Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40](O)=[O:41])=[CH:33][C:32]=2[Cl:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=O)C.[NH2:47][C:48]([CH3:68])([CH3:67])[C:49]([N:51]1[CH2:56][CH2:55][N:54](C(OCC2C=CC=CC=2)=O)[CH2:53][CH2:52]1)=[O:50].C(N1CCNCC1)C1C=CC=CC=1>>[Cl:43][C:32]1[CH:33]=[C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:41])[NH:47][C:48]([C:49]([N:51]2[CH2:52][CH2:53][NH:54][CH2:55][CH2:56]2)=[O:50])([CH3:68])[CH3:67])[CH:35]=[CH:36][C:31]=1[CH2:30][C:29]1[C:25]([O:24][C@@H:6]2[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]2[OH:4])=[N:26][NH:27][C:28]=1[CH:44]([CH3:46])[CH3:45]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: c1ccc(CN2CCNCC2)cc1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)N2CCNCC2)cc1Cl

Procedure:
The title compound was prepared in a similar manner to that described in Example 99 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-2-chlorophenyl}methyl)-5-isopropyl-1H-pyrazole and 1-(2-amino-2-methylpropionyl)-4-(benzyloxycarbonyl)piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-benzyl-piperazine, respectively.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[C:5]([CH3:16])=[C:4]([CH3:17])[CH:3]=1.[C:18](O)(=[O:20])C.C1N2CN3CN(C2)CN1C3.O>C1(C)C=CC=CC=1>[CH:18]([C:3]1[C:4]([CH3:17])=[C:5]([CH3:16])[C:6]2[C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:13])[C:11]=2[C:2]=1[OH:1])=[O:20]
Reactant: CC(=O)O
Reactant: Cc1cc(O)c2c(c1C)C(C)(C)CCC2(C)C
Agent: C1N2CN3CN1CN(C2)C3
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(C)c2c(c(O)c1C=O)C(C)(C)CCC2(C)C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Formylation. 1-Hydroxy-3,4,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene (15 g, 0.0646 mol) was stirred with glacial acetic acid (100 mL), and hexamethylenetetramine (15 g, 0.107 mol) was added in one portion. The mixture was heated at 100° C. for 2 h. Hot water (100 mL) was added and the heating continued for an additional 0.5 h at 100° C. The mixture was cooled to 20° C., toluene (25 mL) was added, and the mixture was stirred vigorously. The organic layer was separated, washed with water (2×10 mL), then neutralized with 5% NaHCO3 solution and finally washed with brine (10 mL). The solvent was removed by distillation, and the residue crystallized from hexane, to give 2-formyl-1-hydroxy-3,4,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene (8.8 g), GLC purity 94%. 1H-NMR (CDCl3) δ12.94 (1H, s), 10.36 (1H, s), 2.43 (3H, s), 2.36 (3H, s), 1.65 (4H, s), 1.48 (6H, s), 1.46 (6H, s). 13C-NMR (CDCl3) δ195.4 (1C, d), 161.4 (1C, s), 156.0 (1C, s), 138.0 (1C, s), 131.9 (1C, s), 126.6 (1C, s), 116.7 (1C, s), 40.2 (1C, t), 37.9 (1C, t), 36.5 (1C, s), 35.1 (1C, s), 29.5 (2C, q), 28.1 (2C, q), 19.3 (1C, q), 14.1 (1C, q). IR (KBr) 1628 cm-1, MS (m/e) 260.3 (M+, 38.6), 245.2 (100.0), 175.1 (28.7), 189.1 (20.1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17]([CH3:18])=[C:16]([CH3:19])[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]#[CH:23]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17]([CH3:18])=[C:16]([CH3:19])[N:15]([CH2:23][C:22]#[CH:21])[C:14]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCBr
Reactant: Cc1[nH]c2c(OCc3ccccc3)nncc2c1C
Product: C#CCn1c(C)c(C)c2cnnc(OCc3ccccc3)c21
Yield: 27.4 %

