Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C@H:39]([NH2:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:34][CH:33]=1>>[CH3:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C@H:39]([NH:46][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:19]([CH:20]=[C:3]([C:1]#[N:2])[CH2:4][CH2:5]2)=[CH:6][CH2:7]4)=[O:30])[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:36][CH:37]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: Cc1ccc(C[C@H](N)c2ccccc2)cc1
Product: Cc1ccc(C[C@H](NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)c2ccccc2)cc1
Yield: 77 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and (S)-2-(4-methylphenyl)-1-phenylethylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 77%.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:17]N(C(N(C)C)C)C>FC(F)(F)C(O)=O>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[C:13](=[CH2:17])[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: CC(N(C)C)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: C=C1CCc2nc3ccccc3c(N)c2C1=O
Temperature: 100 °C

Procedure:
In 25ml of trifluoroacetic acid cooled in ice was dissolved 5.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one. To the solution was added dropwise 6.70ml (2.09 eq) of bisdimethylaminoethane over 5 minutes and thereafter the mixture was maintained at 90°100° C. for 5 hours during which the starting material was converted to a mixture of intermediate and exo-methylene products. The reaction mixture was poured into ice/NaOH to make it basic and the precipitate was extracted with several portions of 5:1 dichloromethane/MeOH. The combined extracts were evaporated to a residue. The residue was refluxed in toluene for 5 hours during which the intermediate was converted to the end product. The reaction mixture was evaporated to a residue which was purified by chromatography on silica gel (EtOAc) to yield about 2 g of a solid. This was recrystallized from dichloromethane/EtOAc to yield 1.79 g (34%) of product as a solid, melting point 119°-193° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([O:23][C:24]([NH:26][C@H:27]([C:34](O)=[O:35])[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:25])([CH3:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.[Cl-].[Na+].O>[C:20]([O:23][C:24](=[O:25])[NH:26][C@@H:27]([CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)[C:34](=[O:35])[N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)([CH3:22])([CH3:19])[CH3:21]
Reactant: c1ccc(Oc2cccc([C@@H]3CCCN3)c2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1c1cccc(Oc2ccccc2)c1)C1CCCCC1
Reaction time: 0.5 h

Procedure:
(S)-2-(3-phenoxy-phenyl)-pyrrolidine (1.2 g, 5.02 mmol) is added to a solution of Boc-L-α-cyclohexylglycine (1.42 g, 5.2 mmol), HOBt (1.0 g, 7.53 mmol) and HBTU (2.86 g, 7.53 mmol) in 10 mL of DMF. Hunig's base (3.6 Ml, 20 mmol) is added and the mixture is stirred for 30 minutes. The mixture is diluted with brine (20 mL) and extracted with EtOAc (3×10 mL). The organics were combined, dried over Na2SO4, filtered, concentrated under reduced pressures and purified by silica gel column chromatography (20% EtOAc/Hexanes) to give {(S)-1-cyclohexyl-2-oxo-2-[(S)-2-(3-phenoxy-phenyl)-pyrrolidine-1-yl]-ethyl}-cabamic acid tert-butyl ester as a white powder (1.65 g, 66%). LCMS m/z 479.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][C:16](=[O:18])[NH:15][CH2:14][CH:13]2[C:19](O)=[O:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][NH2:30])=[CH:24][CH:23]=1.Cl.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:28]([O:29][NH:30][C:19]([CH:13]1[CH2:14][NH:15][C:16](=[O:18])[CH2:17][N:12]1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])=[O:20])[C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)N2CC(=O)NCC2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CC(=O)NCC2C(=O)NOCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
To a solution of 1-(4-methoxybenzenesulfonyl)-5-oxo-piperazine-2-carboxylic acid (166 mg, 0.53 mmol) in methylene chloride (5 ml) is added 0-benzyl hydroxylamine hydrochloride (255 mg, 1.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (153 mg, 0.8 mmol) and triethylamine (370 μL 2.65 mmol). The resulting mixture is stirred overnight, diluted with ethyl acetate and washed with 1N hydrocloric acid. The organic layer is dried (sodium sulfate), filtered and concentrated. The crude product is purified by silica gel chromatography (elution with 5% methanol in methylene chloride) to provide N-(benzyloxy)-1-(4-methoxybenzenesulfonyl)-5-oxo-piperazine-2-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH:15]=[C:14]1[C:23]([OH:25])=[O:24])(=[O:12])=[O:11].[C:26]([O:29][CH2:30]Br)(=[O:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:22][CH2:21][C:16]2([O:17][CH2:18][CH2:19][O:20]2)[CH:15]=[C:14]1[C:23]([O:25][CH2:30][O:29][C:26](=[O:28])[CH3:27])=[O:24])(=[O:12])=[O:11]
