Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([OH:6])[CH3:5].C(N(CC)CC)C.[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[C:18]([CH2:23][O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[N:17]=1>CO.C(#N)C>[Cl:15][C:16]1[N:21]=[C:20]([NH:2][CH2:3][C:4]([CH3:7])([OH:6])[CH3:5])[CH:19]=[C:18]([CH2:23][O:24][CH2:25][C:26]([F:29])([F:27])[F:28])[N:17]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: CC(C)(O)CN
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(O)CNc1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
1-Amino-2-methylpropan-2-ol hydrochloride (221 mg, 1.76 mmol) was suspended in MeOH (2 mL). Triethylamine (0.147 mL, 1.06 mmol) was added and the suspension was filtered. The filtrate was added to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidine (92 mg, 0.35 mmol) in acetonitrile (2 mL). The mixture was stirred for 1 h at rt. The mixture was purified by preparative HPLC to give the title compound (35 mg, 32%).
Reaction SMILES: Cl.[CH:2]1([C:5](=[O:33])[CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]/[C:22]3[CH:26]=[CH:25][N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:23]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1.[C:34]([Cl:37])(=[O:36])[CH3:35].C(N(CC)CC)C.Cl>ClCCl.O1CCOCC1>[ClH:37].[C:34]([S:20][CH:17]1[CH2:18][CH2:19][N:14]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:5]([CH:2]2[CH2:4][CH2:3]2)=[O:33])[CH2:15]/[C:16]/1=[CH:21]\[C:22]1[CH:26]=[CH:25][N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:23]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Cn1ccc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)Cn1ccc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2SC(C)=O)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 46 %

Procedure:
To a solution of (E)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(ethoxycarbonylmethyl)-1H-pyrazol-3-yl]methylidene}-4-sulfanylpiperidine hydrochloride (140 mg) in dichloromethane (5 ml) were added acetyl chloride (0.02 ml) and triethylamine (0.12 ml), and the resulting mixture was stirred at room temperature for 40 minutes. To the resulting reaction mixture were added acetyl chloride (0.02 ml) and triethylamine (0.4 ml), and the resulting mixture was stirred at room temperature for 80 minutes. The reaction mixture was concentrated in vacuo, and the residue was purified by chromatography on a silica gel column using methanol and dichloromethane (1:19) as the eluent. The yellow oily product obtained was dissolved in dichloromethane (3 ml) and a 4N solution of hydrogen chloride in dioxane (0.11 ml) was added to the resulting solution. After evaporation of the solvent of the reaction mixture under reduced pressure, the title compound (70 mg, yield: 46%) was afforded as a pale yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:12]=1.[Mg]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][NH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3Cl)nn2)cc1
Agent: [Mg]
Solvent: ClCCl
Solvent: CO
Product: Clc1ccccc1-c1c[nH]nn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A solution of (17) (1 equiv) in dry MeOH (0.1 M) was added to magnesium powder (10 equiv) under argon at 0° C. and the resulting suspension was stirred at 0° C. for 1 hour, diluted with DCM (3 volumes) and quenched very slowly with 10% HCl (15 ml). The layers were separated and the organic one was washed with 5% aqueous sodium bicarbonate solution and brine, dried (MgSO4), filtered and concentrated in vacuo. An oil was obtained which was purified by flash chromatography (Hex/AcOEt 5:1 and 1:1) to render 4-(2-chlorophenyl)-1H-1,2,3-triazole (18) as a white crystalline solid (42% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:29])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH2:27][CH3:28])[N:6]=2.[CH3:30][S:31]([CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1([CH3:43])[CH3:42])(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:42][C:37]1([CH3:43])[N:36]([CH2:35][CH2:34][S:31]([CH3:30])(=[O:32])=[O:33])[CH2:41][CH2:40][N:39]([CH2:2][C:3]2[N:4]([CH3:29])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH2:27][CH3:28])[N:6]=3)[CH2:38]1
Reactant: CC1(C)CNCCN1CCS(C)(=O)=O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCl)n(C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CCS(C)(=O)=O)C(C)(C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.8 %

