Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][N:14](C)[C@@H:15]1[CH2:21][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[C@H:17]([O:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)[CH2:16]1>CC(C)=O>[CH3:13][NH:14][C@@H:15]1[CH2:21][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[C@H:17]([O:26][C:27]2[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=2)[CH2:16]1
Reactant: CN(C)[C@@H]1CCc2ccccc2[C@H](Oc2ccc([N+](=O)[O-])cc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CC(C)=O
Product: CN[C@@H]1CCc2ccccc2[C@H](Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 26 h
Yield: 64.1 %

Procedure:
348 mg of diethyl azocarboxylate were added to a mixture of 652 mg of cis N,N-dimethyl-5-[4-nitrophenoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-amine in 10 ml of acetone and the mixture was refluxed for 31/2 hours. The acetone was distilled under reduced pressure and 5 ml of N hydrochloric acid were added to the residue. The mixture was stirred at room temperature for 26 hours and was then made alkaline with ammonium hydroxide. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 1.1 g of raw product which was chromatographed over silica gel. Elution with a 7-3 chloroform-methanol mixture yielded 400 mg of cis N-methyl-5-[4-nitrophenoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-amine. The said product was dissolved in ethyl acetate containing gaseous hydrogen chloride and 380 mg of the hydrochloride of the cis compound melting at 265° C. was recovered therefrom.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c2ccccc12
Temperature: 70 °C
Reaction time: 6 h
Yield: 96.6 %

Procedure:
The compound obtained in Example 17-1 (269.9 mg) was dissolved in carbontetrachloride (8 ml), and N-bromosuccinimide (252.6 mg) and azobisisobutylonitrile (22.1 mg) were added to the solution. The mixture was stirred for 6 hours at 70° C. After the completion of the reaction, the solid was removed using a glass filter and the filtrate was concentrated. The residue was dissolved in chloroform and washed with 1 mol/l aqueous solution of sodium hydroxide and saturated brine. The solution was dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was dried under reduced pressure to obtain the title compound (363.3 mg) as pale yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16](O)[C:17]3[C:18](=[O:54])[NH:19][C:20](=[O:53])[N:21]([CH:52]=3)[C@@H:22]3[O:51][C@H:41]([CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[C@@H:32]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C@H:23]3[O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]>C(O)C.[Pd]>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][C:17]3[C:18](=[O:54])[NH:19][C:20](=[O:53])[N:21]([CH:52]=3)[C@@H:22]3[O:51][C@H:41]([CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[C@@H:32]([O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:35])[CH3:36])[C@H:23]3[O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(C(O)c3cn([C@@H]4O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]4O[Si](C)(C)C(C)(C)C)c(=O)[nH]c3=O)ccc21
Agent: [Pd]
Solvent: CCO
Product: CCn1c2ccccc2c2cc(Cc3cn([C@@H]4O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]4O[Si](C)(C)C(C)(C)C)c(=O)[nH]c3=O)ccc21

Procedure:
The product of step (i) (15.83 g) was subjected to hydrogenolysis at 2.5 atmospheres in ethanol (200 ml) using 10% palladium on charcoal (1 g) until reaction was complete by thin layer chromatographical analysis. The catalyst was filtered and the mother liquor collected. The solvent was removed under reduced pressure. The remaining residue was purified by flash silica-gel chromatography to afford 5-(9-ethylcarbazol-3-ylmethyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine as a yellow foam.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][O:5][C:4]=1[N:12]=[C:13]=[O:14])#[N:2].[CH3:15][NH2:16]>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:7]([C:8]([CH3:10])([CH3:11])[CH3:9])=[CH:6][O:5][C:4]=1[NH:12][C:13]([NH:16][CH3:15])=[O:14])#[N:2]
Reactant: CC(C)(C)c1coc(N=C=O)c1C#N
Reactant: CN
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1occ(C(C)(C)C)c1C#N
Yield: 75 %

