Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4](=[O:10])[NH:5][C:6]([CH3:9])=[CH:7][CH:8]=1.C1COCC1.CO>C(Cl)Cl.O=[Mn]=O>[CH3:9][C:6]1[NH:5][C:4](=[O:10])[C:3]([CH:2]=[O:1])=[CH:8][CH:7]=1
Reactant: Cc1ccc(CO)c(=O)[nH]1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(C=O)c(=O)[nH]1
Temperature: 57 °C
Yield: 101 %

Procedure:
3-(hydroxymethyl)-6-methyl-2(1H)-pyridinone (2.0 g, 13 mmol) was dissolved in CH2Cl2(80 mL), THF (80 mL) and MeOH (5 mL), MnO2 (3.7 g, 43 mmol) was added. The reaction mixture was heated at 57° C. for 18 hours. The reaction was filtered through a pad of Celite® and concentrated to give a solid (1.8 g, 90%). LCMS (ES+) m/z 138 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH3:12])[CH2:5]2.Cl[C:16]1[N:21]=[C:20]([NH:22][CH3:23])[C:19]([C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=1>CC(O)(C)C>[CH3:14][O:13][C:3]1[C:2]([NH:1][C:16]2[N:21]=[C:20]([NH:22][CH3:23])[C:19]([C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([CH3:12])[C:7]2=[O:11]
Reactant: COc1c(N)ccc2c1CN(C)C2=O
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Solvent: CC(C)(C)O
Product: CNc1nc(Nc2ccc3c(c2OC)CN(C)C3=O)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 22.7 %

Procedure:
To a solution of 5-amino-4-methoxy-2-methylisoindolin-1-one (81 mg, 0.42 mmol) in t-BuOH (3 mL) was added 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (89 mg, 0.42 mmol). The mixture was heated at 100° C. for 1 h under microwave irradiation. The solvent was evaporated in vacuo and the residue was purified by reverse-phase prep-HPLC to afford the title compound as a white solid (35 mg, yield 23%). m/z (ES+APCI)+: [M+H]+368.1. 1H-NMR (Bruker, 500 MHz, MeOD) δ 8.65 (d, J=8.5 Hz, 1H), 8.13 (s, 1H), 7.43 (d, J=8.5 Hz, 1H), 4.69 (s, 2H), 4.06 (s, 3H), 3.19 (s, 3H), 3.05 (s, 3H)
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH:7]([CH2:11][CH:12]=[CH2:13])[CH2:8][CH:9]=[CH2:10])[C:3](=[O:5])[CH3:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][C:2](=[CH:6][CH:7]([CH2:8][CH:9]=[CH2:10])[CH2:11][CH:12]=[CH2:13])[CH:3]([OH:5])[CH3:4]
Reactant: C=CCC(C=C(C)C(C)=O)CC=C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C=CCC(C=C(C)C(C)O)CC=C

Procedure:
In an analogous manner to that of Example 7, 17.8 g (0.1 moles) 3-methyl-5-allyl-octa-3,7-dien-2-one (according to Example 6) are reacted with 1.1 g (0.029 moles) LiAlH4.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.[OH-].[Na+]>C(OCC)C>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: C=Cc1ccc(OC2CCCCO2)cc1
Reaction time: 20 h