Procedure:
To a solution of 8-chloromethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (107 mg, 0.26 mmol) and 1-(2-methanesulfonylethyl)-2,2-dimethylpiperazine (68 mg, 0.31 mmol) in DMF (3 mL) was added K2CO3 (106 mg, 0.77 mmol). The resulting mixture was allowed to stir at room temperature for 16 h. The reaction mixture was dissolved in EtOAc, washed with H2O (×4) then dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) and (Si—PCC, MeOH:DCM 0-5%). The resulting residue was further purified by reverse phase HPLC (Phenomenex Luna C18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 5:95) to afford 310 as a white solid (40 mg, 26%). LCMS (Method G): RT 6.68 min, [M+H]+ 596.3. 1H NMR (CDCl3, 400 MHz): δ 8.04-7.99 (m, 1 H); 7.77-7.72 (m, 1 H); 7.28-7.23 (m, 2 H); 4.35 (m, 4 H); 3.87 (m, 7 H); 3.69 (s, 2 H); 3.36 (q, J=7.5 Hz, 2 H); 3.11-3.03 (m, 5 H); 2.92 (m, 2 H); 2.62 (m 2 H); 2.51 (m, 2 H); 2.37-2.22 (m, 2 H); 1.45 (t, J=7.5 Hz, 3 H) and 1.09 (s, 6 H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)([O-:3])=[O:2].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]([O:11][CH3:12])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1OC
Yield: 95.2 %

Procedure:
The product was prepared by the alkylation of 4-nitro-2-methoxyphenol (10.0 g, 0.059 mol) with ethyl bromoacetate (10.0 g, 0.06 mol) in acetonitrile (50 mL) in the presence of potassium carbonate (8.0 g) to afford 14.33 g (95%) of ethyl 4-nitro-2-methoxyphenoxyacetate as a yellow solid, m.p. 87°-88° C., after recrystallization from tert-butylmethyl ether; hydrogenation of the latter (13.08 g, 0.051 mol) in THF (125 mL)/ethanol (125 mL) in the presence of 10% Pd/C (1.0 g) to afford 11.5 g (100%) of ethyl 4-amino-2-methoxyphenoxyacetate as a pink oil; and then treatment of the latter (11.5 g, 0.051 mol) in CH2Cl2 (100 mL) with pyridine (10 mL), followed by methanesulfonyl chloride (6.43 g, 0.056 mol) to afford 12.328 g (79.6%) of N-[4-(ethoxycarbonylmethoxy)-3-(methoxy)phenyl]methanesulfonamide, m.p. 118°-119° C., after purification by treatment with charcoal and filtration through silica eluting with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[NH:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][N:19]=3)=[O:17])=[CH:8]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:33]O>C(OCC)(=O)C.CCCCCC>[CH3:33][O:24][C:23]([C:21]1[NH:22][C:18]([C:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:8]=2)=[O:17])=[N:19][CH:20]=1)=[O:25]
Reactant: O=C(O)c1cnc(C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)[nH]1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)[nH]1
Yield: 89 %

Procedure:
A solution of 2-[1-(4-chloro-benzyl)-1H-indole-3-carbonyl]-3H-imidazole-4-carboxylic acid (60 mg) and concentrated sulfuric acid (1 mL) in methanol (100 mL) was heated to reflux overnight. After removal of solvent, the mixture was dissolved in ethyl acetate and washed with 5% sodium hydroxide solution. The organic layers were dried over magnesium sulfate and evaporated to dryness. The product 2-[1-(4-chloro-benzyl)-1H-indole-3-carbonyl]-3H-imidazole-4-carboxylic acid methyl ester (55 mg, yield 89%) was purified by flash column chromatography (ethyl acetate:hexane=1:1). 1H NMR (acetone-d6) δ3.84 (s, 3H), 5.65 (s, 2H), 7.2-7.4 (m, 6H), 7.48 (m, 1H), 7.95 (s, 1H), 8.45 (m, 1H), 9.48(s, 1H) ppm; ESMS calcd (C21H16ClN3O3): 393.09; found: 394.1 (M+H)+.
Reaction SMILES: [Br:1]C1C=C(C2C=CC(C(OCC)=O)=CC=2)C=CC=1O.[H-].[Na+].C(OCCBr)(=O)C.[C:29]([O:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:44][CH:43]=2)=[CH:38][C:37]=1Br)(=[O:31])[CH3:30]>>[C:29]([O:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:44]([Br:1])[CH:43]=2)=[CH:38][CH:37]=1)(=[O:31])[CH3:30]
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(Br)c2)cc1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCOC(C)=O)c(Br)c2)cc1
Agent: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(-c2ccc(OCCOC(C)=O)cc2)cc1Br
Yield: 95 %

