Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:33]#[N:34])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]3([CH3:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:32])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:33]#[N:34])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]3([CH3:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:32])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C)CCOCC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2(C)CCOCC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
210 mg (431 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-methyltetrahydro-2H-pyran-4-yl)propanoate (racemate) in 4.3 ml of dichloromethane and 598 μl (7.76 mmol) of TFA were reacted according to General Method 6A. Yield: 210 mg (purity 83%, 94% of theory)
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2Br)=[N:8][N:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.Cl>C1COCC1.BrCCBr>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[B:17]([OH:22])[OH:18])=[N:8][N:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)n1nnnc1-c1ccccc1Br
Agent: Cl
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)(C)n1nnnc1-c1ccccc1B(O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.6 %

Procedure:
To dry Mg turnings (76 mg, 3.13 mmol) in THF (1 mL) was added a solution of 1-tert-butyl-5-(2-bromophenyl)-1H-tetrazole (733 mg, 2.61 mmol) in THF (1.5 mL), 1,2-Dibromoethane (20 mL) was added and the mixture was warmed slightly with a heat gun. After 5 min, triisopropyl borate (564 mg, 3.00 mmol) was added and the mixture was stirred at room temperature for 23 h. Ice and 0.5 N HCl (7 mL) were added and the mixture was stirred for 5 min. The mixture was extracted with ether, and the combined extracts were extracted with 1N KOH (10 mL). The aqueous extracts were filtered and acidified to pH 3 with 2N HCl. The precipitate was collected by filtration to give 306 mg (48%) of product as an off-white solid, mp 112°-115° C.
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[Na+].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>O.C(OCC)C>[C:22]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11]2[CH:18]=[CH:19][C:8]([N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)=[CH:9][CH:10]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCCOc1ccc(-n2ccnc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)NCCCCOc2ccc(-n3ccnc3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.7 %

Procedure:
A solution of 3.0 g of 4-[4-(1H-imidazol-1-yl)phenoxy]butaneamine dihydrochloride (Example 2) is dissolved in 100 ml H2O and while stirring 3.5 ml of 10N NaOH, and then 2.6 g of 4-(t-butyl)benzenesulfonyl chloride in 100 ml of diethyl ether are added. The mixture is stirred at room temperature for 4 hours. The precipitate is collected, washed with 50 ml of water and 50 ml of diethyl ether, and air dried. Recrystallization from 50% aqueous ethanol gives 2.6 g of the title compound, m.p. 138°-140° C.
Reaction SMILES: NC1C=C(C=CC=1OC)C(O)=O.Cl.[C:14]([NH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21]([OH:23])=[O:22])(=[O:16])[CH3:15].[N+:29]([O-])([OH:31])=[O:30]>>[N+:29]([C:24]1[CH:25]=[C:26]([O:27][CH3:28])[C:18]([NH:17][C:14](=[O:16])[CH3:15])=[CH:19][C:20]=1[C:21]([OH:23])=[O:22])([O-:31])=[O:30]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(=O)O)cc1NC(C)=O
Agent: COc1ccc(C(=O)O)cc1N
Agent: Cl
Product: COc1cc([N+](=O)[O-])c(C(=O)O)cc1NC(C)=O
Temperature: 0 °C
Yield: 72 %

