Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[C:12]1([C:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22]3[N:29]=[CH:30][N:31]=[CH:32][C:21]=3[CH2:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:33](OCCC(C)C)=[O:34]>O1CCCC1>[N:33](=[C:20]1[C:21]2[CH:32]=[N:31][CH:30]=[N:29][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:19]1)[OH:34]
Reactant: CC(C)CCON=O
Reactant: c1ccc(C2=NCc3cncnc3-c3ccccc32)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: ON=c1nc(-c2ccccc2)c2ccccc2c2ncncc12
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a suspension of potassium tert-butoxide (24.9 g, 222 mmole) in 600 ml of dry tetrahydrofuran is added 200 ml of dry tert-butylalcohol at -20° C. under nitrogen. To this solution is then added, via addition funnel, 7-phenyl-5H-pyrimido[5,4-d][2]-benzazepine (25 g) in 260 ml of tetrahydrofuran. The resulting solution is stirred for about 2 hours at -20° C. and treated with 17.4 ml (130 mmole) of isoamyl nitrite. The reaction mixture is warmed to 0° C. over approximately 15 minutes and quenched with the addition of 60 ml of cold water and 20 ml of glacial acetic acid. All solvents are removed under reduced pressure and the residue is partitioned between ethyl acetate (600 ml) and brine (100 ml). The phases are separated and the organic extracts are dried (Na2SO4), concentrated, and triturated with ether.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[N:20]=[C:21](/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])[O:22][CH:23]=2)[CH:14]=[CH:13][C:3]=1[CH2:4][S:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[N:9]1.ClC1C=CC=C(C(OO)=[O:42])C=1>ClCCl.C(OCC)(=O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:26](/[CH:25]=[CH:24]/[C:21]2[O:22][CH:23]=[C:19]([CH2:18][O:17][C:15]3[CH:14]=[CH:13][C:3]([CH2:4][S:5]([CH2:6][CH2:7][N:8]4[CH:12]=[CH:11][N:10]=[N:9]4)=[O:42])=[C:2]([CH3:1])[CH:16]=3)[N:20]=2)=[C:27]([F:33])[CH:28]=1
Reactant: Cc1cc(OCc2coc(/C=C/c3ccc(Cl)cc3F)n2)ccc1CSCCn1ccnn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(OCc2coc(/C=C/c3ccc(Cl)cc3F)n2)ccc1CS(=O)CCn1ccnn1
Temperature: -30 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
To a solution of 710 mg (1.46 mmol) 1-[2-(2-methyl-4-{2-[2-(E)-(4-chloro-2-fluorophenyl)-vinyl]-oxazol-4-ylmethoxy}-benzylsulfanyl)-ethyl]-1H-[1,2,3]triazole in 35 ml dichloromethane at −30° C. were added dropwise during 20 min. 493 mg (2.20 mmol) 3-chloro-perbenzoic acid (77% peracid) dissolved in 20 ml ethyl acetate. After 1 hour stirring at −30° C. the mixture was allowed to warm up over night, stirred another 48 hours at room temperature, diluted with dichloromethane, washed with sodium bicarbonate solution, then with water, dried and evaporated. Elution from silica with ethyl acetate (1–10% methanol gradient) gave as the second fraction 199 mg (27%) title compound as white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][N:5]([CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O.C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>O.CN(C=O)C>[CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][NH:5][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1
Reactant: CN(C)CCN(CCNc1ccc([N+](=O)[O-])cn1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCNCCNc1ccc([N+](=O)[O-])cn1
Temperature: 23 °C
Reaction time: 12 h

Procedure:
To a suspension of resin-bound [2-(dimethylamino)ethyl]{2-[(5-nitro(2-pyridyl))-amino]ethyl}[(2-nitrophenyl)sulfonyl]amine (3.0 g, 2.1 mmol) and DMF (30 mL) at 23° C. was added H2O (2 drops), K2CO3 (2.9 g, 21 mmol) and PhSH (2.2 mL, 21 mmol). The resulting mixture was shaken at 23° C. for 12 h, filtered, washed with NMP, H2O and CH2Cl2 and air dried to yield polymer-bound dimethyl[2-({2-[(5-nitro(2-pyridyl))amino]-ethyl}amino)ethyl]amine.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([C:14]2[S:13][CH:17]=[CH:16][N:15]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)CCCCCCN
Reactant: O=Cc1ccc(-c2nccs2)cc1
Agent: Cl
Product: COC(=O)CCCCCCNCc1ccc(-c2nccs2)cc1

