Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)C>[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[C:15]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Clc1cncc(Cl)c1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1c(Cl)cncc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of lithium diisopropylamide (45 mL, 1.5 M in THF, 67.6 mmol) in 150 mL THF at −78° C. is treated with 3,5-dichloropyridine (10 g, 67.6 mmol) in 40 mL THF over 1.5 hours, stirred for 1 hour at −78° C., treated with ethyl chloroformate (9.5 mL, 100 mmol), stirred for 2 hours, transferred into saturated sodium bicarbonate (200 ml) at 0° C., treated with diethyl ether (200 ml), and extracted with ethyl ether (2×100 mL). The extract is washed sequentially with saturated sodium bicarbonate solution (2×100 mL), brine (2×100 mL), dried (MgSO4), and concentrated. The residue is purified by flash chromatography on silica gel with hexane/ethyl acetate to provide the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]1=[O:19].[NH2:22][C@@:23]1([CH3:44])[CH2:27][CH2:26][C@@H:25]([NH:28][C:29]2[C:30]3[N:31]([CH:38]=[C:39](Br)[CH:40]=3)[N:32]=[CH:33][C:34]=2[C:35]([NH2:37])=[O:36])[C:24]1([CH3:43])[CH3:42].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:22][C@@:23]1([CH3:44])[CH2:27][CH2:26][C@@H:25]([NH:28][C:29]2[C:30]3[N:31]([CH:38]=[C:39]([C:7]4[CH:8]=[CH:9][N:4]([CH2:3][C:2]([OH:1])([CH3:20])[CH3:21])[C:5](=[O:19])[CH:6]=4)[CH:40]=3)[N:32]=[CH:33][C:34]=2[C:35]([NH2:37])=[O:36])[C:24]1([CH3:43])[CH3:42]
Reactant: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)CC[C@]1(C)N
Reactant: CC(C)(O)Cn1ccc(B2OC(C)(C)C(C)(C)O2)cc1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CC(C)(O)Cn1ccc(-c2cc3c(N[C@@H]4CC[C@](C)(N)C4(C)C)c(C(N)=O)cnn3c2)cc1=O
Temperature: 95 °C

Procedure:
A mixture of Pd(OAc)2 (0.570 mg, 2.54 μmol), 1-(2-hydroxy-2-methylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (22.3 mg, 0.076 mmol), 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-bromopyrrolo[1,2-b]pyridazine-3-carboxamide (19.3 mg, 0.051 mmol, Intermediate 48), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (2.42 mg, 5.1 μmol), and 2 M K3PO4 (0.08 mL, 0.15 mmol) in dioxane (0.5 mL) was degassed then heated at 95° C. for 18 h. The reaction mixture was cooled to rt, diluted with MeOH and purified directly via preparative HPLC. 1H NMR (CD3OD, 400 MHz) δ 8.24 (s, 1H), 8.16 (d, J=1.5 Hz, 1H), 7.71 (d, J=7.3 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 6.83 (dd, J=7.0, 2.0 Hz, 1H), 4.71 (t, J=9.0 Hz, 1H), 4.10 (s, 2H), 2.52 (dtd, J=13.7, 9.0, 4.6 Hz, 1H), 2.23-2.00 (m, 2H), 1.92-1.73 (m, 1H), 1.61-1.47 (m, 3H), 1.28-1.16 (m, 9H), 1.16-0.98 (m, 3H). MS (ES+) m/z: 467.19 (M+H); LC retention time: 2.63 min (Analytical HPLC conditions: Chromalith Speedrod, C18, 4.6×50 mm, 10% MeOH/water to 90% MeOH/water with 0.2% H3PO4, 4 min gradient, 4 mL/min)
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:5])C.Cl.[NH:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[NH2:18].C(N(CC)CC)C.O>ClCCl.CO>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:17]([C:19]3[CH:20]=[CH:21][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:23][CH:24]=3)[N:18]=[C:4]([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: CCOC(C)=NC(=O)c1ccc(F)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(F)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Reaction time: 8 h
Yield: 61 %

Procedure:
N-(1-ethoxy-ethylidene)-4-fluoro-benzamide 438 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 4-hydrazinobenzenesulfonamide hydrochloride 515 mg (2.23 mmol) was added to the solution. Then, triethylamine 0.35 ml (2.51 mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-(4-fluoro-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-benzenesulfonamide (424 mg, yield: 61%) was obtained as a solid phase.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2C=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1.CC1(C)S[C@@H]2[C@H](N)C(=O)[N:27]2[C@H]1C(O)=O>>[CH3:1][CH2:2][N:3]1[C:9]2[N:27]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)nc21
Yield: 25 %