Procedure:
A solution of 7.8 g (0.041 mole) of 3-cyano-4-tert.-butyl-fur-2-yl isocyanate in 30 ml of toluene was added dropwise to a solution of 1.6 g (0.052 mole) of methylamine in 30 ml of toluene. Thereafter, the mixture was worked up by concentrating it under reduced pressure and recrystallizing the residue from toluene. 6.8 g of 1-(3-cyano-4-tert.-butyl-fur-2-yl)-3-methylurea of melting point 163° C. were obtained in this manner.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]([CH2:14][NH2:15])[OH:13].Cl>>[OH:13][CH2:12][CH2:14][NH:15][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NCCO
Agent: Cl
Product: O=C(O)c1ccc(Cl)cc1NCCO
Yield: 96.9 %

Procedure:
First, 2,4-dichlorobenzoic acid (VI) (19.1 g) and cupric chloride (200 mg) were added to ethanolamine (XI) (36.6 g) and the solution was reacted at 80 to 90° C. for 4.5 hours. After the reaction, the pH of the reaction solution was adjusted to 1 by addition of concentrated hydrochloric acid, and then the resulting precipitate was collected by filtration to give 20.9 g of 2-(2-hydroxyethylamino)-4-chlorobenzoic acid (IX) (yield, 97%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:19])[CH:14]=[C:15]2[CH2:18][CH2:17][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:19])[CH2:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C=C2CCC2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)CC2CCC2)C1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
Add palladium on carbon (50 mg, catalytic) to 3-(2-cyclobutylidene-acetyl)pyrrolidine-1-carboxylic acid tert butyl ester (850 mg, 3.20 mmol) in ethyl acetate (25 mL) and stir under nitrogen at room temperature. Install a balloon of hydrogen gas and stir overnight. Filter the reaction over celite, rinse with ethyl acetate and concentrate to dryness to afford 391 mg (46%) of the desired compound. MS (m/z)=212.0 (M−55)
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:46])[NH:22][CH2:23][C:24]([N:26]([CH2:33][C:34](=[O:45])[N:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][CH2:37][CH2:36]2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])[CH:17]=[CH:18][CH:19]=1>C(Cl)Cl>[CH3:12][S:13]([C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:46])[NH:22][CH2:23][C:24]([N:26]([CH2:33][C:34](=[O:45])[N:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][CH2:37][CH2:36]2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])[CH:17]=[CH:18][CH:19]=1)=[O:9]
Reactant: CSc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCCc3ccccc32)c2ccccc2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCCc3ccccc32)c2ccccc2)c1
Reaction time: 2 h
Yield: 44 %

Procedure:
1.5 g of m-chloroperbenzoic acid in solution in 10 cm3 of methylene chloride is run, in the course of 10 minutes, into a solution of 1.1 g of 2-[3-(3-methylthiophenyl)ureido]-N-[2-oxo-2-(1,2,3,4-tetrahydro-1-quinolyl)ethyl]-N-phenylacetamide in 10 cm3 of methylene chloride kept at a temperature close to 0° C. The mixture is stirred for 2 hours at a temperature close to 25° C and then diluted with 25 cm3 of methylene chloride. The solution is washed with 20 cm3 of a saturated aqueous sodium thiosulphate solution, 20 cm3 of a saturated aqueous sodium bicarbonate solution and then 20 cm3 of a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The crude product obtained is purified by chromatography on 40 g of silica (0,062-0,200 mm) contained in a column 1.2 cm in diameter [eluent: ethyl acetate/methanol (95/5 by volume)], collecting 10 cm3 fractions. Fractions 6 to 13 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from a diisopropyl ether/ethyl acetate mixture (90/10 by volume), 0.5 g of (RS)-2-[3-(3-methylsulphinylphenyl)ureido]-N-[2-oxo-2-(1,2,3,4-tetrahydro-1-quinolyl)ethyl]-N-phenylacetamide melting at 140° C is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]([OH:12])=[O:11])[CH2:4]1>Cl.[Pt]>[C:2]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:1]
Reactant: NCC1CCCC(CC(=O)O)C1
Agent: [Pt]
Agent: Cl
Product: N#Cc1cccc(CC(=O)O)c1
Yield: 45 %