Procedure:
In a 250 ml round-bottomed flask, 15 g (125 mmol) of 4-hydroxystyrene and 0.4 g (2.3 mmol) of p-toluenesulfonic acid monohydrate are dissolved in 120 ml of diethyl ether. Then, at 5° C., 11.6 g (137 mmol) of 3,4-dihydro-2H-pyran are added dropwise over a period of 10 minutes. The mixture is allowed to reach room temperature and is further stirred for 20 hours. 1N NaOH solution is then added and the organic phase is washed twice with water, dried over magnesium sulfate and concentrated to yield 23.3 g (114 mmol, 90% of the theoretical yield) of 4-tetrahydropyran-2-yloxystyrene in the form of a colourless oil that can be used for the copolymerisation without being further purified. 1H-NMR (CDCl3, 100 mHz): δ7.37/d (J=9 Hz)/2H, 7.02/d (J=9 Hz)/2H, 6.52/dd (J1 =18 Hz, J2 =11 Hz)/1H, 5.50/dd (J1 =18 Hz, J2 =2 Hz)/1H, 5.41/m/1H, 5.11/dd (J1 =11 Hz, J2 =2 Hz)/1H, 4.0-3.7/m/1H, 3.7-3.4/m/1H, 2.2-1.2/m/6H.
Reaction SMILES: [Si]([O:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH:23]([C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[F:41])[S:24]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.CCCCCC>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([CH:23]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[F:41])[CH2:22]/[CH:21]=[CH:20]\[CH2:19][OH:18])(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](OC/C=C\CC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)C(C/C=C\CO)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
In tetrahydrofuran (5 ml) was dissolved (Z)-2-[5-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-3-pentenyl]-1,4-difluorobenzene (Isomer 246-A) (145 mg, 0.237 mmol). After dropwise addition of a tetrahydrofuran solution (1.0M, 0.5 ml, 0.5 mmol) of tetrabutylammonium fluoride, the mixture was stirred at room temperature for 2 hours. Water (0.2 ml) was added to the reaction mixture, followed by concentration under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with hexane, whereby the title compound (51 mg, 0.137 mmol, 58%) was obtained as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][O:14][CH3:15].[OH-].[K+].Cl>C(O)C.O>[CH3:15][O:14][CH2:13][CH2:12][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: COCCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
Commercially available 4-hydroxy benzoic acid (10.0 g, 72.4 mmol) and 2-chloroethylmethylether (13.7 g, 144 mmol) wer added to a stirred, room temperature solution of KOH (8.12 g, 144 mmol) in ethanol (90 mL) water (10 mL) and the resulting yellow solution was heated at reflux for 20 hours. The reaction mixture was cooled to room temperature and concentrated to provide a light yellow powder. The reaction mixtur was diluted with water (100 mL) and addtional KOH (5 g, 89 mmol) was added and the reaction mixture was heated at reflux for two hours. The reaction mixture was cooled to 0° C., and neutralized with 2M HCl (100 mL). The precipitate was filtered and the off white powder (15.5 g) was chromatographed (silica gel, elutent 95:5/methylene chloride: methanol) to provide the title compound as a white powder (8.73 g, 54%): 1HNMR (CDCl3) δ3.37 (s, 3H), 3.69 (t, J=5 Hz, 2H), 4.16 (t, J=5 Hz, 2H), 6.97 (d, J=9 Hz, 2H), 7.86 (d, J=9 Hz, 2H), 12.52 (s, 1); MS (ESI): [M−H]− at m/z 196.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=1)=O)(C)(C)C.[C:39](O)([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[O:37]=[C:25]1[CH2:26][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=2)=[N:7][C:8]2[CH:13]=[C:12]([O:40][CH2:39][C:41]([F:44])([F:43])[F:42])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=2[NH:24]1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(C2=Nc3cc(OCC(F)(F)F)c(C(F)(F)F)cc3NC(=O)C2)ccn1

