Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:25][OH:26].[OH-].[K+].ClCCl>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8](=[N:25][OH:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)c1cc(C(=O)c2ccccc2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)c1cc(C(=NO)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
12.4 g of 3,5-di-t-butyl-4-hydroxybenzophenone and 3.15 g of hydroxylamine hydrochloride were dissolved in 100 ml of ethanol, and with stirring, a solution of 2.77 g of potassium hydroxide in 20 ml of ethanol was added dropwise at room temperature. The mixture was then refluxed for 24 hours with stirring. After cooling, dichloromethane was added to the reaction mixture. The dichloromethane layer was separated, washed with water, and dried. The solvent was distilled off, and n-hexane was added to the residue. The precipitated crystals were collected by filtration, and recrystallized from ether/n-hexane to give 3,5-di-t-butyl-4-hydroxybenzophenone oxime.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:13][CH:12]([C:14]([N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:25]1([CH2:24][N:19]2[CH2:20][CH2:21][CH2:22][N:16]([C:14]([CH:12]3[CH2:13][N:10]([C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[O:9])[CH2:11]3)=[O:15])[CH2:17][CH2:18]2)[CH2:27][CH2:26]1
Reactant: Cc1ccc(C(=O)N2CC(C(=O)N3CCCNCC3)C2)cn1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C(=O)N2CC(C(=O)N3CCCN(CC4CC4)CC3)C2)cn1
Temperature: 70 °C
Yield: 38.3 %

Procedure:
To a stirred solution of 1-({1-[(6-methylpyridin-3-yl)carbonyl]azetidin-3-yl}carbonyl)-1,4-diazepane (100 mg, 0.33 mmol) and 1-(bromomethyl)cyclopropane (53 mg, 0.39 mmol) in ACN (5 mL) was added potassium carbonate (91 mg, 0.66 mmol). The mixture was heated to 70° C. in a sealed tube for 20 hours and then concentrated at reduced pressure. The crude residue was purified by silica FCC (eluting with 97:3:1 DCM/MeOH/NH3) and then preparative HPLC (Method 2) to give the title compound (45 mg, 38% yield) as pale yellow oil
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[OH:10][CH2:11][C:12]1[C:13]([CH3:19])=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][OH:10])[C:13]=1[CH3:19])([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1c(O)cccc1CO
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(CO)cccc1OCC(=O)OC(C)(C)C
Yield: 94.2 %

Procedure:
Tert-butyl bromoacetate (75 g, 385 mmol) was added to a solution/suspension of 3-hydroxymethyl-2-methylphenol (46.6 g, 337 mmol) and finely powdered potassium carbonate (60 g) in acetone (500 mL). The mixture was heated at reflux for about 40 hours or until the reaction was complete. The solids were filtered, and the liquid residue was evaporated. Purification of the residue by silica gel chromatography, eluting with acetone/hexane, gave (3-hydroxymethyl-2-methylphenoxy)acetic acid tert-butyl ester as a pale yellow oil (80.1 g, 96%).
Reaction SMILES: Cl.[CH2:2]([NH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[S:27]1[CH2:31][CH:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[NH:29][CH2:28]1.C(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH2:2]([NH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([N:29]1[CH:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:31][S:27][CH2:28]1)=[O:22])[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCC=CCCCNc1cccc(C(=O)Cl)c1
Reactant: CCOC(=O)C1CSCN1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCC=CCCCNc1cccc(C(=O)N2CSCC2C(=O)OCC)c1

Procedure:
One-tenth mole of 3-(4-pentadecenylamino)benzoyl chloride hydrochloride in methylene chloride is added to a solution of 0.1 mole of ethyl thiazolidine-4-carboxylate in chloroform containing two equivalents of triethylamine. After 5 hours at 20° C. the solution is filtered and evaporated to a white solid which is recrystallized from acetonitrile.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[O:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][NH:45][CH2:46][CH3:47]>CN(C=O)C>[CH2:46]([N:45]([CH2:44][CH:40]1[CH2:41][CH2:42][CH2:43][O:39]1)[C:16]1[C:17]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[CH:12][CH:11]=2)[N:15]=1)[CH3:47]
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: CCNCC1CCCO1
Solvent: CN(C)C=O
Product: CCN(CC1CCCO1)c1nc(Nc2ccc(-n3ccnc3C)cc2)nc2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(4-(2-methyl-1H- imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol, example 69c) was dissolved in DMF (2 mL). N-((tetrahydrofuran-2-yl)methyl)ethanamine (58.2 mg, 0.45 mmol) was added and the reaction mixture was stirred at 85° C. overnight. The reaction was allowed to reach room temperature, the solvent was evaporated under reduced pressure and the crude was used as such in the subsequent step. MS (ES+) m/z 534.4 (M+H)+
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[Na+].CCOC(C)=O>[Pd].CO>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccc(F)cc3)ccc2c1O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1ncc2cc(Oc3ccc(F)cc3)ccc2c1O
Reaction time: 2.5 h
Yield: 97.1 %