Procedure:
In a manner similar to that of Example 6a, by reacting 2 g (6 mmol) of ethyl 3′-bromo-4′-hydroxybiphenyl-4-carboxylate with 320 mg (8 mmol) of 60% sodium hydride and 0.7 mL (7 mmol) 2-bromoethan-1-ol acetate, 2.2 g of ethyl 4′-(2-acetoxyethoxy)-3′-bromobiphenyl-4-carboxylate are obtained (yield=95%) in the form of a colorless oil.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@H:28]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCCC[C@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 19 h
Yield: 81.2 %

Procedure:
To a stirred solution of 37.2 (0.077 g, 0.15 mmol) in THF (2 mL, 0.2 mmol) and EtOH (2 mL, 0.2 mmol) at 23° C. was added a solution of 1 M sodium hydroxide (1.00 mL, 1.0 mmol). The resulting reaction mixture was stirred for 19 hours. The resulting reaction was concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted EtOAc, dried over MgSO4, filtered, and concentrated. The product thus obtained was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 37 (60 mg, 80% yield) as a colorless oil. MS ESI (neg.) m/e: 983.5 (2M−H)+, 491.3 (M−H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl[C:9]1[N:17]=[C:16]([N:18]2[C:22]3[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=3[N:20]=[CH:19]2)[N:15]=[C:14]2[C:10]=1[N:11]([CH3:36])[C:12](=[O:35])[N:13]2[C@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1.[CH2:37]1[C@H:41]([F:42])[CH2:40][NH:39][CH2:38]1.Cl>>[F:27][C:24]1[CH:25]=[CH:26][C:21]2[N:20]=[CH:19][N:18]([C:16]3[N:15]=[C:14]4[C:10]([N:11]([CH3:36])[C:12](=[O:35])[N:13]4[C@H:28]4[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]4)=[C:9]([N:39]4[CH2:38][CH2:37][C@H:41]([F:42])[CH2:40]4)[N:17]=3)[C:22]=2[CH:23]=1
Reactant: F[C@H]1CCNC1
Reactant: Cn1c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(-n3cnc4ccc(F)cc43)nc(Cl)c21
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(-n3cnc4ccc(F)cc43)nc(N3CC[C@H](F)C3)c21