Reactant: O=C(O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OCCO2
Reactant: CC(=O)OCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(=O)OCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
1 g (2.55 mmol) of 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylic acid obtained in Example 47a was dissolved in 20 ml of acetonitrile, and 0.50 ml (5.10 mmol) of bromomethyl acetate, 499 mg (1.53 mmol) of cesium carbonate and 471 mg (1.28 mmol) of tetrabutylammonium iodide were added thereto, followed by stirring for 1 hour at room temperature. 0.1 N hydrochloric acid was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; dichloromethane:methanol=49:1) to give 833 mg of the title compound as an amorphous substance (yield: 70%).
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[CH2:3][CH3:4].[H-].[Na+].Cl[C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:16][O:17][C:18]=2[N:19]=1.O>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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C@H:2]([O:5][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:16][O:17][C:18]=2[N:19]=1)[CH2:3][CH3:4]
Reactant: CC[C@H](C)O
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC[C@H](C)Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of (2S)-butan-2-ol (0.32 mL) in toluene (8 mL) was added sodium hydride (0.28 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (1.0 g), BINAP (0.066 g), Pd2(dba)3 (0.048 g) and toluene (8 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-{[(1S)-1-methylpropyl]oxy}-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.73 g, 65%) as a white powder.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[O:13]1[CH2:16][CH:15]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH:15]3[CH2:16][O:13][CH2:14]3)[CH2:18][CH2:19]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: C1CN(C2COC2)CCN1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCN(C2COC2)CC1
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzonitrile (7 g, 1.2 eq, 41.2 mmol), 1-(oxetan-3-yl)piperazine (5.0 g, 1.0 eq, 35.2 mmol) was dissolved in annhydrous DMF (100 mL). K2CO3 (12.2 g, 2.5 eq, 87.9 mmol) was added to the above solution and the reaction mixture was stirred at room temperature for over night. The reaction mixture was diluted with of EtOAc (100 mL) and partitioned with H2O (100 mL). Layers were separated and the aqueous layer was washed once with of EtOAc (100 mL). Combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to leave a crude oil. Purification of the crude mixture by column chromatography on silica gel (ISCO System) using 20% MeOH in CH2Cl2/CH2Cl2 (gradient system from 1:9 to 4:6) as eluent gave 5-nitro-2-(4-(oxetan-3-yl)piperazin-1-yl)benzonitrile in 97% yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:33])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12](/[CH:16]=[CH:17]/[C:18](=[O:32])[N:19]([CH3:31])[CH2:20][C:21]1[S:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22]=1[CH3:30])=[CH:11][N:10]=2)=[O:5])C.[OH-].[Na+:35]>CO.C(Cl)Cl.O>[Na+:35].[CH3:31][N:19]([CH2:20][C:21]1[S:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[C:22]=1[CH3:30])[C:18](/[CH:17]=[CH:16]/[C:12]1[CH:13]=[C:14]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:33])[C:6]([C:4]([O-:5])=[O:3])=[CH:15]2)=[O:32]
Reactant: CCOC(=O)c1cc2cc(/C=C/C(=O)N(C)Cc3sc4ccccc4c3C)cnc2[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3[nH]c(=O)c(C(=O)[O-])cc3c2)sc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a suspension of (E)-6-{2-[methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)carbamoyl]vinyl}-2-oxo-1,2-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (349 mg, 0.76 mmol) in MeOH (10 mL) and CH2Cl2 (5 mL) was added NaOH (1.53 mL of a 0.995 M solution in H2O, 1.53 mmol) dropwise. The mixture was stirred at room temperature overnight. The solid was collected by filtration and then dried under vacuum at 50° C. for 2 d. Trituration with 5:1 MeCN/H2O gave the title compound (85 mg, 25%) as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6+TFA-d) δ 9.15 (s, 1H), 8.85 (s, 2H), 7.88 (d, J=7.5 Hz, 1H), 7.76-7.58 (m, 2H), 7.46-7.34 (m, 3H), 5.15-4.92 (m, 2H), 3.20-2.98 (m, 3H), 2.44 (s, 3H); MS (ESI) m/e 434 (M−Na+2H)+.
