Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:38])[C@H:24]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:38])=[O:22])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to Nε-Boc-lysine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: CO[C:3]([S:5][S:6][CH2:7][C:8]([NH:10][CH:11]([CH2:15][C:16]([OH:18])=[O:17])[C:12]([OH:14])=[O:13])=[O:9])=O.[CH2:19](S)[CH2:20]C>CO>[CH2:3]([S:5][S:6][CH2:7][C:8]([NH:10][CH:11]([CH2:15][C:16]([OH:18])=[O:17])[C:12]([OH:14])=[O:13])=[O:9])[CH2:19][CH3:20]
Reactant: CCCS
Reactant: COC(=O)SSCC(=O)NC(CC(=O)O)C(=O)O
Solvent: CO
Product: CCCSSCC(=O)NC(CC(=O)O)C(=O)O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A flask was charged with 400 mg (1 eq., 1.5 mmole) of (methoxycarbonyldithio)ethylamidosuccinic acid dissolved in 5 ml methanol, cooled to 0° C., purged with argon, and then treated dropwise with a solution of 135.3 ml (114 mg, 1 eq., 1.5 mmole) propanethiol (purchased from Aldrich) in 4 ml of methanol over a 30 min. period. The reaction was then allowed to warm to room temperature and stirred for 18 hours. The volatiles were then removed by vacuum transfer and the residue applied to a flash silica gel column, eluting with 10% methanol/methylene chloride. 1H NMR (d6DMSO/TMS) δ: 0.92 (3H, t, CH3), 1.61 (2H, m, CH2), 2.30 (2H, m, CH2), 2.39 (2H, m, CH2), 2.69 (2H, m, 2×CH2), 3.31 (2H, m, 2×CH2), 8.03 (1H, t, NH), 12.05 (1H, br. s, CO2H). 13C NMR (d6DMSO/TMS) δ: 173.65 (Q), 170.97 (Q), 39.83 (CH2), 38.00 (CH2), 37.10 (CH2), 29.88 (CH2), 28.99 (CH2), 21.74 (CH2), 12.67 (CH3). 1H NMR(CD3OD/TMS) δ: 0.98 (3H, t, J=7.33 Hz, CH3), 1.69 (2H, h, J=7.22 Hz, CH2), 2.47 (2H, m with fine splitting, CH2), 2.56 (2H, m with fine splitting, CH2), 2.68 (2H, t, J=7.15 Hz, CH2), 2.77 (2H, t, J=6.84 Hz, CH2), 3.46 (2H, t, J=6.84 Hz, CH2). 13C NMR (CD3OD/TMS) δ: 176.72 (Q), 174.75 (Q), 41.87 (CH2), 39.87 (CH2), 38.42 (CH2), 31.77 (CH2), 30.72 (CH2), 23.47 (CH2), 13.40 (CH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:21]=[O:22])C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH:21]=[O:22])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2cncs2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ncc(-c2ccc(F)cc2)s1
Reaction time: 0.33 h
Yield: 69 %

Procedure:
A solution of 5-(4-fluorophenyl)thiazole (0.5 g, 2.78 mmol) and THF (40 mL) was cooled to −78° C., 1.6 M n-BuLi in hexanes (0.7 mL, 8.36 mmol) was slowly added, the solution was stirred for 20 min and DMF in THF (20 mL) was added. The reaction mixture was stirred at −78° C. for 2 h, quenched with saturated ammonium chloride solution and diluted with ethyl acetate (150 mL). The organic layer was separated, washed with ammonium chloride (3×150 mL) and followed by brine solution (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (100-200μ silica gel and 18% ethyl acetate in hexane) to obtain 5-(4-fluorophenyl)thiazole-2-carbaldehyde as off-white solid (0.4 g, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 8.63 (s, 1H), 7.88-7.91 (m, 2H), 7.35 (t, 2H), LC-MS m/z calculated for [M+H]+ 208.02 found 208.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O>[Fe].O1CCOCC1.O>[N:8]1([CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[C:16]([NH2:17])=[CH:15][CH:14]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(CN2CCOCC2)cc1N
Yield: 72.6 %

