Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:17][C:18]([O:20]C(C)(C)C)=O)=[C:5]([NH:9][C:10](OC(C)(C)C)=[O:11])[S:6][C:7]=1[CH3:8])[CH3:2]>C(O)(=O)C.C(OCC)(=O)C(OCC)=O>[CH2:1]([C:3]1[C:4]2[NH:17][C:18](=[O:20])[C:10](=[O:11])[NH:9][C:5]=2[S:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CCc1c(C)sc(NC(=O)OC(C)(C)C)c1NC(=O)OC(C)(C)C
Solvent: CCOC(=O)C(=O)OCC
Solvent: CC(=O)O
Product: CCc1c(C)sc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Yield: 24.9 %

Procedure:
4.5 g of crude di-t-butyl 4-ethyl-5-methylthiophene-2,3-dicarbamate was dissolved in a mixture of 30 ml of acetic acid and 30 ml of diethyl oxalate, and refluxed for six hours. Upon cooling to room temperature, the crystalline precipitate was isolated (900 mg). Recrystallisation from hot acetic acid combined with charcoal (Norit SU 18) yielded 660 mg of the title compound, m.p.>300° C. MS: 210. 1H-NMR (DMSO-d6, δ): 1.0 (t, 3H), 2.2 (s, 3H), 2.6 (q, 2H), 11.9 (br.s, 1H), 12.1 (br.s, 1H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[CH3:3][CH2:2][CH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:17]([CH3:18])=[O:19])=[CH:8][CH:9]=1
Reactant: CCCc1ccc(O)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
4-n-Propylphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (862 mg) and acetyl chloride (692 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed therefrom by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give 4-n-propylphenyl acetate (1.09 g, yield 100%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=2)[N:6]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21]>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:11][C:10]([S:12]([NH:16][C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([O:22][CH3:23])=[O:21])(=[O:14])=[O:13])=[CH:9][CH:8]=2)[N:6]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: Cc1nc(-c2ccc(S(=O)(=O)Cl)s2)cs1
Product: COC(=O)c1cccc(NS(=O)(=O)c2ccc(-c3csc(C)n3)s2)c1

Procedure:
The title compound was prepared according to General Procedure 1, described in Example 1, with 5-(2-methylthiazol-4-yl)thiophene-2-sulphonylchloride (15.4 mg, 0.055 mmol) and methyl 3-aminobenzoate (7.6 mg, 0.050 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.83 (s, 3H), 2.98-2.99 (s, 3H), 6.59-6.62 (m, 2H), 6.67-6.68 (s, 2H), 6.81-6.84 (m, 1H), 6.93-6.94 (m, 1H). MS (ESI+) m/z 395 [M+H]+.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH:5]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6]1>O1CCCC1>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([CH:5]2[CH2:6][CH2:7]2)([OH:9])[CH:1]=[CH2:2])=[CH:15][CH:14]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)(c1ccc(Cl)cc1)C1CC1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
A 1.0 M solution of vinylmagnesium bromide in tetrahydrofuran (110 mL, 0.11 mole) was stirred, and a solution of 18.1 grams (0.1 mole) of commercially available 4-chlorophenyl cyclopropyl ketone in 50 mL of dry tetrahydrofuran was added dropwise during a one hour period. The exothermic reaction caused the reaction mixture to warm to 45° C. Upon completion of addition, the reaction mixture was stirred for two hours as it cooled to ambient temperature. The reaction was quenched with the addition of 50 mL of a saturated, aqueous solution of ammonium chloride. The mixture was extracted with two 50 mL portions of diethyl ether. The combined extracts were dried with potassium carbonate and filtered. The filtrate was concentrated under reduced pressure, yielding 20.0 grams of 1-(4-chlorophenyl)-1-cyclopropyl-2-propen-1-ol.
Reaction SMILES: C[Si](C)(C)[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[Cl:10][Si:11]([Cl:14])(Cl)Cl.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:10][Si:11]([Cl:14])([O:3][Si:4]([CH3:5])([CH3:6])[CH3:7])[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: C[Si](C)(C)O[Si](C)(C)C
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: C[Si](C)(C)O[Si](Cl)(Cl)O[Si](C)(C)C
Yield: 19.8 %

