Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:30])[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][N:12]([CH2:25][CH2:26][C:27](O)=[O:28])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[C:15]([Cl:24])[CH:14]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:3][O:4][C:5](=[O:30])[CH2:6][CH2:7][CH2:8][N:9]1[C:27](=[O:28])[CH2:26][CH2:25][N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:21])[F:23])=[C:15]([Cl:24])[CH:14]=2)[CH2:11][CH2:10]1
Reactant: COC(=O)CCCNCCN(CCC(=O)O)c1ccc(OC(F)(F)F)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCN1CCN(c2ccc(OC(F)(F)F)c(Cl)c2)CCC1=O
Reaction time: 15 h

Procedure:
A solution of 0.16 g (0.3 mmol) of 4-{2-[(2-carboxy-ethyl)-(3-chloro-4-trifluoromethoxy-phenyl)-amino]-ethylamino}-butyric acid methyl ester dihydrochloride in 2.5 ml CH2Cl2 was treated with 0.04 ml (0.3 mmol) of triethylamine and at 0° C. with 0.08 g (0.4 mmol) of EDCI. The cooling bath was allowed to come to RT and after 15 h the reaction was extracted with aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with 10% KHSO4, 10% NaCl and dried over Na2SO4 to yield after evaporation of the solvent 0.11 g (76%) of the title compound as a yellow oil. MS: 409.11 (MH+, Cl).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([SH:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)C.SCC(C(CS)O)O.Cl[C:35]1[N:39]2[N:40]=[C:41]([O:44][CH2:45][CH3:46])[CH:42]=[CH:43][C:38]2=[N:37][N:36]=1>O.P([O-])(O)(O)=O.[K+]>[CH2:45]([O:44][C:41]1[CH:42]=[CH:43][C:38]2[N:39]([C:35]([S:22][C:20]3[CH:19]=[CH:18][C:16]4[N:17]=[C:13]([NH:12][C:10]([NH:9][CH2:8][CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[O:11])[S:14][C:15]=4[CH:21]=3)=[N:36][N:37]=2)[N:40]=1)[CH3:46]
Reactant: CCOc1ccc2nnc(Cl)n2n1
Reactant: O=C(NCCN1CCOCC1)Nc1nc2ccc(S)cc2s1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOc1ccc2nnc(Sc3ccc4nc(NC(=O)NCCN5CCOCC5)sc4c3)n2n1
Yield: 46.8 %

Procedure:
The 1-{6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea was prepared according to the method described in Example 17a, but using 613 mg of 1-[2-(morpholin-4-yl)ethyl]-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea, 20 cm3 of degassed ethanol, 7 mg of potassium dihydrogen phosphate in 0.2 cm3 of water, 699 mg of DL-dithiothreitol and 300 mg of 3-chloro-6-ethoxy[1,2,4]triazolo[4,3-b]pyridazine. 354 mg of 1-{6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.[F:17][C:18]1[CH:19]=[C:20]2[CH:26]=[CH:25][N:24]([NH2:27])[C:21]2=[N:22][CH:23]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[F:17][C:18]1[CH:19]=[C:20]2[CH:26]=[CH:25][N:24]([NH:27][C:8]([C:7]3[C:2]([CH3:1])=[N:3][C:4]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)=[N:5][CH:6]=3)=[O:10])[C:21]2=[N:22][CH:23]=1
Reactant: Nn1ccc2cc(F)cnc21
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1ccc2cc(F)cnc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
A solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (440 mg, 2.28 mmol) and 5-fluoro-pyrrolo[2,3-b]pyridin-1-ylamine (288 mg, 1.9 mmol) in DMF (6 mL) is stirred at 40° C. for 1 h. The mixture is treated with DMTMM (524 mg, 1.9 mmol) and stirred at 40° C. for 1 h. The mixture is diluted with saturated aqueous Na2CO3 (5 mL) and stirred for 5 min. The precipitate is collected by filtration and dried in vacuo to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide (343 mg, 52%). MS: 349 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.17 (s, 1H), 8.81 (d, 1H), 8.53 (d, 1H), 8.27 (s, 1H), 8.01 (m, 1H), 7.90 (m, 1H), 7.77 (d, 1H), 7.57 (m, 1H), 6.60 (d. 1H), 2.84 (s, 3H).
Reaction SMILES: NC1N=C(N)C2C(=NC=C(CN(C3C=CC=CC=3)C3C=CC=CC=3)N=2)N=1.[CH:27]1[C:37]2[C:31](=[N:32][C:33]3[CH:41]=[CH:40][CH2:39][CH2:38][C:34]=3[CH2:35][CH:36]=2)[CH:30]=[CH:29][CH:28]=1.[H-].[Na+].Br.[NH2:45][C:46]1[N:55]=[C:54]([NH2:56])[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([CH2:57]Br)[CH:52]=2)[N:47]=1>>[NH2:45][C:46]1[N:55]=[C:54]([NH2:56])[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([CH2:57][CH:38]3[C:34]4[CH2:35][CH:36]=[C:37]5[CH:27]=[CH:28][CH:29]=[CH:30][C:31]5=[N:32][C:33]=4[CH:41]=[CH:40][CH2:39]3)[CH:52]=2)[N:47]=1
Reactant: C1=CC2=C(CC=c3ccccc3=N2)CC1
Reactant: Nc1nc(N)c2cc(CBr)ccc2n1
Agent: Br
Agent: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Agent: [H-]
Product: Nc1nc(N)c2cc(CC3CC=CC4=C3CC=c3ccccc3=N4)ccc2n1

