Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]([C:27]1[N:28]=[CH:29][N:30]2[CH:34]=[CH:33][S:32][C:31]=12)=O.C(OCC)(=O)C>CO>[CH3:24][O:23][C:21]([CH:20]=[CH:25][C:27]1[N:28]=[CH:29][N:30]2[CH:34]=[CH:33][S:32][C:31]=12)=[O:22]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ncn2ccsc12
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C=Cc1ncn2ccsc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 111.1 %

Procedure:
Methyl triphenylphosphoranylideneacetate (500 mg) was added to a solution of 150 mg of 7-formylimidazo[5,1-b]thiazole in 15 ml of methanol. The mixture was stirred at room temperature for 15 min. Ethyl acetate was added thereto. The mixture was washed with water, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to give 228 mg of 7-(2-methoxycarbonylvinyl)imidazo[5,1-b]thiazole (a mixture of geometrical isomers).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]([N:16]([CH3:18])[CH3:17])=[C:11]1[C:6]=2[CH:7]=[CH:8][C:9]([NH2:19])=[CH:10]1.P(Cl)(Cl)(Cl)=O.[CH2:25]([N:27]([CH2:30][CH3:31])[CH:28]=O)[CH3:26]>CC(C)=O>[CH2:25]([N:27]([CH:28]=[N:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]([N:16]([CH3:17])[CH3:18])=[C:11]1[C:6]=2[CH:7]=[CH:8][C:9]([N:19]=[CH:28][N:27]([CH2:30][CH3:31])[CH2:25][CH3:26])=[CH:10]1)[CH2:30][CH3:31])[CH3:26]
Reactant: CCN(C=O)CC
Reactant: CN(C)c1nc2cc(N)ccc2c2ccc(N)cc12
Solvent: CC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(C=Nc1ccc2c(c1)nc(N(C)C)c1cc(N=CN(CC)CC)ccc12)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A suspension of 3,8-diamino-6-dimethylaminophenanthridine (500 mg) in N,N-diethylformamide (2 ml) was added to a mixture of phosphorus oxychloride (1.5 ml) and N,N-diethylformamide (5 ml), the temperature of the mixture being kept at 5° C. The resulting mixture was stirred for 30 minutes at room temperature, heated at 75°-80° C. for 2 hours, cooled, and diluted with acetone. The precipitate formed was filtered off and dissolved in water. The pH of the clear solution was adjusted to a value of 9 with aqueous ammonia. The solid thus obtained was filtered off, washed with water, dried, and purified by column chromatography over a neutral aluminum oxide column using benzene as the mobile phase. The product crystallized out from chloroform/diisopropyl ether. Yield 71%, melting point 124°-126° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:11][CH:10]([NH2:12])[CH2:9]2)[CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>ClCCl>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]([NH:12][CH:10]1[CH2:11][N:8]([C:6]2[CH:5]=[C:4]([C:13]([F:14])([F:16])[F:15])[CH:3]=[C:2]([CH3:1])[N:7]=2)[CH2:9]1)=[O:26]
Reactant: Cc1cc(C(F)(F)F)cc(N2CC(N)C2)n1
Reactant: O=C=Nc1ccccc1Br
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)cc(N2CC(NC(=O)Nc3ccccc3Br)C2)n1
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 1-(6-methyl-4-trifluoromethylpyridin-2-yl)azetidin-3-ylamine, D12 (100 mg, 0.432 mM) and 2-bromophenyl isocyanate (86 mg, 0.432 mM) in dichloromethane (5 ml) was kept at room temperature overnight. The resultant solid was removed by centrifugation, washed with diethyl ether and dried in vacuo, to give the title compound as a colourless solid, (119 mg, 64%). MH+ 429 and 431; 1H NMR (250 MHz, d6DMSO) δ: 2.39 (3H, s), 3.75-3.88 (2H, dd), 4.30 (2H, t), 4.50-4.66 (1H, m), 6.48 (1H, s), 6.78 (1H,s), 6.92 (1H, m), 7.28 (1H, m), 7.57 (1H, dd), 7.76 (1H, d), 7.86 (1H, s), and 8.04 (1H, dd).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]2[CH2:15][CH:14]([CH2:16][S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:13][C:12]2=[O:24])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH2:31].[OH-].[Li+]>O.C1COCC1>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([CH2:15][CH:14]([OH:31])[CH2:16][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]([OH:13])=[O:24])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: O=C1OC(CSc2ccccc2)CC1NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(CC(O)CSc1ccccc1)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 3 h

