Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([C:12](OCC)=[O:13])[CH2:7]1)=[O:5].[Li+].[Cl-].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(Cl)Cl.O.C(O)C>[OH:13][CH2:12][C@H:8]1[CH2:9][CH2:10][CH2:11][N:6]([C:4](=[O:5])[CH2:3][CH:2]([CH3:1])[CH3:17])[CH2:7]1
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)CC(C)C)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)CC(=O)N1CCC[C@H](CO)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
A solution of (S)-ethyl 1-(3-methylbutanoyl)piperidine-3-carboxylate (Example 5e, 37.4 g, 154.97 mmol) in anhydrous THF (200 mL) was cooled down to 0° C. and treated with LiCl (17 g, 401.04 mmol). After stirring for 5 min, NaBH4 (15 g, 396.50 mmol) was added at the same temperature. The reaction was cooled down further to −20 C and anhydrous ethanol (400 mL) was added dropwise. The reaction was kept on the cooling bath, allowed to warm up slowly to room temperature and stirred overnight. Ethanol (100 mL) was added and the reaction was treated portionwise with saturated aqueous citric acid solution (600 mL) and stirred for another 30 min. Volatiles were removed under vacuum to give a thick colorless material. Water (100 mL) and DCM (800 mL) were added to the residue and the mixture was stirred vigorously for 15 minutes. The phases were separated and the aqueous phase was further extracted with DCM (2×800 ML). The combined organic extract was washed with brine and dried over Na2SO4. The solvent was removed under vacuum to give a colorless residue that was purified by chromatography on silica gel (3eluent: Hex/EtOAc 0-100) to yield the clean product (29.65 g, 148.79 mmol, 96%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[N:13][C:14]([CH:18]2[CH2:20][CH2:19]2)=[C:15]([Cl:17])[CH:16]=1)[C:5]#[N:6].[CH3:21][O:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:17][C:15]1[CH:16]=[C:11]([O:10][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[C:28]2[C:23]([O:22][CH3:21])=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=[N:13][C:14]=1[CH:18]1[CH2:20][CH2:19]1
Reactant: N#Cc1ccc(Oc2cnc(C3CC3)c(Cl)c2)c(Br)c1
Reactant: COc1ncccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncccc1-c1cc(C#N)ccc1Oc1cnc(C2CC2)c(Cl)c1
Temperature: 75 °C
Yield: 92.3 %

Procedure:
3-bromo-4-(5-chloro-6-cyclopropylpyridin-3-yloxy)benzonitrile (Preparation 38, 485 mg, 1.37 mmol), 2-methoxypyridin-3-ylboronic acid (233 mg, 1.53 mmol) and cesium carbonate were suspended in dioxane (6 mL) and water (3 mL). The suspension was degassed 20 minutes with nitrogen then tetrakis-triphenylphosphinepalladium (80 mg, 0.07 mmol) were added and the reaction mixture was heated overnight at 75° C. The solution was concentrated in vacuo to a quarter of the volume then diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford the title compound as a foam (478 mg, 91%).
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[O:59])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[C:39]2[CH:44]=[C:43]([C:45](=[O:58])[NH:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=3)[CH:42]=[CH:41][N:40]=2)[CH:20]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](OC(C)(C)C)=O)[CH2:7][CH2:6]1.ClCCl.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[CH3:1][N:2]([CH2:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[C:25]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]2)=[CH:29][C:28]=1[C:39]1[CH:44]=[C:43]([CH:42]=[CH:41][N:40]=1)[C:45]([NH:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:55])([F:57])[F:56])[CH:49]=1)=[O:58])=[O:59])[CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]1
Reactant: CN(CCN1CCN(C(=O)OC(C)(C)C)CC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(CCN(C)Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Reaction time: 2 h
Yield: 31.5 %

