Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[H][H]>[Pd].O1CCCC1>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Yield: 97 %

Procedure:
A mixture of racemic ethyl 2-ethoxy-3-(4-benzyloxyphenyl)propionate of the formula (12a) (40 g) obtained according to the procedure described in step (iv) above, 5% Pd/C (8 g) and tetrahydrofuran (120 ml) was subjected to hydrogenation at room temperature and 50–60 psi of hydrogen pressure for a period of 8–12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered off and the solvent was removed under reduced pressure to afford the title compound of the formula (13a) (28–29 g, 97–98%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[BH4-].[Na+].Cl>CO.C(O)(=O)C>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[CH:10][CH:9]=1
Reactant: NCCCO
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CNCCCO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a solution of 3-amino-propan-1-ol (15.0 g, 200 mmol) in methanol (300 ml) was added para-methoxybenzaldehyde (28.6 g, 210 mmol) and a few drops of acetic acid at room temperature. The mixture was stirred at room temperature for 2 hours and cooled to 0° C. After the addition of sodium borohydride (11.4 g, 300 mmol), the mixture was stirred at room temperature for another 2 hours and acidified with 3N hydrochloric acid. The biphasic mixture was stirred at room temperature for 10 minutes. The organic solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous phase was washed with ethyl acetate and basified with 6N sodium hydroxide. Extraction with chloroform was performed and the organic phase was dried over sodium sulfate followed by concentration in vacuo to afford 3-(4-methoxy-benzylamino)-propan-1-ol as pale yellow oil (16.4 g, 42%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([C:13]1[O:17][N:16]=[C:15]([N:18]=[C:19]=[O:20])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C1COCC1>[C:9]([C:13]1[O:17][N:16]=[C:15]([NH:18][C:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)=[O:20])[CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1cc(N=C=O)no1
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Temperature: 50 °C
Yield: 80 %

Procedure:
to THF (300 ml, degassed w/ argon) was added 3-aminophenol (4.36 g, 40 mmol) and 5-tert-butyl-3-isocyanatoisoxazole (6.64 g, 40 mmol) and the mixture was heated at 50° C. overnight. After cooling to room temperature, the reaction was concentrated in vacuo, and the resulting foam purified by column chromatography (25-75% EtOAc/hexanes) to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (8.81 g, 32 mmol, 80%). 1H NMR (300 MHz, DMSO-d6) δ 9.39 (s, 1h), 9.37 (s, 1h), 8.69 (s, 1h), 7.06 (t, 1h), 7.01 (s, 1h), 6.78 (d, 1h), 6.49 (s, 1h), 6.41 (d, 1h), 1.29 (s, 9h); LC-MS (ESI) m/z 275 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[NH:11][N:10]=2)[C:5]([F:17])=[CH:4][N:3]=1.Cl.[F:19][C:20]1[CH:21]=[N:22][C:23]([C@@H:26]([NH2:28])[CH3:27])=[N:24][CH:25]=1.CCN(C(C)C)C(C)C>CCCCO>[CH3:15][N:14]([CH3:16])[C:12]1[NH:11][N:10]=[C:9]([NH:8][C:6]2[C:5]([F:17])=[CH:4][N:3]=[C:2]([NH:28][C@H:26]([C:23]3[N:24]=[CH:25][C:20]([F:19])=[CH:21][N:22]=3)[CH3:27])[N:7]=2)[CH:13]=1
Reactant: CN(C)c1cc(Nc2nc(Cl)ncc2F)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncc(F)c(Nc2cc(N(C)C)[nH]n2)n1)c1ncc(F)cn1
Temperature: 160 °C
Yield: 67.8 %

