5-ylsulfanyl)-cyclohexanecarboxylic acid methyl ester prepared using the procedure for the preparation of 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]2[C:24]=1[O:23][C:22](=[O:25])[CH:21]=[C:20]2[NH:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=1[Cl:34]>>[Cl:34][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([Cl:33])[C:27]=1[NH:26][C:20]1[C:19]2[C:24](=[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:6])[C:16]([O:35][CH3:36])=[CH:17][CH:18]=2)[O:23][C:22](=[O:25])[CH:21]=1
Reactant: CNCCN(C)C
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCN(C)CCN(C)C

Procedure:
The title compound was prepared from N1,N1,N2-trimethylethane-1,2-diamine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 8.57 (s, 2H), 7.85 (d, 1H), 7.05 (d, 1H), 4.23 (br s, 1H), 3.96 (t, 2H), 3.87 (s, 3H), 2.65 (m, 4H), 2.55 (m, 2H), 2.34 (s, 6H), 2.31 (s, 3H), 1.69 (m, 2H), 1.51 (m, 4H); MS (ESI): 523.0.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:22])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=C)[CH:15]=2)[CH:10]([CH3:23])[CH2:9]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.C[N+]1([O-])CC[O:29]CC1.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:22])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[O:29])[CH:15]=2)[CH:10]([CH3:23])[CH2:9]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=Cc1cccc(C2(C)CCN(C(=O)CCCCC)CC2C)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCC(=O)N1CCC(C)(c2cccc(C=O)c2)C(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-hexanoyl-3,4-dimethyl-4-(3-vinylphenyl)piperidine (Preparation 8, 2.4 g, 7.67 mmol) in acetone (20 mL) at room temperature was added water (5 mL), 4-methylmorpholine N-oxide (1.1 g, 9.20 mmol) and finally osmium tetroxide (3.83 mL, 2.5 wt % solution in tert-butanol). The yellow solution was stirred at room temperature for 1 hour and then sodium periodate (4.92 g, 23.0 mmol) was added in one portion. After stirring the reaction for 3 hours a heavy precipitate had developed and the reaction mixture was filtered through Celite®, washing with acetone. The filtrate was concentrated in vacuo, the crude oil was dissolved in dichloromethane, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate:hexane (1:1). The title compound was isolated as clear oil (2.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[CH3:18][O:19][CH2:20][C:21](Cl)=[O:22].O>C(Cl)Cl>[CH3:18][O:19][CH2:20][C:21]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5])=[O:22]
Reactant: CNc1cccc(N)c1C#N
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CNc1cccc(NC(=O)COC)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(methylamino)benzonitrile (3.3 g) in methylene chloride (50 ml) is added pyridine (3.6 ml) and thereto is added dropwise methoxyacetyl chloride (4.2 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethyl acetate-hexane to give the title compound (1.9 g) having the following physical properties.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#C.Br[C:17]1C=C2C(C(C)(C)CCC2=O)=C[CH:18]=1>>[C:17]([C:12]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]2=[O:13])=[CH:4][CH:3]=1)#[CH:18]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Product: C#Cc1ccc2c(c1)C(=O)CCC2(C)C

Procedure:
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound K), 7 g (27.6 mmol) of 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) was converted into the title compound using 39 ml (36.6 mmol) of (trimethylsilyl)acetylene, 0.97 g (1.3 mmol) of bis(triphenylphosphine)palladium(II) chloride, 0.26 g (1.3 mmol) of cuprous iodide and 0.6 g (4.3 mmol) of K2CO3.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[NH:8][C:7](=[O:9])[NH:6][C:5]1=[O:10].[Br:12][CH2:13][CH2:14][N+:15]([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[Br-:12].[CH3:3][C:4]1([CH3:11])[C:5](=[O:10])[N:6]([CH2:13][CH2:14][N+:15]([CH3:18])([CH3:17])[CH3:16])[C:7](=[O:9])[NH:8]1
Reactant: C[N+](C)(C)CCBr
Reactant: CC1(C)NC(=O)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(CC[N+](C)(C)C)C1=O
Product: [Br-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of NaH (60% in mineral oil, 1.75 g) in DMF (25 mL) at 5° C. was added 5,5-dimethyl hydantoin (5 g, 39.0 mmol, 1 eq) and the reaction was stirred for 30 min. Added (2-bromoethyl)trimethylammonium (9.6 g, 39.0 mmol, 1 eq) at that temperature and the reaction was heated to 50° C., while stirring overnight. Reaction was cooled to room temperature and the product crashed out of solution as a white solid, which was cooled to 5° C., filtered and washed with cold DMF (30 mL). Purified by prep-HPLC (gradient from 5% to 95% MeOH in H2O; 20 mL/min flow rate; C18 Restek column) to yield the desired product. Yield: 778 mg (7%). 1H-NMR (400 MHz, D2O) δ 4.005 (t, J=7.6 Hz, 2H), 3.643 (t, J=7.6 Hz, 6H), 3.238 (s, 9H), 1.441 (s, 6H) LCMS—[M] m/z 214.05
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[N:7]N(C=O)[CH2:9][CH:10]=3)[C:5]=2C=1)=[O:2].[CH2:19]([OH:21])[CH3:20].[BH4-].[Na+].CC(C)=O.C[N:29](C=O)C>>[OH:21][CH2:19][C:20]1[CH:9]=[CH:10][C:11]2[C:6](=[C:5]3[C:14](=[CH:13][CH:12]=2)[CH:15]=[CH:16][C:3]([CH2:1][OH:2])=[N:29]3)[N:7]=1
Reactant: O=Cc1ccc2ccc3c(c2c1)=NN(C=O)CC=3
Reactant: CCO
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Product: OCc1ccc2ccc3ccc(CO)nc3c2n1
Temperature: 30 °C
Reaction time: 6 h