Procedure:
The tetrabutyl ammonium salt of enoxacin [J. Med. Chem., 27, 292 (1984)] was prepared and converted into the corresponding dimethylacetal, using the procedure described for the corresponding norfloxacin analog in Example 15 (but done on a 0.112 mmol scale). This was coupled to 6-aminopenicillanic acid (24. 2 mg, 0.112 mmol) by following the procedure as described for the preparation of the product in Example 33. The product, which was very unstable, was purified by preparative liquid chromatography (C-18 reverse phase, 0-100% aqueous acetonitrile gradient) to give an amorphous, pale yellow powder after lyophilization (16.4 mg, 25% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1([CH3:18])[CH:13]=[CH:12][C:11]2[C:6](=[C:7]([CH3:17])[C:8]([CH3:16])=[C:9]([OH:15])[C:10]=2[CH3:14])[O:5]1.C>CO.[Pd]>[CH3:20][O:19][CH:3]([O:2][CH3:1])[C:4]1([CH3:18])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH3:17])[C:8]([CH3:16])=[C:9]([OH:15])[C:10]=2[CH3:14])[O:5]1
Reactant: COC(OC)C1(C)C=Cc2c(C)c(O)c(C)c(C)c2O1
Agent: [Pd]
Solvent: CO
Product: COC(OC)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Yield: 97 %

Procedure:
1.74 g (0.63 mmole) of the chromene obtained in Example 7 were hydrogenated in 30 ml of methanol at room temperature and under atmospheric pressure using 0.15 g of a supported catalyst comprising 10% by weight of Pd on active charcoal, in the course of 16 hours. Conventional working up gave the above compound, in 97% yield, as white crystals of melting point 102°-106° C.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]([O:9][C:10]([C:12]1[CH:17]=[C:16]([CH2:18][O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:15]=[C:14]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]3)=[C:28]([O:38][CH3:39])[CH:27]=2)[N:13]=1)=C)[CH3:8].[O:40]1CCOCC1>O>[CH3:39][O:38][C:28]1[CH:27]=[C:26]([NH:25][C:14]2[N:13]=[C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:40])[CH:17]=[C:16]([CH2:18][O:19][CH2:20][C:21]([F:23])([F:24])[F:22])[N:15]=2)[CH:31]=[CH:30][C:29]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1
Reactant: C1COCCO1
Reactant: C=C(OCC)c1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CCOC(=O)c1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1

Procedure:
To a solution of sodium metaperiodate (1.200 g, 5.61 mmol) and 4-(1-ethoxyvinyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-2-amine (1.3 g, 2.81 mmol) in a mixture of water (30 mL) and 1,4-dioxane (60 mL) potassium permanganate (0.066 g, 0.42 mmol) was added in portions of 10-15 mg in intervals of 5-8 min at ambient temperature. The mixture was filtered, the precipitate was washed with dioxane and ethyl acetate. Sodium bicarbonate and sodium chloride were added to the filtrate, the organic phase was separated, and the water phase was additionally extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate and concentrated in vacuum. The residue was separated on a silica gel column using a gradient of 0-5% methanol in dichloromethane as eluent to yield the title product, 0.96 g (74%).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:29][CH2:30][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1.Cl.C([O-])(O)=O.[Na+]>CO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:17]2([CH2:16][C:12]3[N:11]4[CH2:29][CH2:30][N:31]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:32](=[O:33])[C:10]4=[C:9]([OH:8])[C:14](=[O:15])[N:13]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:23][CH:24]=1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccc(Cl)cc4)CCCC3)n2CCN1c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C1c2c(O)c(=O)nc(CC3(c4ccc(Cl)cc4)CCCC3)n2CCN1c1ccccc1
Temperature: 70 °C
Yield: 65.2 %

Procedure:
To a stirred solution of 9-(benzyloxy)-6-((1-(4-chlorophenyl)cyclopentyl)methyl)-2-phenyl-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (49) (88.5 mg, 164 μmol, Eq: 1.00) in methanol (5 ml) was added HCl (conc) (240 mg, 0.2 ml, 6.58 mmol, Eq: 40.2). The reaction mixture was heated at 70° C. for 18 hrs, neutralized with saturated aqueous NaHCO3 solution, extracted with dichloromethane, dried (MgSO4), concentrated, triturated with diethyl ether, filtered, and dried to obtain 6-((1-(4-chlorophenyl)cyclopentyl)methyl)-9-hydroxy-2-phenyl-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (50) (pink powder, 48.2 mg, 107 μmol, 65.4% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:19]([O-])=O>CCO.O=[Pt]=O>[NH2:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:2]=1[NH2:1])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[O:7]
Reactant: Cc1ccc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)cc1C
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C