Procedure:
A microwave reaction vessel was charged with N3-(2-chloro-5-fluoropyrimidin-4-yl)-N5,N5-dimethyl-1H-pyrazole-3,5-diamine (Method 35, 50 mg, 0.2 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 50 mg, 0.23 mmol), and DIPEA (0.15 ml, 0.86 mmol) in n-BuOH (1 ml) was heated in a microwave reactor at 160° C. for 2 hours. Solvent was removed. The residue was purified by silica gel chromatography (by ISCO Combiflash with gradient 0-5% Methanol in methylene chloride with 1% NH4OH) to afford the title compound as a white solid (49 mg, 67%). 1H NMR (CD3OD, 400 MHz) δ 8.77 (s, 2H), 8.23 (s, 1H), 5.32 (br, 1H), 3.92 (q, 1H), 3.13 (s, 6H), 1.71 (d, 3H); m/z 362
Reaction SMILES: C1(C)C=CC=CC=1.C[Al](C)C.[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][CH2:30][CH2:31][C:32]2[N:42]=[CH:41][CH:40]=[CH:39][C:33]=2[C:34](OCC)=[O:35])[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>O.ClCCl>[O:35]=[C:34]1[C:33]2[CH:39]=[CH:40][CH:41]=[N:42][C:32]=2[CH2:31][CH2:30][CH2:29][N:28]1[CH:25]1[CH2:24][CH2:23][N:22]([C:20]([O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:21])[CH2:27][CH2:26]1
Reactant: CCOC(=O)c1cccnc1CCCNC1CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(N2CCCc3ncccc3C2=O)CC1
Yield: 56.1 %

