Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([CH2:23][S:24]C(=O)C)([CH2:8][C:9]1[CH:10]=[N:11][C:12]([NH:15]C(OC(C)(C)C)=O)=[CH:13][CH:14]=1)[CH2:6][CH3:7])C>Cl>[NH2:15][C:12]1[N:11]=[CH:10][C:9]([CH2:8][C:5]([CH2:23][SH:24])([CH2:6][CH3:7])[C:4]([OH:28])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(CC)(CSC(C)=O)Cc1ccc(NC(=O)OC(C)(C)C)nc1
Agent: Cl
Product: CCC(CS)(Cc1ccc(N)nc1)C(=O)O

Procedure:
2-Acetylsulfanylmethyl-2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-butyric acid ethyl ester (12.3 mg, 30 μmol) was dissolved in conc. HCl (2 mL) under argon. The solution was heated to reflux for 24 h. Concentration under reduced pressure gave the title compound as the hydrochloride salt (8.3 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[C:6]([CH:13]=O)=[CH:5][CH:4]=1.[Br-:15].[Li+].C[Si](Cl)(C)C.C[SiH](C)O[SiH](C)C>C(#N)C.ClCCl.CN(C=O)C>[Br:15][CH2:13][C:6]1[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C=O)c2c1OCCO2
Reactant: [Br-]
Agent: C[SiH](C)O[SiH](C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(CBr)c2c1OCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 8-methoxy-1,4-benzodioxane-5-carbaldehyde (12 g, 62 mmol) in acetonitrile (140 mL) was added lithium bromide (12 g, 110 mmol), and then trimethylsilyl chloride (12 mL, 95 mmol) was added dropwise. After 15 minutes, the mixture was ice-cooled, and 1,1,3,3-tetramethyldisiloxane (19 mL, 110 mmol) was added dropwise, followed by stirring at room temperature for 2 hours. The mixture was diluted with dichloromethane, and then was filtered through Celite. The solvent was evaporated in vacuo to give a pale yellow oil. To a solution of the obtained crude 5-bromomethyl-8-methoxy-1,4-benzodioxane in DMF(180 mL) was added sodium cyanide (9.2 g, 190 mmol), followed by stirring at room temperature for 60 hours. To the mixture was added water under ice-cooling, and the precipitated solid was collected by filtration to give Compound 1a (6.8 g, 53%) as an ash-colored solid.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:15][CH2:14][CH2:13][CH2:12][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2CCCCl
Temperature: 25 °C
Reaction time: 96 h
Yield: 59 %

Procedure:
A mixture of adenine (4.05 g, 30 mM), 1-bromo-3-chloropropane (21.3 g, 13.4 mM), and potassium carbonate (10.4 g, 75 mM) in DMF (200 mL) was stirred at room temperature under argon for 4 days, filtrated, and evaporated to dryness. The crude product was washed with water and dried. Recrystallization from ethanol gave 9-(3-chloropropyl)adenine in 59% yield.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([N:19]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:33][CH2:32]2)[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(OCC)C>C(O)(=O)C>[CH2:37]([CH:34]1[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][CH2:28][N:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:17]([CH:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[O:18])[CH2:32][CH2:33]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(OCc1ccccc1)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
The compound obtained in Example 65 (4.89 g, 7.85 mmol) was dissolved in acetic acid (5 ml). To the solution was added 30% solution of hydrogen bromide in acetic acid (15 ml), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added diethylether (60 ml), and supernatant solution was removed by decantation. To the residure was added diethylether (60 ml), and supernatant solution was removed by decantation. These procedure was repeated further three times. To the residue was added aqueous solution of 1N-sodium hydroxide (50 ml) and the mixture was extracted with dichloromethane (80 ml, 30 ml×2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (alumina 200 g, ethyl acetate/methanol=1/0 to 4/1 to 1/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (3.18 g, 6.51 mmol, Yield 83%) as pale brown oily substance.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([O:13]C)[CH:10]=[CH:9][C:4]=1[C:5]([NH:7][NH2:8])=O.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1)([O-:17])=[O:16]>>[OH:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:4]=1[C:5]1[N:24]([C:21]2[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=2)[C:25]([SH:26])=[N:8][N:7]=1
Reactant: COc1ccc(C(=O)NN)c(OC)c1
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Product: O=[N+]([O-])c1ccc(-n2c(S)nnc2-c2ccc(O)cc2O)cc1

