Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:13](O)[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.O>CCCCCCC>[CH3:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1)=[O:10])[CH3:12]
Reactant: COc1cc(CO)ccc1O
Reactant: CC(C)CCCCCCC(=O)O
Solvent: O
Solvent: CCCCCCC
Product: COc1cc(COC(=O)CCCCCCC(C)C)ccc1O
Temperature: 55 °C
Reaction time: 13.5 h
Yield: 90.2 %

Procedure:
8-Methylnonanoic acid (1.54 g, 8.95 mmol) and vanillyl alcohol (1.34 g, 8.70 mmol) were measured and placed in a flask (25 ml) and dissolved in heptane (0.5 ml). Lipase PS-C “Amano” I (enzyme immobilized on ceramic: 335 mg) was added and the mixture was heated with stirring in an oil bath at 55° C. for 13.5 hours. After 2 to 3 hours of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The flask was returned to room temperature, heptane (5 ml) was added to the reaction mixture, and the mixture was stirred for 10 minutes. The immobilized enzyme and a small amount of precipitated vanillyl alcohol were removed by filtration. The filtrate was concentrated under reduced pressure, and the obtained oil (2.42 g) was analyzed by HPLC to find that dihydrocapsiate was contained in 97.2 area %. The mixture was partitioned with heptane (15 ml) and 10% aqueous citric acid solution (15 ml), and the aqueous layer was further extracted with heptane (15 ml). The combined heptane layer was washed with water (10 ml) and saturated brine (10 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give a mixture (2.42 g) of dihydrocapsiate and 8-methylnonanoic acid as a colorless oil. As a result of the analysis, the yield of dihydrocapsiate was 72.3%, and the purity was 99.6 area % by HPLC. The mixture contained 24.8 wt % of 8-methylnonanoic acid relative to dihydrocapsiate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH2:32]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:43]4[CH2:44][CH2:45][N:40]([CH2:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:41][CH2:42]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: c1ccc(CCN2CCNCC2)cc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(CCc2ccccc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-phenethylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z=620.02 (M+H+); retention time=0.63 minutes.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9].Cl.[F:15][C:16]([CH3:21])([CH3:20])[C@H:17]([NH2:19])[CH3:18].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.CO>[F:15][C:16]([CH3:21])([CH3:20])[C@H:17]([NH:19][C:2]1[C:3]2[N:4]([CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9])[CH3:18]
Reactant: C[C@@H](N)C(C)(C)F
Reactant: NC(=O)c1cnn2cccc2c1Cl
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cccc12)C(C)(C)F
Temperature: 25 °C
Yield: 32 %

Procedure:
A solution of 4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 3, 50 mg, 0.26 mmol), (R)-2-Fluoro-1,2-dimethyl-propylamine hydrochloride salt (47 mg, 0.33 mmol, from step 3), and diisopropylethylamine (0.089 mL, 0.51 mmol) in NMP (0.5 mL) was heated to 100° C. for 1 hour in the CEM microwave. The mixture was cooled to rt, diluted with MeOH and purified by reverse-phase Prep HPLC (condition A). The fraction containing the major product was concentrated on the rotovap to remove the MeOH and the aqueous slurry of the product was neutralized by addition of ˜1 mL of saturated aq sodium bicarbonate. Sonication of the slurry followed by vacuum filtration and air drying in the funnel afforded 22 mg (33%) of a pale yellow solid as the title compound. HPLC (condition A): retention time=7.70 min. LCMS (condition B): m/z 265.2. 1H NMR (500 MHz, CD3OD) δ ppm 10.74 (1 H, br. s.), 8.16 (1 H, s), 7.41-7.80 (1 H, m), 7.01 (1 H, dd, J=4.72, 1.39 Hz), 6.72 (1 H, dd, J=4.58, 2.64 Hz), 4.28-4.64 (1 H, m), 1.46-1.55 (6 H, m), 1.44 (3 H, d).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28]>CN(C=O)C>[Cl:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[N:13]([CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=c1[nH]cc(-c2ccc(Cl)nc2)c(=O)[nH]1
