Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].CC([O-])=O.[K+].[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][N:22]([CH2:42][C:41]6[CH:44]=[CH:45][C:38]([F:37])=[CH:39][CH:40]=6)[CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]=1[OH:31]
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCN(Cc4ccc(F)cc4)C5)n[nH]c3c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.35 %

Procedure:
To a solution of 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (Preparation 39, 100 mg, 0.21 mmol) and KOAc (22.75 mg, 0.23 mmol) in MeOH (1 mL), 4-fluorobenzaldehyde (57.54 mg, 0.46 mmol) was added and the mixture stirred at room temperature for 1 hr followed by portionwise addition of sodium triacetoxy borohydride (162.12 mg, 0.76 mmol) over 2 hrs. The mixture was thereafter stirred at room temperature for 18 hrs. The reaction mixture was concentrated and the residue partitioned between saturated sodium bicarbonate solution & ethyl acetate. The organic phase was dried over sodium sulphate, evaporated in vacuo, purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOH-DCM) to afford the title compound as a light yellow solid in 30.35% yield, 35 mg.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C@@H:5]([OH:8])[CH2:6][OH:7].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:9][S:10]([O:7][CH2:6][C@H:5]([O:8][S:10]([CH3:9])(=[O:12])=[O:11])[CH2:4][CH2:3][S:2][CH3:1])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CSCC[C@@H](O)CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CSCC[C@H](COS(C)(=O)=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(R)-4-(Methylthio)-1,2-butanediol (0.47 g, 3.4 mmol) was dissolved in 5 ml of pyridine and cooled to 0° C. Methanesulfonyl chloride (0.66 ml, 8.5 mmol) was added and the mixture stirred for 2 hours while warming to room temperature, by which time tlc (ethyl acetate) indicated complete conversion of starting material (Rf 0.4) to title product (Rf 0.85). The reaction mixture was diluted with 10 ml H2O and extracted 2×15 ml of ethyl acetate. The organic layers were combined, dried (MgSO4) and stripped to in vacuo to yield title product an an oil, all of which was used in the next step; tlc Rf 0.85 (ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[CH3:77][O:78][C:79]1[CH:85]=[CH:84][CH:83]=[CH:82][C:80]=1[NH2:81]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:81][C:80]4[CH:82]=[CH:83][CH:84]=[CH:85][C:79]=4[O:78][CH3:77])[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccccc1N
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccccc4OC)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 115 °C
Reaction time: 15 h
Yield: 31.8 %

Procedure:
In a dry tube under an atmosphere of argon to a solution of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(4R,5R)-4-(5-bromo-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.3) (150 mg, 247 μmol) in dioxane (5 ml) was added consecutively sodium tert-butoxide (26.1 mg, 272 μmol), 2-di-tert-butylphosphino-2′4′,6′-triisopropylbiphenyl (10.5 mg, 24.7 μmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (7.9 mg, 7.41 μmol), and 2-methoxyaniline (60.8 mg, 55.7 μl, 494 μmol). The tube was sealed and heated 115° C. under stirring during 15 hours. For the workup, the reaction mixture was evaporated at reduced pressure, and the residue was purified by chromatography on a silica-NH2 phase using a gradient of heptane/ethyl acetate=100:0 to 60:30 as the eluent. The [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(4R,5R)-5-fluoro-4-[2-fluoro-5-(2-methoxy-phenylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-amine (51 mg, 32% yield) was obtained as a pale yellow foam. MS (ISP): m/z=650.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:22](OCC)=[O:23])=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([CH2:22][OH:23])=[C:10]3[N:14]([C:15]=2[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[CH2:13][CH2:12][CH2:11]3)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)c(-c2ccncc2)n2c1CCC2
Solvent: C1CCOC1
Product: OCc1c(-c2ccc(F)cc2)c(-c2ccncc2)n2c1CCC2

Procedure:
Ethyl 2-(4-fluorophenyl)-3-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate (example 19A, 0.15 g, 0.43 mmol) is dissolved under argon in abs. THF (4 ml) and sodium dihydrido-bis(2-methoxy-ethoxy)aluminate solution (VitrideR, 70% in toluene, 0.9 ml, 4.5 mmol) is added dropwise in 4 portions at 40° C. with exclusion of moisture at in each case an interval of 1 hour. 1 h after the last addition, starting material can no longer be detected by tlc (Al2O3— ethyl acetate/n-hexane 3:7).
Reaction SMILES: CO[C:3](=[O:23])[C:4]([OH:22])=[CH:5][C:6](=[O:21])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:32][N:33](C)[C:34](C1CN(C)C(=O)C=1O)=O>>[C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]2[CH2:32][N:33]([CH3:34])[C:3](=[O:23])[C:4]=2[OH:22])=[O:21])=[CH:16][CH:15]=1)(=[O:20])[CH3:19]
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(NC(C)=O)cc1)OC
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(NC(C)=O)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 43 %