Procedure:
A mixture of 1-Bromo-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (4.34 g, 10 mmol, see example A-75 d), sodium acetate (984 mg, 12 mmol), Pd/C (2.0 g, 10 wt % Pd, 50 wt % water), EtOAc (400 ml) and MeOH (200 ml) was stirred under an H2-atmosphere at ambient pressure and temperature for 2.5 h before the mixture was filtered through a plug of celite. The celite was washed with EtOAc (500 ml). The combined organic phases were concentrated in vacuo. To the residue was added a half concentrated NaHCO3 solution (50 ml) and the mixture was extracted with CH2Cl2 (1×200 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to yield the title compound as a tan oil (3.45 g); MS-(+)-ion M+1=356.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCCn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(cnn4CCCC(=O)O)c3)no2)cc1Cl
Temperature: 100 °C
Yield: 32 %

Procedure:
Ethyl 4-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]butanoate (D63) (127 mg, 0.27 mmol) was dissolved in ethanol (5 ml) and then sodium hydroxide (11 mg) was added. The reaction mixture was heated at 100° C. for 1 hour in a microwave reactor and then allowed to cool. The resultant solid was separated by filtration and then washed with acetone. Purification by MDAP, followed by freeze drying of the resultant material afforded the title compound (38.1 mg). MS (ES): C22H2135ClN4O4 requires 440; found (MH+) 441.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[K].[F:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][CH:42]=[C:41]2[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52](O)=[O:53]>CO>[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:52](=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][C:41]2[C:40]3[C:44](=[CH:45][CH:46]=[C:38]([F:37])[CH:39]=3)[NH:43][CH:42]=2)[CH2:8][CH2:7]1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Reactant: O=C(O)CCCCCc1c[nH]c2ccc(F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Agent: [K]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)CCCCCc2c[nH]c3ccc(F)cc23)CC1
Reaction time: 72 h

Procedure:
A mixture of the diastereoisomers of (4-aminomethyl-1-phenylcyclohexyl)dimethylamine (347 mg, 1.49 mmol.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (620 mg, 2.2 mmol.) was added to a solution of the potassium salt of 6-(5-fluoro-1H-indol-3-yl)hexanoic acid (430 mg, 1.49 mmol.) in abs. methanol (30 ml), and stirring was carried out for 3 d at RT. For working up, the mixture was concentrated, water (10 ml) and 2M HCl (15 ml) were added to the residue, and washing was carried out with ether (25 ml). The diethyl ether phase was separated off. The aqueous phase and oily drops contained therein were adjusted to pH 11 with 5M NaOH and extracted with EE (4×15 ml). The combined EE extracts were washed with 1M NaOH (2×2 ml), dried, filtered and concentrated. The residue was a diastereoisomeric mixture of the bases of the target product, which was separated by flash chromatography on silica gel (75 g) and purified (eluant: 1500 ml of methanol/EE 1:1). 192 mg of the non-polar diastereoisomer of 6-(5-fluoro-1H-indol-3-yl)hexanoic acid (4-dimethylamino-4-phenylcyclohexylmethyl)amide were obtained (m.p. 52–54° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:35])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36](=O)([O-])[O-].[K+].[K+].CI.C(Cl)(Cl)Cl>CN(C)C=O.O>[CH3:22][O:21][C:19]([C:18]1[N:9]([N:8]([CH3:36])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10](=[O:35])[C:11]2[C:16]([C:17]=1[C:23]1[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:20]
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound obtained in Example 67 (1.00 g) is dissolved in dimethylformamide (10 ml), and thereto are added potassium carbonate (382 mg) and methyl iodide (392 mg). The mixture is stirred at room temperature overnight, and thereto are added chloroform and water. The chloroform layer is separated, washed, dried, and concentrated under reduced pressure. The residue is crystallized from diethyl ether to give 3-methoxycarbonyl-2-(N-methyl-N-tert-butoxycarbonylamino)-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone as listed in Table 6, which is used as a starting compound in Example 72 without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][NH2:21])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](N)=[NH:29]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[NH:29][C:28]([C:27]4[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=4)=[N:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: N=C(N)c1cccc(C(F)(F)F)c1
Reactant: NNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: Cl
Solvent: CN(C)C=O
Product: O=c1n(Cc2nnc(-c3cccc(C(F)(F)F)c3)[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 150 °C
Reaction time: 0.75 h

