Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[CH2:19]([N:22]=[C:23](SC)[O:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH3:21]>C(O)CC>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:23]([O:24][CH2:25][CH2:26][CH3:27])[N:22]([CH2:19][CH2:20][CH3:21])[C:4]2=[O:6]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: CCCN=C(OCCC)SC
Solvent: CCN(CC)CC
Solvent: CCCO
Product: CCCOc1nc2ccc(I)cc2c(=O)n1CCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.4 %

Procedure:
To a solution of 0.38 g (1.44 mmoles) of 2-amino-5-iodobenzoic acid and 0.14 g (1.38 mmol) of triethylamine in 7.15 mL of n-propanol was added 0.25 g (1.143 mmol) of S-methyl O-propyl propylcarbonimidothioate. The reaction mixture was stirred at room temperature for 18 h, heated to 60° C. for 24 h, and then heated to reflux for 6 h. The reaction was then concentrated under reduced pressure to give about 0.6 g of crude material, which was purified by flash chromatography on silica (93:7 hexanes:ethyl acetate) to give 0.21 g of the title compound, 1H NMR (400 MHz, CDCl3): δ0.96 (t,3H); 1.06 (t,3H); 1.64-1.79 (m,2H); 1.81-1.92 (m,2H); 4.05 (t,2H); 4.43 (t,2H), 7.19 (d,1H); 7.85 (dd,1H); 8.49 (d,1H). In addition, 0.11 g of propyl-5-iodoanthranilate was obtained from the flash chromatography, 1H NMR (400 MHz, CDCl3): δ1.02 (t,3H); 1.76-1.86 (m,2H); 4.23 (t,2H); 5.8 (br s,2H); 6.45 (d,1H); 7.45 (dd, 1H); 8.13 (d,1H).
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[CH:17]([C:18]2[CH:19]=[C:20]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:16][CH:15]2[CH2:31][CH:12]1[CH2:13][CH2:14]2)[CH3:9]>CC(=O)CC>[ClH:6].[CH3:7][N:8]([CH2:10][CH:11]1[CH:17]([C:18]2[CH:19]=[C:20]([O:24][C:25](=[O:30])[C:26]([CH3:27])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=2)[CH2:16][CH:15]2[CH2:31][CH:12]1[CH2:13][CH2:14]2)[CH3:9]
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CC1C2CCC(C2)CC1c1cccc(OC(=O)C(C)(C)C)c1
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add H2O (9 mg, 0.5 mmol) and TMSCl (39 mg, 0.357 mmol) to a solution of 2,2-dimethyl-propionic acid 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenyl ester (102 mg, 0.297 mmol) in 2-butanone (50 mL). Then stir the reaction mixture at ambient temperature for 4 hours. Evaporate the mixture under vacuum to give 2,2-dimethyl-propionic acid 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenyl ester hydrochloride as white solid (112 mg, Yield: 100%). 1H NMR (400 MHz, Methanol-d4) δ 7.38-7.42 (t, J=15.6, 1H), 7.20-7.22 (d, J=7.6, 1H), 7.05 (s, 1H), 6.94-6.96 (m, 1H), 3.08-3.14 (m, 1H), 2.79 (s, 3H), 2.66 (s, 3H), 2.53-2.57 (m, 2H), 2.36 (s, 2H), 2.23 (m, 1H), 1.61-1.85 (m, 8H), 1.39 (s, 9H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]1([C:15]2[C:19]([O:20][C:21]3[CH:28]=[C:27]([CH3:29])[C:24]([C:25]#[N:26])=[C:23]([CH3:30])[CH:22]=3)=[CH:18][NH:17][N:16]=2)[CH2:14][CH2:13]1.[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1>[CH:12]1([C:15]2[C:19]([O:20][C:21]3[CH:28]=[C:27]([CH3:29])[C:24]([C:25]#[N:26])=[C:23]([CH3:30])[CH:22]=3)=[CH:18][N:17]([CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][O:31]3)[N:16]=2)[CH2:13][CH2:14]1
Reactant: C1=COCCC1
Reactant: Cc1cc(Oc2c[nH]nc2C2CC2)cc(C)c1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1cc(Oc2cn(C3CCCCO3)nc2C2CC2)cc(C)c1C#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 0.1 %