Reaction SMILES: [CH2:1]([C:10](=O)[CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:33].S.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:1]([C:10]1[S:33][C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:12][C:11]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(CC(=O)C(CC(=O)c2ccc(Cl)cc2)Cc2ccc(OC)cc2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: COc1ccc(Cc2cc(-c3ccc(Cl)cc3)sc2Cc2ccc(OC)cc2)cc1
Yield: 153.3 %

Procedure:
In a 1-liter stainless steel autoclave equipped with stirrer were placed 54.5 g (0.133 mole) of 1,2-di-p-anisyl-4-p-chlorophenylbutane-1,4-dione, 100 ml of xylene and 30 g (0.0675 mole) of phosphorus pentasulfide. The autoclave was cooled with a Dry Ice-acetone bath and 130 g (3.81 moles) of hydrogen sulfide was distilled into the autoclave. The vessel was stirred and heated for three hours at 162°-168° C. (1220-1290 psig). After cooling to room temperature the hydrogen sulfide was vented into an aqueous sodium hydroxide solution. Treatment with 150 ml of absolute ethanol to remove unreacted phosphorus pentasulfide gave 77 g of crude product. Recrystallization from 400 ml of absolute ethanol gave 45 g (83.1%) of pure 2,3-di-p-anisyl-5-p-chlorophenylthiophene, m.p. 125°-128° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12]>>[CH2:10]([NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:11][CH3:12]
Reactant: CCCN
Reactant: N#Cc1ccc(F)cc1
Product: CCCNc1ccc(C#N)cc1

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 4-fluorobenzonitrile and n-propylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([F:12])([F:11])[F:10].C([Li])(CC)C.C1CCCCC1.[CH3:24][Si:25](Cl)([CH3:27])[CH3:26]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Si:25]([CH3:27])([CH3:26])[CH3:24])=[C:4]([F:8])[C:3]=1[C:9]([F:12])([F:10])[F:11]
Reactant: Fc1cccc(Cl)c1C(F)(F)F
Reactant: C[Si](C)(C)Cl
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(Cl)c(C(F)(F)F)c1F
Temperature: -70 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
1-Chloro-3-fluoro-2-(trifluoromethyl)benzene (10 g, 50 mmol) was dissolved in tetrahydrofuran (100 ml), cooled to −70° C. under argon, and treated with a 1.4M solution of sec-butyl lithium in cyclohexane (37.5 ml, 52.5 mmol). Stirring was continued for 2 hrs and then trimethylsilyl chloride (6.7 ml, 52.5 mmol) was added and stirring continued, still at −70° C., for a further 1 hr. The mixture was allowed to warm to room temperature and the tetrahydrofuran was then removed in vacuo. The residue was partitioned between diethyl ether and water and then the organic layer was separated and washed with 2N aqueous hydrogen chloride. The organic phase was separated and concentrated to give the crude product which was purified by flash silica-gel column chromatography, eluting with hexane, to give pure [4-chloro-2-fluoro-3-(trifluoromethyl)phenyl](trimethyl)silane as a clear oil (10.35 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[Br:1][C:12]1[CH:13]=[CH:14][C:9]([CH:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(C2CCCNC2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Brc1ccc(C2CCCNC2)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
