Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[C:12]([Cl:21])[CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:21][C:12]1[CH:11]=[C:10]([NH:9][C:4](=[O:5])[C:3]([CH3:8])([CH3:7])[CH2:2][Cl:1])[CH:20]=[CH:19][C:13]=1[C:14]([N:16]([CH3:18])[CH3:17])=[O:15]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: CN(C)C(=O)c1ccc(N)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(NC(=O)C(C)(C)CCl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chloro-2,2-dimethylpropionyl chloride (1.86 g) was added dropwise over 5 minutes to 4-amino-2-chloro-N,N-dimethylbenzamide (2.00 g) suspended in dry methylene chloride (40 ml) and dry triethylamine (1.21 g) with stirring, keeping the temperature below 10° C. After stirring for 1 hour and warming to room temperature, methylene chloride (40 ml) was added and the solution washed with 2M hydrochloric acid, saturated aqueous sodium bicarbonate and then saturated brine. The solution was then dried and evaporated to yield a sticky yellow solid which was recrystallised from ethyl acetate/chloroform to give 2-chloro-4-(3'-chloro-2',2'-dimethylpropionamido)-N,N-dimethylbenzamide, as a white crystalline solid (2.349 g) m.p. 179°-181° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([F:21])([F:20])[F:9])=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: FC(F)(F)c1ccccc1-c1ncc(Br)cn1
Yield: 52 %

Procedure:
Obtained (52% yield) following the procedure described in Intermediate 21, starting with 5-bromo-2-iodopyrimidine and 2-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([N:14]1[C:23]2[C:18](=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[CH3:31])[CH:20]=[CH:21][CH:22]=2)[C:17](=[O:32])[C:16]([CH:33]=O)=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:7]([N:14]1[C:23]2[C:18](=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[CH3:31])[CH:20]=[CH:21][CH:22]=2)[C:17](=[O:32])[C:16]([CH:33]=[CH2:1])=[N:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(-c2cccc3c2c(=O)c(C=O)nn3Cc2ccccc2)c(C)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: C=Cc1nn(Cc2ccccc2)c2cccc(-c3ccc(C)cc3C)c2c1=O
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
To a slurry of 0.081 g (0.72 mmol) of potassium tert-butoxide in 10 mL of ether was added 0.22 g (0.60 mmol) of methyl triphenylphosphonium bromide. The resulting ylide solution was stirred for 30 min then 0.11 g (0.30 mmol) of 1-benzyl-5-(2,4-dimethylphenyl)-4-oxo-1,4-dihydrocinnoline-3-carbaldehyde was added. The reaction mixture was stirred for 3 h, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography eluting with a 9% ethyl acetate/hexanes mixture to give 0.035 g (32%) of the title compound as a light yellow solid.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH:5]1[CH3:25])#[N:2].[F:26][C:27]([F:32])([F:31])[C:28](O)=[O:29]>>[C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:28](=[O:29])[C:27]([F:32])([F:31])[F:26])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH:5]1[CH3:25])#[N:2]
Reactant: CC1CN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CCC1=CC#N
Reactant: O=C(O)C(F)(F)F
Product: CC1CN(c2ccc(N3C[C@H](CNC(=O)C(F)(F)F)OC3=O)cc2F)CCC1=CC#N
Yield: 51 %

Procedure:
The title compound was prepared as per Example-29 by using (S)-N-{3-[4-(4-cyanomethylidene-3-methylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine and trifluoroacetic acid in 51% yield.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:12])=[O:11].[OH-].[Na+].O>C(O)C>[C:2]1([CH:1]=[CH:9][C:10](=[O:11])[CH:12]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
Benzaldehyde (1b, 2.54 ml, 25.0 mmol) and acetone (19, 0.90 ml, 12.2 mmol) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (2.50 g, 62.5 mmol) and water (25 ml) was added and the solution stirred for 3 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol to afford 2.35 g (82%) of yellow crystals: mp 110-112° C. [expected mp 112-114° C.]; 1H NMR: δ 7.07 (d, 2H, J=15.9 Hz), 7.40 (m, 8H), 7.61 (m, 2H), 7.73 (d, 2H, J=15.9 Hz); 13C NMR: δ 125.4, 128.3, 12.9, 130.4, 134.7, 143.2, 188.7.
Reaction SMILES: [O:1]1[C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[CH:3]=[CH:2]1.S(=O)(=O)(O)[OH:12]>>[CH2:3]([C@@H:4]([OH:5])[C@H:6]([OH:7])[C@H:8]([OH:1])[CH2:9][OH:10])[CH:2]=[O:12]
Reactant: OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Reactant: O=S(=O)(O)O
Product: O=CC[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 35 %

