Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][C:4]1([CH3:9])[OH:8].[Cl:10][C:11]1[C:18]([CH3:19])=[C:17](F)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]>>[Cl:10][C:11]1[C:18]([CH3:19])=[C:17]([NH:2][CH:3]2[CH2:7][CH2:6][CH2:5][C:4]2([OH:8])[CH3:9])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].[Cl:10][C:11]1[C:18]([CH3:19])=[C:17]([NH:2][C@@H:3]2[CH2:7][CH2:6][CH2:5][C@:4]2([OH:8])[CH3:9])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: CC1(O)CCCC1N
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: Cl
Product: Cc1c(NC2CCCC2(C)O)ccc(C#N)c1Cl
Product: Cc1c(N[C@@H]2CCC[C@@]2(C)O)ccc(C#N)c1Cl

Procedure:
2-Chloro-4-[[2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile is prepared essentially as described in Example 1 using 2-amino-1-methyl-cyclopentanol, hydrochloride and 2-chloro-4-fluoro-3-methyl-benzonitrile. The crude material was purified using silica gel chromatography (25-55% EtOAc/hexane) to obtain Diastereomer 1 (0.54 g) and Diastereomer 2 (1.56 g). Diastereomer 2 is assigned trans configuration based on co-crystal with AR.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1.C([Li])(C)(C)C.CN([CH:20]=[O:21])C.O.O.C(O)(=O)C(O)=O>CCOCC.O>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:3]1[O:4][CH:5]=[CH:6][C:2]=1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: Brc1ccoc1C1OCCO1
Agent: O=C(O)C(=O)O
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: O=Cc1ccoc1C1OCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
2-(3-Bromo-2-furyl)-1,3-dioxolane (438 mg, 2.0 mmol) is dissolved in Et2O (5 mL) in an oven-dried flask, under nitrogen, cooled to −78° C., treated dropwise with tert-butyllithium (2.59 mL, 4.4 mmol) and stirred for 1 h. DMF (178 μL, 2.3 mmol) in Et2O (2 mL) is added dropwise, the mixture stirred for 4 h at −78° C., then treated with oxalic acid dihydrate (504 mg, 4.0 mmol) followed by water (2 mL). The cooling bath is removed and the mixture allowed to warm to rt over 1 h. The mixture is diluted with water (20 mL) and EtOAc (20 mL), the layers are separated and the aqueous layer extracted with EtOAc (1×20 mL). The organics are dried over Na2SO4 and concentrated to a yellow oil. The crude material is chromatographed over 12 g slurry-packed silica gel, eluting with 15% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 228 mg (68%) of 2-(1,3-dioxolan-2-yl)-3-furaldehyde as a pale yellow oil. MS (EI) m/z: 168 (M+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:15])[C:12]([OH:14])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[N:31]=[N:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1>CN(C=O)C>[Cl:25][C:26]1[N:31]=[N:30][C:29]([NH:32][NH:33][C:12](=[O:14])[CH:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)[CH3:15])=[CH:28][CH:27]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: CC(C(=O)O)c1ccc2ncccc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NNc1ccc(Cl)nn1)c1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 2-(quinolin-6-yl)propanoic acid (3260 mg, 16201 μmol) and DIEA (2830 μl, 16201 μmol) in DMF (25 mL) was added o-(7-azabenzotriazol-1-yl)-n,n,n′,n-tetramethyl uronium hexafluorophosphate (6160 mg, 16201 μmol) whole at 23° C. under nitrogen. The solution was stirred for 60 min, cooled to 0° C., then added 1-(6-chloropyridazin-3-yl)hydrazine (2342 mg, 16201 μmol). After 20 h stirring at 23° C., the reaction was then partitioned between 9:1 CHCl3/IPA (100 mL) and 5% NaHCO3 (50 mL). The organic phase was then dried over MgSO4, concentrated to an oil, then purified on silica (120 g) eluting with 0>10% of 2 M NH3 in MeOH/DCM. The product was isolated as an off white solid. MS (ESI pos. ion) m/z: 328 (MH+). Calc'd exact mass for C16H14ClN5O: 327.