Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:10]([O:12]C)=[O:11])[CH:4]=[N:3]1.[OH-].[Na+]>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=2)[C:10]([OH:12])=[O:11])[CH:4]=[N:3]1
Reactant: COC(=O)c1cc(-c2cnn(C)c2)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(-c2cc(C(=O)O)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)benzoate (Int-5, 22.3 g, 78.5 mmol) in methanol (375 mL), was added 1 N NaOH solution (314 mL, 314 mmol). The reaction was stirred at room temperature for 2 h. The methanol was removed by concentration under reduced pressure and the resulting aqueous mixture was acidified to pH 2 with 1 N HCl. The product was isolated by suction filtration, washed with water and hexane and dried under vacuum to provide 3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)benzoic acid as a white solid (Int-6, 20.3 g, 95.7%). LC-MS: (FA) ES+ 271, ES-269; 1H NMR (400 MHz, d6-DMSO) δ ppm 13.53 (s, 1H), 8.44 (s, 1H), 8.33 (s, 1H), 8.16 (s, 1H), 8.09 (d, J=0.7 Hz, 1H), 7.95 (s, 1H), 3.87 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([CH3:37])[C:27]=1[N:28]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[N:29]1)[O:5][C@H:6]([C:10]1[CH:24]=[CH:23][C:13]([C:14]([NH:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[O:15])=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([CH3:37])[C:27]=1[N:28]1[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[N:29]1)[O:5][C@H:6]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:23][CH:24]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To the solution from step 5 was added methanol (40 mL), water (54 mL) and sodium hydroxide (4.34 g, 108 mmol). The reaction was stirred 1 h at 30° C. The solution was acidified with conc. HCl (9.33 mL) and the aq. phase split. The organic solution was washed with 1 N HCl (40 mL). The organic phase was concentrated and the residue taken up in acetonitrile (300 mL). The solution was cooled to 0° C. and stirred 5 h. The solid product was filtered and washed with cold acetonitrile, giving the desired compound as a white solid (14.6 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ: 7.88 (s, 1H), 7.72 (d, J=8.3 Hz, 2H), 7.65 (s, 1H), 7.38 (d, J=8.3 Hz, 2H), 6.89 (t, J=6.2 Hz, 1H), 6.55 (s, 2H), 5.15 (dd, J=7.8, 4.6 Hz, 1H), 3.68 (q, J=6.2 Hz, 2H), 2.65 (t, J=6.2 Hz, 2H), 1.95 (m, 1H), 1.86 (s, 6H), 1.78 (m, 1H), 1.55-1.38 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). The final compound was recrystallized from acetonitrile (5 vol). The compound was heated to 80° C. and then cooled to 0° C. to provide a purity of 99.01%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:26](=[O:29])[CH2:27][CH3:28])[CH:13]=[C:14]([O:16]CC4C=CC(OC)=CC=4)[CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:26](=[O:29])[CH2:27][CH3:28])[CH:13]=[C:14]([OH:16])[CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCC(=O)c1cc(OCc2ccc(OC)cc2)cc(-c2ccc3c(c2)OCO3)c1
Solvent: CC(=O)O
Product: CCC(=O)c1cc(O)cc(-c2ccc3c(c2)OCO3)c1
Temperature: 100 °C
Yield: 30.5 %

