Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[N:8]2C2CCCCO2)=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:17]([OH:22])[C:18]([F:19])([F:21])[F:20])[NH:8]2)=[C:4]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:3]=1
Reactant: OC(c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: OC(c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1)C(F)(F)F
Temperature: 50 °C
Yield: 95.5 %

Procedure:
1-(2-Chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)-2,2,2-trifluoroethanol (1.3 g, 0.0031 mol) in MeOH (12 mL) was treated with cat. amount of p-toluenesulfonic acid (53 mg, 0.00031 mol). The reaction mixture was heated to 50° C. overnight and was then concentrated under reduce pressure. The residue was partitioned between water and EtOAc. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated to dryness to give 1-(2-chloro-6-morpholino-9H-purin-8-yl)-2,2,2-trifluoroethanol (1 g, 100% yield). LC/MS (ESI+): m/z 338 (M+H)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Li]CCCC.[NH2:12][C:13]1[C:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:17][C:16]([Cl:27])=[CH:15][C:14]=1[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C1COCC1>[NH2:12][C:13]1[C:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:21])[CH3:22])=[CH:17][C:16]([Cl:27])=[CH:15][C:14]=1[C:28]([OH:33])([C:2]#[C:3][CH:4]1[CH2:6][CH2:5]1)[C:29]([F:32])([F:31])[F:30]
Reactant: C#CCCCCl
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)C(F)(F)F)c1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(O)(C#CC2CC2)C(F)(F)F)c1N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 70.4 %

Procedure:
To a stirred, cooled (0° C.) solution of 31.8 mL (300 mmol) of 5-chloro-1-pentyne in 250 mL of THF was added 252 mL (630 mmol) of 2.5M n-BuLi in hexanes over 20 min. Over the course of the addition the internal temperature had warmed to ambient temperature, and the mixture was stirred at this temperature for 40 min. The reaction was cooled to -20° C. and treated with a solution of 32.7 g (97.4 mmol) of 2'-amino-5'-chloro-3'-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone in 50 mL of THF over 10 min. The dark solution was stirred an additional 30 min. and the cold bath was removed. The reaction was stirred 5 min and poured into 800 mL of 0° C. 1N citric acid with rapid stirring. The mixture was extracted twice with ether, and the combined organic extracts were washed with water then brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography on silica gel (elution with hexanes then 3:1 hexanes-ether) afforded 28.8 g (70%) of (±)-2-(2-amino-5-chloro-3-(t-butyldimethylsilyloxy)phenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol as an off-white solid, mp 125°-126° C. 1H NMR (300 MHz, CDCl3) δ7.22(d, 1H, J=2.2 Hz); 6.76(d, 1H, J=2.2 Hz); 4.86(br. s, 1H); 4.39(br. s, 2H); 1.32-1.43(m, 1H); 1.02(s, 9H); 0.79-0.92(m, 4H); 0.27(s, 3H); 0.26(s, 3H). High resolution mass spec: calculated for C19H26NO2ClF3Si(M+H)+ : 420.1373, found: 420.1363.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[Br:12][C:13]1[N:17]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[C:20](F)[N:19]=2)[N:16]=[CH:15][C:14]=1[N+:30]([O-:32])=[O:31].O1CCCC1>C(Cl)Cl>[Br:12][C:13]1[N:17]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[C:20]([NH:4][CH2:1][CH:2]=[CH2:3])[N:19]=2)[N:16]=[CH:15][C:14]=1[N+:30]([O-:32])=[O:31]
Reactant: C=CCN
Reactant: O=[N+]([O-])c1cnn(-c2nc(F)c(C(F)(F)F)cc2Cl)c1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCNc1nc(-n2ncc([N+](=O)[O-])c2Br)c(Cl)cc1C(F)(F)F
Reaction time: 0.08 h