Procedure:
Light brown solid. TFA salt. Synthesized from 6-chloro-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-9-(trans-4-hydroxycyclohexyl)-7-methyl-7H-purin-8(9H)-one and S-(+)-3-fluoropyrrolidine hydrochloride, following the general procedure for displacement reactions of 6-chloropurinones with aliphatic amines. 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 8.99 (s, 1H), 8.27 (dd, 1H), 7.74 (dd, 1H), 7.15 (td, 1H), 5.47 (d, J=52.4 Hz, 1H), 4.51-4.42 (m, 1H), 4.19-3.83 (overlap of 5H), 3.65 (s, 3H), 2.68-2.42 (overlap of 3H), 2.29-2.03 (overlap of 3H), 1.97-1.90 (m, 2H), 1.62-1.49 (m, 2H); MS (EI) m/z 470.3 (MH)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C:8]2([CH2:16][CH2:15][N:14]([C:17]3[CH:26]=[N:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH2:13][CH2:12]2)[C:7]1=[O:27].[NH:31]1[CH:35]=[CH:34][N:33]=[N:32]1.CN[C@@H]1CCCC[C@H]1NC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[N:31]1[N:32]([C:2]2[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=2)[CH2:5][N:6]2[CH2:11][CH2:10][CH2:9][C:8]3([CH2:16][CH2:15][N:14]([C:17]4[CH:26]=[N:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=4)[CH2:13][CH2:12]3)[C:7]2=[O:27])[N:33]=[CH:34][CH:35]=1
Reactant: O=C1N(Cc2cccc(I)c2)CCCC12CCN(c1cnc3ccccc3n1)CC2
Reactant: c1c[nH]nn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: O=C1N(Cc2cccc(-n3nccn3)c2)CCCC12CCN(c1cnc3ccccc3n1)CC2
Temperature: 110 °C
Reaction time: 24 h
Yield: 30.9 %

Procedure:
To a mixture of 2-(3-iodobenzyl)-9-(quinoxalin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one (104 mg, 0.20 mmol), 1H-1,2,3-triazole (28 mg, 0.40 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine [68737-65-5] (6 mg, 0.04 mmol) and K3PO4 (127 mg, 0.60 mmol) in DMF (2 mL), CuI (15 mg, 0.08 mmol) was added and the reaction mixture was stirred at 110° C. for 24 h. The reaction mixture was cooled to it and filtered to remove the solids. The filtrate was concentrated under reduced pressure. The residue was purified by reversed phase preparative HPLC (column AG/PP/C-18-15/025, flow 20 mL/min, mobile phase water (A): acetonitrile (B) gradient) to yield the regioisomeric title compounds (example 8: 28 mg, 31% and example 9: 54 mg, 60%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][C:20]([CH3:53])=[CH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:52])[C:32]([CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)([OH:46])[C:33]2[NH:34][CH:35]=[C:36](COCC[Si](C)(C)C)[N:37]=2)[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:19][C:20]([CH3:53])=[CH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:52])[C:32]([C:33]2[NH:37][CH:36]=[CH:35][N:34]=2)([CH:47]2[CH2:48][CH2:49][CH2:50][CH2:51]2)[OH:46])[CH2:26][CH2:25]1
Reactant: CC(C)=CCCN1CCC(NC(=O)C(O)(c2nc(COCC[Si](C)(C)C)c[nH]2)C2CCCC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)=CCCN1CCC(NC(=O)C(O)(c2ncc[nH]2)C2CCCC2)CC1
Reaction time: 5 h
Yield: 42.9 %

Procedure:
0.3 ml of a 1N tetrabutylammonium fluoride solution in tetrahydrofuran was added to a solution of 44 mg of N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-{[2-(trimethylsilyl)ethoxymethyl]imidazol-2-yl}acetamide in 2 ml of tetrahydrofuran at 60° C., and this mixture was stirred at the same temperature for 5 hours. The reaction mixture was mixed with a saturated aqueous solution of sodium bicarbonate and extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous solution sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by preparative thin layer chromatography [Kieselgel™ 60F254, Art 5744 (manufactured by E. Merck); developing solvent: chloroform/methanol=7/1] to obtain 14 mg of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1([CH3:27])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH:17]=[CH:18][C:19]3[O:25][CH2:24][CH2:23][N:22]=[CH:21][C:20]=3[CH:26]=2)[O:10]1.Cl[C:29]1[C:34]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[C:33]([CH3:43])[N:32]=[CH:31][N:30]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[F:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][C:34]2[C:29]([N:22]3[CH2:21][C:20]4[CH:26]=[C:16]([B:11]5[O:10][C:9]([CH3:27])([CH3:8])[C:13]([CH3:14])([CH3:15])[O:12]5)[CH:17]=[CH:18][C:19]=4[O:25][CH2:24][CH2:23]3)=[N:30][CH:31]=[N:32][C:33]=2[CH3:43])=[CH:41][CH:40]=1
Reactant: CC1(C)OB(c2ccc3c(c2)C=NCCO3)OC1(C)C
Reactant: Cc1ncnc(Cl)c1Cc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncnc(N2CCOc3ccc(B4OC(C)(C)C(C)(C)O4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 42 %

