Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[ClH:13].[CH3:14][O:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[C:19]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:43]=[CH:42][C:41]([C:44](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:45])=[CH:40][CH:39]=3)[N:28]=2)=[CH:18][CH:17]=1>>[ClH:13].[ClH:13].[CH3:12][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:44]([C:41]2[CH:42]=[CH:43][C:38]([N:29]3[N:28]=[C:27]([C:19]4[C:20]5[CH2:21][C:22]([CH3:26])([CH3:25])[O:23][C:24]=5[C:16]([O:15][CH3:14])=[CH:17][CH:18]=4)[C@@H:36]4[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]4)[C:30]3=[O:37])=[CH:39][CH:40]=2)=[O:45])[CH2:10][CH2:11]1
Reactant: CN(C)CCCN1CCNCC1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(CCCN(C)C)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2

Procedure:
Prepared from intermediate product A2 and 1-(3-dimethylaminopropyl)-piperazine as described for compound 8. M.p. 262° C. (with decomposition).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH2:18][C:19]3[CH:20]=[C:21]([C:25]([OH:27])=O)[O:22][C:23]=3[CH3:24])[CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([NH2:39])(=[O:38])=[O:37].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.ClCCl.C(#N)C>[F:28][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH2:18][C:19]3[CH:20]=[C:21]([C:25]([NH:39][S:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH3:29])(=[O:37])=[O:38])=[O:27])[O:22][C:23]=3[CH3:24])[CH3:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: Cc1oc(C(=O)O)cc1CN(C)c1ccc(-c2ccc(OC(F)F)cc2)cc1
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1cc(CN(C)c2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.9 %

Procedure:
A stirred solution of 4-{[(4′-difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carboxylic acid (176) (21 mg, 0.054 mmoles), 2-methyl-benzenesulphonamide (19 mg, 0.108 mmoles) and 4-(N,N-dimethylamino)-pyridine (1 mg) in a mixture of dichloromethane (8 ml) and acetonitrile (2 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.4 mg, 0.060 mmoles). The mixture was stirred at room temperature for 18 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 177(2.9 mg) as a solid. LC/MS System D; Rt=11.21 mins, m/z (ES+)=541 (M+H for C28H26F2N2O5S).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH:49]([CH:51]=[O:52])[NH2:50]>CN(C=O)C>[CH:51]([NH:49][NH:50][C:13](=[O:15])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])[CH3:16])=[O:52]
Reactant: NNC=O
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)NNC=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-2-methylpropanoic acid (Example 8 a, 1.9 g, 8 mmol), HATU (CAN 148893-10-1, 3.97 g, 10 mmol) and N-methylmorpholine (CAN 109-02-4, 2.43 g, 24 mmol) in DMF (20 mL) was stirred at room temperature for 15 min. Then hydrazinecarboxaldehyde (CAN 624-84-0, 0.53 g, 9 mmol) was added and the reaction mixture was stirred at room temperature overnight. After evaporation of solvents, the residue was diluted with ethyl acetate (30 mL) and water (30 mL). The organic layer was washed with saturated sodium bicarbonate solution (30 mL), hydrochloric acid (30 mL, 1 M), brine (30 mL) and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure left the title compounds as yellow oil (2.1 g, 94%); MS: m/e 280.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24](=[O:32])[CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)[CH:6]=[CH:5]2.[NH2:33][CH2:34][CH2:35][OH:36]>C(#N)C>[Cl:1][C:2]1[C:3]([NH:23][C:24](=[O:32])[CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:33][CH2:34][CH2:35][OH:36])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CS(=O)(=O)O[C@@H]1CCCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Reactant: NCCO
Solvent: CC#N
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCCC(NCCO)C3)ccc12
Temperature: 80 °C

Procedure:
N-[6-Chloro-2-[(3R)-3-[(methylsulfonyl)oxy]-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 80(a)) (0.2 g), 2-amino-ethanol (0.075 ml) and acetonitrile (3 ml) were loaded into a 10 ml microwave reaction vial, capped and heated at 80° C. for 90 minutes within a single mode microwave. The solvent was removed under vacuum and the residue was purified by chromatography (SiO2, 7M ammonia in methanol:dichloromethane 1:99 as eluant) to give the title compound as a solid (0.018 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:28][CH:29]=3)[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2cccc(CNC(=O)c3ccc(OC(F)(F)F)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was added 4-trifluoromethoxy-benzoyl chloride (0.34 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.63 mL, 3.6 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-4-trifluoromethoxy-benzamide as a white solid (370 mg, 54% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.54 min (98.6%); mp, 258-260° C.; 1HNMR (DMSO-d6) 2.18-2.23 (m, 1H, CHH), 2.59-2.92 (m, 6H, CHCH2, CH3), 4.98-5.09 (m, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, Ch), 7.34-8.07 (m, 7H, Ar), 9.05 (t, J=5 Hz, 1H, CH2NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.82, 23.29, 30.60, 42.22, 56.54, 117.66, 120.70, 124.15, 125.52, 129.59, 133.30, 133.96, 140.65, 148.51, 150.33, 154.84, 161.10, 165.05, 169.54, 172.63. LCMS MH=489; Anal Calcd For C23H19N4O5F3: C, 56.56; H, 3.92; N, 11.47; F, 11.67. Found: C, 56.32; H, 3.60; N, 11.23; F, 11.56.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[C:14](#[N:18])[CH2:15][C:16]#[N:17].C1(C)C=CC=CC=1.C([O-])(=O)C.[NH4+].C(O)(=O)C>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[C:15]([C:14]#[N:18])[C:16]#[N:17])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: N#CCC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(=C(C#N)C#N)CCC2
Yield: 73.3 %