Procedure:
To a mixture of 4-(3,4-dinitro-benzyl)-morpholine (2.5 g, 9.3 mmol), Fe powder (5.2 g, 93 mmol) and FeSO4.7H2O (1.3 g, 4.6 mmol) was added 1,4-dioxane:water (5:1, 60 ml). The mixture was refluxed for 3 h, filtered through celite, washing with MeOH, and reduced in vacuo azeotroping with toluene. EtOAc (100 ml) was added and insoluble material removed via filtration. The filtrate was reduced in vacuo to give 4-morpholin-4-ylmethyl-benzene-1,2-diamine as a dark brown solid (1.4 g, 73%). (LC/MS: Rt 0.40, no ionization).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:12]=[C:13]([C:25]#[N:26])[C:14]([C:23]#[N:24])=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5]1)([CH3:3])[CH3:2].CC[OH:29]>OO.O.O.O.[O-][Mo]([O-])(=O)=O.[Na+].[Na+]>[C:25]([C:13]1[C:14]([C:23]([NH2:24])=[O:29])=[N:15][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([C:6]2[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[N:12]=1)#[N:26]
Reactant: CC(C)n1nc(-c2nc(C#N)c(C#N)nc2-c2ccccc2)ccc1=O
Reactant: CCO
Agent: O=[Mo](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(C)n1nc(-c2nc(C#N)c(C(N)=O)nc2-c2ccccc2)ccc1=O
Temperature: 42.5 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2,3-pyrazinedicarbonitrile (343 mg) in EtOH (10 ml) was dropwise added a solution of sodium molybdate dihydrate (12.1 mg) in a mixture of 30% hydrogen peroxide solution in water (0.57 ml) and EtOH (1.5 ml) and the mixture was stirred at 40-45° C. for 3 hours. After ice-cooling, a precipitate was collected by filtration to give 3-cyano-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2-pyrazinecarboxamide as a solid (171 mg).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([P+](ON1N=NC2C1=CC=CC=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH:52]C(OC(C)(C)C)=O.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][NH2:52])=[O:16])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccccc2)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: CCOC(C)=O
Solvent: CN(C)C=O
Product: NCCCCNC(=O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
3-(Phenylsulfonyl)aminobenzoic acid as prepared in Example 9 (139 mg, 0.5 mmol), Castro's reagent (benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate) (221 mg, 0.5 mmol), tert-butyl 4-aminobutylaminocarboxylate (100 mg, 0.6 mmol) and triethylamine (0.2 mL) were mixed in dry DMF (5 mL) and stirred at room temperature for 3 hours. The mixture was dissolved in ethyl acetate (100 mL) and washed with saturated NaHCO3 (2×50 mL), brine (2×50 mL) and dried over Na2SO4. After evaporation of the solvent, the residue was mixed with 1:1 trifluoroacetic acid (TFA):CH2Cl2 (10 mL), stirred at room temperature for 2 hours and the solvent evaporated to give the title compound (140 mg, 81%) as the TFA salt. 1H-NMR (300 MHz, DMSO-d6): δ 1.17 (m, 4H), 2.79 (t, 2H), 3.23 (d, 2H), 7.23 (d, 1H), 7.30 (t, 1H), 7.57 (m, 5H), 7.60 (d, 2H), 8.50 (t, 1H). Mass spectrum (MALDI-TOF) calcd. for C17H21 N3O3S: 370.4 (M+Na), Found: 370.7.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.P(Br)(Br)[Br:13]>C(OCC)C>[CH2:1]([Br:13])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: BrCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 182 %