Procedure:
Analogously to Example 8.1, reaction of 2,4-dimethoxybenzhydrazide and 4-nitrophenyl isothiocyanate gives the compound
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[NH:22][C:21]1=[O:31]>>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14]([NH:19][C@@H:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[NH:22][C:21]1=[O:31])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CNC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Product: CC(C)(CNC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2NC1=O

Procedure:
Prepared from 3-(benzyloxycarbonylamino)-2,2-dimethylpropanoic acid and 3(R)-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step E) by the procedure described in Example 1, Step F. 1H NMR (200MHz, CDCl3): 1.19 (s,6H), 1.90 (m,1H), 2.6-3.0 (n,3H), 3.26 (d,6Hz,2H), 4.46 (m,1H), 5.07 (s,2H), 5.7 (br t,1H), 6.62 (d,7Hz,1H), 6.97 (d,8Hz,1H), 7.1-7.3 (m,3H), 7.3 (s,5H), 8.14 (br s,1H). FAB-MS: calculated for C23H27N3O4 409; found 410 (M+H,100%).
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.C(C1C=CC=CC=1)C.[C:33](OCC)(=[O:39])[C:34]([O:36]CC)=[O:35].Cl>C1COCC1.CCCCCCC.C(OCC)(=O)C>[O:39]=[C:33]([CH2:2][C:1](=[O:3])[C:4]1[S:5][C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[CH:7][CH:8]=1)[C:34]([OH:36])=[O:35]
Reactant: CC(=O)c1ccc(Cc2cccc(F)c2)s1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: O=C(O)C(=O)CC(=O)c1ccc(Cc2cccc(F)c2)s1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a cold (−78° C.) solution of 2-acetyl-5-(3-fluorobenzyl)thiophene (315 mg, 1.34 mmol) in anhydrous THF (5 mL) under an atmosphere of argon, LDA (0.7 mL, 2 M in a mixture of heptane, THF and ethylbenzene, 1.40 mmol) was added dropwise over a period of 10 min. After the reaction mixture was stirred at −78° C. for an additional 40 min, diethyl oxalate (0.26 mL, 1.91 mmol) was added over a period of 5 min. The resultant mixture was allowed to warm to rt and stirred overnight. The resultant solution was diluted with ethyl acetate, and neutralized with dilute HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with hexane. The precipitate was filtered to provide the title compound as yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>>[CH:22]1([CH2:21][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(CC2CC2)c(=O)[nH]c1=O
Yield: 46.4 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and bromomethyl cyclopropane were reacted by the same way with the example 1 to obtain the titled compound (146 mg, yield: 46.4%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=O)=[O:4].O[CH:14]1[CH2:19]SC(O)C[S:15]1.[Br-].[Li+]>O1CCOCC1>[CH3:1][O:2][C:3]([CH2:5][C:6]1[S:15][CH:14]=[CH:19][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:4]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: OC1CSC(O)CS1
Agent: [Br-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COC(=O)Cc1sccc1C(=O)OC
Temperature: 25 °C
Yield: 82.4 %