Procedure:
Production of 2DG can be carried out using any known method. For example, 2-DG can be prepared from various starting materials such as D-glucose, D-mannose, calcium D-gluconate, D-arabinose, D-glucosamine hydrochloride, N-acetyl glucosamine, chitin, and chitosan and carboxymethylchitosan. Preparation methods vary with various starting materials. For example, D-glucose can be methylated and brominated, followed by debromination and acid hydrolysis to yield β-2DG. Bergmann et. al. (1992) Berichte der Deutschen Chemischen Gesellschaft Jahrg. 55:158-72. D-glucose or D-mannose can be treated with bromine and acetyl, followed by a Fischer procedure (Fischer et al. (1914) (Berichte der Deutschen Chemischen Gesellschaft Jahrg. 47:196-210), to yield 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol, which is reacted with bromine, then reduced to remove the acetyl group, yielding 2DG (Arita et al. (1972) Bull. Chem. Soc. Japan 45:567-69). The 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol intermediate can be treated with N-bromosuccinimide, followed by hydrogenation and deacetylation to yield 2DG. Monneret and Choay (1981) Carbohydr. Res. 96:299-305. D-glucose can be reacted with ethanethiol and benzoyl chloride, followed by dehydrogenation, reduction, and deprotection to give 2-DG. Wong and Gray (1980) Carbohydr. Res. 80:87-98). Glucal can be deacetylated by reacting with sulfuric acid to give 2-DG with an overall yield of 35%. Overend et al. (1949) J. Chem. Soc., 1:2841-45. D-arabinose can be treated with nitromethane and an acetylating agent, followed by treatment with diluted sodium hydroxide, to yield a-2-DG. Sowden and Fischer (1947)J. Am. Chem. Soc. 69:1048-50. D-arabinose can be condensed, reduced with acetone, then reacted with trifluoromethanesulfonic anhydride, to yield a product that is then reacted with sodium cyanide, followed by hydrogenation, reduction, and hydrolysis, yielding 2-DG. Shiue et al. (1979) Carbohydr. Res. 74:323-26.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][N:14]([C@@H:22]([CH3:38])[C:23](=[O:37])[NH:24][C@H:25]1[CH2:31][O:30][C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[NH:27][C:26]1=[O:36])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[CH2:39]([N:41]1[C:49]2[C:44](=[C:45]([CH2:50]O)[CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42]1)[CH3:40].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:39]([N:41]1[C:49]2[C:44](=[C:45]([CH2:50][N:27]3[C:26](=[O:36])[C@@H:25]([NH:24][C:23](=[O:37])[C@@H:22]([N:14]([CH3:13])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19])[CH3:38])[CH2:31][O:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]3=4)[CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42]1)[CH3:40]
Reactant: CCn1ccc2c(CO)cccc21
Reactant: C[C@@H](C(=O)N[C@H]1COc2ccccc2NC1=O)N(C)C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCn1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc4ccccc43)cccc21
Reaction time: 60 h
Yield: 51 %