Procedure:
The 3-nitrophenylacetic acid described in Example 7 is hydrogenated in methanol in the presence of palladium-charcoal to give a yield of 99% of theory of 3-aminophenylacetic acid (m.p. 116°-121° C.). In a manner analogous to that described for the p-compound (see Example 6), there is obtained therefrom, by diazotisation, 3-cyanophenylacetic acid (yield 45% of theory; m.p. 93°-98° C. (decomp.)) and by hydrogenation in dilute hydrochloric acid in the presence of platinum catalyst there is obtained 3-aminomethylcyclohexylacetic acid; yield 66% of theory; m.p. 127°-130° C. The diphosphonic acid is obtained therefrom by means of phosphorus trichloride/phosphorous acid in the manner described in Example 1 in the form of the monohydrate; yield 28% of theory; m.p. 216°-221° C. (decomp.); Mrel =0.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1.N>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(Cl)cc2)cc1
Reactant: Fc1ccc(I)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2-c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 93, starting with 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 1-fluoro-4-iodobenzene in place of 4-bromothioanisole (yield: 245 mg, 54%). mp 195–197° C. 1H NMR (300 MHz, CDCl3) δ 3.08 (s, 3H), 7.19 (m, 4H), 7.25 (m, 2H), 7.41 (d, J=9 Hz, 2H), 7.70 (m, 2H), 7.95 (d, J=9 Hz, 2H), 8.01 (s, 1H). MS (DCI/NH3) m/z 455 (M+H)+, 472 (M+NH4)+. Anal. calc. for C23H16ClFN2O3S: C, 60.78; H, 3.52; N, 6.17. Found: C, 60.81; H, 3.53; N, 5.93.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:30]=[CH:31]/[C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[N:7][N:8]2[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:38](O)=[O:39].O.[NH2:42][NH2:43]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:30]=[CH:31]/[C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[N:7][N:8]2[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:4][C:3]=1[C:38]([NH:42][NH2:43])=[O:39]
Reactant: O=C(O)c1cc2c(/C=C/c3cccnc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Reactant: NN
Solvent: O
Product: NNC(=O)c1cc2c(/C=C/c3cccnc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Yield: 25.7 %

Procedure:
In accordance with the method as described in Example 127, 110 mg of 6-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carboxylic acid and 210 mg of hydrazine monohydrate were condensed, to afford 29 mg of the title compound as a yellow powder.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([CH:17]([CH3:19])[CH3:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:3].Cl>>[NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([CH:10]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH:12]([CH:17]([CH3:19])[CH3:18])[CH2:11]1)([CH3:8])[CH3:9])[CH3:3]
Reactant: CC(N)CCCC(C)(C)c1ccc(N)c(C(C)C)c1
Agent: Cl
Product: CC(N)CCCC(C)(C)C1CCC(N)C(C(C)C)C1
Reaction time: 46 h