Procedure:
To a solution of 3-[[(1,1′-biphenyl)-4-yl]sulfonyl]amino-2-oxo-5-[(phenylthio)methyl]-tetrahydrofuran 16c (0.18 g, 0.41 mmol) in water (5 mL) and THF (5 mL) is added slowly lithium hydroxide monohydrate (172 mg, 4.1 mmol). The reaction mixture is stirred for 3 hr, then concentrated to dryness. The resulting mixture is diluted with water, and then the mixture is extracted twice with Et2O. The Et2O layer is discarded and the aqueous layer is neutralized carefully with 1N HCl to pH 6, then extracted three times with EtOAc. The combined EtOAc layer is washed with brine, dried over MgSO4 and concentrated to a solid which is recrystallized from EtOAc/hexane to give the desired product.
Reaction SMILES: C(O[C:4](=[O:27])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:10][CH:9]=1)=[O:6])C.[O:28]([C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C)([O-])C.[Li+]>C1(C)C(C)=CC=CC=1>[CH2:15]([O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]([NH:39][C:38]2[CH:37]=[CH:36][C:35]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:41][CH:40]=2)=[O:27])=[CH:13][CH:12]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CCCCCCCCCCCCOc1ccc(NC(=O)C(=O)OCC)cc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCOc1ccc(NC(=O)C(=O)Nc2ccc(Oc3ccccc3)cc2)cc1
Reaction time: 3 h
Yield: 85.6 %

Procedure:
A solution of N-(4-dodecyloxyphenyl)oxalamic acid ethyl ester (10 g, 0.026 mol), 4-phenoxyaniline (5 g, 0.026 mol) and lithium t-butoxide (0.2 g, 0.0026 mol) in xylene (50 mL) isheated to gentle reflux. A distillate of ethanol/xylene is slowly collected; the reaction volume is kept at 50 mL by adding xylene. Heating and distillation continued for 3 hours. The reaction mixture is cooled, the solids are collected and washed sequentially with warm ethyl acetate, ethanol, water and finally ethanol. There is obtained 11.5 g white solid mp: 179–181.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cn1ccc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cn1ccc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A mixture of ethyl 2-(6-nitro-1H-indol-1-yl)acetate (20.96 mmol, 1 equiv.), iron powder (83.8 mmol, 4 equiv.), ammonium chloride (83.87 mmol, 1 equiv.) and ethanol/water (2.5:1, 56 ml) was stirred for 2 h at boiling temperature. The reaction mixture was cooled to 25° C. and filtered over celite. The filtrate was diluted with ethyl acetate and water, the phases were separated, and the organic phase was washed with sodium hydrogen carbonate solution and sat. NaCl solution, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (15% ethyl acetate in hexane). Yield: 55%
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[C:14]([C:13]1[CH:19]=[N:4][C:3]2[C:5]([C:12]=1[OH:11])=[CH:6][CH:7]=[CH:8][C:2]=2[Br:1])([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Nc1ccccc1Br
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc2c(Br)cccc2c1O
Temperature: 100 °C
Yield: 58 %