Procedure:
DEAD 40% w/w (359 mg, 376 μl, 826 μmol, Eq: 3) was added to a mixture of tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)propan-2-yl)carbamate (100 mg, 275 μmol, Eq: 1.00), (1-ethyl-1H-indol-4-yl)methanol (48.2 mg, 275 μmol, Eq: 1.00) and polymer-bound Ph3P (500 mg, 275 μmol, Eq: 1.00) in THF (10 mL). After 2.5 d., additional portions of (1-ethyl-1H-indol-4-yl)methanol (48.2 mg, 275 μmol, Eq: 1.00), polymer-bound Ph3P (1 eq) and DEAD (1 eq), were added. After 1 d, the mixture was filtered and the filter cake washed with MeOH and THF. The filtrate was concentrated and the residue was purified by preparative TLC to afford tert-butyl (S)-1-((S)-5-((l-ethyl-1H-indol-4-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (73 mg, 51%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[CH:34][N:33]=[N:32]4)[CH:26]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-[(2-methoxy-ethyl)-methyl-amino]-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example M14) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (69 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]2=[C:10]([C:17]2[N:22]=[C:21]([NH:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[CH:20]=[N:19][CH:18]=2)[CH:9]=1>C(Cl)Cl>[NH:26]1[CH2:27][CH2:28][CH2:29][C@@H:24]([NH:23][C:21]2[CH:20]=[N:19][CH:18]=[C:17]([C:10]3[CH:9]=[N:8][N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=34)[N:22]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4ccccc34)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccn2ncc(-c3cncc(N[C@@H]4CCCNC4)n3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
Trifluoroacetic acid (0.35 mL, 4.56 mmol) was added to a solution of (R)-tert-butyl 3-(6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-ylamino)piperidine-1-carboxylate (Preparation 28a, 0.30 g, 0.76 mmol) in methylene chloride (10 mL) and the resulting solution was stirred at ambient temperature overnight and then at 50° C. for additional 24 h. The solvent was then evaporated and the residue was redissolved in methylene chloride and washed with a 10% aqueous sodium hydroxide solution. The organic phase was dried over magnesium sulphate, filtered and the solvent was evaporated. The crude product was purified by flash chromatography (10-15% MeOH/CH2Cl2/NH3) to yield the title compound (0.125 g, 56%) as an oil.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[O:27]1[CH2:28][CH2:29][N:24]([C:3]2[N:8]=[C:7]3[N:9]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]3=[CH:5][N:4]=2)[CH2:25][CH2:26]1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: C1COCCN1
Solvent: c1ccncc1
Product: CCCOc1ccccc1-c1nc2nc(N3CCOCC3)ncc2c(=O)[nH]1

Procedure:
A stirred solution of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.60 g) and morpholine (1.25 g) in pyridine (20 ml) was heated under reflux for 45 hours. The reaction mixture was evaporated under reduced pressure to yield a crude product which was washed with water and twice recrystallized from methanol to yield the title compound, 0.25 g., m.p. 175.5-177° C.
Reaction SMILES: Cl.[F:2][C:3]1([F:47])[CH:9]([NH:10]C(=O)C(F)(F)F)[CH2:8][CH2:7][N:6]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:24]([C:26]2[N:27]=[C:28]([C:39]3[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=3[F:46])[S:29][C:30]=2[NH:31]C(=O)OC(C)(C)C)=[O:25])[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CO>[NH2:31][C:30]1[S:29][C:28]([C:39]2[C:40]([F:46])=[CH:41][CH:42]=[CH:43][C:44]=2[F:45])=[N:27][C:26]=1[C:24]([NH:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[N:6]1[CH2:7][CH2:8][CH:9]([NH2:10])[C:3]([F:2])([F:47])[CH2:4][CH2:5]1)=[O:25]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC(NC(=O)C(F)(F)F)C(F)(F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC(N)C(F)(F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.6 %

Procedure:
HCl in 1,4-dioxane (4 M, 2 mL) was added to a solution of Example 55 (20 mg, 0.03 mmol) in MeOH (0.5 mL). This mixture was stirred at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude product re-dissolved in MeOH/water (1:1, 5 mL). K2CO3 (0.3 g, 7, 2.2 mmol) was added and the mixture heated and stirred at 60° C. for 3 hr before being cooled to room temperature. The mixture was concentrated under reduced pressure and the residue purified by preparative HPLC to yield 351 as a white solid (4 mg, 25%). 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 7.88 (s, 1H), 7.37-7.28 (m, 1H), 7.08-6.98 (m, 2H), 6.15 (s, 2H), 3.73 (s, 3H), 3.39-3.13 (m, 6H), 2.46-2.34 (m, 1H), 2.22-2.03 (m, 2H), 1.99-1.89 (m, 1H), 1.83-1.78 (m, 1H). LCMS (ES+) m/z 484.0 (M+1).
Reaction SMILES: [N:1]([C:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH:5]([O:10][C:11]1[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[N+]=[N-]>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH:5]([O:10][C:11]1[N:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([O:17][CH3:18])[N:16]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(N=[N+]=[N-])c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(N)c1ccccc1
Reaction time: 6 h

