Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=O)[CH2:6][CH2:5]2>P(Cl)(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:5][CH2:6][N:7]3[C:8]2=[C:9]([CH:10]=1)[C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[N:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=13
Reactant: CN1CCN(C(=O)Nc2ccccc2N2CCc3cc(Br)ccc32)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3ccccc3N3CCc4cc(Br)cc2c43)CC1
Yield: 52.2 %

Procedure:
A mixture of N-[2-(5-bromo-1-indolinyl)phenyl]-4-methyl-1-piperazinecarboxamide (11.5 g, 27.5 mmoles) and 750 ml of phosphorus oxychloride was stirred until a solution was obtained and then heated under reflux for 40 minutes. The reaction mixture was cooled. Excess phosphorus oxychloride was removed by evaporation at 50°-55° C. The residue was dried for 30 minutes under vacuum. Ice-chilled 2N sodium hydroxide solution (250 ml) and dichloromethane (350 ml) were added to the residue at 4° C. (ice-water bath). The mixture was stirred until all the solid had dissolved. The organic phase was separated and washed with brine (2 times, 200 ml), dried over anhydrous magnesium sulfate and concentrated. Crystallization from ether (100 ml) gave 5.7 g (57%) of product. Recrystallization from isopropanol yielded the analytical sample, mp 203°-204° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[CH:6]1([Mg]Cl)[CH:10]=[CH:9][CH:8]=[CH:7]1>>[CH2:2]([C:10]1[CH2:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: Cl[Mg]C1C=CC=C1
Product: CCCCC1=CC=CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 1-bromobutane (34.2 g of 99 wt %, 0.247 mol) was added cyclopentadienyl magnesium chloride (260 mL of 1 M solution in THF, 0.26 mol) at 0° C. in 25 minutes. After stirring for an additional 15 minutes at 0° C., the mixture was warmed to room temperature. After stirring overnight, the reaction was quenched with a mixture of ice and water. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at room temperature gave a yellow liquid (30.5 g, crude butylcyclopentadiene). To the crude butylcyclopentadiene (20.5 g) dissolved in THF (150 mL) was added n-BuLi (15 mL of 10 M in hexanes, 0.15 mol) at −78° C. The mixture was warmed up to room temperature and stirred for 5 hours. The anion solution was added to benzophenone (28 g, 0.154 mol) dissolved in THF (100 mL) at 0° C. in 13 minutes. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with a mixture of ice and 10% HCl aqueous solution. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at 40° C. gave a dark red viscous oil. The oil was dissolved in heptane and filtered through silica gel. The product was collected by washing the silica gel with 5-10% CH2Cl2 in heptane. Removal of the solvent gave the desired product (22.3 g, 47% yield based on 1-bromobutane) as a dark red viscous oil.
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CCN)CC)C.[S:34](Cl)(=[O:37])(=[O:36])[NH2:35]>ClCCl>[CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH:20]([S:34]([NH2:35])(=[O:37])=[O:36])[CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Reactant: NS(=O)(=O)Cl
Agent: CCN(CC)CCN
Solvent: ClCCl
Product: NS(=O)(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (93 mg, 0.24 mmol) in dichloromethane (3 mL) was added diethylaminoethyl amine (0.13 mL, 0.73 mmol) and sulfamoyl chloride (42 mg, 0.37 mmol). After stirring overnight, another portion of sulfamoyl chloride (42 mg) was added at 0° C., and the resulting mixture stirred for 2 h at room temperature. The resulting mixture was then concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography (gradient 42%→90% TFA-H2O:acetonitrile) to yield 6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-sulfonamide (32 mg).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[O:7]1[CH2:12][CH2:11][CH2:10][O:9][CH:8]1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH:20]([C:19]1[CH:22]=[CH:23][C:16]([O:15][CH2:14][CH2:13][CH:8]2[O:9][CH2:10][CH2:11][CH2:12][O:7]2)=[CH:17][CH:18]=1)=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(OCCC2OCCCO2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=Cc1ccc(OCCC2OCCCO2)cc1
Yield: 77.6 %

