Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:37])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:13][CH:12]([NH:28]C(OC(C)(C)C)=O)[C:11]2=[O:36])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(C(CN1C2C=CC=CC=2N(C(=O)C(C)(C)C)CC(NC(OC(C)(C)C)=O)C1=O)=O)(C)(C)C>>[C:1]1([CH3:37])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:13][CH:12]([NH2:28])[C:11]2=[O:36])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)CN(Cc2ccccc2)c2ccccc21
Agent: CC(C)(C)OC(=O)NC1CN(C(=O)C(C)(C)C)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Product: Cc1ccccc1C(=O)CN1C(=O)C(N)CN(Cc2ccccc2)c2ccccc21

Procedure:
Step 2 of Example 10 was repeated except that 1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-benzyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine that obtained from Step 2 of Example 24 was used instead of 1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine, to thereby obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[N:6]([CH3:14])[C:5](=[O:15])[CH2:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[N:6]([CH3:14])[C:5](=[O:15])[CH2:4][N:3]=[C:2]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:8]=2[CH:9]=1
Reactant: CN1C(=O)CN=C(Cl)c2cc(F)ccc21
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CN1C(=O)CN=C(c2ccccc2)c2cc(F)ccc21
Yield: 75.7 %

Procedure:
As illustrated in the scheme above and following General Procedure 4, 5-chloro-7-fluoro-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (0.201 g, 0.887 mmol), Na2CO3 (0.0940 g, 0.887 mmol), PdCl2(dppf) (0.0362. g, 0.0443 mmol) and phenylboronic acid (0.108 g, 0.886 mmol) were combined and heated for 13 h. After workup, purification of the crude product by silica gel column chromatography (3:1 CH2Cl2:EtOAc) provided the title compound (0.180 g, 76%). 1H-NMR (CDCl3): δ 7.64-7.60 (m, 2H), 7.51-7.45 (m, 1H), 7.44-7.39 (m, 2H), 7.34 (dd, J=4.8 Hz, J=9.2 Hz, 1H), 7.31-7.25 (m, 1H), 7.02 (dd, J=2.8 Hz, J=8.8 Hz, 1H), 4.84 (d, J=10.8 Hz, 1H), 3.78 (d, J=10.8 Hz, 1H), 3.40 (s, 3H). MS (ESI) (M+H)+=269.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:39])[CH:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27][CH2:28][CH2:29][CH2:30][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])[C:16]3[C:11](=[CH:12][C:13]([OH:38])=[CH:14][CH:15]=3)[S:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:40]OS([O-])=O.[K+].O.CCCCCC>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:39])[CH:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27]([CH2:28][CH2:29][CH2:30][C:31]([F:37])([F:36])[C:32]([F:33])([F:34])[F:35])=[O:40])[C:16]3[C:11](=[CH:12][C:13]([OH:38])=[CH:14][CH:15]=3)[S:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=S([O-])OO
Reactant: CC1(c2ccc(F)cc2)CSc2cc(O)ccc2C1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(c2ccc(F)cc2)CSc2cc(O)ccc2C1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 66 %

Procedure:
To a solution of (3RS,4RS)-3-(4-fluorophenyl)-7-hydroxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]thiochroman (107 mg, 0.18 mmol) in tetrahydrofuran (8 ml) was added Oxone® (monopersulfate compound; DuPont product) (60 mg, 0.1 0 mmol), which was then stirred at 0° C. for 5 minutes. Water (0.5 ml) was added thereto, and the resulting mixture was stirred at 0° C. for 1 hour. The reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. The crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=2:1) to give (3RS,4RS)-3-(4-fluorophenyl)-7-hydroxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]thiochroman (73 mg, yield 66%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[C:16](=[O:17])[NH:15][N:14]=[CH:13]2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:35][CH2:36][CH:37]2[CH2:39][CH2:38]2)(=O)=O)=CC=1>CC(C)=O>[CH:37]1([CH2:36][CH2:35][N:15]2[C:16](=[O:17])[N:12]([C:4]3[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=3)[CH:13]=[N:14]2)[CH2:39][CH2:38]1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Reactant: Cc1ccc(S(=O)(=O)OCCC2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(-n2cnn(CCC3CC3)c2=O)nc1C
Temperature: 25 °C
Yield: 63 %