N-Bromosuccinimide (912 mg, 5.12 mmol) was added to a solution of 1.18 g (7.32 mmol) of 3-phenylpiperidine in 50% sulfuric acid (12 ml), and the mixture was stirred at 70° C. for 30 min. A saturated aqueous potassium carbonate solution was added to the reaction solution under ice cooling, and the mixture was extracted twice with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, was filtered, and was then concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol:concentrated aqueous ammonia=9:0.6:0.06) to give 352 mg (yield 20%) of the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:23]=[C:22]2[C:18](=[N:19][CH:20]=[N:21]2)[C:17](=[O:24])[N:16]=1)[CH2:6][CH3:7].[OH-].[NH4+]>S(=O)(=O)(O)O>[CH2:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:1]([O-:4])=[O:2])=[CH:11][C:10]=1[C:15]1[N:23]=[C:22]2[C:18](=[N:19][CH:20]=[N:21]2)[C:17](=[O:24])[N:16]=1)[CH2:6][CH3:7]
Reactant: CCCOc1ccccc1C1=NC(=O)C2=NC=NC2=N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCCOc1ccc([N+](=O)[O-])cc1C1=NC(=O)C2=NC=NC2=N1
Temperature: 0 °C

Procedure:
A mixture of fuming nitric acid (0.23 ml) and sulphuric acid (4 ml) was added dropwise to a stirred solution of 2-(2-propoxyphenyl)purin-6-one (1.0 g) in sulphuric acid (4 ml) at 0° to -5° C. The temperature was maintained between -5° C. and +4° C. for 20 hours and then the mixture was poured into ice-water. The filtered solution was treated with concentrated ammonium hydroxide to pH 9 to give a crude product, 0.55 g. Recrystallisation twice from aqueous ethanol then once from acetonitrile gave the title compound, 0.2 g, m.p. 254°-256° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:7][CH:8]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:13])([CH3:12])[CH3:14])=[N:7][CH:8]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(C=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(=O)Nc1ccc(CO)cn1
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
N-(5-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (6.96 g) under an argon atmosphere in MeOH (120 mL) was cooled to 0° C. and then treated portion wise with sodium borohydride (1.289 g). The cooling bath was removed, stirring was continued for 30 minutes and the reaction mixture was partitioned between half-saturated aqueous NH4Cl and AcOEt. The layers were separated, the organic layer dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (heptane/AcOEt 1:1 to 1:2) to give N-(5-hydroxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (3.4 g) as a crystalline white solid. MS (ESI): 209.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[N:27][CH:28]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1.C(N(CC)CC)C.[C:39](Cl)(=[O:43])[CH2:40][CH2:41][CH3:42]>O1CCCC1>[NH2:29][C:26]1[C:25]([NH:30][C:39](=[O:43])[CH2:40][CH2:41][CH3:42])=[CH:24][C:23]([C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH2:14][CH2:13][N:12]([C:5]4[C:4]5[CH2:3][C:2]([CH3:31])([CH3:1])[CH2:11][CH2:10][C:9]=5[N:8]=[CH:7][N:6]=4)[CH2:18][C:17]=3[CH:19]=2)=[CH:28][N:27]=1
Reactant: CCCC(=O)Cl
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cc(-c2ccc3c(c2)CN(c2ncnc4c2CC(C)(C)CC4)CCO3)cnc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridine-2,3-diamine (32 mg, 0.077 mmol) and triethylamine (11 uL, 0.077 mmol) in tetrahydrofuran (1 mL) was add butyryl chloride (7.0 uL, 0.077 mmol), and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was concentrated to give N-{2-amino-5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridin-3-yl}butanamide crude product (50 mg). MS (EI) for C28H34N6O2: 487 (MH+).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]2[O:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[NH:19][C:18](=[O:27])[C:17]=2[CH:28]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1>[O:27]=[C:18]1[C:17]2[CH:28]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:14]=[CH:15][C:16]=2[O:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[NH:19]1