Procedure:
9-[(2,4-Diaminoquinazolin-6-yl)methyl]-9,10-dihydrodibenz[b,f]azepine (Formula I: Ar=2,4-diaminoquinazolin-6-yl; W=CH2; X=N; Z=CH2CH2; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using 9,10-dihydrodibenz[b,f]azepine (158 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylquinazoline hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]([C:27]2[N:31](C(OC(C)(C)C)=O)[C:30]3[CH:39]=[CH:40][CH:41]=[CH:42][C:29]=3[N:28]=2)=[N:11][C:12]([C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH:20]=2)=[CH:13][N:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:28]1[C:29]2[CH:42]=[CH:41][CH:40]=[CH:39][C:30]=2[N:31]=[C:27]1[C:10]1[C:9]([NH2:8])=[N:14][CH:13]=[C:12]([C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:19][CH:20]=2)[N:11]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C2=CCN(c3ccccc3)CC2)nc1-c1nc2ccccc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(C2=CCN(c3ccccc3)CC2)nc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 14.5 %

Procedure:
A solution of tert-butyl 2-(3-(bis(tert-butoxycarbonyl)amino)-6-(1-phenyl-1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)-1H-benzo[d]imidazole-1-carboxylate (100 mg, 0.1495 mmol) in DCM (1 mL) was treated with TFA (1 mL, 12.98 mmol) and allowed to stir at ambient temperature for 40 minutes. The reaction was concentrated in vacuo and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a pale brown solid (8.0 mg, 14% Yield). 1H NMR (400.0 MHz, DMSO) d 2.84 (2H, m), 3.53 (2H, m), 3.94 (2H, m), 6.76-6.90 (3H, m), 7.20-7.69 (6H, m), 7.70-9.39 (4H, m), 12.88 (1H, m) ppm; MS (ES+) 369.02
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[N:9]=1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([NH:4][C:5]1[NH:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[N:9]=1)[CH3:2]
Reactant: CC(=O)Nc1nc(-c2ccc(N)cc2)c[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1nc(-c2ccc(N)cc2)c[nH]1
Temperature: 60 °C

Procedure:
A suspension of 2-acetamido-4-(4-amino-phenyl)-1H-imidazole (16 g) in anhydrous tetrahydrofuran (160 ml) was added dropwise to a stirred suspension of lithium aluminum hydride (12 g) in anhydrous tetrahydrofuran (240 ml). The mixture was heated at 60° C. for 4 hours.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl.[CH3:31][NH:32][O:33][CH3:34].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C>CN(C)C=O.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=1)[C:10](=[O:12])[N:32]([O:33][CH3:34])[CH3:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Cl)c(F)c1
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6.00 g (19.76 mmol) rac-tert-butoxycarbonylamino-(4-chloro-3-fluoro-phenyl)-acetic acid in 146 ml dimethylformamide were added 20.71 ml (118.6 mmol) N-ethyl-diisopropylamine, 2.07 g (20.75 mmol) N,O-dimethylhydroxylamine hydrochloride and 8.26 g (24.70 mmol) 0-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and the solution stirred at ambient temperature for 30 min. The reaction mixture was diluted with water and the resulting suspension stirred for 15 min. The precipitate was filtered and washed with water and dried: 5.18 g rac-[(4-chloro-3-fluoro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester as colorless solid: MS (ISP): 347.2 (M+H)+ and 247.1 ((M-Boc)+H)+ (100%).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:17][C@H:16]([OH:18])[CH2:15][C@H:10]2[C:11]([O:13][CH3:14])=[O:12])=[O:8])=[CH:3][CH:2]=1.[CH3:25][C:26]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:17][C@H:16]([O:18][Si:29]([C:26]([CH3:28])([CH3:27])[CH3:25])([CH3:31])[CH3:30])[CH2:15][C@H:10]2[C:11]([O:13][CH3:14])=[O:12])=[O:8])=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 24 h