Procedure:
Into a 25-mL round-bottom flask, was placed 160 mg of tert-butyl 4-(2-(methyl(3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)-carbamoyl)benzyl)amino)ethyl)piperazine-1-carboxylate Example 38 and 10 mL of 1:1 dichloromethane/TFA. After stirring for 2 hours, the solvent was evaporated. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was dried and the solvent was evaporated. The residue was treated with triethylamine (78 mg, 0.77 mmol, 6.00 equiv), and dichloromethane (2 mL). This was followed by dropwise addition of a solution of methanesulfonyl chloride (21.9 mg, 0.19 mmol, 1.50 equiv) in dichloromethane (1 mL) with stirring at 0° C. The resulting solution was stirred for 4 h at 25° C. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 45 mg (28%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.31 (s, 1H), 9.55-9.59 (t, J=6.6 Hz, 1H), 8.93-8.94 (d, J=3 Hz, 1H), 8.35 (s, 1H), 8.27-8.30 (d, J=9 Hz, 1H), 8.09 (s, 1H), 7.96-7.98 (d, J=6 Hz, 1H), 7.85-7.86 (d, J=3 Hz, 1H), 7.56-7.76 (m, 7H), 7.31-7.34 (d, J=9 Hz, 1H), 4.62-4.64 (d, J=6 Hz, 2H), 4.39 (s, 2H), 3.34 (s, 4H), 3.22-3.24 (d, J=6 Hz, 6H), 2.90 (s, 5H), 2.74 (s, 3H), 2.69 (s, 4H), 1.75 (s, 4H), 1.60-1.61 (d, J=3 Hz, 2H). MS (ES, m/z): 792 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[NH2:21][C:22]1[CH:35]=[CH:34][C:25]2[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.Cl>O1CCOCC1.COCCO>[Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:21][C:22]3[CH:35]=[CH:34][C:25]4[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=4[CH:23]=3)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Temperature: 25 °C

Procedure:
Combined 3-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (100 mg, 0.3015 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (75 mg, 0.367 mmol), 4 N HCl in dioxane (76 ul) and 2-methoxyethanol (4 mL). Heated reaction to 120° C. for 1.5 hours. Let reaction cool to room temperature and evaporated off solvent. Purified with normal phase and reverse phase chromatography to yield a white solid, 3-Chloro-2-[5-chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide. LCMS: m/z=499.59 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.11 (m, 2H), 7.98 (s, 1H), 7.60 (d, 1H, J=8.1 Hz), 7.52 (d, 1H, J=7.6 Hz), 7.43 (m, 2H), 7.21 (s, 1H), 6.70 (d, 1H, J=8.6 Hz), 6.10 (m, 1H), 4.70 (s, 1H), 2.82 (d, 3H, J=4.8 Hz), 2.35 (m, 2H), 2.06 (m, 2H), 1.32 (s, 6H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:33]2[CH:48]=[CH:47][C:36]([O:37][CH2:38][CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[CH:35][CH:34]=2)O1>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:33]2[CH:48]=[CH:47][C:36]([O:37][CH2:38][CH2:39][CH2:40][N:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)=[CH:35][CH:34]=2)=[CH:3][CH:4]=1
Reactant: CC1(C)OB(c2ccc(OCCCN3CCOCC3)cc2)OC1(C)C
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2ccc(OCCCN3CCOCC3)cc2)o1
Temperature: 120 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (50 mg, 0.155 mmol) in dioxane/water (5% water) was added Cs2CO3 (152 mg, 0.466 mmol) and 4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)morpholine (65 mg, 0.186 mmol). The mixture was degassed with nitrogen for 5 minutes then heated in microwave for 20 minutes at 120° C. The solution was diluted with water and the solid formed was isolated by filtration. The solid was purified by HPLC to yield 5-chloro-3-((5-(4-(3-morpholinopropoxy)phenyl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=465).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[N:5][N:6]=1.[C:14]([C:21](OCC)=[O:22])#[C:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH:8]([N:7]([CH:11]([CH3:13])[CH3:12])[C:4]1[S:3][C:2]2=[N:1][C:21](=[O:22])[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:6]2[N:5]=1)([CH3:9])[CH3:10]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: CC(C)N(c1nnc(N)s1)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2sc(N(C(C)C)C(C)C)nn12

Procedure:
Following the procedure described in Example 5, 4.9 g of 2-amino-5-[di-(isopropyl)-amino]-1,3,4-thiadiazole were reacted with 4.2 g of diethyl acetylenedicarboxylate in the presence of 100 ml of ethanol. The ethyl 2-[di-(isopropyl)-amino]-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin 7-one-5-carboxylate obtained was recrystallized from ethyl acetate.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:13]([C:21]#[N:22])[CH:14]=[C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][C:16]=12.[CH2:23](Br)[CH:24]=[CH2:25]>>[CH2:25]([N:17]1[C:16]2=[C:11]([N:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)[N:12]=[C:13]([C:21]#[N:22])[CH:14]=[C:15]2[CH:19]=[C:18]1[CH3:20])[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: Cc1cc2cc(C#N)nc(N3CCc4ccccc4C3)c2[nH]1
Product: C=CCn1c(C)cc2cc(C#N)nc(N3CCc4ccccc4C3)c21
Yield: 79 %

