Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N:9]([CH3:25])/[C:10](/[C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12)=[CH:11]\[CH:12]=[N+:13](C)C.COC(O)C.[NH2:31][C:32]1[C:33]([N:44]2[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]2)=[CH:34][C:35]([O:42][CH3:43])=[C:36]([NH:38]C(N)=N)[CH:37]=1.CN(C)C(N(C)C)=N>COCCO.CCOC(C)=O>[CH3:43][O:42][C:35]1[CH:34]=[C:33]([N:44]2[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]2)[C:32]([NH2:31])=[CH:37][C:36]=1[NH:38][C:25]1[N:9]=[C:10]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)[CH:11]=[CH:12][N:13]=1
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1NC(=N)N
Reactant: CN(C)/C(=C\C=[N+](C)C)c1cnn2ccccc12
Agent: CN(C)C(=N)N(C)C
Agent: COC(C)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: COCCO
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
A solution of [(Z)-3-(dimethylamino)-3-pyrazolo[1,5-a]pyridin-3-yl-prop-2-enylidene]-dimethyl-ammonium hexafluorophosphate (Intermediate 70, 116 mg, 0.3 mmol) in 2-s methoxyethanol (2 mL) was added dropwise to a stirred solution of 1-(5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)guanidine (Intermediate 72, 84 mg, 0.30 mmol) and 1,1,3,3-tetramethylguanidine (0.056 mL, 0.45 mmol) in 2-methoxyethanol (2 mL) at r.t. under N2. The resulting solution was sealed into a microwave tube and heated to 120° C. for 0.25 h then cooled to r.t. Further 1,1,3,3-tetramethylguanidine (0.056 mL, 0.45 mmol) was then added and the mixture was stirred at 120° C. for 0.25 h, then at 140° C. for 0.25 h. The mixture was cooled, diluted with EtOAc (10 mL), and washed with water (2×5 mL). The aqueous solution was extracted with EtOAc (5 mL) and the organic solution was washed with water (2×3 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1.5-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (69 mg, 53%) as a yellow foam; 1H NMR: 2.25 (3H, d), 2.51 (4H, m), 2.87 (4H, t), 3.73 (3H, s), 4.37 (2H, s), 6.72 (1H, s), 7.07 (1H, m), 7.22 (1H, d), 7.33 (1H, s), 7.40 (1H, m), 7.98 (1H, s), 8.31 (1H, d), 8.52 (1H, d), 8.76 (1H, s), 8.79 (1H, d); m/z: ES+ MH+ 431.
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[Br:15]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][Br:15])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: FC(F)C(F)(F)Oc1cccc(CBr)c1
Yield: 93.7 %

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (15 g, 72.1 mmol) in chloroform (200 ml) were added N-bromosuccinimide (14.11 g, 79.3 mmol) and 2,2′-azobis(isobutyronitrile) (590 mg, 3.60 mmol), and the mixture was heated under reflux for 30 min. The reaction solution was cooled and water (100 ml) was added. The mixture was extracted with chloroform. The extract was washed successively with water (100 ml) and saturated brine (100 ml), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene (19.4 g, purity 56%, 53%). This compound was used for the next reaction without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=O)C.CC(C[AlH]CC(C)C)C.CCCCCC.C(OCC)(=O)C>C(Cl)Cl.O.CO>[CH:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:3]
Reactant: CCOC(=O)c1cc(C)n(-c2ccccc2)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: O
Solvent: CO
Product: Cc1cc(C=O)nn1-c1ccccc1
Yield: 81.7 %