Procedure:
1-[3-Benzo[1,3]dioxol-5-yl-5-(4-methoxy-benzyloxy)-phenyl]-propan-1-one (135 mg) was dissolved in glacial acetic acid (2 mL) and heated at 100° C. for 2 days. The solvent was removed under reduced pressure and the residue was purified on a silica gel column using ethyl acetate and hexanes to yield 28.5 mg of the title compound (30% yield). HRMS calcd for C16H14O4 [M+H]+ 271.0965, observed 271.0964.
Reaction SMILES: [N+:1]([C:4]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2)([O-])=[O:2].[N:14]#[C:15][NH2:16].[CH]Cl.[OH-].[Na+]>O>[N+:1]1([O-:2])[C:4]2[C:5]3[CH2:6][CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11][C:12]=2[N:13]=[C:15]([NH2:16])[N:14]=1
Reactant: Nc1ccc2c(c1[N+](=O)[O-])CCC2
Reactant: N#CN
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2ccc3c(c2[n+]([O-])n1)CCC3
Temperature: 50 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
A mixture of 4-nitro-5-indanamine (3) (0.67 g, 3.8 mmol) and cyanamide (0.63 g, 15.0 mmol) were mixed together at 100° C., cooled to 50° C., cHCl (5 mL) added carefully and the mixture heated at 100° C. for 4 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (100 mL), filtered, washed with water (3×20 mL), washed with ether (3×5 mL) and dried. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give amine 4 (279 mg, 37%) as a yellow powder: mp (MeOH/DCM) 270-274° C.; 1H NMR [(CD3)2SO] δ 7.56 (d, J=8.4 Hz, 1H, H-6), 7.31 (d, J=8.4 Hz, 1H, H-5), 6.79 (br s, 2H, NH2), 3.55 (br t, J=7.5 Hz, 2H, H-9), 2.95 (br t, J=7.7 Hz, 2H, H-7), 2.09-2.20 (m, 2H, H-8); 13C NMR [(CD3)2SO] δ 159.4, 148.7, 140.9, 136.0, 131.6, 128.1, 123.9, 34.6, 32.1, 24.1. Anal. calcd for C10H10N4O: C, 59.4; H, 5.0; N, 27.7. Found: C, 59.5; H, 5.0; N, 27.7%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8]COC)[CH:5]=[C:4]([O:12]COC)[C:3]=1[C:16](=[O:29])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]COC)=[CH:21][CH:20]=1.Cl.C(O)C>CO>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:12])[C:3]=1[C:16](=[O:29])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1
Reactant: COCOc1ccc(CCC(=O)c2c(O)cc(OCOC)cc2OCOC)cc1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: O=C(CCc1ccc(O)cc1)c1c(O)cc(O)cc1O
Temperature: 0 °C
Yield: 64.4 %

Procedure:
Then, 5.94 g of 1-[2-hydroxy-4,6-bis(methoxymethoxy)phenyl]-3-(4-methoxymethoxyphenyl)-1-propanone was stirred with 87 ml of methanol and 52 ml of a hydrochloric acid/ethanol reagent at 60° C. for 35 minutes. Then, the reaction mixture was poured into ice water and the precipitated crystal was recovered by filtration and dried. The crystal was subjected to the column chromatography [330 g of 270-400 mesh Kieselgel 60; 0.5 kg/cm2 ; eluting solvent=hexane/ethyl acetate (2/1)]. Fractions of 50 ml were collected and the 11th to 42nd fractions were combined to obtain 2.58 g (yield=64.4%) of 1-(2,4,6-trihydroxyphenyl)-3-(4-hydroxyphenyl)-1-propanone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:11]=1[C:12]([O:14]C)=O)=[O:8])[CH3:2].CC([O-])(C)C.[K+].O.Cl>C1COCC1>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][C:7](=[O:8])[NH:9][C:10]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:11]=2[C:12]1=[O:14])=[O:21])[CH3:2]
Reactant: CCOC(=O)CCC(=O)Nc1ccc(I)cc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CC(=O)Nc2ccc(I)cc2C1=O
Reaction time: 2.5 h

Procedure:
To a solution of methyl 2-(4-ethoxy-4-oxobutanamido)-5-iodobenzoate (ii-a) (22.0 g, 54 mmol) in 125 mL of THF was added a 1 M solution of KOt-Bu in THF (119 mL, 119 mmol). The reaction was complete after 2.5 h at 22° C. H2O (250 mL) and 1N HCl (60 mL) were added to the solution, and the resulting precipitate was filtered, washed with 2×50 mL Et2O, and dried in vacuo to give iii-a (16.1 g, 83%) as a whitish/gray solid as a mixture of ethyl and methyl esters: MS m/z=374 (M+H) and 360 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)[C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[CH2:31]Br)=[CH:24][CH:23]=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[CH:28]([C:25]2[CH:24]=[CH:23][C:22]([OH:21])=[CH:27][CH:26]=2)[C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)[CH2:10][CH2:9]1
Reactant: Oc1ccc(C(c2ccc(O)cc2)c2ccccc2CBr)cc1
Reactant: Clc1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Oc1ccc(C(c2ccc(O)cc2)c2ccccc2CN2CCN(c3ccccc3Cl)CC2)cc1
Yield: 14.6 %

Procedure:
In 50 ml of tetrahydrofuran were dissolved 1.5 g of 1-(2-chlorophenyl)piperazine and 5 ml of triethylamine, and 3.4 g of 2-[bis(4-hydroxyphenyl)methyl]benzylbromide was added thereto. The mixture was heated under reflux for 3.5 hours, and then insoluble substances were filtered off. The filtrate was concentrated, and the residue was subjected to extraction with the addition of water and ethyl acetate. The organic layer was separated, and the aqueous layer was then extracted with ethyl acetate. The organic layers were combined and then dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel chromatography to afford 0.54 g of the desired compound (Compound 89).
Reaction SMILES: [OH:1][C:2]([CH3:13])([CH3:12])[CH2:3]/[CH:4]=[N:5]/[S:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7].[CH:14]1([Mg]Br)[CH2:16][CH2:15]1.[NH4+].[Cl-]>C(Cl)Cl>[CH:14]1([CH:4]([NH:5][S:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[CH2:3][C:2]([OH:1])([CH3:13])[CH3:12])[CH2:16][CH2:15]1
Reactant: CC(C)(O)C/C=N/S(=O)C(C)(C)C
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(O)CC(NS(=O)C(C)(C)C)C1CC1
Temperature: 25 °C