Reactant: COC(CCBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2ccc(Cl)nc2)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
A mixture of 5-(6-chloro-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep91, 1.05 g, 4.10 mmol), and K2CO3 (565 mg, 4.10 mmol) in DMF (20 ml) was stirred 20 minutes at room temperature. 3-Bromo-1,1dimethoxy-propane (635 μl, 4.65 mmol) was added in three portions over 6 days. Solvent was then removed under vacuum at 40° C. and the residue washed once with petroleum ether and twice with ethyl acetate. Ethyl acetate phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98:2:0.2) to give 534 mg of the title compound as a white solid (40% yield).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[C:31]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:30]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:57][O:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][CH:60]=1>C(Cl)Cl>[CH3:57][O:58][C:59]1[C:64]2[C:34]3[C:29](=[CH:30][C:31]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:33]=3)[C:14]3[C:15](=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=3)[C:63]=2[C:62]([O:65][CH3:66])=[CH:61][CH:60]=1
Reactant: COc1ccc(OC)cc1
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(OCCCCCCCCCC)c(OCCCCCCCCCC)c2)cc1OCCCCCCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCOc1cc2c3cc(OCCCCCCCCCC)c(OCCCCCCCCCC)cc3c3c(OC)ccc(OC)c3c2cc1OCCCCCCCCCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
Solid 3a (5.50 g, 7.06 mmol) was added to an ice cold suspension of anhydrous FeCl3 (9.16 g, 56.5 mmol) in dry CH2Cl2 (250 mL). Within 2 min 1,4-dimethoxybenzene (3.90 g, 28.2 mmol) was added to the green reaction mixture. The reaction mixture was allowed to warm slowly to room temperature and then stir for an additional 12 h. The reaction mixture was quenched with anhydrous MeOH (30 mL). The volume of the mixture was reduced to 50 mL under reduced pressure and MeOH (200 mL) was added to the resulting oil. The slightly violet product was colled on a frit and washed with MeOH. The product was further purified by column chromatography using a 50% CH2Cl2/50% hexane solvent mixture to afford 4a (RF=0.24) as a colorless solid in 84% yield (mp 69-70° C.).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C@@H:10]1[C:15]([C:16]#[N:17])=[C:14]([CH3:18])[N:13]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:12](=[O:29])[NH:11]1.[ClH:30].O.N([O-])=O.[Na+].[S:36](=[O:38])=[O:37]>O.C(O)(=O)C.[Cu]Cl>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([C@@H:10]2[C:15]([C:16]#[N:17])=[C:14]([CH3:18])[N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:12](=[O:29])[NH:11]2)=[C:2]([S:36]([Cl:30])(=[O:38])=[O:37])[CH:7]=1)#[N:9]
Reactant: Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2N)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: O=S=O
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
Under argon, (4R)-4-(2-amino-4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (3.0 g, 7.55 mmol) was initially charged in a 2:1:1 mixture of acetic acid/conc. hydrochloric acid/water (50 ml in total) at −10° C. A solution of sodium nitrite (547 mg, 7.93 mmol) in water (6 ml) was added, and the mixture was stirred at −10° C. for 15 min. This solution was then added to a suspension, pre-cooled to −10° C. and saturated with sulfur dioxide, of copper(I) chloride (75 mg, 755 μmol; 0.1 eq.) in glacial acetic acid (60 ml). The reaction was stirred at −10° C. (internal temperature) for 60 min and then slowly, over a period of 3 h, warmed to +15° C. (reaction monitored by HPLC and LC-MS). The reaction mixture was then once more cooled to 0° C., and then pipetted into about 300 ml of ice-cold water. The aqueous phase was extracted repeatedly with MTBE. The combined organic phases were washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound was obtained as a solid (1.67 g, 73% pure according to LC-MS, 32% of theory) and used without further purification for subsequent reactions.