Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:19]2[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(O)cc1
Reactant: N#Cc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(Oc2ncc(C#N)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 1A (1.18 g, 7.75 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (1.1 g, 7.96 mmol), 2-chlorothiazole-5-carbonitrile (CAS 51640-36-9, 1.12 g, 7.75 mmol) and then the reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (3×50 mL) and brine (50 mL). The organics were dried over magnesium sulfate, filtered, and evaporated. The product was purified via silica-gel column chromatography using dichloromethane as the eluent. The title compound was obtained as white solid (2.0 g), 1H NMR (300 MHz, CDCl3) δ ppm 7.76 (s, 1H) 7.12-7.23 (m, 2H) 6.87-7.00 (m, 2H) 4.44-4.65 (heptet, J=6.25 Hz, 1H) 1.36 (d, J=6.25 Hz, 6H), MS (DCI): m/z 261 (M+H)+.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH:8]1([SH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:15][C:16]1[N:24]=[C:23](Cl)[N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>[Cl-].[Na+].O>[NH2:15][C:16]1[N:24]=[C:23]([S:14][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: SC1CCCCC1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(SC2CCCCC2)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Yield: 84.6 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (256 mg, 6.4 mmol, 60% in mineral oil) were added cyclohexanethiol (2 ml, 16 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was heated at 100° C. for 3.5 hours. Brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtrated and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (112 mg, yield 86%).
Reaction SMILES: C[Li].[CH2:3](OCC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:23]([CH3:36])=[C:24]([CH3:35])[C:25]4[O:29][C:28]([CH3:31])([CH3:30])[C:27](=[O:32])[C:26]=4[C:33]=3[CH3:34])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>C1COCC1.O>[CH3:30][C:28]1([CH3:31])[C:27]([CH3:3])([OH:32])[C:26]2[C:33]([CH3:34])=[C:22]([N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:15][CH:14]=4)[CH2:21][CH2:20]3)[C:23]([CH3:36])=[C:24]([CH3:35])[C:25]=2[O:29]1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Reactant: CCOCC
Agent: [Li]C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(C)(O)C(C)(C)O4)CC2)cc1
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
A solution of methyllithium in diethyl ether (1.14 M, 5.60 mL, 6.38 mmol) was added dropwise to a solution of 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine (2.00 g, 5.06 mmol) obtained in Reference Example 13 in THF (20 ml) under ice cooling and the mixture was stirred for 10 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was crystallized from hexane to obtain 2.00 g (yield 96%) of the title compound. mp. 139–141° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[NH:23]1[C:27]([C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=2[CH:30]=O)=[N:26][N:25]=[N:24]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[C:27]4[NH:23][N:24]=[N:25][N:26]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1-c1nnn[nH]1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccccc4-c4nnn[nH]4)c23)c1

Procedure:
Analogously to Example 32, 521 mg (2.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine and 343 μl of acetic acid are dissolved in 50 ml of methanol and reacted with 523 mg (3.0 mmol) of 2-(tetrazol-5-yl)-benzaldehyde (Step 61.1) to form 4-(3-chloro-phenylamino)-3{[2-(tetrazol-5-yl)-phenyl]-methyleneamino}-1H-pyrazolo[3,4-d]pyrimidine. The above intermediate is reduced in 30 ml of DMEU with 16 ml (16 mmol) of DIBAL-H and the reaction mixture is hydrolyzed analogously. The DMEU solution is poured into water, adjusted to pH=3 with 1 N HCl and extracted with ethyl acetate. The organic phase yields, after washing 10× with water and 1× with brine, drying (Na2SO4), concentration by evaporation and digestion in diethyl ether, 4-(3-chloro-phenylamino)-3-[2-(tetrazol-5-yl)-benzylamino]-1H-pyrazolo-[3,4-d]pyrimidine; TLC: Rf=0.19 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=7.7; FAB-MS: (M+H)+=419.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH:18]([C:20]3[NH:29][C:28](=[O:30])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH3:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:31]1(I)[CH2:35][CH2:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].CC#N>CN(C=O)C>[CH:31]1([O:30][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([CH:18]([CH:15]3[CH2:16][CH2:17][N:12]([S:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)(=[O:10])=[O:11])[CH2:13][CH2:14]3)[CH3:19])[N:29]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: IC1CCCC1
Reactant: COc1ccc(S(=O)(=O)N2CCC(C(C)c3nc4ccccc4c(=O)[nH]3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCC(C(C)c3nc(OC4CCCC4)c4ccccc4n3)CC2)cc1
Temperature: 70 °C