Procedure:
To a suspension of ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate (0.25 g, 0.98 mmol) and potassium carbonate (0.20 g, 1.47 mmol) in acetone (20 mL) was added 2-cyclopropylethyl 4-methylbenzenesulfonate (0.28 g, 1.18 mmol). The reaction mixture was heated to reflux for 24 hours, cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo to afford ethyl 2-(1-(2-cyclopropylethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylate in 63% yield (0.20 g): MS (ES+) m/z 323.3 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]([CH3:31])[CH2:14][CH2:15][C:16]1([OH:30])[CH2:21][CH:20]2[CH2:22][CH2:23][CH:17]1[CH:18]=[C:19]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(CC)CC.[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41]>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]([CH3:31])[CH2:14][CH2:15][C@:16]1([O:30][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH2:21][C@H:20]2[CH2:22][CH2:23][C@@H:17]1[CH:18]=[C:19]2[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)C(=O)Cl
Reactant: CN(CCCc1nc2ccccc2[nH]1)CCC1(O)CC2CCC1C=C2c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)O[C@@]1(CCN(C)CCCc2nc3ccccc3[nH]2)C[C@H]2CC[C@@H]1C=C2c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 150 mg of rac-(1R*,2R*,4R*)-2-(2-{[3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol and 0.176 mL of NEt3 in 4 mL DCM 0.1 mL of isobutyrylchloride was added at 0° C. The yellow reaction mixture was stirred for 3 h at rt and then quenched with sat. aq. NaHCO3. The product was extracted with DCM, the organic phase was evaporated to dryness. The residue was dissolved in EtOAc, silica gel and a few drops of MeOH were added and the mixture was stirred vigorously for 5 h. The mixture was filtered, the filtrate evaporated and the residue purified by CC with EtOAc-MeOH (3:1) to yield 86 mg of pure rac-isobutyric acid (1R*,2R*,4R*)-2-(2-{[3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester as colorless foam.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Cl[C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.CN(C=O)C>O>[CH2:1]([S:3][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:18]=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC[S-]
Reactant: O=C(Nc1cc(C(F)(F)F)ccn1)c1ncccc1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cccnc1C(=O)Nc1cc(C(F)(F)F)ccn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
0.86 g of sodium ethanethiolate was added to a mixture of 1.23 g of 3-chloro-N-(4-trifluoromethylpyridin-2-yl)picolinamide and 3 mL of DMF, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture cooled to room temperature was poured to water, and the precipitated solid was taken by filtration. The resulting solid was dissolved in ethyl acetate, and the mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.23 g of 3-ethylsulfanyl-N-(4-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 8).
Reaction SMILES: [C:1]12([SH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[NH2:14][C:15]1[C:20](Br)=[N:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1>C(#N)C>[NH2:14][C:15]1[C:20]([S:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)=[N:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1
Reactant: SC12CC3CC(CC(C3)C1)C2
Reactant: Nc1ncc(-c2ccccc2)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(-c2ccccc2)nc1SC12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 59.3 %