Procedure:
3-[(4-Acetylaminobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 63-D) was treated with paraformaldehyde and methylamine as described in the preparation Compound 12 to give the title compound as a white solid (43% yield); mp 110° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.18 (3H, s, COCH3), 3.1 (3H, s, NCH3), 3.71 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.83 (2H, s, NCH2), 7.29 (2H, d, J=8.6 Hz, aromatics), 7.34 (1H, broad s, NH), 7.50 (2H, d, J=8.6 Hz, aromatics). HRMS (ES+) calculated for C16H20N3O5: [M+H]+: 334.140296. found: 334.139137.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].[I:12]N1C(=O)CCC1=O>CN(C)C=O>[I:12][C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5](=[O:9])[NH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc[nH]c(=O)c1C#N
Solvent: CN(C)C=O
Product: COc1c(I)c[nH]c(=O)c1C#N
Temperature: 70 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a mixture of 4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (3.00 g) and N,N-dimethylformamide (70 mL) was added N-iodosuccinimide (5.84 g) at room temperature, and the mixture was stirred at 70° C. for 16 hr. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. To the residue was added methanol, and the precipitate was collected by filtration to give the title compound (4.60 g).
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[N:11](COCC[Si](C)(C)C)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])[C:8]2=[CH:7][N:6]=1.Cl>>[F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])[C:8]2=[CH:7][N:6]=1
Reactant: Cc1cc(O)ccc1-c1nn(COCC[Si](C)(C)C)c2nc(Oc3ccc(F)cc3F)ncc12
Agent: Cl
Product: Cc1cc(O)ccc1-c1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12

Procedure:
4-[6-(2,4-Difluoro-phenoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3-methyl-phenol was treated with HCl using the procedure described in step 8 of Example 11 to afford 0.20 g of 4-[6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3-methyl-phenol. Mass Spec. M+H=355.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.[CH3:13][O:14][C:15](=[O:30])[C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>CO.C(Cl)(Cl)Cl>[CH3:13][O:14][C:15](=[O:30])[C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1ccccn1

Procedure:
Following General Procedure C and using 2-pyridylacetic acid hydrochloride (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester hydrochloride (Sigma) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=137-139° C.). The reaction was monitored by tlc (Rf=0.4 in 8% MeOH/CHCl3) and the product was purified by silica gel chromatography using 8% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:13]1)=[O:11].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]([O:27][C:28]([N:30]1[CH2:31][CH:32]=[C:33]([C:21]2[C:16]([CH:14]3[CH2:15][N:12]([C:10]([C:2]4[NH:3][C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[N:1]=4)=[O:11])[CH2:13]3)=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:34][CH2:35]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(c1nc2ccccc2[nH]1)N1CC(c2nccnc2Cl)C1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2nccnc2C2CN(C(=O)c3nc4ccccc4[nH]3)C2)CC1
Yield: 80 %

Procedure:
To a mixture of (1H-Benzoimidazol-2-yl)-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-methanone (188 mg, 0.6 mmol) in 1,4-dioxane/water (5:1, 12 mL) was added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (278 mg, 0.9 mmol), K3PO4 (254 mg, 1.2 mmol) and Pd(dppf)Cl2 (44 mg, 0.06 mmol). The mixture was refluxed overnight. The reaction mixture was filtered and concentrated. The residue was purified by ISCO silica gel column (10% to 80% EtOAc in petroleum ether) to give 4-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (221 mg, 0.48 mmol, yield 80%). ESI-MS (M+1): 461 calc. for C25H28N6O3 460.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>C(O)C>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[O:7][CH:15]=1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: Fc1ccc(-c2nc(CCl)co2)cc1
Yield: 28.3 %

