Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C@@H:12]1[C@H:17]([CH3:18])[CH2:16][CH2:15][NH:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[CH:11][C:4]=12.O=C1CCC(=O)N1[O:26][C:27](=O)[CH2:28][C:29]#[N:30].C(O)C>>[CH3:18][C@@H:17]1[CH2:16][CH2:15][N:14]([C:27](=[O:26])[CH2:28][C:29]#[N:30])[CH2:13][C@@H:12]1[N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[CH:11][C:4]=12
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: C[C@@H]1CCNC[C@@H]1N(C)c1ccnc2[nH]ccc12
Solvent: CCO
Product: C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)c1ccnc2[nH]ccc12
Reaction time: 8 h
Yield: 182.5 %

Procedure:
A mixture of N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-N-(1H-pyrrolo [2,3-b]pyridin-4-yl)-amine (43.0 mg, 0.000176 mol) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (38 mg, 0.00021 mol) in ethanol (1 mL, 0.02 mol) was stirred overnight. The reaction mixture was partitioned between ethyl acetate/THF and sat. NaHCO3, and the organic layer was washed by sat. NaCl. The solvent was removed under vacuum to give 100 mg of an orange solid which was chromatographed with 7% MeOH/DCM, 0.7% NH4OH to give 17 mg of pale orange solid. The crude product was triturated with Et2O and the resulting solid was filtered and washed to give 9.4 mg of wet pale orange solid which was dried at from room temperature to about 60° C. for 3.5 h to give 6.5 mg of the final product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:10][CH2:9][C:8]([O:12][CH3:13])=[O:11]
Reactant: NCc1cccs1
Reactant: C=CC(=O)OC
Solvent: CCO
Product: COC(=O)CCNCc1cccs1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of thiophen-2-ylmethanamine (20.0 g, 176.7 mmol) in ethanol (1 L) at 0° C. was added methyl acrylate (15.21 g, 176.7 mmol). The reaction was allowed to warm to room temperature overnight, at which point HPLC analysis indicated that the reaction was complete. The solvent was removed in vacuo to give methyl 3-(thiophen-2-ylmethylamino)propanoate (Compound 1040) as a pale tan oil (35.21 g, 99%); 1H NMR (300 MHz, CDCl3): δ 7.28 (s, CHCl3), 7.22 (dd, J=1.5, 4.7 Hz, 1H), 6.97-6.95 (m, 2H), 4.16 (q, J=7.1 Hz, 2H), 4.02 (s, 3H), 3.69 (d, J=5.0 Hz, 2H), 2.95 (t, J=6.5 Hz, 2H) and 2.57-2.48 (m, 2H).
Reaction SMILES: [C:1](=[NH:20])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:21]([CH:23]([CH2:28][C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[N:33][CH:34]=1)[C:24](OC)=O)=[O:22].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:24]=[C:23]([CH2:28][C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[N:33][CH:34]=4)[C:21](=[O:22])[N:20]=3)=[CH:11][CH:10]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Temperature: 135 °C
Yield: 18.4 %

Procedure:
A mixture of 4-(4-fluorophenoxy)phenethyl carbamimidate (50 mg, 0.182 mmol), methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (49.0 mg, 0.219 mmol) and K2CO3 (101 mg, 0.729 mmol) in NMP (2 mL) was heated with a microwave reactor at 135° C. for 2 h. Purification via MDAP then afforded the title compound (15 mg, 18.35% yield). LCMS: rt=3.14 min, [M+H+]=449
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:29]=1[CH:30]=[O:31].[Cl-].[NH4+]>O1CCCC1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:29]=1[CH:30]([OH:31])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: Cc1ccccn1
Reactant: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C=O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(O)Cc2ccccn2)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
2-Picoline (40 μl) was dissolved in tetrahydrofuran (2 ml), and the solution was cooled to −78° C. under an argon atmosphere. n-Butyllithium (1.56 M hexane solution) (260 μl) was added to the cooled solution, and the mixture was stirred for 2 hr. A solution of 2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methoxy-benzaldehyde (100 mg) in tetrahydrofuran (2 ml) was then added to the reaction solution, and the mixture was stirred at −78° C. for one hr. A saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (37 mg, yield 29%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:9]2)[CH:3]=1.C(N(CC)C(C)C)(C)C>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:8]=[C:4]2[CH:3]=1
Reactant: COc1ccc(C2=NC2c2cc(Br)ccn2)cc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc3cc(Br)ccn3n2)cc1
Temperature: 175 °C
Yield: 69.8 %