Procedure:
To a solution of 7-methoxy-3,4-dihydronaphthalen-1(2H)-one 46.1 (10.0 g, 56.7 mmol, Aldrich) and malononitrile (4.07 mL, 64.7 mmol) in toluene (40.0 mL, 378 mmol) was added ammonium acetate (0.938 mL, 13.1 mmol) and acetic acid (3.90 mL, 68.1 mmol). The mixture was refluxed vigorously for 17 hours and water was removed using a Dean Stark trap under the reflux condenser. The resulting mixture was concentrated and purified by silica gel column chromatography to give 48.1 (9.32 g, 73.2% yield). MS ESI (pos.) M/E: 225 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH:11]O>C(O)(=O)C>[CH3:1][S:2]([C:3]1[NH:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])=[O:11]
Reactant: OO
Reactant: CSc1[nH]ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: CS(=O)c1[nH]ccc1[N+](=O)[O-]

Procedure:
A solution of 2-methylthio-3-nitropyrrole (2.5 g, 0.016 mol) in glacial acetic acid (70 ml) and hydrogen peroxide (2 ml, 0.017 mol, 100 vol) was heated at 60° for 41/2 hours. The solvent was removed in vacuo (after first checking that no peroxide remained), and the residue was recrystallised from propan-2-ol to give 2-methylsulphinyl-3-nitropyrrole (2.3 g, 85% m.p. 162°-164°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH:19]=1)[CH:17]=O>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH2:17][C:5]2[S:1][C:2]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)=[CH:3][CH:4]=2)[CH:19]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: c1csc(-c2cccs2)c1
Product: Clc1ccc(Br)cc1Cc1ccc(-c2cccs2)s1

Procedure:
2,2′-Bithiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were used and treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 369/371 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].Br[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([NH:18][C:19](=[O:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:10]([Cl:26])[CH:9]=1>C1(C)C=CC=CC=1>[Cl:26][C:10]1[CH:9]=[C:8]([N:18]2[CH2:19][CH2:20][C:5]3[C:2](=[CH:3][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=3)[CH2:1]2)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]=1[NH:18][C:19](=[O:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)CC(=O)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(=O)Nc1c(Cl)cc(N2CCc3cc(C(F)(F)F)ccc3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol), 6-trifluoro-1,2,3,4-tetrahydroisoquinoline (154 mg, 0.65 mmol) and N-(4-bromo-2-chloro-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide (200 mg, 0.54 mmol) were then added, and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid
Reaction SMILES: Cl[Si](C)(C)C.[NH2:6][C@@H:7]([CH2:11][CH2:12][CH2:13][CH:14]1[O:18][CH2:17][CH2:16][O:15]1)[C:8]([OH:10])=[O:9].S(OC)(O[CH3:22])=O>CO>[NH2:6][C@@H:7]([CH2:11][CH2:12][CH2:13][CH:14]([O:18][CH3:17])[O:15][CH3:16])[C:8]([O:10][CH3:22])=[O:9]
Reactant: COS(=O)OC
Reactant: N[C@@H](CCCC1OCCO1)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)[C@@H](N)CCCC(OC)OC
Temperature: 42 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
Under nitrogen, chlorotrimethyl silane (532 g) was added to a slurry of (S)-α-amino-1,3-dioxolane-2-pentanoic acid (380 g) and dimethyl sulfite (228 g) in methanol (4560 ml) to afford a homogeneous solution. Following the observation of an exotherm to 29° C., the solution was heated to 42° C., stirred at that temperature for 8 hours at about 22° C. for 16 hours. In process HPLC analysis showed that a 93 M % yield of product was obtained. A portion of the resulting solution containing 53.4 g of title product was cooled to -5 to -10 °C. with stirring and the apparent pH of the mixture was adjusted from -0.38 to about 8.32 by the slow careful addition of 32% methanolic potassium methoxide solution (2×100 ml). The pH of the mixture was further adjusted to 11.45 by the careful addition of potassium methoxide (16 ml) maintaining the temperature below 5° C. In process 1H NMR analysis of the product slurry indicated that the neutralization was complete. The solvent of the product slurry was exchanged with ethyl acetate (total 3160 ml) via a vacuum distillation at less than 30° C., concentrated to 400 ml volume, diluted with tert-butyl methyl ether (800 ml), cooled to 0° C., agitated for 30 minutes, and filtered. The filtrate was treated with calcium chloride dihydrate (135 g in 9 portions) until in-process GC assay indicated that ethylene glycol was absorbed by the calcium chloride dihydrate. The resulting slurry was filtered to afford a filtrate containing 49.7 g of title product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:27][C:23]1[CH:22]=[C:21]([CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CCOC(=O)c1cccc(-c2ccc(O)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cccc(-c2ccc(OCc3cccc(F)c3)cc2)n1
Yield: 76.4 %

