Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([CH:42]=[C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:44]=1)[CH2:28][N:29]1[CH:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([CH:40]=O)=[CH:30]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH2:46]([O:45][C:43]1[CH:42]=[C:27]([CH:26]=[C:25]([O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:44]=1)[CH2:28][N:29]1[CH:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31](/[CH:40]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:30]1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: O=Cc1cn(Cc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1-c1ccccc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cn(Cc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Sodium hydride (60%, oily, 2.11 g) was added to a mixture of ethyl diethylphosphonoacetate (10.5 ml) and tetrahydrofuran (150 ml) at 0° C., which was stirred at room temperature for 30 minutes. A solution of 1-(3,5-dibenzyloxybenzyl)-4-phenylpyrrole-3-carbaldehyde (22.7 g) in tetrahydrofuran (20 ml) was slowly added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl (E)-3-[1-(3,5-dibenzyloxybenzyl)-4-phenyl-3-pyrrolyl]propenoate (21.9 g, yield: 84%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 98–99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[O:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(CBr)c1cc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Cl)cnc1=O)c1cc2ccccc2o1
Temperature: 25 °C
Yield: 35.9 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (522 mg) and 2-bromoacetylbenzo[b]furan (960 mg) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 50 min the reaction mixture was cooled to 3° C. and the solid collected. The filtrate was evaporated and the residue was subjected to preparative thin-layer chromatography developing with chloroform-ethanol (50:1) (4 runs) which gave a yellow solid. The two solids were combined and crystallised twice from acetone to give the title pyrimidinone (415 mg) m.p. 202°-205° C., λmax (EtOH) 227.5 nm (ε14,060), 298 nm (ε20,930).
Reaction SMILES: [BrH:1].[OH:2][C:3]1[C:14]([OH:15])=[CH:13][C:6]2[CH2:7][CH2:8][N:9]([CH3:12])[CH2:10][CH2:11][C:5]=2[C:4]=1[C:16]([F:19])([F:18])[F:17].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[BrH:1].[OH:15][C:14]1[C:3]([OH:2])=[C:4]([C:16]([F:19])([F:17])[F:18])[C:5]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7][C:6]=2[C:13]=1[S:40][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Sc1ccccc1
Reactant: CN1CCc2cc(O)c(O)c(C(F)(F)F)c2CC1
Agent: Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: CN1CCc2c(c(C(F)(F)F)c(O)c(O)c2Sc2ccccc2)CC1

Procedure:
Following the procedures outlined in Example 2 the 7,8-dihydroxy-3-methyl-6-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide is treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to give the 7,8-dione which is then reacted with, for example, thiophenol to yield 7,8-dihydroxy-3-methyl-6-phenylthio-9-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][C:5]1=O)(=O)[CH3:2].O.[NH2:15][NH2:16]>C(O)C>[CH3:2][C:1]1[C:4]2[C:9](=[O:10])[CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][C:5]=2[NH:16][N:15]=1
Reactant: CC(=O)C1C(=O)CC(C)(C)CC1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-acetyl-5,5-dimethyl-cyclohexane-1,3-dione (2 g, 11.04 mmol), prepared as described in example 2, and hydrazine hydrate (1.66 ml, 33.13 mmol) in ethanol (25 ml) was stirred at room temperature for about 3 hours and then the solvent was evaporated. The residue was dissolved in dichloromethane, washed with water and brine, dried over sodium sulfate and evaporated. The title compound was obtained after chromatography on silica gel (dichloromethane:methanol=95:5) as a colourless solid (0.8 g, 45%): m.p. 103-104° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH:9]=[CH:10][CH3:11])[C:3]=1[OH:12].O[C@@H:14]([CH:27]=[CH2:28])[CH2:15][O:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([O:16][CH2:15][C@H:14]([O:12][C:3]2[C:4]([CH:9]=[CH:10][CH3:11])=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Br:1])[CH:27]=[CH2:28])(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: CC=Cc1cc(F)cc(Br)c1O
Reactant: C=C[C@H](O)COS(=O)(=O)c1ccc(C)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C[C@H](COS(=O)(=O)c1ccc(C)cc1)Oc1c(Br)cc(F)cc1C=CC
Temperature: 25 °C
Reaction time: 19 h
Yield: 82 %