Procedure:
In a 20 mL microwave reactor was placed a solution of 4-bromo-2-(3-(4-methoxyphenyl)-2H-azirin-2-yl)pyridine (1.3 g, 4.3 mmol) and N,N-diisopropylethylamine (375 μL, 2.2 mmol) in 1,2-dichloroethane (10 mL). The mixture was heated to 175° C. for 1 hour. The cooled mixture afforded a precipitate which was filtered and dried under reduced pressure to afford the title compound as a white solid (910 mg, 70%). LCMS m/z 303.0, 305.0 (M+H)+, ret. time=2.88 min.
Reaction SMILES: C(N(CC)C(=O)C1C(=CC=CC=1)O)C.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:32]1[CH:33]=[C:34]([CH3:39])[CH:35]=[C:36]([CH3:38])[CH:37]=1.[OH-].[NH4+].CCCCCCCCCCCC>[Cu]I.O.C(OCC)(=O)C>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(N)cc1
Reactant: Cc1cc(C)cc(Br)c1
Agent: [Cu]I
Agent: CCN(CC)C(=O)c1ccccc1O
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCCCCCCCC
Product: Cc1ccc(Nc2cc(C)cc(C)c2)cc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
CuI (10 mg, 0.05 mmol), N,N-diethylsalicylamide (10 mg, 0.05 mmol), 4-toluidine (161, 1.5 mmol) and K3PO4 (425 mg, 2.0 mmol) were put into a screw-capped test tube with a Teflon-lined septum. The tube was then evacuated and backfilled with argon (3 cycles). 5-Bromo-m-xylene (136 μL, 1.0 mmol) was added by a syringe. The reaction mixture was stirred at 100° C. for 20 h. The reaction mixture was allowed to reach room temperature. Ethyl acetate (˜2 mL), water (˜10 mL), ammonium hydroxide (˜0.5 mL) and dodecane (227 μL) were added. The organic phase was analyzed by GC and 22% conversion of 5-bromo-m-xylene and 9% GC yield of the desired product was obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]#[CH:17])=[CH:14][C:13]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]#[CH:17])=[CH:14][C:13]([C:18]3[CH:23]=[N:22][C:21]([N:24]4[CH2:25][CH2:26][C:27]([CH3:35])([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]4)=[N:20][CH:19]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: C#Cc1cc(-c2cnc(N3CCC(C)(C(=O)OCC)CC3)nc2)cc2nc(NC(=O)NCC)sc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C#Cc1cc(-c2cnc(N3CCC(C)(C(=O)O)CC3)nc2)cc2nc(NC(=O)NCC)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To an ice-cold solution of ethyl 1-[5-[2-(ethylcarbamoylamino)-7-ethynyl-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (1.1 g, 2.23 mmol) in DMSO (10 mL) was added potassium tert-butoxide (1.25 g, 11.1 mmol) and the mixture stirred at rt for 1 h. After completion of reaction (by TLC), water (100 mL) was added, followed by extraction with EtOAc (2×100 mL) and the organic layer then discarded. The pH of the aqueous layer was adjusted up to 4-5, extracted with hot EtOAc (3×100 mL) and the combined organic layer dried over Na2SO4, filtered and evaporated under reduced pressure. The residue thus obtained was triturated with ether to obtain the desired product as off-white solid (0.9 g, 87% yield). 1H NMR (DMSO-d6): δ 1.14 (t, J=7.20 Hz, 3H), 1.21 (s, 3H), 1.42 (m, 2H), 2.04 (m, 2H), 3.20 (m, 2H), 3.33 (q, J=7.20, 2H), 4.25 (m, 2H), 4.67 (s, 1H), 6.80 (br s, 1H), 7.61 (s, 1H), 7.94 (s, 1H); 8.86 (s, 2H), 10.78 (br s, 1H) and 12.46 (br, s, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:15]=[N:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:15]=[N:14]2)=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cnn(-c2ccc(N)cc2)c1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2ccc(NS(C)(=O)=O)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.3 %