Procedure:
0.3 g (0.00565 mol) of allylamine and 0.6 g (0.00565 mol) of triethylamine were added to a mixture of 2.2 g (0.00565 mol) of 5-bromo-4-nitro-1-(3-chloro-6-fluoro-5-trifluoromethyl-2-pyridyl)pyrazole and 50 ml of tetrahydrofuran at 22° C. with stirring in the course of 5 minutes and the mixture was subsequently stirred for 21/2 hours. After working up according to the above example and chromatographing with methylene chloride on silica gel, 0.9 g (37% of theory) of the title compound was obtained as a colorless resin. 1H-NMR (CDCL3 /TMS) δ (ppm) allyl 3.95 (s/2), 5.05 (tr/2), 5.85 (m/1); NH 7.6 (tr/1); pyrid 8.4 (s/1); pyraz. 8.8 (s/1) (Active Compound Example No. 9.022).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][O:8][C:9]([CH:11]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([N+:21]([O-:23])=[O:22])[C:15]=1[CH3:24])[CH3:12])=[O:10]>>[CH3:7][O:8][C:9]([CH:11]([N:13]([C:4](=[O:5])[CH2:3][O:2][CH3:1])[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([N+:21]([O-:23])=[O:22])[C:15]=1[CH3:24])[CH3:12])=[O:10]
Reactant: COCC(=O)Cl
Reactant: COC(=O)C(C)Nc1c(C)ccc([N+](=O)[O-])c1C
Product: COCC(=O)N(c1c(C)ccc([N+](=O)[O-])c1C)C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
15.2 g of methoxyacetyl chloride are added dropwise at room temperature to 32 g of N-(1'methoxycarbonylethyl)-2,6-dimethyl-3-nitroaniline. After the weakly exothermic reaction has subsided, the reaction solution is stirred for 20 hours at room temperature. The solvent is then removed and the dark red oily residue is distilled in a high vacuum. Compound 28 distills at a temperature of 170°-174° C. and a pressure of 0.07 mbar as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[O:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[CH2:14]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[N:30]2[N:34]=[C:35]([CH:37]=O)[N:36]=[C:29]2[N:28]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[O:18][C:17](=[O:19])[C:16]([CH2:37][C:35]3[N:36]=[C:29]4[N:28]=[C:27]([CH3:26])[CH:32]=[C:31]([CH3:33])[N:30]4[N:34]=3)=[C:15]([OH:20])[CH2:14]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CC(C)(C)c1cccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c1
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4cccc(C(C)(C)C)c4)(C4CCCC4)OC3=O)nc2n1

Procedure:
The title compound was prepared by coupling the 6-[2-(3-tert-Butyl-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Step 1 to 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31). 1H NMR (DMSO-d6): d 1.29 (s, 9H), 1.46-1.76 (br m, 8H), 2.19 (m, 2H), 2.47 (s, 3 Hz), 2.56-2.70 (m, 7H), 2.87 (d, 1H, J=17.5 Hz), 3.80 (d, 1H, J=16.2 Hz), 3.90 (d, 1H, J=16.2 Hz), 7.12 (m, 2H), 7.28 (m, 3H), 10.92 (s, 1H). Anal. Calcd. For C30H38N4O3.0.4AcOH: C, 70.24; H, 7.58; N, 10.64. Found: C, 70.27; H, 7.42; N, 10.59.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:17][CH2:18][F:19])=[O:16])=[C:11]([F:20])[CH:10]=2)[CH2:4]1.[C:21](SCC)(=[S:23])[CH3:22]>CN(C=O)C>[C:21]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:17][CH2:18][F:19])=[O:16])=[C:11]([F:20])[CH:10]=2)[CH2:4]1)(=[S:23])[CH3:22]
Reactant: NC[C@H]1CN(c2ccc(S(=O)CCF)c(F)c2)C(=O)O1
Reactant: CCSC(C)=S
Solvent: CN(C)C=O
Product: CC(=S)NC[C@H]1CN(c2ccc(S(=O)CCF)c(F)c2)C(=O)O1