Reactant: O=C(NC(=S)Nc1ccc2c(c1)C(=O)Nc1ccccc1O2)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=S)Nc1ccc2c(c1)C(=O)Nc1ccccc1O2

Procedure:
To a mixture of 1-benzoyl-3-(11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-2-yl)-thiourea (Example 15) in 15 mL of THF was added 1.0 mL of 2.0 N aqueous sodium hydroxide. The resulting solution was heated for 3 hr under reflux. The mixture was concentrated and the residue was triturated with 50 mL of a 10% THF:90% dichloromethane solution. The solid was filtered and washed with 30 mL of water (yield 201 mg, 78%). H1 NMR (CDCl3) δ: 10.3 (bs, 1H), 7.74-7.61 (m, 3H), 7.28-7.15 (m, 3H), MS (ES): MH+ 286.1.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[K].S([O-])([O-])(=O)=O.[Mg+2].CC1[N+](CC2C=NC(C)=NC=2N)=CSC=1CCO.Cl.[Cl-].[OH:47][C:48](CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=[O:49].[C:63]([NH2:71])(=O)[C:64]1[CH:69]=[CH:68][CH:67]=[N:66]C=1.NC(C(O)=O)C>>[NH2:71][C@H:63]([C:48]([OH:49])=[O:47])[CH2:64][CH2:69][CH2:68][CH2:67][NH2:66]
Reactant: NC(=O)c1cccnc1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CC(N)C(=O)O
Agent: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Agent: Cl
Product: NCCCC[C@H](N)C(=O)O

Procedure:
An aqueous solution medium having a composition of 10% of glucose, 2% of ammonium sulfate, 0.1% of potassium primary phosphate, 0.04% of magnesium sulfate, 0.001% of ferrous sulfate, 200 μg/l of thiamine hydrochloride, 500 μg/l of biotin, 5 ml/dl of Aji-Eki®, 1 mg/dl of nicotinamide and 0.1% of DL-alanine, at pH 7.0, was charged in an amount of 300 ml into separate small sized glass jar fermenters. After sterilizing in a conventional manner, the various L-lysine-producing bacterial strains shown in Table 11, which had been previously grown in bouillon slants at 30° C. for 48 hours, were inoculated thereon. Then, incubation was carried out at 31.5° C. for 48 hours at 1200 rpm at an aeration rate of 1/2 volume per minute, while keeping the pH at 7.0 by the addition of ammonia gas. After completion of the fermentation, the yield of L-lysine produced and accumulated in the solution based on glucose was determined and is shown in Table 11.
Reaction SMILES: ClCC#N.Cl([O-])(=O)(=O)=O.[Li+].[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:31])[C:27]([O:29]C)=[O:28])=[CH:22][CH:21]=1)([O-:13])=[O:12]>>[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:31])[C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1)([O-:13])=[O:12]
Reactant: COC(=O)C(C)c1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: N#CCCl
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CC(C(=O)O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1

Procedure:
The 2-(2'-nitro-4-biphenylyl)propionic acid is readily prepared in the following manner: 2-nitrobiphenyl is acylated with acetyl chloride, giving 4-acetyl-2'-nitrobiphenyl. This is converted with chloroacetonitrile under alkaline conditions to the intermediate isomeric 2-methyl-2-[4-(2'-nitrophenyl)]glycidonitriles which, when treated with lithium perchlorate and then base, is isomerized to methyl 2-(2'-nitro-4-biphenylyl)propionate. Saponificiation of the latter gives the desired 2-(2'-nitro-4-biphenylyl)propionic acid. The esters are readily converted to the acid and the acid to the esters by conventional means.