Procedure:
The title compound was prepared following the procedure described in Step A of Example 1 from 7-amino-heptanoic acid methyl ester hydrochloride, of Preparation 1, and 4-thiazol-2-yl-benzaldehyde, of Preparation 25. 1H NMR (400 MHz, CDCl3) δ 7.91 (d, 2H), 7.84 (d, 1H), 7.38 (d, 2H), 7.30 (d, 1H), 3.82 (s, 2H), 3.65 (s, 3H), 2.62 (t, 2H), 2.29 (t, 2H), 1.61 (m, 2H), 1.51 (m, 2H), 1.33 (m, 4H); MS 333 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:18]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC1CCC(=O)C(CC(=O)c2ccccc2)C1
Product: CC1CCc2c(cc(-c3ccccc3)n2-c2ccc(C(=O)O)cc2)C1
Yield: 73 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-(2-oxo-2-phenylethyl)cyclohexanone and 4-aminobenzoic acid, the title compound was isolated in 73% yield (95% purity by HPLC). MS(ESI+): 332.5; MS(ESI−): 330.4.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1([C@H:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:20])[CH2:18][O:17]1>CN(C=O)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]([OH:17])([C@H:19]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH3:20])[CH2:18][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: C[C@@H](OC1CCCCO1)C1(c2cc(F)ccc2F)CO1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](OC1CCCCO1)C(O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
To a stirred suspension of NaH (60% in oil, 21.0 g, 0.525 mol) in DMF (300 ml) was added portionwise 1,2,4-triazole (43.3 g, 0.627 mol) at the inner temperature from 2° C. to 11° C. over 30 min. The resulting mixture was stirred at r.t. for 1.5 hrs. To this mixture was added a solution of 2-(2,5-Difluorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane (48.3 g, 0.170 mol) in DMF (50 ml). The mixture was stirred at 60° C. for 1 hr. and then at 65° C. for 14 hrs. The reaction mixture was cooled down to 10° C. and then poured into ice-water (800 mL ). The resulting mixture was extracted with EtOAc (400 ml+200 ml×2 ). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silicagel (n-hexane: EtOAc=4:1˜1:5) to give (3R)-2-(2,5difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (43.9 g, 73% ) and recovered starting material (13.2 g, 27%). Physical form: colorless syrup; FAB-MS: m/z 354 (M+H)+; 1H-NMR(CDCl3): 1.00(3H×½,d,J=6.6Hz),1.13(3H×½,d,J=6.6Hz), 1.42˜1.88(6H,m)3.38˜3.60(1H,m),3.80˜4.00(1H,m),4.32˜5.02(5H,m),6.83˜6.99 (2H,m),7.14˜7.21(1H,m),7.73(1H×½,s),7.74(1H×½,s),7.92(1H×½,s)7.95(1H×½,s),
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]#[N:16])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5].Cl[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>ClCCl>[CH3:21][O:20][C:18]([NH:2][C@H:3]([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]#[N:16])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5])=[O:19]
Reactant: COC(=O)Cl
Reactant: CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1CCC[C@H]1C#N
Yield: 95.1 %

Procedure:
A solution of (2S)-1-(isoleucyl)pyrrolidine-2-carbonitrile hydrochloride (300 mg, 1.22 mmol; prepared according to Jenkins et al., WO95/15309), methyl chloroformate (125 mg, 1.3 mmol) and triethylamine (150 mg, 1.50 mmol) in dichloromethane (40 ml) was stirred at room temperature for 18 hours. After this time the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (EtOAc:Pet. Ether 60–80° C.; 4:6) yielding a colourless oil identified as the title compound (310 mg, 1.16 mmol, 95%).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:20]=[N:21][CH:22]=2)[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:6]([C:8](O)=[O:9])[CH:7]=1.[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:23]([O:25][CH2:26][CH2:27][O:28][NH:29][C:8]([C:6]1[CH:7]=[C:2]([F:1])[C:3]2[N:4]([CH:20]=[N:21][CH:22]=2)[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:9])=[CH2:24]
Reactant: C=COCCON
Reactant: O=C(O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
8-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (0.20 g, 0.48 mmol), O-(2-vinyloxyethyl)-hydroxylamine (55 mg, 0.53 mmol), EDCI (102 mg, 0.53 mmol), HOBt (72 mg, 0.53 mmol) and DIPEA (90 μL, 0.53 mmol) were dissolved in DMF (10 mL) and the reaction mixture stirred at room temperature for 16 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM) to yield the title compound as a pale yellow solid (200 mg, 83%). LCMS (Method B): RT=3.41 min, [M+H]+=501.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2.[F:40][C:41]([F:47])([F:46])[S:42](Cl)(=[O:44])=[O:43]>>[CH:27]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:42]([C:41]([F:47])([F:46])[F:40])(=[O:44])=[O:43])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)C(F)(F)F)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 49 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 5, Example 1 )was added trifluoromethylsulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 49% yield.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH:25]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:29]3[CH:30]=[CH:31][N:32]=[C:28]3[CH:25]([CH3:27])[CH3:26])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:8][CH:9]=1
Reactant: Cc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: CC(C)c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1OCCCc1oc(-n2ccnc2C(C)C)nc1-c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 1 h

