Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:5][N:6]2[CH2:10][CH2:9][O:8][C:7]2=[O:11])[CH2:4][O:3]1.Cl[C:13]1[NH:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[N:17]=1.C([O-])(=O)C.[Na+].[H-].[Na+]>C(O)C>[CH3:1][C:2]1([CH2:5][N:6]2[CH2:10][CH2:9][O:8][C:7]2=[O:11])[O:3][C:13]2=[N:17][C:16]([N+:18]([O-:20])=[O:19])=[CH:15][N:14]2[CH2:4]1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CC1(CN2CCOC2=O)CO1
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CC1(CN2CCOC2=O)Cn2cc([N+](=O)[O-])nc2O1
Yield: 31.5 %

Procedure:
A mixture of 3-(2-methyloxiran-2-ylmethyl)-oxazolidin-2-one (2.87 g, 18.23 mmol), 2-chloro-4-nitro-1H-imidazole (2.7 g, 18.23 mmol), sodium acetate (1.64 g, 20.05 mmol) and ethanol (30 ml) was stirred under reflux for 10 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, methylene chloride was added, and the resulting solution was washed with water, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in 1,4-dioxane (50 ml). To the solution, sodium hydride (610 mg, 15.25 mmol) was added followed by stirring under reflux overnight. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, water was added, and the solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford 3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)oxazolidin-2-one (1.54 g, yield 40%) as a white powder.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[C:22]([OH:24])=[O:23])=O>C1COCC1>[NH:14]1[N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[C:22](=[O:23])[O:24]1
Reactant: O=NN1CCCCC1C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1ONN2CCCCC12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic anhydride (1.93 g) was added to the THF (92 mL) solution of crude (2RS)-1-nitrosopiperidine-2-carboxylic acid under a nitrogen atmosphere at 0° C. and stirred for 5 h at 0° C. and for 2 h at room temperature. The solution was concentrated under a reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with n-hexane-AcOEt (1/1-0/1). The titled compound was obtained as colorless crystals (1.10 g, 33%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].[Li+].C[Si](Cl)(C)C.C[SiH](C)O[SiH](C)C.BrCC1C=CC(OC)=C(OC2CCCC2)C=1.[C-:47]#[N:48].[Na+]>C(#N)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:10][C:47]#[N:48])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: COc1ccc(CBr)cc1OC1CCCC1
Agent: C[SiH](C)O[SiH](C)C
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: O
Product: COc1ccc(CC#N)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
To a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (20 g, 90.8 mmol) in acetonitrile (100 mL) was added lithium bromide (15 g, 173 mmol) followed by the dropwise addition of trimethylsilylchloride (17.4 mL, 137 mmol). After 15 min, the reaction mixture was cooled to 0° C., 1,1,3,3-tetramethyldisiloxane (26.7 mL, 151 mmol) was added dropwise and the resulting mixture was allowed to warm to room temperature. After stirring for 3h, the mixture was separated into two layers. The lower layer was removed, diluted with methylene chloride and filtered through Celite. The filtrate was concentrated under reduced pressure, dissolved in methylene chloride and refiltered. The solvent was removed in vacuo to provide a light tan oil. To a solution of this crude a-bromo-3-cyclopentyloxy-4-methoxytoluene in dimethylflormamide (160 mL) under an argon atmosphere was added sodium cyanide (10.1 g, 206 mmol) and the resulting mixture was stirred at room temperature for 18 h, then poured into cold water (600 mL) and extracted three times with ether. The organic extract was washed three times with water, once with brine and was dried (potassium carbonate). The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 10% ethyl acetate/hexanes, to provide an off-white solid (17.7 g, 84%): m.p. 32°-34° C.; an additional quantity (1.3 g) of slightly impure material also was isolated.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([CH:8]=[CH:9][CH:10]=[N:11]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C>[Br:21][C:13]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: c1cnc2cc(C3CC3)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Brc1c(C2CC2)ccc2cccnc12
Yield: 35.8 %