Procedure:
About 1.9 ml of a 25% solution of phosphonitrile chloride in methylene chloride are added at room temperature with stirring to a mixture containing 486 g (3.0 mol) of hexamethyldisiloxane and 170 g (1.0 mol) of tetrachlorosilane. After the mixture has been stirred at room temperature for 8 hours, the catalyst is deactivated by adding 2.2 ml of tri-n-butylamine. Distillation of the reaction mixture at 18° to 34° C. and at 2 mbar gives 55 g of 3,3-dichlorohexamethyltrisiloxane, but no 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane. Likewise the desired 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane is neither found in the distillation residue (12 g) nor in the cold trap (583 g of a mixture of trimethylchlorosilane and 1,1,1-trichloro-3,3,3-trimethyldisiloxane).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1>C(Cl)Cl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1
Reactant: C1=COCCC1
Reactant: OCCCBr
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: BrCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a solution of 3-bromopropan-1-ol (8 g, 57.9 mmol) in DCM (100 mL) was added PPTS (891 mg, 3.6 mmol), then dihydropyran (7.3 g, 86.9 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature overnight. It was partitioned between DCM and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether/ethyl acetate (50:1) to give 2-(3-bromopropoxy)tetrahydro-2H-pyran (8.9 g, 69.0% yield) as a light yellow oil.
Reaction SMILES: [CH2:1]([N:9]1[C:18]2[C:13](=[C:14]([CH3:26])[C:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([CH3:19])[CH:17]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N+:27]([O-])([OH:29])=[O:28].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[CH2:1]([N:9]1[C:18]2[C:13](=[C:14]([CH3:26])[C:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([CH3:19])[C:17]=2[N+:27]([O-:29])=[O:28])[CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCCCN1CCCc2c1cc(C)c(CC(=O)OCC)c2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCN1CCCc2c(C)c(CC(=O)OCC)c(C)c([N+](=O)[O-])c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
1 -Octyl-6-ethoxycarbonylmethyl-5,7-dimethyl-1,2,3,4-tetrahydro-quinoline (1.0 g) was dissolved in acetic anhydride (5 ml), and a solution of 70% nitric acid (517 mg) in acetic anhydride (3 ml) was dropwise added, which was followed by stirring at the same temperature for 0.5 hr. The reaction mixture was poured into ice water (50 ml), neutralized with saturated aqueous solution of sodium hydrogencarbonate, and extracted with chloroform (50 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate/n-hexane=1/5) to give 700 mg of oily 1-octyl-6-ethoxycarbonylmethyl-5,7-dimethyl-8-nitro-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: O[C@@H:2]1[CH2:22][C:21]2[C@:16]([CH3:24])([CH:17]=[CH:18][C:19](=[O:23])[CH:20]=2)[C@@H:15]2[C@@H:3]1[C@H:4]1[C@:12]([CH3:25])([CH2:13][CH2:14]2)[C@@H:7]([CH:8]([CH:10]=O)[CH3:9])[CH2:6][CH2:5]1.[CH3:26][C:27]([CH3:32])([CH2:30][OH:31])[CH2:28][OH:29].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:26][C:27]1([CH3:32])[CH2:30][O:31][CH:10]([CH:8]([C@@H:7]2[C@:12]3([CH3:25])[C@H:4]([C@H:3]4[C@H:15]([CH2:14][CH2:13]3)[C@:16]3([CH3:24])[C:21](=[CH:20][C:19](=[O:23])[CH:18]=[CH:17]3)[CH:22]=[CH:2]4)[CH2:5][CH2:6]2)[CH3:9])[O:29][CH2:28]1
Reactant: CC(C)(CO)CO
Reactant: CC(C=O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 30.7 %