Procedure:
To a solution of 2-bromo-4-fluoro-6-(prop-1-enyl)phenol, prepared in Example 37, step 4 (4.5 g, 0.019 mol) and (S)-toluene-4-sulfonic acid 2-hydroxy-but-3-enyl ester (7.07 g, 0.028 mol) and triphenylphosphine (11.22 g, 0.043 mol) in anhydrous THF (200 mL) at room temperature was added diethyl azodicarboxylate (7.7 mL, 0.047 mol) then the reaction mixture stirred at room temperature for 19 hours. The reaction was quenched by the addition of water (100 mL), stirred vigorously for 5 minutes and the resulting oily suspension extracted with methylene chloride (300 mL). The organic phase was separated, washed with water (2×100 mL), and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. Purification by flash chromatography using a solvent gradient of 0 to 20% ethyl acetate in hexane gave 7.26 g (82%) of (R)-2-[2-bromo-4-fluoro-6-(prop-1-enyl)phenoxy]but-3-enyl 4-methylbenzenesulfonate as a colorless oil. MS (ES) m/z 472.1 ([M+NH4]+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][CH:20]=[C:5]([O:6][CH2:7][C:8]3[N:9]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:11][C:12]=3[CH3:13])[CH:4]=2)=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH3:24]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Reactant: CCOC(=O)CCc1cc(O)ccc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)cc1CCC(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.65 g), ethyl 3-(2-ethoxy-5-hydroxyphenyl)propionate (0.46 g), anhydrous potassium carbonate (0.30 g) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 5 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over, anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to acidify the residue. The precipitated solid was collected by filtration and dried with air to give crystals (0.89 g, 95%) of 3-[2-ethoxy-5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 136-137° C.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(N(CC)CC)C.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH:20]([C:36]2[CH:46]=[C:45]([O:47][CH3:48])[C:39]3[O:40][CH2:41][CH2:42][CH2:43][O:44][C:38]=3[C:37]=2[F:49])[C:21]2[NH:25][C:24](=[O:26])[N:23]([C:27]3[N:35]=[CH:34][CH:33]=[CH:32][C:28]=3[C:29]([OH:31])=[O:30])[N:22]=2)=[CH:15][CH:14]=1)#[N:12]>CO>[F:49][C:37]1[C:38]2[O:44][CH2:43][CH2:42][CH2:41][O:40][C:39]=2[C:45]([O:47][CH3:48])=[CH:46][C:36]=1[CH:20]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([C:11](=[NH:12])[NH:3][OH:2])=[CH:18][CH:17]=1)[C:21]1[NH:25][C:24](=[O:26])[N:23]([C:27]2[N:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29]([OH:31])=[O:30])[N:22]=1
Reactant: COc1cc(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCCO2
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(C(=N)NO)cc2)c2nn(-c3ncccc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCCO2
Temperature: 60 °C
Yield: 39.3 %

Procedure:
After adding 114 mg of hydroxylammonium chloride and 267 μl of triethylamine to a solution of 146 mg of 2-{3-[(4-cyanophenylamino)-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}nicotinic acid in 10 ml of methanol, the mixture was heated for 28 hours at 60° C. After cooling the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (61 mg) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=1.[H-].[Na+].[C:17]([Si:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28]I)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].O>CN(C=O)C>[C:17]([Si:21]([CH3:22])([CH3:23])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][N:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:9][C:10]1=[O:14])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCCCCI
Reactant: O=c1nc(-c2ccccc2F)cc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCn1ccc(-c2ccccc2F)nc1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1H-pyrimidin-2-one (375 mg, 1.97 mmol) in dry DMF (50 ml), 60% NaH (103 mg, 2.56 mmol) was added portionwise. After heating the mixture at 100° C. for 1 hour, tert-butyl-(4-iodo-butoxy)-dimethyl-silane (664 μl 2.56 mmol) was added at room temperature and the mixture was stirred overnight. Water was added and the mixture extracted with diethyl ether; the organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography with petroleum ether-ethyl acetate (1-1) to give 370 mg of the title compound as a yellow solid (50% yield).
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:34][C:35]1[N:36]=[CH:37][C:38]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:4][CH2:3][C:2]([F:1])([F:33])[CH2:7][CH2:6]2)=[O:9])=[CH:39][CH:40]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCOCC2)CC1
Reactant: OB(O)c1ccc(Cl)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(Cl)nc1)N1CCC(N2CCOCC2)CC1
Yield: 31 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone (example 170), 2-chloropyridine-5-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a yellow solid (31%).
Reaction SMILES: C([Mg]Br)C.[CH:5](=[N:12][CH2:13][C:14]#[CH:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>O1CCCC1.[Cl-].[Na+].O>[CH:5](=[N:12][CH2:13][C:14]#[C:15][Si:17]([CH3:19])([CH3:18])[CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: C#CCN=Cc1ccccc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCN=Cc1ccccc1
Reaction time: 0.5 h