Procedure:
A solution of 4-amino-N-(3,4-dimethylphenyl)-3-nitro-benzamide (2.0 g) in EtOH (40 mL) was hydrogenated at 1 atm over PtO2 (200 mg, 10% w) for 18 hrs. The catalyst was filtered through Celite and the solvent was removed under reduced pressure to afford 3,4-diamino-N-(3,4-dimethylphenyl)-benzamide as a yellow solid. MS (ESI)m/z 256 (M+H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:26][CH:25]=1
Reactant: Nc1cccc2c(Nc3cccc(C(F)(F)F)c3)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4cccc(C(F)(F)F)c4)ncnc23)c1F
Yield: 19.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-7, 80 mg, 0.263 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 150 mg, 0.521 mmol), oxalyl chloride (98 mg, 0.78 mmol), DMF (1 drop) and DIPEA (101 mg, 0.79 mmol) in CH2Cl2 (3 mL) to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.64 (s, 1H), 10.14 (s, 1H), 8.80 (d, J=7.5 Hz, 1H), 8.71 (s, 1H), 8.37 (s, 2H), 8.23-8.17 (m, 2H), 7.72-7.65 (m, 2H), 7.50-7.39 (3H), 4.30 (d, 2H), 1.14 (s, 9H); MS [M+H]+: 574.14.
Reaction SMILES: [NH2:1][C:2](=[N:46][C:47]([O:49][CH2:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C:33]2[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][CH2:42][CH2:43][OH:44])[C:34]=2[F:45])[C:11]2[N:12]=[C:13]([O:22][CH2:23][O:24][C:25]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[N:14]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:77](O)(=[O:79])[CH3:78]>CN(C1C=CN=CC=1)C.CN(C=O)C.ClCCl>[C:77]([O:44][CH2:43][CH2:42][O:41][C:35]1[C:34]([F:45])=[C:33]([C@@H:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([NH2:1])=[N:46][C:47]([O:49][CH2:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])=[CH:8][CH:7]=2)[C:11]2[N:12]=[C:13]([O:22][CH2:23][O:24][C:25]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:26])[N:14]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:15]=2)[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=1)(=[O:79])[CH3:78]
Reactant: CC(=O)O
Reactant: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCOC(=O)C3CCCCC3)n(-c3ncccn3)n2)c1
Agent: CN(C)C(F)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OCCOC(C)=O)c(F)c([C@@H](Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCOC(=O)C3CCCCC3)n(-c3ncccn3)n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cyclohexanecarboxylic acid 5-{(R)-(4-{amino[2,2-dimethylpropoxycarbonylimino]methyl}phenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}-2-pyrimidin-2-yl-2H-[1,2,4]-triazol-3-yloxymethyl ester (42 mg), DMAP (1 mg), and triethylamine (0.0648 mL) were dissolved in DMF (3 mL) and dichloromethane (3 mL). To the solution, a mixture of TFFH (30.7 mg), acetic acid (0.00665 mL), and dichloromethane (3 mL) was slowly added, and the resulting mixture was stirred at room temperature for 3 hours. After concentrating the reaction mixture under reduced pressure, ice, THF, saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous ammonium chloride solution were added to the residue obtained, and the resulting mixture was extracted with a mixture of THF and ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was crudely purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain a crudely purified product of the captioned compound.