Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1.[C:14]([N:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C1COCC1>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][CH2:24][C:23]([C:10]2[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=2)([OH:27])[CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: Brc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc(Br)cc2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 8.2 mL, 20.5 mmol) was added over 10 min to a solution of 1-bromo-4-iodobenzene (5.79 g, 20.5 mmol) in THF (100 mL) at −78° C. After 15 min, a solution of 1-boc-3-piperidone (3.71 g, 18.6 mmol) in THF (10 mL) was added and the resultant reaction mixture was left to stir at −78° C. for 1 h, then warmed to 0° C. and quenched by the addition of saturated aqueous ammonium chloride (50 mL). The mixture was allowed to warm to ambient temperature and partitioned between ethyl acetate (400 mL) and water (150 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography (silica, 80 g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the title compound as a colourless gum (3.69 g, 56%). 1H NMR (CDCl3, 300 MHz): 7.52-7.46 (m, 2H); 7.42-7.36 (m, 2H); 4.16-3.87 (m, 2H); 3.13 (d, J=13.7 Hz, 1H); 2.92-2.77 (m, 1H); 2.03-1.53 (m, 4H); 1.47 (s, 9H).
Reaction SMILES: [C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])([OH:3])=[O:2].[CH2:24](O)[CH3:25].C1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O>C1C=CC=CC=1>[C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)=[O:17])([O:3][CH2:24][CH3:25])=[O:2]
Reactant: CCO
Reactant: O=C(O)CSCCCCCCCCCCC(=O)N1CCOCC1
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Solvent: c1ccccc1
Product: CCOC(=O)CSCCCCCCCCCCC(=O)N1CCOCC1

Procedure:
6 g (0.017 mole) of 11-(Carboxymethylthio)undecanoylmorpholine, 4.8 g (0.11 mole) of anhydrous ethyl alcohol and 1 g of 2-naphthalenesulfonic acid were placed in a flask equipped with reflux condenser, and refluxed for 16 hours. The mixture was dissolved in benzene, washed with water, dried over anhydrous sodium sulfate, filtered, passed through a column of activated alumina and stripped of solvent. The product, 11-(carbethoxymethylthio)undecanoylmorpholine, had a nitrogen content of 3.66% (theory, 3.75%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[C:11]1([N:17]=C=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[O-]CC.[Na+].O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1ccccc1)c1ccc(O)cc1
Temperature: 23 °C
Reaction time: 1.57 h

Procedure:
p-Hydroxybenzoic acid (96.68 grams, 0.70 mole), sodium ethoxide catalyst (0.218 gram, 0.225% wt. of the p-hydroxybenzoic acid used) and N,N'-dimethylacetamide solvent (550 grams) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere at 23° C. to provide a solution. Phenyl isocyanate (87.55 grams, 0.735 mole) is added inducing a maximum exoptherm of 46° C. four minutes later. Three minutes after the maximum exotherm temperature is achieved, heating of the reactor commences and a 160° C. reaction temperature is achieved 94 minutes later. After three hours at the 160° C. reaction temperature, the reactor is cooled to 50° C. then the contents poured into 4 liters of deionized water. A precipitated product is recovered via filtration of the aqueous slurry, washed with deionized water (500 milliliters) then dissolved into boiling methanol (850 milliliters) and refluxed therein (67° C.). After cooling the methanol solution to room temperature (23° C.) and maintaining therein for sixteen hours, a white crystalline product is filtered off, washed with methanol (100 milliliters) and dried in a vacuum oven at 80° C. and 1 mm Hg to a constant weight of 99.49 grams. Fourier transform infrared spectrophotometric analysis of a potassium bromide pellet of a portion of the product revealed the presence of the expected hydroxyl group O--H and secondary amide (solid state) N-H stretching at 3336 cm-1 (sharp) with a shoulder at 3409 cm-1 and the secondary amide carbonyl stretching (solid state) at 1656 cm-1 (sharp).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH3:28])[S:11]([CH:14]=[C:15](C(=O)C)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)(=[O:13])=[O:12])[CH3:2].[CH3:30][O:31][C:32](=[O:37])/[CH:33]=[C:34](\[NH2:36])/[CH3:35].[CH2:38](O)[CH3:39]>>[CH3:30][O:31][C:32](=[O:37])[C:33]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:14]([S:11](=[O:12])(=[O:13])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:29])[CH3:28])=[C:38]([CH3:39])[NH:36][C:34]=1[CH3:35]
Reactant: CCO
Reactant: COC(=O)/C=C(/C)N
Reactant: CCOC(=O)CCCCCN(C)S(=O)(=O)C=C(C(C)=O)c1cccc([N+](=O)[O-])c1
Product: CCOC(=O)CCCCCN(C)S(=O)(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Yield: 65 %