Procedure:
3-Ethoxycarbonyl-1-phenyl-5-methylpyrazole (3.482 g, 15.12 mmol) was dissolved in 20 mL of purified methylene chloride, and then dropwisely added with DIBAL (45.36 mL, 45.36 mmol) at −78° C. and stirred. Termination of the reaction was confirmed by TLC (hexane:ethyl acetate=5:1). Upon completion of reaction, the reaction mixture was dropwisely added with methanol and water, and then extracted with methylene chloride. The resulting organic layer was dried with anhydrous magnesium sulfate and filtered, and the filtrate was concentrated and dried in vacuo to obtain the target compound, 3-formyl-5-methyl-1-phenylpyrazole.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:31]2[CH2:30][CH2:29][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:33][CH2:32]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisopropylethylamine (4.00 ml) was added to a solution of 4-bromobenzenesulfonyl chloride (3.00 g) and 1-(tert-butoxycarbonyl)piperazine (2.40 g) in methylene chloride (50 ml) at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column (hexane:ethyl acetate=4:1→1:1), followed by reprecipitation in a hexane—methylene chloride system, whereby the title compound (4.47 g) was obtained as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:19]3[S:18][CH:22]=[CH:21][N:20]=3)=[CH:30][CH:29]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reactant: O=Cc1ccc(-c2nccs2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A solution of (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester (0.14 g, 0.59 mmol) and 4-thiazol-2-yl-benzaldehyde (0.105 g, 0.55 mmol) in 2 mL MeOH was stirred at room temperature for 1.5 hours. After cooling to 0° C., NaBH4 (0.033 g, 0.88 mmol) was added and the reaction was stirred for 10 minutes. The mixture was quenched with aqueous saturated NaHCO3:H2O (1:1) and the MeOH was removed in vacuo. The product was extracted into CH2Cl2 and the organic solution was dried over MgSO4, filtered, and concentrated in vacuo to afford a brown oil. The product was purified via flash chromatography on silica gel (6/4 EtOAc/Hexanes) to afford the title compound of Step A (0.140 g). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, 2H), 7.82 (s, 1H), 7.40 (d, 2H), 7.23-7.38 (m, 2H), 6.94 (m, 2H), 6.78 (d, 1H), 4.49 (s, 2H), 3.80 (s, 2H), 3.76 (s, 2H), 1.45 (s, 9H); MS 411 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[SH:13].[Al+3].[Cl-].[Cl-].[Cl-].[Li]CCCC.O>CCCCCC.C(OCC)(=O)C>[SH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][C:5]1[CH:4]=[C:3]([OH:2])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(Cc2ccccc2S)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Oc1cccc(Cc2ccccc2S)c1
Yield: 40 %

Procedure:
To a mixture of 0.61 g 2-(3-methoxybenzyl)benzenethiol (L) (2.65 mmol) and 1.94 g AlCl3 was added slowly 1.2 eq n-BuLi. The reaction was stirred overnight before 30 ml water was added. The mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over magnesium sulfate. The volatiles were removed by distillation under nitrogen. Flash silica chromatography (hexane:ethyl acetate 80:20) afforded 0.23 g product (1.06 mmol, 40% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH:21]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:28]([CH3:31])([O-:30])=[O:29]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:21]=[CH:31]/[N+:28]([O-:30])=[O:29])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1-c1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1-c1ccccc1
Temperature: 50 °C
Yield: 98 %

Procedure:
Nitromethane (1.4 mL) was added to a mixture of aldehyde 6a (0.16g, 0.56 mmol) and ammonium acetate (77 mg, 1.0 mmol) and heated to 50° C. Upon completion (˜15-30 min), the reaction mixture was cooled to RT and purified without work-up by column chromatography (SiO2, 3:1, Hex:EtOAc) to afford nitrostyrene 7a as a yellow oil (182 mg, 0.55 mmol, 98%). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=13.6 Hz, 1H), 7.64 (d, J=9.5 Hz, 1H), 7.50-7.35 (m, 10H), 7.31 (d, J=2.1 Hz, 2H), 7.04 (d, J=2.5 Hz, 1H), 5.15 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 161.8, 146.1, 138.1, 136.4, 136.3, 135.5, 131.8 131.7, 129.9, 129.2, 128.8, 128.0, 121.3, 117.3, 116.3, 116.0, 115.6, 70.7; HRMS (FAB) m/z: [M+Na+] for C21H18NO3, calcd, 332.1281. found, 332.1290.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH2:9]([Sn](CCCC)(CCCC)C=C)[CH2:10]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH:9]=[CH2:10])[CH:7]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccnc(Br)c1
Agent: [Pd]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(C)ccn1
Temperature: 100 °C
Yield: 52.3 %

Procedure:
A yellow mixture of 2-bromo-4-methyl-pyridine (Aldrich, 5.2 9, 30.5 mmol, 1.0 eq), 2,6-di-tert-butyl-4-methyl-phenol (Aldrich, 67 mg, 0.3 mmol, 1 mol %), tributyl-vinyl-stannane (Aldrich, 26.8 mL, 91.5 mmol, 3.0 eq) and tetrakis(triphenylphosphine) palladium (0) (Strem, 1.8 9, 1.5 mmol, 5 mol %) in toluene (100 mL) was degassed and purged with argon. An amber solution was obtained after the mixture was warmed to 100° C. The reaction mixture was quenched after 18 hours by the addition of 1.0 M HCl. The acidic extract was washed with ether, adjusted to pH 9 with solid sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product (3.7 g of a brown oil) was purified by flash chromatography (silica) and eluted with 0–5% ethyl acetate-dichloromethane, which gave a clear oil (1.9 g, 53%). 1H NMR (DMSO-d6, 300 MHz) δ 8.39 (1H, d, J=4.9 Hz), 7.33 (1H, s), 7.10 (1H, dd, J=5.0, 0.8 Hz), 6.77 (1H, dd, 17.5, 10.8 Hz), 6.20 (1H, dd, J=17.5, 1.7 Hz), 5.44 (1H, dd, J=10.8, 1.8 Hz), 2.31 (3H, s). ESIMS m/z 120 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19]([O:26][C:27]([C:29]1[O:30][C:31]([CH:34]=O)=[CH:32][CH:33]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C:27]([C:29]1[O:30][C:31]([CH:34]=[CH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:16])=[CH:32][CH:33]=1)=[O:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=Cc1ccc(C(=O)OCc2ccccc2)o1
Temperature: 0 °C
Yield: 87.8 %