Procedure:
The title compound was prepared as a pale yellow powder in 27.40% yield in a similar procedure to that described in Example 41 by using 7-benzyloxy-2,3-dimethylpyrrolo[2,3-d]pyridazine and 3-bromo-1-propyne.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]([O:11][C:12]([N:14]1[C:23]2[C:18](=[N:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[C@H:17]([NH:26][CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[CH2:16][C@@H:15]1[CH2:42][CH3:43])=[O:13])([CH3:10])[CH3:9].N1C=CC=CC=1>ClCCl>[CH:8]([O:11][C:12]([N:14]1[C:23]2[C:18](=[N:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[C@H:17]([N:26]([C:1](=[O:3])[CH3:2])[CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[CH2:16][C@@H:15]1[CH2:42][CH3:43])=[O:13])([CH3:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@H]1C[C@@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nc(OC)ccc2N1C(=O)OC(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2nc(OC)ccc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.6 %

Procedure:
Add acetic anhydride (0.023 mL, 1.205 mmol) to a solution of (+/−)-cis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (125 mg, 0.241 mmol) and pyridine (0.097 mL, 1.205 mmol) in dichloromethane (2 mL), and stir at room temperature for 14 h. Remove the solvent under reduced pressure and purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (105 mg, 78%). 1H NMR (CDCl3, 300 MHz): δ 0.66-0.72 (m, 3H), 1.20-1.29 (m, 7H), 1.33-1.69 (m, 3H), 2.01-2.21 (m, 3H), 2.26-2.33 (m, 1H), 3.82, 3.86 (s, 3H), 4.22-4.28 (m, 1H), 4.81-5.01 (m, 2H), 6.59, 6.65 (d, J=8.7 Hz, 1H), 7.61-7.73 (m, 4H). MS (ES+): 562 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH:12](O)[CH3:13])=[N:10][CH:11]=2)=[CH:2]1.P(Br)(Br)[Br:16]>C(Cl)(Cl)Cl.C(OCC)(=O)C.C(=O)(O)[O-]>[Br:16][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:11][N:10]=1)[CH3:13]
Reactant: CC(O)c1ccc(-c2ccoc2)cn1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(Br)c1ccc(-c2ccoc2)cn1
Temperature: 2.5 °C
Yield: 73.8 %

