Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:13][C:14]2[CH:15]=[C:16]([N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH:17]=[CH:18][C:19]=2[N+:20]([O-:22])=[O:21])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[ClH:36]>ClCCl.C(OCC)C>[ClH:36].[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]([NH:13][C:14]2[CH:15]=[C:16]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:17]=[CH:18][C:19]=2[N+:20]([O-:22])=[O:21])[CH3:12])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(C(C)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2[N+](=O)[O-])c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(OC)cc(C(C)Nc2cc(N3CCNCC3)ccc2[N+](=O)[O-])c1
Reaction time: 4 h
Yield: 76 %

Procedure:
To a solution of t-butyl 4-(3-(1-(3,5-dimethoxyphenyl)ethylamino)-4-nitrophenyl)piperazine-1-carboxylate (327 mg, 0.67 mmol) in dry dichloromethane (2.0 mL) was added a saturated solution of HCl in diethyl ether (15 mL). The reaction mixture was stirred for 4 hours. The product was collected by filtration and dried in vacuo to afford the title compound (216 mg, 76% yield). 1H NMR (400 MHz, CD3OD): δ 8.03 (d, 1H), 6.55 (s, 2H), 6.36 (m, 2H), 5.95 (s, 1H), 4.67 (m, 1H), 3.73 (s, 6H), 3.49 (m, 4H), 3.29 (m, 4H), 1.60 (d, 3H); MS (ESI) m/z: Calculated for C20H27N4O4: 387.2; Observed: 387.3 (M++1) [corresponding to the free base].
Reaction SMILES: [C:1](O)(=O)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:17][NH:18][C:19]([C:21]1[C:22]2[CH:23]=[CH:24][C:25]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])=[N:26][C:27]=2[CH:28]=[CH:29][CH:30]=1)=[NH:20]>C1COCC1>[CH3:40][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][NH:31][C:25]1[CH:24]=[CH:23][C:22]2[C:27](=[CH:28][CH:29]=[CH:30][C:21]=2[C:19]2[N:20]=[C:1]([CH3:2])[O:17][N:18]=2)[N:26]=1
Reactant: CC(=O)O
Reactant: COc1ccccc1CNc1ccc2c(C(=N)NO)cccc2n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccccc1CNc1ccc2c(-c3noc(C)n3)cccc2n1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 50.3 %

Procedure:
To a stirred solution of acetic acid (48 mg, 0.8 mmol) in THF (7.5 ml) was added at room temperature 1,1′-carbonyl-diimidazole (151 mg, 0.93 mmol). The mixture was allowed to stir for 15 min at room temperature and for 90 min at 70° C., cooled to room temperature and N-hydroxy-2-(2-methoxy-benzylamino)-quinoline-5-carboxamidine (200 mg, 0.62 mmol) was added. The reaction mixture was allowed to stir at room temperature for 30 min, evaporated to dryness and diluted with acetic acid (7.5 ml). The reaction mixture was allowed to stir for 2 h at 100° C., evaporated, poured into saturated NaHCO3 solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/hexane) to yield the title compound as white solid (108 mg, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][C:11](=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:15]([NH:22][CH:11]1[CH2:12][CH2:13][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(C2CCC(=O)C2)cc1
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc(C2CCC(NCc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 12.5 h
Yield: 91.8 %