Procedure:
A mixture of 50 g (0.291 mol) of 2-bromoaniline and 63 g (0.291 mol) of diethyl ethoxymethylenemalonate was heated at 100° C. under a reduced pressure for 3 hours, followed by heating at 200° C. for further 12 hours. After the completion of the reaction, the solid matter in the resulting reaction mixture was washed with ethyl acetate, and the crystals were collected by filtration and dried, to give 50 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[C:21]1[C:22]([Cl:34])=[C:23]2[N:32]=[CH:31][N:30]([CH3:33])[C:24]2=[N:25][C:26]=1[C:27]([OH:29])=[O:28]>C1COCC1>[Cl:34][C:22]1[C:21]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=2[F:1])=[C:26]([C:27]([OH:29])=[O:28])[N:25]=[C:24]2[N:30]([CH3:33])[CH:31]=[N:32][C:23]=12
Reactant: Cn1cnc2c(Cl)c(Br)c(C(=O)O)nc21
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cnc2c(Cl)c(Nc3ccc(I)cc3F)c(C(=O)O)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-fluoro-4-iodo-aniline (2.9 g, 22.1 mmol) in THF (20 ml) at −78° C. is added LiHMDS (33.3 ml, 1 M in THF, 33.3 mmol) dropwise. The reaction mixture is stirred for 10 min and a solution of 6-bromo-7-chloro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (WO 2005/051906) (5.63 g, 10.1 mmol) in THF (30 ml) is added to the mixture. The reaction is slowly warmed to room temperature and stirred at this temperature for 16 h. The mixture is concentrated, quenched with 10% HCl solution (70 ml), and extracted with EtOAc (2×200 ml). The combined organic solution is dried over MgSO4 and concentrated to dryness. Purification by trituration with boiling CH2Cl2 gives the title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:28]=[C:29]1[NH:37][C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C@@:30]21[CH2:48][C:40]1=[N:41][CH:42]=[C:43]([C:45]([OH:47])=O)[CH:44]=[C:39]1[CH2:38]2.Cl.[NH2:50][C@H:51]1[CH2:56][C@@H:55]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([CH3:63])[C:58]=2[F:64])[C@@H:54]([CH3:65])[N:53]([CH2:66][C:67]([F:70])([F:69])[F:68])[C:52]1=[O:71].C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:64][C:58]1[C:59]([CH3:63])=[CH:60][CH:61]=[CH:62][C:57]=1[C@H:55]1[C@@H:54]([CH3:65])[N:53]([CH2:66][C:67]([F:69])([F:70])[F:68])[C:52](=[O:71])[C@@H:51]([NH:50][C:45]([C:43]2[CH:44]=[C:39]3[CH2:38][C@@:30]4([C:31]5[C:32](=[N:33][CH:34]=[CH:35][CH:36]=5)[NH:37][C:29]4=[O:28])[CH2:48][C:40]3=[N:41][CH:42]=2)=[O:47])[CH2:56]1
Reactant: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: Cc1cccc([C@@H]2C[C@H](N)C(=O)N(CC(F)(F)F)[C@@H]2C)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc([C@@H]2C[C@H](NC(=O)c3cnc4c(c3)C[C@@]3(C4)C(=O)Nc4ncccc43)C(=O)N(CC(F)(F)F)[C@@H]2C)c1F
Temperature: 23 °C
Reaction time: 16 h

Procedure:
(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (239 mg, 0.416 mmol) was added to a solution of (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (described in Intermediate 1) (140 mg, 0.499 mmol), (3S,5S,6R)-3-amino-5-(2-fluoro-3-methylphenyl)-6-methyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride (described in Intermediate 5) (147 mg, 0.416 mmol), and N,N-diisopropylethylamine (0.363 mL, 2.08 mmol) in DMF (4.0 mL), and the resulting mixture was stirred at 23° C. for 16 h. The reaction mixture was purified by reverse-phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 95% acetonitrile in water. The desired fractions were partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the title compound. HRMS: m/z=582.2134, calculated m/z=582.2123 for C30H28F4N5O3. 1H NMR (500 MHz, CDCl3) δ 8.90 (s, 1H), 8.34 (s, 1H), 8.17 (dd, 1H, J=5.4, 1.5 Hz), 8.05 (s, 1H), 7.27 (obscured m, 1H), 7.29 (t, 1H, J=7.3 Hz), 7.12 (dd, 1H, J=7.3, 1.5 Hz), 7.03 (t, 1H, J=7.8 Hz), 6.98 (t, 1H, J=6.8 Hz), 6.89 (dd, 1H, J=7.3, 5.1 Hz), 4.96-4.87 (m, 1H), 4.55 (dt, 1H, J=11.5, 5.8 Hz), 4.09 (p, 1H, J=5.8 Hz), 3.94 (dt, 1H, J=13.4, 3.2 Hz), 3.78 (d, 1H, J=17.3 Hz), 3.67 (d, J=16.4 Hz), 3.36-3.28 (m, 1H), 3.28 (d, 1H, J=17.3 Hz), 3.18 (d, 1H, J=16.4 Hz), 2.75 (m, 1H), 2.57 (q, 1H, J=12.5 Hz), 2.30 (s, 3H), 1.08 (d, 3H, J=6.6 Hz).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C[O:11][C:12]([C:14]1[O:18][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:16][C:15]=1[CH3:25])=O>C1(C)C=CC=CC=1.C1COCC1>[CH3:25][C:15]1[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:18][C:14]=1[CH2:12][OH:11]
Reactant: COC(=O)c1oc(-c2ccccc2)nc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccccc2)oc1CO
Temperature: -78 °C
Reaction time: 8 h

