Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:7]=2[C:8]([NH:10][C:11]2([C:20](O)=[O:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:9])[CH2:4][CH2:3][CH2:2]1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30].Cl.CN(C)CCCN=C=NCC.CO>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:1]1([O:5][C:6]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:7]=2[C:8]([NH:10][C:11]2([C:20]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:9])[CH2:4][CH2:3][CH2:2]1
Reactant: CS(N)(=O)=O
Reactant: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1OC1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC2(C(=O)NS(C)(=O)=O)Cc3ccccc3C2)c1OC1CCC1
Reaction time: 144 h
Yield: 87.7 %

Procedure:
A 30 mL vial is charged with 2-[(2-cyclobutoxy-3-methyl-benzoyl)-amino]-indan-2-carboxylic acid (245 mg, 0.67 mmol) and dry DCM (5.0 mL). A stirring bar is added and stirring is initiated. The methanesulfonamide (89 mg, 0.936 mmol) is added. To the resultant suspension, (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (120 mg, 0.624 mmol) and 4-dimethylaminopyridine (76 mg, 0.62 mmol) are added. After 6 days, tlc analysis (silica, 10% MeOH in DCM) indicates that the starting acid is consumed. The reaction mixture is diluted with EtOAc (50 mL), transferred to a separatory funnel and washed with dilute aqueous HCl (3 N, 3×20 mL) and brine, dried over MgSO4, filtered and evaporated by pumping to constant weight gives 0.26 g of amorphous white foam. This material is dissolved in DCM (5 mL) and applied to a 12 g column (silica) on an ISCO Companion. The column is eluted with 1% iPrOH in DCM for 3 column volumes followed by a linear gradient to 30% iPrOH in DCM over 15 column volumes. 12 mL fractions of UV active eluent are collected. Fractions 4 through 9 are combined and evaporated to a constant weight to give 0.2 g of white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20](=[S:22])[NH2:21])=[N:14]2)[CH:7]=1)[CH3:2].Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)=O>CCO>[CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]3[S:22][CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[N:21]=3)=[N:14]2)[CH:7]=1)[CH3:2]
Reactant: O=C(CBr)c1ccncc1
Reactant: CCOC(=O)Nc1cccc(Cn2nc(C(N)=S)ccc2=O)c1
Agent: Br
Solvent: CCO
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3nc(-c4ccncc4)cs3)ccc2=O)c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
100 mg (0.30 mmol) of ethyl[3-(6-oxo-3-thiocarbamoyl-6H-pyridazin-1-yl-methyl)phenyl]carbamate are suspended in 2 ml of EtOH, and 101 mg (0.36 mmol) of 2-bromo-1-(4-pyridinyl)ethanone hydrobromide are added. The reaction mixture is stirred at 80° C. for 15 h. The precipitate formed is filtered off with suction and washed with ethanol and dried in vacuo. The crude product is purified by means of preparative HPLC.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.O.CO>[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[N:13]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(ccc3nnc(C)n32)n1CCc1ccccc1
Reaction time: 0.17 h
Yield: 20.7 %

Procedure:
Sodium hydride (6.4 mg, 0.16 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (15 mg, 0.080 mmol, Example 2, Step 5) in DMF (2.2 mL). After stirring for 10 minutes, 1-bromo-2-phenylethane (22 μL, 0.16 mmol, Aldrich) was added dropwise. After stirring for 1 hour, additional sodium hydride (3.2 mg, 0.080 mmol, 60% in mineral oil) and 1-bromo-2-phenylethane (11 μL, 0.080 mmol) were added. The crude reaction mixture was diluted with water and MeOH, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product as a light yellow powder (4.8 mg, 20%).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1C(Cl)=O)([F:4])[F:3].[CH3:14][CH:15]([CH3:25])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24].[C:26](=O)([O-])[O-:27].[K+].[K+]>ClCCl>[CH3:14][CH:15]([CH3:25])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:26](=[O:27])[C:12]1[CH:11]=[CH:10][CH:6]=[C:5]([C:2]([F:1])([F:3])[F:4])[CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)COc1ccccc1N
Agent: [K+]
Solvent: ClCCl
Product: CC(C)COc1ccccc1NC(=O)c1cccc(C(F)(F)F)c1

Procedure:
A solution of 12.5 g of 3.(trifluoromethyl)benzoyl chloride in 60 ml of dichloromethane is added dropwise to a suspension of 9.9 g of 2-(2-methylpropoxy)benzenamine and 33 g of potassium carbonate in 90 ml of dichloromethane, cooled in an ice-bath.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].O>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(Br)n1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cccc(Br)n1
Temperature: 0 °C
Yield: 96.5 %