Procedure:
100.0 g of dimethyl 1,3-acetonedicarboxylate was dissolved in 2,800 ml of dioxane, and added thereto were 52.5 g of 2,5-dihydroxy-1,4-dithiane and 5.0 g of lithium bromide. The resulting mixture was refluxed for 15 hours, cooled to room temperature, and concentrated by evaporation. To the residue, 1,000 ml of n-hexane was added, stirred, and the hexane layer was separated. This extraction procedure was repeated twice using 500 ml portions of n-hexane. The separated n-hexane layers were combined and concentrated under reduced pressure to obtain 60.9 g (yield of 49%) of the title compound as an oil, which was directly used in the next step without any purification. An analytical sample of the title compound could be obtained by vacuum distillation.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[N:6][CH:7]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:13][C:8]([C:5]1[C:4]([N+:15]([O-:17])=[O:16])=[CH:3][C:2]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:7][N:6]=1)([CH3:14])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(C)(C)c1ncc(Br)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)c1ncc(N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A stirred mixture of methyl 2-(5-bromo-3-nitropyridin-2-yl)-2-methylpropanoate (1.2 g, 3.96 mmol), morpholine (0.34 mL, 3.96 mmol), Pd2dba3 (181 mg, 0.20 mmol), XPhos (189 mg, 0.40 mmol) and sodium tert-butoxide (1.1 g, 11.88 mmol) in toluene (30 mL) was heated at reflux for two h. After this time the reaction was cooled to rt and partitioned between EtOAc (300 mL) and water (100 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Column chromatography gave methyl 2-methyl-2-(5-morpholino-3-nitropyridin-2-yl)propanoate as a yellow oil.
Reaction SMILES: CS(C)=[O:3].[I-].C[S+](C)C.[H-].[Na+].C(C1([CH:17]([C:34]2[CH:39]=[CH:38][CH:37]=CC=2)[CH2:18][C:19]([CH2:21][CH:22]([C:28]2C=CC=CC=2)[C:23]2([C:26]#[N:27])[CH2:25][CH2:24]2)=O)CC1)#N>O>[C:26]([C:23]1([C:22]2([CH2:21][CH2:19][C:18]3[CH:17]=[CH:34][CH:39]=[CH:38][CH:37]=3)[CH2:28][O:3]2)[CH2:24][CH2:25]1)#[N:27]
Reactant: N#CC1(C(CC(=O)CC(c2ccccc2)C2(C#N)CC2)c2ccccc2)CC1
Reactant: CS(C)=O
Agent: C[S+](C)C
Agent: [H-]
Agent: [I-]
Solvent: O
Product: N#CC1(C2(CCc3ccccc3)CO2)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
10 ml of abs. DMSO are added dropwise at 10° C. to 2 g (10 mmol) of trimethylsulphonium iodide and 0.2 g (7 mmol) of sodium hydride (80% in oil). The mixture is stirred for 1 h at 20° C. After this, a solution of 1 g (5 mmol) of 1-cyanocyclopropyl 2-phenylethyl-ketone (compound II-16, Example 32) in 5 ml of abs. DMSO is added dropwise and the mixture is allowed to react for 4 h at 20° C. The solution is poured into water and extracted using ethyl acetate, the organic phase is dried with Na2SO4 and the solvent is evaporated in vacuo. 0.8 g (75% of theory) is obtained in the form of a colorless oil,
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][CH:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=O)[O:32]C2C=CC=CC=2)=[CH:26][C:25]=1[F:40])[CH2:22][OH:23]>CC#N>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:31]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([CH:21]([CH2:20][OH:19])[CH2:22][OH:23])=[C:25]([F:40])[CH:26]=2)=[O:32])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Reactant: O=C(Nc1ccc(C(CO)CO)c(F)c1)Oc1ccccc1
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(C(CO)CO)c(F)c2)n(-c2cccc(Cl)c2)n1
Yield: 88.1 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (synthesis described for example A153) (102 mg, 0.387 mmol, 1.0 eq) in MeCN (9 mL) was added TEA (0.2145 mL, 1.55 mmol, 4.0 eq) followed by phenyl 4-(1,3-dihydroxypropan-2-yl)-3-fluorophenylcarbamate (120 mg, 0.395 mmol, 1.02 eq) at RT and the mixture was stirred at reflux for 16 h. The solvent was evaporated and the crude product was purified by CC using EtOAc as eluent to get 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(4-(1,3-dihydroxypropan-2-yl)-3-fluorophenyl)urea (162 mg; 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.C([O:14][CH:15]1[CH2:23][C:22]([CH3:25])([CH3:24])[CH:21]2[CH:17]([CH2:18][N:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:20]2)[C:16]1=[O:33])(=O)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH2:26]([N:19]1[CH2:18][CH:17]2[CH:21]([C:22]([CH3:25])([CH3:24])[CH2:23][CH:15]([OH:14])[C:16]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:33])[CH2:20]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(=O)OC1CC(C)(C)C2CN(Cc3ccccc3)CC2C1=O
Reactant: COc1ccccc1[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1C1(O)C(O)CC(C)(C)C2CN(Cc3ccccc3)CC21
Temperature: 0 °C
Yield: 35.1 %