Procedure:
In another 2 liter flask, 57.2 g of methyl triphenylphosphonium bromide was placed. 500 ml of anhydrous ether was poured and then, stirred. To the resulting solution was slowly added 18.0 g of potassium tert-butoxide and reacted at room temperature for 3 hrs. 25.6 g of the above 4-(2-[1,3]-dioxane-2-yl-ethoxy)benzaldehyde was dissolved in 200 ml of anhydrous ether and was slowly added to the reaction mixture and then subjected to reaction at room temperature for 4 hrs. After completion of the reaction, the produced solid by-product was filtered off and washed with distilled water and saturated saline. The organic phase washed was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The reaction mixture was purified by Silica gel column chromatography to obtain 19.7 g of 2-[2-(4-vinylphenoxy)ethyl]-[1,3]-dioxane, represented by the following formula: ##STR9##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H][H]>CO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: Fc1ccc(C(=C2CCN(Cc3ccccc3)CC2)c2ccc(F)cc2)cc1
Solvent: CO
Product: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1

Procedure:
A mixture of 1.6 parts of 4-[bis(4-fluorophenyl)methylene]-1-(phenylmethyl)piperidine and 80 parts of methanol was hydrogenated at normal pressure and at room temperature with 1 part of rhodium-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 1.2 parts of 4-[bis(4-fluorophenyl)methylene]piperidine as a residue (intermediate 14).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[C:28]2[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:35])=[CH:22][CH:21]=1)[C:6]([NH:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])=[O:7])C.[OH-].[K+]>CCO.C1COCC1.O>[Cl:34][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:35])[C:28]=1[C:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:5]([C:6]([NH:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:7])[C:4]([OH:37])=[O:3])=[CH:21][CH:22]=1)=[O:36]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)Nc1c(OC)cccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cccc(OC)c1NC(=O)C(Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O
Reaction time: 2.5 h
Yield: 52.7 %

Procedure:
A solution of the compound of Example 5 (0.59 g, 1.1 mmol) in EtOH (5 ml), THF (2 ml) and water (2 ml) was treated with KOH (1M aqueous solution, 1.62 ml, 1.62 mmol) and the reaction stirred for 2.5 h. The mixture was concentrated in vacuo and acidified to pH1 with 10% hydrochloric acid, to give a white precipitate which was isolated by filtration and washed with water, triturated with boiling MeOH and washed with Et2O to give the title compound as a white solid (300 mg, 54%). δH (DMSO d6) 10.65 (1H, s, NH), 9.04 (1H, s, NH), 7.6-7.46 (5H, m, Ar—H), 7.28-7.16 (3H, m, Ar—H), 6.65 (2H, d, J 8.4 Hz, Ar—H), 3.74 (1H, m, CHCH2), 3.68 (6H, s, OMe), 3.30 (1H, m, CHCHAHB) and 3.06 (1H, m, CHCHAHB). m/z (ESI, 60V) 517, 519 (MH+).
Reaction SMILES: C([O:4][CH:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)/[C:9](=[CH:16]/[C:17]2[NH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])/[C:8]1=[O:24])[CH3:6])(=O)C.C(#N)C>C(O)=O>[CH3:22][C:21]1[CH:20]=[C:19]([CH3:23])[NH:18][C:17]=1/[CH:16]=[C:9]1\[C:8](=[O:24])[N:7]([CH:5]([OH:4])[CH3:6])[C:15]2[C:10]\1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: CC(=O)OC(C)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21
Solvent: CC#N
Solvent: O=CO
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(C)O)c3ccccc32)[nH]1
Yield: 90 %