Procedure:
The title compound was prepared from [2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M75) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (100 mg).
Reaction SMILES: [C:1](=O)([O-:44])[O:2][C@@:3]1(N2C(=O)CCC2=O)[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[C:15]([F:16])=[CH:14][N:13]=[C:12]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[C:23]([F:26])[CH:24]=4)[N:19]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:18]=3)[N:11]=2)[CH2:4]1.[F:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1>C(#N)C>[F:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:1]([O:2][C@H:3]2[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]3[C:15]([F:16])=[CH:14][N:13]=[C:12]([C:17]4[C:25]5[C:20](=[N:21][CH:22]=[C:23]([F:26])[CH:24]=5)[N:19]([S:27]([C:30]5[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=5)(=[O:29])=[O:28])[CH:18]=4)[N:11]=3)[CH2:4]2)=[O:44])[CH2:48]1
Reactant: F[C@@H]1CCNC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4CCC[C@@](OC(=O)[O-])(N5C(=O)CCC5=O)C4)n3)c3cc(F)cnc32)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4CCC[C@H](OC(=O)N5CC[C@@H](F)C5)C4)n3)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To (2,5-dioxopyrrolidin-1-yl) [(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbonate, 75c, (0.125 g, 0.195 mmol) already in acetonitrile was added (3R)-3-fluoropyrrolidine (0.445 g, 4.991 mmol) and the reaction mixture was stirred at room temperature for 20 hours; The reaction was monitored by HPLC until no more starting material was remaining. The reaction mixture was concentrated in vacuo and was carried on into the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C@H:9]1[CH2:44][C@@:43]2([CH3:45])[C@@H:20]([CH2:21][CH2:22][C@:23]2([O:46][C:47](=[O:50])[CH2:48][CH3:49])[C:24](=[O:42])[CH:25]([O:27][C:28](=[O:41])[C@H:29]([CH:38]([CH3:40])[CH3:39])[NH:30]C(OC(C)(C)C)=O)[OH:26])[C@H:19]2[C@H:10]1[C@:11]1([CH3:53])[C:16]([C@@H:17]([CH3:51])[CH2:18]2)=[CH:15][C:14](=[O:52])[CH:13]=[CH:12]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C@H:9]1[CH2:44][C@@:43]2([CH3:45])[C@@H:20]([CH2:21][CH2:22][C@:23]2([O:46][C:47](=[O:50])[CH2:48][CH3:49])[C:24](=[O:42])[CH:25]([O:27][C:28](=[O:41])[C@H:29]([CH:38]([CH3:39])[CH3:40])[NH2:30])[OH:26])[C@H:19]2[C@H:10]1[C@:11]1([CH3:53])[C:16]([C@@H:17]([CH3:51])[CH2:18]2)=[CH:15][C:14](=[O:52])[CH:13]=[CH:12]1
Reactant: CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](N)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
Under initial cooling, 5 ml of trifluoroacetic acid is poured over 896 mg (1.42 mmol) of N-(1,1-dimethylethoxycarbonyl)valine [11β,21-dihydroxy-3,20-dioxo-6α-methyl-17-propionyloxy-pregna-1,4-dien-21-yl] ester, and it is stirred for 1-2 hours at room temperature. Then, the trifluoroacetic acid is evaporated in a vacuum. The residue is taken up in a little dichloromethane, 5 ml of toluene is added and then evaporated to dryness in a vacuum. The residue is crystallized. 728 mg (80%) of valine [11β,21-dihydroxy-3,20-dioxo-6α-methyl-17-propionyloxy -pregna-1,4-dien-21-yl] ester trifluoroacetate is obtained. Melting point 148° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[F:9][C:4]1[CH:3]=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: OB(O)c1ccccc1
Product: Fc1cc(F)cc(-c2ccccc2)c1
Yield: 91.1 %

Procedure:
Combine 1-bromo-3,5-difluorobenzene (0.863 mL, 7.50 mmol) and phenylboronic acid (1.22 g, 10.00 mmol) and subject to conditions described in Method G to yield 1.3 g of 3,5-difluorobiphenyl.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH3:6])=[C:2]=[O:3].[OH:7][C@H:8]1[CH2:27][N:11]2[C:12](=[O:26])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:14][C@@H:10]2[CH2:9]1.O>C1COCC1.N1C=CC=CC=1>[O:26]=[C:12]1[N:11]2[CH2:27][C@H:8]([O:7][C:2](=[O:3])[NH:1][CH2:4][CH2:5][CH3:6])[CH2:9][C@H:10]2[CH2:14][N:13]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](O)CN12
Reactant: CCCN=C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CCCNC(=O)O[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Yield: 25.8 %

