Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:7][C:8]1[NH:13][C:12]2=[N:14][CH:15]=[CH:16][C:11]2=[CH:10][N:9]=1)(=O)C(C)(C)C.C(Cl)Cl>CCO.[Cl-].[Cl-].[Zn+2]>[NH2:7][C:8]1[NH:13][C:12]2=[N:14][CH:15]=[CH:16][C:11]2=[CH:10][N:9]=1
Reactant: CC(C)(C)C(=O)Nc1ncc2ccnc-2[nH]1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCO
Product: Nc1ncc2ccnc-2[nH]1

Procedure:
A suspension of 2-(pivaloylamino)-pyrrolo[2,3-d]pyrimidine and ZnCl2 (3-20 equiv.) in wet EtOH (5 vol % water) was heated to 80 AC, and monitored by HPLC. When the reaction reached completion, DCM was added, and the organic layer was washed with sat. aq. NaHCO3 and brine. Drying (Na2SO4) and concentration afforded the desired 2-amino-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[N:21][C:20]=1[CH3:34]>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[S:23][C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)=[N:21][C:20]=2[CH3:34])[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1Cn1c(C)cc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 5-(chloromethyl)-4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole: 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), 7.52 (d, J=7.8 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 6.65 (s, 1H), 5.46 (s, 2H), 2.60 (s, 3H), 2.53 (s, 3H); MS (ES) m/z 480 (M+1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([N:17]([S:34]([C:31]3[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:33][CH:32]=3)(=[O:35])=[O:36])[S:34]([C:31]3[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=3)(=[O:36])=[O:35])=[N:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)Oc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2cnc(N(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)S(=O)(=O)c3ccc([N+](=O)[O-])cc3)c(Cc3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
Under an argon atmosphere, 5-(4-acetoxyphenyl)-2-amino-3-benzylpyrazine (c-19) (140 mg, 438 μmol) was dissolved in pyridine (2 mL) and to this was added 4-(dimethylamino)pyridine (6.0 mg, 49 μmol). To this was added p-nitrobenzenesulfonyl chloride (293 mg, 1.32 mmol) while stirring at room temperature and stirred for 1.5 h at the same temperature. To this was further added p-nitrobenzenesulfonyl chloride (195 mg, 880 μmol) and stirred for 17 h. To this was added saturated aqueous solution of sodium bicarbonate to stop the reaction and the product was extracted twice with dichloromethane. The organic layer was washed once with water and once with saturated aqueous solution of sodium sulfate and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (24 g, n-hexane/ethyl acetate=4/1→3/1→7/3→ethyl acetate alone) to give 5-(4-acetoxyphenyl)-3-benzyl-2-bis(4-nitrophenylsulfonyl)aminopyrazine (c-40) as a dark brown solid (157 mg, 52.1%). Rf=0.62 (n-hexane/ethyl acetate=3/2). Mp. 227-229.5° C. (dec.). UV (MeOH, 0.3% DMSO) λmax (log ε) 309 (3.99), 258 (4.21). 1H NMR (400 MHz, DMSO-d6) δ 2.30 (s, 3H), 4.22 (s, 2H), 7.19-7.27 (m, 1H), 7.29-7.35 (m, 6H), 8.05-8.10 (AA′BB′, 4H), 8.14-8.19 (AA′BB′, 2H), 8.39-8.44 (AA′BB′, 4H), 9.13 (s, 1H). 13C NMR. (75.5 MHz, DMSO-d6) δ 20.9, 38.0, 122.8 (2C), 124.8 (2C×2), 126.6, 128.3 (2C), 128.7 (2C), 129.6 (2C), 130.7 (2C×2), 131.9, 137.3, 139.8, 140.3, 142.1 (1C×2), 151.1 (1C×2), 151.9, 152.7, 156.2, 169.0. I,R (KBr, cm−1) 548, 598, 617, 687, 737, 775, 810, 854, 880, 897, 916, 935, 1013, 1165, 1180, 1206, 1315, 1348, 1368, 1385, 1404, 1418, 1435, 1530, 1603, 1755, 3107. HRMS (FAR) m/z 690.0975 (M+H, C31H24N5O10S2 requires 690.0965).