Procedure:
To a stirred solution of N-[(1E)-3-hydroxy-3-methylbutylidene]-2-methylpropane-2-sulfinamide (0.6 g, 2.9 mmol) in DCM (18 mL) was added cyclopropylmagnesium bromide (0.5 M in THF, 17.5 mL, 8.8 mmol) at −78° C. The reaction mixture was allowed to warm to room temperature as the bath did (2 h). The mixture was treated with sat'd NH4Cl solution, and extracted with EtOAc. The organic layer was washed with brine, dried (sodium sulfate), concentrated, and purified by flash chromatography to give the title compound.
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.[F:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[C:15]=1[C:16]([NH:18][CH3:19])=[O:17]>>[NH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:14]([F:13])[C:15]=1[C:16]([NH:18][CH3:19])=[O:17]
Reactant: CNC(=O)c1c(F)cccc1[N+](=O)[O-]
Agent: CNC(=O)c1cc(F)ccc1N
Product: CNC(=O)c1c(N)cccc1F

Procedure:
The title compound was prepared according to the procedure for Compound 102A (2-Amino-5-fluoro-N-methylbenzamide) using 2-fluoro-N-methyl-6-nitrobenzamide (Compound 155B). 1H NMR (CDCl3, 400 MHz): δ=2.99 (dd, J=4.80, 1.26 Hz, 3 H), 6.35 (ddd, J=12.88, 8.08, 1.01 Hz, 1 H), 6.44-6.49 (m, 1 H), 7.09 (td, J=8.21, 6.57 Hz, 1 H). MS (ES+): m/z 169.08 [MH+] (TOF, polar).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[N:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:2].[Cl:15]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:15][C:5]1[C:4]([O:3][CH2:1][CH3:2])=[N:13][C:12]([NH2:14])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOc1cc2cccnc2c(N)n1
Solvent: ClCCl
Product: CCOc1nc(N)c2ncccc2c1Cl
Yield: 62.8 %

Procedure:
To a 200 mL round bottom flask was added 6-ethoxy-1,7-naphthyridin-8-amine (3.42 mmol), DCM (75 mL), followed by N-chlorosuccinimide (3.77 mmol). The mixture was heated at reflux for 18 h under Ar. The mixture was then cooled, the solvent evaporated and the resultant crude residue purified by silica gel to yield 5-chloro-6-ethoxy-1,7-naphthyridin-8-amine (480 mg, 63%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.89 (d, J=3.95 Hz, 1H), 8.43 (d, J=8.79 Hz, 1H), 7.66 (dd, J=8.79, 3.95 Hz, 1H), 4.13 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[Br:13][CH2:14][CH2:15]Br.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:15][CH2:14][Br:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrCCBr
Reactant: COC(=O)c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCBr)c(Br)c1
Temperature: 60 °C
Yield: 80 %