Procedure:
1-Isocyanatopropane (30 mg, 0.4 mmol) was added to a solution of (6R,7aS)-6-Hydroxy-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 1, step e) (60 mg, 0.2 mmol) in anhydrous THF (10 mL) and pyridine (2 mL). The mixture was refluxed overnight. The mixture was cooled and poured into water (20 mL), extracted with ethyl acetate (3×20 mL). The organic layers was combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to give final compound 20 mg (26%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.60 (d, 2H, J=9.0 Hz), 7.19 (d, 2H, J=8.7 Hz), 5.35 (t, 1H, J=5.7), 4.71 (s, 1H), 4.17-4.00 (m, 3H), 3.74 (d, 1H, J=7.2 Hz), 3.22-3.12 (m, 3H), 2.23 (dd, 1H, J1=12.9 Hz, J2=3.3 Hz), 1.71-1.48 (m, 3H), 0.94 (t, 3H, J=7.2 Hz); LC-MS: 388.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:46])=[O:37]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])=[O:37])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.103 g, 0.27 mmol) and triethylamine (0.06 mL, 0.40 mmol) in CH2Cl2 (1 mL) was added 2-chlorobenzyl chloroformate (0.06 mL, 0.40 mmol), and the reaction was stirred at room temperature for 1 hour. The mixture was diluted with CH2Cl2 and H2O, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, decanted, and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: C(O)(=O)C.[I:5]Cl.[CH3:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.C([O-])(=O)C.[Na+]>O>[I:5][C:11]1[CH:10]=[N:9][N:8]([CH3:7])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=1
Reactant: ClI
Reactant: Cn1nccc1-c1ccc(C(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1ncc(I)c1-c1ccc(C(F)(F)F)cc1
Reaction time: 4 h
Yield: 83.8 %

Procedure:
An acetic acid (3.3 mL) solution of iodine monochloride (2.64 g) was added dropwise to an acetic acid (22 mL) solution that contained 1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole (3.70 g) and sodium acetate (1.38 g) at a room temperature, and the obtained solution was then stirred for 4 hours. Thereafter, water (250 mL) was added to the reaction solution, and the obtained solution was then stirred for 30 minutes. Then, a precipitated solid was collected by filtration, and was then washed with water. The obtained solid was dissolved in ethyl acetate, and the obtained solution was then washed with water and a saturated sodium hydrogencarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. Thereafter, the residue was purified by column chromatography (silica gel 60N, hexane:ethyl acetate=5:1 to 7:3), so as to obtain the title compound (4.80 g) in the form of a brownish-red oily substance.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[C:10]([O:11][CH:12]([F:14])[F:13])=[C:9](F)[N:8]=[C:7]([NH:16][CH3:17])[N:6]=1>CO>[Cl:4][C:5]1[C:10]([O:11][CH:12]([F:14])[F:13])=[C:9]([O:2][CH3:1])[N:8]=[C:7]([NH:16][CH3:17])[N:6]=1
Reactant: CNc1nc(F)c(OC(F)F)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CNc1nc(Cl)c(OC(F)F)c(OC)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.7 g (0.026 mol) of 30% strength sodium methylate were added to 6.0 g (0.0263 mol) of 4-chlorodifluoromethoxy-6-fluoro-2-methylaminopyrimidine in 100 ml of methanol in the course of 10 minutes while stirring at 0° C. Stirring was continued for 1 hour at 0° C. and for 1 hour at 25° C. Conventional working up gave 6.3 g (100% of theory) of the title compound of melting point 49°-53° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:14]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[N:17]=[N:16][N:15]=1>O1CCCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:14]2[N:18]([C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)[N:17]=[N:16][N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2Cl)cc1
Reactant: OCCCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-n2nnnc2OCCCC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Cyclohexylpropyl alcohol (237 mL, 1.56 mol) was added to a suspension of NaH (66.0 g, 1.65 mol) in tetrahydrofuran (1.40 L). A solution of 5-Chloro-1-(4-nitro-phenyl)-1H-tetrazole (320 g, 1.42 mol) in tetrahydrofuran (900 mL) was added dropwise over 1.5 hours. The reaction was allowed to cool to room temperature and stirred overnight. The mixture was concentrated in vacuo to a solid. The solid was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride solution (2×), dried (Na2SO4), and filtered through silica gel (700 g). The red filtrate was concentrated in vacuo until product began to precipitate from solution. Hexane was added and the slurry filtered to provide a tan solid (320 g, 64%). Mp 82-88° C. (dec); 1H NMR (CDCl3, 300 MHz) δ 8.43 (d, 9.2 Hz, 2H), 8.04 (d, 9.2 Hz, 2H), 4.70 (t, 7.0 Hz, 2H), 1.96 (m, 2H), 1.75-1.64 (m, 5H), 1.39-1.13 (m, 6H), 0.97-0.87 (m, 2H); MS (CI) m/z 332 (MH+); Anal. calcd for C16H21N5O3: C, 57.99; H, 6.39; N, 21.13. Found: C, 57.80; H, 6.35; N, 21.02; Rf=0.43 (N).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=2)=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl.CO>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=2)=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(-c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ncc2Cl)c(C)c1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(-c2cc(N3CCNCC3)ncc2Cl)c(C)c1
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To a solution of tert-butyl 4-(5′-chloro-3,5-dimethyl-2,4′-bipyridin-2′-yl)piperazine-1-carboxylate (5.6 g, 14 mmol) in CH2Cl2 (50 mL) was added TFA (25 mL). Then the mixture was stirred for 18 hours. TLC (CH2Cl2/MeOH=10:1) showed the starting material was consumed completely. After removal of the solvent, the residue was dissolved in CH2Cl2 (180 mL), basified with 3 N aq. NaOH until pH=11, washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford title compound (4.1 g, 97%) as orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([Sn](C)(C)C)=[CH:22][N:21]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][CH:24]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: Cc1ccc([Sn](C)(C)C)cn1
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(C)nc3)cccc2c1N
Yield: 76.5 %