Procedure:
4.0 g (23.1 mmol) of 6-bromo-2-aminopyridine from example 14.1 were dissolved in 25 ml of dichloromethane and admixed with 4.1 ml (2.92 g, 28.9 mmol) of triethylamine. After cooling to 0° C., a solution of 3.1 ml (3.06 g, 25.4 mmol) of pivaloyl chloride in 5.0 ml of dichloromethane was added dropwise over a period of 10 min. The reaction mixture was allowed to warm to room temperature overnight and, for workup, poured onto 100 ml of dist. H2O. The phases were separated, the aqueous phase was extracted twice with 100 ml each time of ethyl acetate and the combined organic phases were dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane and filtered through a short silica gel column (3×10 cm). After the solvent had been removed under reduced pressure, 5.73 g (22.3 mmol, 96.5%) of 6-bromo-2-pivaloylaminopyridine were obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:48])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)=[C:25]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:48])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCOCC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCOCC4)c(NS(C)(=O)=O)c3)cc12
Yield: 19.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-morpholino phenyl)methanesulfonamide (150 mg, 0.205 mmol) was hydrolyzed with lithium hydroxide (43.2 mg, 1.02 mmol) in THF/Methanol/water (2/3/1 ml). This yielded 23 mg (19.49% yield) of pure compound. 1H NMR (CDCl3, 300 MHz): δ 9.17 (s, 1H), 8.55 (s, 1H), 7.86 (s, 2H), 7.75 (s, 1H), 7.32 (s, 3H), 6.99-6.97 (m, 2H), 6.90-6.80 (d, 1H), 5.31 (s, 2H), 3.91-3.88 (m, 4H), 3.10 (s, 3H), 2.92-2.89 (m, 4H), 2.26 (s, 3H), 2.17 (s, 3H). MS: m/z=575.1 (M+1), HPLC Purity: 98.92% Method: B.
Reaction SMILES: C(#N)C.N1C=CC=CC=1.F.[O:11]([C@@H:19]1[CH2:23][C:22]([CH3:24])=[C:21]([S:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C@H:20]1/[CH:32]=[CH:33]/[CH:34]([O:42][Si](C(C)(C)C)(C)C)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[Si](C(C)(C)C)(C)C>N1C=CC=CC=1>[CH2:26]([S:25][C:21]1[C@@H:20](/[CH:32]=[CH:33]/[CH:34]([OH:42])[CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C@H:19]([OH:11])[CH2:23][C:22]=1[CH3:24])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCSC1=C(C)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1/C=C/C(Cc1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCSC1=C(C)C[C@@H](O)[C@@H]1/C=C/C(O)Cc1ccccc1
Reaction time: 20 h

Procedure:
To a solution of ice-cooled acetonitrile (2 ml) and pyridine (0.5 mL) was added hydrogen fluoride-pyridine (0.5 mL). To this solution was added (3S,4R)-4-(tert-butyldimethylsiloxy)-2-hexylthio-3-[(1E)-4-phenyl-3-(tert-butyldimethylsiloxy)-1-butenyl]-1-methyl-1-cyclopentene (295 mg) in pyridine (1.5 mL). The ice bath was removed and the solution was agitated for 20 hours while returning it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The desired product was extracted from this mixed solution with ethyl acetate and was washed with brine, then was dried over anhydrous sodium sulfate. This was concentrated under reduced pressure, then was purified by silica gel column chromatography (30% ethyl acetate/hexane) to obtain stereoisomers of (3S,4R)-2-hexylthio-4-hydroxy-3-[(1E)-4-phenyl-3-hydroxy-1-butenyl]-1-methyl-1-cyclopentene separately (less polar compounds: 48.6 mg, 27%; more polar compounds: 53.5 mg, 30%).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:22][CH3:23])=[CH:4][C:5]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.[N+:24]([O-])([OH:26])=[O:25]>C(Cl)Cl>[OH:1][C:2]1[C:7]([N+:24]([O-:26])=[O:25])=[C:6]([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[C:5]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)c2ccccc2)cc1O
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: COc1cc(-c2noc(C)n2)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1O
Reaction time: 0.33 h