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=3)(=[O:19])=[O:18])[C:13]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:12]([O:36][CH3:37])[N:11]=2)[CH:7]=[CH:6][N:5]=1.C(N(C(C)C)C(C)C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49].Cl>C(Cl)Cl.C(Cl)Cl.CO>[CH3:47][S:48]([NH:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=3)(=[O:19])=[O:18])[C:13]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:12]([O:36][CH3:37])[N:11]=2)[CH:7]=[CH:6][N:5]=1)(=[O:50])=[O:49]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(CN)c2)nc1OC
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(CNS(C)(=O)=O)c2)nc1OC

Procedure:
A solution of 70 mg of 5-methyl-pyridine-2-sulfonic acid [2-(2-aminomethyl-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide hydrochloride, product of example 30 b), in CH2Cl2 (5 ml), was treated at RT with 50 mg of N-ethyldiisopropylamine, 15 mg of methanesulfonyl chloride and then refluxed for 18 h until the reaction was complete according to TLC analysis (CH2Cl2/MeOH: 95/5). The mixture was poured into cold diluted HCl and the product extracted into CH2Cl2. The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The residue was purified on a silica gel chromatography column (eluted with Me2Cl2/MeOH: 95/5). Combination of the purified fractions and evacuation in vacuo afforded 5-methyl-pyridine-2-sulfonic acid [2-[2-(methanesulfonylamino-methyl)-pyridin-4-yl]-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide as a light yellow solid. ISN mass spectrum, m/e 585 (M−1 calculated for C25H26N6O7S2: 585).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].IC.CN(C=O)C>O>[CH3:12][O:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ncccc1O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ncccc1OC
Reaction time: 8 h
Yield: 44.5 %

Procedure:
A mixture of methyl 3-hydroxypyridine-2-carboxylate (Intermediate 96, 1.2 g, 7.8 mmol), potassium carbonate (1.2 g, 8.7 mmol), iodomethane (0.63 ml, 1.0 mmol) and DMF (10 ml) was stirred overnight. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with water and concentrated under vacuum. The residue (0.82 g) was purified by flash column chromatography (5 g silica; heptane-ethyl acetate, 1:0-5:1-2:1) to give the title compound as a clear oil (0.58 g, 45%). Method C HPLC-MS: MH+ requires m/z=168. Found: m/z=168, Rt=0.76 min (100%).
Reaction SMILES: [CH3:1][CH:2]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[NH:4][CH2:3]1.CC1N([C:26]([CH2:28][C:29]#[N:30])=[O:27])N=C(C)C=1.C(N(CC)C(C)C)(C)C.[Cl-].[Na+]>O.O1CCOCC1>[CH3:1][CH:2]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[N:4]([C:26](=[O:27])[CH2:28][C:29]#[N:30])[CH2:3]1
Reactant: CC1CNC12CCCN(c1ncnc3[nH]ccc13)C2
Reactant: Cc1cc(C)n(C(=O)CC#N)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC1CN(C(=O)CC#N)C12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 100 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
An optically-active compound of 4-(3-methyl-1,6-diazaspiro[3.5]non-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (1.8 g) was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (2.3 g), N,N-diisopropylethylamine (2.4 ml) and 1,4-dioxane (18 ml), and the mixture was stirred at 100° C. for 3 hours. The mixture was cooled to room temperature. Then, thereto were added water and saturated aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted with chloroform, and the combined organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=1/1, followed by chloroform/methanol=20/1 to 10/1). The resulting residue was purified by silica gel column chromatography (eluent: chloroform/acetone=10/1 to 1/1) again. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 10/1) again to give the titled compound (1.8 g).