Procedure:
3.7 g (10 mmol) of methyl 3-azido-3-phenyl-2-(4,6-dimethoxypyrimidin-2-yl)oxybutyrate (Ex. 2) are dissolved in 20 ml of methanol/ethyl acetate (1:1), treated with 400 mg of Pd/C 10% and stirred for 6 h under a hydrogen atmosphere. After filtering off the catalyst and concentrating, a colorless oil is obtained which solidifies after a few days.
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH3:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1>>[CH3:15][C:16]1[N:17]=[CH:18][N:19]([CH2:2][CH2:3][S:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH:20]=1
Reactant: N#Cc1ccc(S(=O)(=O)CCBr)cc1
Reactant: Cc1c[nH]cn1
Product: Cc1cn(CCS(=O)(=O)c2ccc(C#N)cc2)cn1

Procedure:
270 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with 4-methylimidazole to yield 4-(2-(4-methyl-1H-imidazole-1-yl)ethylsulfonyl)benzonitrile. 320 mg of 4-(2-(4-methyl-1H-imidazole-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(4-methyl-1H-imidazole-1-yl)ethylsulfonyl)benzoic acid.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]=[C:17]=[S:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([CH2:21][NH2:22])[OH:20]>C(OCC)C.C(O)(C)C>[Cl:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:16][C:17](=[S:18])[N:22]([CH2:21][CH2:19][OH:20])[C:1]2([OH:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1N=C=S
Solvent: CC(C)O
Solvent: CCOCC
Product: OCCN1C(=S)Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reaction time: 8 h
Yield: 93 %

Procedure:
Using the general procedure already described above, a solution containing 10.92 grams (40 moles) of 2-benzoyl-4-chlorophenylisothiocyanate in about 100 ml of ethyl ether was added dropwise to a stirred solution of 2.83 grams (44 moles) of ethanolamine in 200 ml of isopropanol. The reaction mixture was stirred overnight. The 6-chloro-3,4-dihydro-4-hydroxy-3-(2-hydroxyethyl)-4-phenyl-2(1H)-quinazolinethione precipitated as a white solid. The product was washed with a mixture of ethyl ether and isopropanol to give the final product which had a melting point of 238°-240° C. Final yield was 93%.
Reaction SMILES: [O:1]1[CH2:12][C@H:2]1[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCCCCC>[CH2:5]([O:4][CH2:3][C@H:2]([OH:1])[CH2:12][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH2:16][CH:13]1[CH2:14][CH2:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1ccccc1OCC1CC1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: O[C@@H](COCc1ccccc1)COc1ccccc1OCC1CC1
Temperature: 25 °C