Procedure:
To a mixture of [5-hydroxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]phenylmethanone (reference example 21-1) (383 mg) and methylene chloride (10 mL) was added fuming nitric acid (68 μL) at room temperature, and the mixture was stirred for 20 minutes. The separated organic layer was washed with water, a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The residue was triturated with hexane:methylene chloride=4:1 to give the title compound (377 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]([CH3:14])[C:11]([Cl:13])=[O:12]>>[Cl-:13].[CH3:1][C:2]1[CH:3]=[N+:4]([O:8][C:11](=[O:12])[N:10]([CH3:14])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc[n+]([O-])c1
Reactant: CN(C)C(=O)Cl
Product: Cc1ccc[n+](OC(=O)N(C)C)c1
Product: [Cl-]

Procedure:
Also, Fife et al., cited hereabove and Heterocycles 22:93-96(1984), reported the reaction of 3-methylpyridine-1-oxide with dimethyl-carbamoyl chloride to give 3-methyl-1-dimethylcarbamoyloxypyridinium chloride. Reaction of this pyridinium salt with potassium cyanide in water gave 3-methyl-2-cyanopyridine (89%) and the 6-isomer (11%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.C[I:10].[C:11](OCC)(=O)C>CN(C)C=O>[IH:10].[NH:8]=[C:7]1[N:6]([CH3:11])[C:4](=[O:5])[CH2:3][N:2]1[CH3:1]
Reactant: CI
Reactant: CCOC(C)=O
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Product: CN1CC(=O)N(C)C1=N
Product: I
Temperature: 50 °C
Reaction time: 8 h

Procedure:
16.9 g (150 mmol) of creatinine was dissolved in 100 ml of N, N-dimethylformamide. Then, 27.6 g (194 mmol) of methyl iodide was added thereto, and the mixture was heated to 50° C. and stirred at that temperature for 2 hours and further at room temperature overnight. To the reaction mixture, 500 ml of ethyl acetate was added, and crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and dried to obtain 26.2 g of 2-imino-1,3-dimethylimidazolidin-4-one hydroiodide as white crystals.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[Cl:7][C:8]1[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]([Cl:24])[C:9]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14]>CO>[Cl:7][C:8]1[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]([Cl:24])[C:9]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13](=[N:2][OH:3])[NH2:14]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C#N)c1Cl
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(Cl)c(Nc2ccccc2C(N)=NO)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
To a room temperature solution of hydroxylamine hydrochloride (1.362 g, 19.62 mmols) in 40 mL of methanol is added sodium methoxide (1.030 g, 19.06 mmols). The mixture is stirred at room temperature for 15 minutes, then filtered. The filtrate is added to a suspension of 2-(2,6-dichloro-3-methylanilino)benzonitrile (3.109 g, 11.20 mmols) [prepared according to Juby, J. Med. Chem., 11, 111 (1968)] in 70 mL of methanol and the mixture is heated at reflux overnight. The clear yellow solution is cooled and concentrated in vacuo. Flash chromatography eluting with 6:1 hexane: ethyl acetate provides 2.079 g (60%) of 2-(2,6-dichloro-3-methylanilino)benzamide oxime as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: COc1cccc(CN)c1
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(CNC(=O)c2ccc(Br)c(C)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-3-methylbenzoic acid (100 mg, 0.465 mmol) in DCM (2 mL) were added (3-methoxyphenyl)methanamine (70.2 mg, 0.512 mmol), DIEA (0.244 mL, 1.395 mmol) and HATU (212 mg, 0.558 mmol) at RT. The reaction was stirred under argon at RT for 1 h. The crude product was purified by normal phase chromatography. 58A was obtained as white solid (155 mg, 0.464 mmol, 100% yield). LCMS (ESI) m/z: 336.0 (M+H)+; 1H NMR (400 MHz, CHLOROFORM-d) δ 7.67 (d, J=2.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.46-7.39 (m, 1H), 7.30-7.24 (m, 1H), 6.92 (dd, J=7.6, 0.6 Hz, 1H), 6.88 (t, J=1.8 Hz, 1H), 6.84 (dt, J=8.1, 1.3 Hz, 1H), 6.38 (br. s., 1H), 4.60 (d, J=5.7 Hz, 2H), 3.80 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([NH:12][C:13]3[C:14]([NH2:23])=[CH:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:18]=3)=[O:11])[CH:8]=2)[CH:3]=[N:2]1.COC(C1C=C(N[C:36](=[O:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=2)C(N)=CC=1)=O.N1C2C(=CC=C(C(O)=O)C=2)C=N1>>[C:43]([C:40]1[CH:39]=[CH:38][C:37]([C:36]([NH:23][C:14]2[C:13]([NH:12][C:10]([C:7]3[CH:8]=[C:9]4[C:4]([CH:3]=[N:2][NH:1]4)=[CH:5][CH:6]=3)=[O:11])=[CH:18][CH:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=2)=[O:47])=[CH:42][CH:41]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3cn[nH]c3c2)c(N)c1
Reactant: COC(=O)c1ccc(N)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Agent: O=C(O)c1ccc2cn[nH]c2c1
Product: COC(=O)c1ccc(NC(=O)c2ccc3cn[nH]c3c2)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
By methods substantially equivalent to those described in Example 9-C, N2-(4-t-butylbenzoyl)]-N1-(6-indazolylcarbonyl)-4-methoxycarbonyl-1,2-benzenediamine (0.1 g, 5%) was prepared from 4-methoxycarbonyl-N2-(4-t-butylbenzoyl)-1,2-benzenediamine and 6-indazolecarboxylic acid.
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[C:8]2=[N:9][C:10]3[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]([OH:17])=[C:7]2[C:6](=[N:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[O:5]1)[CH3:3].[C:29]([OH:32])(=[O:31])[CH3:30]>>[C:29]([O:32][CH:4]([C:8]1[C:7]([C:6]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:5])=[C:16]([OH:17])[C:15]2[C:10](=[C:11]([C:18]([F:21])([F:19])[F:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1)[CH:2]([CH3:3])[CH3:1])(=[O:31])[CH3:30]
Reactant: CC(C)C1OC(=Nc2ccccn2)c2c1nc1c(C(F)(F)F)cccc1c2O
Reactant: CC(=O)O
Product: CC(=O)OC(c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1ccccn1)C(C)C