Procedure:
p-Toluenesulphonic acid (20 mg, 0.12 mmol) was added to a solution of the benzonitrile of Example 16 (1 g, 3.94 mmol) in tetrahydrofuran (30 ml). 3,4-Dihydro-2H-pyran (664 mg, 7.9 mmol) was then added dropwise at room temperature. The reaction mixture was stirred at room temperature, under nitrogen, for 15 hours. It was then evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and aqueous sodium bicarbonate (50 ml). The organic layers were washed with brine (50 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure to provide the title compound (1.93 mg, 100%).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:78][C:79]1[C:84]([C:85]([C:87]2[C:92]([F:93])=[CH:91][CH:90]=[CH:89][C:88]=2[F:94])=[O:86])=[CH:83][CH:82]=[C:81]([NH2:95])[N:80]=1>O1CCOCC1.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].O>[NH2:78][C:79]1[N:80]=[C:81]([NH:95][C:15]2[CH:16]=[CH:17][C:12]([S:9]([N:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:11])=[O:10])=[CH:13][CH:14]=2)[CH:82]=[CH:83][C:84]=1[C:85](=[O:86])[C:87]1[C:88]([F:94])=[CH:89][CH:90]=[CH:91][C:92]=1[F:93]
Reactant: Nc1ccc(C(=O)c2c(F)cccc2F)c(N)n1
Reactant: O=S(=O)(c1ccc(I)cc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(Nc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2)ccc1C(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A N,N-Dibenzyl-4-iodobenzenesulfonamide Compound 2a (20.4 mg, 0.044 mmol), Pd2(dba)3 (1.0 mg), BINAP (1.8 mg) and cesium carbonate (13 mg, 0.04 mmol) were added to a solution of Compound 1 (10 mg, 0.04 mmol) in dioxane (0.20 mL) and toluene (0.25 mL). The resulting mixture was stirred in an oil-bath (at a temperature of from about 90 to about 100° C.) for about 24 hours. The mixture was cooled to rt then water (20 mL) was added and extracted with methylene chloride (4×20 mL). The organic layers were combined, dried and evaporated, then separated by chromatography (on silica gel, eluting with 1:1 ethyl acetate:hexane) to give a 4-[[6-amino-5-(2,6-difluorobenzoyl)-2-pyridinyl]amino]-N,N-bis(phenylmethyl)benzenesulfonamide Compound 2b (11 mg, 46% yield) as a yellow powder. 1H NMR (300 MHz, CDCl3) δ 9.0 (s, br, 2H), 7.80 (d, 2H), 7.62 (d, 2H), 7.40–7.58 (m, 2H), 7.35–6.95 (m, 12H), 6.40 (s, br, 1H), 6.12 (d, 1H), 7.35 (s, 4H); MS (ESI) m/z: 585 (M+H+), 607 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:17]([CH:21]=2)[C:18]([OH:20])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:17]([CH:21]=2)[C:18]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:20])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccc(OC)c3)c(C(=O)O)c2)=C(C)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccc(OC)c3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.8 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-methoxyphenyl)benzoic acid (100 mg, 0.2369 mmol) and morpholine (41 mg, 0.4712 mmol) were dissolved in methylene chloride (20 ml), then 4-dimethylaminopyridine (6 mg, 0.0491 mmol) and WSC-HCl (136 mg, 0.7094 mmol) were added thereto and the mixture was stirred for 6 hours at room temperature. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3) to give the title compound (80 mg, 0.1629 mmol, 69%).
Reaction SMILES: [NH2:1][CH:2]([CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1>CC(C)=O>[NH:20]1[CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH:2]([CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3]
Reactant: CC(N)C(O)c1ccccc1
Reactant: O=[N+]([O-])NC1=NCCN1
Solvent: Cc1ccccc1C
Solvent: CC(C)=O
Product: CC(NC1=NCCN1)C(O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of 6.5 parts of α-(1-aminoethyl)benzyl alcohol (also known as morephedrine), 5.2 parts of 2-(nitramino)-2-imidazoline and 8 parts of xylene is stirred for 30 minutes while heating at 160°-170°C. The reaction mixture is cooled and diluted with acetone. The latter is removed in vacuo, yielding α-[1-(2-imidazolin-2-ylamino)-ethyl]benzyl alcohol as an oily residue.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 72 h