Procedure:
In accordance with the same procedures as in Example 657, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Step 2 and allyl bromide, the titled compound was obtained as a white solid. (Yield: 79%)
Reaction SMILES: [OH:1][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1)[C:3]([OH:5])=[O:4].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CCOC(C)=O>[OH:1][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1)[C:3]([O:5][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: Cc1cccc(C[C@@H](O)C(=O)O)c1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cccc(C[C@@H](O)C(=O)OCc2ccccc2)c1

Procedure:
A solution of (R)-2-hydroxy-3-(3-methylphenyl)-propionic acid (6.3 g, 35.0 mmol), benzyl bromide (5.4 mL, 45.5 mmol) and triethylamine (7.31 mL, 52.4 mmol) in EtOAc (100 mL) is refluxed for 6 hours. After cooling, the solution is washed with 1 N HCl (150 mL), water (200 mL), sat'd NaHCO3 (200 mL) and brine (300 mL), dried (MgSO4), evaporated and chromatographed (silica, 10% EtOAc/hexane) to yield benzyl (R)-2-hydroxy-3-(3-methylphenyl)-propionate, as a clear oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si](C)(C)C)=[CH:12][N:11]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:9][CH2:8][CH2:7][N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[N:11][CH:12]=1)#[CH:17]
Reactant: C[Si](C)(C)C#Cc1ccc(NCCN2CCOCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1ccc(NCCN2CCOCC2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-(2-morpholinoethyl)-5-(2-(trimethylsilyl)ethynyl)pyridin-2-amine (2.0 g, 6.60 mmol) was dissolved in methanol (30 mL) before it was cooled to 0° C. and potassium carbonate (1.0 g, 7.26 mmol) added. The reaction mixture was stirred for 1 h at ambient temperature, then diluted with 50 mL EtOAc, washed with 20 mL saturated, aqueous NaHCO3, and dried over anhydrous Na2SO4 to give the title compound. MS (ES+): 232 (M+H).
Reaction SMILES: Br[C:2]1[C:7]([CH2:8]Cl)=[CH:6][C:5]2[O:10][CH2:11][O:12][C:4]=2[CH:3]=1.C([Li])(C)(C)C.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:30]=[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27]>>[C:37]([C:31]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:8][C:7]2[C:2](=[CH:3][C:4]3[O:12][CH2:11][O:10][C:5]=3[CH:6]=2)[CH:30]1[C:22]1[CH:21]=[C:20]([O:19][CH3:18])[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=1)([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)C(=Cc1cc(OC)c(OC)c(OC)c1)C(=O)OCC
Reactant: ClCc1cc2c(cc1Br)OCO2
Agent: [Li]C(C)(C)C
Product: CCOC(=O)C1(C(=O)OCC)Cc2cc3c(cc2C1c1cc(OC)c(OC)c(OC)c1)OCO3
Yield: 80.4 %