Reaction SMILES: [I:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[C:13]([S:15][C:16]3[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=3)[CH:14]=2)[C:10]#N)=[CH:4][CH:3]=1.C(O)C.[OH-:27].[Na+].[OH2:29]>>[I:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[C:13]([S:15][C:16]3[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=3)[CH:14]=2)[C:10]([OH:29])=[O:27])=[CH:4][CH:3]=1
Reactant: O
Reactant: Cn1ccnc1Sc1cc(C#N)cc(Oc2ccc(I)cc2)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: Cn1ccnc1Sc1cc(Oc2ccc(I)cc2)cc(C(=O)O)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
A mixture of 3-(4-iodo-phenoxy)-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzonitrile (1.60 g, 3.69 mmol), 12 mL, of ethanol, 1.2 mL of water and 1 mL of 50% w/w NaOH in water (18.45 mmol) was microwave heated at 130° C. for 5 min and then cooled to rt. The mixture was concentrated by evaporation and diluted with 20 mL of water, then with stirring, 20 mL of 1 M aqueous NaHSO4 was added. The resulting solid was collected by filtration and dried at 0.1 mm/23° C. for 16 h to provide 1.5 g (90%) of the title compound as a white solid: 1H NMR (500 MHz, DMSO-d6): δ 3.63 (s, 3H), 6.91 (d, 2H, J=8 Hz), 6.94 (t, 1H, J=2 Hz), 7.14 (d, 1H, J=1 Hz), 7.21 (dd, 1H, J=2, 1 Hz), 7.28 (dd, 1H, J=2, 1 Hz), 7.51 (d, 1H, J=1 Hz), 7.75 (d, 2H, J=8 Hz); LCMS (m/z): 453.5 [C17H13IN2O3S+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[S:9][C:8]2[C:10]([CH3:17])=[C:11]([OH:16])[C:12]([CH3:15])=[C:13]([CH3:14])[C:7]=2[O:6]1.[I-:18].[Na+].O>CC(C)=O>[OH:16][C:11]1[C:12]([CH3:15])=[C:13]([CH3:14])[C:7]2[O:6][CH:5]([CH2:4][CH2:3][CH2:2][I:18])[S:9][C:8]=2[C:10]=1[CH3:17]
Reactant: [I-]
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCCl)O2
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)SC(CCCI)O2

Procedure:
120 mg of 2-(3-chloropropyl)-5-hydroxy-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 77) were dissolved in 2 ml of acetone, after which 660 mg of sodium iodide were added, and the reaction mixture was heated under reflux for 10 hours. The reaction mixture was cooled and then poured into water, and the resulting precipitate was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure and the resulting crude product was purified in the same manner as described in (a), to give the title compound having the same Rf value and mass spectrum as the product of (a) above.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].N>[Ni].CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH2:6]
Reactant: N#Cc1cc(F)cc(F)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cc(F)cc(F)c1
Reaction time: 2.5 h
Yield: 99.6 %

Procedure:
A slurry of Raney nickel in methanol was added to a solution of 3,5-difluorobenzonitrile (12.0 g, 0.0863 mole) in methanol (100 ml) saturated with ammonia and th emixture was hydrogenated for 2.5 hours at 50 pounds pressure. The solution was decanted from the catalyst and the catalyst washed four times with methanol and decanted. The combined decanted solvent was evaporated and the residue dissolved in ethyl acetate and extracted twice with 1N hydrochloric acid (50 ml). The acid solution was made basic with 10% sodium hydroxide and extracted with three portions of ethyl acetate. The ethyl acetate was washed with water, brine, dried over sodium sulfate and the solvent removed to give 3,5-difluorobenzylamine as an oil (12.3 g, 100%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N+:13]([C:16]1[O:20][C:19]([C:21]([NH:23][NH2:24])=[O:22])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:24][NH:23][C:21]([C:19]1[O:20][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1)=[O:22]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc([N+](=O)[O-])o1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc([N+](=O)[O-])o1