Procedure:
To a mixture of 2.0 g of dialdehyde 26 in 40 mL of DMF and 5 Ml of ethanol was added 800 mg of NaBH4. The solution was stirred 6 hours at 30° C. then 5 mL of acetone was added. The solvent was removed under vacuum and the residue recrystallized from 50 mL of H2O to yield 1.7 g of diol (27). 1H NMR (DMSO-d6) 4.7 (s, 4H); 5.45 (broad s, 2H); 7.6 (ABq, 2H); 7.7 (s, 2H); 8.25 (ABq, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:39]N1C(=O)CCC1=O>O.C(Cl)(Cl)Cl>[Br:39][CH2:17][C:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:15][CH:14]=1)=[O:18]
Reactant: CC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)CBr)cc1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a chloroform (7.5 mL) solution of 1-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]ethanone (0.23 g), under ice cooling in a nitrogen atmosphere, 2,6-lutidine (0.17 mL) and trimethylsilyl trifluoromethanesulfonate (0.19 mL) were added, and the resultant was stirred for 30 minutes. Then, N-bromosuccinimide (0.17 g) was added thereto, and the resultant was stirred for 30 minutes under ice cooling. Water was added to the reaction solution, and the resultant was stirred for 10 minutes, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=100/0→75/25) to obtain the title compound (0.26 g) as a colorless oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:5]2[N:4]=1.C(Cl)Cl.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:5]2[N:4]=1)=[O:30]
Reactant: CSc1ncc2ccc(-c3ccccc3O)n2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(-c3ccccc3O)n2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
2-(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenol (1.915 g, 7.442 mmol) and Methylene chloride (50 mL, 800 mmol) were combined in a flask. m-CPBA 70-75% (70:30, m-Chloroperbenzoic acid:3-Chlorobenzoic acid, 1.835 g, 7.444 mmol) was added over 10 minutes. The reaction was stirred at room temperature for 10 minutes. Reaction was concentrated and purified by normal phase silica gel chromatography eluting with ethyl acetate to obtain a brown solid, 2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenol (1.2 g, 60%). LCMS: m/z=274.01 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 9.98 (br s, 1H), 9.29 (s, 1H), 7.80 (m, 1H), 7.46 (d, 1H, J=4.7 Hz), 7.30 (m, 2H), 7.03 (d, 1H, J=8.2 Hz), 6.96 (m, 1H), 2.93 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][OH:5].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(O)(=O)C.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.C(O)(=O)C>[C:12]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:14])[CH3:13]
Reactant: CCCCCCC(C)=CCO
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCC(C)=CCOC(C)=O

Procedure:
156 G. (1 mole) of 3-methyl-2-nonen-1-ol, 122 g. (1.2 moles) of acetic anhydride and 264 ml. of toluene were combined in a reaction flask and heated. The formed acetic acid-toluene azeotropic mixture consisting of 34 parts of acetic acid and 66 parts of toluene and boiling at 105° C. was removed by distillation through a 11/2 ft. Vigreux column. After termination of the reaction, the reaction mass was washed with 100 ml. of aqueous sodium carbonate solution, 100 ml. of aqueous sodium bicarbonate solution, and finally twice with 100 ml. of water. The desired ester, 3-methyl-2-nonen-1-yl-acetate, having a b.p. of 119°-121° C. at 10 mm. and an R.I. at 20°:1.445, was recovered by fractional distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:26][CH:27]1[CH2:31][CH2:30][CH:29]([CH3:32])[NH:28]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:28]1[CH:29]([CH3:32])[CH2:30][CH2:31][CH:27]1[CH3:26])=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC1CCC(C)N1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2C(C)CCC2C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 2,5-dimethylpyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.53 minutes; C23H24Cl2N4O2 (459.38); mass spectrum: (N−H)−=458/460/462 (chlorine isotope).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:11]C(=O)C)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.CN(C)C1C=CC=CC=1>CC(C)=O>[OH:11][C:4]1[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][C:5]=1[C:6]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:8]
Reactant: CC(=O)Oc1cc(C)ccc1C(=O)O
Reactant: COc1ccc(N)cc1
Solvent: CN(C)c1ccccc1
Solvent: CC(C)=O
Product: COc1ccc(NC(=O)c2ccc(C)cc2O)cc1
Yield: 80 %