Procedure:
To a solution of piperonyl alcohol (5.0 g, 32.86 mmol) in anhydrous diethyl ether (80 mL) was added PBr3 (1.56 mL, 16.43 mmol) in one portion, and the resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with diethyl ether (100 mL) and washed with H2O (2×50 mL), saturated NaHCO3 (2×50 mL), and brine (2×50 mL). The ether layer was dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to afford piperonyl bromide (6.43 g, 91%) as a yellow-grey solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([NH:8][C:9]2[O:10][C:11]3[C:17]([F:18])=[C:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([NH:8][C:9]2[O:10][C:11]3[C:17]([F:18])=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3cc(F)ccc3C)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(F)cc1Nc1nc2ccc(CC(=O)O)c(F)c2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
In THF/methanol (2:1, v/v, 90 ml) was dissolved methyl (2-(5-fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (810 mg, 2.44 mmol). To the resulting solution was added 1N NaOH (30 ml). After stirring at room temperature for 12 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (2-(5-fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetic acid (700 mg, 90%) as a pale brown solid.
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9]([OH:11])=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Cc1ccccc1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 50.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-phenylacetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 249, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-phenylacetamido)propanamide (3 mg, 50.1%). MS (EI) for C30H27FN2O4. found 499.6 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:14])[CH:10]2[CH3:13])=[CH:5][CH:4]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][C:10]1([CH3:13])[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14])[CH3:21]
Reactant: COc1ccc2c(c1)C(C)C(=O)CC2
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CC1(C)C(=O)CCc2ccc(OC)cc21

Procedure:
The compound 3,4-dihydro-7-methoxy-1-methyl-2(1H)-naphthalenone (VIIIb) (28.23 g, 148 mmol) was reacted with ethyl bromoacetate by the method of Example 5 to yield 36.0 g (88%) (IXb) b.p. 138°-140°/0.1 mm Hg; IR (neat) 1740 cm-1 (unresolved ketone and ester bands); NMR δ, 1.05 and 3.93 (triplet and quartet for CO2CH2CH3), 1.37 (s, 3, CH3), 3.80 (s, 3, OCH3), 6.6-7.3 (m, 3, ArH). The distillate crystallized on standing. A sample recrystallized from ethanol melted at 55°-55.5°.
Reaction SMILES: [F:1][C:2](=[CH:6][CH2:7][C:8]([F:21])=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]([O-])=[O:4].CC(C[AlH]CC(C)C)C>CCOCC.CCCCCC>[F:1][C:2](=[CH:6][CH2:7][C:8]([F:21])=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][OH:4]
Reactant: CCCCCC=CCCCCC=C(F)CC=C(F)C(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCC=CCCCCC=C(F)CC=C(F)CO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
The ester prepared in 1F (0.39 g, 1.18 mmoles) in anhydrous ether 5 ml was added at -78° C. to a mixture of DIBAL, 1M solution in hexane, (2.5 mL) and ether (20 ml). The mixture was stirred 30 min. at -78° C., the overnight at room temperature. The excess of DIBAL was destroyed with methanol (2 ml) and the aluminum salts were precipitated with an aqueous saturated solution of ammonium chloride. The mixture was filtrated and the precipitate washed with ethyl acetate. The solvents were evaporated under reduced pressure. Flash chromatography over silica gel and elution with a 8:2 mixture of hexane and ethyl acetate afforded the expected alcohol as an oil (0.33 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.C[O:15][NH3+:16].[Cl-].C([O-])(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7]/[C:8]/2=[N:16]/[OH:15]
Reactant: COc1cccc2c1CCCC2=O
Reactant: CO[NH3+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc2c1CCC/C2=N/O
Temperature: 60 °C
Yield: 96.5 %

Procedure:
To a solution of 5-methoxy-3,4-dihydronaphthalen-1(2H)-one (200 mg, 1.14 mmol) and hydroxylamine methyl ether hydrochloride (284 mg, 3.40 mmol) in MeOH (5 mL) was added sodium acetate (279 mg, 3.40 mmol). The reaction mixture was heated at 60° C. for 1 h, cooled and partitioned between H2O and EtOAc. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give Intermediate 34A (0.20 g, 1.1 mmol, 92% yield) which was used directly in the next step without further purification. LCMS=1.78 min [M+1]=192.1 (Method B).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([O:20]C)=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.[OH-].[Na+]>CO>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: COC(=O)c1cccc2c(NCc3cccc(C(F)(F)F)c3)ncnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc2c(NCc3cccc(C(F)(F)F)c3)ncnc12
Yield: 89 %