Procedure:
Alternatively, (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-1-(1-hydroxyethyl)-1,3-dihydro-2H-indol-2-one was prepared in >90% yield by treating 1-{(3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-2-oxo-2,3-dihydro-1H-indol-1-yl}ethyl acetate (500 mg) with aqueous acetonitrile (10 mL) and formic acid (200 mg) overnight.
Reaction SMILES: [CH3:1][C:2]([CH2:16][OH:17])([C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.C1(C)C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl.O>[CH3:1][C:2]([CH2:16][O:17][S:33]([CH3:32])(=[O:35])=[O:34])([C:7]([C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(CO)C(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)C(C)(COS(C)(=O)=O)C(=O)c1ccc(Cl)cc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
Into a 5 liter RBF is placed 100 g (4.37 mole) of methyl 2-methyl-2-hydroxymethyl-3-(4-chlorophenyl)-3-keto-propanoate, 473 g (4.25 mole) of triethylamine, and 2 liters of toluene. This mixture is cooled to -10° C. and methane sulfonyl chloride, 488 g (4.25 mole), is added over 30 minutes. The internal temperature rose to 40° C. by the end of the addition. After stirring at room temperature for 2 hours, the mixture is worked up with 4 liters of cold water and 1 liter methylene chloride. The resulting red semisolid (1400 g) is crystalized using 200 ml of hot ethyl acetate and adding 1500 ml of hexane. Yielding 1060 g (74%) of a light yellow solid mp 85°-86° C., methyl 2-methyl-2-mesyloxymethyl-3-(4-chlorophenyl)-3-keto-propanoate. NMR data was consistent with the structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])/[CH:14]=[C:15](\[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2].[C:31]([O:35][C:36](=[O:52])[CH2:37][N:38]=[C:39]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:34])([CH3:33])[CH3:32].[OH-].[K+].O>C(#N)C>[C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])[CH2:14][C:15]([CH:37]([N:38]=[C:39]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:52])([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:16]([F:17])([F:19])[F:18])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C(=O)CC(c2cc(Cl)cc(Cl)c2)(C(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Yield: 21.3 %

Procedure:
4-[(E)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (0.100 g, 0.218 mmol) and (benzhydrylidene-amino)-acetic acid tert-butyl ester (0.079 g, 0.261 mmol) were dissolved in acetonitrile (5.0 ml). Potassium hydroxide (0.013 g, 0.239 mmol) and antracen-9-yl-methyl quininium chloride (0.030 g, 0.054 mmol) were added and the resulting mixture was heated at 90 C for 6 days. At this time water was added and the reaction mixture was extracted with dichloromethane (3×). The crude product was purified by flash chromatography (0% to 15% ethyl acetate in cyclohexane) to afford 4-[3-[(Benzhydrylidene-amino)-tert-butoxycarbonyl-methyl]-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoic acid tert-butyl ester (0.035 g, 21%) as a white solid. Chiral HPLC analysis (Chiralpack IA, heptanes:t-buthanol=98:2, 1 ml/min, retention time 8.50 minutes and 9.23 minutes (enantiomers of the minor diasteromer); 13.37 minutes and 14.81 (enantiomers of the major diastereomer) indicated that the reaction products were formed in diastereomeric ratio 2:1.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[NH2:20])=[C:10]([C:22](OCC)=[O:23])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC1C=CC=CN=1>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]2[C:12](=[O:21])[C:11]3[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:8][NH:9][C:10]=3[C:22](=[O:23])[NH:20][C:14]=2[CH:15]=1
Reactant: CCOC(=O)c1[nH]nc(-c2ccccc2)c1C(=O)c1ccc(Cl)cc1N
Agent: Oc1ccccn1
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c2c(-c3ccccc3)n[nH]c12
Yield: 51.6 %

Procedure:
A mixture of ethyl 3-phenyl-4-(4-chloro-2-aminobenzoyl)-1H-pyrazole-5-carboxylate (0.84 g, 2.28 mmol) and 2-hydroxypyridine (0.217 g, 2.28 mmol) in toluene (12 mL) was distilled at 160° C. until all the toluene was removed. The residue was heated at the same temperature for 18 hours. The reaction residue was washed with water to remove the 2-hydroxypyridine. The insoluble material was added to methanol (225 mL) and heated to boiling. Ethyl acetate (100 mL) was added and the solution heated for an additional 2 minutes, then concentrated to 100 mL. The solution was filtered to remove some insoluble material and the filtrate concentrated via rotovap until a precipitate formed which was filtered to give the title compound as a tan solid (0.381 g, 51%, mp 328.1-330.9° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:13][C:14]#[N:15])[CH:9]=[CH:10][C:11]=1[CH3:12].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CN(C=O)C.CCCCCC>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:13][C:14]1[NH:23][N:22]=[N:21][N:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(CC#N)cc1OCc1c(C)cccc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(Cc2nnn[nH]2)cc1OCc1c(C)cccc1C
Temperature: 90 °C