Procedure:
A mixture of 2-{1-[1-(4-Methoxy-benzenesulfonyl)-piperidin-4-yl]-ethyl}-3H-quinazolin-4-one (34 mg, 0.08 mmol), cyclopentyl iodide (18 μL, 0.16 mmol), and potassium carbonate (55 mg, 0.4 mmol) in DMF (1 mL) was heated to 70° C. for 1 day. The reaction mixture was partitioned between dichloromethane and water. The organic layer was concentrated in vacuo and the residue was purified by HPLC (in the absence of TFA) to yield the product. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J=7.6 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.75 (t, J=7.0 Hz, 1H), 7.67 (d, J=8.9 Hz, 2H), 7.46 (t, J=7.5 Hz, 1H), 6.97 (d, J=8.9 Hz, 2H), 5.63 (m, 1H), 3.68 (s, 3H), 3.80 (d, J=11.6 Hz, 1H), 3.67 (dd, J=11.2, 1.6 Hz, 1H), 2.81 (quintet, J=7.3 Hz, 1H), 2.28 (t, J=11.8 Hz, 1H), 2.17 (m, 1H), 1.93 (m, 10H), 1.44 (m, 3H), 1.29 (d, J=6.9 Hz, 3H); HPLC ret. time 3.24 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 496.3 (M+1)+
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([O:18][CH:19]([CH3:21])[CH3:20])[CH:10]=2)=[CH:5][CH:4]=1.[H][H]>CO.O.[Pt]=O>[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:18][CH:19]([CH3:21])[CH3:20])[CH:10]=2)[CH2:5][CH2:4]1
Reactant: CC(C)Oc1cc(-c2cc[n+](C)cc2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]
Agent: [I-]
Solvent: O
Solvent: CO
Product: CC(C)Oc1cc(C2CCN(C)CC2)ccc1N
Yield: 96.7 %

Procedure:
A solution of 10 g of 1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodide in 280 ml of methanol is hydrogenated in an autoclave on 2.9 g of platinum oxide hydrate, at a hydrogen pressure of 15 bar and at ambient temperature for 4 h. The catalyst is removed by filtration on Clarcel and the mixture is concentrated under vacuum. The residue is taken up in 200 ml of ethyl acetate and washed with 200 ml of 1M sodium hydroxide and then with a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated under vacuum, so as to obtain 6.0 g of 4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)aniline.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27]>CN(C)C=O>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Reactant: FC(F)(F)CCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC(F)(F)F
Yield: 55 %

Procedure:
8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.5 g, 6.64 mmol), sodium carbonate (844 mg, 7.9 mmol) and 4-bromo-1,1,1-trifluorobutane (1.39 g, 7.3 mmol) were stirred in dimethylformamide (25 ml, dry) for seven days. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated and washed with hydrochloric acid (2N), brine, dried (MgSO4) and then evaporated to dryness. The crude product was triturated with ether and the solid collected by filtration to afford 8-chloro-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione as a white solid (1.23 g, 57%). m/z 337 [MH+].
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[Cl-].[Na+]>CN(C)C=O>[Si:9]([O:8][C@H:6]1[CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:3]([CH:2]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[NH2:1])[CH2:7]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC(N)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 6 h

Procedure:
To a solution of (2S,4R)-2-aminomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (5 g) and triethylamine (1.87 ml) in N,N-dimethylformamide (50 ml) was dropwise added ethyl bromoacetate (1.49 ml) at ambient temperature with stirring. The mixture was stirred at 40° C. for 30 minutes and then allowed to stand at ambient temperature for 6 hours. The reaction mixture was poured into saturated aqueous sodium chloride (100 ml) and extracted twice with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was subjected to a column chromatography on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (20:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-t-butyldimethylsilyloxy-2-[(ethoxycarbonylmethyl)-aminomethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3.52 g).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]5)=[N:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:33][N:34](C)C=O.C(N(CC)C(C)C)(C)C.CN.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>O1CCCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:23][CH2:24][N:25]([CH2:28][C:29]([NH:34][CH3:33])=[O:30])[CH2:26][CH2:27]5)=[N:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCN(CC(=O)O)CC3)nc1OCC2
Reactant: CN(C)C=O
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)CN1CCN(c2ccc3c(n2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CC1
Temperature: 25 °C