Procedure:
In 200 ml of benzene were dissolved 5.00 g (14.6 moles) of 7α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde and 4.56 g (43.8 mmoles) of 2,2-dimethyl-1,3-propanediol, followed by addition of 100 mg of p-toluenesulfonic acid. The mixture was refluxed for 5 hours, with the byproduct water being constantly removed from the reaction system by means of a Dean-Stark trap. The reaction mixture was cooled to room temperature and washed with aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ether-hexane (70:30, v/v) and the extract was combined with the organic layer. This mixture was washed with aqueous sodium chloride solution and dried over magnesium sulfate and the solvent was distilled off under reduced pressure. Finally the residue was purified by silica gel chromatography (eleuent: ethyl acetate-hexane=1:10, v/v) to recover 5.53 g of 20-(5,5-dimethyl-1,3 -dioxan-2-yl)pregna-1,4,6-trien-3-one (yield: 92%).
Reaction SMILES: NC1C=CC2C=CC3N=C(NC(=O)C(C)(C)C)NC(=O)C=3C=2C=1.ClS([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)(=O)=O>N1C=CC=CC=1.O>[C:32]([OH:34])(=[O:33])[C:31]1[CH:35]=[CH:36][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)C(=O)Nc1nc2ccc3ccc(N)cc3c2c(=O)[nH]1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1
Reaction time: 72 h
Yield: 59.8 %

Procedure:
To a solution of N-(9-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (1.38 g, 4.5 mmoles) in dry pyridine (10 ml) was added 4-(chlorosulfonyl)benzoic acid (5.0 g, 22.6 mmoles) at room temperature under a nitrogen atmosphere. After stirring for 3 days, the pyridine was removed under reduced pressure to leave a gummy brown residue which was suspended in water (30 ml), filtered, washed with water and dried to give 4-((N-(1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide)-9-yl)amino)sulfonyl)benzoic acid (1.65 g).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([C:14]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][N:21]=2)[CH2:16][CH2:15]1)[CH3:13].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CO>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:23]2[CH:22]=[N:21][C:20]([N:17]3[CH2:18][CH2:19][C:14]([CH2:12][CH3:13])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:15][CH2:16]3)=[N:25][CH:24]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3ccc(N)c([N+](=O)[O-])c3)cn2)CC1

Procedure:
To a solution of 4-bromo-2-nitroaniline (10.0 g, 46.07 mmol) in 1,4-dioxane (240 mL) and MeOH (140 mL) was added ethyl 4-ethyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperidine-4-carboxylate (21.59 g, 55.28 mmol) and potassium phosphate (14.69 g, 69.10 mmol) and the mixture degassed by purging N2 for 15 min
Reaction SMILES: [OH:1][C:2]1([CH2:8][C@H:9]2[CH2:14][CH2:13][C@H:12](OS(C)(=O)=O)[CH2:11][N:10]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C)C=O>[N:27]([C@H:12]1[CH2:11][N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:9]([CH2:8][C:2]2([OH:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)[CH2:14][CH2:13]1)=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)CC[C@@H]1CC1(O)CCOCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])CC[C@@H]1CC1(O)CCOCC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 82.5 %