Procedure:
To a stirred solution of methyl 3-bromo-4-hydroxybenzoate (5.0 g, 1.0 eq) in 20 mL DMF were added BrCH2CH2Br (11 mL, 6.0 eq) and K2CO3 (6.0 g, 2.0 eq). The mixture was heated to 60° C. for 6 h and purified by column chromatography with petroleum ether:EtOAc=3:1 to give the desired product (6.0 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.96 (d, J=8.8 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 4.40 (t, J=6.8 Hz, 2H), 3.90 (s, 3H), 3.71 (t, J=6.4 Hz, 2H)
Reaction SMILES: C1(CC([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:26]([O:28]CC4C=CC(OC)=CC=4)=[O:27])=[C:15]([CH:18]=[CH:19][C:20]4[S:24][CH:23]=[N:22][C:21]=4[CH3:25])[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.[Cl-].[Na+]>C(Cl)Cl.CO>[NH2:10][CH:11]1[C:38](=[O:39])[N:13]2[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH:18]=[CH:19][C:20]3[S:24][CH:23]=[N:22][C:21]=3[CH3:25])[CH2:16][S:17][C@H:12]12
Reactant: COc1ccc(COC(=O)C2=C(C=Cc3scnc3C)CS[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1ncsc1C=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
p-Methoxybenzyl 7-phenylacetamido-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylate (trans-isomer) (0.720 g, 1.28 mmol) was dissolved in methylene chloride (3 ml). The resultant solution was poured into a solution of phosphorus pentachloride (0.800 g, 3.84 mmol) and pyridine (1.04 ml, 12.8 mmol) in methylene chloride (20 ml) at -30° C. The resultant solution was stirred for 3 hours under ice-cooling and poured into methanol (20 ml) as pre-cooled to -30° C., followed by stirring the mixture for 1 hour at ambient temperature. The reaction solution obtained was poured into a mixture of aqueous saturated sodium chloride solution (20 ml) and methylene chloride (20 ml), and the resulting mixture was stirred for 1 hour. The mixture was cooled to stand until it separated into the aqueous phase and organic solvent phase. The aqueous phase separated out was extracted with methylene chloride (20 ml) and the methylene chloride extract was combined with the organic phase mentioned above. The combined organic phase was washed with aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified chromatographically on a column of silica gel (Wako gel C-300) (20 g) as developed with benzene-ethyl acetate (3:1) as the development solvent. The titled compound, 7-amino-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid (trans-isomer) p-methoxybenzyl ester (0.443 g, 78%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=O)[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[NH2-].[Na+].[CH2:28](Cl)[CH:29]=[CH2:30].[Cl-].[Na+].CN(C)C=[O:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([O:37][CH2:28][CH:29]=[CH2:30])[CH:15]=2)[C:10]([OH:12])=[O:11])=[O:7])=[CH:24][CH:25]=1
Reactant: C=CCCl
Reactant: CN(C)C=O
Reactant: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH2-]
Agent: [Na+]
Product: C=CCOn1cc(CC(NC(=O)c2ccc(Cl)cc2)C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
479 Milligrams of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate prepared in Example 3 and 0.05 g of sodium amide were admixed in 5 ml of dimethylformamide, and the mixture was stirred at a room temperature for 2 hours. Then 0.17 g of allyl chloride was added to the mixture and the resulting reaction mixture was stirred at a room temperature for 10 hours. The reaction mixture was poured into 13 ml of a saturated sodium chloride aqueous solution, and the organic material was extracted with chloroform. The chloroform layer was washed with water, dried, then chloroform was removed by evaporation. The residure thus obtained was purified by means of a silica gel column chromatography to yield 85 mg of 2-(4-chlorobenzoylamino)-3-(1-allyloxyindol-3-yl)propionic acid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[C:22]([O:30][CH2:31][C@@H:32]2[CH2:34][O:33]2)[CH:21]=1>>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:34][C@H:32]([OH:33])[CH2:31][O:30][C:22]4[CH:21]=[C:20]([O:19][CH3:18])[CH:25]=[CH:24][C:23]=4[NH:26][C:27](=[O:29])[CH3:28])[CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(NC(C)=O)c(OC[C@@H]2CO2)c1
Reactant: O=c1[nH]c2cc(F)ccc2n1C1CCNCC1
Product: COc1ccc(NC(C)=O)c(OC[C@@H](O)CN2CCC(n3c(=O)[nH]c4cc(F)ccc43)CC2)c1

Procedure:
The title compound was prepared according to the procedure described in Example 30 above from 5-fluoro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one and N-{4-methoxy-2-[(2S)oxiranylmethoxy]phenyl}acetamide. The product was purified by preparative HPLC (Kromasil column; eluent: acetonitrile/water) to afford a colourless solid (84%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([CH3:25])([C:17]([NH:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1)=[O:18])[CH2:5]2.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:25][C:6]1([C:17]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:18])[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:3]=2)[CH:7]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C(=O)Nc2nccs2)Cc2cc(O)ccc2C1c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C(=O)Nc2nccs2)Cc2cc(Oc3ccccc3)ccc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of Example 36 (11.3 mg, 0.032 mmol), Cu(OAc)2 (8.9 mg, 1.5 eq), phenylboronic acid (11.3 mg, 2.9 mmol), triethylamine (22.6 μL, 5 eq) and powdered 4 Å molecular sieve (33.7 mg) in CH2Cl2 (2.5 mL) was stirred at room temperature for 16 h while open to the atmosphere. After filtration to remove the molecular sieve, the filtrate was concentrated and purified by reverse-phase HPLC (80-100% solvent B gradient) to give Example 155. (4.9 mg, 36%). MS Found: (M+H)+=427.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:10]2[CH:5]([CH:6]([OH:11])[CH2:7][CH2:8][CH2:9]2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14].[CH3:16][O:17][CH2:18]OC>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH:10]2[CH:5]([CH:6]([O:11][CH2:16][O:17][CH3:18])[CH2:7][CH2:8][CH2:9]2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14]
Reactant: COCOC
Reactant: CC1C(C)(C)C2CCCC(O)C2C1(C)C
Solvent: Cc1ccccc1
Product: COCOC1CCCC2C1C(C)(C)C(C)C2(C)C
Temperature: 100 °C
Yield: 55 %

