Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>CN(C)C1C=CN=CC=1>[C:15]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2)(=[O:17])[CH3:16]
Reactant: COC(=O)c1cc2c(O)cccc2[nH]1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: COC(=O)c1cc2c(OC(C)=O)cccc2[nH]1
Temperature: 80 °C

Procedure:
Methyl 4-hydroxyindole-2-carboxylate (0.5 g) and 4-dimethylaminopyridine (50 mg) were dissolved in acetic anhydride (5 ml) and heated at 80° C. for 3 hours. The reaction was allowed to cool overnight to precipitate white crystals, which were filtered and dried in vacuo (0.44 g, 72%); NMR δ (CD3SOCD3) 2.34 (s, 3H), 3.85 (s, 3H), 6.80 (d, 1H), 7.06 (s, 1H), 7.23 (t, 1H), 7.29-7.35 (m, 1H), 12.1 (bs, 1H); M/z (−) 232 (M−H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.CO[C:21](OC)([N:23]([CH3:25])[CH3:24])[CH3:22]>>[CH3:24][N:23]([CH2:21][CH:22]=[N:18][C:16]([C:15]1[CH:14]=[N:13][N:12]2[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=[N:10][C:11]=12)=[O:17])[CH3:25]
Reactant: COC(C)(OC)N(C)C
Reactant: NC(=O)c1cnn2c(-c3cccnc3)ccnc12
Product: CN(C)CC=NC(=O)c1cnn2c(-c3cccnc3)ccnc12
Temperature: 120 °C

Procedure:
A mixture of 10.0 g of 7-(3-pyridinyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide (prepared as described in Example 9) and 50.0 ml of N,N-dimethylacetamide dimethyl acetal are heated at 120° C. for 2 hours. After cooling, the reaction mixture is evaporated in vacuo to give an oil. The oil is triturated with diethyl ether to separate a yellow solid. The solid is collected by filtration, washed with ether, air dried, then dried in vacuo to give 12.37 g of the desired product as a tan solid, mp 124°-127° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12](=[O:20])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cu](C#N)[C:22]#[N:23].O.N>N1C=CC=CC=1>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12](=[O:20])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:23]
Reactant: N#C[Cu]C#N
Reactant: O=C1CCCC(c2ccc(Cl)cc2)N1c1ccccc1
Agent: N
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccc(C2CCCC(=O)N2c2ccccc2)cc1
Temperature: 240 °C
Reaction time: 19 h
Yield: 42.1 %

Procedure:
To 8.55 g of 6-(4-chlorophenyl)-1-phenyl-2-piperidone were added 5.58 g of copper cyanide and 14 ml of pyridine, and the mixture was heated with stirring at 240° C. for 19 hours. The mixture was treated with diluted ammonia water, and then extracted with ethyl acetate. The extracts were washed with water, dried and treated with activated charcoal. After removal of charcoal and the solvent, the residue was purified by silica gel column chromatography (solvent; ethyl acetate:n-hexane=1:1 to 3), and recrystallized from a mixture of ethyl acetate and isopropyl ether to give 3.48 g of 6-(4-cyanophenyl)-1-phenyl-2-piperidone as pale yellow prisms.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][C:25]2[CH:26]=[N:27][N:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:29]=2)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>>[CH:14]([C:17]1[CH:18]=[CH:19][C:20]([N:23]([CH2:24][C:25]2[CH:26]=[N:27][N:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:29]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:21][CH:22]=1)([CH3:16])[CH3:15]
Reactant: O=C(O)C1CCCc2ccccc21
Reactant: CC(C)c1ccc(NCc2cnn(-c3ccccc3)c2)cc1
Product: CC(C)c1ccc(N(Cc2cnn(-c3ccccc3)c2)C(=O)C2CCCc3ccccc32)cc1
Yield: 47 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.35 g) and (4-isopropylphenyl)[(1-phenylpyrazol-4-yl)methyl]amine (0.58 g) as starting materials, N-(4-isopropylphenyl)-N-[(1-phenylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) was obtained.