Reaction SMILES: O1CCCC1.[CH3:6][S:7]([C:10]1[N:15]=[C:14]([CH3:16])[C:13]([C:17]([O:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:18])=[CH:12][N:11]=1)(=O)=O.[C:27]1(S)[CH:32]=[CH:31]C=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:16][C:14]1[C:13]([C:17]([O:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:18])=[CH:12][N:11]=[C:10]([S:7][C:6]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)[N:15]=1
Reactant: CC(CCOC(=O)c1cnc(S(C)(=O)=O)nc1C)=C(F)F
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CCOC(=O)c1cnc(Sc2ccccc2)nc1C)=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To 5 ml of tetrahydrofuran were dissolved 0.56 g (1.8 mmol) of 4,4-difluoro-3-methyl-3-butenyl 2-methanesulfonyl-4-methylpyrimidine-5-carboxylate and 0.21 g (1.9 mmol) of thiophenol, followed by the addition of 0.30 g (2.8 mmol) of sodium carbonate and stirring at room temperature for 1 hour. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:8) to obtain 0.54 g (yield: 88%) of 4,4-difluoro-3-methyl-3-butenyl 4-methyl-2-(phenylthio)pyrimidine-5-carboxylate.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)[C:7]([CH:29]=[CH:30][CH2:31][CH2:32][CH3:33])=[C:6]([CH:34]([CH3:36])[CH3:35])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:16]=2)[C:7]([CH:29]=[CH:30][CH2:31][CH2:32][CH3:33])=[C:6]([CH:34]([CH3:35])[CH3:36])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1cccc(OCc2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(OCc2ccccc2)c1

Procedure:
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): δ 0.74 (t, J=7.4 Hz, 3 H), 1.25 (m, 14 H), 1.90 (m, 2 H), 3.39 (m, 2 H), 4.39 (d, J=6.0 Hz, 2 H), 5.07 (s, 2 H), 5.32 (m, 1 H), 5.97 (m, 1 H), 6.74 (m, 2 H), 6.95 (m, 1 H), 7.35 (m, 7 H). FAB-MS: calculated for C30H37NO2, 444; found 444 (M+H, 100%). Elemental analysis: calculated for C30H37NO2: C 81.22; H 8.41; N 3.16, found: C 80.51; H 8.41; N 3.36. Rf 0.5 (25% ethyl acetate/n-hexane).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH3:52])[CH2:11][O:12][N:13]=[C:14]([C:18]1[N:19]=[C:20]([NH:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:21][CH:22]=1)[C:15](O)=[O:16].[NH2:53][CH:54]1[C:79](=[O:80])[N:56]2[C:57]([C:63]([O:65][CH:66]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[O:64])=[C:58]([CH2:61][Cl:62])[CH2:59][S:60][C@H:55]12.CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>>[Cl:62][CH2:61][C:58]1[CH2:59][S:60][C@@H:55]2[CH:54]([NH:53][C:15](=[O:16])[C:14](=[N:13][O:12][CH2:11][C:10]3[CH:43]=[CH:44][C:45]([O:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH3:52])=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:9]=3)[C:18]3[N:19]=[C:20]([NH:23][C:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[S:21][CH:22]=3)[C:79](=[O:80])[N:56]2[C:57]=1[C:63]([O:65][CH:66]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1)=[O:64]
Reactant: COCCOCOc1ccc(CON=C(C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1OCOCCOC
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COCCOCOc1ccc(CON=C(C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1OCOCCOC
Reaction time: 0.5 h

Procedure:
1.0 g (1.4 mmol) of 2-[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino]-2-(2-tritylaminothiazol-4-yl)acetic acid (syn-isomer) and 0.56 g (1.4 mmol) of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate were dissolved in 0.77 ml (6.3 mmol) of N,N-dimethylaniline at 0° C., and 0.12 ml (1.7 mmol) of phosphorus oxychloride was dropwise added thereto. The mixture was stirred for 30 minutes and the reaction solution was washed with sequentially with 1 N hydrochloric acid, a 10% sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution. The water layer was further extracted with ethyl acetate, and the organic layer was added thereto. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain benzhydryl 3-chloromethyl-7-{2-[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino]-2-(2-tritylaminothiazol-4-yl)acetamido}-3-cephem-4-carboxylate (syn-isomer), which was used for the next reaction without purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].C(O)[C:16]1[CH:21]=[CH:20]C=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.[C-]#N.[K+]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:2]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC1(C#N)CCCCC1