Procedure:
A solution of 4.27 g (0.01 mol) of 6-(α-acetyl-N-methyl-3-nitrostyrenesulfonamido)caproic acid ethyl ester in 30 ml of ethanol is treated with 1.15 g (0.01 mol) of 3-aminocrotonic acid methyl ester and 1.16 g (0.005 mol) of DL-camphor-10-sulfonic acid analogously to Example 1. After chromatography on silica gel with methylene chloride/ethyl acetate (9:1) as the elution agent the crude product is recrystallized from methylene chloride/ether. There are obtained 3.4 g (65%) of 5-{[5-(ethoxycarbonyl)pentyl]methylsulfamoyl}-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinic acid methyl ester, m.p. 83°-86°, as a colorless crystalline powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH2:13].[Si:14]([CH2:21][CH2:22][CH2:23]Cl)([O:19][CH3:20])([O:17][CH3:18])[O:15][CH3:16].[CH3:25][OH:26]>O>[CH3:16][O:15][Si:14]([CH:21]([Si:14]([O:17][CH3:18])([O:15][CH3:16])[O:26][CH3:25])[CH2:22][CH2:23][NH:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2][NH2:1])([O:19][CH3:20])[O:17][CH3:18]
Reactant: CO
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: NCCNCCNCCNCCN
Solvent: O
Product: CO[Si](OC)(OC)C(CCNCCNCCNCCNCCN)[Si](OC)(OC)OC
Temperature: 65 °C

Procedure:
In a reaction flask, equipped as in example 1, there was placed 20 gms. (0.1 mole plus 10% mole excess) of tetraethylenepentamine, 40 gms. (0.2 moles) of distilled (CH3O)3Si(CH2)3Cl and 40 gms. of CH3OH. This mixture was refluxed (about 65° C.) for 3 hours where a titration showed 0.07 equiv. of Cl-. The reaction was continued at reflux for an additional 21 hours whereupon the reaction mass titrated at 0.19 equiv. of Cl-. A crude sample of this material (10 weight %) gave an initial hazy solution in acidic water or basic water but the material cleared within about 30 minutes to give stable solutions.
Reaction SMILES: [CH3:1][C:2]12[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:26]=1[C:27]([F:30])([F:29])[F:28])=O)(=O)OC.O.[NH2:36][NH2:37]>>[C:31]([N:25]1[C:26]([C:27]([F:30])([F:29])[F:28])=[C:22]([C:20]2[CH:19]=[C:4]3[C:3]([C@:2]4([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]3[CH2:6][CH2:7]4)=[N:37][N:36]=2)[CH:23]=[N:24]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC12CCC(C(=O)C1=O)C2(C)C
Reactant: NN
Reactant: COP(=O)(CC(=O)c1cnn(C(C)(C)C)c1C(F)(F)F)OC
Solvent: O
Product: CC(C)(C)n1ncc(-c2cc3c(nn2)[C@@]2(C)CC[C@@H]3C2(C)C)c1C(F)(F)F

Procedure:
yellow solid. MS (ESI): 379.2 (MH+). Prepared from 1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [2-(1-tert-Butyl-5-trifluoromethyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:17])[C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH2:32])[CH:30]=2)[CH:25]=[CH:24][N:23]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH:32][C:10](=[O:12])[C@@H:9]([N:8]([CH3:17])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH:30]=2)[CH:25]=[CH:24][N:23]=1
Reactant: Nc1ccc2ccncc2c1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1ccc2ccncc2c1)N(C)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
To (S)-2-(tert-butoxycarbonyl(methyl)amino)-4-methylpentanoic acid in DMF was added EDC, DMAP and isoquinolin-7-amine. This mixture was stirred for 4 hours and the reaction was washed with NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, Hexanes/EtOAc) gave pure (S)-tert-butyl 1-(isoquinolin-7-ylamino)-4-methyl-1-oxopentan-2-yl(methyl)carbamate (E87).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:69][CH:70]1[CH2:72][NH:71]1.O>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[N:71]2[CH2:72][CH:70]2[CH3:69])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Reactant: CC1CN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CN1c1c(C=O)c2ccccc2n1-c1ccc(C(C)(C)C)cc1
Yield: 65.6 %