Procedure:
100 mg (0.33 mmol) of the compound from Example 21A were dissolved in 1.6 ml of DMF, 109 mg (0.49 mmol) of 3-trifluoromethylbenzamidine hydrochloride were added and the mixture was stirred in a microwave oven at 150° C. for 45 min. After cooling, the reaction was concentrated under reduced pressure on a rotary evaporator and the residue that remained was purified chromatographically [Method 19]. This gave 70 mg (47% of theory) of the target compound as a colorless solid.
Reaction SMILES: [C:1]([CH:4]([CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:5][OH:6])([CH3:3])=[CH2:2].C1(C)C=CC=CC=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH3:26][S:27]([O:6][CH2:5][CH:4]([C:1]([CH3:3])=[CH2:2])[CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])(=[O:29])=[O:28]
Reactant: C=C(C)C(CO)CC=C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)C(CC=C(C)C)COS(C)(=O)=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
2-Isopropenyl-5-methyl-4-hexen-1-ol (154.25 g, 1.00 mol), toluene (775.6 g) and triethylamine (122.5 g, 1.21 mol) were charged in a four-neck flask (inner volume 2 L) equipped with a thermometer, a stirrer and a dropping funnel, and the mixture was cooled to 5° C. Then, methanesulfonyl chloride (137.5 g, 1.20 mol) was added dropwise to this mixture over 30 min. After the completion of the dropwise addition, the reaction mixture was further stirred at 25° C. for 1 hr. Water (462.4 g) was added to the obtained reaction mixture, the mixture was stirred for 15 min, and the organic layer was separated. The obtained organic layer was washed with 5 mass % aqueous solution of sodium hydrogencarbonate (488.0 g) and water (464.1 g) and concentrated to give 2-isopropenyl-5-methyl-4-hexen-1-yl methanesulfonate (237.73 g, 0.972 mol, yield 97.2%, purity 95%). The result of 1H-NMR measurement of 2-isopropenyl-5-methyl-4-hexen-1-yl methanesulfonate is shown below. The present compound is a novel substance.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:11])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.C(O)(=O)C>C(O)C.CCOC(C)=O.O.C([O-])([O-])=O.[Na+].[Na+].[Fe]>[I:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[CH3:11]
Reactant: Cc1ncc([N+](=O)[O-])cc1I
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1ncc(N)cc1I
Temperature: 85 °C

Procedure:
To a solution of 3-iodo-2-methyl-5-nitropyridine (125 mg, 0.4734 mmol) in ethanol (3 mL) was added acetic acid (0.50 mL, 8.8 mmol) and iron powder (140 mg, 2.6 mmol). The reaction was heated at 85° C. for 30 minutes and was diluted with EtOAc, water, and saturated Na2CO3. Then it was filtered and extracted with EtOAc and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and stripped in vacuo. 1H NMR (400 MHz, CDCl3): δ 7.96 (d, 1H), 7.44 (d, 1H), 3.57 (br s, 2H), 2.61 (s, 3H); MS (ES) (M+H)=235.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[I:12]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([I:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of 5-chloro-2-nitroaniline (20.1 g, 116 mmol) and N-iodosuccinimide (26.2 g, 116 mmol) in 260 mL of acetic acid was heated at 55° C. for 16 h and then cooled in an ice-bath. The resulting yellow solid was collected by filtration and rinsed with acetic acid, water, aqueous NaHCO3 and water, and let stand in air for 2 h to provide 5-chloro-4-iodo-2-nitroaniline 1-5 as a yellow solid. 1H NMR (500 MHz, DMSO-d6): δ 7.23 (s, 1H), 8.32 (s, 1H), 7.57 (s, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]#[C:13][Si](C)(C)C)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:12]([C:11]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[CH:9][CH:10]=1)#[CH:13]
Reactant: C[Si](C)(C)C#Cc1ccnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
To a solution of 1-phenyl-5-[(trimethylsilyl)ethynyl]-1H-pyrazole (1.20 g) in methanol (20.0 mL) was added potassium carbonate (0.173 g), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound (0.72 g).
Reaction SMILES: Cl.O1CCCC1.COC[O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][S:44]([CH2:47][CH2:48][CH2:49][C:50]([F:56])([F:55])[C:51]([F:54])([F:53])[F:52])(=[O:46])=[O:45])=[CH:34][CH:33]=3)[C:16]([C:22]3[CH:27]=[CH:26][C:25]([O:28]COC)=[CH:24][CH:23]=3)([CH3:21])[CH2:17][S:18]2)=[CH:13][CH:12]=1>O>[OH:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][S:44]([CH2:47][CH2:48][CH2:49][C:50]([F:55])([F:56])[C:51]([F:52])([F:53])[F:54])(=[O:46])=[O:45])=[CH:34][CH:33]=3)[C:16]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)([CH3:21])[CH2:17][S:18]2)=[CH:13][CH:12]=1
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(OCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1c1ccc(OCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc1
Reaction time: 1 h
Yield: 66.8 %