Procedure:
To a solution of 1-adamantanethiol (0.07 g, 0.4 mmol) in dry acetonitrile (10 mL), sodium hydride (NaH) (9 mg, 0.4 mmol) was added and the resulting mixture was stirred for 15 min. After this time 2-amino-3-bromo-5-phenylpyrazine 17b (0.05 g, 0.2 mmol) was added and the mixture heated at 80° C. for 4 h, cooled and quenched with water. Then EtOAc was added and the organic layer was anidrified over Na2SO4, filtered and the solvent removed under reduced pressure to get a crude that was purified by flash chromatography using petroleum ether-EtOAc (7:3 v/v) as eluent, to obtain 0.04 g of the title compound 18o as a yellow oil (62% yield). 1H-NMR (CDCl3): 1.73 (s, 6H), 2.08 (s, 3H), 2.23 (s, 6H), 5.13 (br s, 2H), 7.32-7.36 (m, 1H), 7.42-7.46 (m, 2H), 7.91-7.93 (m, 2H), 8.29 (s, 1H). MS (ESI): m/z 338 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH3:16])[N:10]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[CH2:17]([NH:24][C:13]1[CH:12]=[C:11]([CH3:16])[N:10]=[C:9]([NH2:8])[N:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cc(NCc2ccccc2)nc(N)n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
Triethylamine (3.4 mL, 24.6 mmol) was added to a suspension of 2-amino-4-chloro-6-methylpyrimidine (Aldrich, 1.77 g, 12.3 mmol) and benzylamine (1.98 g, 18.5 mmol) in anhydrous dioxane (20 mL). The reaction was heated to 80° C. and allowed to run for 12 h. Upon cooling to room temperature, a white precipitate formed which was collected by vacuum filtration. The solid was recrystallized from acetone: hexanes to afford N4-benzyl-6-methylpyrimidine-2,4-diamine (2.33 g, 89% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[CH:3]1[CH3:13].[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>>[C:15]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([CH3:12])([CH3:11])[CH:3]([CH3:13])[C:2]2([CH3:14])[CH3:1])(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: CC1C(C)(C)c2ccccc2C1(C)C
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1ccc2c(c1)C(C)(C)C(C)C2(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture, stirred at ambient temperature in the absence of the humidity of the air, of 25 g of 1,1,2,3,3-pentamethyl indane and 13 cm3 of acetyl chloride, there are added, in small portions, 23 g of aluminum chloride in a manner such that the temperature does not exceed 40° C. Stirring is maintained for 2 hours after the end of the addition and the reaction mixture is left overnight. The next day, it is poured into 200 cm3 of ice water and then extracted three times with 150 cm3 of dichloromethane. The organic phases are combined, washed with sodium bicarbonate and then with water and dried on magnesium sulfate. The solvent is removed by evaporation under a vacuum and 31 g of 5-acetyl-1,1,2,3,3-pentamethyl indane in liquid form which is directly used for the following reactions are obtained.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][S:13]([C:16]3[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:22][C:23]([O:25]CC)=[O:24])[O:3]1.[Li+].[OH-].Cl>CCO>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][S:13]([C:16]3[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:22][C:23]([OH:25])=[O:24])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(OS(=O)(=O)c3ccnn3C)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OS(=O)(=O)c2ccnn2C)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
To a solution of ethyl 2-(1-hydroxy-4-methyl-6-(1-methyl-1H-pyrazol-5-ylsulfonyloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (100 mg, 0.25 mmol) in EtOH (4 ml) was added aqueous LiOH (1 ml, 10% aq). The mixture was stirred at 0° C. for 3 h. The reaction was acidified with 1N HCl to pH=2-4, extracted with DCM, washed with brine. The organic layer was dried over Na2SO4 and concentrated. Purify via prep. HPLC to get white solid 72 mg. NMR: 1H NMR (DMSO-d6, 400 MHz): δ=12.15 (br, 1H), 9.30 (s, 1H), 8.00 (s, 1H), 7.19 (d, J=2 Hz, 1H), 6.98 (d, J=2 Hz, 1H), 6.80 (d, J=2 Hz, 1H), 5.47 (d, J=6 Hz, 1H), 3.42 (d, J=6 Hz, 1H), 2.25 (s, 3H), 2.12 (d, 1H), 1.03 (s, 3H) ppm. MS (ESI) m/z=365.0 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][CH:7]=1)=[O:5])[CH3:2].[Br:12]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:12][CH2:11][C:9]1[S:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cnc(C)s1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(CBr)s1

Procedure:
2-Methyl-5-thiazolecarboxylic acid ethyl ester (3.9 g) (J. Am. Chem. Soc. 1982, 104, 4461), N-bromosuccinimide (4.1 g) and catalytic azoisobutyronitrile in ethyl acetate (150 ml) was heated at reflux and under a 500 W halogen lamp for 16 hours. The solution was washed with water, dried (MgSO4) and evaporated. Purification was by chromatography eluting with 50% ethyl acetate in isohexane. Yield 1.5 g.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C:4]([O-:6])=[O:5].[K+:7].O.[NH2:9][NH2:10]>>[NH:9]([CH2:3][C@H:2]([OH:1])[C:4]([O-:6])=[O:5])[NH2:10].[K+:7]
Reactant: O=C([O-])[C@@H]1CO1
Reactant: NN
Agent: [K+]
Solvent: O
Product: NNC[C@H](O)C(=O)[O-]