Procedure:
In ethanol (10 ml), 1-tert-butoxycarbonyl-4-[(methoxycarbonyl)methylene]piperidine (875 mg) was dissolved, followed by the addition of 10% palladium carbon (water content: about 50%, 730 mg). The resulting mixture was subjected to catalytic hydrogenation under normal pressure at room temperature for 3 days. After the removal of the catalyst by filtration, the solvent was distilled off under reduced pressure, whereby the title compound (871 mg, 99%) was obtained.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[C:30]([N:32]([CH2:36][C:37]2[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=2[O:45][CH2:46]CO)[C:33](=[O:35])[CH3:34])[CH:31]=1>CCOCC>[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[C:30]([N:32]([CH2:36][C:37]2[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=2[O:45][CH2:46][CH2:1][Br:5])[C:33](=[O:35])[CH3:34])[CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(OCCO)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: COc1ccc(OCCBr)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a stirred solution of 1.69 g (5.1 mmol) CBr4 and 2.89 g (11 mmol) PPh3 in dry dichloromethane (35 mL) 2.04 g (4.8 mmol) (1e) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight, then diluted with ether and filtered through sintered funnel. The filtrate was concentrated and the residue was purified by silica column chromatography (gradient hexane-ethyl acetate 6:1→2:1). The desired product 6a was obtained in 64% yield (1.37 g, 3.07 mmol).
Reaction SMILES: [H-].[Na+].C1(S([CH2:12][C:13]2[N:17]=[C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[NH:15][N:14]=2)(=O)=O)C=CC=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]#[N:33])=[CH:26][CH:25]=1.CO>O1CCCC1>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:31]=[C:32]([NH2:33])[N:14]3[N:15]=[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:13]3[CH:12]=2)=[CH:28][CH:29]=1
Reactant: N#CC=Cc1ccc(Cl)cc1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(-c2ccc(Cl)cc2)cc2nc(-c3ccco3)nn12
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
0.7 g (0.015 mol) sodiumhydride (55%) were added to a solution of 1.50 g (0.005 mol) 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole in 50 ml tetrahydrofuran. The mixture was refluxed and 0.85 g (0.005 mol) 3-(4-chlorophenyl)-2-propenenitrile in 30 ml tetrahydrofuran were added during, aperiod of 5.5 hours. Boiling was continued for 30 minutes and then 20 ml methanol were added at room temperature. Evaporation of the solvent and chromatography on silicagel with dichloromethane/methanol 99/1 gave 0.57 g (35%) 7-(4-chloro-phenyl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine as pale crystals. MS m/e (%): 311 (M+H+, 100).
Reaction SMILES: CO.[C:3](Cl)(=[O:5])C.C(Cl)Cl.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH:24]=[N:23][CH:22]=[CH:21]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1.C(OCC)(=O)C.CO>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH2:24][NH:23][CH2:22][CH:21]2[O:5][CH3:3])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)Cl
Reactant: COc1cc2cnccc2cc1OCc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OCc1ccccc1)C(OC)CNC2
Temperature: 25 °C
Yield: 45 %

Procedure:
F11 (5.4 g, 13.5 mmol) was stirred in THF (80 mL) and methanol (10 mL) and cooled to 0° C. before acetyl chloride (5.8 mL, 80 mmol) was added drop wise. The solution was stirred at rt o/n, After addition of DCM (100 mL), the organic layer was successively washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated to afford 4.2 g of a crude dark yellow solid. Column chromatography (petroleum ether/ethyl acetate 9/1 to 0/1 then ethyl acetate/methanol 1/0 to 10/1) afforded 1.8 g (45%) of 6-Benzyloxy-4,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline F12 and 6-benzyloxy-7-methoxyisoquinoline F13 (400 mg, 11%);
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([F:14])=[C:7]([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=1.C(O)(=O)C.Cl>C(O)C.[Fe]>[CH3:21][CH:2]([CH3:1])[CH2:3][NH:4][C:5]1[CH:6]=[C:7]([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]([F:14])=[CH:9][C:10]=1[NH2:11]
Reactant: CCOC(=O)Nc1cc(NCC(C)C)c([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)Nc1cc(NCC(C)C)c(N)cc1F
Yield: 82.5 %