Procedure:
3-(4-Methoxyphenyl) cyclopentanone (7.37 g) and benzylamine (4.15 g) were refluxed for 1.25 hours in benzene (150 ml) in the presence of p-toluenesulfonic acid (820 mg) using a Dean-Stark apparatus while removing the water generated. After distilling off the benzene under reduced pressure, it was dissolved in methanol (150 ml) while cooling on ice, sodium borohydride (1.63 g) was gradually added and the mixture was stirred at room temperature for 12.5 hours. After concentrating the reaction solution, water was added, and extraction with chloroform was followed by washing with saturated sodium bicarbonate water and saturated saline. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to produce a light yellow oily substance which was then purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to give 10.0 g of N-benzyl-N-[3-(4-methoxyphenyl)cyclopentyl]amine (91.7% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([NH:12]C(=O)C(F)(F)F)=[C:5]([CH3:19])[CH:4]=1)#[N:2].N>CO>[NH2:12][C:6]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:19]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1NC(=O)C(F)(F)F
Agent: N
Solvent: CO
Product: Cc1cc(C#N)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of N-(4-cyano-2-methyl-6-nitro-phenyl)-2,2,2-trifluoro-acetamide (5 g, 18.3 mmol) and 2 M ammonia in methanol (80 mL) was heated to reflux for 14 h and then cooled to room temperature. After concentration in vacuo, the residue was purified by flash chromatography (20% EtOAc/hexane) to yield the title compound (3.24 g, 100%, ca 80% pure). 1H NMR (300 MHz, CDCl3) δ 8.40 (1H, s), 7.47 (1H, s), 6.6-6.8 (2H, broad s), 2.89 (3H, s).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=C)=[CH:23][CH:22]=5)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([N:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[O:35])=[CH:23][CH:22]=5)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a clear solution of 3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 89A, 0.15 g, 0.368 mmol) in THF (1.5 mL) were added NMO (50% in water, 0.092 mL, 0.442 mmol) and osmium tetroxide (4% in water, 0.068 mL, 0.011 mmol) at room temperature. The solution was vigorously stirred at room temperature overnight. Sodium periodate (0.102 g, 0.479 mmol) in water (0.5 mL) was added. The mixture was stirred vigorously at room temperature under nitrogen for 30 min. Water (5 mL) was added and the mixture was extracted with ethyl acetate (3×2 mL). The combined ethyl acetate extracts were dried (sodium sulfate), filtered through a pad of silica gel which was then rinsed with ethyl acetate and concentrated to give 3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.15 g, 0.366 mmol, 100% yield) as a green solid. The compound had an HPLC retention time=3.64 min. (condition C); LC/MS M+1=409.9.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C:4]1([C:16]([CH3:18])=[CH2:17])[CH2:8][CH2:7][N:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]1=[O:15].[Li+].CC([N-]C(C)C)C.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH3:19][CH:2]([CH3:1])[CH2:3][C:4]1([C:16]([CH3:18])=[CH2:17])[CH2:8][CH2:7][N:6]([CH:9]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]1=[O:15]
Reactant: C=C(C)C1(CC(C)C)CCN(CC(=O)OCC)C1=O
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)C1(CC(C)C)CCN(C(Cc2ccccc2)C(=O)OCC)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of ethyl 3-(2-methylpropyl)-2-oxo-3-(propen-2-yl)-1-pyrrolidineacetate (Example 20, step 5; 1.63 g, 6.10 mmol) and THF (15 mL) is cooled to -78° C. and LDA (2.0M, 3.2 mL, 6.4 mmol) is added. The solution is stirred at -78° C. for 30 minutes and then benzyl bromide (0.80 mL, 6.7 mmol) is added. The solution is allowed to warm to 0° C. over 2 hours, and then stirred at 0° C. for 1 hour. After quenching with saturated aqueous ammonium chloride (10 mL), aqueous workup (EtOAc, MgSO4) and purification by column chromatography (10% EtOAc/hexane) provided 1.94 g (89%) of the title compound as an oil in a 1:1 mixture of diastereomers.
Reaction SMILES: [N:1]#[N:2].[C:3]([C@@H:5]([NH:14][C@H:15]([C:27]([OH:29])=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)#[N:4].Cl.[OH-:31].[Na+]>>[N:1]#[N:2].[C:3]([C@@H:5]([NH:14][C@H:15]([C:27]([OH:29])=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:31])[NH2:4]
Reactant: [OH-]
Reactant: N#C[C@H](CCc1ccccc1)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Agent: Cl
Agent: N#N
Agent: [Na+]
Product: NC(=O)[C@H](CCc1ccccc1)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Temperature: 0 °C