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:33]=1[C:34](Cl)=[O:35]>ClCCl.O>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:34]([C:33]2[C:32]([Cl:31])=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:41])=[O:35])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 100.3 %

Procedure:
To a solution of 4-(amino)-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (2.6 g, 8.6 mmol) in dichloromethane (20 mL) were added diisopropylethylamine (2.3 mL, 13 mmol) followed by 2,6-dichlorobenzoyl chloride (1.99 g, 9.5 mmol) at room temperature. The mixture was stirred for 15 h at which time a white precipitate was formed. The mixture was diluted with 30 mL of dichloromethane and 50 mL of water. The layers were separated and the aqueous layer was extracted with 100 mL (2×50 mL) of dichloromethane. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration of the solvent gave 4.03 g (quantitative) of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(1,1-dimethylethoxy)-carbonyl]-L-phenylalanine methyl ester as a white solid, mp 148-151° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][CH:12]=[N:11]1.[H-].[Na+]>CN(C=O)C.O.CCOC(C)=O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: N#Cc1ccc(F)cc1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-n2cccn2)cc1
Temperature: 145 °C
Yield: 76.6 %

Procedure:
To a solution of 4-fluorobenzonitrile (1.5 g, 12.35 mmol) and pyrazole (0.843 g, 12.38 mmol) in DMF (10 mL) was added NaH (60% in oil, 0.644 g, 16.09 mmol). The reaction was heated to 145° C. for 20 h. The reaction was cooled to room temperature and was diluted with water and EtOAc The aqueous layer was washed with EtOAc (3×) and the combined organic layers were washed with water (4×). The organic solution was dried (MgSO4, filtered, and concentrated. Medium pressure chromatography (4:1 hexanes:EtOAc) provided 4-pyrazol-1-yl-benzonitrile (1.6 g) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 1H), 7.82 (d, 2H), 7.73 (m, 3H), 6.87 (d, 1H); MS 170 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:26][C@H:27]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:28][C:29](O)=[O:30])(=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(Cl)CCl.CI>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:14])[C@@H:10]([CH2:12][OH:13])[NH:11][C:29](=[O:30])[CH2:28][C@H:27]([O:26][C:15](=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCCCC
Reactant: N[C@H](CO)C(=O)OCc1ccccc1
Solvent: ClCCCl
Solvent: CI
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@H](CO)C(=O)OCc1ccccc1)OC(=O)CCCCCCCCC
Yield: 91.2 %

Procedure:
In the same manner as described in Example 2-(5), D-serine benzyl ester (390 mg, 2.0 mmol) was acylated with (R)-3-decanoyloxytetradecanoic acid (875 mg, 2.2 mmol) in the presence of EDC·MeI (745 mg, 2.5 mmol) in CH2Cl2 to afford 1.05 g (91%) of N-[(R)-3-decanoyloxytetradecanoyl]-D-serine benzyl ester: mp 51-52° C.; 1H NMR (CDCl3) δ 0.88 (m, 6H), 1.1-1.7 (m, 34H), 2.30 (t, 2H, J=7.7 Hz), 2.50 (m, 2H),3.68 (s, 1H), 3.93 (d, 2H, J=3.1 Hz), 4.62 (m, 1H), 5.22 (m, 3H), 6.63 (d, 1H, J=6.9 Hz), 7.35 (br s, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([O:13][CH:14](O)[CH3:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19](Cl)(=[O:22])(=[O:21])[NH2:20].C(N(CC)CC)C.[OH2:31]>C(#N)C>[C:2]1([CH2:1][O:8][C:9]2[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][O:21][S:19](=[O:22])(=[O:31])[NH2:20])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)Oc1ccc(OCc2ccccc2)cc1