Procedure:
A mixture of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazepine trifluoroacetate salt (2.9 g, 8.00 mmol, 4-chloro-5-[(4-fluorophenyl)methyl]-6-methylpyrimidine (reagent preparation 5) (1.9 g, 8.00 mmol) and N,N-diisopropylethylamine (7.0 mL, 40.0 mmol) in N-methyl-2-pyrrolidone (10 mL) was reacted in a microwave apparatus (250 W) for 2 h at 150° C. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (500 mL) and brine (100 mL). The organic layer was separated, washed with brine (100 mL), dried over sodium sulfate then filtered and concentrated. Column chromatography of the residue on silica (gradient 20 to 40% ethyl acetate in hexane) gave 4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (1.6 g, 42% yield). 1H NMR (400 MHz, DMSO-D6): 8.58 (s, 1H), 7.62 (dd, 1H), 7.08 (m, 4H), 7.02 (d, 1H), 6.96 (d, 1H), 4.36 (s, 2H), 4.30 (m, 2H), 3.92 (s, 2H), 3.84 (m, 2H), 2.26 (s, 3H), 1.36 (s, 12H); MS (EI) for C27H31BFN3O3: 476 (MH+).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:31]=[CH:30][C:10]([O:11][CH2:12][C@H:13]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:8]=1.[B:32](OC(C)C)([O:37]C(C)C)[O:33]C(C)C.O>O1CCCC1.C(OCC)(=O)C>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][CH2:14][C@@H:13]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:12][O:11][C:10]2[CH:30]=[CH:31][C:7]([B:32]([OH:37])[OH:33])=[CH:8][CH:9]=2)[CH:17]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H](CCc1cccnc1)COc1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
A solution of n-butyllithium (2.5 M in hexanes, 6.9 ml, CAUTION) was added dropwise to a stirring solution of (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)butane (1.50 g, Example 21b)) and triisopropyl borate (4.3 ml) in tetrahydrofuran (200 ml) at −70° C. After the addition was complete the reaction mixture was allowed to warm to room temperature. After 1 hour water (200 ml) and ethyl acetate (200 ml) were added. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give an oil. This was partly purified by column chromatography over silica eluting with dichloromethane then ethyl acetate then methanol to give the sub-title compound as a glass (2 g).
Reaction SMILES: [ClH:1].Cl.C(OC([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][CH:31]=[C:30]4[O:35][CH2:36][O:37][C:29]=24)=[N:20][CH:21]=[N:22]3)[CH2:12][CH2:11]1)=O)(C)(C)C.Cl>>[ClH:34].[ClH:1].[Cl:34][C:33]1[C:28]([NH:27][C:19]2[C:18]3[C:23](=[CH:24][CH:25]=[CH:26][C:17]=3[O:16][CH:13]3[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]3)[N:22]=[CH:21][N:20]=2)=[C:29]2[O:37][CH2:36][O:35][C:30]2=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Agent: Cl
Product: Clc1ccc2c(c1Nc1ncnc3cccc(OC4CCNCC4)c13)OCO2
Yield: 195.7 %

Procedure:
Using an analogous procedure to that described in Example 31, 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(6-chloro-2,3-methylenedioxyanilino)quinazoline dihydrochloride (0.14 g) was reacted with hydrogen chloride to give the title compound (0.113 g); NMR Spectrum: (DMSOd6) 2.15–2.34 (m, 4H), 3.15 (m, 2H), 3.3 (m, 2H), 5.17 (m, 1H), 6.17 (s, 2H), 7.07 (d, 1H), 7.16 (d, 1H), 7.58 (m, 1H), 8.06 (m, 1H), 8.88 (s, 1H), 9.14 (br s, 1H), 9.32 (br s, 1H), 10.28 (s, 1H); Mass Spectrum: M+H+ 399 and 401.
Reaction SMILES: C([C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:10])[CH:5]=[CH:6][N:7](C)[CH3:8])#N.[ClH:16]>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:11](=[O:12])[C:3]1[C:4]([CH3:10])=[CH:5][CH:6]=[N:7][C:8]=1[Cl:16])[CH3:15]
Reactant: CCOC(=O)C(C#N)=C(C)C=CN(C)C
Reactant: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)ccnc1Cl
Temperature: 50 °C