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methylphenoxy)propyl]oxazole (1.00 g), 2-isopropylimidazole (661 mg), potassium carbonate (830 mg) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 1 hour. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (10 ml×2). The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-(2-isopropyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole was obtained as an oil (333 mg, 28%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: O([C:8]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])C1C=CC=CC=1.[CH2:28]([NH2:34])[C:29]1[O:33][CH:32]=[CH:31][CH:30]=1.Cl>C(O)(=O)C>[O:33]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:28][NH:34][C:8]1[C:9](=[CH:13][C:14]([S:24](=[O:26])(=[O:27])[NH2:25])=[C:15]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=1)[C:10]([OH:12])=[O:11]
Reactant: NCc1ccco1
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(Oc2ccccc2)cc1Oc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Oc1ccccc1
Temperature: 80 °C

Procedure:
43 g (1.0 mol) of the 2,4-diphenoxy-5-sulfamoyl-benzoic acid prepared according to (d) were stirred for 4 hours under nitrogen at 135° C with 90 ml of freshly distilled furfurylamine. The faintly yellow reaction solution, which had been cooled to about 80° C, was then introduced while stirring into 1 l of 10 % acetic acid, and the pH of the mixture was then adjusted to 3 by means of 5N HCl. After standing for a short time at room temperature, the N-(2-furylmethyl)-4-phenoxy-5-sulfamoyl-anthranilic acid which had precipitated in crystals was suction-filtered, washed with water and ethanol and dried on a steam bath.
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[CH:26][C:5]([NH:6][C:7]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:8]=2[C:9]([OH:11])=[O:10])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Nc2cc(-c3ccccc3)ccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-(4-methylanilino)-4-phenylbenzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 2-(4-methylanilino)-4-phenylbenzoic acid 8.7 mg of white solid.
Reaction SMILES: O=O.[CH3:3]C(C)([O-])C.[K+].[C:9]([CH2:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.IC>N#N.O>[C:10]1([C:9](=[O:16])[CH:17]([CH3:3])[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:25])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: N#N
Agent: O=O
Agent: [K+]
Solvent: O
Solvent: CI
Product: CC(C(=O)c1ccccc1)C(=O)c1ccccc1
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a three-neck flask in N2 atmosphere free of water and oxygen were successively added 0.066 mol potassium tert-butoxide and 150 mlTHF. Then to the resulting mixture was slowly added dropwise 0.06 mol dibenzoylmethane with stirring while cooling the mixture with ice-bath. The reaction was allowed to continue at room temperature for 1 hour, then 0.07 mol iodomethane was added dropwise at room temperature. Next, the reaction was allowed to continue at room temperature for further 48 hours. After the reaction was finished, the solvent was removed by distillation. To the solid mixture was added saturated saline until the solid mixture was just completely dissolved. The solution was extracted with suitable amount of anhydrous ethyl ether for three times. The organic phase was combined and dried over anhydrous sodium sulfate. The solvent was removed to give 12 g product.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:31](=O)[CH:32]([CH3:34])[CH3:33].C([BH3-])#N.[Na+]>CO>[CH2:31]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH:32]([CH3:34])[CH3:33]
Reactant: NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Reactant: CC(C)C=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)CNCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 159 from (Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride, isobutyraldehyde and sodium cyanoborohydride in methanol.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][C:18]([O:20]CC)=[O:19])[CH:13]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23]I.[OH-].[K+].Cl>O.CC(C)=O>[CH3:23][N:8]1[C:9]2[C:14](=[CH:13][C:12]([CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)[CH2:15][CH2:16][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: CCOC(=O)Cc1ccc2c(c1)CCC(c1ccccc1)N2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CN1c2ccc(CC(=O)O)cc2CCC1c1ccccc1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
The compound (3 g) of Example 2 was dissolved into acetone and, after methyl iodide (0.8 ml) and potassium hydroxide (3.7 g) were added, the mixture was stirred at 40° C. for 20 hours under heat. After water was added and the reaction mixture was acidified with hydrochloric acid, it was extracted with methylene chloride. The residue obtained by drying methylene chloride layer over anhydrous sodium sulfate and then concentrating under reduced pressure was recrystallized from ethanol-hexane to obtain aimed product (1.25 g) as pale yellow powdery crystals. Melting point: 110°-111° C.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1([CH2:20][NH2:21])[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][NH:21][C:8](=[O:9])[CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18]1
Reactant: NCC1CC1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: O=C(NCC1CC1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 130° C. and MS: m/e=265 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and cyclopropylmethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]([CH3:15])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:13]([CH3:15])([CH3:12])[O:8][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)c2cc(Br)ccc2O1