Reactant: O
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)OCCOc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
To a stirred suspension of 30.0 g (0.12 mole) of 4-(benzyloxy)phenoxyethanol in 150 ml of acetonitrile was added simultaneously 59 ml (0.18 mole) of sulfamoyl chloride solution (3.14M solution in acetonitrile) and 19.5 g (0.19 mole) of triethylamine. The resulting clear solution was stirred at ambient temperature for 5 hr and then poured into 2L of water. The resulting solid was collected by filtration and the filter cake was washed with 1.5L of water and dried (air). The solid was recrystallized from chloroform to yield 31.1 g (78%) of a white solid, mp 125°-128° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][Mg]Br.[CH2:12]([N:19]1[CH2:24][CH2:23][O:22][CH:21]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[O:26])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>O1CCCC1>[CH2:12]([N:19]1[CH2:24][CH2:23][O:22][CH:21]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)([OH:26])[CH2:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1cccc(F)c1)C1CN(Cc2ccccc2)CCO1
Reactant: COc1ccccc1C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1CC(O)(c1cccc(F)c1)C1CN(Cc2ccccc2)CCO1
Temperature: 25 °C

Procedure:
A magnetically stirred 0.25M tetrahydrofuran solution of commercially available 2-methoxybenzylmagnesium bromide (available from Rieke-Metals) (80 ml, 3 equiv.) under nitrogen atmosphere was cooled to −10° C. and to this was added neat (4-Benzyl-morpholin-2-yl)-1-(3-fluoro-phenyl)-methanone (2.1 g, 1 equiv.). The solution was allowed to warm to room temperature and reaction progress followed using mass spectrometry. After 1.5 hours 2-methoxybenzylmagnesium bromide solution (14 ml, 0.5 equiv.) was again added to the reaction and after a further 0.5 hours an aqueous saturated solution of NaHCO3 (50 mL) was added to halt the reaction. The aqueous solution was extracted with diethyl ether, the organic phase dried with MgSO4, evaporated in vacuo to give 2.8 g of a yellow amorphous solid. The compound was taken without further purification in the next step. LCMS (6 minutes method) [M+H]+=422 @ Rt 3.03 and 2.86 min. major peaks.
Reaction SMILES: [CH2:1]([N:5]1[C:11]([CH3:13])([CH3:12])[C:9](=[O:10])[NH:8][C:6]1=[O:7])[C:2](=[CH2:4])[CH3:3].[H-].[Na+].[CH2:16](Cl)[C:17](=[CH2:19])[CH3:18].O>CN(C=O)C>[CH2:1]([N:5]1[C:11]([CH3:13])([CH3:12])[C:9](=[O:10])[N:8]([CH2:18][C:17](=[CH2:16])[CH3:19])[C:6]1=[O:7])[C:2](=[CH2:3])[CH3:4]
Reactant: C=C(C)CCl
Reactant: C=C(C)CN1C(=O)NC(=O)C1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)CN1C(=O)N(CC(=C)C)C(C)(C)C1=O
Temperature: 15 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
In a 100 ml three necked flask is placed 10 g (0.055 mol) of N-methallyl-5,5-dimethylhydantoin in 100 ml DMF under nitrogen. The solution is cooled to 15° C. and 2.7 g of sodium hydride/mineral oil is added. The reaction is stirred for 2 hours at 15° C. and then warmed to 25°C. Methallyl chloride (5.1 g, 0.056 mol) is added dropwise over 10 minutes, keeping the temperature at 30° C. The reaction is stirred overnight, then poured into 200 ml water, extracted with 2 X 100 ml ether and dried over magnesium sulfate. After removing the ether in vacuo, the residue is distilled under vacuum (BP 100°-105°0 C. 0.3 mm Hg) to give 11.9 g N,N'-bismethallyl-5,5-dimethylhydantoin.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:11]1([CH2:21][CH2:22]O)[C:20]2[C:15](=CC=CC=2)[CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:22][CH2:21][C:11]2[CH:20]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: OCCc1cccc2ccccc12