Temperature: 100 °C
Yield: 74 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 5-nitro-2-furohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 158 mg of the title compound (74%) as a Orange solid in 98.3% purity by HPLC (Rt: 5.31, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:69])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH2:66][CH2:67][OH:68])[N:64]=[CH:65][C:52]3=[CH:51][CH:50]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:78]>CO.O>[ClH:78].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:69])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH2:66][CH2:67][OH:68])[N:64]=[CH:65][C:52]3=[CH:51][CH:50]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5cnn(CCO)c54)c3=O)cc2)CCC1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5cnn(CCO)c54)c3=O)cc2)CCC1
Yield: 74 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[1-(2-hydroxy-ethyl)-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (2 mL), water (8 mL) and 1 M HCl (0.2 mL) and chromatographed on a 5 g C18 cartridge {gradient 20 to 60% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound (33.5 mg, 74%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.60 (br s, 3H), 8.33 (s, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.57-7.55 (m, 2H), 7.51-7.37 (m, 5H), 7.32 (d, J=8.4 Hz, 2H), 4.95 (t, J=5.1 Hz, 1H), 4.80 (t, J=5.6 Hz, 2H), 3.89 (q, J=5.5 Hz, 2H), 2.63-2.52 (m, 4H), 2.24-2.13 (m, 1H), 1.87-1.76 (m, 1H). LCMS (Method E): RT=3.00 min, [M+H]+=452.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH2:29][CH:30](Cl)[C:31]([O:33]CC)=O)[CH:25]=[CH:26][C:27]=1[CH3:28])([CH3:19])[CH2:9][C:8]2=[O:37])(=O)C.[NH2:38][C:39](N)=[S:40].S1(CCCC1)(=O)=[O:43].Cl>COCCO>[C:15]([C:14]1[CH:13]=[C:12]2[C:7]([C:8](=[O:37])[CH2:9][C:10]([CH2:20][O:21][C:22]3[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=3[CH3:28])[CH2:29][CH:30]3[S:40][C:39](=[O:43])[NH:38][C:31]3=[O:33])([CH3:19])[O:11]2)=[CH:6][C:5]=1[OH:4])([CH3:17])([CH3:18])[CH3:16]
Reactant: CCOC(=O)C(Cl)Cc1ccc(C)c(OCC2(C)CC(=O)c3cc(OC(C)=O)c(C(C)(C)C)cc3O2)c1
Reactant: NC(N)=S
Reactant: O=S1(=O)CCCC1
Agent: Cl
Solvent: COCCO
Product: Cc1ccc(CC2SC(=O)NC2=O)cc1OCC1(C)CC(=O)c2cc(O)c(C(C)(C)C)cc2O1

Procedure:
the procedure described in Example 3 was repeated, but using 2,4 g of ethyl 3-[3-(6-acetoxy-7-t-butyl-2-methyl-4-oxochroman-2-ylmethoxy) -4-methylphenyl]-2-chloropropionate (prepared as described in Preparation 42), 0.7 g of thiourea, 5 ml of sulfolane, 10 ml of 2N aqueous hydrochloric acid and 15 ml of ethylene glycol monomethyl ether, to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CCO>[CH2:23]1[O:24][C:7]2[CH:6]=[C:5]3[C:10]([C:11]([C:13]4[CH:18]=[CH:17][C:16]5[O:19][CH2:20][O:21][C:15]=5[CH:14]=4)=[N:12][C:3]([CH2:2][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[N:4]3)=[CH:9][C:8]=2[O:22]1
Reactant: C1CNCCN1
Reactant: ClCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Solvent: CCO
Product: c1cc2c(cc1-c1nc(CN3CCNCC3)nc3cc4c(cc13)OCO4)OCO2
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.9 %

Procedure:
A suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxy-phenyl)quinazoline (96 mg, 0.3 mmol) in EtOH (9 mL) was treated with piperazine (860 mg, 10 mmol). The mixture was stirred at rt for 15 h, then it was poured into ice cold dilute NaHCO3 solution. On standing at rt for 72 h the title compound was crystallized out as colorless plates. It was collected by, filtration, washed with water, and dried to give 74 mg of solid; mp 73-76° C. 1H NMR (CDCl3) 7.37 (d, J=8.4, 1H), 7.16-7.24 (m, 3H), 6.97 (d, J=8.4, 1H), 6.14 (s, 2H), 6.07 (s, 2H), 3.95 (s, 2H), 2.97 (bs, 4H), 2.65 (bs, 41H).