Reaction SMILES: [CH3:1][N:2]([C:20]1[C:21]2[CH:28]=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1)[C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([OH:19])[CH2:14]2)(=[O:12])=[O:11])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[C:38](Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[C:38]([O:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:13]([S:10]([CH2:9][C@H:6]2[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:8][CH2:7]2)(=[O:12])=[O:11])[CH2:14]1)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN(c1ncnc2[nH]ccc12)[C@H]1CC[C@H](CS(=O)(=O)N2CCC[C@@H](O)C2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncnc2[nH]ccc12)[C@H]1CC[C@H](CS(=O)(=O)N2CCC[C@@H](OC(=O)C(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-(R)-1-((4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methylsulfonyl)piperidin-3-ol (0.400 g, 0.98 mmol), DMF (10 mL), and DIEA (0.25 mL, 1.4 mmol) was treated with pivaloyl chloride (0.10 mL, 0.81 mmol) and the mixture stirred at ambient temperature overnight. The mixture was concentrated and the resulting residue chromatographed over SiO2 using 0→5% MeOH in CH2Cl2. The desired product fractions were pooled and concentrated to afford the title compound (0.182 g, 38%). MS for C24H37N5O4S (ESI) (MH)+ m/z=492.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.Cl>C(O)C.O.[OH-].[Na+]>[Br:1][C:2]1[C:3]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1
Reactant: CCOC(=O)COc1cc2onc(-c3ccccc3F)c2cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1cc2onc(-c3ccccc3F)c2cc1Br

Procedure:
A suspension of 4 g of ethyl {[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate in 125 ml of ethanol, 50 ml of water and 4 ml of 50% sodium hydroxide solution is refluxed for several hours, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract is dried, the solvent is removed and the residue is recrystallized from acetonitrile to give {[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp 223°-224° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:38])=[CH:4][C:5]([N+:35]([O-:37])=[O:36])=[C:6]([O:8][C:9]2[C:10]([F:34])=[C:11]([CH2:16][NH:17][C:18]([C:20]3[N:24](COCC[Si](C)(C)C)[CH:23]=[N:22][C:21]=3[Cl:33])=[O:19])[CH:12]=[CH:13][C:14]=2[Cl:15])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:38])=[CH:4][C:5]([N+:35]([O-:37])=[O:36])=[C:6]([O:8][C:9]2[C:10]([F:34])=[C:11]([CH2:16][NH:17][C:18]([C:20]3[NH:24][CH:23]=[N:22][C:21]=3[Cl:33])=[O:19])[CH:12]=[CH:13][C:14]=2[Cl:15])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Br)c(F)cc2[N+](=O)[O-])c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)c(Oc2cc(Br)c(F)cc2[N+](=O)[O-])c1F)c1[nH]cnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of N-({3-[(5-bromo-4-fluoro-2-nitrophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5carboxamide (55.0 mg, 0.084 mmol) in DCM (6 ml) was added TFA (3.00 ml) and the reaction mixture was stirred at RT for 2 hours. The solvent was removed and the crude material was purified via reverse phase HPLC to give N-({3-[(5-bromo-4-fluoro-2-nitrophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (33 mg, 0.063 mmol, 75% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.03 (d, 1H), 7.74 (s, 1H), 7.32-7.45 (m, 2H), 7.10 (d, 1H), 4.65 (s, 2 H). LC-MS (ES+) m/z 520.92, [M+H].
