Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([C@@H:19]2[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:24]([N:21]1[CH2:22][CH2:23][C@@H:19]([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:14][N:15]=2)=[O:9])[CH2:20]1)(=[O:26])[CH3:25]
Reactant: ClCCN1CCCC1
Reactant: CC(=O)N1CC[C@@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)C1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CC[C@@H](N(C(=O)Nc2ncc(SCCN3CCCC3)s2)C2CCCCC2)C1

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-1-[1-(acetyl)-pyrrolidin-3(R)-yl]-urea, dithioerythritol and N-(2-chloroethyl)pyrrolidine.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[C:23]([CH3:25])[CH:24]=2)[C:20]#[N:21])=[O:16])[C:12]([C:26]([CH3:29])([CH3:28])[CH3:27])=[C:11]([O:30]CC2C=CC=CC=2)[N:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[C:26]([C:12]1[C:11](=[O:30])[NH:10][C:9](=[O:8])[NH:14][C:13]=1[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[C:20]#[N:21])=[O:16])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1cc(C#N)cc(C(=O)c2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
The solution of (57) (1.1 g, 2.237 mmol) in ethanol (20 ml) was stirred in the presence of 10% palladium on carbon under an atmosphere of hydrogen. After 1.5 hr., the mixture was filtered through celite pad and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, methanol:chloroform (5:95)) to afford 786 mg (quantitative) of the title compound as a white solid. m.p. 270-271° C.; 1H NMR (200 MHz, CDCl3) δ 1.00 (9H, s), 2.47 (3H, s), 7.70 (1H, s), 7.86 (1H, s), 8.02 (1H, s), 10.74 (1H, s), 11.01 (1H, s); m/z (EI) 311 (M+).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[CH:29]=[C:28](/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[OH:38])[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][C:17]1[CH:29]=[C:28](/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[OH:38])[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccccc2O)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(/C=C/c2ccccc2O)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
3.0 mL of trifluoroacetic acid suspension containing 0.17 g of tert-butyl 2-(benzamido)-4-((E)-2-(2-hydroxyphenyl)vinyl)benzoate was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, toluene was added, and the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue and a solid substance was separated by filtration to obtain 0.12 g of 2-(benzamido)-4-((E)-2-(2-hydroxyphenyl)vinyl)benzoic acid as yellow solid.
Reaction SMILES: C[Li].Br[C:4]1[CH:19]=[CH:18][C:7]2[C@:8]3([CH3:17])[C@@H:13]([CH2:14][CH2:15][C:6]=2[CH:5]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3.C([Li])(C)(C)C.CN(C)[CH:27]=[O:28]>C(OCC)C.C1COCC1.CCCCC>[CH:27]([C:4]1[CH:19]=[CH:18][C:7]2[C@:8]3([CH3:17])[C@@H:13]([CH2:14][CH2:15][C:6]=2[CH:5]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3)=[O:28]
Reactant: CN(C)C=O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Br)ccc12
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: C[C@]12CCC(=O)N[C@@H]1CCc1cc(C=O)ccc12
Reaction time: 0.5 h