Procedure:
A solution of diethylphosphonoacetic acid tert-butyl ester (1.54 g, 6.09 mmol) in tetrahydrofuran (3 mL) was added dropwise to a suspension of 60% sodium hydride (0.19 g, 4.87 mmol) in tetrahydrofuran (50 mL) with stirring at 0° C. After stirring at room temperature for 20 minutes, a solution of 5-formyl-2-furancarboxylic acid benzyl ester (1.0 g, 4.06 mmol) in tetrahydrofuran (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was worked up according to a conventional method, and the object product was extracted by column chromatography (10-30% ethyl acetate/hexane mixed solvent) to give the title compound (1.17 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24].C(N(CC)CC)C.C(Cl)(Cl)Cl>C(Cl)Cl>[C:16]1([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][C:6]3[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:22](=[O:25])[CH2:23][CH3:24])=[CH:8][CH:7]=3)[CH2:15][CH2:14]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC(=O)Cl
Reactant: NCc1ccc(CN2CCN(c3ccccc3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(=O)NCc1ccc(CN2CCN(c3ccccc3)CC2)cc1

Procedure:
A solution of 4-((4-(aminomethyl)phenyl)methyl)-1-phenylpiperazine (0.62 g), propionyl chloride (0.23 ml) and triethylamine (0.37 ml) in methylene chloride (20 ml) was stirred at room temperature for 4 hr. To this reaction mixture was added chloroform (100 ml), and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-brown solid (0.9 g). The obtained solid was crystallized from ethyl acetate (50 ml) to give the title compound (0.5 g) as pale-yellow white crystals, m.p.=140-141° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([OH:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH3:4])([CH3:3])[CH3:2].[CH2:40]([O:47][C:48]([CH2:50][S:51][CH2:52][C:53](O)=[O:54])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([O:21][C:53](=[O:54])[CH2:52][S:51][CH2:50][C:48]([O:47][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:49])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[O:32][C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: O=C(O)CSCC(=O)OCc1ccccc1
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)OC(=O)CSCC(=O)OCc2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Preparation 25, but using N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 12) and 2-(benzyloxycarbonylmethylthio)acetic acid as starting materials, in relative proportions similar to those used in that Preparation, the title compound was obtained as a foam-like material.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][O:13][CH2:12]1)([O-])=O>CCOC(C)=O.[Pd]>[O:13]1[CH2:14][CH2:15][CH2:16][CH:11]([NH:10][C:5]2[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:12]1
Reactant: O=[N+]([O-])c1ccccc1NC1CCCOC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccccc1NC1CCCOC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of (2-nitrophenyl)(tetrahydropyran-3-yl)amine (0.72 g, 3.24 mmol) and 10% Pd/C (200 mg) in EtOAc (30 mL) was degassed with a stream of nitrogen and stirred at RT under a hydrogen atmosphere for 3 days. The suspension was then filtered through a pad of celite and the filtrate was concentrated in vacuo affording N-(Tetrahydropyran-3-yl)benzene-1,2-diamine as a colourless oil (quantitative). 1H NMR (CDCl3, 400 MHz): δ 6.80 (1H, t, J=7.55 Hz), 6.75-6.62 (3H, m), 4.00 (1H, d, J=11.24 Hz), 3.84-3.71 (1H, m), 3.67-3.16 (6H, m), 2.07-1.92 (1H, m), 1.87-1.73 (1H, m), 1.72-1.56 (2H, m).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:24][CH2:25][C@H:26]([NH:28][CH3:29])[CH3:27])[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[OH:30]>>[Cl:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:24][CH2:25][C@H:26]([N:28]([CH3:29])[C:1](=[O:5])[CH2:2][OH:3])[CH3:27])[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[OH:30]
Reactant: CN[C@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: O=C(O)CO
Product: C[C@H](COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12)N(C)C(=O)CO
Yield: 100 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 2-chloro-4-[(5-{[(2R)-2-(methylamino)propyl]oxy}quinazolin-4-yl)amino]phenol to give N-[(1R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-2-hydroxy-N-methylacetamide in 100% yield; Mass spectrum MH+ 416.9.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3](=[O:5])[CH3:4].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1.C(Cl)Cl>[CH3:9][S:10]([O:7][CH2:6][C:2]([CH3:8])([CH3:1])[C:3](=[O:5])[CH3:4])(=[O:12])=[O:11]
Reactant: CC(=O)C(C)(C)CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)C(C)(C)COS(C)(=O)=O
Reaction time: 12 h
Yield: 85.5 %