Procedure:
19.0 mL of 1.0M DIBAL-H solution in toluene is added slowly to a solution of 1.63 g (7.5 mmol) of 4-methyl-2-phenyl-oxazole-5-carboxylic acid methyl ester (J. Chem. Soc., Chem. Comm. 1995, 22, 2335) in 30 mL of THF at −78° C. The cooling bath is removed, and the reaction mixture is stirred overnight. The reaction mixture is cooled to −78° C. and quenched with 9 mL of MeOH. The cooling bath is removed, and 9 mL of brine and 6.5 g of Na2SO4 are added, and the reaction mixture is stirred vigorously for 2 h, and then filtered off, and concentrated in vacuo to produce (4-methyl-2-phenyl-oxazol-5-yl)-methanol as a solid; 1H NMR (250 MHz, CDCl3) δ7.93-8.01 (m, 2H), 7.37-7.43 (m, 3H), 4.65 (s, 2H), 2.61 (br s, 1H), 2.18 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]([C:28]2[C:36]([OH:37])=[CH:35][C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=2)[C:20]1=[O:38])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>C1COCC1>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][C:21]1([C:28]2[C:36]([OH:37])=[CH:35][C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=2)[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:20]1=[O:38])[CH3:45]
Reactant: CCCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Reactant: CCOC(=O)CBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCCN1C(=O)C(CC(=O)OCC)(c2cc3c(cc2O)OCO3)c2ccccc21
Temperature: -75 °C
Yield: 8 %

Procedure:
To a solution of diisopropylamine (1.14 g, 11.0 mmol) in THF (10.0 mL) was added n-butyl lithium (7.00 mL, 11.0 mmol, 1.6 M solution in hexane) at −75° C. The resulting mixture was stirred at −75° C. for half an hour and added slowly to a solution of 1-hexyl-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one in THF (20.0 mL) at −75° C. After stirring at −75° C. for another half an hour, ethyl bromoacetate was added. The mixture was stirred at ambient temperature for 18 hrs and quenched with saturated ammonim chloride solution. The organic solvent was removed in vacuo and the aqueous residue was diluted with ethyl acetate (100 mL). The orgnic layer was washed with saturated ammonium chloride (25.0 mL), brine (50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with 40% EtOAc/Hexanes to yield the title compound (0.19 g, 8%) as an oil: MS (ES+) m/z 440.5 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([N:17]2[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18]2)[CH:13]=[CH:14][C:15]=1[Cl:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:58]([O:62][C:63]([N:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1)=[O:64])([CH3:61])([CH3:60])[CH3:59]>>[C:58]([O:62][C:63]([N:65]1[CH2:70][CH2:69][N:68]([C:22]([CH:19]2[CH2:20][CH2:21][N:17]([C:12]3[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([C:2]4[NH:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)[CH:11]=3)[CH2:18]2)=[O:23])[CH2:67][CH2:66]1)=[O:64])([CH3:61])([CH3:59])[CH3:60]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)C1CCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCN(c3ccc(Cl)c(-c4nc5ccccc5[nH]4)c3)C2)CC1
Temperature: 35 °C
Yield: 83 %