Procedure:
Using the procedure of Example 13, 6 g of 1,3-dihydro-3-(1-methylethyl)-1-[(2-pyridinyl)-imino]-5-trifluoromethyl furo-[3,4-b]-quinolin-9-ol and 120 ml of acetic acid were reacted to obtain 3.5 g of 1-[4-hydroxy-3-[(2-pyridinyl)-aminocarbonyl]-8-trifluoromethyl-2-quinolinyl]-2-methylpropyl acetate melting at 230° C.
Reaction SMILES: [CH3:1][S:2][C:3]1C=[CH:7][CH:6]=[CH:5][C:4]=1CCl.[Br:11]Br.Cl[CH2:14][Cl:15].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Fe].C(OCC)(=O)C.O>[Br:11][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[C:14]([Cl:15])[CH:7]=1
Reactant: BrBr
Reactant: ClCCl
Reactant: CSc1ccccc1CCl
Agent: [Fe]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1ccc(Br)cc1Cl
Reaction time: 2 h
Yield: 87 %

Procedure:
Combine 1-methylsulfanyl-2-chloromethyl-benzene (3.7 g, 23 mmol), iron (130 mg, 2.3 mmol), bromine (1.2 mL, 238 mmol), and dichloromethane (150 mL). Stir for 2 hours. Add water (10 mL), aqueous saturated sodium thiosulfate (100 mL) and ethyl acetate (100 mL). Separate the organic layer and wash with brine, dry with MgSO4, filter and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with hexane to give 4.8 g of 4-bromo-2-chloro-1-methylsulfanyl-benzene (87%).
Reaction SMILES: C(OCC1C(N2CCN3C4CCCCC=4C=C3C2=O)=CC=CC=1C1C=C(NC2C=CC([F:39])=CN=2)C(=O)N(C)C=1)(=O)C.[C:42]([O:45][CH2:46][C:47]1[C:52](B2OC(C)(C)C(C)(C)O2)=[CH:51][CH:50]=[CH:49][C:48]=1[N:62]1[C:74](=[O:75])[C:73]2[S:72][C:71]3[CH2:70][CH2:69][CH2:68][CH2:67][C:66]=3[C:65]=2[CH2:64][CH2:63]1)(=[O:44])[CH3:43].Br[C:77]1[CH:78]=[C:79]([NH:85][C:86]2[CH:91]=[CH:90][C:89]([N:92]3[CH2:97][CH2:96][N:95]([CH:98]([CH3:100])[CH3:99])[CH2:94][CH2:93]3)=[CH:88][N:87]=2)[C:80](=[O:84])[N:81]([CH3:83])[CH:82]=1>>[C:42]([O:45][CH2:46][C:47]1[C:48]([N:62]2[C:74](=[O:75])[C:73]3[S:72][C:71]4[CH2:70][CH2:69][CH2:68][CH2:67][C:66]=4[C:65]=3[CH2:64][CH2:63]2)=[CH:49][C:50]([F:39])=[CH:51][C:52]=1[C:77]1[CH:78]=[C:79]([NH:85][C:86]2[CH:91]=[CH:90][C:89]([N:92]3[CH2:97][CH2:96][N:95]([CH:98]([CH3:100])[CH3:99])[CH2:94][CH2:93]3)=[CH:88][N:87]=2)[C:80](=[O:84])[N:81]([CH3:83])[CH:82]=1)(=[O:44])[CH3:43]
Reactant: CC(C)N1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(F)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C(C)C)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O