Reactant: OCc1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#CC1(CC(=O)OCc2ccccc2)CCCCC1
Yield: 68 %

Procedure:
401 mg (2 mmol) of (1-cyanocyclohexyl)acetic acid ethyl ester, 1.09 g (10 mmol) of benzyl alcohol and 6 mg (0.1 mmol) of potassium cyanide were refluxed for 24 hours in 5 ml of toluene. Then the solution was washed with 25 ml of water, freed of solvent and distilled in high Vacuum. 350 mg of (1-cyanocyclohexyl)acetic acid benzyl ester was obtained, corresponding to a yield of 68 percent (relative to the (1-cyanocyclohexyl)acetic acid ethyl ester used). Data for the product was:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=2[CH3:24])=[N:3][CH:4]=1
Reactant: Cc1ccc(O)c(C)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(C)cc2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2,4-dimethylphenol: 1H-NMR (CDCl3) δ 8.56 (1H, d, J=2.8 Hz), 8.32 (1H, d, J=7.5 Hz), 8.11 (1H, d, J=2.6 Hz), 8.02–7.98 (2H, m), 7.43 (2H, d, J=8.3 Hz), 7.26–7.09 (2H, m), 6.99 (1H, d, J=8.1 Hz), 5.45–5.36 (1H, m), 3.90 (3H, s), 2.36 (3H, s), 2.10 (3H, s), 1.59 (3H, d, J=7.0 Hz); MS (ESI) m/z 439 (M+H)+, 437 (M−H)−.
Reaction SMILES: [N:1]#[C:2][C@@H:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:4].[CH:10](OC(=O)C)=[O:11]>CCOCC>[CH:10]([NH:4][C@H:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:2]#[N:1])=[O:11]
Reactant: CC(=O)OC=O
Reactant: CCOC(=O)[C@@H](N)C#N
Solvent: CCOCC
Product: CCOC(=O)[C@H](C#N)NC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 3-nitriloalaninate (26.9 g, 210 mmol) is dissolved in anhydrous ether (200 mL), and cooled in an ice/water bath. Acetic formic anhydride (prepared as a mixture as described above) is added dropwise. When the addition is finished, the reaction mixture is allowed to warm to RT and stirred at RT overnight. Most volatiles are removed in vacuo, and the residue solvents are removed by co-evaporation with toluene (100 mL×4). The red oil obtained precipitates upon scratching in ether, and the resulting solids are recrystallized in ether to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) 8.32 (1H, s), 7.26 (1H, s), 6.46 (1H, bs), 5.56 (1H, d, J 7.8), 4.39 (2H, q), 1.37 (3H, t).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:24](=[O:25])[C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[N:21]=[N:20]3)[CH2:14][CH:15]=2)=[CH:2]1.I[CH3:31]>>[CH3:31][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:24](=[O:25])[C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[N:21]=[N:20]3)[CH2:12][CH:11]=2)=[CH:2]1
Reactant: CI
Reactant: O=c1c2ccccc2nnn1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Product: Cn1cc(C2=CCN(CCCn3nnc4ccccc4c3=O)CC2)c2ccccc21
Yield: 35.3 %

Procedure:
Starting from 3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-1,2,3-benzotriazin-4(3H)-one (0.83 g, 2.2 mmol) and iodomethane (0.14 mL, 2.2 mmol), and following the same procedure as in example 21, 0.31 g of 3-[3-(4-(1-methyl-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-1,2,3-benzotriazin-4(3H)-one was isolated as an orange solid. Yield 35%; mp 70° C.; MS: 400.3 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 2.20 (m, 2H), 2.54 (m, 2H), 2.66 (t, 2H), 2.72 (t, 2H), 3.21 (m, 2H), 3.75 (s, 3H), 4.60 (t, J=5.34 Hz, 2H), 6.11 (t, 1H), 6.99 (s, 1H), 7.15 (t, 1H), 7.22 (t, 1H), 7.27 (m, 2H), 7.75 (t, 1H), 7.87 (m, 1H), 8.12 (d, 1H), 8.36 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20](OC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[N:29]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20]([NH:37][CH2:36][CH2:35][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:26])([F:28])[F:27])[CH:3]=1
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O
Reactant: NCCN1CCOCC1
Product: O=C(NCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O

Procedure:
This compound was prepared from methyl 7-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and [2-(4-morpholinyl)ethyl]amine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.72 (1H, s), 10.34 (1H, br t, J=5 Hz), 8.45 (1H, d, J=1.2 Hz), 7.67 (1H, dd, J=9.3, 2.6 Hz), 7.59-7.50 (4H, m), 7.29 (1H, s), 4.29 (2H, s), 3.56 (4H, m), 3.46 (2H, q, J=6 Hz), 2.40 (4H, m); HRMS calcd for C23H22F4N4O4+H+: 495.1655. Found: 495.1659.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)[C:5]([Cl:21])=[CH:4][N:3]=1.[CH2:22]([N:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:27]=2[CH2:26][CH2:25]1)[CH3:23].Cl.C(=O)([O-])[O-]>COCCO.O1CCOCC1>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)=[N:7][C:2]([NH:35][C:32]2[CH:33]=[CH:34][C:27]3[CH2:26][CH2:25][N:24]([CH2:22][CH3:23])[CH2:30][CH2:29][C:28]=3[CH:31]=2)=[N:3][CH:4]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: Clc1ncc(Cl)c(Nc2cccc(N3CCOCC3)c2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCO
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4cccc(N5CCOCC5)c4)n3)cc2CC1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(3-morpholin-4-yl-phenyl)-amine (96 mg, 0.29 mmol) was added into a vial, followed by a solution of 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (52 mg, 0.27 mmol) in 2-Methoxyethanol (2.7 mL). 4 M of Hydrogen chloride in 1,4-Dioxane (0.10 mL) was added and the reaction was heated at 120° C. After 6 h, the reaction was cooled and Macroporous carbonate resin (3.16 mmol/g loading; 400 mg, 1.25 mmol) was added and the reaction was stirred overnight, then was concentrated in vacuo onto Celite, and chromatographed (24 g alumina column, EtOAC-5% MeOH:EtOAC-5% MeOH:DCM). 5-Chloro-N*2*-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo-[d]azepin-7-yl)-N*4*-(3-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine was isolated as a yellow foam (64 mg, 49%). LCMS (m/e) 479 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 7.47 (m, 2H), 7.37 (d, 1H, J=2.0 Hz), 7.14 (dd, 1H, J=2.3, 8.1 Hz), 6.96 (d, 1H, J=7.9 Hz), 6.92 (m, 3H), 6.82 (s, 1H), 3.89 (t, 4H, J=4.8 Hz), 3.16 (t, 4H, J=4.8 Hz), 2.85 (m, 4H), 2.63 (m, 4H), 2.57 (q, 2H, J=7 Hz), 1.10 (t, 1H, J=7 Hz).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[C:13]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:14][OH:15])[O:12][CH:11]([O:25][CH3:26])[CH:10]1[OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][CH:9]1[CH:10]([OH:27])[CH:11]([O:25][CH3:26])[O:12][C:13]1([CH2:14][O:15][N:29]1[C:33](=[O:34])[C:32]2[C:31](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:30]1=[O:39])[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COC1OC(CO)(COCc2ccccc2)C(OCc2ccccc2)C1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1OC(COCc2ccccc2)(CON2C(=O)c3ccccc3C2=O)C(OCc2ccccc2)C1O

Procedure:
The O-phthalimido compound is prepared following the reference cited and the procedures illustrated in Example 13 above. The reaction can be adjusted to preferentially react at the primary hydroxyl e.g. the 4′-C-hydroxymethyl group (Bhat, B., et. al., J. Org. Chem. 1996, 61, 8186-8199). Generally, a solution of 21 (1 eq.), N-hydroxyphthalimide (1.1 eq.), and triphenylphosphine (1.1 eq.) in anhydrous tetrahydrofuran is treated with diethyl azodicarboxylate (1.1 eq.). After several hours at room temperature, the mixture is concentrated and subjected to silica gel chromatography to give Compound 22.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[C:20]([OH:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33]>O1CCOCC1>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][S:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[C:20]([OH:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: O=C(O)[C@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1oc(-c2ccccc2)nc1CSc1ccc(S(=O)(=O)N2c3ccccc3C[C@@H]2C(=O)O)cc1
Reaction time: 1.5 h
Yield: 80.4 %

Procedure:
To a solution of the title D compound, (R)-1-(4-mercapto-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylic acid (0.56 g, 1.67 mmol) in dioxane (8 mL) is added 1N aqueous sodium hydroxide (3.4 mL) and water (2 mL) at room temperature. The resulting solution is treated dropwise with a solution of 4-chloromethyl-5-methyl-2-phenyl-oxazole (0.423 g, 2.04 mmol) in dioxane (4 mL). After stirring 1.5 hours, the reaction mixture is concentrated to near dryness in vacua. The residue is taken into water, the aqueous phase is washed with ether, acidified with 2N aqueous hydrochloric acid and extracted into ethyl acetate. The combined organic phases are washed with water, brine and dried over sodium sulfate. The organic phase is concentrated in vacuo and dried overnight at high vacuum to give 0.68 g of (R)-1-[4-(5-methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylic acid as gum: [M−1]−=504.9.