Procedure:
To a suspension of 33.8 g of 2-methoxyphenylmagnesium bromide in 75 cm3 of tetrahydrofuran is added dropwise, at room temperature and with stirring, a solution of 6.6 g of (3aRS,5RS,7aRS)-5-acetoxy-2-benzyl-7,7-dimethyl-4-perhydroisoindolone in 75 cm3 of tetrahydrofuran. The reaction mixture is stirred at room temperature for 15 hours, treated with 200 cm3 of saturated aqueous ammonium chloride solution and taken up in 200 cm3 of ethyl ether and 100 g of ice. The organic phase is extracted with 3 times 100 cm3 of ethyl ether, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 500 cm3 of petroleum ether. 2.8 g of (3aRS,4RS,5RS,7aRS)-2-benzyl-7,7-dimethyl-4-(2-methoxyphenyl)-4,5-perhydroisoindolediol are obtained, melting at 190° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:15])[C@H:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4]([OH:6])=[O:5].CS(C)=O.F[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[C:24]#[N:25].C(=O)(O)[O-].[Na+]>C([O-])([O-])=O.[Na+].[Na+]>[C:11]([O:10][C:8]([NH:7][C@@H:3]([C@@H:2]([NH:1][C:21]1[CH:22]=[C:23]([C:24]#[N:25])[CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[CH3:15])[C:4]([OH:6])=[O:5])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[C@H](N)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@H](Nc1cc(C#N)ccc1[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 55 °C
Reaction time: 3 h
Yield: 108.6 %

Procedure:
A mixture of (2S,3S)-3-amino-2-(tert-butoxycarbonylamino)butanoic acid (3.14 g, 14.4 mmol), dimethylsulfoxide (40 ml), 3-fluoro-4-nitrobenzonitrile (2.63 g, 15.8 mmol), and sodium bicarbonate (4.83 g, 57.5 mmol) was stirred at 55° C. for 3 h. Additional NaHCO3 (0.9 g) was added and the mixture was stirred at 60° C. for 1 hour, then cooled to RT, diluted with cold sat. Na2CO3, and washed with MTBE. The aqueous phase was carefully acidified to pH ˜4 with solid citric acid and extracted with EtOAc (three times). The combined organic layers were washed with H2O twice and brine, dried over Na2SO4, filtered, and concentrated to provide (2S,3S)-2-(tert-butoxycarbonylamino)-3-(5-cyano-2-nitrophenylamino)butanoic acid (5.7 g, quant.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:20][C:19]=3[CH:28]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH2:26]([O:25][C:23]([C:21]1[S:20][C:19]2[CH:28]=[C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:16]=[CH:17][C:18]=2[CH:22]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)c1cc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2s1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2ccc(OC3CCNCC3)cc2s1
Reaction time: 2 h
Yield: 105 %

Procedure:
The above prepared 4-(2-ethoxycarbonyl-benzo[b]thiophen-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (0.330 g, 0.814 mmol) was dissolved in 2 mL of dioxane and treated with HCl (4.1 mL of 4N [dioxane], 20 eq.) and the mixture kept at ambient temperature for 2 h. Reducing the volume, adding heptane, and direct crystallization produced 0.261 g of 6-(piperidin-4-yloxy)-benzo[b]thiophene-2-carboxylic acid ethyl ester as hydrochloride as white crystals, which was further processed as follows:
Reaction SMILES: [CH:1]1([C:4]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[CH:7]=[C:6]3[O:22][CH2:23][CH2:24][N:25]([CH2:26][CH2:27][O:28][C:29]4[C:34]([F:35])=[CH:33][C:32]([CH:36]=[O:37])=[CH:31][C:30]=4[F:38])[C:5]=23)[CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([C:4]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10][CH2:9][C:8]=3[CH:7]=[C:6]3[O:22][CH2:23][CH2:24][N:25]([CH2:26][CH2:27][O:28][C:29]4[C:30]([F:38])=[CH:31][C:32]([CH2:36][OH:37])=[CH:33][C:34]=4[F:35])[C:5]=23)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(c(C4CC4)c2CC1)N(CCOc1c(F)cc(C=O)cc1F)CCO3
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2cc3c(c(C4CC4)c2CC1)N(CCOc1c(F)cc(CO)cc1F)CCO3
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
To a solution of 270 mg of t-butyl 5-cyclopropyl-4-[2-(2,6-difluoro-4-formylphenoxy)ethyl]-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate in 6 ml of MeOH was added 30 mg of sodium borohydride, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc)) to obtain 220 mg of t-butyl 5-cyclopropyl-4-{2-[2,6-difluoro-4-(hydroxymethyl)phenoxy]ethyl}-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a white solid.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])(=[O:4])=[O:3].[CH3:14][C:15]([CH3:20])=[CH:16][C:17]([OH:19])=[O:18].S(=O)(=O)(O)O>>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][C:10]([C:15]([CH3:20])([CH3:14])[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][C:6]=1[O:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: COc1ccccc1OS(C)(=O)=O
Reactant: CC(C)=CC(=O)O
Agent: O=S(=O)(O)O
Product: COc1ccc(C(C)(C)CC(=O)O)cc1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 23.4 %