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(OCCc2ccccc2)c1
Reaction time: 8 h

Procedure:
A stirred solution of 3-nitrophenol (1.39 g, 10 mmol), 1-naphthaleneethanol (1.89 g, 11 mmol), and triphenylphosphine (2.9 g, 11 mmol) in 100 ml of tetrahydrofuran was treated with a solution of 2.22 g (11 mmol) of diisopropylazodicarboxylate added dropwise. The resulting mixture was stirred overnight, and then concentrated and redissolved in a minimum amount of ethyl acetate. Purification on a silica gel column, eluting with 10% ethyl acetate in hexane, delivered 2.0 g of the ether.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11](C)[CH:10]=[CH:9][C:8]=1[S:14][CH3:15].[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.Cl.[O:30]1CCC[CH2:31]1>>[CH3:31][O:30][C:11]1[CH:10]=[CH:9][C:8]([S:14][CH3:15])=[CH:7][C:12]=1[B:16]([OH:21])[OH:17]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CSc1ccc(C)cc1Br
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]CCCC
Product: COc1ccc(SC)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
1.6M butyllithium in hexanes (3.5 ml, 5.6 mmol) was added dropwise to a stirred solution of 2-bromo-4-methylthioanisole (1.165 g, 5 mmol) in anhydrous tetrahydrofuran (30 ml) at −100° C. under nitrogen and stirred for 5 minutes then warmed to −78° C. for 1 hour. Triisopropyl borate (2.82 g, 15 mmol) was added dropwise and the mixture allowed to warm to room temperature. Hydrochloric acid (30 ml, 30 mmol) were added and the mixture stirred vigorously for 1 hour. The organic phase was separated, washed with brine, dried (MgSO4), evaporated to dryness and the residue purified on Biotage using ethyl acetate/iso-hexane (3:7) to yield the title compound as a white solid. (616 mg, 62%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH3:9])[C:5]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:4]=2[N:3]=1.S(Cl)([Cl:19])=O>ClC(Cl)Cl>[ClH:19].[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH3:9])[C:5]2[CH:10]=[CH:11][C:12]([C:14]([Cl:19])=[O:16])=[CH:13][C:4]=2[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCCn1c(C)nc2cc(C(=O)O)ccc21
Solvent: ClC(Cl)Cl
Product: CCCn1c(C)nc2cc(C(=O)Cl)ccc21
Product: Cl
Reaction time: 0.33 h

Procedure:
To a stirred mixture of 18 parts of 2-methyl-1-propyl-1H-benzimidazole-5-carboxylic acid and 150 parts of trichloromethane are added dropwise 29.8 parts of thionyl chloride. Upon completion, stirring is continued for 20 minutes at reflux. The reaction mixture is cooled, dried, filtered and evaporated, yielding 22.5 parts of 2-methyl-1-propyl-1H-benzimidazole-5-carbonyl chloride monohydrochloride as a residue.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:17]=1)[CH3:14].[CH2:26]([NH2:29])[CH:27]=[CH2:28]>CO>[CH2:26]([NH:29][C:7]1[C:3]([NH:25][CH2:24][CH2:23][S:22][CH2:21][C:19]2[O:20][C:16]([CH2:15][N:13]([CH3:12])[CH3:14])=[CH:17][CH:18]=2)=[N:4][S:5](=[O:10])(=[O:11])[N:6]=1)[CH:27]=[CH2:28]
Reactant: C=CCN
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CO