Procedure:
A solution of 7-cyclopropylquinoline (3.45 g, 19.7 mmol) and NBS (4.03 g, 22.66 mmol) in DMF (50 mL) was heated at 65° C. for 2 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, concentrated, and purified by chromatography with a gradient elution of 1-10% EtOAc/CH2Cl2 to yield 8-bromo-7-cyclopropylquinoline (1.75 g, 35% yield).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[CH:14][CH:13]=1)(=O)=O.O>CN(C)C=O>[O:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[O:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][N:1]=[N+:2]=[N-:3])=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OCCc1ccc(CCOC2CCCCO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCc1ccc(CCOC2CCCCO2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
Sodium azide (1.73 g, 26.61 mmol) was added to a solution of 4-(2-(tetrahydropyran-2-yloxy)ethyl)phenethyl methanesulfonate (5.24 g, 15.95 mmol) in N,N-dimethylformamide (50 ml). The mixture was stirred at 100° C. for 1 hour. Water (40 ml) was added to the reaction mixture. The mixture was extracted with ethyl ether and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=20/1) to give the desired 4-(2-(tetrahydropyran-2-yloxy)ethyl)-1-(2-azidoethyl)benzene (4.30 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:37][CH:38]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:39]1([N:44]([CH3:46])[CH3:45])[CH2:43][CH2:42][CH2:41][CH2:40]1.C(N(C(C)C)CC)(C)C.C(O)C(N)(CO)CO>C(Cl)Cl.CN1CCCC1=O>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:37][CH:38]([C:39]1([N:44]([CH3:46])[CH3:45])[CH2:43][CH2:42][CH2:41][CH2:40]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:6]
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1(C(NC(=O)c2c(Cl)cccc2Cl)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of 2,6-dichlorobenzoic acid (20 mg; 0.105 mmol) in DCM (2 ml) and N-methylpyrrolidinone (0.1-0.5 ml) was added 1-hydroxybenzotriazole (18 mg; 0.11 mmol) and PL-dicyclohexylcarbodiimide (88 mg; 0.14 mmol; Polymer Labs 1.59 mmol/g). The mixture was shaken at room temperature for 1 hour and then 1-[amino(phenyl)methyl]cyclopentyl}dimethylamine dihydrochloride D2 (20 mg; 0.07 mmol) and PS-diisopropylethylamine (82 mg; 0.21 mmol; Polymer Labs 2.59 mmol/g) were then added and shaking continued overnight at room temperature. An excess of PS-Trisamine was then added and after shaking for a further 4 h, the mixture was filtered and the resins washed well with DCM and methanol. The filtrate was reduced in volume by evaporation in vacuo and loaded onto an SCX cartridge (500 mg). Washing with DCM, then methanol followed by elution with 1M ammonia in methanol afforded the title product (22.8 mg). 1H NMR (CDCl3) δ: 0.98 (1H, m), 1.26 (1H, m), 1.40 (2H, m), 1.68 (2H, m), 1.85 (2H, m), 2.22 (6H, s), 5.08 (1H, bs), 7.27 (7H, m), and 7.47 (2H, m). Mass Spectrum (Electrospray LC/MS): Found 391 (MH+). C21H2435Cl2N2O requires 390. Ret. time 1.88 min.
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C@H:14]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]2)=[O:13])=[CH:6][C:5]=1[O:42][CH3:43].C1COCC1.O.[OH-].[Li+]>O>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C@@:17]2([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:40])([CH3:41])[CH3:39])[NH:15][C@@H:14]([C:12]([NH:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:44])=[O:2])=[C:5]([O:42][CH3:43])[CH:6]=3)=[O:13])[C@@H:18]2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=2[F:26])=[C:30]([F:36])[CH:31]=1
Reactant: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)O
Temperature: 25 °C
Yield: 90.3 %

Procedure:
In a manner similar to the method described in Example 380, rac-4-({[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester (75.2 mg, 0.117 mmol), was combined with THF (7 ml) and lithium hydroxide hydrate (33.5 mg, 0.798 mmol) in water (3.5 mL). It was stirred at room temperature to give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid as a white lyophilized solid (66.6 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH2:9])[CH:3]=1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH:9][C:17](=[O:19])[CH3:18])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cc(Br)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.5 %