Procedure:
Potassium (S)-oxirane-2-carboxylate LVIII (0.63 g, 5 mmol) and hydrazine hydrate (2.57 g, 51 mmol) were heated at 95° C. for 3 days. Hydrazine and water were removed and the residue was dried at 40° C. under vacuum to produce potassium (S)-3-hydrazinyl-2-hydroxypropanoate LIX (0.75 g), which was used without purification in the next step. ESIMS found for C3H7N2O3K m/z 119 (M)−.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[N+:17]([O-])=O)[C:8]2=[O:20])=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.O1CCCC1>>[NH2:17][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:15]=[CH:16][N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:22][CH:21]=1)[C:8]2=[O:20]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccc(F)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc2c(=O)n(Cc3ccc(F)cc3)ccc12

Procedure:
2-(4-Fluorobenzyl)-5-nitroisoquinolin-1(2H)-one (0.66 g, 0.0022 mol) and tin dichloride dihydrate (2 g, 0.009 mol) were stirred in tetrahydrofuran (20 mL, 0.2 mol) at room temperature overnight. The volatiles were removed via rotovapor, and the residue was dissolved in MeOH, filter through a pad of basic alumina and concentrated to dryness to give the title compound as a brown oil. MS m/z (M+H) 268.8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([N:12](S(C1C(C)=CC(OC)=C(C)C=1C)(=O)=O)[CH2:13][C:14]#[CH:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CSCC>ClC(Cl)C.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:30])[CH:4]([NH:12][CH2:13][C:14]#[CH:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCN(C(Cc1ccccc1)C(=O)OC)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Agent: CCSC
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C#CCNC(Cc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-[(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-prop-2-ynyl-amino]-3-phenyl-propionic acid methyl ester (150 mg, 0.349 mmol) in anhydrous dichloroethane (1.5 mL), trifluoroacetic acid (3.5 mL) and ethyl methyl sulfide (0.16 mL, 1.75 mmol) were added. The reaction mixture was stirred at room temperature under a N2 atmosphere for 12 h. Excess of solvents were removed under reduced pressure and the residue was extracted between saturated NaHCO3 solution and ethyl acetate. The organic layer was separated, dried (Na2SO4), concentrated. The crude product was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 3-Phenyl-2-prop-2-ynylamino-propionic acid methyl ester as a thick syrup, 70 mg (92%). 1H NMR (CDCl3, 400 MHz): δ7.32-7.19 (m, 5H), 3.78 (t, 1H), 3.68 (s, 3H), 3.40 (ABq, 2H), 3.03 (dd, 1H), 2.98 (dd, 1H), 1.99 (t, 1H).
Reaction SMILES: O[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:22])[C:4](=[O:23])[C:3]=1[CH3:24].P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:22])[C:4](=[O:23])[C:3]=1[CH3:24]
Reactant: COc1ccc(Cn2cnc3c(c(O)c(C)c(=O)n3C)c2=O)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cn2cnc3c(c(Cl)c(C)c(=O)n3C)c2=O)cc1
Temperature: 80 °C
Yield: 87.7 %

Procedure:
5-Hydroxy-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (10 g, 30.6 mmol, compound 8B) was suspended in phosphorus oxychloride (28 mL, 306 mmol) and heated at 80° C. for 5 hours. The solution was evaporated in vacuo, and the residue taken up in DCM and washed with saturated sodium bicarbonate solution until the neutral pH was observed. The organic layer was dried over magnesium sulfate and evaporated to dryness. The residue was purified by silica chromatography using 1% methanol in DCM as eluent to yield 9.28 g of title compound (89%). [M+H] calc'd for C17H16ClN3O3, 346; found, 346.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CSC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH:15]=[C:11]([CH2:12][OH:13])[CH:10]=1)[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(benzyloxy)-5-(methoxycarbonyl)benzoic acid (1 eq.) from the previous step in THF (0.2 M) at 0° C. was added borane-dimethylsulfide (1.5 eq.) and stirred at rt for 18 h. Additional borane-dimethylsulfide (3 eq.) was added and the reaction was stirred for another 2 h at rt. The reaction was slowly quenched with methanol and then concentrated in vacuo. The residue was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution, and brine. The organic extract was dried over MgSO4 and concentrated in vacuo to give the title compound.
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].[F:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][CH2:16][NH:15][C:14]=2[CH:19]=1>C(Cl)Cl>[F:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][CH2:16][N:15]([N:1]=[O:2])[C:14]=2[CH:19]=1
Reactant: CC(C)CCON=O
Reactant: Fc1ccc2c(c1)NCCO2
Solvent: ClCCl
Product: O=NN1CCOc2ccc(F)cc21