Procedure:
10 g of ethyl magnesium bromide was added over 30 minutes to a stirred solution of 10.2 g of 1A in 100 ml of tetrahydrofuran at 0° C. The resulting mixture was stirred at that temperature for 30 minutes, then a solution of 7.75 g of trimethylsilyl chloride in 30 ml of tetrahydrofuran was added over 30 minutes. The mixture then was stirred at 0° C. for 90 minutes, treated with brine, dried (MgSO4) and the solvent was evaporated. The residue was distilled at 85°-90° C., 0.3 Torr., to give N-benzylidene-3-(trimethylsilyl)-2-propyn-1-amine (1B), as a water-white oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:13]([F:14])=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[F:15])=[CH:3][CH:2]=1.[C:16](=[O:19])([O-:18])N>>[C:16]([NH:11][C:10]1[CH:9]=[C:8]([F:15])[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[C:13]([F:14])[CH:12]=1)([O:18][CH2:4][C:7]1[CH:13]=[CH:12][CH:10]=[CH:9][CH:8]=1)=[O:19]
Reactant: NC(=O)[O-]
Reactant: Nc1cc(F)c(-c2ccncc2)c(F)c1
Product: O=C(Nc1cc(F)c(-c2ccncc2)c(F)c1)OCc1ccccc1

Procedure:
Following the general procedure of PREPARATION 3 and making non-critical variations 4-(4-pyridyl)-3,5-difluoroaniline (PREPARATION 8, 236 mg, 1.15 mmol) is converted to the carbamate derivative. The crude product is purified by silica gel chromatography (100 g of SG, eluted with a 3-5% acetonitrile/chloroform gradient), the title compound is recovered as a solid, mp 185°-186°; FTIR (neat) cm-1 1743, 1642, 1605, 1254, 1072; HRMS calc'd for C19H14F2N2O2 =340.1023, found=340.1029; MS (EI, m/z) 340, 232, 108, 91, 79, 43; NMR (CDCl3) δ 8.67, 7.43-7.38, 7.15, 5.23.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[O:5][CH:6]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][NH+:8]([CH2:11][CH3:12])[CH2:9][CH3:10].C(N(CC)CC)C>O1CCCC1>[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[O:5][CH:6]([C:13](=[O:18])[C:14]([CH3:16])([CH3:17])[CH3:15])[CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10]
Reactant: CC[NH+](CC)CC(Oc1ccc(Cl)cc1Cl)C(=O)C(C)(C)C
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)CC(Oc1ccc(Cl)cc1Cl)C(=O)C(C)(C)C
Temperature: 25 °C
Yield: 89.2 %

Procedure:
38.1 g (0.1 mole) of [2-(2,4-dichlorophenoxy)-4,4-dimethyl-pentan-3-onyl]-diethylammonium chloride were dissolved in 200 ml of anhydrous tetrahydrofuran and 20.2 g (0.2 mole) of triethylamine were added dropwise at room temperature. After stirring for quarter of an hour at room temperature, the triethylammonium chloride which had precipitated was filtered off and the solvent was distilled off in vacuo. 30.9 g (90% of theory) of [2-(2,4-dichlorophenoxy)-4,4-dimethyl-pentan-3-onyl]-diethylamine were obtained as a yellow oil, which was immediately dissolved in 300 ml of anhydrous acetonitrile (0.09 molar batch). 21.3 g (0.15 mole) of methyl iodide were added dropwise thereto at room temperature, while stirring. The reaction mixture was stirred for 1 hour at room temperature and for 30 minutes under reflux and thereafter the solvent was distilled off under reduced pressure. The oil residue was taken up in 200 ml of a mixture of ethyl acetate and methyl ethyl ketone (1:1) and the whole was heated to the boil. This produced a crystalline residue, which was filtered off and rinsed with ether. 22.8 g (51.6% of theory) of [2-(2,4-dichlorophenoxy)-4,4-dimethyl-pentan-3-onyl]-diethylmethylammonium iodide of melting point 114°-118° C were obtained. ##STR155##
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[CH:15]=[C:14]([C:25]3[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].B(Br)(Br)Br>ClC(Cl)C.C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[CH:15]=[C:14]([C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)[N:13]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2cc(Nc3cc(C)n[nH]3)nc(Sc3ccc(NC(C)=O)cc3)n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)cc(-c3ccc(O)cc3)n2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A solution of [2-(4-acetamido-phenyl-sulfanyl)-6-(4-methoxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (100 mg, 2.24.10−4 mol) in dichloroethane (5 mL) is treated with 1M BBr3 in DCM (896 μL, 8.96.10−4 mol). The mixture is then heated at 80° C. for 4 hours before 1M BBr3 in DCM (896 μL, 8.96.10−4 mol) is added. The reaction mixture is then heated at 80° C. for a further 3 hours. The solvent is evaporated and methanol is added to the residue to quench any residual BBr3. The solvent is evaporated in vacuo and this evaporation step is repeated 3 times. 1M HCl(8 mL) is added to the solid residue and the suspension is stirred at room temperature for 15 hours. The solid is collected by filtration and suspended in a mixture of water/EtOH (3/1, 24 mL). The mixture is neutralized with NaHCO3 and stirred for 2 hours at room temperature. The solid is then collected by filtration, rinsed with water and with diethyl ether to give-[2-(4-acetamido-phenyl-sulfanyl)-6-(4-hydroxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:24]>C(Cl)Cl>[F:24][C:10]([CH:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of Boc-L-Proline (4.5 g, 0.02 mmol) and pyridine (8.45 mL, 0.104 mmol) in DCM (20 mL) cooled in an ice bath was added dropwise cyanuric fluoride (5.35 mL, 0.0627 mmol). After the addition the reaction became milky. The solution was stirred at 0° C. for 10 min then warmed to RT and stirred for 4 h. The reaction was quenched with water, and thrice extracted with DCM. The combined organic extracts were washed with brine, dried, and concentrated in vacuo to afford tert-butyl 2-(fluorocarbonyl)pyrrolidine-1-carboxylate. The crude acid fluoride was used in next coupling reaction immediately.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[C:18]1([CH2:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:25](=[O:26])[CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
Proline methyl ester hydrochloride (3.3 g) and triethylamine (2.8 ml) were suspended in dry methylene chloride (30 ml). Under cooling, phenylacetylchloride (3.4 g) and triethylamine (3.1 ml) were simultaneously added dripwise to the suspension. Thereafter, the mixture was stirred at room temperature for 2 hours, and the reaction mixture was washed successively with water, 1N HCl, water, saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under vacuum. The resulting crude product was purified by medium-pressure liquid column chromatography on silica gel (solvent: carbon tetrachloride) to obtain the end compound an an oil (3.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[CH:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:5][C:20]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:21]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)C1CCCCC1
Reaction time: 2 h