Procedure:
To a stirred solution of tert-butyl trans-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]-5-[(methylsulfonyl)oxy]piperidine-1-carboxylate (673 mg, 1.71 mmol, step 3 of Example 2) in N,N-dimethylformamide (4 mL) was added sodium azide (334 mg, 5.13 mmol) at room temperature and the mixture was stirred at 80° C. for 24 h. After cooling, the mixture was quenched with water (50 mL), and extracted with ethyl acetate (50 mL×4). The combined organic layer was washed with water (50 mL×4), brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (2:1) to give 480 mg (82%) of the title compound as a white crystal.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[CH3:11][C:12]([CH3:17])([CH3:16])[C:13](Cl)=[O:14].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:9][OH:10])[C:2]=1[NH:1][C:13](=[O:14])[C:12]([CH3:17])([CH3:16])[CH3:11]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1c(Cl)cccc1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1c(Cl)cccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To the crude (2-amino-3-chlorophenyl)methanol(1.08 g, 6.88 mmol) in CH2Cl2 (15 mL) was fast dropwise added trimethylacetyl chloride (0.89 mL, 7.23 mmol), followed by DIEA (2.4 mL, 13.8 mmol) at 0° C. 5 min later, the reaction mixture was stirred at room temperature for 1 hr. Normal aqueous work-up to afford the expected product as a white solid (1.58 g, 95% yield), which was pure enough to be used in next step; 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (s, 9 H), 3.35 (s, 2 H), 4.36 (d, J=6.29 Hz, 1 H), 7.06-7.22 (m, J=7.81, 7.81 Hz, 1 H), 7.29-7.33 (m, 2 H), 7.58 (s, 1 H); Mass spec. 242.08 (MH+), Calc. for C12H16ClNO2 241.09.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:29])[C:12]([N:14]3[CH2:19][CH2:18][C:17](=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:21]#[N:22])[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:10][C:3]=12.C([Sn](CCCC)(CCCC)[C:35]1[O:36][CH:37]=[CH:38][N:39]=1)CCC.O1CCOCC1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:36]1[CH:37]=[CH:38][N:39]=[C:35]1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:29])[C:12]([N:14]3[CH2:19][CH2:18][C:17](=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:21]#[N:22])[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:10][C:3]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(Cl)ccnc23)CC1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(-c4ncco4)ccnc23)CC1)c1ccccc1
Temperature: 120 °C
Yield: 35.1 %

Procedure:
A mixture of compound of example 101 (30 mg, 0.074 mmol), 2-tributylstannanyl oxazole (106 mg, 0.30 mmol), Pd(PPh3)4 (129 mg, 0.112 mmol) and dioxane (1 mL) in a sealed tube was heated at 120° C. for 15 h. The reaction mixture was diluted with MeOH, filtered through Celite and concentrated. The residue was purified by preparative HPLC to yield title compound (11.3 mg, 0.026 mmol, 39%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH2:11](Br)[CH2:12][Br:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:13][CH2:12][CH2:11][O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:9][CH3:10]
Reactant: BrCCBr
Reactant: COc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1OCCBr
Temperature: 80 °C
Yield: 66.2 %