Procedure:
3-amino-4-methoxybenzoic acid ("19") (Aldrich Chemical; Milwaukee, Wis.) (5 g or 29.9 mmol) was suspended in 40 ml acetic acid. Acetic anhydride (3 ml or 1:04 eq) was added by stirring. The reaction mixture was stirred for 2 hours at room temperature. 25 ml of 0.1N HCl was added and the precipitate was filtered off and washed with 3×10 ml of 0.1N HCl and 5×10 ml water to produce 5.97 g (about 95%). 3-(N-acetyl) amino-4-methoxybenzoic acid ("20") (5 g or 23.5 mmol) was added to 20 ml of fuming nitric acid at 0° C. on vigorous stirring. The solution was stirred at 0° C. for an additional hour and poured onto 200 g of ice. Precipitate was filtered off, washed with 5×20 mls of water and dried to produce 4.38 g (about 72%) of 2-nitro-4-methoxy-5 (N-acetyl)aminobenzoic acid ("21"), which was converted into 2-nitro-4-methoxy-5-(N-acetyl)aminoacetophenone ("22") (about 63% yield) as described. 2-nitro-4-methoxy-5-(N-acetyl)aminoacetophenone ("22") (1 g or 4.76 mmol) was dissolved in 5 ml of DMF and the solution was added to 5-biotinamidocaproyl chloride prepared separately from 5-biotinamidocaproic acid (1.55 g or 1 eq.) and 5 ml thionyl chloride. The reaction mixture was stirred overnight at room temperature and added to 100 ml of diethyl ether. Precipitate was purified using small silica gel column and a step gradient of MeOH in CHCl3 to give 1.16 g (about 47%) of 2-nitro-4-methoxy-5-(5-biotinamidocaproamido) acetophenone ("23"). This intermediate was converted into its corresponding alcohol (about 85% yield) and into the reactive NHS ester derivative 5-(5-biotinamidocaproamido)-4-methoxy-1-(2-nitro)phenylethyl-N-hydroxysuccinimidyl carbonate ("25") with about a 69% yield.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[CH3:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](OC)=[O:16].C(O)(=O)C>C1COCC1>[CH3:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COCCCCCC(=O)OC
Reactant: COP(C)(=O)OC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCCCCCC(=O)CP(=O)(OC)OC
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of dimethyl methylphosphonate (8.88 g) in THF (60 ml) was cooled to -60° C. , to which n-butylithium (1.55-M, 46.2 ml) was added dropwise. After addition, the solution was stirred at -60° C. for 30 minutes. A solution of methyl 6-methoxy-caproate (5.65 g) in THF (50 ml) was added dropwise to the resulting solution and held at -60° C. overnight, and at room temperature for 2 hours. After the reaction solution was cooled to 0° C., the reaction was neutralized by addition of acetic acid (4 ml). The crude product obtained after the usual work-up was chromatographed (dichloromethane/methanol (5%)).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][NH2:17].C(OCC)(=O)C>CO.[Pd]>[CH3:16][NH:17][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: CN
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCc1ccc(Oc2ccccc2)cc1
Yield: 80 %

Procedure:
4-Phenoxybenzaldehyde (10.0 g, 0.05 mol), excess methylamine and 1.5 g of 10% Pd/C in 200 mL of methanol were stirred under an atmosphere of hydrogen for 16 hours. After removal of the catalyst by filtration through Celite®, the filtrate was concentrated under reduced pressure to give the crude product as an oil. Chromatography on silica gel eluting with ethyl acetate gave the title compound in 80% yield.
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH:15]=[CH2:16])[C:5]1=[O:6])[CH:2]=[CH2:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:22]=[CH:23][C:24](O)=O>>[CH2:14]([N:7]1[C:8](=[O:9])[C:10]2[NH:13][C:24](/[CH:23]=[CH:22]/[C:21]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:19]([O:18][CH3:17])[CH:20]=3)=[N:12][C:11]=2[N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1=[O:6])[CH:15]=[CH2:16]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: C=CCn1c(N)c(N)c(=O)n(CC=C)c1=O
Product: C=CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3)nc2n(CC=C)c1=O
Yield: 54.2 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.9 g (13.1 mmol) of 1,3-diallyl-5,6-diaminouracil and 2.99 g (14.4 mmol) of 3,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.80 g (yield 54%) of Compound 190 as pale yellow flocculent precipitates.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:15]1[C:24]2[CH:23]([NH2:25])[CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:25][CH:23]2[C:24]3[N:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH2:20][CH2:21][CH2:22]2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC2CCCc3cccnc32)CC1
Yield: 98 %

Procedure:
Using general procedure B: Reaction of Boc-4-piperidone (641 mg, 3.22 mmol 5,6,7,8-Tetrahydro-quinolin-8-ylamine (476 mg, 3.22 mmol), sodium triacetoxyborohydride (1.36 g, 6.44 mmol) and acetic acid (0.25 mL) in THF (25 mL) at room temperature under N2 for 20 min afforded the title compound (1.05 g, 98%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][C:39]#[CH:40])[CH3:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:40]#[C:39][CH2:38][N:37]([CH2:41][CH3:42])[CH2:35][CH3:36])[S:17][C:10]=12
Reactant: C#CCN(CC)CC
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(Cl)c2)CC1
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3Cl)c2s1
Yield: 28.7 %