Procedure:
Prepared analogously to the Method A of General Methods of Preparation of 5-(S)-Thioamidomethyloxazolidinones (Example 1) from 5-(S)-aminomethyl-3-[4′-(2″-fluoroethyl)sulfinyl-3′-fluorophenyl]oxazolidine-2-one (0.100 g, 0.329 mmol) and ethyl dithioacetate. Reaction was performed in DMF overnight. Yield 0.114 g (96%). M.p. 161° C. MS (m/z): [M+H]+=363.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([CH:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCCC1.CC(C)=O.[CH:41]1[CH:46]=[CH:45][C:44]([C:47]([O:49][C@H:50]([C:64]([OH:66])=[O:65])[C@H:51]([O:55][C:56]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:57])[C:52]([OH:54])=[O:53])=[O:48])=[CH:43][CH:42]=1>C(#N)C>[C:56]([O:55][C@@H:51]([C@H:50]([O:49][C:47](=[O:48])[C:44]1[CH:43]=[CH:42][CH:41]=[CH:46][CH:45]=1)[C:64]([OH:66])=[O:65])[C:52]([OH:54])=[O:53])(=[O:57])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Agent: O=C(O[C@H](C(=O)O)[C@H](OC(=O)c1ccccc1)C(=O)O)c1ccccc1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC#N)C4CCCC4)c3)ncnc21
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 79.2 %

Procedure:
A solution of racemic (4-(1-(2-Cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 200 mg, 0.47 mmol) in a mixture of acetonitrile, tetrahydrofuran, and acetone (4 mL, 6:1:1) at room temperature was warmed to 50° C. before being treated with (+)-2,3-dibenzoyl-D-tartaric acid (16, 84 mg, 0.235 mmol, 0.5 equiv) in one portion. The resulting homogeneous solution was then stirred at 50° C. for 10 minutes before being cooled gradually to room temperature and stirred at room temperature for 23 hours. The solids were then collected by filtration, rinsed with a small volume of hexane, and dried under reduced pressure to afford (2S,3S)-2,3-bis(benzoyloxy)succinic acid-(R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (1:1; 22, 145 mg, 183 mg theoretical, 79.2% yield) as white crystals. The enantiomeric purity of the isolated salt was analyzed by chiral HPLC and found to be in a ratio of 87:13 favoring the desired R-enantiomer. For 22: C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421.4 (M++H).
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([NH:18][C:19](=[O:36])[CH:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:24]=2)[NH2:21])=[O:17])[CH2:12][CH2:11]1)=O)(C)(C)C.C(OCC)C.[ClH:42].O1CCOCC1>>[ClH:42].[NH2:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([NH:18][C:19](=[O:36])[CH:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:24]=2)[NH2:21])=[O:17])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(=O)C(N)Cc2cccc(Oc3ccccc3)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NC[C@H]1CC[C@H](C(=O)NC(=O)C(N)Cc2cccc(Oc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (I) (0.25 g) was dissolved in a 4N-hydrogen chloride/1,4-dioxane solution (0.76 ml) and the solution was stirred at room temperature for 30 minutes. Diethyl ether (10 ml) was added and the precipitated substance was recovered by filtration. After drying, N-(trans-4-aminomethylcyclohexylcarbonyl)-3-phenoxy-DL-phenylalanine amide hydrochloride (0.18 g), which was confirmed by an IR analysis, was obtained in the form of a white powder.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:12][CH:11]=1)(C)(C)C.ClCCl>FC(F)(F)C(O)=O>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH2:7])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ccccn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[2-(4-Pyridin-2-yl-phenyl)-ethyl]-carbamic acid tert-butyl ester was dissolved in a 1:1 mixture of trifluroacetic acid:dichloromethane. The reaction mixture was stirred at room temperature overnight after which the product was recovered upon solvent removal. The TFA salt was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:9](F)=[CH:8][C:7]([O:11][CH3:12])=[CH:6][C:5]=1[F:13])([O-:3])=[O:2].[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.O.C(OCC)(=O)C>CN(C)C=O.C(N(C(C)C)CC)(C)C>[N+:1]([C:4]1[C:5]([F:13])=[CH:6][C:7]([O:11][CH3:12])=[CH:8][C:9]=1[NH:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]1)([O-:3])=[O:2]
Reactant: COc1cc(F)c([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)c([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Nitro-3,5-difluoroanisole (D11) (370 mg, 2 mmol) was dissolved in dry dimethylformamide (3 ml) and diisopropylethylamine (0.4 ml), and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (400 mg, 2 mmol) were added at room temperature. The mixture was stirred at room temperature for 18 h, then cooled to room temperature and water and ethyl acetate added. The organic layer was dried over MgSO4, filtered and evaporated, and the residue crystallised from diethyl ether to afford the title compound, 380 mg. M−−H=368.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.C(O[C:32]1(O[Si](C)(C)C)[CH2:34][CH2:33]1)C.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][N:19]1[CH:32]1[CH2:34][CH2:33]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CCCC1CCNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCC1CCC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(C2CC2)CC1
Yield: 59 %