Procedure:
5.2 Parts of 2-amino-6-(4-amino-3-isopropylphenyl)-6-methylheptane in 61 parts of 1N aqueous hydrochloric acid were hydrogenated at room temperature and atmospheric pressure using 1.0 parts of Nishimura catalyst. Thereafter at 7 and 24 hours respectively further 1.0 and 0.5 part additions of catalyst was made and the hydrogenation was complete after 46 hours with a 103% theory uptake. The work up followed Example 1, and gave, on distillation, 4.2 parts 2-amino-6-(4-amino-3-isopropylcyclohexyl)-6-methylheptane b12 182°-4° with the following percentage composition by weight.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:20]([NH2:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:11][C:12]([NH:22][CH2:20][CH3:21])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCN
Reactant: N#Cc1ccc(N(CC(=O)O)CC(F)(F)F)cc1Cl
Product: CCNC(=O)CN(CC(F)(F)F)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 3 using N-(3-chloro-4-cyanophenyl)-N-(2,2,2-trifluoroethyl)glycine and ethylamine: MS (ES) m/z 320 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:16](N(CC)CC)[CH3:17].ICC>O1CCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCN(CC)CC
Reactant: COC1(c2cc(F)cc(F)c2)CCNC1
Solvent: CO
Solvent: CCI
Solvent: C1CCOC1
Product: CCN1CCC(OC)(c2cc(F)cc(F)c2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (+)-3-(3,5-difluorophenyl)-3-methoxypyrrolidine (0.01 g, 0.047 mmol) and triethylamine (13.1 μL, 0.0938 mmol) in tetrahydrofuran (3 ml), was added iodoethane (5.6 μL, 0.070 mmol). The resulting mixture was stirred at ambient temperature for 24 h and then diluted with methanol and analyzed by GCMS and LCMS. Analysis show 64% conversion. MS m/z (relative intensity, 70 eV) 241 (M+, 10), 226 (86), 211 (33), 141 (49), 71 (bp).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]([CH:14]2[CH2:16][CH2:15]2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([Si](C)(C)C)=[CH:20][C:19]=1[F:28])=[O:4].[I:29]Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:13]([CH:14]2[CH2:16][CH2:15]2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:29])=[CH:20][C:19]=1[F:28])=[O:4]
Reactant: COC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2cnccc2n1C1CC1
Reactant: ClI
Solvent: ClCCl
Product: COC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
To a stirred solution of 1-cyclopropyl-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (265.0 mg, 0.67 mmol) in anhydrous DCM at −10° C. was added iodine monochloride (1.0 M in DCM, 0.80 mL, 0.80 mmol, 1.2 eq). The reaction mixture was then stirred at ambient temperature for 15 minutes then quenched with saturated aqueous sodium thiosulfate solution (3 mL). The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous NaHCO3 solution, water, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica, ISCO, 45 mL/min, 25 to 100% ethyl acetate in hexane) to give the desired product as a yellow solid (159.0 mg, 52.9%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.53 (s, 1H), 8.33 (dd, J=6.0 Hz, J=1 Hz, 1H), 7.89 (s, 1H), 7.67-7.46 (m, 2H), 7.32 (m, 1H), 6.66 (dd, J=13.20 Hz, J=4.6 Hz, 1H), 3.81 (d, J=1.0 Hz, 3H), 3.61-3.41 (m, 1H), 1.22-1.10 (m, 2H), 0.90-0.79 (m, 2H); LC-MS (method C): [M+H]+=452.0, RT=0.79 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CCC(=O)c1ccc(OCc2ccccn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(=O)c1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-Butyl 4-(4-((2-pyridinyl)-methoxy)phenyl)-4-oxobutyrate (Step C, 1.27 g, 4.2 mmol) in dichloromethane (25 ml) was treated with trifluoroacetic acid (5 ml). The mixture was stirred at ambient temperature for 3 hours and concentrated in vacuo. The purification was done by flash chromatography on silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to provide the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([OH:13])[CH2:9][CH2:10][C:11]#[CH:12].C(N(CC)CC)C.O>C(Cl)Cl.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.[Cu]I.C(OCC)(=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][CH2:8][OH:13])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: OCCCC#Cc1cccnc1
Yield: 8.8 %