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[NH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8].P(Cl)(Cl)([Cl:19])=O>>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([Cl:19])[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:6]=1
Reactant: Cc1ccc(-c2nc(C)c(C)c(=O)[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2nc(C)c(C)c(Cl)n2)cc1

Procedure:
A mixture of 5,6-dimethyl-2-(4-methylphenyl)-3H-pyrimidin-4-one (6 g) and phosphorus oxychloride (40 ml) was refluxed for 2 hours. Excess phosphorus oxychloride was removed under reduced pressure, ice added to the residue, and the mixture extracted with methylene chloride, the organic layer washed with brine, dried over sodium sulfate, the solvent evaporated under reduced pressure, to yield 6.2 g of 4,5-dimethyl-6-chloro-2-(4-methylphenyl)pyrimidine, m.p. 165° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH3:12])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.Br[C:14]([CH3:19])([CH3:18])[C:15](Br)=[O:16]>ClC1C=CC=CC=1>[CH3:18][CH:14]1[CH2:19][C:8]2[C:9](=[CH:10][C:5]([CH3:12])=[CH:6][C:7]=2[CH3:11])[C:15]1=[O:16]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Cc1cccc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1cc(C)c2c(c1)C(=O)C(C)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
A 500 mL, 3-neck rounded bottom flask equipped with a magnetic stirring bar and a reflux condenser, was filled with nitrogen atmosphere and charged with 71.16 g of AlCl3 (0.53 mol, 2.3 eq.) dissolved in 240 mL of chlorobenzene. At room temperature 28.38 mL of m-xylene (0.23 mol, 1 eq.) were added dropwise obtaining a light yellow suspension. The flask was then cooled to 0° C. and 28.68 mL of 2-bromoisobutyryl bromide (0.23 mol, 1 eq.) were slowly added. At the end of the addition a dark-red slurry was obtained. The reaction mixture was then allowed to warm up to r.t. and stirred for 2 hours. Then it was transferred into a flask containing a solution of ice/HCl 37%=3/1. The organic phase was extracted with Et2O (3×200 mL): the combined organic phases were dried over Na2SO4, filtered and the solvent was removed in vacuo. An orange oil was obtained as product (37.48 g, yield 93.5%). The latter was used as such without further purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[C:24]([N:14]1[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:16][CH2:15]1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(CCNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
0.5 g of 4-(2-tert-butoxycarbonylaminoethyl)-piperidine and 0.61 ml of triethylamine are dissolved in 5 ml of dichloromethane and, at 0° C., 0.22 ml of acetyl chloride is added. The reaction mixture is stirred at room temperature for 7 hours and then washed with water. The organic phase is concentrated by evaporation and purified by FC (10 g of silica gel, ethyl acetate/methanol=9:1). The title compound is obtained: Rf (ethyl acetate/methanol=9:1)=0.39.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][NH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[CH2:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:25]=1)(=O)=O.CN(C)C=O>O>[CH2:39]([O:38][C:26]1[CH:25]=[C:24]([CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=1)[CH2:23][N:12]1[CH:13]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CS(=O)(=O)OCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: COC(=O)c1c[nH]cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Sodium hydride (60%, oily, 2.20 g) was added to a mixture of methyl 4-phenylpyrrole-3-carboxylate (11.10 g), 3,5-dibenzyloxybenzyl methanesulfonate (21.9 g) and N,N-dimethylformamide (200 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and methyl 1-(3,5-dibenzyloxybenzyl)-4-phenylpyrrole-3-carboxylate (26.4 g, yield: 95%) was obtained as an oily substance from the fraction eluted with tetrahydrofuran-hexane (1:2, volume ratio).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[CH:5]=[N:4][C:3]=1[C:12]#[C:13][Si](C)(C)C.O.O.O.O.O.O.O.O.O.[S-2:27].[Na+].[Na+]>CN(C)C=O>[CH3:11][C:9]1[N:10]=[C:6]2[CH:5]=[N:4][C:3]3[CH:12]=[CH:13][S:27][C:2]=3[N:7]2[CH:8]=1
Reactant: Cc1cn2c(Cl)c(C#C[Si](C)(C)C)ncc2n1