Procedure:
Methanesulfonyl chloride (80 mg) was added to a mixture of ethyl 1-(4-aminophenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylate (150 mg), triethylamine (76 mg) and THF (2 ml) under ice-cooling, followed by stirring at room temperature for 4 hours. Thereafter, the same treatment of Example 2 was carried out to give ethyl 1-(4-methanesulfonylaminophenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylate (29 mg) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2([OH:19])[CH2:17][CH2:18][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Product: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as a white solid from 4-fluoro-phenyl-bromide (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([O:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17]Br)=[CH:9][CH:8]=1)C.[F:22][C:23]1[CH:37]=[CH:36][CH:35]=[CH:34][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)=[O:26]>>[F:22][C:23]1[CH:37]=[CH:36][CH:35]=[CH:34][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:19][CH3:20])[C:4]([OH:3])=[O:21])=[CH:12][CH:11]=2)=[CH:29][CH:28]=1)=[O:26]
Reactant: O=C(c1ccc(O)cc1)c1ccccc1F
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCBr)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(C(=O)c3ccccc3F)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 24, Step A and 2-fluoro-4′-hydroxybenzophenone in a manner analogous to that described for Example 24, Step B. MS(ES) for C28H25FO5[M+H]+:461.2.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=1)([CH3:4])[CH3:3].[CH2:16]([Mg]Cl)[CH:17]=C.Cl>O1CCOCC1.O1CCCC1.[Cu]I>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]([CH:11]([C:12]#[N:13])[C:14]#[N:15])[CH:16]=[CH2:17])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: C=CC[Mg]Cl
Reactant: CC(C)(O)c1cc(C=C(C#N)C#N)no1
Agent: [Cu]I
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C=CC(c1cc(C(C)(C)O)on1)C(C#N)C#N
Reaction time: 1 h

Procedure:
2.26 g of {[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]methylidene}malononitrile was dissolved in 50 ml of 1,4-dioxane. Thereto, 0.08 g of copper(I) iodide was added and 18.6 ml of a 1.4 M solution of allylmagnesium chloride in tetrahydrofuran was then added under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. The reaction mixture was added to 0.1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.56 g of {1-[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]allyl}malononitrile.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:20])=[N:11][N:12]([CH3:19])[C:13]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16])C1C=CC=CC=1>CO.[Pd]>[CH3:19][N:12]1[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:9]([OH:8])[C:10]([CH3:20])=[N:11]1
Reactant: COC(=O)Cc1c(OCc2ccccc2)c(C)nn1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1c(O)c(C)nn1C

Procedure:
A solution of 10.3 g (37.5 mmol) of methyl (4-benzyloxy-1,3-dimethylpyrazol-5-yl)acetate in 200 ml of methanol is hydrogenated in the presence of 1 g of 10% Pd/C. When the reaction is complete, the reaction mixture is filtered and the filtrate is concentrated under vacuum. The residue is recrystallised from dichloromethane/n-hexane, giving methyl (1,3-dimethyl-4-hydroxypyrazol-5-yl)acetate; m.p. 119°-120° C.
Reaction SMILES: [N:1]1([S:6]([CH:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH3:10])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([NH:25][C:26](=O)[O:27]C2C=CC=CC=2)[N:18]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([O:16][CH3:15])[N:18]=[C:19]([NH:25][C:26](=[O:27])[NH:14][S:11]([CH:9]([S:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:8])[CH3:10])(=[O:13])=[O:12])[N:20]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CC(S(N)(=O)=O)S(=O)(=O)N1CCCC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)C(C)S(=O)(=O)N2CCCC2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 3.6 g (0.015 mol) of 1-pyrrolidinosulfonylethanesulfonamide (Example 1a) and 4.0 g (0.019 mol) of phenyl 4,6-dimethoxypyrimidin-2-ylcarbamate in 40 ml of acetonitrile there are added 2.9 g (0.019 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). After the mixture has been stirred for five hours at room temperature, it is treated with 250 ml of ice/water and acidified with HCl to pH 2. Extraction with dichloromethane, drying and evaporation give crude 3-(4,6-dimethoxypyrimidin-2-yl)-1-(1-pyrrolidinosulfonylethylsulfonyl)urea, which is purified by trituration with diisopropyl ether (yield: 4.6 g; 73% of theory; melting point 145°-146° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:38][CH3:39])[C:13]([O:36][CH3:37])=[C:14]([CH:16]=[CH:17][C:18]([N:20]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22](C(C)(C)C(O)=O)[NH:21]3)=[O:19])[CH:15]=2)=[CH:4][N:3]=1.NC1N=C(N)C(CC2C=C(OC)C(OC)=C(C=CC(N3CC4C(=CC=CC=4)[CH:61]([C:69](C)([CH3:73])[C:70]([O-:72])=[O:71])N3)=O)C=2)=CN=1>CO.[OH-].[Na+]>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:38][CH3:39])[C:13]([O:36][CH3:37])=[C:14](/[CH:16]=[CH:17]/[C:18]([N:20]3[N:21]=[CH:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:29]3[C:69]([CH3:73])([CH3:61])[C:70]([OH:72])=[O:71])=[O:19])[CH:15]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(C=CC(=O)N2Cc3ccccc3C(C(C)(C)C(=O)[O-])N2)c1OC
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(C=CC(=O)N2Cc3ccccc3C(C(C)(C)C(=O)O)N2)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(Cc2cnc(N)nc2N)cc(/C=C/C(=O)N2N=Cc3ccccc3C2C(C)(C)C(=O)O)c1OC