Procedure:
A reaction flask was charged with 300 g (1.4 mole) 1,1,2,3,3-pentamethyl-hexahydro-4-indanol, 306 g (4 mole) dimethoxymethane, 0.25 liter toluene, and 3 g boron trifluoride etherate complex. The reaction mass was heated to 100° C. and methanol and lite organics were collected in a Dean Stark trap (337 g recovered). After aging the reaction for 3 hrs the reaction was cooled to 25° C. and acid catalyst was quenched with 100 g of 10% aqueous sodium carbonate. The mass was transferred to a separatory funnel and water washed. The organic layer was separated and purified by fractional distillation. The procedure affords a 55% yield (196 g) of 1,1,2,3,3-pentamethyl-octahydro-4-(methoxymethoxy)-1H-indene.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=3)[NH:11][C:10]=2[CH3:19])=[CH:6][CH:5]=1.[CH2:22]([O:24][C:25](=[O:28])[CH2:26]Br)[CH3:23]>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=3)[N:11]([CH2:26][C:25]([O:24][CH2:22][CH3:23])=[O:28])[C:10]=2[CH3:19])=[CH:6][CH:5]=1
Reactant: Cc1[nH]c2ccc(F)cc2c1Oc1ccc(Cl)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% disp. in oil) (0.12 g) was added portionwise to a stirred solution of the product from step (i) (0.75 g) in DMF (10 ml) at RT. After 10 min, ethylbromoacetate (345 ul) was added, the mixture stirred at RT for 3 h then quenched with water and extracted with diethylether. The organics were washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 15% ethylacetate/iso-hexane. Yield 0.38 g
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[C:17](=[CH:18][C:19](I)=[CH:20][CH:21]=2)[N:16]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:14][C:15]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[C:17](=[CH:18][C:19]([S:1][C:2]3[CH:3]=[C:4]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=3)=[CH:20][CH:21]=2)[N:16]=1
Reactant: CCC(O)(CC)c1cccc(S)c1
Reactant: Clc1cc(-c2ccccc2)c2ccc(I)cc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCC(O)(CC)c1cccc(Sc2ccc3c(-c4ccccc4)cc(Cl)nc3c2)c1
Temperature: 60 °C

Procedure:
10l (900 mg, 4.6 mmol), 2-chloro-7-iodo-4-phenyl-quinoline (10m, 1.6 g, 4.6 mmol), iPr2NEt (1.6 mL, 9.2 mmol), Pd2dba3 (104 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (132 mg, 0.2 mmol) were dissolved in 1,4-dioxane (15 mL) and degassed with N2 for 10 minutes. The reaction was heated to 60° C. for 1 hour, and then diluted with saturated aqueous NH4Cl and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 10n.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](F)=[C:12]([F:17])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][C:20]=1[OH:29]>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][C:20]=1[O:29][C:13]1[CH:14]=[CH:15][C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:11][C:12]=1[F:17]
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(F)c1
Product: O=C(O)Cc1ccc(Cl)c(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (i) and the product of example 1 step (iii).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH3:11][Mg]I.[Mg].CI>C(OCC)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[C:4]([F:10])[CH:3]=1
Reactant: C[Mg]I
Reactant: O=Cc1ccc(Br)cc1F
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Product: CC(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-bromo-2-fluorobenzaldehyde (5 g, 24.62 mmol) in diethyl ether (10 ml) was added to an ice-cold solution of methylmagnesium iodide prepared from magnesium (1.7 g, 73.88 mmol) and methyliodide (4.58 ml, 73.88 mmol) in diethyl ether (50 ml). The mixture was warmed stirred at RT. for 12 h, and cooled to 0° C., quenched with dil. 6N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as red colour liquid (5 g, 94%). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.40 (t, J=8.2 Hz, 1H), 7.30 (dd, J=8.3, 1.7 Hz, 1H), 7.21 (dd, J=9.9, 1.9 Hz, 1H), 5.17 (q, J=6.4 Hz, 1H), 1.49 (d, J=6.5 Hz, 3H).