Procedure:
A 2 M toluene solution (14.6 mL) of trimethylaluminum was added at 0° C. to a mixture of ethyl 2-(3-((1-((benzyloxy)carbonyl)piperidin-4-yl)amino)propyl)nicotinate (2.4 g) and dichloromethane (60 mL), and the resultant mixture was stirred at room temperature for 36 hours. Water was added to the reaction mixture, and then, the mixture was neutralized by the addition of hydrochloric acid. The organic layer was separated, and then, the aqueous layer was subjected to extraction with dichloromethane. Combined organic layers were washed with water and saturated saline and dried over sodium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol/dichloromethane) to obtain the title compound (1.2 g).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:3][C:2]1[CH2:4][O:5][C:6](=[O:7])[C:1]=1[C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: O=C1COC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a stirring solution of 650 mg (6.5 mmol) of tetronic acid in 20 mL of dimethylformamide is added 1.0 mL (7.17 mmol) of triethylamine and 230 mg (1.88 mmol) of 4-dimethylaminopyridine at 0° C. Next, 1.50 g (7.81 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.0 g (7.81 mmol) of palmitic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is recrystallized from pentane to give 2.0 g (91%) of 4-hydroxy-3-[1-oxohexadecyl]-2(5H)-furanone, mp 81°-83° C.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:24](C)=O.[Na+]>ClC(Cl)C>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:11]1[C:9]([N:3]1[CH2:4][C@@H:5]2[CH2:8][C@H:2]1[CH2:7][N:6]2[CH3:24])=[O:10]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(c1cc2ccccc2[nH]1)N1C[C@@H]2C[C@H]1CN2
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN1C[C@@H]2C[C@H]1CN2C(=O)c1cc2ccccc2[nH]1
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of (S,S)-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-(1H-indol-2-yl)-methanone hydrochloride (50 mg, 0.18 mmol), TEA (50 μL, 0.36 mmol), and formaldehyde (6 μL, 0.22 mmol) in dichloroethane (DCE)/MeOH (10:1, 3 mL) was added NaB(OAc)3H (115 mg, 0.54 mmol). After 2 h at rt, the mixture was diluted with satd. aq. NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were washed with satd aq. NaCl, dried (Na2SO4), and concentrated to yield an orange solid (44 mg, 96%). MS (ESI): mass calcd. for C15H17N3O, 255.14; m/z found, 256.4 [M+H]+. 1H NMR (mixture of rotamers; CDCl3): 10.34-10.08 (m, 1H), 7.64-7.54 (m, 1H), 7.44-7.35 (m, 1H), 7.24-7.16 (m, 1H), 7.09-7.00 (m, 1H), 6.80 (s, 0.5H), 6.67 (s, 0.5H), 4.99-4.86 (m, 1H), 4.05-3.95 (m, 0.7H), 3.84-3.77 (m, 0.3H), 3.71-3.62 (m, 1H), 3.55-3.46 (m, 1H), 3.18-3.10 (m, 0.3H), 2.98-2.88 (m, 0.7H), 2.82-2.69 (m, 1H), 2.46-2.31 (m, 3H), 1.98-1.88 (m, 1H), 1.79-1.70 (m, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O>C1COCC1.CCCCCC>[CH2:11]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCBr
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCc1cccs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a cooled (−70° C.) mixture of thiophene (17.6 g, 0.21 mol) in anhydrous THF (100 mL) was added dropwise a solution of n-BuLi (137.5 ml, 1.6 M, 0.22 mol) in hexane. After stirring for 1 hour at 0° C., the mixture was cooled to −40° C. followed by addition of 1-hexylbromide (0.22 mol). The mixture was slowly heated to r.t. Water (250 mL) was added and the mixture was extracted with diethylether (3×150 mL). The combined organic fractions were dried over MgSO4 and concentrated in vacuo. The product was purified by means of vacuum distillation. This product was prepared according to the general procedure and obtained as a colourless oil (26.5 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:43]([C:39]2[CH:38]=[C:37]3[C:42](=[CH:41][CH:40]=2)[N:34]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:22]4[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:32][CH:31]=2)[C:35]([CH3:47])=[C:36]3[CH3:46])=[O:44])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1ccc(Cl)cc1C(F)(F)F
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc(Cl)cc3C(F)(F)F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (4-chloro-2-(trifluoromethyl)phenyl)methanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 591 [M+H]+.
Reaction SMILES: C([CH2:20][CH2:21][O:22][CH:23]([OH:25])[CH3:24])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[I:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[I:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:20][CH2:21][O:22][CH:23]([OH:25])[CH3:24])=[CH:29][CH:28]=1
Reactant: Oc1ccc(I)cc1
Reactant: CC(O)OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(O)OCCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 13 was allowed to react with 4-iodophenol as described in example 1. When the reaction was completed (ca. 2 h) the solvent was evaporated off and the residue was suspended in diethyl ether and passed though a short column of silica gel. The eluent was removed in vacuo and the residue was dissolved in the mixture of TFA and ethanol (9:1, v/v) and stirred overnight at ambient temperature after being concentrated. The residue was taken in methylene chloride and washed with sat. NaHCO3, dried (Na2SO4) and concentrated. Purification was performed on silica gel. The column was eluted initially with methylene chloride to remove trityl carbinol and then with the mixture of CH2Cl2:MeOH (9:1, v/v) to elute the desired product. Compound 14: 1H NMR (CDCl3): δ 7.53 (2H, d, J 9.0); 6.68 (2H, d, J 9.0); 4.07 (2H, m); 3.83 (2H, m); 3.73 (2H, m); 3.64 (2H, m); 2.26 (1H, br).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[O:2]1.O.[NH2:13][NH2:14]>>[C:3]1(=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1](=[O:2])[N:14]=[N:13]1
Reactant: NN
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Product: O=C1N=NC(=O)c2ccccc21