Procedure:
Methyl (4R)-1-(1,1′-biphenyl-4-ylcarbonyl)-4-hydroxy-L-prolinate (intermediate 2a, 2.07 g, 6.35 mmol) was dissolved in DCM (30 ml) and treated with 4-DMAP (776 mg, 6.35 mmol), TEA (2.21 ml, 15.88 mmol) and TBDMS-Cl (1.91 g, 12.7 mmol). The reaction was monitored by LC/MS. After 24 h, as the reaction was not completed, TBDMS-CL (300 mg, 2 mmol) and TEA (1 ml) were added. After 48 h, the reaction was completed. The mixture was washed with sat. NH4Cl and brine (twice), dried over magnesium sulfate, filtered and concentrated. The crude (2.85 g) was purified by flash chromatography using EtOAc/cHex 50:50 as eluant.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH2:11]([O:13][CH2:14][CH2:15]Cl)[CH3:12]>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:12][CH2:11][O:13][CH2:14][CH3:15])=[CH:4][C:3]=1[CH3:10]
Reactant: CCOCCCl
Reactant: Cc1cc(O)cc(C)c1Br
Product: CCOCCOc1cc(C)c(Br)c(C)c1

Procedure:
According to a method described in [WO 2005/063729 pamphlet, (Reference Example 31)], from 4-bromo-3,5-dimethylphenol (10.0 g) and 2-chloroethyl ethyl ether (5.94 mL), the subject compound (12.8 g) was obtained as a colorless oil.
Reaction SMILES: [N:1]([C:4]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=O)=[N+]=[N-].O=P(Cl)(Cl)[Cl:23]>>[Br:20][C:18]1[CH:17]=[CH:16][C:5]2[C:4]([CH:19]=1)=[N:1][N:8]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6]=2[Cl:23]
Reactant: O=P(Cl)(Cl)Cl
Reactant: [N-]=[N+]=Nc1cc(Br)ccc1C(=O)Nc1ccc(F)cc1
Product: Fc1ccc(-n2nc3cc(Br)ccc3c2Cl)cc1
Temperature: 95 °C
Yield: 64 %

Procedure:
A mixture of compound (xii) (6.44 g, 19.20 mmol) and POCl3 (50 mL) was heated at 95° C. for 6 h. The volatiles were removed under reduced pressure and the residue was basified by the addition of an ice-cold saturated solution of sodium carbonate. The solid obtained was filtered and dried (Na2SO4) to give the crude product which was purified by column chromatography on 100-200 mesh silica gel eluting with EtOAc/hexane (3-5%) to give 6-bromo-3-chloro-2-(4-fluorophenyl)-2H-indazole (xiii) (4 g, 64%) as a white solid. ESI-MS m/z calculated for [M+H]+: 326.95; found: 326.95.
Reaction SMILES: [CH:1]([NH:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=O.C(N)=O.CC1C=CC(CC(Cl)=O)=CC=1.C(N(C)C(=O)CC1C=CC=CC=1)=O>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11]([CH:10]=1)=[CH:1][NH:3][C:4](=[O:13])[CH:5]=2
Reactant: Cc1ccc(CC(=O)NC=O)cc1
Agent: CN(C=O)C(=O)Cc1ccccc1
Agent: Cc1ccc(CC(=O)Cl)cc1
Solvent: NC=O
Product: Cc1ccc2cc(=O)[nH]cc2c1