Procedure:
A solution of methyl 4-{[3-(trifluoromethyl)benzyl]amino}quinazoline-8-carboxylate (95 mg, 0.26 mmol) in 5 mL of MeOH was treated with 2N NaOH (650 μL, 1.3 mmol, 5 equiv.) under refluxing for 5 h. After removal of MeOH, water was added to the residue and pH was adjusted to ˜4 with 2N HCl. The precipitate was collected as the desired acid by filtration, and washing with water in 89% yield. 1HNMR (in DMSO): 4.96 (d, J=5.8 Hz, 2H), 7.56-7.61 (m, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.74-7.78 (m, 2H), 8.54 (dd, J=1.2 and 7.4 Hz, 1H), 8.63 (dd, J=1.2 and 7.3 Hz, 1H), 8.69 (s, 1H), 9.68 (d, J=5.8 Hz, 1H). Mass: M+H+: 348.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C@H:10]([CH2:10][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:12])[C:11]([O:13][CH2:9][C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Reactant: C1COCCN1
Product: COc1ccc(C[C@H](CC(=O)N2CCOCC2)C(=O)OCc2ccccc2)cc1

Procedure:
A procedure similar to those described in Preparations 12-14 was repeated, but using 3-(4-methoxyphenyl)propionic acid as one of the starting materials and morpholine as the amine, to afford benzyl 2(R)-(4-methoxybenzyl)-3-(morpholinocarbonyl)propionate. 1.62 g (4.08 mmole) of this compound was dissolved in 50 ml of ethanol, and the solution was stirred at room temperature for 4 hours under an atmosphere of hydrogen and in the presence of 160 mg of 10% w/w palladium-on-charcoal. At the end of this time, the catalyst was removed by filtration and the filtrate was concentrated by distillation under reduced pressure, to afford 1.25 g of the title compound as a colorless oily substance.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[CH3:11][NH:12][C:13](=[S:16])[NH:14][NH2:15]>N1C=CC=CC=1>[N:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:15][NH:14][C:13]([NH:12][CH3:11])=[S:16])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CNC(=S)NN
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=S)NNC(=O)c1ccncc1
Reaction time: 8 h

Procedure:
4-Pyridoyl chloride hydrochloride (10.0 g, 5.62×10-2 mole) and 4-methylthiosemicarbazide (5.91 g, 5.62×10-2 mole) was stirred at room temperature in pyridine (150 ml). After stirring overnight, the pyridine was evaporated at reduced pressure and the concentrate was washed with H2O. The undissolved product was collected by filtration and dried by suction.
Reaction SMILES: [C:1](O)(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][CH2:38][CH:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)[N:31]=[CH:30][N:29]=[C:28]2[NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([Br:53])[CH:48]=1>O1CCCC1.N1C=CC=CC=1>[Br:53][C:49]1[CH:48]=[C:47]([NH:46][C:28]2[C:27]3[C:32](=[CH:33][C:34]([O:35][CH2:36][CH2:37][CH2:38][CH:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)=[C:25]([NH:24][C:1](=[O:7])[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6])[CH:26]=3)[N:31]=[CH:30][N:29]=2)[CH:52]=[CH:51][CH:50]=1
Reactant: CN1CCC(CCCOc2cc3ncnc(Nc4cccc(Br)c4)c3cc2N)CC1
Reactant: C/C=C/C=C/C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC=CC=CC(=O)Nc1cc2c(Nc3cccc(Br)c3)ncnc2cc1OCCCC1CCN(C)CC1
Reaction time: 0.02 h