Procedure:
To a solution of 1-(5-(furan-3-yl)pyridin-2-yl)ethanol (0.075 g, 0.403 mmol) in chloroform (5 ml) was added PBr3 (0.321 g, 1.209 mmol), at 0-5° C., the reaction maintained at the same temperature for 15 min, the reaction was slowly warmed to rt and was maintained at rt for another 2 h. The contents were diluted with ethyl acetate (100 mL), bicarbonate solution (10 mL) was added, the organic layer was separated, the organic layer dried over sodium sulphate and distilled to provide 2-(1-bromoethyl)-5-(furan-3-yl)pyridine (0.075 g, 75% yield). LC-MS m/z calcd for [M+H]+ 253.99. found 254.0.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[N:12]=[C:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=3[O:26][CH3:27])[N:14]=[CH:15][C:5]=2[N:4]([CH3:28])[C:3]1=[O:29].C(N(C(C)C)C(C)C)C.[O:40]1[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]1>CN(C)C=O>[F:30][C:2]1([F:1])[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[N:12]=[C:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:46][CH:43]4[CH2:44][CH2:45][O:40][CH2:41][CH2:42]4)=[O:22])=[CH:19][C:18]=3[O:26][CH3:27])[N:14]=[CH:15][C:5]=2[N:4]([CH3:28])[C:3]1=[O:29]
Reactant: NC1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a mixture of 0.08 g (0.19 mmole) of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-292), 0.13 mL (0.76 mmole) of ethyldiisopropyl amine and 0.021 g (0.21 mmole) of tetrahydro-pyran-4-ylamine in 2.0 mL of dimethylformamide was added 0.082 g (0.21 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.086 g of give 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-297) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH3:19])=[C:4]([CH3:17])[C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:35])(=O)=O)=CC=1.[Cl-].[NH4+]>O1CCCC1>[Si:10]([O:9][CH2:8][C:5]1[C:4]([CH3:17])=[C:3]([O:18][CH3:19])[C:2]([F:35])=[CH:7][N:6]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COc1c(Br)cnc(CO[Si](C)(C)C(C)(C)C)c1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(F)cnc(CO[Si](C)(C)C(C)(C)C)c1C
Temperature: -68 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
The above 5-bromo-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methoxy-3-methylpyridine (734 mg) was dissolved in tetrahydrofuran (30 ml), and butyllithium (1.59 M solution, 2.42 ml) was then added dropwise to the solution at −110° C. The resulting mixture was stirred at the same above temperature for 1 hour, and a tetrahydrofuran (5 ml) solution of N-fluorobenzenesulfonimide (3.03 g) was then added dropwise to the reaction solution at the same temperature. The temperature of the resulting mixture was gradually raised to −68° C. over 3 hours, and the mixture was then stirred at room temperature for 30 minutes. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was then concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain the title compound (353 mg) as an oily substance.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]2)[CH:20]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:27]3[CH:28]=[CH:29][N:25]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[N:26]=3)=[O:31])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1ccn(-c2cccnc2)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccn(-c2cccnc2)n1
Yield: 90.5 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.058 g, 0.307 mmol), 1-(pyridin-3-yl)-1H-pyrazole-3-carboxylic acid (0.080 g, 0.307 mmol), DIPEA (0.160 ml, 0.921 mmol), HOBt hydrate (0.071 g, 0.460 mmol) and EDCI (0.088 g, 0.460 mmol) using the method of Example 274 affording 0.120 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.18 (d, 3H), 4.38 (m, 2H), 4.50 (m, 1H), 6.89 (d, 1H), 6.95 (d, 1H), 7.59 (m, 1H), 7.90 (m, 3H), 8.04 (d, 1H), 8.30 (m, 1H), 8.38 (d, 1H), 8.60 (d, 1H), 8.65 (d, 1H), 9.19 (d, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:14][C:15]2[C:16](=[O:34])[N:17]([C:21]3[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:24]([NH:26][CH:27]3[CH2:29][CH2:28]3)=[O:25])[CH:18]=[CH:19][N:20]=2)[CH2:13][CH2:12]1.[NH2:35][CH2:36][C@@H:37]([OH:39])[CH3:38]>O1CCOCC1>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:35][CH2:36][C@@H:37]([OH:39])[CH3:38])[CH2:13][CH2:12]4)[C:16]3=[O:34])[CH:22]=2)[CH2:29][CH2:28]1
Reactant: C[C@H](O)CN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCNC[C@H](C)O)CC2)c1=O

Procedure:
3-(3-(1-(2-(2-Chloroethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 167e, 100 mg) and (S)-(+)-1-amino-2-propanol (0.247 mL) were stirred together in dioxane (3 mL) in a sealed tube at 100° C. for 24 h. Purification of the cooled solution by preparative HPLC (Xbridge column—acetonitrile/0.2% ammonia mobile phase) afforded the title compound (60 mg).
Reaction SMILES: [H-].[Na+].O1CCCC1.C(OCC)(=O)[CH2:9][C:10]([CH3:12])=[O:11].F[C:18]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]>C(O)(=O)C>[F:24][C:23]1[C:18]([CH2:9][C:10](=[O:11])[CH3:12])=[C:19]([N+:26]([O-:28])=[O:27])[CH:20]=[CH:21][C:22]=1[F:25]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Reaction time: 1 h
Yield: 90 %