Procedure:
After stirring a mixture of 12 g of N2 -(1(S)-cyano-3-phenylpropyl)-N6 -trifluoroacetyl-L-lysine and 40 ml of concentrated hydrochloric acid for 5 hours at room temperature, 200 ml of ice-water was added thereto and after adjusting the pH thereof to about 4.5 with an aqueous sodium hydroxide solution with stirring, the mixture was stirred for 30 minutes at 0° C. The crystals thus deposited were washed with water, recovered by filtration, and dried in vacuo at 45° C. to provide 8.3 g of N2 -(1(S)-carbamyl-3-phenylpropyl)-N6 -trifluoroacetyl-L-lysine.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.[Cl-].[Na+]>CN(C=O)C>[CH3:13][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:12])[CH:9]=[C:10]([CH3:11])[C:2]=1[NH2:1]
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc(C)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1218.4 %

Procedure:
To a 500 mL round-bottom flask, 0.2 mol of 2-amino-3-methyl-5-chlorobenzoic acid having the structural formula of IV-5, 300 mL of DMF and 2.0 grams of potassium carbonate were added, stirred at room temperature for 0.5 hour, dimethyl sulfate was dripped, reacted at 110° C. for 7 hours, and cooled to room temperature, poured into a saturated sodium chloride solution, extracted with acetate ethyl, dried over anhydrous sodium sulfate, filtered and the solvent was removed to obtain a crude product, 35.2 grams of 2-amino-3-methyl-5-chlorobenzoic acid methyl ester having a structural formula of VIII-3 was obtained by column chromatography, and the yield was 88.4%;
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)CBr
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)oc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
A solution of 6-nitrobenzo[d]oxazol-2(3H)-one (0.500 g, 2.78 mmol) in DMF (10 ml) was cooled to 0° C. NaH (60% w/w dispersion in mineral oil, 0.133 g, 3.33 mmol) was added, and the reaction was allowed to warm to room temperature and stirred for 15 minutes. The mixture was cooled to 0° C., methyl 2-bromoacetate (0.309 ml, 3.33 mmol) was added, and the reaction was warmed to room temperature and stirred for 4 hours. The mixture was partitioned between ethyl acetate and 1N HCl. The organic phase was washed several times with brine and dried over sodium sulfate. The solvent was removed, and the crude was purified by trituration with diethyl ether (50 ml) affording methyl 2-(6-nitro-2-oxobenzo[d]oxazol-3(2H)-yl)acetate (0.570 g, 2.260 mmol, 81% yield). MS/ESI+ 252.9 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]O>C1COCC1>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: CN(C)CCO
Reactant: Nc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CN(C)CCOc1cccc(N)c1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with 3-[2-(dimethylamino)ethoxy]aniline to generate the title compound. The 3-[2-(dimethylamino)ethoxy]aniline was prepared by treating commercial 3-aminophenol with diethyl azo dicarboxylate, φ3P, and 2-(dimethylamino)ethanol in THF.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.C1(C)C(C)=CC=CC=1.Cl[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[N:30][N:29]=1>O>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]3=[N:10][N:9]=[C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:29]3[N:30]=2)=[CH:39][CH:40]=1
Reactant: NNC(=O)c1ccccc1
Reactant: COc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nn3c(-c4ccccc4)nnc3c3ccccc23)cc1
Yield: 99.3 %

Procedure:
163 mg (1.2 mmol) of benzohydrazide and 165 mg (1.2 mmol) of triethylamine hydrochloride were added to a xylene solution (5 ml) of 271 mg (1.0 mmol) of the obtained 1-chloro-4-(4-methoxyphenyl)-phthalazine, and then stirred under reflux for 2 hours. Water was added to the reaction liquid, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 350 mg of a crude product of 6-(4-methoxyphenyl)-3-phenyl-[1,2,4]triazolo[3,4-a]phthalazine.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:6][CH:5]([OH:7])[CH2:4]1.[F:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1F)[C:12]([O:14][CH3:15])=[O:13]>CN(C=O)C>[F:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:7][CH:5]1[CH2:6][O:3][CH2:4]1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: OC1COC1
Reactant: COC(=O)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2COC2)c(F)c1
Temperature: 80 °C