Procedure:
Method G—Step a To a mixture of 1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-pyrrolidine-3-carboxylic acid (obtained as described in general method 2, step e) (0.01 g, 0.26 mmol) in dcm (4 mL), HATU (0.10 g, 0.29 mmol), diisopropylethylamine (DIPEA) (0.14 mL, 0.76 mmol) and tert-butyl-1-piperazine carboxylate (0.06 g, 0.32 mmol) were added. The reaction mixture was heated at 35° C. overnight, cooled to room temperature and washed with water (2×5 mL) and saturated Na2CO3 solution (2×5 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to obtain a crude that was triturated with diethylether (3 mL), filtered and dried. The precipitate was then purified by flash chromatography (eluent gradient: EtOAc 100% to EtOAc:NH3 in MeOH (2M)/4:0.8), and then a filtration on an SCX cartridge was run (eluent gradient: DCM:MeOH/1:1 to NH3 in MeOH), to obtain 0.11 g of the title compound (67%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:23])[CH:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37]O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:7]([NH:6][C:5]4[C:4]([F:23])=[CH:3][C:2]([Cl:1])=[CH:21][C:20]=4[F:22])=[N:8][CH:9]=[N:10]3)=[CH:15][C:14]=2[O:17][CH3:18])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: COc1cc2c(Nc3c(F)cc(Cl)cc3F)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: COc1cc2c(Nc3c(F)cc(Cl)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 48 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 9, 4-(4-chloro-2,6-difluoroanilino)-7-hydroxy-6-methoxyquinazoline (150 mg, 0.44 mmol) was reacted with 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (150 mg, 0.88 mmol), (prepared as described for the starting material in Example 1), to give 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(4-chloro-2,6-difluoroanilino)-6-methoxyquinazoline (113 mg, 59%).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13]>N1C=CC=CC=1>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[Cl:6]
Reactant: Oc1ccccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=P(Cl)(Cl)Oc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a reaction vessel there is added 113 g..phosphoryl chloride and 0.8 g. pyridine. Over a period of one hour, a total of 64 g. o-chlorophenol is added and the pot temperature is raised from 100° to 110°C. and held at 110°C. for one hour and then allowed to gradually cool to room temperature. The reaction mixture is stripped and there is obtained 108 g. product which affords, on distillation, 93.7 percent o-chlorophenyl phosphorodichloridate and 7.3 percent di-o-chlorophenyl phosphorochloridate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:10]1[CH:15]=[C:14]([Cl:16])[N:13]=[N:12][C:11]=1[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[Cl:16][C:14]1[N:13]=[N:12][C:11]([CH3:17])=[C:10]([O:8][C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=1
Reactant: Cc1nnc(Cl)cc1Cl
Reactant: Nc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nnc(Cl)cc1Oc1cccnc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
2-Aminopyridin-3-ol (5.0 g, 45.4 mmol) and 4,6-dichloro-3-methylpyridazine (7.4 g, 45.4 mmol, prepared according to WO 2003/041712) were dissolved in DMSO (100 mL). Cs2CO3 (16.3 g, 49.9 mmol) was added and the reaction stirred at ambient temperature for one hour. The reaction was diluted with water and the material was extracted with CH2Cl2, dried (Na2SO4), filtered and concentrated. Flash chromatography followed by trituration of the concentrated solid with EtOH gave 3-(6-chloro-3-methylpyridazin-4-yloxy)pyridin-2-amine (5.98 g, 25.3 mmol, 55%) as a solid.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[O:12]1[CH:18]2[CH:13]1[C:14]([CH3:31])([CH3:30])[O:15][C:16]1[CH:22]=[CH:21][C:20]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:19][C:17]=12.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[O:3]=[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]1[C@@H:18]1[C:17]2[CH:19]=[C:20]([S:23]([C:26]([F:27])([F:29])[F:28])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=2[O:15][C:14]([CH3:30])([CH3:31])[C@H:13]1[OH:12]
Reactant: C[Si](C)(C)Oc1ccccn1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2C2OC21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](n2ccccc2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.4 %

Procedure:
1.63 g of 2-trimethylsilyloxypyridine was added to a solution of 1.00 g of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-trifluoromethylsulfonyl-2H-1-benzopyran (prepared as described in Preparation 8) in 1.2 ml of anhydrous tetrahydrofuran, and a solution of 2.54 g of tetrabutylammonium fluoride in anhydrous tetrahydrofuran was added to the resulting mixture through a syringe, whilst ice-cooling and under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 72 hours, after which it was poured into water and extracted with ethyl acetate. The extract was then washed with water, with a 5% w/v aqueous solution of hydrochloric acid, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of ethyl acetate and cyclohexane as the eluent, to afford 503 mg of the title compound as about a 1:1 mixture of rotational isomers, melting at 219°-220° C.
Reaction SMILES: CCN(CC)CC.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[N:16]1[C:25]2[C:20](=[C:21]([C:28]3[CH:33]=[CH:32][C:31](F)=[CH:30][C:29]=3F)[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[CH2:19][CH2:18][C:17]1=[O:36].C(Cl)[Cl:38]>>[Cl:38][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:21]1[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[C:25]2[C:20]=1[CH2:19][CH2:18][C:17](=[O:36])[N:16]2[C:10]1[C:9]([Cl:8])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:15]
Reactant: ClCCl
Reactant: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Solvent: CCN(CC)CC
Product: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Reaction time: 16 h

Procedure:
A solution of 5 in 100 mL of CH2Cl2 was added Et3N (4.28 mL, 30.72 mmol) and 2 (26.88 mmol) in 27 mL of CH2Cl2. After 16 h at rt, it was loaded on silica gel and eluted with EtOAc:hexane=1:3 give 6 (16.62 g). Mass spectrum (ESI) for 6, 703 (M+1).