Procedure:
Prepared from N-(3-chloro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl) -N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.160 g, 0.132 mmol), and N, N-diethylprop-2-yn-1-amine (0.0132 g, 0.118 mmol) according to the procedure for Example 6, Step B. The product was purified by Horizon reverse phase using Biotage 12M C18 column. The crude was loaded to the samplet with EtOAc and dried under vacuum. The product was eluted with 55-75% acetonitrile in water and was obtained as a white powder (20 mg, 26%). 1H NMR (CDCl3, 400 MHz) δ 10.14 (s, 1H), 8.50 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 7.90 (s, 1H), 7.54 (s, 1H), 7.46 (m, 3H), 7.20 (d, J=8.6 Hz, 1H), 7.05 (t, J=8.8 Hz, 2H), 6.42 (d, J=5.5 Hz, 1H), 3.71 (s, 2H), 2.65 (q, J=7, 14 Hz, 4H), 1.77 (m, 4H), 1.13 (t, J=7.2 Hz, 6H). LRMS (ESI pos) m/e 591 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9](CC3C=CC(OC)=CC=3OC)[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31]C(=O)OC(C)(C)C)[N:3]=1.CC1(C)C(C)(C)OB([C:47]2[S:48][CH:49]=[CH:50][CH:51]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[NH2:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:4]1[N:3]=[C:2]([C:47]2[S:48][CH:49]=[CH:50][CH:51]=2)[C:7]2[C:8](=[O:22])[NH:9][CH2:10][C:6]=2[C:5]=1[F:23]
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N[C@H]1CCCC[C@H]1Nc1nc(-c2cccs2)c2c(c1F)CNC2=O
Temperature: 80 °C
Yield: 43.9 %

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (300 mg, 0.546 mmol), 4,4,5,5-tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane (172 mg, 0.820 mmol), and trans-dichloro-bis(triphenylphosphine)palladium-II (38.4 mg, 0.055 mmol) were dissolved in dioxane (5 mL). An aqueous solution of 2N Na2CO3 (0.5 mL) was added, the cap was sealed, and the mixture was allowed to react at 85° C. for 3 h. The reaction mixture was subsequently diluted with water (5 mL) and extracted into EtOAc (2×30 mL). The organic layer was dried over sodium sulfate and evaporated. The resulting residue was treated with TFA (4 mL) and heated at 80° C. for 1 h to remove the protecting groups. Next, TFA was evaporated from the reaction mixture. The product was reconstituted in DMSO (8 mL) and was then purified via preparative HPLC eluting with water (0.05% TFA) and ACN (15-45% gradient, 0.035% TFA). The pure fractions were combined and evaporated to a minimal volume. Saturated aq NaHCO3 (10 mL) was added and the mixture was extracted with EtOAc (3×25 mL). The organic layers were combined, dried over sodium sulfate, and evaporated to give the title compound as a pale yellow solid (83 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.80 (m, 8H), 3.18 (br s, 1H), 3.86-4.11 (m, 1H), 4.39 (s, 2H), 6.60 (d, J=6.57 Hz, 1H), 7.13 (dd, J=5.05, 3.79 Hz, 1H), 7.60 (dd, J=5.18, 1.14 Hz, 1H), 8.39 (s, 1H), 9.00 (dd, J=3.79, 1.01 Hz, 1H). [M+H] calc'd for C17H19FN4OS, 347. found, 347.
Reaction SMILES: C([O:9][C:10]1[C:11]([C:22]([O:24]C)=O)=[N:12][C:13]([C:20]#[N:21])=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=O)C1C=CC=CC=1.[CH3:26][O:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].CCOCC>C1(C)C=CC=CC=1>[C:20]([C:13]1[N:12]=[C:11]([C:22]([NH:31][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:28]=2[O:27][CH3:26])=[O:24])[C:10]([OH:9])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2)#[N:21]
Reactant: COc1cccc(CN)c1OC
Reactant: COC(=O)c1nc(C#N)c2cccnc2c1OC(=O)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cccc(CNC(=O)c2nc(C#N)c3cccnc3c2O)c1OC