Procedure:
5-propyl-azepane-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide prepared as described in example 47 (68 mg, 0.16 mmol) in MeOH (2 mL), acetic acid (0.1 mL) was added, followed by 1-[(ethyoxycyclopropyl)oxy]trimethylsilane (0.2 mL, 0.96 mmol), sodium cyanoborohydride (41 mg, 0.64 mmol), and 3 Å molecular sieves, heated to reflux for 3 h. Molecular sieves were filtered out and the reaction solvent was removed to obtain the crude material. Purification was carried by silica gel column chromatography (10% MeOH/DCM) and HPLC to provide the title compound (44 mg, 59%).
Reaction SMILES: [CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH:5]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH:5]=[C:17]1[NH:11][C:12](=[O:13])[NH:14][C:15]1=[O:16]
Reactant: CC(C)(CCC=O)[N+](=O)[O-]
Reactant: O=C1CNC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(CCC=C1NC(=O)NC1=O)[N+](=O)[O-]
Reaction time: 72 h
Yield: 49.6 %

Procedure:
Oily 4-methyl-4-nitropentanal (4.0 g, 28 mmol), hydantoin (4.0 g, 40 mmol) and sodium carbonate (2.8 g, 20 mmol) were added to 50% aqueous acetonitrile (200 ml) and the mixture was refluxed with stirring for 3 days. The reaction mixture was concentrated and extracted three times with ethyl acetate. The organic layer was concentrated to dryness to give 5-(4-methyl-4-nitropentylidene)hydantoin (3.15 g, 13.9 mmol, yield 50.0%).
Reaction SMILES: CON(C)[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH3:26])=[CH:16][C:15]=3[CH:27]=2)[CH:6]=1.[CH:30]1([Mg]Br)[CH2:32][CH2:31]1>>[CH:30]1([C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[CH:12]=[CH:13][C:14]4[O:18][C:17]([CH2:19][CH2:20][N:21]5[CH2:25][CH2:24][CH2:23][C@H:22]5[CH3:26])=[CH:16][C:15]=4[CH:27]=3)[CH:6]=2)=[O:28])[CH2:32][CH2:31]1
Reactant: CON(C)C(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Reactant: Br[Mg]C1CC1
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C(=O)C4CC4)c3)ccc2o1
Yield: 48 %

Procedure:
The product from Example 145 and cyclopropylmagnesium bromide were processed as described in Example 146 to provide the title compound (48% yield). MS (ESI APCI) m/z 374 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.08-1.22 (m, 7 H), 1.39-1.53 (m, 1 H), 1.73-1.86 (m, 2 H), 1.95-2.08 (m, 1 H), 2.23-2.35 (m, 1 H), 2.41-2.60 (m, 2 H), 2.87-3.15 (m, 3H), 3.19-3.35 (m, 2 H), 6.63 (s, 1 H), 7.48-7.55 (m, 2 H), 7.60,(dd, 1 H), 7.78-7.81 (m, 1 H), 7.89 (ddd, 1 H), 8.02 (ddd, 1 H), 8.25 (dd, 1 H).
Reaction SMILES: C(OC([N:11]1[CH2:17][C@@H:16]([OH:18])[C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13][C@H:12]1[CH3:27])=O)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[C:23]([O:22][C:20](=[O:21])[NH:19][C@@H:15]1[CH2:14][CH2:13][C@@H:12]([CH3:27])[NH:11][CH2:17][C@H:16]1[OH:18])([CH3:25])([CH3:24])[CH3:26]
Reactant: C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)CN1
Reaction time: 8 h