Procedure:
2-(4-(2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-yl)piperazin-1-yl)acetic acid (0.050 g, 0.00011 mol) was dissolved in N,N-Dimethylformamide (1.79 mL, 0.0231 mol) and treated sequentially with N,N-Diisopropylethylamine (0.119 mL, 0.000686 mol) 2.00 M of Methylamine in Tetrahydrofuran (0.228 mL) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.0521 g, 0.000137 mol). Stir at r.t. 2 h. Add sat. sodium bicarbonate, extract with ethyl acetate. Dry organics over sodium sulfate and concentrate to give 334, analyzed by rHPLC. MS: (ESI+)=452.2
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:8]=2/[CH:9]=[C:10]2/[C:11](=[O:16])[NH:12][C:13](=[O:15])[S:14]/2)[CH2:3]1.[CH3:22][N:23]1[CH:27]=[CH:26][N:25]=[C:24]1[C:28](O)=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:8](/[CH:9]=[C:10]2/[C:11](=[O:16])[NH:12][C:13](=[O:15])[S:14]/2)[C:7]=1[N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:28]([C:24]2[N:23]([CH3:22])[CH:27]=[CH:26][N:25]=2)=[O:29])[CH2:3]1
Reactant: Cn1ccnc1C(=O)O
Reactant: N[C@H]1CCN(c2c(Cl)cccc2/C=C2\SC(=O)NC2=O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccnc1C(=O)N[C@H]1CCN(c2c(Cl)cccc2/C=C2\SC(=O)NC2=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.1 %

Procedure:
To a 50 mL vial charged with a magnetic stir bar was added (S,Z)-5-(2-(3-aminopyrrolidin-1-yl)-3-chlorobenzylidene)thiazolidine-2,4-dione (75 mg, 0.23 mmol) (Example 86), 1-methyl-1H-imidazole-2-carboxylic acid (87 mg, 0.69 mmol), HATU (220 mg, 0.58 mmol) and dichloromethane (5 mL). Hunig's base (0.202 mL, 1.16 mmol) was then added and the mixture was stirred at rt for 4 h. The reaction was then diluted with dichloromethane and washed with water. The mixture was separated with a phase separator tube and the organic phase was evaporated to dryness. The residue was purified by reverse phase chromatography to afford the title compound as a yellow solid (21 mg, 21%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (s, 1 H) 7.51 (dd, 1 H) 7.41 (dd, 1 H) 7.18-7.27 (m, 2 H) 7.01 (s, 1 H) 4.67-4.77 (m, 1 H) 4.00 (s, 3 H) 3.63-3.75 (m, 2 H) 3.47-3.54 (m, 1 H) 3.36-3.47 (m, 1 H) 2.39-2.51 (m, 1 H) 2.14 (dd, 1 H); m/z 432.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)[Cl:20]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([C:15]([Cl:20])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccnc1Nc1cccc(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccnc1Nc1cccc(Cl)c1

Procedure:
Stirring 2-[(3-chloro-phenyl)amino]-3-pyridinecarboxylic acid (30.8 g, 124 mmol) with SOCl2 (50 mL, 680 mmol) and DMF (0.5 mL) at 25° C. for 1 hr gave a solution which deposited a precipitate. Excess thionyl chloride was evaporated, the residue was mixed with benzene, and the solvent was evaporated to give crude, solid 2-[(3-chlorophenyl)amino]-3-pyridinecarbonyl chloride which was used directly in the next step C. Collecting, washing with benzene and petroleum ether, and drying the precipitate gave 2-[(3-chlorophenyl)amino]-3-pyridinecarbonyl chloride (32 g, 96%) as a yellow solid, mp 112°-115° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH:6]=[N:7][OH:8].CN(C=O)C.[Cl:14]N1C(=O)CCC1=O>[Cl-].[Na+].O>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6](=[N:7][OH:8])[Cl:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=CC1CCCO1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ON=C(Cl)C1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
A 250 mL round-bottomed flask was charged with tetrahydrofuran-2-carbaldehyde oxime (2.0 g, 17 mmol) and DMF (100 mL). 1-Chloropyrrolidine-2,5-dione (2.3 g, 17 mmol) was added and stirred at ambient temperature overnight. The reaction was poured into 1:1 brine:water (800 mL) and extracted with EtOAc). The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated to afford tetrahydrofuran-2-carbonyl chloride oxime (2.6 g, 100%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:13][C:14]([CH3:28])([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]O)[CH2:21][CH2:20]1)=[O:18])[CH3:15]>>[CH3:15][C:14]([CH3:28])([O:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH2:1])[CH2:23][CH2:24]1)=[O:18])[CH3:13]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Product: CC(C)(C)OC(=O)N1CCN(CCOC(=O)[C@@H](N)Cc2ccccc2)CC1
Yield: 78 %

Procedure:
N-(2-Chloro-6-methylbenzoyl)-4-[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine 2-[4-[(1,1-dimethylethoxy)carbonyl]-1-piperazinyl]ethyl ester was prepared in 78% yield from N-(2-chloro-6-methylbenzoyl)4-[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine and 2-[4-[(1,1-dimethylethoxy)carbonyl]-1-piperazinyl]ethanol using the procedure described in example 129. HR MS: Obs. mass, 717.1995. Calcd. mass, 717.2013 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)=[N:13][CH:14]=[CH:15][CH:16]=2)=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:11]2[C:12]([NH:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cccnc1NCC1CCN(c2ccncc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: Clc1ccc(NCc2cccnc2NCC2CCN(c3ccncc3)CC2)cc1
Temperature: 65 °C
Yield: 62.3 %