Procedure:
Methyllithium (1.5 mL, 2.1 mmol of a 1.4M solution in diethyl ether) was added to (4aR)-(10bR)-8-bromo-10b-methyl-1,2,3,4,-4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (0.500 g, 1.7 mmol) in 25 mL of anhydrous THF which had been cooled in a dry ice/isopropanol bath under nitrogen, and was stirred for 15 min before addition of t-butyllithium (2.0 mL, 3.4 mmol of a 1.7M solution in pentane). After 30 min, dimethylformamide (0.4 mL) was added, and the mixture was allowed to warm to 0°, and additional dimethylformamide (0.2 mL) was added. The ice bath was removed and the reaction was quenched with 1N hydrochloric acid to make pH=2, and then the mixture was extracted with 10% isopropanol/chloroform. The combined organic extracts were washed well with water, dried over sodium sulfate, and evaporated. The resulting product was slurried in diethyl ether before recrystallizing from 50% ethyl acetate/hexane to give off-white crystals: mp 185°-189°. FD MS 243M +; Calcd for C15H17 N1O2 : C, 74.05; H, 7.04; N, 5.76. Found: C, 73.85; H, 7.11; N, 5.91.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1)[CH3:19]>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:18]([C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=2)[CH3:19])[C:10](=[O:14])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CC(Br)c1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccc(I)cc1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
To a solution of Boc-3-oxopiperazine (67 mg, 0.328 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 13 mg, 0.328 mmol). After cooling to 0° C., 1-(1-Bromo-ethyl)-4-iodo-benzene (100 mg, 0.273 mmol) was added. The ice bath was removed and the mixture stirred at RT for 2 h and then partitioned between EtOAc and a solution of NH4Cl. After separation, the aqueous phase was re-extracted twice with DCM and the combined organic extracts were washed with H2O, saturated brine, dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM/EtOac] 1:0→0:1)) to yield the title intermediate (90 mg, 0.188 mmol, 68%) as a colorless solid. HPLC: FtRet=1.276.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([C:11]1[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=1)[C:15]#[N:16])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:7]([C:11]1[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=1)[C:15]#[N:16])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccccc2)cc1C#N
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture is prepared by adding 104 grams (1.1 moles) of phenol, 173 grams (1 mole of 4-nitrophthalonitrile, and 207 grams of potassium carbonate in 1667 ml of dimethylformamide. The mixture is heated to 70° C. and mechanically stirred. Samples are taken of this reaction mixture periodically and analyzed by GLC. After five hours, the reaction is complete. The 4-phenoxyphthalonitrile is isolated by quenching the crude reaction mixture in ice water. The product is further purified by washing the crude precipitate with dilute sodium carbonate and then water. Finally the 4-phenoxyphthalonitrile is vacuum dried at 60° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][C:6]#[CH:7])[CH3:2].[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[CH:25]=[C:26](I)[S:27][C:20]=12)[NH2:14]>>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][C:6]#[C:7][C:26]1[S:27][C:20]2[C:21](=[N:22][CH:23]=[CH:24][C:19]=2[O:18][C:17]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=2[F:10])[CH:25]=1)[CH3:2]
Reactant: C#CCCN(CC)CC
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Product: CCN(CC)CCC#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Temperature: 50 °C
Yield: 6 %