Procedure:
232 g (2 mol) of 3,3-dimethyl-4-hydroxy-2-butanone (for the preparation, see Beilstein H 1 E III 3239, IV 4030 and Bull.Soc. Chim. France 1964, 2849) were reacted with 229 g (2 mol) of methanesulphonyl chloride in 700 ml of absolute pyridine at 0° to 5° C. After leaving the mixture to stand at 20° C. for 12 hours, it was diluted with methylene chloride and extracted by shaking with ice-water. The organic phase was dried, and freed from solvent in vacuo, and the residue was fractionated over a column. 332 g (86% of theory) of 2,2-dimethyl-3-oxo-butyl methanesulphonate of boiling point 106°-120° C./0.12 mm Hg were obtained.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:27])[CH2:7][C@@H:8]([C:20]1[CH:21]=[N:22][C:23]([CH3:26])=[N:24][CH:25]=1)[CH2:9][CH2:10][CH2:11][N:12]1[C@H:16]([CH3:17])[CH2:15][C@H:14]([NH2:18])[C:13]1=[O:19])[CH3:4].C(N(CC)CC)C.[N:35]1[C:44]2[NH:43][CH2:42][CH2:41][CH2:40][C:39]=2[CH:38]=[CH:37][C:36]=1[CH:45]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[CH2:3]([O:5][C:6](=[O:27])[CH2:7][C@@H:8]([C:20]1[CH:25]=[N:24][C:23]([CH3:26])=[N:22][CH:21]=1)[CH2:9][CH2:10][CH2:11][N:12]1[C@H:16]([CH3:17])[CH2:15][C@H:14]([NH:18][CH2:45][C:36]2[CH:37]=[CH:38][C:39]3[CH2:40][CH2:41][CH2:42][NH:43][C:44]=3[N:35]=2)[C:13]1=[O:19])[CH3:4]
Reactant: CCOC(=O)C[C@H](CCCN1C(=O)[C@@H](N)C[C@H]1C)c1cnc(C)nc1
Reactant: O=Cc1ccc2c(n1)NCCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)C[C@H](CCCN1C(=O)[C@@H](NCc2ccc3c(n2)NCCC3)C[C@H]1C)c1cnc(C)nc1
Reaction time: 1.5 h

Procedure:
To a stirred suspension of 5-5 (170 mg, 0.44 mmol), triethylamine (61 mL, 0.44 mmol), and 5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carbaldehyde (72 mg, 0.44 mmol) in 1,2-dichloroethane (4 mL) was added sodium triacetoxyborohydride (112 mg, 0.53 mmol) and the resulting mixture was stirred for 1.5 hours. The reaction mixture poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was then washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and filtered. Following evaporative removal of the solvent, the residue was purified by flash column chromatography (silica gel, 95:5:0.5:0.5% ethyl acetate/ethanol/NH4OH/H2O) to give 5-6 as a colorless oil.
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:3]=1.P(Cl)(Cl)([Cl:20])=O.[OH-].[Na+]>CN(C)C=O>[Cl:20][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(Nc2ccc(F)cc2)nc(Cl)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
40.5 g(174.1 mmole) of 2-(4-fluorophenylamino)-4-hydroxy-5,6-dimethylpyrimidine produced in Example 1 was suspended in 80 ml of N,N-dimethylformamide and the resulting suspension was heated to 80° C. 31.9 g(19.4 ml, 210.1 mmole) of phosphorus oxychloride was added thereto over one hour at constant temperature of 85° C. The reaction solution was stirred for 30 minutes and then 400 g of ice-water was added thereto with stirring. The mixture was adjusted to pH 11 by adding sodium hydroxide and then the resulting solid product was filtered. The separated solid product was washed with 150 ml of 50% aqueous methanol solution and then dried to obtain 42.3 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1>CCOC(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)C(=Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-tert-Butoxycarbonylamino-3-{(R)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-acrylic acid methyl ester (4.9 g) was suspended in 300 mL EtOAc. 400 mg (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I) trifluoromethanesulfonate in 30 mL DCM was added. The mixture was then degassed and a hydrogen balloon was added. The mixture was stirred at room temperature for 2 hours and the solvent was evaporated. The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc) to give 4.8 g after drying. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.34 (m, 2H), 7.24-7.28 (m, 1H), 6.98 (m, 2H), 6.87 (d, 1H), 6.69 (d, 1H), 6.62 (m, 1H), 5.07-4.96 (m, 4H), 4.54 (m, 1H), 4.30 (m, 1H), 4.0 (m, 1H), 3.74 (s, 3H), 3.0 (m, 2H), 1.43 (s, 9H).