Reaction SMILES: [C:1]1([NH:11][C:12](=S)[NH:13][NH2:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[CH:17]([C:23]([CH3:25])=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl>C(O)C>[CH3:25][C:23]1[NH:14][N:13]=[C:12]([NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NNC(=S)Nc1cccc2ccccc12
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2cccc3ccccc23)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
A suspension of 15.0 g (0.069 mole) of 4-(1-naphthalenyl)-3-thiosemicarbazide and 11.4 g (0.069 mole) of ethyl 2-chloroacetoacetate in 100 mL of absolute ethanol was stirred at room temperature for 1 hr. Alcoholic hydrogen chloride (2N, 50 mL) was added, the mixture refluxed for 1 hr, filtered while hot and the filtrate evaporated under reduced pressure. The residue was recrystallized twice from 190 ethanol then twice from absolute ethanol to give 6.2 g of product, mp 199°-202° C. The sample was dried at 56° C./4 hr/0.1 mmHg then at 25° C./0.1 mmHg/for ~16 hr.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:5])=[O:4].C[Al](C)C.[Cl:10][C:11]1[CH:21]=[C:20](/[CH:22]=[CH:23]/[CH:24]([C:29]2[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[C:31]([Cl:37])[CH:30]=2)[C:25]([F:28])([F:27])[F:26])[CH:19]=[CH:18][C:12]=1[C:13](OCC)=[O:14]>C(Cl)Cl>[Cl:10][C:11]1[CH:21]=[C:20](/[CH:22]=[CH:23]/[CH:24]([C:29]2[CH:30]=[C:31]([Cl:37])[C:32]([Cl:36])=[C:33]([Cl:35])[CH:34]=2)[C:25]([F:26])([F:27])[F:28])[CH:19]=[CH:18][C:12]=1[C:13]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:14]
Reactant: CCOC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Reactant: NCC(N)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(CNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl)NCC(F)(F)F
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a stirred solution of glycine amide (0.15 g, 0.58 mmol) in CH2Cl2 (5 mL) was added trimethylaluminum (2 M solution in toluene; 1.45 mL, 2.91 mmol) dropwise, and the reaction mixture was stirred at 28° C. for 30 min A solution of (E)-ethyl 2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoate (0.3 g, 0.58 mmol) in CH2Cl2 (5 mL) was added drop wise to the reaction mixture at 28° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 1N HCl solution (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 40% EtOAc in n-hexane) to afford the title compound as yellow solid (0.15 g, 50%): mp 83-85° C.; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.40 (s, 2H), 7.36 (d, J=6.8 Hz, 1H), 7.05 (t, J=5.2 Hz, 1H), 6.70 (t, J=5.2 Hz, 1H), 6.57 (d, J=15.6 Hz, 1H), 6.44 (dd, J=15.6, 8.0 Hz, 1H), 4.23 (d, J=5.6 Hz, 2H), 4.15 (m, 1H), 4.01 (m, 2H); ESIMS m/z 580.72 ([M−H]−).