Procedure:
Prepared from N,N-diethylbut-3-yn-1-amine (30 mg, 1.04 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 200 mg, 0.518 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated to 50° C. for 7 hours. The crude was purified by preparative TLC (10% MeOH/EtOAc). The product was obtained as a waxy solid (12 mg, 6%). 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=6 Hz, 1H), 7.52 (s, 1H), 7.03 (m, 1H), 6.52 (m, 3H), 3.85 (s, 2H), 2.88 (m, 2H), 2.67 (m, 6H), 1.12 (m, 6H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@@H:11]([N:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:27]=2)=[CH:22][C:21]1=[O:39])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.Cl>C(Cl)(Cl)Cl.O1CCOCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:11]([N:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)[N:27]=3)=[CH:22][C:21]2=[O:39])[CH2:10][CH2:9][OH:8])=[CH:13][C:14]=1[F:19]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(NC3CCOCC3)n2)cc1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1[C@H](CCO)c1ccc(Cl)c(F)c1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
(R)-1-(3-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)propyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.056 g, 0.098 mmol) was dissolved in chloroform (1 mL), and 4M HCl in dioxane was added. After agitating for 30 minutes, the mixture was evaporated and dried in vacuo to give (R)-1-(1-(4-chloro-3-fluorophenyl)-3-hydroxypropyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.045 g, 0.098 mmol, quantitative yield) as a solid. 1H NMR (400 MHz, CDCl3) δ 9.22 (d, J=5.0 Hz, 1H), 8.37 (d, J=5.0 Hz, 1H), 7.42 (t, J=5.0 Hz, 1H), 7.36 (s, 1H), 7.28-7.10 (m, 4H), 6.77 (d, J=5.0 Hz, 1H), 6.45 (m, 1H), 4.25 (br s, 1H), 4.20-4.00 (m, 2H), 3.80-3.42 (m, 9H), 2.55 (m, 1H), 2.20 (m, 1H), 2.02 (m, 2H), 1.82 (m, 2H); m/z (APCI-pos) M+1=459.0.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:7]2[CH2:8][CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH2:12][C:6]=2[C:5]2[CH:20]=[CH:21][C:22]([N:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)=[CH:26][C:25]3=[O:40])=[N:23][C:4]1=2>CO.CCOCC>[ClH:1].[CH3:2][N:3]1[C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[C:5]2[CH:20]=[CH:21][C:22]([N:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)=[CH:26][C:25]3=[O:40])=[N:23][C:4]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc31)CCNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
1.25 M HCl in MeOH (3.2 mL) was added to tert-butyl 10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (55 mg, 0.10 mmol), and the resulting solution was stirred under N2 at ambient temperature for 18 h. The solution was diluted with MeOH (2.2 mL) and Et2O (25 mL), and the resulting solids were collected by filtration to provide the title compound (37 mg, 76%) as a yellow powder: mp 320-325° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 9.28 (s, 2H), 9.21 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.5, 2.0 Hz, 1H), 8.10-8.04 (m, 3H), 7.41 (d, J=8.0 Hz, 2H), 7.03 (d, J=1.5 Hz, 1H), 6.85 (dd, J=7.5, 3.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 3.76 (s, 3H), 3.41-3.40 (m, 2H), 3.33-3.31 (m, 2H, overlaps with solvent), 3.17 (t, J=5.5 Hz, 2H); ESI MS m/z 440 [M+H]+; HPLC (Method A) 99.0% (AUC), tR=13.6 min.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[S:11][CH:10]=[N:9][C:8]=3[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.I[C:14]1[C:15]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2)=[N:16][C:17]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:18][C:19]=1[O:20][CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:1]1([C:4]2[C:12]3[S:11][C:10]([C:14]4[C:15]([NH:28][C@@H:29]5[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]5)=[N:16][C:17]([N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)=[N:18][C:19]=4[O:20][CH3:21])=[N:9][C:8]=3[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1I
Reactant: c1cc(C2CC2)c2scnc2c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cccc(C3CC3)c2s1

Procedure:
Following the same procedure as in step 3 of Example 337 using 7-cyclopropyl-1,3-benzothiazole (61.4 mg, 0.35 mmol, 1.80 equiv), tert-butyl (3R)-3-[[5-iodo-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (100.0 mg, 0.19 mmol, 1.00 equiv) and cesium carbonate (370 mg, 1.14 mmol, 6.00 equiv), Pd(PPh3)4 (40.4 mg, 0.03 mmol, 0.18 equiv) and copper (I) iodide (6.7 mg, 0.04 mmol, 0.18 equiv) in DMF (6 mL). The crude product was purified by flash chromatography on silica gel, eluting with petroleum ether/ethyl acetate (15:1-5:1) to provide the title compound as a light yellow solid. MS m/z [M+H]+ (ESI): 567.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.[C:14]([O:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)CCl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:22][CH2:21][CH2:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:23])=[O:10])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1