Procedure:
To 31 mg of sorbic acid in 1 ml of tetrahydrofuran are added 40 μl of isobutyl chloroformate followed by 45 μl of N-methylmorpholine whilst cooling with an ice bath. The white suspension is stirred for one minute, then a solution of 100 mg of 6-amino-4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]quinazoline in 1.5 ml of pyridine is added. The ice bath is removed and the reaction mixture is stirred overnight. For working up, it is poured onto 20 ml of ice water, stirred for 30 minutes and adjusted to pH 9-10 with a few drops of 2 N sodium hydroxide solution. The aqueous phase is extracted with methylene chloride, the combined organic phases are dried over sodium sulfate and concentrated by evaporation. The resin-like crude product is purified by chromatography over an aluminium oxide column (activity III) with methylene chloride/methanol (99.5:0.5). Yield: 62 mg (52% of theory); Rf value: 0.29 (aluminium oxide, activity III; methylene chloride/methanol=98:2); mass spectrum (EI): m/z=563, 565 [M]+.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C:3]1=[O:13].[F:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.[OH-].[K+]>CCO>[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH:2]2[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C:3]2=[O:13])=[CH:17][CH:16]=1
Reactant: Fc1ccc(S)cc1
Reactant: CCOC(=O)C1CCC(Br)C(=O)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CCC(Sc2ccc(F)cc2)C(=O)C1
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
To a solution of ethyl 4-bromo-3-oxocyclohexanecarboxylate (5.2 g, 20.9 mmol) in EtOH (120 mL) at 80° C. was added a solution of 4-fluorobenzenethiol (2.22 mL, 20.9 mmol) and KOH (1.29 g, 22.9 mmol) in EtOH (50 mL). The suspension was stirred for 30 min then filtered. The filtrate was concentrated in vacuo then diluted with water and extracted with diethyl ether. The organic layer was washed with water then brine, then was dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica gel (15% EtOAc in hexane) afforded the title compound (3.08 g, 51%) as a white solid: mp 96-97° C.; MS (+) 297 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([C:9]2[O:10][C:11]3[C:18]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:16]=[C:15]([O:22]CC4C=CC=CC=4)[C:12]=3[C:13]=2[CH3:14])=O)=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:9]2[O:10][C:11]3[C:18]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:16]=[C:15]([OH:22])[C:12]=3[C:13]=2[CH3:14])=[CH:30][CH:31]=1
Reactant: CCCc1ccc(OCc2ccccc2)c2c(C)c(C(=O)c3ccc(OC)cc3)oc12
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc(O)c2c(C)c(Cc3ccc(OC)cc3)oc12

Procedure:
A mixture of 2-(p-methoxybenzoyl)-3-methyl-4-benzyloxy-7-propylbenzofuran (0.10 gm, 0.24 mmole) in ethanol was hydrogenated in a Parr hydrogenator in the presence of 10% palladium on charcoal at 40 psi for a period of 7 hours. The catalyst was filtered off, washed with some ethanol, and the filtrate was concentrated in vacuo to yield 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-7-propylbenzofuran.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][C:13]([F:18])=[C:12]([F:19])[C:11]=2[F:20])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][C:13]([F:18])=[C:12]([F:19])[C:11]=2[F:20])=[O:9])=[CH:6][N:5]=[C:4]([NH:42][CH:39]2[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2c(OC)cc(F)c(F)c2F)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(2,3,4-trifluoro-6-methoxy-phenyl)-methanone (Example 194) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C18H21N5O4SF3[(M+H)+] 460.1261, observed 460.1267. CDK4 IC50=0.001; CDK1 IC50=0.005; CDK2 IC50=0.002; HCT 116 IC90=0.630 μM.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33].C(=O)(O)[O-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:37]3[CH:38]=[CH:39][C:34]([CH:32]=[O:33])=[CH:35][CH:36]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc(C=O)cc3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 8A) (2.85 g, 4.86 mmol) and 4-formylphenylboronic acid (1.094 g, 7.30 mmol) in N,N-dimethylformamide (36.5 ml) was added saturated aqueous bicarbonate solution (12.16 ml) followed by bis(triphenylphosphine)palladium dichloride (0.239 g, 0.341 mmol). The mixture was heated to 70° C. for 2 hours, cooled to room temperature, and quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 70% ethyl acetate in hexane, to afford the title compound. MS ESI(+) m/z 564.5 [M+H]+.