Procedure:
A stirred mixture of 2.7 grams (0.009 mole) of N-(2-methylpropyl)-3-ethoxycarbonylamino-4-fluoro-6-nitroaniline, 2.0 grams (0.036 mole) of iron powder, 15 mL of acetic acid, and 0.5 mL (0.009 mole) of concentrated hydrochloric acid in 75 mL of ethanol was heated at reflux for about five hours. The reaction mixture was then concentrated under reduced pressure to a residue, which was taken up in ethyl acetate and washed with aqueous solutions saturated with sodium bicarbonate and sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. NMR analysis of the residue indicated the presence of product and acetic acid. The residue was washed with several portions of an aqueous solution saturated with sodium bicarbonate, and then was extracted thoroughly with ethyl acetate. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 2.0 grams of 2-(2-methylpropylamino)-4-ethoxycarbonylamino-5-fluoroaniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[CH:7]=[CH:6]2.P(Cl)(Cl)([Cl:16])=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:16][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: COc1ccc2[nH]c(=O)ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc2nc(Cl)ccc2c1
Temperature: 95 °C

Procedure:
A suspension of 6-methoxy-1H-quinolin-2-one of Step B (5.136 g, 29.2 mmol) in toluene (100 mL) is treated with phosphorous oxychloride 913.8 mL) and heated at 95° C. under nitrogen for 2 hours. The crude mixture is poured into ice water and basified with 50% aqueous sodium hydroxide. The solution is extracted with ethyl acetate, the extracts are dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is pre-absorbed on silica gel Merck-60 and flash chromatographed using a gradient of ethyl acetate (10–20%) in hexane to provide the title compound (5.25 g) as a white crystalline solid, m.p. 105–107° C.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[C:13]1([CH2:19][CH2:20]O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7]
Reactant: Cc1ccccc1C=CC(=O)O
Reactant: OCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1C=CC(=O)OCCc1ccccc1
Reaction time: 15 h
Yield: 74 %

Procedure:
A solution of 324.0 g (2.00 moles) of o-methylcinnamic acid, 428.0 g (3.5 moles) of 2-phenylethanol, 10.0 g (0.058 moles) of p-toluenesulfonic acid and 1,200 ml of toluene was refluxed under a water separator. After 15 hours, the calculated amount of water had separated off. The reaction solution was washed first with water and then with saturated sodium bicarbonate solution. The combined washwater was extracted once with ether, and the ether phase was combined with the organic phase. The combined, organic phases were fractionated over a 10 cm Vigreux column. The solvents were separated off under atmospheric pressure and in a vacuum from a water pump. The Vigreux column was replaced by a column head and the product was distilled under 0.01 mm Hg (b.p. 154°-155° C./0.01 mm Hg). 394.0 g of phenylethyl o-methylcinnamate of melting point 52° to 53° C. were obtained.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:8]1[CH:9]=[C:10]([C:14]2[C:15](=[O:26])[C:16]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][N:18]([CH3:20])[CH:19]=2)[CH:11]=[CH:12][CH:13]=1)([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:32]O>>[CH3:32][O:6][C:5]([C:8]1[CH:9]=[C:10]([C:14]2[C:15](=[O:26])[C:16]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][N:18]([CH3:20])[CH:19]=2)[CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: CO
Reactant: Cn1cc(-c2cccc(C(=O)O)c2)c(=O)c(-n2cccn2)c1
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(-c2cn(C)cc(-n3cccn3)c2=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
24 ml (0.33 mole) of thionyl chloride are added dropwise to 30 g (0.09 mole) of 5-(3-carboxyphenyl)-1-methyl-3-(pyrazol-1-yl)-4-pyridone-sulphuric acid adduct in 100 ml of methanol at 0° C. to 10° C.; when the addition has ended, the mixture is stirred at room temperature for 12 hours and concentrated in vacuo, the oil which remains is taken up in 100 ml of water and the mixture is rendered weakly alkaline with aqueous sodium carbonate solution and extracted three times with 100 ml of methylene chloride each time. The combined organic phases are washed with water, dried over sodium sulphate and concentrated in vacuo. The crystals which remain are digested with ether, filtered off with suction and dried. 20 g (91% of theory) of 5-(3-methoxycarbonylphenyl)-1-methyl-3-(pyrazol-1-yl)-4-pyridone of melting point 144° C. are obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[CH:7][N:8]=1)#[N:2].C(O)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[C:1]([CH2:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)#[N:2]
Reactant: N#CCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N#CCc1ncc[nH]1
Reaction time: 3 h