Procedure:
A side-arm tube under a nitrogen atmosphere is charged with 1-(4-tert-butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde (100 mg, 0.321 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (20 mg, 0.032 mmol) and sodium tert-butylate (46 mg, 0.479 mmol). To this is added toluene (3.0 mL), a solution of 2-methylaziridine (37 mg, 0.678 mmol) in toluene (1.0 mL) and the resulting mixture is stirred overnight at 80° C. The reaction is cooled, water added and the mixture is extracted with ethyl acetate. The combined ethyl acetate layer are washed with water, with brine, dried over sodium sulfate, filtered and the solvent concentrated to give an oil that is purified by chromatography eluting with heptane-5 to 30% ethyl acetate. Product containing fractions are combined and concentrated to afford 1-(4-tert-butyl-phenyl)-2-(2-methyl-aziridin-1-yl)-1H-indole-3-carboxaldehyde (70 mg, 66% yield) as a yellow solid. TLC (heptane-30% ethyl acetate/) Rf 0.20; ESI/MS 333 (M+H); RT 4.15 min; NMR 10.16 (1H, s); 8.08 (1H, d, J=6 Hz); 7.70 (2H, d, J=9 Hz); 7.49 (2H, d, 9 Hz); 7.21 (2H, m); 6.91 (1H, d, J=9 Hz); 2.43 (2H, m); 2.28 (1H, d); 1.38 (9H, s); 0.79 (3H, d, J=6 Hz).
Reaction SMILES: [C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].Cl>CN(C)C=O>[C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1ccccc1O)c1ccccc1Oc1ccccc1
Reactant: COC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1CN(C(C)=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 666 mg of N-acetyl-N-(2-hydroxybenzyl)-2-phenoxyaniline in 10 ml of N,N-dimethylformamide was added 80 mg of 60% NaH/oil, followed by stirring at room temperature for 30 minutes. To this was added 0.3 ml of methyl bromoacetate, followed by stirring at room temperature for 30 minutes. The reaction solution was poured into 0.5 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with 0.5 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude N-acetyl-N-(2-methoxycarbonylmethoxybenzyl)-2-phenoxyaniline.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[N:35]1([C:40]2[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=2)[CH:39]=[CH:38][N:37]=[CH:36]1.[B][B][B][B][B][B][B][B][B][B].C(O)(C(F)(F)F)=O>>[CH2:31]([N:30]([CH2:33][CH3:34])[C:28](=[O:29])[C:25]1[CH:26]=[CH:27][C:22]([C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:44][C:43]3[CH:42]=[CH:41][C:40]([N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)=[CH:47][CH:46]=3)[CH:3]=2)[N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:23][CH:24]=1)[CH3:32]
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(N)c2)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NCc3ccc(-n4ccnc4)cc3)c2)N2CCNCC2)cc1
Yield: 78.7 %