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([OH:8])[C:6]([CH3:10])([CH3:9])[O:5][C:4]2[CH:11]=[CH:12][S:13][C:3]1=2.[C:14]([C@@:22]([C:37]([OH:39])=[O:38])([OH:36])[C@@:23]([C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([OH:27])[C:24]([OH:26])=[O:25])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:28]([C@@:23]([C:24]([OH:26])=[O:25])([OH:27])[C@@:22]([C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([OH:36])[C:37]([OH:39])=[O:38])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[NH2:1][C@H:2]1[C@H:7]([OH:8])[C:6]([CH3:9])([CH3:10])[O:5][C:4]2[CH:11]=[CH:12][S:13][C:3]1=2
Reactant: CC1(C)Oc2ccsc2C(N)C1O
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Product: CC1(C)Oc2ccsc2[C@@H](N)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-amino-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (1.73 g, 9.69 mmol) was treated with dibenzoyl-L-tartaric acid (3.3 g, 8.69 mmol) and stirred at rt for 30 min. The mixture was concentrated in vacuo and recrystallized from ethanol to yield 1.8 g (37%) of trans-7-amino-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran dibenzoyl-L-tartrate: mp 171°-172° C.; MS: m/z 200(MH+); αD20° =-84.1° (MeOH). Anal. Calcd. for C27H27NO10S: C,58.16; H,4.88; N,2.51.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13].[Br:14]N1C(=O)CCC1=O>CC#N.C(C1C=C(O)C=C(C(C)(C)C)C=1C)(C)(C)C>[I:1][C:2]1[CH:7]=[C:6]([Br:14])[C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13]
Reactant: COCOc1cc(OC)ccc1I
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1c(C(C)(C)C)cc(O)cc1C(C)(C)C
Solvent: CC#N
Product: COCOc1cc(OC)c(Br)cc1I
Temperature: 23 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a stirred solution of 2-iodo-5-methoxy-1-methoxymethoxybenzene (5.24 g, 17.8 mmol) in MeCN (55 mL) was added silica gel (1.32 g), 2,6-di-tert-butyl-4-hydroxytoluene (60 mg), and then N-bromosuccinimide (3.17 g, 17.8 mmol). The mixture was stirred at 23° C. for 1 hour and then filtered. The filtrate was concentrated in vacuo and the residue was dissolved in CH2Cl2 (100 mL). To this solution was added water (100 mL) and the resulting mixture was vigorously stirred for 5 min. The layers were then separated and the aq. phase was extracted with CH2Cl2 (2×100 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash-column chromatography (SiO2, petroleum ether:Et2O 8:1) to provide 2-iodo-4-bromo-5-methoxy-1-methoxymethoxybenzene as a yellow oil (5.05 g, 76%).
Reaction SMILES: [N:1]1([CH:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[C:24]([NH:26][CH:27]2[CH:32]3[CH2:33][CH:29]([CH:30]=[CH:31]3)[CH:28]2[C:34]([NH2:36])=[O:35])[C:23]([Cl:37])=[CH:22][N:21]=1>>[Cl:37][C:23]1[C:24]([NH:26][CH:27]2[CH:32]3[CH2:33][CH:29]([CH:30]=[CH:31]3)[CH:28]2[C:34]([NH2:36])=[O:35])=[N:25][C:20]([NH:18][C:15]2[CH:16]=[CH:17][C:10]3[CH2:9][CH2:8][CH:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH2:13][CH2:12][C:11]=3[CH:14]=2)=[N:21][CH:22]=1
Reactant: NC(=O)C1C2C=CC(C2)C1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Product: NC(=O)C1C2C=CC(C2)C1Nc1nc(Nc2ccc3c(c2)CCC(N2CCOCC2)CC3)ncc1Cl