Procedure:
When R7 and R8 are cyclopentylene or cyclohexylene, the dichloro intermediate is conveniently prepared from a 4,5,6,7-tetrahydro-4,7-(methano or ethano)isobenzofuran-1,3-dione. Diels and Alder, Ann., 478, 149 (1930); Ann., 490, 236 (1931). The dione compound is reacted with excess hydrazine hydrate in an exothermic reaction to produce the corresponding hexahydro-5,8-(methano or ethano)phthalazine-1,4-dione. Additional heating at 100°-170° C. for 10-30 minutes may be useful to complete the reaction. The phthalazine-1,4-dione is then reacted with excess phosphorus oxychloride heated at reflux for about 2-4 hours, cooled and the product hydrolyzed by careful addition of ice and water to produce the dichloro intermediate.
Reaction SMILES: [F:1][C:2]([F:15])([C:11]([F:14])([F:13])[F:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].N1C=CC=CC=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O>[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:15])([F:1])[C:11]([F:12])([F:13])[F:14])(=[O:30])=[O:29]
Reactant: OCCCCCCCC(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCCCCCC(F)(F)C(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
3.0 g of 8,8,9,9,9-pentafluorononan-1-ol are dissolved in 26 ml of abs. pyridine, 3.1 g of p-toluenesulphonyl chloride are added at 0° C. and the mixture is stirred in the cold for 1.5 hours. The reaction mixture is then added to water, extracted 3 times with ether, dried over magnesium sulphate and concentrated in vacuo. Preparative column chromatography on silica gel using a hexane-ethyl acetate gradient leads to 4.1 g of 8,8,9,9,9-pentafluorononyl tosylate as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[NH:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=1)[C:7]#N.O=[CH:24][C:25](=C)[CH3:26]>>[CH3:26][C:25]1[CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)[N:5]([C:4]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:2]([CH3:1])[CH:3]=2)[CH:24]=1
Reactant: Cc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1C
Reactant: C=C(C)C=O
Product: Cc1cc(-c2ccc(S(N)(=O)=O)cc2)n(-c2ccc(C)c(C)c2)c1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(3,4-dimethylanilino)-α-(4-sulfamoylphenyl)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a slightly yellow powder (yield 43%), melting at 118-120° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[F:17])[CH:5]=[CH:4][N:3]=1.[H][H]>C(O)C.[Pt](=O)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=2[F:17])[CH:5]=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccnc(Cl)n2)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ccc(F)c(-c2ccnc(Cl)n2)c1

Procedure:
A solution of 2-chloro-4-(2-fluoro-5-nitrophenyl)pyrimidine (800 mg, 3.2 mmol) in ethanol (300 ml) was reduced under 40 psi hydrogen with platinum(IV) oxide (100 mg) for 30 minutes then filtered to give a solution of 3-(2-chloropyrimidin-4-yl)-4-fluorophenylamine: MS (ES+) m/z 224 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:22][CH:21]=[CH2:20])[O:8][C:7](=[O:13])[CH:6]=[CH:5]2
Reactant: C=CCBr
Reactant: Cc1cc2ccc(=O)oc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc2oc(=O)ccc2cc1C

Procedure:
A mixture of 6-methyl-7-hydroxycoumarin (I) (14.5 g), anhydrous K2CO3 (5 g), allyl bromide (15 ml) and acetone (400 ml) was refluxed for 12 h under stirring. From the refluxed mixture the solid was filtered and washed several times with acetone. The acetonic solution and the pooled washings were concentrated to dryness and the residue crystallized from MeOH, yielding 6-methyl-7-allyloxycoumarin (IV) (11.4 g; m.p. 124°-5° C.). ##STR10##
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)[NH:16][C:15]([C:24]2[S:25][CH:26]([CH2:29][C:30](O)=[O:31])[CH2:27][N:28]=2)=[CH:14]3)=[CH:6][CH:5]=1.Cl.[CH2:34]([N:36]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.CN>O.CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)[NH:16][C:15]([C:24]2[S:25][CH:26]([CH2:29][C:30]([NH:36][CH3:34])=[O:31])[CH2:27][N:28]=2)=[CH:14]3)=[CH:6][CH:5]=1
Reactant: COCc1ccc(Oc2cc(OC(C)C)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COC)nc4)cc(OC(C)C)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 13 h
Yield: 68.1 %

Procedure:
A mixture of {2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg), 1-hydroxybenzotriazole (130 mg), methylamine hydrochloride (90 mg), triethylamine (150 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 13 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give the title compound (210 mg, 68%) as a yellow amorphous solid. MS 469 (MH+).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:51])[N:23]([C:27]2[C:32]([CH3:33])=[CH:31][C:30]([NH:34][CH2:35][C@@H:36]([OH:49])[CH2:37][N:38]3[C:46](=[O:47])[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:39]3=[O:48])=[CH:29][C:28]=2[CH3:50])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:52](N1C=CN=C1)(N1C=CN=C1)=[O:53].O.ClCCl>C1(C)C=CC=CC=1>[Si:1]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:51])[N:23]([C:27]2[C:28]([CH3:50])=[CH:29][C:30]([N:34]3[CH2:35][C@H:36]([CH2:37][N:38]4[C:46](=[O:47])[C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[C:39]4=[O:48])[O:49][C:52]3=[O:53])=[CH:31][C:32]=2[CH3:33])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(NC[C@@H](O)CN2C(=O)c3ccccc3C2=O)cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(N2C[C@H](CN3C(=O)c4ccccc4C3=O)OC2=O)cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Temperature: 25 °C