Product: C=CCNC1=NS(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.08 g; 11.7 mmoles) in 200 ml of methanol that had been cooled to 0° in an ice-water bath was added dropwise over a period of 45 minutes a solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine in 30 ml of methanol. When the addition was completed, 10.5 ml of allylamine was added and the solution was allowed to stir at ambient temperature for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was placed on 120 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fractions were combined, evaporated under reduced pressure and the residue crystallized with isopropyl alcohol to give the title compound, mp 83°-86°; the NMR spectrum (100 MHz) in d6 dimethyl sulfoxide showed the presence of approximately 0.9 moles of isopropyl alcohol.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH:9]([CH3:12])[CH:10]=[O:11].[CH3:14][C:15]([CH3:18])([O-])[CH3:16].[K+].C(Cl)C(=C)C>CN(C=O)C>[CH3:12][C:9]([CH:6]1[CH2:5][CH2:4][CH:3]2[CH2:8][CH:7]1[C:2]2([CH3:13])[CH3:1])([CH2:16][C:15]([CH3:18])=[CH2:14])[CH:10]=[O:11]
Reactant: CC(C)(C)[O-]
Reactant: CC(C=O)C1CCC2CC1C2(C)C
Agent: C=C(C)CCl
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)CC(C)(C=O)C1CCC2CC1C2(C)C
Yield: 72.4 %

Procedure:
In a similar manner to Example 6, 100 g of the aldehyde from Example 58 at a purity of 85% (0.47 mole) in 75 ml of DMF, 82 g of potassium t-butoxide (0.69 mole) in 500 ml of DMF, and 78 g of methallyl chloride (0.86 mole) in 50 ml of DMF were reacted in the usual way. In this way 116.2 g of crude O- and C-alkylates (58.1:33.8) were obtained. The crude product was heated at 165°-170° C. for 2 hours. The crude aldehyde was distilled to afford 94.1 g of purified product (85% yield). BP 85° C./0.05 mmHg; 1H-NMR (300 MHz), δ 0.95 (3H, s), 0.96 (3H, s), 1.18 (3H, s), 1.2-1.4 (2H, m), 1.59 (3H, s), 1.7-2.5 (9H, m), 4.64 (1H, s), 4.80 (1H, s), 9.57 (1H, s); 13C-NMR (75 MHz), spectra consistent with assigned structures; IR (Neat), 2960, 2700, 1725, 1645, 1470, 1370, 895 cm-1 ; MS (m/e), 234 (M+), 219, 203, 191, 177, 163, 151, 135, 123, 109, 97, 81, 41 (Base);
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C([SiH](CC)CC)C.[C:44]1([S:50]([C:53]2[CH:60]=[CH:59][CH:58]=[CH:57][C:54]=2[CH:55]=O)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:3]=1[CH2:55][C:54]1[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=1[S:50]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:52])=[O:51]
Reactant: CCOC(=O)Cn1c(C)cc(-c2ccccc2)c1-c1ccccc1
Reactant: O=Cc1ccccc1S(=O)(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
In a scintillation vial, ethyl 2-(5-methyl-2,3-diphenyl-1H-pyrrol-1-yl)acetate (0.3 g, 0.939 mmol) was dissolved in 10 mL of DCM and the mixture cooled to −78° C. Trimethylsilyl trifluoromethanesulfonate (0.382 ml, 2.113 mmol) was then added followed by triethylsilane (0.450 ml, 2.82 mmol). The resulting mixture was stirred at −78° C. for 30 minutes. At this time, 2-(phenylsulfonyl)benzaldehyde (0.231 g, 0.939 mmol) was added portionwise as a solution in 2.0 mL of DCM and the reaction evolution was monitored by LC/MS. Following addition of the aldehyde, the cold bath was removed and the reaction was stirred overnight (gradually warming to room temp). The reaction was quenched with a sodium bircarbonate solution and moved to a separatory funnel. Layers were separated and the aqueous portion was extracted 2 additional times with DCM. The organics were combined, dried, filtered, and concentrated. The