Procedure:
4-Acetylbenzoic acid (2.45 g, 14.9 mmol), beta-alanine t-butyl ester hydrochloride (4.0 g, 22 mmol), DIEA (3.9 ml, 22 mmol) and DMAP (100 mg) were dissolved in DCM (100 ml). EDC hydrochloride (3.5 g, 18 mmol) was added in portions. Additional EDC (0.7 g) was added one hour later to complete the reaction. After a total of 3 hours, the reaction was partitioned between ethyl acetate and 0.5 N HCl. The organic layer was washed with 0.5 N HCl 3×, 5% K2CO3 2×, brine 2×. Evaporation of solvent, and chromatography over SiO2 (10-20% ethyl acetate in DCM) afforded tert-butyl N-(4-acetylbenzoyl)-β-alaninate as a while solid. NMR (500 MHz, CD3OD) δ: 1.44 (s, 9H); 2.57 (t, J=7.0 Hz, 2H); 2.63 (s, 3H); 3.61 (t, J=7.0 Hz, 2H); 7.89 (d, J=8.5 Hz, 2H); 8.05 (d, J=8.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16](=[O:17])[CH2:15][N:14]([CH2:12][CH3:13])[C:10]1=[S:11]
Reactant: Cc1ccc(N=C=S)c(Cl)c1
Reactant: CCNCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccc(C)cc2Cl)C1=S
Yield: 21.7 %

Procedure:
The title compound was prepared by the procedure described in Example 28 using 18.3 g of 2-chloro-4-methylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethyl acetate afforded the title compound (5.8 g) as a peach solid, m.p. 126°-128° C. Anal. Calcd. for. C12H13Cl N2O S: C, 53.63; H, 4.88; N, 10.42. Found: C, 53.50; H, 4.76; N, 10.28. Mass spectrum (+FAB, IM+H]+) m/z 269/271.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH2:21][CH:20]([N:22](OC)[CH3:23])[CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1>C(O)(=O)C.O.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH2:21][CH:20]([NH:22][CH3:23])[CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:26][CH:27]=1
Reactant: CON(C)C1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CNC1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)C1

Procedure:
To a solution of crude N-(4-fluorobenzyl)-3-hydroxy-8-[methoxy(methyl)amino]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide in acetic acid/water (2:1) was added zinc dust (300% in weight). The mixture was stirred at room temperature and after 1.5 h further zinc dust (300% in weight) was added. After 24 h zinc was filtered off and the filtrate was concentrated to dryness. The residue was dissolved in methanol and applied on a SCX resin cartridge. The cartridge was washed with water and methanol and then eluted with ammonia in methanol (2N). The eluent was concentrated to dryness. The crude product so obtained was used in the subsequent step without further purification.
Reaction SMILES: C([N:8]1[C:12]([CH:13]([OH:29])[CH2:14][CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[NH:10]1[CH:11]=[C:12]([CH:13]([OH:29])[CH2:14][CH2:15][CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:8]=[CH:9]1
Reactant: OC(CCC(c1ccccc1)c1ccccc1)c1cncn1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: OC(CCC(c1ccccc1)c1ccccc1)c1c[nH]cn1