Procedure:
12.1 g (303 mmol) of 60% sodium hydride was added to 45 ml of tetrahydrofuran, and while cooling with a freezing mixture, 90 ml of tetrahydrofuran containing 39.0 g (300 mmol) of ethyl acetoacetate was dropped to the solution below 20° C. through 30 minutes. After the solution was stirred for 1 hour as was, 90 ml of tetrahydrofuran solution containing 26.6 g (150 mmol) of 2,3,4-trifluoronitrobenzene was dropped to the solution below 10° C. through 30 minutes, and the solution was stirred overnight at room temperature. 27 ml of acetic acid was added to the solution, and the solvent was removed by distillation. The solution was extracted with 500 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. 30 ml of 4N hydrochloric acid and 25 ml of acetic acid were added to the solution, and the solution was heated at reflux for 24 hours. 550 ml of concentrated hydrochloric acid and 550 ml of acetic acid were added to the solution, and the solution was heated at reflux for 16 hours. After air-cooling, the solution was extracted with 1 l of chloroform and was washed with 500 ml of water two times. The solution was further washed with 300 ml of aqueous saturated sodium hydrogen carbonate solution two times, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by the column chromatography (silica gel 300 g, eluent solvent; chloroform: n-hexane=1:3) to obtain 31.2 g of the subject compound (148) in a 90% yield.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:18]O>>[I:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:18])=[O:8]
Reactant: Cc1cc(C)c(C(=O)O)cc1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(I)c(C)cc1C
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3, 10.0 g, 32.6 mmol, 90%) and sulfuric acid (10 mL) in methanol (100 mL) was stirred overnight at 80° C. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was diluted with of ethyl acetate (200 mL). The resulting mixture was washed with water (3×50 mL), sodium bicarbonate (aq. sat., 2×50 mL, caution: gas evolution), followed by brine (2×50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 9.2 g (88%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[Br:12][C:10]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]([NH2:11])=[N:8][CH:9]=1
Reactant: CC(C)(C)c1ccnc(N)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)c1cc(N)ncc1Br
Yield: 43.6 %

Procedure:
Dissolve 4-tert-butyl-pyridin-2-ylamine (3 g, 20 mmol) in anhydrous acetonitrile (25 mL). Add N-bromosuccinimide (3.56 g, 20 mmol). Stir the reaction in the dark for overnight at room temperature. Dilute with EtOAc and wash with 1 N NaOH (aq.) and saturated aqueous sodium bicarbonate. Extract the organic layer. Wash the aqueous layer further with DCM. Dry the combined organic layers (MgSO4), and purify by silica gel column chromatography (EtOAc/hexane) to yield 2 g of the title compound (44%). LCMS (ES), m/z 231 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:25]=[CH:26][CH:27]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:23][CH3:24])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:36][C:37]#[N:38]>CC(N(C)C)=O>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:25]=[CH:26][CH:27]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:23][CH3:24])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:36][C:37]#[N:38])[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(CC#N)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 37.3 %

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline (Example 2, 70 mg, 0.17 mmol) was dissolved in DMA (5 ml). Potassium carbonate (96 mg, 0.70 mmol) and chloroacetonitrile (17 μl, 0.25 mmol) were added. The mixture was stirred at 60° C. for 4 hours. The solvent was evaporated and the residue was partitioned between DCM (20 ml) and water (20 ml). The aqueous layer was extracted with DCM (2×10 ml) and the extractions combined with the DCM layer. The combined DCM fractions were filtered through a silicone-treated filter paper and evaporated. The residue was purified by chromatography, eluting with 0 to 2% (7:1 MeOH/concentrated aqueous NH4OH) in DCM. The appropriate fractions were combined and evaporated, and the residue triturated with diethyl ether, giving the product as a white solid (28 mg, 36%); 1H NMR: 1.67-1.80 (m, 2H), 2.03-2.13 (m, 2H), 2.46 (m, 2H), 2.77-2.85 (m, 2H), 3.76 (s, 2H), 3.92 (s, 3H), 4.55 (m, 1H), 7.20 (s, 1H), 7.27 (dd, 1H), 7.47 (dd, 1H), 7.52 (dd, 1H), 7.80 (s, 1H), 8.35 (s, 1H), 9.54 (s, 1H); Mass Spectrum: 412.4, 444.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@H:9]1[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:23][C:24]1[CH:29]=[C:28](Br)[CH:27]=[C:26]([Br:31])[CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH2:12][C@H:9]1[CH:10]([OH:11])[C:28]1[CH:29]=[C:24]([Br:23])[CH:25]=[C:26]([Br:31])[CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1cc(Br)cc(Br)c1
Yield: 57 %