Procedure:
6-bromo-3,4-methylenedioxybenzyl chloride (364 mg, 1.45 mmol) is reacted as in Example 2 with t-butyllithium (0.98 ml, 1.5 mmol, 1.55 M in pentane) and diethyl (3,4,5-trimethoxyphenyl)methylenemalonate (490 mg, 1.45 mmol) to provide the title compound (551 mg, 81% yield).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[C:11]([NH:13][C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.CN([CH:48]=[O:49])C>C1COCC1>[O:1]([C:8]1[CH:25]=[CH:24][CH:23]=[C:10]2[C:9]=1[CH:48]([OH:49])[N:13]([C:14]([CH3:15])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:22])[C:11]2=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)(NC(=O)c1cccc(Oc2ccccc2)c1)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(c1ccccc1)N1C(=O)c2cccc(Oc3ccccc3)c2C1O
Yield: 90.1 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-phenoxy-N-(1-methyl-1-phenylethyl)benzamide (4.00 g, 12.1 mmol) was dissolved in THF (160 mL), and the solution was treated with TMEDA (5.80 mL, 38.7 mmol), sec-butyllithium-hexane solution (0.99 mol/L, 39.0 mL, 38.7 mmol) and DMF (2.10 mL, 26.6 mmol), followed by purification by slurry using diisopropylether to obtain 4-phenoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (3.92 g, yield 90%).
Reaction SMILES: CO.C[O-].[Na+].[CH3:6][O:7][C:8]([CH2:10]P(OC)(OC)=O)=[O:9].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[N:31]=[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:33][CH:34]=1)[CH:23]=O)[CH3:18]>CN(C)C=O>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[N:31]=[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:33][CH:34]=1)[CH:23]=[CH:10][C:8]([O:7][CH3:6])=[O:9])[CH3:18]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CCOc1cc(C=O)ccc1OCc1coc(-c2ccccc2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1cc(C=CC(=O)OC)ccc1OCc1coc(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
A methanol solution of sodium methoxide (28%, 3.4 g) was added dropwise to an ice-cooled solution of trimethyl phosphonoacetate (3.2 g) and 3-ethoxy-4-(2-phenyl-4-oxazolylmethoxy)benzaldehyde (5.1 g) in N,N-dimethylformamide (DMF) (30 ml). The mixture was stirred for 5 minutes under ice-cooling, then for 4 hours at room temperature. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated to yield methyl 3-ethoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnamate (5.5 g, 91%), which was recrystallized from chloroform-ether to give colorless prisms, m.p.125-126° C.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH3:40].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.CO.C(OCC)(=O)C>[OH:3][C:2]1[CH2:4][O:5][C:6](=[O:7])[C:1]=1[C:27](=[O:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: O=C1COC(=O)C1
Reactant: CCCC/C=C\CCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCC/C=C\CCCCCCCC(=O)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.8 %

Procedure:
To a stirring solution of 111 mg (1.11 mmol) of tetronic acid in 5 mL of dimethylformamide is added 185 μL (1.33 mmol) of triethylamine and 100 mg of 4-dimethylaminopyridine at 0° C. Next, 303 mg (1.33 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 300 mg (1.33 mmol) of myristoleic acid are added and the reaction mixture is stirred 3 days at room temperature. The reaction is acidified with 1.0N HCl and extracted with four 100 mL portions of ethyl acetate. The combined organic layers are dried over MgSO4 and concentrated in vacuo affording crude compound. Pure material is obtained by flash chromatography with 10% methanol/ethyl acetate as eluant affording 280 mg (82%) of 4-hydroxy-3-((Z)-1-oxo-9-tetradecenyl)-2(5H)-furanone.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:17][N:18]([CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[CH3:19]>>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)=[N:4][C:5]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][CH2:20][N:18]([CH3:17])[CH3:19])=[CH:30][CH:29]=2)=[N:6][CH:7]=1
Reactant: CN(C)CCCOc1ccc(N)cc1
Reactant: Cc1cccc(Nc2nc(Cl)ncc2Br)n1
Product: Cc1cccc(Nc2nc(Nc3ccc(OCCCN(C)C)cc3)ncc2Br)n1

Procedure:
Using an analogous method to that described in Example 136, but starting from 5-bromo-2-chloro-4-[(6-methylpyrid-2-yl)amino]pyrimidine (Method 84) and 4-[3-(N,N-dimethylamino)propoxy]aniline (obtained as described in WO 9909030), the product was obtained. MS (MH+): 457, 459; HPLC (RT): 5.26.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:17]=[C:16]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:40])C.[OH-].[Na+].Cl>C(O)C>[CH3:40][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=3)[CH:17]=[C:16]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:41])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(Oc3cccc(C(F)(F)F)c3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(Oc3cccc(C(F)(F)F)c3)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(3-trifluoromethyl-phenoxy)phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (160 mg; 0.27 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 128 mg (84%). HPLC-MS: m/z: 558.4 (M+H)+; Rt: 1.91 min. δH (400 MHz; CDCl3) 2.26 (s, 3H), 3.05-3.55 (m, 4H), 3.91-4.04 (m, 4H), 4.11 (s, 2H), 4.70 (s, 2H), 6.71-6.78 (m, 3H), 6.81-6.84 (m, 1H), 7.11-7.16 (m, 1H), 7.19-7.23 (m, 1H), 7.27-7.33 (m, 2H), 7.37-7.41 (m, 1H), 7.43-7.49 (m, 1H).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[C:14](=[O:15])[NH:13][C@H:12]1[C:16](OC)=O)=[O:9])([CH3:6])([CH3:5])[CH3:4].OCC1CCN1.CC1C=CC(S(O)(=O)=O)=CC=1.[N-:37]=[N+:38]=[N-:39].[Na+]>>[N:37]([CH2:16][C@H:12]1[C@@H:11]([NH:10][C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:9])[C:14](=[O:15])[NH:13]1)=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1NC(=O)[C@@H]1NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OCC1CCN1
Agent: [BH4-]
Product: CC(C)(C)OC(=O)N[C@H]1C(=O)N[C@H]1CN=[N+]=[N-]