Procedure:
A solution of N-(4-chlorophenyl)-2-[1-(4-pyridyl)piperidin-4-ylmethyl]aminopyridine-3-carboxamide (25 mg, 0.059 mmol) in THF (1 mL) was treated with lithium aluminum hydride (1.0 M in THF, 0.21 mL, 0.21 mmol). The mixture was heated at 65° C. for 4 days, cooled, diluted with methanol (5 m), and loaded onto an SCX ion exchange resin. The resin was eluted with methanol followed by 2 N NH3 in methanol and fractions containing the desired material were concentrated. The residue was triturated with EtOAc, yielding 15 mg (62%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]2[O:11][CH2:10][O:9][CH2:8][CH2:7][C:6]=2[CH:12]=1.C([Li])CCC.[CH:20](N1CCOCC1)=[O:21].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:14][O:13][C:4]1[C:5]2[O:11][CH2:10][O:9][CH2:8][CH2:7][C:6]=2[CH:12]=[C:2]([CH:20]=[O:21])[CH:3]=1
Reactant: COc1cc(Br)cc2c1OCOCC2
Reactant: O=CN1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C=O)cc2c1OCOCC2
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a solution of 420 mg of 2-bromo-4-methoxy-8,9-dihydro-5,7-dioxa-benzocycloheptene in 10 ml of THF there was added dropwise 0.7 ml of n-butyllithium (2.66 M, hexane solution) at −70° C. under a nitrogen atmosphere. After stirring at −70° C. for 10 minutes, 0.5 ml of N-formylmorpholine was added and the temperature was raised from −70° C. to 0° C. over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (235 mg) as an oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH:9]=[CH2:10].C1(C(C2C=CC=CC=2)CCP)C=CC=CC=1.[Cl:33][C:34]1[CH:60]=[CH:59][C:37]([O:38][C:39]2[C:48]3[C:43](=[CH:44][C:45](OS(C(F)(F)F)(=O)=O)=[C:46]([O:49][CH3:50])[CH:47]=3)[N:42]=[CH:41][N:40]=2)=[C:36]([F:61])[CH:35]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:60]=[CH:59][C:37]([O:38][C:39]2[C:48]3[C:43](=[CH:44][C:45]([CH:10]=[CH:9][C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:46]([O:49][CH3:50])[CH:47]=3)[N:42]=[CH:41][N:40]=2)=[C:36]([F:61])[CH:35]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: PCCC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1C=CC(=O)OC(C)(C)C
Temperature: 82.5 °C
Reaction time: 6 h
Yield: 48.7 %

Procedure:
Triethylamine (33 mg, 0.33 mmol) and tert-butyl acrylate (77 mg, 0.6 mmol) followed by diphenylpropylphosphine (3.4 mg, 0.008 mmol) and palladium(II) acetate (1.7 mg, 0.0075 mmol) were added to a solution of 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline (136 mg, 0.3 mmol) in DMF (1.5 ml) under argon. When the addition was complete the reaction flask was purged with argon. The mixture was stirred at 80-85° C. for 6 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH6 with 2M hydrochloric acid. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride followed by methylene chloride/ether (95/5). After removal of the solvent under vacuum, the solid was triturated with pentane/ether, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(2-(tert-butoxycarbonyl)vinyl)quinazoline (63 mg, 49%).
Reaction SMILES: N1C=CC=CC=1.Cl.[C:8]([O:13][CH2:14][CH2:15][NH2:16])(=[O:12])[C:9]([CH3:11])=[CH2:10].[CH2:17]=[C:18]1[O:22][C:20](=[O:21])[CH2:19]1>CN(C)C=O>[C:8]([O:13][CH2:14][CH2:15][NH:16][C:20](=[O:21])[CH2:19][C:18]([CH3:17])=[O:22])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)OCCN
Reactant: C=C1CC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCNC(=O)CC(C)=O
Temperature: 20 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
Pyridine (16 g, 0.2 mole) was added dropwise at 0° C. to a solution of 2-aminoethyl methacrylate hydrochloride (33 g, 0.2 mole) and diketene (16.8 g, 0.2 mole) in N,N-dimethylformamide (600 ml). After the addition, the solution was stirred at 20° C. for 20 hours. The solvent was then removed at low vacuum. The residue was dissolved in chloroform (1200 ml), washed with water (twice with 200 ml), dried over anhydrous magnesium sulfate and filtered. Excess solvent was then removed. Distillation of the residue gave acetoacetamidoethyl methacrylate (b.p.=113°-132° C./5μ) at a yield of 60%.