Procedure:
(2S,4R)-N-t-Butoxycarbonyl-4-t-butyldimethylsiloxy-2-(α-hydroxy-3,5-dibromobenzyl)pyrrolidine (19.6 g, yield: 56.9%) was prepared as a yellow oily substance, from (2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (20 g, 60.8 mmol), 1,3,5-tribromobenzene (19.13 g, 60.8 mmol) and 1.6M n-butyl lithium-hexane solution (49.4 ml, 79.04 mmol), in the same manner as in Reference Example 111-1.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9].[CH3:11]O>>[NH:5]1[CH:1]=[C:2]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])[N:3]=[CH:4]1
Reactant: O=C(O)/C=C/c1cnc[nH]1
Reactant: CO
Product: COC(=O)C=Cc1c[nH]cn1
Reaction time: 1 h

Procedure:
Through a suspension of urocanic acid (5.0 g) in methanol at 0° C. was bubbled HCl gas until the solution was saturated. The reaction was stirred for one hour, then concentrated in vacuo to dryness to provide the crude product 2 which was used in the next step without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=[CH:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:32](P(C(C)(C)C)C(C)(C)C)(C)(C)[CH3:33].C([Sn](CCCC)(CCCC)C=C)CCC>O1CCOCC1>[CH:32]([C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=[CH:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1)=[CH2:33]
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Reactant: Ic1ccc(N=C(C=COc2ccccc2)Oc2ccccc2)cc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=Cc1ccc(N=C(C=COc2ccccc2)Oc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
Phenyl N-(4-iodophenyl)-3-(phenoxy)acrylimidate (0.50 g), bis(benzylideneacetone)palladium (0) (0.023 g) and cesium carbonate (0.82 g) were suspended to dioxane (15 ml). Tri-t-butylphosphine (10 wt % in hexane: 0.24 g) and tributyl (vinyl) tin (0.44 g) were added thereto and it was stirred for four hours at room temperature and 60° C. for five hours. The unsolved matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to obtain phenyl N-(4-vinylphenyl)-3-(phenoxy)acrylimidate (0.29 g) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][O:22][CH2:23][C:24](O)=[O:25].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[CH3:21][O:22][CH2:23][C:24]([NH:11][CH2:10][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)=[O:25]
Reactant: COCC(=O)O
Reactant: NCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)NCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C

Procedure:
A mixture of 8.6 g of 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butylamine (obtained according to PREPARATION (I), step (b)), 2.46 g of methoxyacetic acid, 5.55 g of triethylamine in 50 ml of dichloromethane is cooled to 0° C. and 14.5 g of BOP is added thereto.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[N:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)=[N:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:30]2[CH2:29][CH2:28][N:27]([C:25]([CH:22]3[CH2:23][CH2:24][N:19]([C:16]4[CH:17]=[CH:18][N:13]=[CH:14][N:15]=4)[CH2:20][CH2:21]3)=[O:26])[CH2:32][CH2:31]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(C1CCN(c2ccncn2)CC1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCN(C(=O)C3CCN(c4ccncn4)CC3)CC2)cc1
Yield: 42.4 %

Procedure:
A solution of 4 -cyanobenzenesulphonyl chloride (363 mg) in methylene chloride (10 ml) was added to a stirred mixture of 1-[1-(4-pyrimidinyl) piperidin-4-ylcarbonyl]piperazine (412.5 mg) and triethylamine (0.28 ml) in methylene chloride (15 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between methylene chloride and water. The organic phase was washed with water, dried (Na2SO4) and evaporated. The residue was purified by column chromatography using 0.5% methanol in methylene chloride. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-(4-cyanobenzenesulphonyl)-4-[1-(4-pyrimidinyl)piperidin-4-ylcarbonyl]piperazine (280 mg), mp 180-181° C.;