Procedure:
3.0 g of 1-(3-benzyl-3H-imidazol-4-yl)-4,4-diphenylbutan-1-ol was dissolved in 150 ml of ethanol. The solution was hydrogenated at 45° C. with 10% palladium on carbon as catalyst for 5 hours. The reaction mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:18])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[OH:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:18][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([OH:25])[CH:27]=2)[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)C(C)C)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](NC(=O)c3cccc(O)c3)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate (Example 95b) and 3-hydroxybenzoic acid as brown solid (35%). MS 452 (MH+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].ClN([C:25]1[C:34]2[C:29](=[CH:30][C:31](O)=[C:32](OC)[CH:33]=2)[N:28]=[CH:27][N:26]=1)C1C=CC=CC=1F.N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:27]1[N:26]=[CH:25][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc2c(N(Cl)c3ccccc3F)ncnc2cc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ncc2ccccc2n1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
Trifluoromethanesulphonic anhydride (0.55 ml, 3.3 mmol) was added to a stirred suspension of 4-(chloro-2-fluoroanilino)-7-hydroxy-6methoxyquinazoline (959 mg, 3 mmol), (prepared as described for the starting material in Example 2), in methylene chloride (2.2 ml) and pyridine (2.2 ml) under argon at 0° C. The reaction mixture was stirred for 1 hour at 0° C., allowed to warm to ambient temperature and stirred for a further 1.5 hours. The volatiles were removed by evaporation, the residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether/petroleum ether to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(trifluoromethylsulphonyloxyquinazoline (270 mg, 60%) as a beige solid.
Reaction SMILES: C(OC1CCN([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)CC1)(=O)C.BrC1C=CC([O:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=CC=1>CCOC(C)=O.O>[CH3:38][N:35]1[CH2:36][CH2:37][CH:32]([O:31][C:11]2[CH:12]=[CH:13][C:14]([B:17]3[O:18][C:19]([CH3:24])([CH3:25])[C:20]([CH3:22])([CH3:23])[O:21]3)=[CH:15][CH:16]=2)[CH2:33][CH2:34]1
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CN1CCC(Oc2ccc(Br)cc2)CC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCC(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate, except substituting 4-(4-bromophenoxy)-1-methylpiperidine (300 mg, 1.11 mmol). The reaction was then allowed to cool to rt and was diluted with EtOAc and water was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated to give the crude product. Crude product was purified by flash chromatography using MeOH/CH2Cl2 (2:98 to 15:85) to give the title compound as a brown solid (200 mg, 57%). 1H NMR (400 MHz, CD3OD) δ 7.68 (d, J=7.6 Hz, 2H), 6.94 (d, J=7.7 Hz, 2H), 4.53 (br s, 1H), 2.94-2.91 (m, 2H), 2.58-2.50 (m, 2H), 2.40 (s, 3H), 2.18-2.00 (m, 2H), 1.93-1.78 (m, 2H), 1.34 (m, 12H); MS ESI 318.1 [M+H]+, calcd for [C18H28BNO3+H]+ 318.22.
Reaction SMILES: C(OC([N:8]([C:40](OC(C)(C)C)=O)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH2:37][CH3:38])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.N1C[CH2:51][O:50][CH2:49][CH2:48]1>>[CH2:37]([C:33]1[CH:34]=[C:35]([CH3:36])[C:30]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]3[CH2:40][CH2:51][O:50][CH2:49][CH2:48]3)=[O:39])=[O:23])[CH2:25][CH2:26]2)=[N:31][CH:32]=1)[CH3:38]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: C1COCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N3CCOCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 809 and morpholine (41 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (19 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.CS(C)=O.[Cl-]>C1COCC1>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=3)[CH:5]=[CH:4][N:3]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(F)cc1
Reactant: Nc1ncc(-c2ccnc(Cl)n2)cn1
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccnc(Nc3ccc(F)cc3)n2)cn1
Temperature: 150 °C
Yield: 12.7 %

Procedure:
To a suspension of 2-chloro-4,5′-bipyrimidin-2′-amine (30) (110 mg, 0.530 mmol) in THF (5298 μl), 4-Fluoroaniline (100 μl, 1.060 mmol) was added. DMSO (1 mL) was added to dissolve the starting chloride, and the suspension was heated to 150° C. in the microwave for 2 hours. The crude reaction mixture was filtered through a syringe filter, then purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] to obtain a reddish purple product. The product was triturated with acetone and acetonitrile, then filtered to obtain a slightly gray solid as the desired product (19 mg, 13% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.15 (t, J=9.09 Hz, 2 H) 7.22 (s, 2 H) 7.31 (d, J=5.05 Hz, 1 H) 7.79 (dd, J=9.09, 5.05 Hz, 2 H) 8.44 (d, J=5.05 Hz, 1 H) 8.99 (s, 2 H) 9.59 (s, 1H). HRMS (ES+) for C14H11FN6.H+ [MH+]: calcd, 283.1107. found, 283.1108. UV-LC: 100/100% UV purity at 214/254 nm; tR=1.07 minutes over 7.75 minutes.