Procedure:
Sodium borohydride reduction of methyl cis-3-t-butoxycarbonylamino-4-oxoazetidine-2-carboxylate as described in Preparation 3, followed by conversion of the 2-hydroxymethylazetidine product to the p-toluenesulfonate derivative, mp 160°-162°(d), and the reaction of the derivative with sodium azide as described in Preparation 4 gives the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:25])=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[NH:26]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:37][NH2:38])[CH2:27]1>>[NH2:38][CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH:28]1[CH2:29][CH2:30][N:26]([C:11]2[CH:10]=[C:9]3[C:4]([C:5](=[O:24])[C:6]([C:21]([OH:23])=[O:22])=[CH:7][N:8]3[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])=[C:3]([CH3:25])[C:2]=2[F:1])[CH2:27]1
Reactant: NCc1ccccc1C1CCNC1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Product: Cc1c(F)c(N2CCC(c3ccccc3CN)C2)cc2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Yield: 72 %

Procedure:
Starting from 6,7-difluoro-1-(2,4 difluorophenyl)-1,4 dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid (0.40 g, 1.1 mmol) and 2-(3 pyrrolidinyl)benzenemethanamine, a procedure analogous to that given in Example 1, provided the title compound (0.40 g, 72%) as a beige solid, mp 283°-285° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[C:15](=[O:21])[CH2:16][CH2:17][C:18]=3[O:19][CH3:20])[C:11]([CH3:22])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:31]([CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32]>O1CCCC1.CCCCCC.O1CCCC1.C(C1C=CC=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[C:15](=[O:21])[CH:16]([CH:31]([OH:32])[CH:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:17][C:18]=3[O:19][CH3:20])[C:11]([CH3:22])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=CC1CCOCC1
Reactant: COC1=C(c2nc(-c3ccc(Cl)cc3)ncc2C)C(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCC
Product: COC1=C(c2nc(-c3ccc(Cl)cc3)ncc2C)C(=O)C(C(O)C2CCOCC2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.5 %

Procedure:
A solution of 2-[2-(4-Chloro-phenyl)-5-methyl-pyrimidin-4-yl]-3-methoxy-cyclopent-2-enone (69.5 mg, 0.22 mmol) in anhydrous tetrahydrofuran (3 ml), under nitrogen, was cooled to −78° C. and stirred for 10 minutes before the drop wise addition of lithium diisopropylamide (as a 2.0M solution in hexane/tetrahydrofuran/ethylbenzene) (0.14 ml, 0.28 mmol). The resulting brown solution was stirred at −78° C. for a further 45 minutes before the drop wise addition of 4-formyltetrahydropyran (34 mg, 0.30 mmol). The orange solution was then warmed to room temperature. After 2.5 h the reaction was shown to have reached a steady state and was therefore quenched with saturated ammonium chloride (5 ml), ethyl acetate (5 ml) and water (1 ml). The biphasic mixture was separated and the aqueous layer further extracted with ethyl acetate (2×5 ml). Combined organics were dried over magnesium sulphate, filtered and stripped to dryness to yield a yellow oil. This was purified by normal phase chromatography (100% dichloromethane−5% methanol:dichloromethane) to give 2-[2(4-Chloro-phenyl)-5-methyl-pyrimidin-4-yl]-5-[hydroxy-(tetrahydro-pyran-4-yl)-methyl]-3-methoxy-cyclopent-2-enone as a dark yellow oil (50.3 mg, 0.12 mmol, 53% yield).