Procedure:
The N-formyl-2-(p-methylphenyl)-acetamide (m.p. 144°-146°C.) used as starting material was prepared from formamide and 4-methyl-phenyl-acetyl chloride in the manner described in Example 2 for the preparation of N-formyl-N-methyl-2-phenyl-acetamide.
Reaction SMILES: [BH4-].[Na+].[CH:3]12[CH2:10][C:9](=[O:11])[CH2:8][CH:7]1[CH2:6][C:5](=[O:12])[CH2:4]2.CC(C)=O.C(O)(=O)C>C(Cl)Cl.C(O)C.O>[OH:12][CH:5]1[CH2:4][CH:3]2[CH:7]([CH2:8][C:9](=[O:11])[CH2:10]2)[CH2:6]1
Reactant: O=C1CC2CC(=O)CC2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC2CC(O)CC2C1
Reaction time: 0.75 h
Yield: 77.3 %

Procedure:
1.1 g of sodium borohydride (0.029 mol) is added with stirring to a solution of 11.6 g of bicyclo[3.3.0]octane-3,7-dione (8.4×10-2 mol) in 100 ml of methylene chloride and 100 ml of ethanol. After 45 minutes at this temperature, the excess reagent is decomposed by slowly adding 20 ml of acetone. The mixture is then neutralized with 1.4 ml of acetic acid, and evaporated under vacuum to afford a residue which is taken up in water and methylene chloride. The organic phase is evaporated to dryness and filtered on silica gel (70:30 hexane:ethyl ether as eluent) to afford 9.1 g of 7ξ-hydroxy-bicyclo[3.3.0]octan-3-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26]C)[C:5]([N:7]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=1)=[O:6].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[OH:26])[C:5]([N:7]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:6]
Reactant: COc1ccc(N(C(=O)c2ccc(OC)c(F)c2)c2ccc(F)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)c(F)c1)N(c1ccc(O)cc1)c1ccc(F)cc1
Temperature: 0 °C
Yield: 81.6 %

Procedure:
Compound 3-fluoro-N-(4-fluorophenyl)-4-methoxy-N-(4-methoxyphenyl)benzamide (2a) (138.0 g, 0.374 mol) was dissolved in dry CH2Cl2 (600 mL) at room temperature under an argon. BBr3 (374.75 g, 1.496 mol) was added dropwise with stirring via a syringe at 0° C. in an ice-bath under an argon. The reaction solution was allowed to stir at room temperature overnight. Then, the solution was poured to 1 L of ice water with stirring. The slurry mixture was stirred at room temperature for 2 hours. The white precipitate was filtered, washed with water (2×100 mL) and dried under vacuum. The CH2Cl2 layer was separated, dried over anhydrous MgSO4 (50 g), filtered and concentrated under reduced pressure to dryness. The white precipitate and residue from CH2Cl2 solution were combined and purified by flash column chromatography (silica gel, CH2Cl2/acetone/MeOH=90/7/3 v/v/v) to give a light tan solid which was recrystallized from hot EtOAc/hexanes solution twice to afford a white crystalline solid, 104.0 g, 81.6% yield. M.p. 110-112° C. MS (ESI) m/z 364.1 [M+Na]+, 1H NMR (DMSO-d6) δ10.14 (bs, 1H), 9.71 (bs, 1H), 7.25-7.11 (m, 5H), 7.05-6.99 (m, 3H), 6.78 (t, J=8.6 Hz, 1H), 6.68 (d, J=8.7 Hz, 2H).
Reaction SMILES: O[C:2]1([CH3:14])[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[C:9]([CH3:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[C:9]([CH3:12])[CH:10]=2)[CH2:5][CH2:4][CH:3]=1
Reactant: Cc1cc(C)c2c(c1)C(C)(O)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=CCCc2c(C)cc(C)cc21
Yield: 85 %

Procedure:
Following the procedure of Example 1, step 2, 26.64 g (0.140 mol) of 1-hydroxy-1,5,7-trimethyl-1,2,3,4-tetrahydronaphthalene in 300 ml of toluene was reacted with 0.30 g of p-toluenesulphonic acid monohydrate. Vacuum distillation yielded 20.49 g (85%) of the title product as a pale yellow liquid, b.p. 67°-70° C./0.12 mm of Hg. NMR δ(CDCl3) 2.04 (3H, m), 2.21-2.25 (2H, m), 2.25 (3H, s), 2.30 (3H, s), 2.66 (2H, t, J=8.1 Hz), 5.83 (1H, m), 6.87 (1H, s), 6.94 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].Br[C:17]1[CH:22]=[C:21]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)[C:20]([N+:38]([O-:40])=[O:39])=[CH:19][N:18]=1>CN(C=O)C.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:26]3)[C:20]([N+:38]([O-:40])=[O:39])=[CH:19][N:18]=2)=[N:3][CH:4]=1)#[N:9]
Reactant: N#Cc1cnc(N)cn1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Br)ncc2[N+](=O)[O-])C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2[N+](=O)[O-])C1
Temperature: 150 °C