Procedure:
Into a 500-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (4-bromopyridin-2-yl)methanamine (compound 39.1, 4.5 g, 24.1 mmol) in dichloromethane (160 mL). Triethylamine (6.72 mL, 48.2 mmol) and acetic anhydride (2.29 mL, 24.2 mmol) were carefully added and the resulting solution was stirred at room temperature for 12 h. The volatiles were removed under reduced pressure and the residue was slowly quenched with water (200 mL). The pH of the solution was slowly adjusted to 9-12 with aqueous sodium carbonate (3 M) and the aqueous phase was extracted with ethyl acetate (3×60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane/methanol (100:1-10:1) as the eluent to yield 4.0 g (73%) of the title compound as yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:10][C:11]1[C:14](=O)[C:13](=[O:16])[C:12]=1[O:17]CCCC)[CH2:7][CH2:8][CH3:9]>>[CH2:6]([O:10][C:11]1[C:12](=[O:17])[C:13](=[O:16])[C:14]=1[NH:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Reactant: NCCCBr
Product: CCCCOc1c(NCCCBr)c(=O)c1=O
Yield: 84 %

Procedure:
The solution of bromopropylamine base, cooled to 0° C., was slowly added dropwise with vigorous stirring and cooling to maintain the temperature below to the methanolic solution of Step A containing 1,2-dibutoxy-1-cyclobutene-3,4-dione. The mixture was stirred at 20° C. for 2 hours, polish filtered through diatomaceous earth, washed with methanol (2×0.25L) and the filtrate was added over a period of 1 hour with vigorous stirring to water (31.1L). The mixture was stirred at 0° C. for 2 hours. The solid was collected by filtration, washed with water (3×2L) and dried to vacuo at 50° C. to give 2137 g (84% yield) of the title compound as an off-white solid; m.p.=69° C.
Reaction SMILES: O.O.Cl.[NH2:4][C:5]1[N:14]=[C:13]([NH2:15])[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:16][N:17]([CH3:27])[C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[N:11]=2)[N:6]=1.NC1N=C(N)C2C(=NC=C(CN(C3C=CC(C(O)=O)=CC=3)C)N=2)N=1.O.O.C(P(=O)(OCC)OCC)#N.CCN(C(C)C)C(C)C.C(O)(=O)C.[CH2:77]([O:79][C:80](=[O:96])[C@@H:81]([N:83]([CH2:93][CH2:94][NH2:95])[PH:84]([O:86][C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)=[O:85])[CH3:82])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80](=[O:96])[CH:81]([N:83]([CH2:93][CH2:94][NH:95][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([N:17]([CH2:16][C:10]2[N:11]=[C:12]3[C:7](=[N:8][CH:9]=2)[N:6]=[C:5]([NH2:4])[N:14]=[C:13]3[NH2:15])[CH3:27])=[CH:26][CH:25]=1)[PH:84]([O:86][C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)=[O:85])[CH3:82])[CH3:78]
Reactant: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)[C@H](C)N(CCN)[PH](=O)Oc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N(CCNC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1)[PH](=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.6 %

Procedure:
To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acid hemihydrochloride dihydrate (39.6 mg, 104.0 mmol) in DMF (1.2 mL) were added diethyl cyanophosphonate (20.6 μL, 136.1 μmol) and DIEA (36.0 μL, 209.4 μmol). The solution was stirred at ambient temperature for 3 hours, when (S)-2-[(2-aminoethyl)phenoxyphosphinoylamino]propionic acid ethyl ester mono acetic acid salt (mixture of diastereomers at phosphorus; 104.0 μmol) in DMF (200 μL) was added. The solution was stirred for 30 minutes when complete consumption of the starting materials was observed. An aliquot (66%) of the reaction was purified by silica gel chromatography using MeOH—CH2Cl2 (10-30%), yielding 27.2 mg of crude product. A small amount of the product (10 mg) was repurified by RP HPLC on C18 column using H2O/acetonitrile (2-95%) to provide 4.2 mg (26%) of the pure product. 1H NMR (300 MHz, DMSO-d6) δ 1.11 (t, 3H, J=6.9 Hz), 1.18 (d, 3H, J=7.2 Hz), 2.06-2.17 (m, 2H), 3.20 (s, 3H), 3.51 (m, 2H), 3.88 (m, 1H), 4.02 (m, 2H), 4.79 (s, 2H), 5.61 (m, 1H), 6.80 (d, 2H, J=9 Hz), 6.98 (br s, 1H), 7.18 (m, 3H), 7.32 (m, 2H), 7.67 (d, 2H, J=9 Hz), 8.20 (br s, 1H), 8.59 (s, 1H) 31P (121.4 MHz, DMSO-d6) δ 29.5, 30.1. MS (m/z) 608.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25].[H-].[Na+]>CN(C=O)C.O>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH2:18])[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Nc1ccccc1O
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1Oc1cc(-c2ccc(C(F)(F)F)cc2)ncn1
Temperature: 50 °C