Procedure:
A mixture of 2-(3-(2,6-dimethylbenzyloxy)-4-methylphenyl)acetonitrile (Step B, 1.12 g, 4.2 mmol), sodium azide (0.400 g, 6.1 mmol) and ammonium chloride (0.350 g, 6.5 mmol) in dry DMF (15 ml) was heated under argon at 90° C. for 16 hours or until all the starting material is consumed, the reaction mixture was cooled, diluted with water and extracted with EtOAc (30 ml×4). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol 95:5→92.5:7.5) to give semi solid product. The semi solid was stirred with 1:2 ethyl acetate:hexane (15 ml) for 10 minutes, and filtered to give product as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][N:27]1[C:31](=[O:32])[CH:30]([CH3:33])[NH:29][C:28]1=[O:34]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:29]5[CH:30]([CH3:33])[C:31](=[O:32])[N:27]([CH3:26])[C:28]5=[O:34])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: CC1NC(=O)N(C)C1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)N(C)C(=O)C3C)nc2)CC1
Yield: 11.6 %

Procedure:
Using (6-bromopyridin-3-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (100 mg) described in Preparation Example 144 and 3,5-dimethylimidazolidine-2,4-dione (64 mg) described in Preparation Example 217 and by the reaction and treatment in the same manner as in Example 536, the title compound (13 mg) was obtained.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[NH2:11][C@@H:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=2)=[CH:27][N:26]=1>CN(C)C=O>[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([NH:11][C@@H:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[O:38])=[N:35][CH:36]=2)=[CH:27][N:26]=1
Reactant: Nc1ncc(-c2ccc(C(=O)O)nc2)cn1
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc(N)nc2)cn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.2 %