Procedure:
A suspension of 10.0 g of 5-fluoro-2-methoxyphenol, 52.9 g of ethylenebromide and 14.6 g of potassium carbonate in 50 ml of N,N-dimethylformamide was heated for 11 hours at 80° C. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was chromatographed on silica gel using 50% chloroform-n-hexane as an eluent to give 11.6 g of the desired compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](I)=[CH:4][N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1c(I)cnc(N)c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C#C[Si](C)(C)C)cnc(N)c1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 5.1 grams (0.020 mole) of 2-amino-3-cyano-5-iodo-4-methylpyridine (prepared as in Step E of Example 9) and 4.2 mL (0.030 mole) of trimethylsilylacetylene in 40 mL of acetonitrile is stirred, and 10.5 mL (0.078 mole) of triethylamine, 0.1 gram of copper(I) iodide, and 0.3 gram of bis(triphenyl-phosphine)palladium(II) chloride are added in order. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 20 hours and then is warmed to 70 ° C., where it stirred for about 7.5 hours. The reaction is monitored by thin layer chromatography. Upon completion of the reaction, the reaction mixture is concentrated under reduced pressure to a residue. The residue is dissolved in ethyl acetate, and the solution is washed with 50 mL of aqueous dilute hydrochloric acid. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2-amino-3-cyano-4-methyl-5-(trimethylsilylethynyl) pyridine.
Reaction SMILES: [C:1]1([CH:7]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)(=[O:15])=[O:14])[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][CH:27]1[CH2:36][CH2:35][CH2:34][C:33]2[CH:32]=[C:31]([O:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])[CH:30]=[CH:29][C:28]1=2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:1]1([CH:7]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)(=[O:15])=[O:14])[CH2:8][C:9]([NH:26][CH:27]2[CH2:36][CH2:35][CH2:34][C:33]3[CH:32]=[C:31]([O:37][S:38]([C:41]([F:44])([F:42])[F:43])(=[O:40])=[O:39])[CH:30]=[CH:29][C:28]2=3)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: O=C(O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1)NC1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-phenyl-3-(3-trifluoromethyl-benzenesulfonylamino)-propionic acid (4.31 g, 11.56 mmol), trifluoro-methanesulfonic acid 5-amino-5,6,7,8-tetrahydro-naphthalen-2-yl ester (Step D, 3.10 g, 10.51 mmol), HOBt (Aldrich, 1.28 g, 9.46 mmol), and CH2Cl2 (30 mL) was added EDC (Aldrich, 3.02 g, 15.76 mmol). The reaction was stirred at RT overnight and diluted with CH2Cl2 (100 mL). The organic phase was washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography (16-30% EtOAc-hexane) to afford the title compound as an off-white solid. MS (ESI): 651 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[CH3:15][O-:16].[Na+]>CO>[CH3:14][O:13][C:12]1[C:3]([CH2:2][O:16][CH3:15])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(OC)c1CBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1c(OC)cccc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a 100 mL flask containing 10.1 g (0.039 mol) of methyl 2-bromomethyl-3-methoxybenzoate in 50 mL of CH3OH, were added 19 g of a 25% wt. solution of NaOMe (4.74 g, 0.087 mol). The reaction was stirred at room temperature for 2 hours and then evaporated on a rotary evaporator to remove the CH3OH. About 200 mL of water were added to the residue and the resulting solution was extracted with CHCl3. The CHCl3 extract was dried and evaporated to yield 6.27 g of crude methyl 3-methoxy-2-methoxymethylbenzoate (77% yield). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7-7.4 (multiple, 3H), 4.783 (s, 2H), 3.897 (s, 3H), 3.864 (s, 3H), 3.37 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH:20][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 800 mg, 4.1 mmol) in DMF (40 mL) was added glycine ethyl ester hydrochloride (625 mg, 4.5 mmol), HOBt (0.55 g, 4.1 mmol) and DIPEA (2.13 mL, 12.2 mmol). After 5 min, EDCI (1.01 g, 5.3 mmol) was added and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the solid partitioned between water (100 mL) and ethyl acetate (3×80 mL). The combined organic fractions were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol/dichloromethane (4:96) to give the title compound as a yellow solid. δH (CD3OD): 1.28 (3H, t), 4.14 (2H, s), 4.23 (2H, q), 7.10 (1H, s), 7.68 (1H, s), 8.59 (1H, s); m/z (ES+)=282 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:6]([F:22])=[C:7]([O:14]CC2C=CC=CC=2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)(=O)[CH3:2]>C(O)C.C(O)(=O)C.[Pd]>[F:22][C:6]1[C:7]([OH:14])=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[C:1]([CH3:2])[NH:11]2
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc2c(F)c(O)ccc2[nH]1
Reaction time: 2 h

Procedure:
A solution of 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (300 mg, 0.99 mmol) in ethanol (10 ml) and acetic acid (1 ml) containing 10% palladium on charcoal (30 mg) was hydrogenated at 2 atmospheres pressure for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in ethyl acetate and the organic layer was washed with aqueous sodium hydrogen carbonate, brine and evaporated to give 4-fluoro-5-hydroxy-2-methylindole. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (317) to give 4-fluoro-5-hydroxy-2-methylindole (63 mg, 30%).