Procedure:
NaH (80 mg, 2.0 mmol) was added to a mixture of oxetan-3-ol (150 mg, 2.0 mmol) and DMF (2 mL) at 0° C. The reaction was allowed to stir for 10 minutes before methyl 3,4-difluorobenzoate (170 mg, 1.0 mmol) was added. The reaction was then heated at 80° C. overnight. The reaction was quenched with brine and was extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate and the solvent was removed to give methyl 3-fluoro-4-(oxetan-3-yloxy)benzoate. ESI-MS m/z calc. 226.1. found 227.2 (M); Retention time: 2.36 minutes (4 min run).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.CS(O)(=O)=O.[CH2:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[OH:1][C:2]1[C:7]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1
Reactant: C=CCCCCCCCC
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Agent: CS(=O)(=O)O
Product: CCCCCCCCCCc1cc(C)cc(-n2nc3ccccc3n2)c1O

Procedure:
Using the general procedure of Example 1, 225 grams of 2-(2-hydroxy-5-methylphenyl)-2H-benzotriazole, 65 ml of methanesulfonic acid and 188 ml of 1-decene are heated at 160° C., for a 5-hour period during which time another 564 ml of 1-decene is gradually added to the reaction mixture. The mixture is then cooled and the product isolated by the method described in Example 1 to give 183 grams of the above-named product as a yellow liquid.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][C:6]1[CH:7]=[C:8]([CH3:23])[C:9]2[C:15](=[O:16])[N:14]([CH3:17])[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=3[NH:11][C:10]=2[N:22]=1.C(C(CC)=O)C.N1C=CC=CC=1>C1(C)C=CC=CC=1.O>[Cl:4][C:1]([N:11]1[C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[N:14]([CH3:17])[C:15](=[O:16])[C:9]2[C:8]([CH3:23])=[CH:7][C:6]([CH3:5])=[N:22][C:10]1=2)=[O:2]
Reactant: Cc1cc(C)c2c(n1)Nc1ccccc1N(C)C2=O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCC(=O)CC
Product: Cc1cc(C)c2c(n1)N(C(=O)Cl)c1ccccc1N(C)C2=O
Temperature: 110 °C

Procedure:
50 ml of a 20% solution of phosgene in toluene were added dropwise over a period of 10 minutes to a mixture consisting of 10.0 gm of 6,11-dihydro-2,4,6-trimethyl-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one, 100 ml of diethyl ketone, 50 ml of toluene and 5 ml of pyridine. The resulting mixture was heated at 60° C. for 2 hours, at 80° C. for one hour and at 110° C. for one hour, while stirring. After cooling to room temperature, 100 ml of water were added. The organic phase was dried with sodium sulfate and then evaporated in vacuo. The residue was recrystallized twice from ethanol, yielding 7.3 gm of 11-chloroformyl-6,11-dihydro-2,4,6-trimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, m.p. 205°-207° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19]CC)=[O:18].[OH-].[Na+].O>O1CCOCC1>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1Oc1cccc(CC(=O)O)c1N
Yield: 71.6 %

Procedure:
A mixture of ethyl 2-[2-amino-3-(o-tolyloxy)phenyl]acetate (3.1 g.), sodium hydroxide (0.9 g.), water (20 ml.) and dioxane (20 ml.) was treated in a similar manner to that of Example 2-(2) to give crystals of 2-[2-amino-3-(o-tolyloxy)phenyl]acetic acid (2.0 g.). Thus obtained compound was dissolved in a solution of sodium bicarbonate (0.343 g.) in water (50 ml.) under heating and filtered. The filtrate was lyophilized to give sodium 2-[2-amino-3-(o-tolyloxy)phenyl]acetate (1.1 g.). mp >150° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][N:19]=[C:18]([C:21]([O:23]CC)=[O:22])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].O1CCOCC1>O>[C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][N:19]=[C:18]([C:21]([OH:23])=[O:22])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc(C(=O)O)n[nH]3)c2nc1NC(C)(C)C
Temperature: 100 °C