Procedure:
4-Fluorobenzamide (10.0 g) and 1,3-dichloroacetone (9.5 g) were dissolved in ethanol (100 mL), and the mixture was refluxed for 8 hr. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 7:1) to give the title compound (4.3 g) as a white solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[Cl:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=1>CCCCCC.C(OCC)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:21]=[C:20]([S:24][CH3:25])[N:19]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CSc1nccc(Cl)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CSc1nc(Cl)cc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
31.3 ml 1.6M n-butyllithium in hexane are added at −70° C. to a solution of 11.25 g 4-bromo-benzotrifluorid in 50 ml diethylether. After stirring for 15 min. the solution is warmed to −30° C. and added to a −30° C. cold solution of 8.0 g 4-chloro-2-methylthio-pyrimidine in 50 ml ether. The mixture is stirred for 30 min. at −30° C. and another 30 min. at 0° C., then quenched with a mixture of 3.2 ml acetic acid, 0.5 ml water and 10 ml tetrahydrofuran (THF). Immediately after quenching, a solution of 11.8 g dichlorodicyanobenzoquinone (DDQ) in 50 ml THF is added and stirring is continued for 5 min. at room temperature. It is again cooled to 0° C. and 20 ml 10% aqueous sodium hydroxide are added. After stirring for 5 min. at 0° C. the organic layer is separated, dried and chromatographed to yield 10.3 g of the title compound (m.p. 93-96° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[CH:25]=[C:24]1[CH3:33]>>[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[C:25]([CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:24]1[CH3:33]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1ccccc1S(=O)(=O)c1ccc(F)cc1
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccc(F)cc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 27c using 2-(4-fluorobenzenesulfonyl)benzaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>CN1C(=O)CCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=3)[N:3]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ccc2nc(Cl)nc(N3CCOCC3)c2c1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(N3CCOCC3)c3cc(Cl)ccc3n2)CC1
Yield: 42 %

Procedure:
A mixture of 2,6-dichloro-4-morpholin-4-yl-quinazoline (0.9 g, 3.17 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.27 g, 6.33 mmol, 2.0 equiv; commercially available) in anhydrous NMP (8 mL) and triethylamine (2 mL) was heated by microwave irradiation to 170° C. for 1 h. The organic phase was concentrated under reduced pressure and the residue extracted with dichloromethane (3×50 mL) from a sat. solution of sodium bicarbonate (100 mL). The combined organic phases were dried over MgSO4 and the product purified by column chromatography on silica eluting with a gradient of toluene/ethyl acetate (4:1→2:1) providing 0.6 g (42%) of the title compound. MS (ISP): 448.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([NH2:15])=O)[C:7](=[CH:11][CH:12]=1)[C:8]([NH2:10])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.Cl>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([C:13]#[N:15])[C:7](=[CH:11][CH:12]=1)[C:8]#[N:10])([O-:3])=[O:2]
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1C(N)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc([N+](=O)[O-])cc1C#N

Procedure:
4-nitrophthalamide (220g; 1.05 moles) is suspended in pyridine (840 ml). Into this vigorously stirred suspension, phosphorus oxychloride (220 ml; 2.40 moles) is added at such a rate that the reaction maintains a temperature range of 65°-70° C during the 30 minute addition time. The same temperature is maintained an additional hour by external heating. The resulting mixture is neutralized with 12 N hydrochloric acid (150 ml). The purple solid is collected by filtration and dried. The residue is extracted with ethyl acetate (3 × 700 ml) and the purple extract is decolorized with activated charcoal, washed first with 0.4 N sodium hydroxide saturated with sodium chloride (3 × 70 ml) and then with water (4 × 70 ml). Drying and evaporation of the extract leaves 91g of II as pale yellow crystals; yield, 50%, mp 142°-144° C; lit. (7) mp 138°-139° C; lit. (4) 142° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1.S(Cl)([Cl:29])=O>C1(C)C=CC=CC=1>[Cl:29][CH2:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Solvent: Cc1ccccc1
Product: COc1cc(CCl)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Yield: 97.8 %

Procedure:
To a mixture of 3-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (10.0 g) and toluene (200 mL) was added thionyl chloride (3.74 g), and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated and ethyl acetate was added to the residue. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (10.3 g, yield 98%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 150-151° C.
Reaction SMILES: [Cl:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[C:3](Cl)=[O:4].N1C=CC=CC=1.[CH:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH2:18]>ClCCl>[CH2:20]([O:19][CH:17]=[CH:18][C:3](=[O:4])[C:2]([Cl:1])([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:21][CH2:22][CH3:23]
Reactant: C=COCCCC
Reactant: O=C(Cl)C(F)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOC=CC(=O)C(F)(Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 15 h