Procedure:
To a mixture of 2-methoxyphenyl methanesulfonate (Example 50b) (82 g, 406.4 mmol) and 3-methylbut-2-enoic acid (20.3 g, 203.2 mmol), was added concentrate sulfuric acid (11 mL, 96%, 206.3 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min, then heated to 70° C. and stirred under nitrogen overnight. Upon completion, the reaction was cooled to room temperature, quenched with ice water (500 mL) and extracted with ether (1×). The phases were separated, and the organic layer was washed with 2N NaOH (1×). The combined aqueous layers were acidified to pH 1 with 12N HCl at 0° C. and extracted with ether (1×). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a red-brown oil (14.4 g, contained<20% 3-methylbut-2-enoic acid)1H NMR (400 MHz, DMSO-d6) δ 1.33 (s, 6H), 2.53 (s, 2H), 3.31 (s, 3H), 3.79 (s, 3H), 7.08-7.31 (m, 3H), 11.87 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16]N=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.CC1[N:30]=[CH:29]C(NN)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:29]=[N:30][C:17]([CH3:16])=[CH:18][CH:19]=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1ccc(NN)cn1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: Cl
Product: Cc1ccc(-n2nc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)cn1

Procedure:
785 g (2.25 mmol) of the compound of Example 1A is reacted analogously to the synthesis of the compound of Example 20A with 599 mg (3.38 mmol) of 6-methylpyridin-3-yl-hydrazine hydrochloride. After hydrolysis, 60 mg (8% of theory) of the title compound is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[N:24]=[CH:23][CH:22]=[CH:21][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])=[O:11])([O-])=O.[H][H]>CO.O1CCCC1.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[N:24]=[CH:23][CH:22]=[CH:21][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])=[O:11]
Reactant: [H][H]
Reactant: O=C(NCc1ccccc1Cl)c1cccnc1Oc1cccc([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(Oc2ncccc2C(=O)NCc2ccccc2Cl)c1

Procedure:
To a solution of 2-(3-Nitro-phenoxy)-N-(2-chloro-benzyl)-nicotinamide (0.530 g 1.38 mmole) in methanol (15 ml) and tetrahydrofuran (20 ml) was added 10% PtO2 (0.0.50 g). This was shaken under 35 psi hydrogen for 1 hour 40 minutes. The catalyst was removed by filtration, and the solution was concentrated to give an oil that was purified by chromatography on silica gel eluting with 2.5% methanol/methylene chloride. Recrystalization from ethyl acetate/hexane gave crystals. (0.327 g). M.P. 101-103° C.; Anal. calcd. for C19H16N3O2Cl: C, 64.5; H, 4.56; N, 11.88. Found: C, 64.15; H,4.07; N, 11.80.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[O:15][C:14](=O)[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:20]>>[C:1]1([CH:7]2[C:16]3[NH:20][C:14](=[O:15])[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1ccccc1)CCC2
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)CCCC2c1ccccc1
Yield: 100 %

Procedure:
A solution of 8-phenyl-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (415.0 mg, 1.706 mmol) in concentrated ammonium hydroxide (35 mL, 899 mmol) was stirred at 100° C. in a high-pressure vessel (75 mL) for 6 h. The formation of white precipitate was observed during the heating. The LC/MS analysis of the filtrate shows the presence of the product with the desired mass (M+H)=243.20. The solvent was removed in vacuum to provide 8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (435 mg, 1.706 mmol, 100% yield) as off-white solid. LC-MS (M+H)+=243.2. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.2 (2H, br. s.), 7.34 (2H, t, J=7.5 Hz), 7.26 (1H, t, J=7.3 Hz), 7.14 (2H, d, J=7.3 Hz), 3.80 (1H, br. s.), 2.32-2.43 (1H, m), 2.15 (1H, ddd, J=16.9, 10.5, 6.1 Hz), 1.93-2.04 (1H, m), 1.67-1.75 (1H, m), 1.56 (1H, ddd, J=7.8, 5.2, 2.6 Hz), 1.36 (1H, dt, J=13.1, 2.7 Hz).