Procedure:
N,N-Diisopropylethylamine (1.13 mL, 6.48 mmol) was added to a mixture of tert-butyl(2S)-2-amino-3,3-dimethylbutanoate hydrochloride (0.250 g, 1.12 mmol), and 5-(2-aminopyrimidin-5-yl)pyridine-2-carboxylic acid (0.242 g, 1.12 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at RT for 3 h, and filtered. The filtrate was diluted with methanol (10 mL). The resulting solution was purified by RP-HPLC (pH 10) to give the desired product (182 mg, 42.3%). LCMS: (M+H)=386.2.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:6]2[N:13]([CH3:14])[CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1>CC(O)=O.C(Cl)Cl.[Fe]>[CH3:14][N:13]1[C:6]2[C:5]([O:4][C:3]3[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:2]=3[F:1])=[N:10][CH:9]=[N:8][C:7]=2[CH:11]=[CH:12]1
Reactant: Cn1ccc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c21
Agent: [Fe]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1ccc2ncnc(Oc3ccc(N)cc3F)c21
Reaction time: 0.17 h
Yield: 53.1 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-5-methyl-5H-pyrrolo[3,2]-4 pyrimidine (29) (253.6 mg, 0.879 mmol) in AcOH (3 mL) at 90° C. was added iron powder (245 mg, 4.4 mmol). The mixture was stirred vigorously for 10 min and filtered. The filtrate was concentrated under reduced pressure to produce a solid, which was dissolved in DCM. The resultant solution was washed with cold NaHCO3 solution and water, dried over Na2SO4 and concentrated to provide a residue which was purified by column chromatography (eluent MeOH—CH2Cl2 1:20) to afford the title compound 30 as a brown solid (120.6 mg, 53% yield). LRMS (M+1) 240.1 (100%).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N:15]1[N:19]2[C:20]([CH:24]([OH:26])[CH3:25])=[CH:21][CH:22]=[N:23][C:18]2=[N:17][CH:16]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Mg+2].[Cl-]>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([O:26][CH:24]([C:20]2[N:19]3[N:15]=[CH:16][N:17]=[C:18]3[N:23]=[CH:22][CH:21]=2)[CH3:25])=[CH:30][CH:29]=1
Reactant: CC(O)c1ccnc2ncnn12
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Cl-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(Cl)cc1)c1ccnc2ncnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
A solution of diisopropyl azodicarboxylate (11 g, 1.1 eq) in toluene (20 ml) was added dropwise to a stirred mixture of 1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (8.1 g, recrystallised from tetrahydrofuran, 49 mmol), 4-chlorophenol (6.35 g, 1 eg), triphenylphosphine (12.95 g, 1 eq) and toluene (200 ml) under nitrogen at 0-5° C. and the mixture then stirred at ambient temperature overnight. Magnesium chloride (9.5 g, -˜2 eq) was added and the stirred mixture heated under reflux for 1.5 hours, cooled to −5° C. and filtered, washing the filter pad with further toluene (2×50 ml). ml). The combined filtrate was washed with water (2×200 ml), sodium hydroxide solution (1M, 2×50 ml), and then water (2×50 ml) and then the solvent evaporated. Propan-2-ol (50 ml) was added to the residue and the solvent evaporated; this was repeated. The residue was dissolved in propan-2-ol (50 ml), seeded with a crystal of product, and left to stand at 0-5° C. for 72 hours. The product was collected by filtration, washed with cold propan-2-ol (2×20 ml) and dried in vacuo to yield 7-[1-(4-chlorophenoxy)ethyl]1,2,4-triazolo[1,5-a]pyrimidine (7.1 g, 53%), which was analysed for triphenylphosphine oxide content.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]2=[O:14].C[Si]([C:25]#[N:26])(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(#N)C.C1COCC1.[I-].[Zn+2].[I-]>[NH2:26][CH2:25][C:7]1([OH:14])[C:8]2[C:3](=[C:2]([OH:1])[C:11]([O:12][CH3:13])=[CH:10][CH:9]=2)[CH2:4][CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6]1
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc2c(c1O)CC(c1ccccc1)CC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc2c(c1O)CC(c1ccccc1)CC2(O)CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
To a suspension of 5-hydroxy-6-methoxy-3-phenyl-1,2,3,4-tetrahydro-1-naphthalenone (1.13 g, 4.2 mmol), from Step 2, in 8 mL of anhydrous acetonitrile, was added 2.4 mL (18 mmol) of trimethylsilylcyanide and a catalytic amount of zinc iodide. The reaction mixture was heated at reflux for 4 h and then cooled and concentrated. The residue was kept overnight at 0° C. under nitrogen atmosphere and then dissolved in 16 mL of anhydrous THF. The THF solution was added dropwise to a suspension of 0.77 g (20 mmol) of lithium aluminum hydride (LAH) in 8 mL of THF at 0° C. under a nitrogen atmosphere. The mixture was allowed to warm to ambient temperature and then was heated at reflux for 1 h, allowed to cool to ambient temperature and was stirred at ambient temperature for 2 h. The reaction was quenched by the sequential addition of 0.8 mL of water, 0.8 mL of 15% aqueous sodium hydroxide solution and 2.8 mL of water. Anhydrous magnesium sulfate was added to the mixture and the suspension was diluted with 50 mL of methylene chloride and filtered. The filter cake was washed with 200 mL of methylene chloride and 300 mL of ethyl acetate and discarded. The combined filtrates were evaporated to give 0.95 g (75.4% yield) of the title compound. This product was taken on to the next step without purification.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[C:8]([C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=2)[NH2:23])=[C:13]([CH2:29][CH2:30][C:31]([F:34])([F:33])[F:32])[C:12]=1[O:35][CH3:36])(=[O:10])[CH3:9].N(CCO)(CCO)CCO>C(Cl)Cl>[C:8]([C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([NH:23][C:1](=[O:6])[C:2]([O:4][CH3:5])=[O:3])[CH:24]=[CH:25][CH:26]=2)=[C:13]([CH2:29][CH2:30][C:31]([F:33])([F:32])[F:34])[C:12]=1[O:35][CH3:36])(=[O:10])[CH3:9]
Reactant: COc1c(C(C)=O)ccc(OCCCOc2cccc(N)c2)c1CCC(F)(F)F
Reactant: COC(=O)C(=O)Cl
Solvent: OCCN(CCO)CCO
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cccc(OCCCOc2ccc(C(C)=O)c(OC)c2CCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3.45 ml of methyl chlorooxalate in 10 ml of methylene chloride is added dropwise to a solution of 9.2 g of 3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-aniline and 4.3 ml of triethanolamine in 90 ml of methylene chloride in the course of 10 minutes. After stirring at room temperature for 5 hours, the mixture is poured onto water and extracted with methylene chloride. Evaporation of the extracts and recrystallisation of the residue from ether gives methyl N-{{3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-phenyl}}-oxamate.