Procedure:
A solution of ethyl 6-(4-hydroxyphenyl)-2-pyridinecarboxylate (D2, 100 mg, 0.41 mmol), 1-(bromomethyl)-3-fluorobenzene (117 mg, 0.62 mmol) and potassium carbonate (138 mg, 1.0 mmol) was stirred at 60° C. for 4 h. Then the solvent was evaporated under reduced pressure and the resulting crude material was purified by chromatography on silica gel using ethyl acetate/cyclohexanes (1:1) to afford the title compound (110 mg, 76%); MS: (ES/+) m/z: 352 [MH+], C21H18FNO3 requires 351; 1H-NMR (300 MHz, CDCl3) δ (ppm): 8.05 (d, 2H), 8.0 (m, 1H), 7.80 (d, 2H), 7.35 (m, 1H), 7.20 (m, 2H), 7.05 (d, 2H), 7.00 (m, 1H), 5.15 (s, 2H), 4.50 (q, 2H), 1.45 (t, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][C:14]1[CH:19]=[C:18]([OH:20])[C:17]2[O:21][C:22]3[C:27]([C:28]([O:30][CH2:31][C:16]=2[CH:15]=1)=[O:29])=[C:26]([O:32][CH3:33])[C:25]([C@@H:34]([OH:39])[CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:24][CH:23]=3>C(Cl)Cl>[OH:39][CH:34]([C:25]1[CH:24]=[CH:23][C:22]2[O:21][C:17]3[C:18]([O:20][S:9]([CH3:8])(=[O:11])=[O:10])=[CH:19][C:14]([CH3:13])=[CH:15][C:16]=3[CH2:31][O:30][C:28](=[O:29])[C:27]=2[C:26]=1[O:32][CH3:33])[CH2:35][CH:36]([CH3:37])[CH3:38]
Reactant: COc1c([C@@H](O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(O)c1O2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(OS(C)(=O)=O)c1O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.14 ml (1.0 mmol) of triethylamine and 86 μl (1.1 mmol) of methanesulphonyl chloride are added at 0° C. under argon to 150 mg (0.4 mmol) of penicillide (Ib) in 3 ml of methylene chloride and the mixture is stirred at 25° C. for 12 h. Acidifying to pH 2, extracting with methylene chloride, washing, drying and evaporating yields, after chromatography on silica gel Si60 in ether/petroleum ether 2:1, 75 mg (41% of theory) of colorless solid
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[Cl:9][C:10]1[C:11]([F:36])=[C:12]([CH:33]=[CH:34][CH:35]=1)[NH:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:31][CH3:32])=[C:21]([O:24][C@H:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[CH:22]=2)[N:17]=[CH:16][N:15]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:25]([O:24][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][C:20]=2[O:31][CH3:32])[N:17]=[CH:16][N:15]=[C:14]3[NH:13][C:12]2[CH:33]=[CH:34][CH:35]=[C:10]([Cl:9])[C:11]=2[F:36])[CH2:26]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCCN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of acetic anhydride (42 μl) in methylene chloride (5 ml) was added dropwise to a stirred solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-piperidin-3-yloxy]quinazoline hydrochloride (0.175 g, 0.4 mmol; prepared as described in Example 49) and diisopropylethylamine (208 μl) in methylene chloride (20 ml) at 0° C. and the mixture was stirred for 2 hours and allowed to warm to room temperature. The reaction mixture was washed with saturated sodium bicarbonate solution, dried (MgSO4), filtered and evaporated to give a white foam. This was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the desired product were combined and evaporated under vacuum to give the title product as a colourless foam (0.117 g, 66%); 1H NMR Spectrum: (DMSO d6 at 373K) 1.40-1.65 (m, 1H), 1.70-1.94 (m, 2H), 2.00 (s, 3H), 1.95-2.20 (m, 1H), 3.20-3.70 (m, 3H), 3.70-4.10 (m, 1H), 3.95 (s, 3H), 4.40-4.70 (m, 1H), 7.15-7.33 (m, 2H), 7.33-7.50 (m, 1H), 7.50-7.70 (m, 7.90 (s, 1H), 8.40 (s, 1H), 9.25 (s, 1H); Mass Spectrum: (M+H)+ 445.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:21]2[C:29]3[C:24](=[C:25]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)([CH2:19][CH3:20])[CH:17]=[O:18])=[CH:12][CH:11]=1>CS(C)=O.C1COCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:21]2[C:29]3[C:24](=[C:25]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)([CH:17]2[CH2:4][O:18]2)[CH2:19][CH3:20])=[CH:12][CH:11]=1
Reactant: CCC(C=O)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCC(c1ccc(Cl)cc1)(C1CO1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C