Procedure:
Preparation of (E)-(RS)-2-(2-{3-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl -acryloyl}-1,2-dihydro-phthalazin-1-yl)-2-methyl-propionic acid ##STR14## To the solution of 50 mg of methyl (E)-(RS)-2-(2-{3-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl -acryloyl}-1,2-dihydro-phthalazin-1-yl)-2-methyl-propionate (Example 1.12) in 5 ml of methanol are added 3 drops of 2N sodium hydroxide solution and the mixture is held at reflux for 45 min. Subsequently, the mixture is concentrated, the residue is treated with ice-water and neutralized with 2N hydrochloric acid. The insoluble material is recrystallized from methylene/methanol. 41 mg of (E)-(RS)-2-(2-{3-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl]-acryloyl}-1,2-dihydro-phthalazin-1-yl)-2-methyl-propionic acid are isolated as a colorless solid. M.p=245° C., dec.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][N:43]1[CH:47]=[C:46]([S:48](Cl)(=[O:50])=[O:49])[N:45]=[C:44]1[CH3:52]>C(#N)C>[CH3:42][N:43]1[CH:47]=[C:46]([S:48]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:50])=[O:49])[N:45]=[C:44]1[CH3:52]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cn1C
Yield: 51.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0316 g, 0.0685 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0570 mL, 0.411 mmol) and 1,2-dimethylimidazole-4-sulfonyl chloride (0.0400 mL, 0.205 mmol) to obtain 4-(1,2-dimethylimidazol-4-ylsulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0217 g, yield 51%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CC(N(C)C)C(O)C1C=CC=CC=1.C(NC1C=CC=CC=1)C.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1/[CH:37]=[C:38](/[N:45]1[CH:49]=[N:48][CH:47]=[N:46]1)\[C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41].Cl>C(OCC)C>[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1/[CH:37]=[C:38](/[N:45]1[CH:49]=[N:48][CH:47]=[N:46]1)\[CH:39]([OH:44])[C:40]([CH3:41])([CH3:42])[CH3:43]
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Agent: CC(C(O)c1ccccc1)N(C)C
Agent: Cl
Agent: [Al+3]
Solvent: CCOCC
Solvent: CCNc1ccccc1
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Temperature: -73 °C
Reaction time: 5 h
Yield: 25.2 %