Procedure:
To a mixture of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.52 g, 2.0 mmol) and 2-aminophenol (0.26 g, 2.4 mmol, Aldrich) in DMF (10 mL) was added sodium hydride (0.09 g, 2.2 mmol, 60% dispersion in mineral oil, Aldrich). The mixture was heated at 50° C. for 2 h, allowed to cool to room temperature and diluted with H2O. The resulting solid was filtered, washed with H2O and dried in vacuum at room temperature for 20 h to afford the title compound as a white powder. Mp: 188° C., MS (ESI, pos. ion) m/z: 332 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([O:21][CH2:31][C:30]4[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 49 %

Procedure:
Using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[S:3]([O:6][C:7]1[C:12](C=O)=[C:11]([CH3:15])[N:10]=[C:9]2[N:16]([CH3:19])[CH2:17][CH2:18][C:8]=12)(=[O:5])=[O:4].OO.[C:24]([O-])([OH:26])=[O:25].[Na+]>ClCCl>[CH:24]([O:26][C:12]1[C:7]([O:6][S:3]([C:2]([F:21])([F:1])[F:20])(=[O:5])=[O:4])=[C:8]2[CH2:18][CH2:17][N:16]([CH3:19])[C:9]2=[N:10][C:11]=1[CH3:15])=[O:25]
Reactant: Cc1nc2c(c(OS(=O)(=O)C(F)(F)F)c1C=O)CCN2C
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc2c(c(OS(=O)(=O)C(F)(F)F)c1OC=O)CCN2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 80 mg (0.24 mmol) of aldehyde 31 in 3 mL of dichloromethane was added 1 mg (0.09 mmol) of SeO2 and 1.5 mL of H2O2 (30% in H2O). The reaction mixture was stirred at room temperature for 16 h then cooled to 0° C., 12 mL of 5% of NaHCO3 was added slowly. The mixture was stirred for additional 20 min then extracted with three portions of 15 mL of ethyl acetate. The combined organic layer was washed with brine and dried over Na2SO4. After solvent was removed, the residue was purified by flash chromatography on a silica gel column (15×2 cm). Elution with 1:10 EtOAc-hexanes gave product 32 as light yellow solid: yield 47.6 mg (57%). Silica gel TLC Rf 0.28 (4:1 EtOAc-hexanes); 1H NMR (CDCl3, ppm): δ 2.25 (s, 3H), 2.94 (s, 3H), 3.08 (t, J=8.4 Hz, 2H), 3.57 (t, J=8.4 Hz, 2H), 8.23 (s, 1H). 13C NMR (CDCl3, ppm): δ 19.21, 23.69, 32.36, 52.10, 113.38, 116.76, 119.95, 126.71, 150.24, 158.20, 162.82; 19F NMR (CDCl3, ppm): δ−73.77 (s, 3F); HRMS (ESI+) calculated for C11H11N2O5SF3 (M+H+) 340.0414. found 340.0413.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[CH:10][C:9]3[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:8]=3[O:7][C:6]=2[CH:17]=1.CO/[CH:20]=[CH:21]/[C:22]([O:24][Si](C)(C)C)=[CH2:23].C1COCC1.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:20]=[CH:21][C:22](=[O:24])[CH2:23][CH:10]3[C:9]3[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:8]=3[O:7][C:6]=2[CH:17]=1
Reactant: Cc1cccc2c1C=Nc1ccc(Br)cc1O2
Reactant: C=C(/C=C/OC)O[Si](C)(C)C
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cccc2c1C1CC(=O)C=CN1c1ccc(Br)cc1O2
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of 7-bromo-1-methyldibenz[b,f][1,4]oxazepine (25.05 g, 86.98 mmol) and Ytterbium(III) triflate (2.8 g, 4.5 mmol) in toluene (0.21 L) at 0° C., (E)-1-methoxy-3-trimethylsilyloxy-1,3-butadiene (18 mL, 95.7 mmol) was added dropwise. THF (0.1 L) was added to dissolve the formed precipitate and the solution was stirred for 15 min. 1N hydrochloric acid (50 mL) was added and the resulting mixture was stirred for an additional 15 min, after which it was diluted with ethyl acetate and washed with brine. After drying (Na2SO4) the solvent was evaporated under reduced pressure to yield the crude compound which was triturated in methanol to give the title compound (25.4 g, 82%). Data: 1H-NMR (400 MHz, CDCl3) δ 2.31 (s, 3H), 2.43 (m, 1H), 3.00 (m, 1H), 5.23 (m, 1H), 5.41 (m, 1H), 6.99-7.52 (m, 7H). (m/z)=356+358 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:23][C:24]1[CH:30]=[C:29]([F:31])[C:27]([NH2:28])=[C:26]([F:32])[CH:25]=1.[H-].[Na+]>CN(C=O)C>[Cl:23][C:24]1[CH:30]=[C:29]([F:31])[C:27]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[C:26]([F:32])[CH:25]=1
Reactant: Nc1c(F)cc(Cl)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(F)cc(Cl)cc3F)ncnc2cc1OCC1CCN(C)CC1
Yield: 61.2 %