Procedure:
To a 10-mL reaction vial was added ethyl 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylate (467a) (94 mg, 0.27 mmol), LiOH hydrated (56 mg, 1.33 mmol), dioxane (4 mL), and water (1 mL). The reaction mixture was heated at 50° C. for 1 h and at 100° C. for 2 h and then cooled to RT. The solvent was removed under vacuum and HCl (1N, 3 mL) was added, the yellow precipitate obtained was filtered off, washed with water, and dried. 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylic acid (467b) was obtained as a yellow solid and used without further purification. To a 50-mL round-bottomed flask was added 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylic acid (467b) (77 mg, 0.24 mmol), DCM (3 mL), DMF (1 mL), DIPEA (82 μL, 0.47 mmol), ammonia (0.95 mL, 0.47 mmol, 0.5 M in dioxane), and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (123 mg, 0.24 mmol) (Sigma-Aldrich). The reaction mixture was stirred at RT for 30 min, concentrated to half of its volume, and diluted with EtOAc (20 mL). The organic extract was washed with sat NaHCO3 (10 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 30% to 40% EtOAc in hexanes to give 5-(3-(tert-butylamino)-2-methyl-quinoxalin-5-yl)-1H-pyrazole-3-carboxamide (467) (65 mg, 85% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.38 (br. s, 1H), 7.85 (dd, J=1.08, 7.34 Hz, 1H), 7.76 (d, J=7.63 Hz, 1H), 7.53 (br. s., 1H), 7.41 (t, J=7.73 Hz, 1H), 7.30 (s, 1H), 7.18 (br. s, 1H), 6.06 (br. s., 1H), 2.58 (s, 3H), 1.52 (s, 9H). m/z (ESI, +ve) 325.1 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:11][NH:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:14]([N:13]1[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1NCCN(Cc2ccccc2)[C@@H]1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(C[C@@H]2CNCCN2Cc2ccccc2)cc1
Yield: 83.4 %

Procedure:
A solution of (3R)-3,4-dibenzylpiperazin-2-one (2.5 g; 9.0 mmol) in dry tetrahydrofuran (30 ml) was placed under an atmosphere of nitrogen and stirred on an ice-bath. Lithium aluminiumhydride (5.0 ml; 1.0M in tetrahydrofuran) was added dropwise during 15 minutes. The mixture was then heated at reflux temperature for 2 h and then allowed top cool. Another portion of lithium aluminiumhydride (4.0 ml; 1.0M in tetrahydrofuran) was added and the mixture was refluxed for 1 h. The mixture was allowed to cool and then quenched with water and a 4N sodium hydroxide solution. Ethyl acetate (50 ml) was added and the mixture was filtered. The solvent was evaporated in vacuo to give 2.0 g of (2R)-1,2-dibenzylpiperazine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[N:12][C:13]#[N:14])[CH3:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][CH:23]=[C:24]([Cl:26])[Cl:25].[I-].[Cs+]>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:22][CH:23]=[C:24]([Cl:26])[Cl:25])[C:10](=[N:12][C:13]#[N:14])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(=NC#N)NCc1ccc(Cl)nc1
Reactant: ClC(Cl)=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CC(=NC#N)N(CC=C(Cl)Cl)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
174 mg (0.83 mmol) of N-[(6-chloropyridin-3-yl)methyl]-N′-cyanoethanimidamide are stirred into 5 ml of acetonitrile, and 543 mg (1.67 mmol) of cesium carbonate, 166 mg (0.88 mmol) of 3-bromo-1,1-dichloroprop-1-ene and 22 mg (0.08 mmol) of cesium iodide are added successively. The reaction mixture is then stirred at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure and then taken up in ethyl acetate, washed successively with 1 N aqueous hydrochloric acid, 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by column chromatography on silica gel using the mobile phase mixture ethyl acetate:cyclohexane (2:1) gives 215 mg (77% of theory) of N-[(6-chloropyridin-3-yl)methyl]-N′-cyano-N-(3,3-dichloroprop-2-en-1-yl)ethanimidamide