Procedure:
Palladium (II) acetate (39 mg, 0.17 mmol) was added to (±)-2,2″-bis(diphenylphosphino)-1,1″-binaphthalene (321 mg, 0.51 mmol) in DMF/toluene (1/1 15 mL) and the resulting mixture was degassed under a stream of nitrogen gas for 10 min. 2-Amino-5-cyanopyrazine (210 mg, 1.7 mmol), sodium tert-butoxide (250 mg, 2.6 mmol) and tert-butyl 3-((2-bromo-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate (713 mg, 1.7 mmol) were added and the mixture was degassed for a further 5 minutes then heated at 150° C. for 30 min using microwave irradiation. The mixture was concentrated in vacuo and water and ethyl acetate were added. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography on silica, eluting with a gradient of ethyl acetate in hexane, 10-100% over 50 min. The fractions containing the product contaminated with 2-amino-5-cyanopyrazine were combined, evaporated and repurified by silica column chromatography, eluting with a gradient of ethyl acetate in hexane, 10-50% over 45 min. Tert-butyl 3-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate was obtained as a yellow solid (265 mg, 34%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][CH2:18]2)=[CH:13][CH:12]=1)=[O:10].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28](O)=[O:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28]([N:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][C:11]([C:9]([NH:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[O:10])=[CH:12][CH:13]=2)[CH2:18]1)=[O:29]
Reactant: O=C(O)Cc1ccccn1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CNCC2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CN(C(=O)Cc1ccccn1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide, 138 mg 2-pyridylacetic acid, 98 mg HOBt, 278 mg EDC, 0.6 ml triethylamine and 8 ml DMF is stirred overnight at ambient temperature. The mixture is evaporated. 0.98 g of the residue are purified by silica gel flash chromatography. 130 mg of the title compound are obtained after drying as colorless foam.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:24])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[C:25](O)(=[O:27])[CH3:26]>>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][C@@H:2]([NH:1][C:25](=[O:27])[CH3:26])[CH3:24])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[OH:22]
Reactant: CC(=O)O
Reactant: C[C@H](N)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Product: CC(=O)N[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 100 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using acetic acid and 4-[(5-{[(2S)-2-aminopropyl]oxy}quinazolin-4-yl)amino]-2-chlorophenol (obtained as described in Example 59, preparation of starting materials) to give N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]acetamide in >100% yield; Mass spectrum MH+ 387.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]#[N:23])([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:25].[OH-].[NH4+]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)([C:22]([NH2:23])=[O:25])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(NC2(C#N)CCN(Cc3ccccc3)CC2)c1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-benzyl-4-cyano-4-(3-methylphenylamino)-piperidine (7.6 g) and 90% sulfuric acid (53 mL) was heated 70° C. until all the solid dissolved (˜1 h). The resultant mixture was stirred at the temp. for 30 min., and poured into a mixture of ice (80 g) and concentrated ammonium hydroxide (75 g). The solution was basified with ammonium hydroxide, and extracted with chloroform. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19]>C(OCC)C.ClCCl.C(N(CC)CC)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: NCCOCCO
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: OCCOCCNc1ccnc2cc(Cl)ccc12
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 4,7-dichloroquinoline (5.0 g, 25.0 mmol) and of 2-(2-aminoethoxy)ethanol (10.51 g, 100.0 mmol) is heated at 135° C. for 5 h, with magnetic stirring. After cooling, the reaction medium is taken up in 200 ml of diethyl ether and the stirring is maintained overnight at ambient temperature. The solid residue formed is isolated, and then dissolved in a mixture of 500 ml of dichloromethane/triethylamine (9/1, v/v) and filtered through sintered glass containing a bed of silica (SiO2 60 AAC 70-200 μm). The product is then eluted from the silica with ethanol (2 l). The ethanolic phases are combined and evaporated. 50 ml of dichloromethane are added to the residue and the organic phase is washed with twice 50 ml of water. The organic phase is recovered, dried over Na2SO4, and then evaporated in a rotary evaporator. After drying under vacuum, the compound 21 is obtained in the form of a beige powder: 5.03 g (yield=75%).