Procedure:
A chiral metal-hydrogen complex was formed in a manner similar to that in Example 1 by adding to 20 cc of an ethyl ether solution containing 0.63 g of LiAlH4 50 cc of an ethyl ether solution containing 3.05 g of N-methylephedrine followed by 20 cc of an ethyl ether solution containing 4.12 g of N-ethylaniline. To the resulting solution, was added at -70° C. 30 cc of an ethyl ether solution containing 1.62 g of (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one. The resulting mixture was stirred at -73° C. for 5 hours under adiabatic conditions and left standing overnight at room temperature. To the mixture was added 60 cc of 2 N hydrochloric acid to effect decomposition. The organic layer was washed successively with 100 cc of a saturated sodium hydrogencarbonate solution and 100 cc of ice-cooled water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.82 g of crude crystals. The crude crystals were recrystallized three times from a cyclohexane-methanol mixture to obtain 0.41 g of (+)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol: [α]D24 +29.2 (c=1.0, CHCl3); melting point 160°-161° C. The NMR spectrum was identical with that of the racemate described in Reference Example 2.
Reaction SMILES: O1C=CC=C1C([O:8][C:9]1[C:10]([CH3:24])=[N:11][CH:12]=[C:13]([CH2:15][O:16][C:17]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)=[O:18])[CH:14]=1)=O.Cl>>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]([O:16][CH2:15][C:13]1[CH:14]=[C:9]([OH:8])[C:10]([CH3:24])=[N:11][CH:12]=1)=[O:18]
Reactant: Cc1ncc(COC(=O)c2ccco2)cc1OC(=O)c1ccco1
Agent: Cl
Product: Cc1ncc(COC(=O)c2ccco2)cc1O

Procedure:
0.98 G. of 3-(2-furoyloxy)-5-(2-furoyloxymethyl)-2-methylpyridine was heated at 75°C for 1 hour in 20 ml. of 2N hydrochloric acid.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])(=O)=O.O1[CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]12.C1CCN2C(=NCCC2)CC1.N>C1C=CC=CC=1>[CH3:8][Si:7]([CH3:10])([CH3:9])[O:6][CH:19]1[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1
Reactant: C1CCC2OC2C1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: N
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: C[Si](C)(C)OC1C=CCCC1
Reaction time: 20 h
Yield: 86.9 %

Procedure:
Into a solution of 2.26 g (0.0102 mole) of trimethylsilyl trifluoromethanesulfonate in 20 ml of benzene was added dropwise a mixed solution of 1.06 g (0.0107 mole) of 1,2-epoxycyclohexane and 2 ml of DBU in 5 ml of benzene at room temperature under an atmosphere of argon. After further agitation for 20 hours at room temperature, the reaction mixture was subjected to column chromatography with silica gel treated with ammonia as the adsorbent. Subsequent distillation of a chromatographic fraction gave 1.51 g of 3-trimethylsiloxycyclohexene boiling at 50° to 60° C. under a pressure of 50 mmHg. The yield was about 87% of the calculated value.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]=[CH:3]1.[H][H]>C(O)(=O)C.[Pd].[Zn]>[NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][CH2:3]1
Reactant: [H][H]
Reactant: NC1C=Nc2ccccc2NC1=O
Agent: [Pd]
Agent: [Zn]
Solvent: CC(=O)O
Product: NC1CNc2ccccc2NC1=O

Procedure:
Reduction of intermediate 21 using, for example, zinc dust in glacial acetic acid then provides 3-amino-1,3-dihydro-1,5-benzodiazepin-2-one 22. This reaction is typically conducted at ambient temperature for about 0.5 to about 6 hours. Alternatively, intermediate 21 can be reduced with hydrogen using a catalyst, such as palladium on carbon, to afford 3-amino-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one 23. Typically, this reaction is conducted at ambient temperature for about 12 to about 48 hours. If desired, compounds 22 and 23 can then be coupled with an amino acid derivative using the procedures described herein.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[C:6]([C:12]#[C:13][CH3:14])=[CH:5][N:4]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][C:13]1[NH:11][C:9](=[O:10])[C:7]2[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=2[CH:12]=1
Reactant: CC#Cc1cnc(SC)nc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CSc1ncc2cc(C)[nH]c(=O)c2n1
Temperature: 90 °C
Yield: 55.5 %

Procedure:
To a solution of 2-(methylthio)-5-(prop-1-yn-1yl)pyrimidine-4-carboxamide (Preparation 50, 270 mg, 1.303 mmol) in toluene (30 mL) was added pTSA (50 mg, 0.261 mmol). The reaction mixture was heated to 90° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in NH3 in MeOH (7M, 10 mL) and heated to 80° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography eluting with 0-5% MeOH in DCM to give the title compound (150 mg, 56%).