Procedure:
4-Methyl-acetylsalicylic acid (5 g.) was converted to its acid chloride by a conventional method and dissolved in acetone (200 ml.). Then p-anisidine (3.2 g.) and dimethylaniline (3.1 g.) were dissolved in acetone (100 ml.) and the above acid chloride solution was added by drops while cooling and mixing; agitation was maintained for 1 to 2 hours. Then the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and treated as in the similar method of Example 5 to give 2-hydroxy-4-methyl-4'-methoxybenzanilide (5.3 g.). Yield: 80%, melting point: 185°-186° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:12]([CH2:18][O:19]C(=O)C)[O:11][C@H:7]([S:8][CH2:9][CH3:10])[C@H:6]1[N:23]=[N+:24]=[N-:25])(=[O:3])[CH3:2].CC(O)=O.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CO>[C:1]([O:4][C@H:5]1[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:12]([CH2:18][O:19][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[O:11][C@H:7]([S:8][CH2:9][CH3:10])[C@H:6]1[N:23]=[N+:24]=[N-:25])(=[O:3])[CH3:2]
Reactant: CCS[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1N=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CC(=O)O
Solvent: CO
Product: CCS[C@H]1O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of 22 (3.71 g, 9.88 mmol) in MeOH (30 mL) NaOMe (1 M) was added. The mixture was neutralized with AcOH after 1 h and concentrated. The dry residue was dissolved in pyridine (15 mL) and tert-butyldimethylsilyl chloride (1.94 g, 12.87 mmol) was added. The reaction mixture was stirred at rt overnight. Acetylation with acetic anhydride, dilution with toluene, filtration (silica), concentration and purification by chromatography (1:0→1:1 toluene-EtOAc) gave 23 (4.357 g, 9.73 mmol, 99%); [α]D+109° (c 1.0, CHCl3); 13C NMR δ −5.33, −5.28 (CH3Si), 14.7 (SCH2CH3), 18.4 ((CH3)3CSi), 20.7, 20.9 (CH3CO), 25.0 (SCH2CH3), 25.9 ((CH3)3CSi), 62.6, 62.9, 67.0, 71.7, 71.9 (C-2-6), 81.5 (C-1), 169.7, 170.1 (CH3CO); 1H NMR δ 0.05 (s, 3H), 0.05 (s, 3H), 0.90 (s, 9H), 1.30 (t, 3H), 2.05 (s, 3H), 2.10 (s, 3H), 2.55-2.75 (m, 2H), 3.60-3.75 (m, 2H), 4.10 (m, 1H), 4.15-4.20 (m, 1H), 5.20-5.25 (m, 1H), 5.30-5.35 (m, 1H); HRMS calcd for C18H33N3NaO6SSi [M+Na]+ 470.1757, found 470.1750.
Reaction SMILES: [H-].[Na+].[C:3]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17](=[O:20])[CH2:16]2)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:21](=O)([O:25]CC)[O:22][CH2:23][CH3:24]>CN(C)C=O>[C:3]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17](=[O:20])[CH:16]2[C:21]([O:22][CH2:23][CH3:24])=[O:25])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1Cc2cccc(C(=O)c3ccccc3)c2N1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Reaction time: 0.17 h

Procedure:
To a slurry of 365 mg. of sodium hydride in 8 ml. of dimethylformamide at 0° C. was gradually added 1.0 g. (4.22 mmoles) of 7-benzoyloxindole, and the mixture allowed to stir for 10 minutes in an ice bath. Diethyl carbonate (1.53 g., 12.7 mmoles) was added and the reaction mixture allowed to stir at ice bath temperatures for 3 hours. The mixture was then poured into 200 ml. of ice and water and the resulting precipitate filtered, washed with water and vacuum dried, 940 mg. The crude product was slurried in diethyl ether, filtered and the filtrate extracted with 0.1N aqueous sodium hydroxide solution. The base layer was separated and acidified with hydrochloric acid. The resulting precipitate was filtered and dried, 109 mg., m.p. 134° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[F:44][C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][C:46]=1[CH2:52][CH2:53][O:54][CH2:55][C:56]([NH2:58])=[NH:57]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:58][C:56](=[NH:57])[CH2:55][O:54][CH2:53][CH2:52][C:46]1[CH:47]=[C:48]([F:51])[CH:49]=[CH:50][C:45]=1[F:44])=[O:6]
Reactant: N=C(N)COCCc1cc(F)ccc1F
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(COCCc1cc(F)ccc1F)NC(=O)c1cc(Cl)cnc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.2 %

Procedure:
2,5-Dichloronicotinic acid (50 mg, 260 μmol), TBTU (88 mg, 273 μmol) and DIPEA (130 μl, 781 μmol) were added to a solution of 2-[2-(2,5-difluoro-phenyl)-ethoxy]-acetamidine hydrochloride (65 mg, 260 μmol) in DMF (1 ml). The solution was stirred for 72 h at ambient temperature and poured onto ice water/dichloromethane 1/1. The layers were separated, the aqueous layer was extracted two times with dichloromethane, the combined extracts were washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure yielded 2,5-dichloro-N-{2-[2-(2,5-difluoro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide (97 mg, 250 μmol; 96%) as orange oil which was used in the next step without further purification. MS: m/e=388.2 [M+H+].