Procedure:
Isoamyl nitrite is added to a solution of 6-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine (1 g) in DCM (15 mL) and heated to reflux overnight. The reaction mixture is concentrated in vacuo and the residue is purified by silica gel chromatography eluting with 10% EtOAc in heptane to give 6-Fluoro-4-nitroso-3,4-dihydro-2H-benzo[1,4]oxazine (0.83 g).
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][C:16](C(OC)=O)([C:17]([O:19]C)=[O:18])[C:12]2=[C:11](Br)[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1(C(=O)OC)CCn2c(C(=O)c3ccccc3)cc(Br)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1)c1ccc2n1CCC2C(=O)O
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Dimethyl 5-benzoyl-7-bromo-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate (2.04 g 5.0 mmoles) was dissolved in methanol (100 ml) and water (10 ml), and sodium hydroxide (0.40 g, 10 mmoles) was added. This solution was heated at reflux temperature in an argon atmosphere for 2 hours. The reaction mixture was evaporated to dryness in vacuo, the residue was dissolved in 50% aqueous methanol (125 ml), magnesium oxide (1.0 g) and 5% palladium on charcoal (0.400 g) were added and the mixture was hydrogenated at room temperature and atmospheric pressure for 2 hours. A sample withdrawn at this time, after workup, was analyzed by NMR and shown to contain 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylic acid as the sodium salt. (This material is, of course, extremely unstable in acid and decarboxylates immediately to the corresponding monocarboxylic acid if acid is added during the analytical process.) The rest of the solution was filtered through celite, the solid filter cake was washed well with methanol and water. Evaporation of most of the methanol was carried out at reduced pressure. The resulting aqueous material was made acidic with 1N, hydrochloric acid and the product was extracted into ethyl acetate (200 ml). The aqueous phase was further acidified with a few ml of concentrated hydrochloric acid and extracted with an additional quantity (150 ml) of ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness to give a colorless solid (1.19 g, 93%) which was homogeneous by TLC. Recrystallization of this material from dichloromethane-hexane gave a first crop (0.699 g) melting point (154°-154.5°) corrected and a second crop (0.170 g) melting point (149°-151.5°) corrected. A third crop of the product was obtained by treatment of the residue obtained by evaporation of the mother liquors with activated charcoal in ethyl-acetate. Recrystallization from methanol-water of the material isolated from the ethyl-acetate gave the third crop (0.038 g) melting point (148°-150°) corrected. An authentic sample prepared by a well established alternative route had melting point (154.5°) corrected. The total crystallized yield of 5-benzoyl,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid was (0.907 g, 71%) based on starting material.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([NH:17][CH:18]1CCCC[CH2:19]1)=[O:16].NC1C=[N:29][CH:28]=[C:27]([Cl:31])[N:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:31][C:27]1[N:26]=[C:18]([NH:17][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:16])[CH:19]=[N:29][CH:28]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CN1C(C(=O)NC2CCCCC2)=C(O)c2ccccc2S1(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O

Procedure:
This compound was prepared from 4-hydroxy-2-methyl-N-cyclohexyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, 2-amino-6-chloro-pyrazine and p-toluenesulfonic acid analogous to Example 14.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14]>>[C:15]1([CH:13]([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CCc1ccccc1
Product: CC(ON1C(C)(C)CC(O)CC1(C)C)c1ccccc1
Temperature: 133 °C
Yield: 45.3 %

Procedure:
A mixture of 17.23 g (0.10 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 106.17 g (1.0 mol) of ethylbenzene under a nitrogen atmosphere is heated at 133° C. for 26 hours. The volatiles are removed in vacuo and the residue is triturated with diethyl ether. The precipitate of 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine is collected by filtration to give 12.57 g of an off-white solid.