Procedure:
Aqueous 6N--HCl solution (1 ml) was added to tetrahydrofuran solution (1.5 ml) of (3RS,4RS)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-4-[4-(5-(4,4,5,5,5-pentafluoropentylsulfonyl)pentyloxy)phenyl]thiochroman (37 mg, 0.050 mmol) and then stirred for one hour. After adding water, the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. The crude product thus obtained was purified using silica gel plate (ethyl acetate:hexane=1:2) to obtain 22 mg (yield: 70%) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=O.[CH3:28][NH2:29].O>CCO>[CH3:28][NH:29][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:2]
Reactant: CN
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Solvent: CCO
Solvent: O
Product: CNC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Temperature: 80 °C

Procedure:
A mixture of 7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (20 mg, 0.054 mmol) and methylamine (0.8 mL, 2M in THF) in EtOH (2 mL) was heated in a sealed tube at 80° C. for 16 h. After cooling the mixture to r.t., water (2 mL) was added. The resulting precipitate was isolated by filtration, washed with cold MeOH/H2O (5 mL, 1:1), and dried under vacuum to give 9 mg of the title compound. MS: (+) m/z 370.28 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: Nc1ccc(F)c(F)c1
Agent: Br
Product: CC(Nc1ccc(F)c(F)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 28.3 %

Procedure:
3,4-difluoroaniline (0.105 mL, 1.06 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (130 mg, 0.27 mmol) using a procedure similar to the one described in Example 3.00 to give 8-(1-(3,4-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (35.0 mg, 28.8%) as a white solid. Mass Spectrum: M+H+ 458. NMR Spectrum: (DMSOd6) 1.50 (d, 3H), 2.70 (s, 3H), 2.94 (s, 3H), 3.50-3.63 (m, 4H), 3.71-3.79 (m, 4H), 4.92-5.01 (m, 1H), 5.60 (s, 1H), 6.25 (d, 1H), 6.46 (ddd, 1H), 6.54 (d, 1H), 7.05 (dd, 1H), 7.54 (d, 1H), 7.78 (d, 1H).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH3:18])[N:11]=1)([CH3:3])[CH3:2].[C:25]1(=O)[CH2:28]C[CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([CH:19]2[CH2:24][CH2:23][N:22]([CH:25]([CH3:28])[CH3:26])[CH2:21][CH2:20]2)[CH3:18])[N:11]=1)([CH3:2])[CH3:3]
Reactant: O=C1CCC1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C2CCNCC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C2CCN(C(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.8 %

Procedure:
A solution of (S)-4-Isopropyl-3-[2-((S)-1-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-oxazolidin-2-one (20 mg, 0.060 mmol) in THF (2 mL) was added cyclobutanone (10 mg, 0.17 mmol) and sodium triacetoxyborohydride (20 mg, 0.09 mmol). The reaction was stirred at room temperature for 18 hours. The solvent is then removed under vacuum. The crude material was then purified using reverse phase C18 ODB column water-acetonitrile 0.1% TFA modifier to give (S)-4-Isopropyl-3-{2-[(S)-1-(1-isopropyl-piperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-oxazolidin-2-one (20 mg) in 62% yield.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:18]([CH3:30])=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH:31]O>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:18]([CH3:30])=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:27])([CH3:28])[C:21]=3[CH:29]=2)=[O:31])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: OO
Reactant: CC(=O)Nc1ccc(SCCCCOc2cc3c(cc2C)NC(=O)OC3(C)C)cc1
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2cc3c(cc2C)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-acetamido-phenylmercapto)-butoxy]-4,4,7-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.