Procedure:
Using the same method as for COMPOUND 17 and using INTERMEDIATE 5a (206 mg, 0.44 mmol), 4-(1H-imidazol-1-yl)benzaldehyde (83.6 mg, 0.49 mmol), and decaborane (16.4 mg, 0.13 mmol) afforded COMPOUND 53 (181 mg, 42% yield) as its TFA salt. This material was lyophilized from CH3CN/H2O to produce a colourless solid. Purity (HPLC): >99%; Optical purity (Chiral HPLC): >99%; 1H NMR (400 MHz, CD3OD) δ 1.09 (br t, J=6.7 Hz, 3H), 1.21 (br t, J=6.7 Hz, 3H), 2.63 (br s, 4H), 3.15-3.28 (m, 6H), 3.51 (q, J=6.1 Hz, 2H), 4.32 (s, 1H), 4.43 (s, 2H), 6.47-6.52 (m, 1H), 6.71-6.76 (m, 2H), 7.02 (t, J=8.0 Hz, 1H), 7.26 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.6 Hz, 2H), 7.76 (s, 1H), 8.05 (s, 1H), 9.44 (s, 1H). Found: C, 51.44; H, 4.89; N, 9.63. C32H38N6O×1.2 H2O×3.0 CF3COOH has C, 51.49; H, 4.94, N, 9.48%. [α]D17=−2.1 deg [c 0.872, MeOH].
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:42])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:40])(=[O:39])[N:26]([CH:36]([CH3:38])[CH3:37])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:41])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[F:41][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:42])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:39])(=[O:40])[N:26]([CH:36]([CH3:38])[CH3:37])[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)C(C)C)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(CN(C(C)C)S(=O)(=O)c2ccc(-c3c(C)c(CC(=O)O)cc4ccc(F)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
Lithium hydroxide monohydrate (0.051 g, 1.23 mmol) was added to a solution of (6-fluoro-4-{4-[isopropyl-(4-methoxy-benzyl)-sulfamoyl]-phenyl}-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (0.17 g, 0.30 mmol) in a 3:1 mixture of THF—H2O mixture (15 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove the THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave (6-fluoro-4-{4-[isopropyl-(4-methoxy-benzyl)-sulfamoyl]-phenyl}-3-methyl-naphthalen-2-yl)-acetic acid (0.138 g, 82%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.49 (br. s, 1 H), 7.98-8.04 (m, 3 H), 7.90-7.92 (m, 1 H), 7.47 (d, J=7.80 Hz, 1 H), 7.39 (td, J=8.60, 2.40 Hz, 1 H), 7.33 (d, J=8.00 Hz, 2 H), 6.91 (d, J=8.20 Hz, 2 H), 6.67 (dd, J=11.00, 2.60 Hz, 1 H), 4.41-4.44 (m, 2 H), 4.13 (spt, J=6.80 Hz, 1 H), 3.86 (s, 2H), 3.74 (s, 3H), 2.08 (s, 3H), 0.93 (d, J=6.85 Hz, 6 H). MS calcd. for C30H29FNO5S [(M−H)−] 534, obsd. 534.3.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2.[CH2:10]([O:12][CH:13](OCC)[CH:14]=[CH2:15])[CH3:11].[Cl-].[NH4+]>O1CCCC1.[Cu]Br>[CH2:10]([O:12][CH:13]=[CH:14][CH2:15][CH2:2][CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)[CH3:11]
Reactant: C=CC(OCC)OCC
Reactant: BrCC1CC2C=CC1C2
Agent: [Cu]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC=CCCC1CC2C=CC1C2
Reaction time: 20 h

Procedure:
A Grignard reagent was customarily prepared from 200 g of 5-bromomethyl-2-norbornene in 500 ml of dry tetrahydrofuran. The Grignard reagent was added dropwise over one hour to a mixture of 130 g of 3,3-diethoxy-1-propene, 1.0 g of copper (I) bromide and 300 ml of dry tetrahydrofuran at 20° C. Stirring was continued for 20 hours whereupon the reaction solution was added to a saturated aqueous solution of ammonium chloride to stop reaction. After hexane extraction, the organic layer was successively washed with water, saturated sodium bicarbonate water and saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated in vacuum, yielding 5-(4-ethoxy-3-buten-1-yl)-2-norbornene.
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C=CC(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=1.[CH2:20]([O:27][C:28]1[C:29]([O:36][CH3:37])=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO>COCCOC.O>[CH2:20]([O:27][C:28]1[C:29]([O:36][CH3:37])=[C:30]([CH2:31][C:16]#[N:17])[CH:33]=[CH:34][CH:35]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1c(C=O)cccc1OCc1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: COCCOC
Product: COc1c(CC#N)cccc1OCc1ccccc1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
9.3 g (83 mmol) Potassium tert-butoxide in 30 mL 1,2-dimethoxyethane are cooled to −30° C. 9.1 g (45 mmol) toluene-4-sulfonylmethylisocyanide in 30 mL 1,2-dimethoxyethan are added slowly and the resulting mixture is cooled to −50° C. A mixture of 10.0 g (41.3 mmol) 3-benzyloxy-2-methoxy-benzaldehyde (see CN 102451178) in 80 mL 1,2-dimethoxyethane are added within 30 min and stirred for 2 h at −50° C. After that time 60 mL MeOH are added and stirred for 2 h under reflux. The mixture is cooled to r.t., diluted with water and extracted with DCM. The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel; cyclohexane/EtOAc 4:1) to yield the desired product.
Reaction SMILES: CO[CH:3]1[O:7][CH:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][CH2:4]1.CO[P:19]([O:23][CH3:24])([O:21][CH3:22])=[O:20].[C:25](O)(=[O:27])C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:24][O:23][P:19]([CH2:25][O:27][CH:4]1[CH2:3][O:7][CH:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5]1)([O:21][CH3:22])=[O:20]
Reactant: COP(=O)(OC)OC
Reactant: COC1CCC(n2cc(C)c(=O)[nH]c2=O)O1
Reactant: CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COP(=O)(COC1COC(n2cc(C)c(=O)[nH]c2=O)C1)OC
Temperature: 100 °C