crude oil was purified by column chromatography (SiO2) using a 0-40% EtOAc/hexane gradient to give ethyl 2-(2-methyl-4,5-diphenyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (294 mg, 0.535 mmol, 56.9% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.31-8.29 (m, 1H), 7.84-7.82 (m, 2H), 7.52-7.48 (m, 2H), 7.42-7.38 (m, 3H), 7.28-7.21 (m, 4H), 7.15-7.13 (m, 2H), 6.93-6.86 (m, 3H), 6.75-6.73 (m, 2H), 4.51 (s, 2H), 4.21 (q, 2H), 4.04 (s, 2H), 1.79 (s, 3H), 1.25 (t, 3H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)[CH:8]=[O:9].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1>ClC(Cl)C>[Cl:3][C:19]([C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[F:11])=[C:20]([C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1)[CH:8]=[O:9]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ccc(CC(=O)c2ccc(F)cc2F)cc1
Solvent: CC(Cl)Cl
Product: CSc1ccc(C(C=O)=C(Cl)c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of phosphorus oxychloride (3.2 ml) and N,N-dimethylformamide (3.4 ml) in dichloroethane (25 ml) was stirred at ambient temperature for 1 hour and 2',4'-difluoro-2-[4-(methylthio)phenyl]acetophenone (6.2 g) was added thereto. The mixture was refluxed for 8 hours, washed with water twice, dried and evaporated to give 3-chloro-3-(2,4-difluorophenyl)-2-[4(methylthio)phenyl]propenal as a solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:30]1[CH:35]=[C:34]([CH:36]2[CH2:38][CH2:37]2)[N:33]=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[CH:36]1([C:34]2[N:33]=[CH:32][N:31]=[C:30]([N:20]3[CH2:21][CH2:22][C:16]4[C:15]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[N:14][C:13]([C:10]5[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=5)=[N:18][C:17]=4[CH2:19]3)[CH:35]=2)[CH2:38][CH2:37]1
Reactant: Clc1cc(C2CC2)ncn1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cc(C4CC4)ncn2)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0597 g, 0.156 mmol), 4-chloro-6-cyclopropylpyrimidine (0.046 g, 0.30 mmol), N,N-Diisopropylethylamine (0.0570 mL, 0.327 mmol), and dry N,N-Dimethylformamide (0.84 mL, 11 mmol) were combined, the reaction was microwaved on 200 watts, 120° C. for 20 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 8.37 (s, 1H), 8.21 (d, J=8.8, 2H), 7.50 (d, J=8.8, 2H), 6.91 (s, 1H), 6.21 (t, J=5.5, 1H), 4.70 (s, 2H), 3.88 (s, 2H), 3.73 (d, J=4.5, 4H), 3.48 (d, J=4.3, 4H), 3.16-3.08 (m, 2H), 2.75 (s, 2H), 2.01-1.91 (m, 1H), 1.06 (t, J=7.2, 3H), 1.02-0.88 (m, 4H). LC/MS-m/z+501.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[N:4]([CH3:6])C.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:14]N(C)C=O>[Pd]>[CH3:1][O:2][C:3]1[CH:14]=[C:11]2[CH:12]=[CH:13][NH:9][C:10]2=[CH:6][N:4]=1
Reactant: CN(C)C=O
Reactant: COC(OC)N(C)C
Reactant: C1CCNC1
Agent: [Pd]
Product: COc1cc2cc[nH]c2cn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
10.76 g of N,N-dimethylformamide dimethyl acetal and 2.45 ml of pyrrolidine are added, in succession, to a solution of 5 g of the product obtained in Step 1 in 60 ml of dimethylformamide. The mixture obtained is first heated at 100° C. for 8 hours and then at 150° C. for 1 hour. Concentration is carried out under a vacuum of 10−1 mbar and the residue is taken up in 150 ml of tetrahydrofuran. The solution obtained is hydrogenated under a pressure of 10 bars for 4 hours in the presence of 10% Pd/C. After filtration and concentration, the residue is chromatographed over silica (eluant CH2Cl2/EtOH: 95/5) to yield the expected product.