Procedure:
5 g of 5-bromosalicylic acid were heated under reflux with 6.7 g of acetone in a mixture of 25 ml of trifluoroacetic acid with 5 ml of trifluoroacetic anhydride for 5 h. For workup, the reaction mixture was concentrated under reduced pressure. The residue was neutralized with sodium hydrogencarbonate solution and extracted repeatedly with diethyl ether. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel; 9/1 n-heptane/ethyl acetate). 244.1 was obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[NH2:15][CH2:16][CH:17]([OH:26])[CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1>>[OH:26][CH:17]([CH2:18][N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1)[CH2:16][NH:15][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13]
Reactant: CN1CCN(CC(O)CN)CC1
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Product: Cc1[nH]c2c(c1C(=O)NCC(O)CN1CCN(C)CC1)CCCC2=O
Yield: 71.7 %

Procedure:
Similar procedure as Example 13, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 1-amino-3-(4-methylpiperazin-1-yl)propan-2-ol 0.36 g (2.1 mmol) was reacted to give 0.25 g (72%) of the titled compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][C:21]=1[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][C:37]([CH3:40])=[N:38][N:39]=2)=[C:31]([CH3:41])[CH:30]=1>>[CH3:19][C:20]1[CH:25]=[C:24]([C:26]([N:15]2[C:16]3[CH:17]=[C:18]4[C:5]5([CH2:8][O:9][C:10]4=[CH:11][C:12]=3[CH2:13][CH2:14]2)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[O:27])[CH:23]=[CH:22][C:21]=1[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][C:37]([CH3:40])=[N:38][N:39]=2)=[C:31]([CH3:41])[CH:30]=1
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3C)cc2C)o1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3C)cc2C)o1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8) and 2,3'-dimethyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (D36) using a similar procedure to Example 1 (31%). This was converted to its oxalate salt and crystallised from acetone/methanol as a pale yelloe solid mp. 193-195° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][O:6][CH2:7][CH:8]=C.C(Cl)Cl.[CH3:22][OH:23]>>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][O:6][CH2:7][CH:8]([O:23][CH3:22])[N:10]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:18]
Reactant: CO
Reactant: C=CCOCC(NC(=O)OC(C)(C)C)C(=O)OC
Solvent: ClCCl
Product: COC(=O)C1COCC(OC)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
A solution containing 3-allyloxy-2-tert-butoxycarbonylamino-propionic acid methyl ester (30.0 g, 116 mmol) in 550 mL of 10:1 CH2Cl2/MeOH is cooled to −78° C. and purged with ozone until a blue color persisted (45 min). The solution is then purged with N2 to remove excess ozone and treated with dimethylsulfide (35 mL). The solution is allowed to warm to room temperature overnight and the next morning concentrated in vacuo. The resulting solid is re-dissolved in 400 mL of MeOH and treated with 500 mg of p-toluenesulfonic acid. After stirring for 4 hours, the volume of solvent is reduced to about 100 mL and toluene (250 mL) is added. The solution is re-concentrate in vacuo and purified over silica gel (EtOAc/hexane) to afford 25 g (78%) of the desired product. 1H NMR (CDCl3) δ 5.21 (br s, 0.5H), 5.05 (br s, 0.5H), 4.65–4.45 (m, 2H), 3.98 (dd, J=12.8, 12.5 Hz, 1H), 3.79 (s, 3H), 3.66 (br d, J=11.3 Hz, 1H), 3.56 (dd, J=9.9, 9.9 Hz, 1H), 3.42 (s, 3H), 1.54 (s, 0.5×9H), 1.50 (s, 0.5×9H); MS 276 (M+H)+.