Procedure:
190 g (204 mmol) of the compound from Example 66A are dissolved in 1.01 l of toluene. 66.0 g (407 mmol) of 1,1′-carbonyldiimidazole are then added, and the mixture is heated at reflux for one hour. The mixture is then cooled to room temperature, and water and dichloromethane are added. The phases are separated and the organic phase is dried over sodium sulphate. After filtration, the mixture is evaporated to dryness under reduced pressure. The residue is triturated with methanol, and the solid which remains is filtered off and washed with methanol. This gives 130 g (87% of theory) of the desired product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:18][C:17]([OH:28])=[N:16]2)=[CH:11][CH:10]=1.Br[CH2:30][C:31]#[CH:32].C(OCC)(=O)C>CN(C)C=O.O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:18][C:17]([O:28][CH2:32][C:31]#[CH:30])=[N:16]2)=[CH:13][CH:14]=1
Reactant: C#CCBr
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCOc1nc(-c2ccc(OC)cc2)n(-c2ccc(OC)cc2)n1
Reaction time: 0.08 h
Yield: 43.9 %

Procedure:
Potassium carbonate (279 mg, 2.02 mmol) was added to a solution of 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol (200 mg, 0.673 mmol) in dimethylformamide (2 mL). After 5 minute stirring, 3-bromo-1-propyne (0.18 mL, 2.02 mmol) was added to the mixture and the mixture was stirred for 4 hours. Ethyl acetate and water were poured into the mixture. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (toluene-ethyl acetate 4:1). The desired product was washed with isopropyl ether, isolated by filtration, and dried in vacuo to give 1,5-bis(4-methoxyphenyl)-3-(2-propynyloxy)-1H-1,2,4-triazole (99 mg, 43.9% yield).
Reaction SMILES: ClC1C=C(C=C(C(F)(F)F)C=1)C=O.Cl[C:15]1[N:16]=[N:17][C:18]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([Cl:31])[CH:22]=2)=[CH:19][CH:20]=1.[CH:32]([NH:34][NH2:35])=O>C(O)CCC>[Cl:31][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([CH:32]=[N:34][N:35]=3)[N:17]=2)[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=1
Reactant: NNC=O
Reactant: FC(F)(F)c1cc(Cl)cc(-c2ccc(Cl)nn2)c1
Agent: O=Cc1cc(Cl)cc(C(F)(F)F)c1
Solvent: CCCCO
Product: FC(F)(F)c1cc(Cl)cc(-c2ccc3nncn3n2)c1

Procedure:
As described in Example 35, 3-chloro-5-(trifluoromethyl)benzaldehyde is converted to 3-chloro-6-[3-chloro-5-(trifluoromethyl)phenyl]pyridazine. This compound is reacted with formylhydrazine in refluxing n-butanol for 24 hours to give the product of the example.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14].C(N([CH2:20][CH3:21])CC)C>CCC(O)CC>[CH2:11]([CH:12]([O:13][CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14])[CH2:20][CH3:21])[CH3:10]
Reactant: CCN(CC)CC
Reactant: O=C1CCCc2c1ccc(O)c2CCl
Solvent: CCC(O)CC
Product: CCC(CC)OCc1c(O)ccc2c1CCCC2=O
Yield: 189.1 %

Procedure:
According to step (a) in the method of example 19a, 5-Chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.211 g, 1.0 mmol) was combined with triethylamine (0.167 ml, 1.2 mmol) in pentan-3-ol (3 ml, Aldrich Chemical) to produce 248 mg of desired product as an orange-red oil. Low resolution mass spectrum (APCI) m/z 263 [M+H]+.