Procedure:
Following the procedures as described for 148b and starting with 400 mg of (4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 212b and 340 mg 5-bromo-3-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one 220a, compound 220b was obtained as a yellow solid (446 mg, 82%).MS: [M+H]+ 699
Reaction SMILES: CCCCCC.[CH3:7][C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([OH:16])[CH:15]=1)=[O:9].C(OCC)(=[O:19])C>>[OH:16][C:14]1[CH:15]=[C:10]([C:8]([CH:7]=[O:19])=[O:9])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: O=CC(=O)c1cccc(O)c1

Procedure:
Using 1:1 hexane:ethyl acetate as eluant, the method of Preparation 68 was employed to convert 3-hydroxyacetophenone (15.0 g., 0.11 mol) to present title product, 7.4 g.; 1H-nmr (DMSO-d6) 7.09 (m, 2H), 7.43 (m, 3H), 9.75 (br m, 1H).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[F:12][C:13]1[C:14]([C:22](F)=[O:23])=[N:15][C:16]([F:21])=[C:17]([F:20])[C:18]=1[F:19]>O>[F:12][C:13]1[C:14]([C:22]([O:4][CH:2]([CH3:3])[CH3:1])=[O:23])=[N:15][C:16]([F:21])=[C:17]([F:20])[C:18]=1[F:19]
Reactant: CC(C)O
Reactant: O=C(F)c1nc(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)OC(=O)c1nc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Anhydrous 2-propanol (0.361 g, 6 mmol) and anhydrous tri-ethylamine (0.405 g, 4 mmol) were added drop-wise at room temperature to the 3,4,5,6-tetrafluoropicolinoyl fluoride provided above. The mixture was stirred at room temperature overnight, poured into a separatory funnel with water and extracted with ethyl ether. The organic phase was then washed with water and dried over MgSO4. The solvent was removed with a rotary evaporator. The concentrated crude product was purified using column chromatography (silica gel) with ethyl acetate/hexanes mixture (1/10) as eluent to give 0.454 g (48% yield, 96% GC purity, 93% LC purity) of desired product as a pale yellow liquid. GC/MS results were consistent with the chemical formula of isopropyl 3,4,5,6-tetrafluoropicolinate: 70 eV EIMS (GC) m/z=196 (31%), 178 (100%), 150 (45%), 100 (26%), 43 (34%). 1H NMR (400 MHz, CDCl3) δ 5.32 (hept, J=6.3 Hz, 1H), 1.42 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 159.81 to 159.74 (m), 149.22 to 148.78 (m), 148.04 to 147.86 (m), 146.49 to 146.10 (m), 145.65 to 145.47 (m), 138.53 (dd, J=34.3, 11.2 Hz), 135.79 (dd, J=34.4, 11.2 Hz), 129.02 to 128.74 (m), 70.97 (s), 21.60 (s). 19F NMR (376 MHz, CDCl3) δ−80.31 to −80.49 (m), −136.04 to −136.18 (m), −137.10 to −137.25 (m), −149.81 to −149.95 (m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(O)(=O)C.C(O)(=O)C.[I:18]C1C=CC=CC=1.II.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([I:18])[CH:3]=1
Reactant: Ic1ccccc1
Reactant: COc1ccc(Br)cc1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc(Br)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Bromo-anisole (4.417 g, 23.6 mmol) was dissolved in acetonitrile (200 mL) and placed under an argon atmosphere in the absence of light. Iodobenzene diacetate (9.18 g, 28.5 mmol) was added followed by iodine (3.6 g, 14.2 mmol). The mixture was stirred for 16 hours at ambient temperature. The mixture was then poured into 1M Na2S2O3 (200 mL) and stirred until the solution was colourless. The solution was then extracted with diethyl ether (3×100 mL). The combined organic extracts were then washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The crude product was filtered through a silica gel plug eluting with heptane/ethyl acetate (3:1) (200 mL). The filtrate was concentrated and the residue was distilled using a Kugelrohr apparatus collecting the compound at 75° C., 0.01 mbar.