Procedure:
The title compound was prepared from 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and 3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 179. Product was isolated as a tan solid. LCMS (m/e) 510 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.71 (d, 1H, J=6.8 Hz), 7.53 (d, 1H, 8.86 Hz), 7.41 (s, 1H), 7.26 (s, 1H), 7.00 (d, 1H, J=8.3 Hz), 6.31 (m, 1H), 6.28 (m, 1H), 4.13 (t, 1H, J=8 Hz), 3.54 (s, 4H), 2.88 (s, 1H), 2.46-2.78 (m, 11H), 2.11 (d, 1H, J=9 Hz), 1.95 (m, 2H), 1.41 (d, 1H, J=9 Hz), 1.31 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[C:10]([NH:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:14])[C:10]([NH:12][CH3:13])=[O:11])=[CH:7][CH:8]=1
Reactant: CNC(=O)C(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CNC(=O)C(=O)c1ccc(O)cc1
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To a solution of 2-(4-methoxy-phenyl)-N-methyl-2-oxo-acetamide (74a) (1.35 g, 6.99 mmol) in 25 mL of CH2Cl2 was added 1.0 M BBr3 in CH2Cl2 (14 mL, 28.0 mmol) at 0° C. The mixture was stirred at 0° C. to room temperature for two hours. The reaction was quenched with MeOH, neutralized with concentrated aqueous NH4OH to pH ˜7. The resulting mixture was stirred at room temperature for one hour. Water was added, and the mixture was extracted with CH2Cl2. The organic phase was dried over Na2SO4, concentrated, and purified by flash column chromatography eluting with 1:1 EtOAc and hexanes to provide 0.53 g off-white solid as the intermediate 74b. 1H NMR (300 MHz, CD3OD) δ 7.03 (d, 2H, J=8.86 Hz), 6.75 (d, 2H, J=8.86 Hz), 2.76 (s, 3H). LCMS (ESI+) [M+Na]/z Calc'd 202, found 202.
Reaction SMILES: I.[CH3:2][N:3]1[CH2:8][CH2:7][CH2:6][N:5]=[C:4]1SC.[C:11]1([CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][NH2:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[ClH:26]>CO.[OH-].[Na+].C(Cl)Cl>[ClH:26].[C:20]1([CH:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:18][NH:19][C:4]2[N:3]([CH3:2])[CH2:8][CH2:7][CH2:6][N:5]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CSC1=NCCCN1C
Reactant: NCC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: I
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCCN=C1NCC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A flask containing 1-methyl-2-methylthio-1,4,5,6-tetrahydropyrimidine hydroiodide (9.80 g, 3.60×10-2 mole) and 2,2-diphenylethylamine (7.49 g, 3.80×10-2 mole) was immersed in an oil bath which had been preheated to ca. 155° C. The reaction was stirred at between 150°-170° C. for 45 minutes. The resulting yellow glass was dissolved in methanol. Most of the methanol was evaporated at reduced pressure and isopropanol was added. The evaporation was continued, being stopped periodically for the addition of small portions of isopropanol. A solid forms which was collected by filtration affording a colorless solid. This was dissolved in a two phase mixture of 50% aqueous NaOH (60 ml) and CH2Cl2 (100 ml). After stirring overnight, the CH2Cl2 layer was separated. The aqueous alkaline layer was extracted with CH2Cl2 (2×). The CH2Cl2 layers were combined, washed with H2O (2×), washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving a foam which was dissolved in methanol (40 ml). This solution was cooled to 0° C. before being treated with a methanolic solution of HCl. The methanol was partially evaporated and isopropanol was added. The evaporation was continued, being stopped periodically for the addition of small portions of isopropanol. A solid formed and the flask was placed in the refrigerator. After several hours, the product was collected by filtration. Crystallization from isopropanol afforded 2-(2,2-diphenylethylamino)-1-methyl-1,4,5,6-tetrahydropyrimidine hydrochloride as a colorless solid: 2.66 g (22%), m.p. 155°-157° C.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)=[O:5].[N:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[N:26][CH:25]=1.[BH4-].[Na+]>CS(C)=O>[F:19][C:13]([F:18])([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:20]=[CH:21][CH:22]=[N:23][C:2]=2[NH:1][CH2:30][C:27]2[CH:28]=[CH:29][N:24]=[CH:25][N:26]=2)=[CH:8][CH:9]=1)[C:14]([F:15])([F:16])[F:17]
Reactant: O=Cc1ccncn1
Reactant: Nc1ncccc1C(=O)Nc1ccc(C(F)(F)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cccnc1NCc1ccncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-N-(4-pentafluoroethyl-phenyl)-nicotinamide (180 mg), TSOH (40 mg) and a solution of pyrimidine-4-carboxaldehyde in DMSO (10 ml) were stirred at 60 C for 6 h. Treated with NaBH4 (200 mg) and stirred for 2 h at RT. MS (ES+): 566.3 (M+H)+; Calc'd for C26H28F5N7O2−565.
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:7]2[C:8]([O:12]COC)=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][O:4]1>CO.ClCCl>[CH3:2][CH:3]1[C:7]2[C:8]([OH:12])=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][O:4]1
Reactant: COCOc1cccc2c1C(C)OC2
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC1OCc2cccc(O)c21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 123.2 %

Procedure:
In a 8 ml vial 1-methyl-7-{[(methyloxy)methyl]oxy}-1,3-dihydro-2-benzofuran (Intermediate 97, 25.2 mg) was dissolved in methanol (1 ml) to give a colourless solution. A solution of HCl (2M/H2O) (0.259 ml, 0.519 mmol) was added. The reaction mixture was shaken at 80° C. After 30 minutes, the reaction mixture was diluted with 10 ml of dichloromethane. The phases were separated through a phase separator cartridge. The organic phase was mixed with the fraction obtained before and evaporated under vacuum to afford a residue which was purified by silica gel chromatography (Biotage SP1 system, 10 g-SNAP Silica column) with Cyclohexane/EtOAc as eluents (from 100/0 to 3/1 in 10 CV; then 3/1 for 5 CV; then from 3/1 to 1:1 in 5 CV; then 1:1 for 5 CV). The collected fractions afforded the title compound (24 mg).