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn2c(cnc3ccsc32)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
A mixture of 5-chloro-2-methyl-6-[(trimethylsilyl)ethynyl]imidazo[1,2-a]pyrazine (0.400 g, 1.52 mmol), and sodium sulfide nonahydrate (1.09 g, 4.55 mmol) in N,N-dimethylformamide (6.0 mL) was heated in a preheated oil bath at 100° C. with stirring for 1 h. The reaction was cooled and partitioned between EtOAc and water. The organic layer was washed with water, brine, dried and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with EtOAc and 3% MeOH in EtOAc to give the desired product (0.15 g, 52%). LCMS calculated for C9H8N3S (M+H)+: m/z=190.0. Found: 190.0.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:18][O:17][CH2:16][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[F:15])[N:7]=1.[Na+].[I-:20]>I>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C:6]2[N:7]=[C:2]([I:20])[C:3]3[CH2:18][O:17][CH2:16][C:4]=3[N:5]=2)[CH:13]=1
Reactant: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)COC2
Reactant: [I-]
Agent: I
Agent: [Na+]
Product: Fc1ccc(Cl)cc1-c1nc(I)c2c(n1)COC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-2-(5-chloro-2-fluorophenyl)-5,7-dihydrofuro[3,4-d]-pyrimidine (78 mg, 0.275 mmol, 1 eq) in 57% HI(aq) (2 ml) at r.t. was added NaI (206 mg, 1.37 mmol, 5 eq). The reaction mixture was stirred at r.t. overnight and then was poured onto ice. The product was extracted with chloroform and the aqueous layer was neutralized with NaHCO3 and extracted further with chloroform. The organic layers were combined washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude residue of 2-(5-Chloro-2-fluorophenyl)-4-iodo-5,7-dihydro-furo[3,4-d]pyrimidine which was not further purified.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[NH:28]1[CH:32]=[C:31]([CH2:33][CH2:34][C:35](O)=[O:36])[N:30]=[CH:29]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:35](=[O:36])[CH2:34][CH2:33][C:31]4[N:30]=[CH:29][NH:28][CH:32]=4)[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: O=C(O)CCc1c[nH]cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CN(C(=O)CCc2c[nH]cn2)C1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.10 g, 0.00028 mol), 3-(1H-4-imidazolyl)propanoic acid (0.050 g, 0.00035 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0068 g, 0.00035 mol), N,N-diisopropylethylamine (0.068 g, 0.00053 mol) and 1-hydroxy-7-azabenzotriazole (0.038 g, 0.00028 mol) in anhydrous N,N-dimethylformamide (13 mL) was stirred for eighteen hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-3-(1H-4-imidazolyl)-1-propanone (0.040 g, 0.00008 mol).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:36]>C1COCC1.CCOC(C)=O>[NH2:36][CH2:24][C:21]1[N:20]=[C:19]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[O:23][N:22]=1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Temperature: 40 °C
Yield: 94 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (1.2 g, 2.37 mmol) in THF (40 ml) was treated with concentrated ammonia solution and heated in a bomb at 40° C. for 18 hours. The reaction mixture was diluted with EtOAc and washed with sat. NaHCO3 solution followed by brine. The organic extract was dried over anhydrous MgSO4, filtered and the solvent removed under reduced pressure. The colourless oil was purified on a silica column eluting with a solvent gradient of pentane:EtOAc (4:1) gradually changing to (1:1) and then changing to DCM:MeOH:NH3 (95:5:0.5) to afford the title compound as a colourless oil (782 mg, 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]2O)[CH:5]=[CH:6][C:7]=1[OH:8].CCN(S(F)(F)[F:29])CC>C(Cl)Cl>[F:29][C@H:10]1[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=2)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)c(F)c2)[C@H](O)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)c(F)c2)[C@H](F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 129 %

Procedure:
To (3S,4S)-tert-butyl 4-(3-fluoro-4-hydroxyphenyl)-3-hydroxypiperidine-1-carboxylate (2.99 g, 9.60 mmol) in DCM (75 mL) at 0° C. was added DAST (6.34 mL, 48.0 mmol) dropwise. The reaction was then allowed to warm to room temperature and stir for 2 h. The reaction was slowly quenched with ice water. The reaction was then extracted with dichloromethane, washed with additional water, dried with magnesium sulfate, filtered and concentrated in vacuo to afford (3S,4S)-tert-butyl 3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate (3.88 g, quantitative yield) as a yellow viscous oil: LC-MS [M−H]+ 312.2; 1H NMR (500 MHz, DMSO-d6) δ 7.22-7.10 (m, 1H), 7.00-6.76 (m, 3H), 5.76 (s, 2H), 4.60 (td, J=10.1, 5.2 Hz, 1H), 4.50 (td, J=10.1, 5.2 Hz, 1H), 4.27 (br. s., 1H), 4.07-3.78 (m, 2H), 3.66-3.50 (m, 1H), 3.00-2.65 (m, 4H), 1.81-1.69 (m, 1H), 1.63-1.50 (m, 1H), 1.46-1.30 (m, 14H), 1.20-1.01 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.[CH2:21]([O:23][C:24](=[O:38])[CH:25]=[C:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[CH2:27]Br)[CH3:22]>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([NH:6][CH2:27][C:26]([O:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)=[CH:25][C:24]([O:23][CH2:21][CH3:22])=[O:38])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)C=C(CBr)Oc1ccc(OC)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C=C(CN[C@@H](CC(C)C)C(=O)OC)Oc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.64 g, 3.56 mmol) in acetonitrile (8.9 mL) was treated with N,N-diisopropylethylamine (0.57 mL, 3.49 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.57 mL, 3.49 mmol) and acetonitrile (8.9 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(4-methoxy-phenoxy)-but-2-enoic acid ethyl ester (1.02 g, 3.23 mmol) in acetonitrile (8.09 mL). After the addition was complete, the reaction mixture was heated to 100° C. where it stirred overnight. At this time, the reaction mixture was cooled to 25° C. and was concentrated in vacuo. The residue was diluted with dichloromethane (75 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 20-30% ethyl acetate/hexanes) afforded (S)-2-[3-ethoxycarbonyl-2-(4-methoxy-phenoxy)-allylamino]-4-methyl-pentanoic acid methyl ester (0.84 g, 68%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (d, J=6.3 Hz, 3H), 0.88 (d, J=6.3 Hz, 3H), 1.30-1.50 (m, 2H), 1.63-1.81 (m, 1H), 3.60 (s, 3H), 3.77 (s, 3H), 3.88 (dd, J=6.5, 3.2 Hz, 1H), 3.96 (d, J=6.9 Hz, 1H), 4.01 (d, J=6.9 Hz, 1H), 4.61 (s, 1H), 7.02 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:18])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=C(Cl)N=1.[CH3:19][O:20][C:21](=[O:28])[C:22]#[C:23][C:24]([O:26][CH3:27])=[O:25]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:3](=[O:18])[N:4]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH:5]=[C:22]([C:21]([O:20][CH3:19])=[O:28])[C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COc1ccc(Cn2cc(Cl)nc(Cl)c2=O)cc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: Cc1ccccc1C
Product: COC(=O)c1cn(Cc2ccc(OC)cc2)c(=O)c(Cl)c1C(=O)OC
Temperature: 150 °C
Yield: 33.4 %

Procedure:
Compound (8) (2.0 g, 7.01 mmol) and 2-butynedioic acid dimethyl ester (2.99 g, 21.04 mmol) were added to xylene (40 ml). The reaction was heated at about 150° C. for about 16 h. The reaction was cooled to about 25° C. The reaction mixture was filtered through a Büchner funnel to afford the title compound (0.9 g, 2.338 mmol, 33.3% yield). LC-MS (ESI+): m/e 366 (M+H)+, Rt: 1.98 min; 1H-NMR (DMSO-d6, 400 MHz): δ=3.73 (s, 3H), 3.79 (s, 3H), 3.88 (s, 3H), 5.21 (s, 2H), 6.91 (d, 2H, J=6.8 Hz), 7.34 (d, 2H, J=6.8 Hz), 8.81 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][C:35]([CH3:39])=[N:36]2)=[CH:31][CH:30]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][C:35]([CH3:39])=[N:36]2)=[CH:31][CH:30]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Reactant: Cc1ccc2ccc(O)cc2n1
Product: COc1cc2c(Oc3ccc4ccc(C)nc4c3)ncnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Yield: 81.4 %

Procedure:
Using an analogous procedure to that described in Example 42, 4-chloro-6-methoxy-7-(1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)quinazoline (156 mg, 0.38 mmol), (prepared as described for the starting material in Example 12), was reacted with 7-hydroxy-2-methylquinoline (66 mg, 0.4 mmol), (J. Med. Chem. 1998, 41, 4062), to give 6-methoxy-7-(1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)-4-(2-methylquinolin-7-yloxy)quinazoline (166 mg, 82%).