Procedure:
Using method C, 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (178 mg, 0.500 mmol) and 2-methyl-5-(trimethylstannyl)pyridine (270 mg, 1.058 mmol) were reacted to afford the title compound (123 mg, 76% yield). 1H NMR (300 MHz, CDCl3) δ 8.75 (bs, 1H), 8.55 (br, 1H), 8.03 (m, 1H), 7.91 (m, 1H), 7.84-7.70 (m, 2H), 7.30 (m, 1H), 3.47 (apparent quartet, J=7.0 Hz, 2H), 2.64 (s, 3H), 1.67 (apparent sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H). MS APCI, m/z=322 (M+H). HPLC 1.41 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2[CH:16]=[N:17][C:18]([Cl:20])=[N:19][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21]N(C)C(=O)C.IC.[H-].[Na+]>O>[CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH3:21])[C:10]2[CH:16]=[N:17][C:18]([Cl:20])=[N:19][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N(C)C
Reactant: O=C1CCN(Cc2ccccc2)c2nc(Cl)ncc2N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN1C(=O)CCN(Cc2ccccc2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.144 g (0.0005 mole) of 9-benzyl-2-chloro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-22), 1 mL of N,N-dimethylacetamide and 0.047 mL (0.00075 mole) of iodomethane at 0 degrees was added 0.03 g (0.00075 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.134 g of 9-benzyl-2-chloro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-22) as an yellow solid.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH2:11][C:12]1[C:17]([SH:18])=[N:16][C:15]([Cl:19])=[C:14]([Cl:20])[N:13]=1>>[Cl:20][C:14]1[N:13]=[C:12]2[N:11]=[CH:1][S:18][C:17]2=[N:16][C:15]=1[Cl:19]
Reactant: CCOC(OCC)OCC
Reactant: Nc1nc(Cl)c(Cl)nc1S
Product: Clc1nc2ncsc2nc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
To 100 ml. of triethyl orthoformate was added 9.8 g (0.05 mole) of 2-amino-5,6-dichloro-3-mercaptopyrazine. The whole was heated to boiling under reflux for 20 hours, cooled to room temperature and filtered, washed with petroleum-ether and dried to give 7.7 g. (75% yield) of the desired product, m.p. 124°-5° C.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:15]2[CH:14]=[C:13]([CH:18]=[C:17]([CH3:19])[CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1
Reactant: COC(=O)CCc1ccc(Oc2cc(C)cc(Br)c2)cc1C
Reactant: Oc1ccc(Cl)cc1Oc1ccccc1
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(Cl)cc2Oc2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-chloro-2-phenoxy-phenol as in Example 18 to afford 0.118 g (22%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C29H25O5Cl 489.1469, found 489.1457.