Procedure:
To a solution of methyl 8-(benzoyloxy)-5-cyano-1,6-naphthyridine-7-carboxylate (264 mg, 0.792 mmol) in anhydrous toluene (12 ml) was added 2,3-dimethoxybenzyl amine (132 mg, 0.79 mmol) and the solution was stirred at reflux under argon overnight. The solvent was removed under reduced pressure to give a brown syrup which was subsequently taken up into ether (10 ml). After stirring for 4 hours the solids were collected by vacuum filtration and dried overnight on an aberhalden to give an off white solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=3[F:21])[CH2:10][C:9]2=[O:22])=[CH:5][N:6]=1.[CH3:23][NH:24][CH3:25].O[Li].O>C1COCC1.O>[CH3:23][N:24]([CH3:25])[C:2]1[S:3][C:4]([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=3[F:21])[CH2:10][C:9]2=[O:22])=[CH:5][N:6]=1
Reactant: CNC
Reactant: O=C1CC(c2cc(F)cc(F)c2F)CN1Cc1cnc(Cl)s1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ncc(CN2CC(c3cc(F)cc(F)c3F)CC2=O)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.3 %

Procedure:
In a sealed tube fitted with a magnetic stirrer, 1-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one 250 (0.3 g, 0.87 mmol) is dissolved in a mixture of THF (4 ml) and H2O (0.1 ml). Dimethylamine (0.85 ml, 1.7 mmol) and LiOH.H2O (0.043 g, 1 mmol) are added and the mixture is stirred at room temperature for 12 h and heated at 50° C. overnight. Dimethylamine (3×3.4 mmol, then 1×5.1 mmol) is added after 24 h, 48 h, 72 h and 96 h heating. THF is evaporated, the residue is dissolved in water and CH2Cl2, the pH of the aqueous phase is brought to 9 and the aqueous phase is extracted with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and concentrated. The crude product is purified by chromatography on silicagel and recrystallized from diisopropylether to afford 0.1 g of 1-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one 251.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][C:8]1([C:28]([O:30][CH:31]2[CH:36]([CH:37]([CH3:39])[CH3:38])[CH2:35][CH2:34][CH:33]([CH3:40])[CH2:32]2)=[O:29])[N:13]2[CH:14]=[CH:15][CH:16]=[C:12]2[C:11](=[O:17])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=2[F:26])[C:9]1=[O:27])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:10]2[C:9](=[O:27])[C:8]([C:28]([O:30][CH:31]3[CH:36]([CH:37]([CH3:39])[CH3:38])[CH2:35][CH2:34][CH:33]([CH3:40])[CH2:32]3)=[O:29])([CH2:7][C:6]([OH:41])=[O:5])[N:13]3[CH:14]=[CH:15][CH:16]=[C:12]3[C:11]2=[O:17])=[C:20]([F:26])[CH:21]=1
Reactant: CC1CCC(C(C)C)C(OC(=O)C2(CC(=O)OC(C)(C)C)C(=O)N(Cc3ccc(Br)cc3F)C(=O)c3cccn32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCC(C(C)C)C(OC(=O)C2(CC(=O)O)C(=O)N(Cc3ccc(Br)cc3F)C(=O)c3cccn32)C1

Procedure:
A mixture of 2-(4-bromo-2-fluorobenzyl)-4-(-)-menthyloxycarbonyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-acetic acid tert-butyl ester (Diastereomer A) (30.0 g) and trifluoroacetic acid (112.5 g, 76.0 ml) in anhydrous dichloromethane (120 ml) was refluxed for 1.5 hours and concentrated under reduced pressure. The residue was dissolved in a mixture of acetonitrile and toluene. The resulting solution was evaporated under reduced pressure to give the title compound (Diastereomer A) (27.3 g, quantitative) as a brown oil.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[O:22]([CH2:29][CH2:30]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:30][CH2:29][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCOc2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.25 g--see Preparation 8), 2-phenoxyethyl bromide (0.18 g), anhydrous potassium carbonate (0.3 g) and acetonitrile (10 ml) was heated under reflux for 1.5 hours. On cooling to room temperature, water (60 ml) was added and the mixture extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated vacuo to give a foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.18 g.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([N:4]1[N:3]=[C:2]([Br:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1[nH]nc(Br)c2ccccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2c(Br)nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
4-Bromo-2H-phthalazin-1-one (10.38 g, 46 mmol) was dissolved in dimethylformamide (DMF) (60 ml). To this was added NaH (60%, 1.55 g, 46.2 mmol) as a DMF suspension (20 ml). The mixture was stirred at room temperature for 30 mins then benzyl bromide (13.82 g, 50.8 mmol) was added in one portion as a solution in DMF (20 ml). The reaction mixture was stirred for 2 hours then the DMF was removed under reduced pressure and the resulting crude material purified by column chromatography (gradient elution: 100% heptane to 20% ethyl acetate: heptane) to give the title compound (8.16 g, 56% yield) as a white solid. 1H-NMR: (400 MHz, D6-DMSO), 8.30 (1H, dd), 8.03 (1H, ddd), 7.97–7.91 (2H, m), 7.34–7.27 (5H, m), 5.31 (2H, s); MS (ESI+)=(M+H)+ 315 & 317
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:23])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:23])[CH3:2]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CC[C@@H]2O
Yield: 96.5 %