Procedure:
(2R,5R,6R)-5-tert-Butoxycarbonylamino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester (0.9 g, 2.4 mmol) was dissolved in EtOAc (40 ml), then 10% Pd/C (0.45 g) was added and the reaction mixture was degasses by bubbling argon for 5 minutes. Then, the reaction was stirred overnight under a balloon filled with hydrogen gas. The reaction mixture was filtered through Celite, concentrated in vacuo by rotary evaporation and was azeotroped with toluene (20 ml), then was used in the next reaction without further purification (0.58 g, quantitative): Electrospray mass spec: M+H+=245.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([CH3:30])[N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:27]=[C:28]([CH3:30])[N:29]=[C:2]([N:35]4[CH2:36][CH2:37][CH:32]([CH3:31])[CH2:33][CH2:34]4)[CH:3]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: Cc1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc(Cl)n1
Reactant: CC1CCNCC1
Product: Cc1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc(N2CCC(C)CC2)n1

Procedure:
Compound is formed by reacting 2-chloro-6-methyl-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide with 4-methylpiperidine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.22 (m, 1H), 7.85 (m, 1H), 7.57 (m, 2H), 7.34 (d, 1H), 7.18 (s, 1H), 7.04 (m, 2H), 4.41 (d, 2H), 4.31 (t, 2H), 3.60 (t, 4H), 2.90-2.78 (m, 7H), 2.56 (t, 4H), 1.67 (m, 4H), 1.13 (m, 1H), 0.95-0.86 (m, 3H). MS: 489.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: Nc1ccccc1
Product: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccccc3)nc21
Temperature: 195 °C

Procedure:
A mixture of 0.134 g (0.33 mmol) of 6-(2,6-dichlorophenyl)-8-ethyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 68 and 0.500 g (5.40 mmol) of aniline was heated with stirring in a 195° C. oil bath to reflux. The resulting solution was maintained at reflux for 5 minutes. Most of the excess aniline was evaporated at reduced pressure. The residual gum was dissolved in 15 mL of ethyl acetate. After filtration of a relatively small amount of insoluble material, the solution was filtered through a layer of silica gel to remove violet color. The filtrate was concentrated to 2 mL volume. Petroleum ether was added until slight turbidity. The crystals that separated on inducement were filtered and washed with 50% ether/petroleum ether; wt 0.068 g; mp 223°-225° C.
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[CH3:19][N:20]([CH3:30])[C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]3[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=3[CH3:13])=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: Cc1oc(C(=O)O)cc1COc1ccc(I)cc1
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2ccc(N(C)C)cc2)cc1

Procedure:
Compound (113) was prepared from compound (26) and (4-dimethylamino-phenyl)-boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt=1.83 mins, m/z (ES−)=350 (M−H for C21H21NO4).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]2[CH2:29][CH2:28]2)[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]2[CH2:28][CH2:29]2)[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:11]1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(C4CC4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)NN=C2COc3cc(C4CC4)c(NC4CNC4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 3-(7-cyclopropyl-4(R)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 12) Rt=6.01 min., 0.300 g, 0.702 mmol) in DCM (9 mL) was added TFA (1.5 mL) and the reaction mixture was stirred for 2 h at ambient temperature. The solution was concentrated in vacuo to give 6-(azetidin-3-ylamino)-7-cyclopropyl-4(R)-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (Example #64-1, Enantiomer 1, SFC (Table 1, Method 1) Rt=4.205 min., 0.291 g, 0.661 mmol, 94%). LC/MS (Table 1, Method 4) Rt=1.333 min.; MS m/z: 328 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](Cl)=[O:14]>>[OH:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[NH:1][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=1[F:10]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: Cc1cccc(O)c1N
Product: Cc1cccc(O)c1NC(=O)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15a), from 2-amino-3-methylphenol (283 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[CH2:27](O)[CH3:28]>>[CH2:27]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[C:4]([C:12]([F:13])([F:14])[F:15])[CH:5]=1)[CH3:28]
Reactant: CCO
Reactant: O=C(O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 80 °C
Yield: 77 %

Procedure:
4-(bromomethyl)-3-(trifluoromethyl)benzoic acid 35 (650 mg, 2.296 mmol) was dissolved in ethanol (30 mL). Concentrated H2SO4 (1.224 mL, 22.96 mmol) was slowly added. The resulting mixture was heated at 80° C. overnight. The reaction mixture was cooled and neutralized with saturated Na2CO3 Solution. The resulting precipitate was collected to give crude 4-bromomethyl-3-trifluoromethyl-benzoic acid ethyl ester 36 (550 mg, 77%) which was used without further purification. (m/z)=311 an 313 (M+H)+.