Procedure:
2-Cyanomethyl-1-tritylimidazole (25 g) was dissolved in trifluoroacetic acid (70 ml). After stirring for 3 hours, to the reaction mixture was added ethanol (70 ml) and the solvent was removed in vacuo. Resulting solid was collected and washed with diisopropyl ether to give 2-cyanomethylimidazole trifluoroacetate (12.67 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([O:30]CC)=[O:29])=[O:21])=[CH:14][C:13]=3[N+:33]([O-:35])=[O:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO.[OH-].[Na+]>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([OH:30])=[O:29])=[O:21])=[CH:14][C:13]=3[N+:33]([O-:35])=[O:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared by the hydrolysis of the compound of Example 203 under basic conditions (aq. NaOH/EtOH), producing a light yellow solid:, mp 165° C.(dec.). 1H NMR (DMSO-d6, 300 MHz) δ 1.15-1.52 (m, 3H), 1.46-1.62 (m, 2H), 2.32 (m, 1H), 2.80 (m, 1H), 3.45(br, 1/2H), 4.00 (br, 1/2H), 4.44 (br, 1/2H), 4.800 (br, 1/2H), 6.83 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 7.09 (dd, J=2.0, 14.0 Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 7.20 (d, J=15.5 Hz. 1H), 7.35 (d, J=15.5 Hz, 1H), 7.73 (m, 1H), 8.52 (m, 1H). MS (ESI) m/z 469 (M−H)+, 471 (M+H)+. Anal. calcd. for C23H21N2l O7SNa.NaOH.2.7 H2O: C, 47.54; H, 4.75; N, 4.82. Found: C, 47.18; H, 4.36; N, 4.89.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:10]=2)[C:5]([F:8])=[N:6][CH:7]=1.FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cc(Cl)cnc2F)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
4-(5-Chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (3.87 g, 8.06 mmol) (Example 313, Step 1) was dissolved in TFA (81 mL), trifluoromethanesulfonic acid (2.1 mL, 24 mmol) was added, and the resulting mixture was stirred at 80° C. for 2 h. The reaction mixture was then concentrated in vacuo. The residue was partitioned between EtOAc (150 mL) and sodium bicarbonate (saturated, aqueous). The organic layer was the separated, washed 2 times with 100 mL of sodium bicarbonate (saturated, aqueous), dried over sodium sulfate, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 40% EtOAc/hexanes) provided the title compound (51% yield). m/z (ESI, +ve ion) 240.1 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][CH3:22])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:19]([O:18][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:9]=1[OH:8])[NH:15][CH:14]=[CH:13]2)[CH2:20][CH2:21][CH3:22]
Reactant: [H][H]
Reactant: CCCCOc1cc2cc[nH]c2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCOc1cc2cc[nH]c2cc1O
Yield: 90.2 %

Procedure:
6-Benzyloxy 5-butoxy indole (4 g, 0.0135 mole) is hydrogenated under 50 atmospheres of hydrogen in a reactor with 40 ml of ethanol and 0.6 g 10% palladium on carbon for 3 hours. After filtration and evaporation of the solvent, the residue is recrystallized in a mixture of benzene-hexane to produce 5-butoxy 6-hydroxy indole (2.5 g, yield 90%).