Procedure:
To a solution of 1-(5-methoxytetrahydro-2-furyl)thymine (5.2 g, 23 mmol) and dimethylphosphonomethanol (6.5 g, 44 mmol) in toluene was added acetic acid (5 mL) and p-toluenesulfonic acid monohydrate (500 mg, 2.6 mmol). The solution was heated at 100° C. for 2 hr and the resulting insoluble solid was removed by suction filtration. After removal of the solvent under reduced pressure, the residual oil was chromatographed on silica gel using CH2Cl2 /5% MeOH as eluent to give the title compound as a cis/trans mixture (6:4): yield 5.0 g (60%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]=[N:8][N:7]=1)(=O)C.[OH-].[Li+].Cl>O.CO.O1CCCC1>[OH:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]=[N:8][N:7]=1
Reactant: CC(=O)OCc1nnnn1-c1ccc(C#N)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(-n2nnnc2CO)cc1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
To a solution of [1-(4-cyanophenyl)-1H-tetrazol-5-yl]methyl acetate (2.48 g, 10.2 mmol, Intermediate 8) in water (15 mL), methanol (15 mL) and tetrahydrofuran (THF) (30 mL), cooled in an ice bath, was added lithium hydroxide (0.244 g, 10.2 mmol). The reaction mixture was stirred at 0-5° C. for 1.5 hours. The reaction mixture was acidified with the addition of 2N HCl (5.5 ml). The majority of the organic solvent was then removed from the reaction mixture under vacuum leading to precipitation of a white solid which was filtered then dried under vacuum at 40° C. for 18 hours to yield the title compound as a white solid (1.43 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=3)[CH:25]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH:13]=1.Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>>[CH3:41][O:40][C:38](=[O:39])[CH2:37][NH:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]2[CH:13]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=[C:11]2[CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=3)[CH:25]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc2cc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc([N+](=O)[O-])cc3)ccc2c1
Reactant: COC(=O)CBr
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc3cc(OC)ccc3c2)cc1

Procedure:
4-(2,4-Dichloro-phenyl)-1-(4-nitro-phenyl)-2-(6-methoxy-naphthalen-2-ylmethyl)-1H-imidazole (252 mg, 0.5 mmol) was reduced to amine and was reacted with methyl bromoacetate following general procedures D & E to give {4-[4-(2,4-dichloro-phenyl)-2-(6-methoxy-naphthalen-2-ylmethyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.C(#N)C.C[Si]([CH:19]=[N+:20]=[N-:21])(C)C.C(OCC)C>C1COCC1>[N+:20](=[CH:19][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)=[N-:21]
Reactant: O=C(Cl)Cc1ccc(I)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under an argon atmosphere, 4-iodophenylacetyl chloride (12) obtained above was dissolved in THF (2 mL) and acetonitrile (2 mL) and cooled to 0° C. To this was slowly added a solution of trimethylsilyldiazomethane in diethyl ether (2.0 M, 4.00 mL, 8.00 mmol), which was stirred overnight (14 h) after warming up to room temperature. After concentrating under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/diethyl ether═1/1) to give 1-diazo-3-(4-iodophenyl)propan-2-one (13) as a pale yellow solid (635 mg, 4.44 mmol, 55.5%, 2 steps).