Procedure:
1-Cyano-4-(N,N-dimethylamino)-1-ethoxycarbonyl-2-methyl-1,3-butadiene (25.0 g, 0.12 mol) prepared in a manner analogous to that described in Example (i) above in toluene (250 ml) was heated to 50° C. for 3 hours with stirring whereupon a steady stream of hydrogen chloride was passed through the reaction mixture. After cooling, the mixture was washed with water (250 ml). The aqueous layer was then extracted with toluene (3×100 ml). The pooled organic layers were dried with sodium sulphate and evaporated. Distillation of the residue in high vacuo yielded 2-chloro-4-methylnicotinic acid ethyl ester as colourless oil (15.3 g, 64% of theoretical yield) with b.pt.0.04 Torr 97° C.-98° C.
Reaction SMILES: Br[C:2]1([CH:9]=[CH:8][CH:7]=[N:6][CH2:5]1)[C:3]#[N:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][Si](C)(C)C)=[CH:13][C:12]=1[NH2:23]>>[NH2:23][C:12]1[CH:13]=[C:14]([C:17]#[C:18][C:8]2[CH:7]=[N:6][CH:5]=[C:2]([CH:9]=2)[C:3]#[N:4])[CH:15]=[CH:16][C:11]=1[F:10]
Reactant: N#CC1(Br)C=CC=NC1
Reactant: C[Si](C)(C)C#Cc1ccc(F)c(N)c1
Product: N#Cc1cncc(C#Cc2ccc(F)c(N)c2)c1
Yield: 64.5 %

Procedure:
Prepare essentially as described in EXAMPLE 138 using 3-bromonicotinonitrile (3.4 g, 18.3 mmol) and 2-fluoro-5-trimethylsilanylethynyl-phenylamine, (prepared as described in PREPARATION 41), (3.8 g, 18.3 mmol) to give the title compound as a white solid (2.8 g, 65%).
Reaction SMILES: [Na][CH:2]([C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([O:5]C)=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.C(O)(=O)C>C1(C)C(C)=CC=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([CH2:2][C:3]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[O:5])=[O:16])=[CH:9][CH:10]=1
Reactant: Cc1ccc(N)cc1
Reactant: COC(=O)C([Na])C(=O)c1ccc(OC)cc1
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: COc1ccc(C(=O)CC(=O)Nc2ccc(C)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of the methyl 2-sodio-2(4′-methoxybenzoyl) acetate salt prepared in Example 1(44.60 g, 0.194 mol) and 4-toluidine (20.85 g, 0.195 mol) in xylene (300 ml) was stirred and heated over 1 hour. Glacial acetic acid (11.7 g, 0.195 mol) in xylene (100 ml) was added which caused the mixture to become viscous. The mixture was then heated at reflux for 6 hours and allowed to cool to room temperature. Xylene (200 ml) was added to reduce the viscosity of the mixture. This solution was heated at reflux for 4 hours and allowed to cool to room temperature. The solid N-(4′-methoxybenzoylacetyl)-4-methylaniline product obtained was collected by filtration and washed with toluene and heptane. After removal of the residual organic solvent by drying, the solid product was re-suspended with water (250 ml) and stirred. The solid product was collected by filtration and dried (7.13 g, 13%); m.p. 122-126° C. The solvent was removed from the filtrate. The residue crystallized upon standing and was recrystallized in ethanol to give an additional purified solid product (6.83 g, 12 wt. %); m.p. 127-130° C.