Procedure:
A mixture of (S)-benzyl 2,3-epoxypropyl ether (8.95 g as described in Heterocycles Vol. 16, 381, 1981), o-cyclopropylmethoxyphenol (8.95 g) in 36 ml acetone and 4 ml hexane, to which is added powdered potassium carbonate (6.9 g), is stirred at reflux in nitrogen atmosphere for 74 hours. After cooling to room temperature the solid is filtered off and washed with acetone. The filtrate is concentrated under reduced pressure, the residue is dissolved in ether, the ether solution is washed 2x with water and dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness. The crude oil is distilled in vacuo, at 199°-212°/0.2 mm to yield (S)-1-benzyloxy-3-[o-(cyclopropylmethoxy)phenoxy]-2-hydroxypropane.
Reaction SMILES: [C:1](/[N:3]=[C:4](\[N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)/[N:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=3[CH3:27])[CH2:15][CH2:14]2)=[O:12])[C@@H:7]([C:28](OC)=[O:29])[CH2:6]1)#[N:2].[NH2:38][OH:39]>CO>[C:1](/[N:3]=[C:4](\[N:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)/[N:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=3[CH3:27])[CH2:17][CH2:18]2)=[O:12])[C@@H:7]([C:28]([NH:38][OH:39])=[O:29])[CH2:6]1)#[N:2]
Reactant: NO
Reactant: COC(=O)[C@H]1CN(/C(=N/C#N)N2CCCCC2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Solvent: CO
Product: Cc1cc(C#N)ccc1N1CCN(C(=O)[C@H]2CCN(/C(=N/C#N)N3CCCCC3)C[C@@H]2C(=O)NO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl(3R,4S)-1-[(E)-(cyanoimino)(piperidin-1-yl)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate (53.30 mg, 0.0001054 mol) in anhydrous methanol (1.110 mL, 0.02740 mol) at rt was added the above 1.50 M of hydroxylamine in methanol (1.40 mL). The reaction mixture was stirred at rt for 2 h. LCMS showed the reaction was done. The reaction was quenched with saturated aqueous NH4Cl, extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC with 5-95% MeCN/H2O to give the product. MS (ESI): (M+H)+=507.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N+:20]([O-:22])=[O:21])[C:14]=2Cl)(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[OH2:26]>>[N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N+:20]([O-:22])=[O:21])[C:14]=2[OH:26])(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCN2CCOCC2)c1Cl
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCN2CCOCC2)c1O
Yield: 157.7 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-[2-(morpholinyl)ethyl]-2,6-dichloro-3-nitrobenzenesulfonamide (400 mg, 1.04 mmol), 60% NaH (125 mg, 3.12 mmol) and water (23 μL, 1.25 mmol) were reacted to form the crude product (600 mg) which was carried onto the hydrogenation without purification. EI-MS (m/z) 363.95, 365.94 (M−).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:32])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:17]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1([CH3:33])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:32])[CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)CCc3ccccc3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)CCc2ccccc2)c1
Yield: 66.1 %

Procedure:
To a mixture of methyl 3,3-dimethyl-2-(3-(3-phenylpropanamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (222 mg, 0.50 mmol) in methanol (6 mL) and water (3 mL) was added a solution of sodium hydroxide (341 mg, 8.53 mmol) in water (3 mL). The resultant mixture was heated to reflux for 1 hour. The methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=5-6. The precipitates were collected by filtration, purified by preparative Thin layer chromatography (petroleum ether/ethyl acetate=3:1) to afford 3,3-dimethyl-2-(3-(3-phenylpropanamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a solid. (134 mg, yield: 66.1%); MS (ES+APCI) M+1-water=411.1
Reaction SMILES: Cl.[NH:2]1[CH2:23][CH2:22][CH2:21][C@H:3]1[C:4]([NH:6][C@H:7]([C:18]([OH:20])=[O:19])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:17])[NH:13][N+:14]([O-:16])=[O:15])=[O:5].[N:24]1([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]1[C:30](O)=[O:31]>CN(C=O)C.CC(O)=O>[N:24]1([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]1[C:30]([N:2]1[CH2:23][CH2:22][CH2:21][C@H:3]1[C:4]([NH:6][C@H:7]([C:18]([OH:20])=[O:19])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:17])[NH:13][N+:14]([O-:16])=[O:15])=[O:5])=[O:31]
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCN1)C(=O)O)N[N+](=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)O)N[N+](=O)[O-]
Yield: 53.4 %

Procedure:
After 2.25 g (5.0 mmols) of HCl.H-Pro-Arg(NO2)-CHA was dissolved in 10 ml (15.0 mmols) of 1.5N NEM/DMF, 1.93 g (5.0 mmols) of Z-PyroGlu-SDP was added to the solution at 0° to 5° C. The resulting mixture was reacted at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with 300 ml of AcOH followed by washing 4 times with 100 ml of cold 5% hydrochloric acid and twice with 100 ml of saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate and decoloring with activated charcoal, the AcOEt phase was distilled under reduced pressure. The residue was recrystallized from MeOH/AcOEt/ether to give 1.86 g (53.4%) of Z-PyroGlu-Pro-Arg(NO2)-CHA.