Procedure:
To a solution of NaH (41 mg, 0.764 mmol, 60% in oil) in DMSO (15 mL) at 0° C. was added trimethylsulfoxonium iodide (235 mg, 1.07 mmol) divided into several portions. The mixture was stirred at room temperature until the mixture became clear. To the solution of tert-butyl 1-(2-(4-chlorophenyl)-1-oxobutan-2-yl)-1H-indol-4-ylcarbamate (210 mg, 0.509 mmol), as described in Example 21 Step B, in THF (15 mL) was added the upper solution dropwise at 0° C. Then the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography with PE/EA (10/1 to 3/1, v/v) to afford the title compound as a colorless solid. LC/MS m/z=448.9[M+Na]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([O:20][C:21]2[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([O:20][C:21]2[CH:26]=[CH:25][C:24]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(Oc2ccc(OC3CCNCC3)cc2)cc1
Temperature: 0 °C
Yield: 153.8 %

Procedure:
To a solution of t-butyl-4-hydroxy-1-piperidinecarboxylate (0.40 g, 1.99 mmol) in anhydrous THF (8 mL) was added 4-(4-chloro-phenoxy)-phenol (0.58 g, 2.61 mmol) and triphenylphosphine (0.63 g, 2.40 mmol). The resulting mixture was cooled to 0° C. Diisopropylazodicarboxylate (0.47 mL, 2.43 mmol) was added portionwise over a ten minute period. The reaction mixture was warmed to ambient temperature for an hour and then heated to 47° C. for 64 h. The solvent was removed in vacuo. The crude residue was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.93 g, 100%) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([C:51]1[CH:57]=[CH:56][CH:55]=[CH:54][C:52]=1[NH2:53])[CH2:48][CH2:49][CH3:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:53][C:52]4[CH:54]=[CH:55][CH:56]=[CH:57][C:51]=4[CH2:47][CH2:48][CH2:49][CH3:50])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCCCc1ccccc1N
Product: CCCCc1ccccc1NC(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2-n-butylaniline (Aldrich) to give the title product. LC-MS (ES+) 796 [(M+H)+].
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+].[I-].[K+]>C(O)(=O)C.O>[C:12]([O:15][CH2:2][CH2:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:14])[CH3:13]
Reactant: O=C(CCCl)c1ccccc1
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCCC(=O)c1ccccc1
Temperature: 130 °C

Procedure:
To a solution of 3-chloro-1-phenylpropan-1-one (1.0 g, 5.93 mmol) in acetic acid (8 mL) was added sodium acetate (2.43 g, 29.7 mmol) and potassium iodide (100 mg). The mixture was heated in a sealed tube at 130° C. overnight. After cooling, the reaction was diluted with water (20 mL) and extracted with methylene chloride (3×20 mL). The combined organic extracts were washed with water (2×50 mL), saturated solution of sodium bicarbonate (2×50 mL) and brine (20 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The title compound was obtained (1.0 g, 88%) as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(N(C(C)C)CC)(C)C.[CH3:19][O:20][CH2:21]Cl>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:19][O:20][CH3:21]
Reactant: COCCl
Reactant: Oc1cc(F)ccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
2-Bromo-5-fluorophenol (30 g, 0.16 mol) is dissolved in dichloromethane (170 mL) and cooled to 0° C. To this solution is added diisopropylethylamine (36 mL, 0.20 mol) via syringe followed by chloromethyl methyl ether (16 mL, 0.20 mol) via an addition funnel. The solution is stirred and warmed to room temperature. After 2 h, the mixture is washed with saturated aqueous NH4Cl, water, and brine. The organic portion is dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (Biotage® Si65M, 20% AcOEt/hexane) to yield 26.1 g (71%) of the title compound as a clear colorless oil. 1H NMR 400 MHz (CDCl3) δ 7.46-7.53 (m, 1H), 6.92-6.99 (m, 1H), 6.63-6.70 (m, 1H), 5.26 (s, 2H), 3.55 (s, 3H).