Procedure:
Phenylalanine methyl ester (1 g., 0.0046 moles) is dissolved in pyridine 5 mL. Cyclohexanoyl chloride (0.62 mL) is added and the mixture is stirred for 2 hours. The reaction mixture is poured onto hydrochloric acid (1N) and crushed ice. The aqueous mixture is extracted twice with toluene. The combined toluene extracts are concentrated in vacuo to give 1.1 g of crude N-cyclohexanoylphenylalanine methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]2[O:10][CH:9]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH2:8][CH2:7][C:6]=2[CH:19]=1.CO[CH:23]1[CH2:27][CH2:26][CH:25](OC)O1.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH:23]=[CH:27][CH:26]=[CH:25]2)[C:5]2[O:10][CH:9]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH2:8][CH2:7][C:6]=2[CH:19]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1cc(F)cc2c1OC(COC1CCCCO1)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: Fc1cc2c(c(-n3cccc3)c1)OC(COC1CCCCO1)CC2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
A mixture of intermediate 16-b (0.036 mol), 2,5-dimethoxytetrahydrofuran (0.22 mol) and PTSA (catalytic quantity) in DMF (140 ml) was stirred for 90 min at 100° C. The solvent was evaporated. The residue was dissolved in CH2Cl2. The organic solution was washed once with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2). The pure fractions were collected and the solvent was evaporated, yielding 6.6 g (55.3%) of (±)-6-fluoro-3,4-dihydro-8-(1H-pyrrol-1-yl)-2-[[(tetrahydro-2H-pyran-2-yl)oxy]-methyl]-2H-1-benzopyran (interm. 17-b).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[N:3]=[C:2]1[C:18]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21])=[CH:10][CH:9]=[CH:8][CH:7]=3.C(=O)([O-])[O-].[Cs+].[Cs+].O.C(OCC)(=O)C.[Cl:41][CH2:42]I>>[Cl:41][CH2:42][N:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[N:3]=[C:2]1[C:18]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: ClCI
Reactant: N#Cc1cccc(C#N)c1-c1nc2c3ccccc3c3ccccc3c2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(C#N)c1-c1nc2c3ccccc3c3ccccc3c2n1CCl
Temperature: 80 °C
Yield: 31 %

Procedure:
2-(1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile from Step 2 (1 g, 2.91 mmol) was mixed with cesium carbonate (1.14 g, 3.49 mmol) in chloroiodomethane (10 mL). The mixture was heated to 80° C. overnight. The reaction was cooled to room temperature and poured into 200 mL water and 500 mL ethyl acetate. The layers were separated, and the organic layer was washed with 200 mL water, 200 mL saturated aqueous sodium bicarbonate solution, 100 mL brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The crude solid was purified by flash column chromatography using 40% ethyl acetate in hexane to give 357 mg of 2-[1-(chloromethyl)-1H-phenanthro[9,10-d]imidazol-2-yl]isophthalonitrile (31%) plus 650 mg of a mixture of product and starting material.