Procedure:
Using an analogous procedure to that described in Example 4, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (246 mg, 0.764 mmol), (prepared as described for the starting material in Example 2c), was reacted with 4-chloro-2,6-difluoroaniline (250 mg, 1.53 mmol), (see WO 97/30035 Example 15), in DMF (9 ml) and in the presence of sodium hydride (60%, 76.5 mg, 1.9 mmol) to give 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (210 mg, 61%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[C:15]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
Into a 500-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-bromopyrazin-2-amine (4 g, 22.99 mmol, 1.00 equiv) in 1,4-dioxane (68 mL) and methanol (23 mL), 3-(trifluoromethyl)phenylboronic acid (4.46 g, 23.48 mmol, 1.02 equiv), a solution of sodium carbonate (4.88 g, 46.04 mmol, 2.00 equiv) in water (23 mL), and Pd(PPh3)4 (532 mg, 0.46 mmol, 0.02 equiv). The resulting solution was stirred overnight at 135° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5). This resulted in 4.4 g (80%) of 5-(3-(trifluoromethyl)phenyl)pyrazin-2-amine as a yellow solid.
Reaction SMILES: NCC1C=C(N[C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[NH:12][N:11]=2)C=CC=1.C1COCC1>C(OCC)C>[Cl:26][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[N:16]=[CH:15][N:14]=[C:13]3[NH:12][N:11]=[CH:10][C:18]=23)[CH:25]=[CH:24][CH:23]=1
Reactant: NCc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1cccc(Nc2ncnc3[nH]ncc23)c1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
A mixture of 300 mg (0.805 mmol) of 3-(3aminomethyl-phenylamino)-4-(3chloro-phenylamino)-1H-pyrazoio[3,4-d]pyrimidine (water content: 1.79%; see Step 90.5), 230 mg (0.845 mmol) of Boc-glycine hydroxysuccinimide ester (Fluka) and 5 ml of THF is stirred at 20° C. for 1.5 hours. The addition of 5 ml of diethyl ether to the reaction mixture, filtration and washing the filter residue with diethyl ether yield 3-13-(N-{N-tert-butyloxy-carbonyl-glycyl}aminomethyl)-phenylamino]4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 181-183° C.