Procedure:
To a stirred solution of 3-bromopyridine (4.09 g, 26 mmol), 4-pentyn-1-ol (2.58 g, 31 mmol) and triethylamine (12 ml) in anhydrous DCM (20 ml) was added bis(triphenylphosphine)-palladium dichloride (0.05 g, 0.07 mmol) and copper(I) iodide (0.05 g, 0.26 mmol). The mixture was refluxed for 20 h under argon. After cooling, water (20 ml) was added and the products extracted into DCM. The combined organic extracts were washed with saturated potassium carbonate (50 ml) dried over anhydrous magnesium sulphate, filtered and evaporated to provide a brown oil. Column chromatography (flash silica gel, ethyl acetate) gave 5-(3-pyridyl)-1-pent-4-ynol (0.37 g, 7%) as a colourless oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH2:17][CH:16]3[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]3)[CH:12]=2)=[CH:3][N:2]=1>CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]2[CH2:17][CH:16]3[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]3)[CH2:12]2)=[CH:3][N:2]=1
Reactant: CN1C2C=C(c3cncc4ccccc34)CC1CC2
Solvent: CO
Product: CN1C2CCC1CC(c1cncc3ccccc13)C2

Procedure:
A mixture 3-(isoquinolin-4-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene and 5-palladium on carbon in methanol is stirred at room temperature for 3 days under a hydrogen atmosphere. The reaction mixture is then filtered and the filtrate concentrated under reduced pressure. The residue is subjected to flash silica gel chromatography. Fractions containing product are combined and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1O)([CH3:4])([CH3:3])[CH3:2].C1(S(O)(=O)=O)C=CC=C(S(O)(=O)=[O:19])C=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)c1cccc(S(=O)(=O)O)c1
Reactant: CC(C)(C)c1ccccc1O
Product: CC(C)(C)c1ccc(O)cc1
Temperature: 150 °C
Yield: 84 %

Procedure:
Two grams of ortho-tertiary-butyl phenol was mixed with 1% of meta-benzenedisulfonic acid and heated in a test tube for 1.5 hours with occasional stirring at 150°C. Analysis gave 84.0% para-tertiary-butyl phenol; the remaining components consisted of its isomers.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].[CH:14]1([CH2:20][CH2:21][C@H:22]2[CH2:24][O:23]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[CH2:7]([O:6][CH2:5][C@H:2]([NH:1][CH2:24][C@@H:22]([OH:23])[CH2:21][CH2:20][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:3][OH:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CCC(CC[C@H]2CO2)CC1
Reactant: N[C@H](CO)COCc1ccccc1
Solvent: CCO
Product: OC[C@H](COCc1ccccc1)NC[C@@H](O)CCC1CCCCC1
Temperature: 80 °C
Yield: 57.2 %

Procedure:
Dissolve (R)-(+)-2-amino-3-benzyloxy-1-propanol (317 mg, 1.75 mmol) and 2-(S)-(2-cyclohexylethyl)-oxirane (270 mg, 1.75 mmol) in absolute ethanol (8 mL) and heat at 80° C. in a sealed glass pressure vessel overnight. Concentrate and purify (silica gel chromatography, eluting with 8:92 to 10:90 methanol:dichloromethane) to give the desired compound (336 mg, 57%).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][OH:25])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].C([O-])(=O)C.[Na+].[CH2:32]=[C:33]1[O:37][C:35](=[O:36])[CH2:34]1.C(OCC)(=O)C>ClCCl>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:25][C:35](=[O:36])[CH2:34][C:33](=[O:37])[CH3:32])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: C=C1CC(=O)O1
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CC(C)=O

Procedure:
In 30 ml of dichloromethane is dissolved 0.8 g of 16β-ethyl-17β-glycoloyloxy-4-estren-3-one, and 0.24 g of anhydrous sodium acetate and 0.3 ml of diketene are added. The mixture is refluxed for 4 hours. After cooling, 100 ml of ethyl acetate is added and the mixture is washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following serial passage of 400 ml of diisopropyl ether and 400 ml of diisopropyl ether-ethyl acetate (10:1), elution is carried out with 600 ml of isopropyl ether-ethyl acetate (2:3). The eluate is evaporated under reduced pressure to remove the solvent, giving 1.0 g of the above-identified compound as a light-yellow viscous oil.