Procedure:
With stirring and at 0° C., 9.59 g (48.2 mmol) of 2-chlorotetrafluoropropionyl chloride were added dropwise to a mixture of 4.19 g (50.0 mmol) of pyridine and 4.83 g (48.2 mmol) of butyl vinyl ether in 75 ml of dichloromethane. After the addition, stirring was continued at room temperature for another 15 h. The mixture was then washed with 1N hydrochloric acid and 2×100 ml of water, and the organic phase was separated off, dried and concentrated. This gave 6.33 g (50% of theory) of a brown oil.
Reaction SMILES: [Br:1]CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:26]1>>[Br:1][CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:26]1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCCO)C1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Product: O=C(OCc1ccccc1)N1CCCC(CCCBr)C1

Procedure:
Prepared similarly to Intermediate 30 from phenylmethyl 3-(3-hydroxypropyl)-1-piperidinecarboxylate.
Reaction SMILES: C([O:5][C:6]([CH:8]([NH:35]C(=O)OC(C)(C)C)[CH2:9][O:10][P:11]([OH:34])(=[O:33])[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:32])[CH2:21][CH2:22][CH:23]([P:28](=[O:31])([OH:30])[OH:29])[P:24]([OH:27])([OH:26])=[O:25])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:35][CH:8]([C:6]([OH:7])=[O:5])[CH2:9][O:10][P:11](=[O:33])([OH:34])[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:32])[CH2:21][CH2:22][CH:23]([P:24]([OH:26])([OH:27])=[O:25])[P:28](=[O:29])([OH:30])[OH:31]
Reactant: CC(C)(C)OC(=O)NC(COP(=O)(O)OCCCCCCNC(=O)CCC(P(=O)(O)O)P(=O)(O)O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: NC(COP(=O)(O)OCCCCCCNC(=O)CCC(P(=O)(O)O)P(=O)(O)O)C(=O)O

Procedure:
60 mg of 16-(tert-butoxycarbonyl)-13-hydroxy-20,20-dimethyl-13-oxido-4,18-dioxo-1-phosphono-12,14,19-trioxa-5,17-diaza-13-phosphahenicos-1-yl-phosphonic acid are stirred in 1 ml of TFA for 2 hours.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:14])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9].[CH3:15][O:16][CH2:17]Cl>CN(C)C=O.C(OCC)C>[CH3:15][O:16][CH2:17][O:14][C:6]1[CH:5]=[C:4]([CH3:3])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(C)cc1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCOc1cc(C)ccc1C(=O)OC
Reaction time: 0.25 h
Yield: 112.3 %

Procedure:
To a suspension of sodium hydride (1.62 g, 0.0675 mol) in 90 mL of dimethylformamide was added dropwise a solution of methyl 4-methylsalicylate (10.2 g, 0.0614 mol) in 20 mL of diethyl ether. After stirring for 15 minutes, a solution of chloromethyl methyl ether (5.6 mL, 0.0737 mol) in 10 mL of diethyl ether was added. The reaction mixture was stirred at room temperature for 18 hours and then it was partitioned between water and diethyl ether. The layers were separated and the aqueous layer was extracted an additional three times with diethyl ether. The combined organic extracts were washed with brine, dried with magnesium sulfate, and concentrated in vacuo to give 14.5 g of an oil. The product was purified by flash chromatography on silica gel eluting with 10%-15% ethyl acetate in hexane to give 9.41 g (73%) of product as an oil.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30](=O)[CH2:31][CH3:32]>>[CH2:31]([C:30]1[N:26]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:27][CH:29]=1)[CH3:32]
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CCC(=O)CBr
Product: CCc1csc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
220 mg (about 0.384 mmol) of the compound from Example 53A and 70 mg (0.460 mmol) of 1-bromobutan-2-one were reacted according to the General Method 3. Yield: 63 mg (36% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[N:4]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: S=C=Nc1ccc(Cl)cc1Cl
Yield: 63.5 %

Procedure:
The title compound was prepared following the procedure described for intermediate-2 using 2,4-dichloro aniline (5.0 g, 30.86 mmol), thiophosgene (3.54 g, 30.86 mmol) and N-ethyl di-isopropyl amine (7.94 g, 61.55 mmol) to afford 4.0 g of the desired product. 1HNMR (CDCl3): δ 7.39 (s, 1H), 7.39-7.12 (m, 2H).