Procedure:
Dissolve dl-13-ethyl-3-methoxy-6-methylgona-1,3,5(10)-trien-17-one (7.0 g) in methanol (300 ml) and treat with sodium borohydride (3.0 g). After spontaneous reflux ceases, acidify the reaction mixture with 50% acetic acid (20 ml). Work up by the usual procedures to obtain dl-13-ethyl-3-methoxy-6-methylgona-1,3,5(10) -trien-17β-ol (6.8 g), m.p. 158°-160°; infrared absorption peaks (potassium bromide) at 3.05 μ, 6.45 μ.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:26])[CH:3]=1.[CH3:27][N:28]1[C:32](=[O:33])[CH2:31][NH:30][C:29]1=[O:34]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:30]5[CH2:31][C:32](=[O:33])[N:28]([CH3:27])[C:29]5=[O:34])=[CH:3][C:4]=4[F:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Reactant: CN1C(=O)CNC1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(=O)N(C)C3=O)cc2F)CC1
Yield: 59.4 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (167 mg) described in Preparation Example 121 and 3-methylimidazolidine-2,4-dione (68 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Example 536, the title compound (107 mg) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].C([Li])CCC.Cl[CH2:14][C:15]1[N:24]=[C:23]([N:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH3:26])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>C1COCC1>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([N:25]([CH3:26])[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH2:14][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]3=[O:7])[N:24]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Reactant: O=C1CCCCN1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(N(C)c2nc(CN3CCCCC3=O)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To 2-piperidone (149 mg, 1.5 mmol) in THF (1 mL) at 0° C. was added n-butyllithium (2.5 M, 0.60 mL, 1.5 mmol) followed by a solution of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.43 mmol) in THF (1.5 mL). The reaction was heated to reflux for 2 h, cooled to room temperature, quenched with H2O and diluted with ether. The aqueous phase was extracted with ether (3×10 mL) The combined organic phases were washed with brine, dried (MgSO4), concentrated and purified by gradient MPLC (SiO2, 0-20% MeOH/CH2Cl2 with 0.1% NH4OH) to give 133 mg (82%) of the title compound as a yellow oil. 1H NMR (MeOH-d4) δ 7.73 (d, 1H), 7.52 (dd, 1H), 7.71 (d, 2H), 6.98-6.96 (m, 2H), 6.90 (d, 2H), 4.82 (s, 2H), 3.84 (s, 3H), 3.55 (s, 3H), 3.52 (m, 2H), 2.53 (m, 2H), 1.92-1.88 (m, 4H); LC-MS (ESI+; 377 ([M+H]+)).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[N:7][C:8]#[N:9])[S:5][CH3:6])[CH3:2].[CH:10](N)(C)C.C(N)C>>[CH:1]([NH:3][C:4](=[N:7][C:8]#[N:9])[S:5][CH3:6])([CH3:10])[CH3:2]
Reactant: CC(C)N
Reactant: CCNC(=NC#N)SC
Agent: CCN
Product: CSC(=NC#N)NC(C)C

Procedure:
1-Isopropyl-2-methyl-3-cyanoisothiourea was prepared following the same procedure as for 1-ethyl-2-methyl-3-cyanoisothiourea (see EXAMPLE 250) except isopropylamine was used in lieu of ethylamine. 1H NMR (CDCl3) δ 1.25 (d, 6H, J=6 Hz), 2.49 (br s, 3H), 3.84 (br s, 1H), 6.22 (br s, 1H).