Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>CN(C)C=O>[C:10]1([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:3][C:4]=2[C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:18])=[O:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1ccc(O)cc1C(=O)c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OCc2ccccc2)cc1C(=O)c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 144.6 %

Procedure:
To a solution of N-[4-hydroxy-2-(phenylcarbonyl)phenyl]benzamide (4.0 g, 12.6 mmol) in dimethyl formamide (DMF) (15 mL) was added potassium carbonate (K2CO3) (large excess) then benzyl bromide (660 μL, 5.5 mmol). The reaction was stirred overnight. It was added to water (100 mL) then extracted with ethyl acetate (3×40 mL). The combined organic layers were dried (Na2SO4) then concentrated under vacuo to give a solid which was recrystallized with ethyl acetate/hexane to give the title compound (3.24 g, 63% yield, analytical).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([NH:12][C:13]([CH3:15])=[O:14])=[CH:9][CH:10]=2)[C:5](=[O:19])[NH:4][C:3]1=[O:20].C(Cl)(=O)[C:23]1[CH:28]=[CH:27]C=[CH:25][CH:24]=1>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([NH:12][C:13](=[O:14])[C:15]3[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=3)=[CH:9][CH:10]=2)[C:5](=[O:19])[NH:4][C:3]1=[O:20]
Reactant: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])C(=O)NC(=O)C2(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1C
Product: CC1(C)C(=O)NC(=O)c2c1ccc(NC(=O)c1ccccc1)c2[N+](=O)[O-]
Yield: 67.8 %

Procedure:
43.8 gm of 4,4-dimethyl-7-acetamino-8-nitro-2H,4H-isoquinoline-1,3-dione were admixed with 200 gm of xylene with 104 gm of benzoyl chloride, and the mixture was refluxed for 10 hours while stirring. After cooling, the reaction mixture was suction-filtered, and the filter cake was washed with toluene and petroleum ether, yielding 36 gm (68% of theory) of 4,4-dimethyl-7-benzoylamino-8-nitro-2H,4H-isoquinoline-1,3-dione, m.p. above 270° C.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[NH3:20]>C(N)=O>[NH2:1][C:4]1[C:17]2[C:16](=[NH:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: N
Solvent: NC=O
Product: N=C1c2ccccc2C(=O)c2cccc(N)c21
Reaction time: 4 h

Procedure:
26.3 g of 1-nitro-anthraquinone (96%) is suspended in 110 g of formamide. If ammonia gas is introduced at 155° C, no more starting material may be detected by thin layer chromatography after 4 hours. After complete removal of the solvent by distillation under vacuum, 22.5 g of an 80% 1-amino-anthraquinone (80% of the theoretical yield) which contains 4%, by weight of 1-amino-anthraquinone imine are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1([C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][NH:26][CH2:27]3)=[CH:22][CH:21]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][C:20]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[CH:21][CH:22]=4)[CH2:27]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc2c(cc1N1CCOCC1)CNCC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2ccc(N3CCOCC3)cc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[OH:17])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[O:17][CH2:39][CH:36]2[CH2:38][CH2:37]2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: BrCC1CC1
Reactant: COc1ccc(CC2c3c(O)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: COc1ccc(CC2c3c(OCC4CC4)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with cyclopropyl-methyl bromide
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>>[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Oc1nc(Cl)nc2c1CCCC2
Product: Oc1nc(N2CCc3ccccc3C2)nc2c1CCCC2
Yield: 26.3 %

Procedure:
In accordance with the same procedure as in Step 2 of Example 57, except that 2-chloro-4-hydroxy-5,6,7,8-tetrahydroquinazoline (2.0 g, 10.8 mmol) prepared in Step 1 of Example 82 and 1,2,3,4-tetrahydroisoquinoline (2.8 g, 22.4 mmol) were used as starting materials, 0.8 g of the titled compound was prepared. (Yield: 26.3%)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CC(C)=O>[C:2]([C:4]1[CH:12]=[CH:11][C:9]([O:10][CH2:20][CH2:21][CH2:22][Cl:23])=[C:6]([O:7][CH3:8])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)ccc1OCCCCl

Procedure:
To a solution of 88.0 g (0.53 mole) of acetovanillone in 375 ml of acetone was added 69.1 g (0.5 mole) of K2CO3. The mixture was allowed to reflux for 30 min. A solution of 110.2 g (0.70 mole) of 1-bromo-3-chloropropane in 75 ml of acetone was added dropwise. The mixture was heated at reflux for 20 h. The mixture was filtered and the filtrate concentrated under vacuum. The residual oil was distilled. An oil which weighed 110 g was obtained at 141°-143° C.0.1 mm Hg. The oil crystallised upon standing.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.C1C[O:28][CH2:27]C1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH:27]=[O:28])=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nccs1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Nc1ncc(C=O)s1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-tert-butyloxycarbonylaminothiazole (88.0 g, 439 mmol) in THF (1760 ml) was added dropwise a 1.59M solution of n-butyllithium in hexane (729 ml, 1159 mmol) over 20 minutes at −78° C., and the mixture was warmed to −10° C. over 1 hour. The mixture was cooled again to −78° C. and thereto was added DMF (102 ml, 0.132 mmol) in one portion. The acetone-dry ice bath was removed. The mixture was stirred for 30 minutes, and then poured into cold water (1000 ml) and thereto was added ethyl acetate (2000 ml). The organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate and the solvents were removed. The residue was recrystallized from ethyl acetate to give 2-tert-butyloxycarbonylaminothiazole-5-carbaldehyde (74.8 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[C:22]1[N:27]=[C:26]([NH2:28])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][CH:23]=1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:22]3[N:27]=[C:26]([NH2:28])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][CH:23]=3)[N:9]=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:5]2=[N:6][CH:7]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Fc1cnc2c(Cc3ccccc3F)n[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
192 mg (approx. 0.517 mmol) of the compound from example 38A were dissolved in dimethylformamide (4 ml), then 34.5 mg (0.862 mmol) of sodium hydride (60% in mineral oil) were added and the mixture was stirred at RT for 30 min. Then 129 mg (0.744 mmol) of 6-chloro-3-nitropyridin-2-amine were added and the reaction mixture was stirred at RT for 1 h. The mixture was added to water, and the solids were filtered off, washed repeatedly with water and dried under high vacuum overnight. This gave 348 mg (85% purity, 84% of theory) of the title compound in solid form.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>O>[CH:9]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([CH3:11])[CH2:13][CH2:14]2)=[O:10]
Reactant: CN(C)C=O
Reactant: CN1CCc2ccccc21
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
Phosphorus oxychloride (1.23 g., 0.0080 mole) was slowly added dropwise to 5 ml. of DMF which was cooled in an ice bath. The solution was stirred for 5 minutes and to it there was added dropwise a solution of 1-methylindoline (1.0 g., 0.0075 mole) in 2 ml. of DMF. The resulting mixture was stirred in the ice bath for 5 minutes, then at room temperature for 1 hour and finally at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, slowly poured into water with stirring and extracted with ethyl ether. The crude oil was chromatographed on silica gel with 80/20 (v/v) CH2Cl2 /EtOAc to yield 0.745 g. (62% yield) of 5-formyl-1-methylindoline as a yellow solid, m.p. 39°-41° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]12([P:25]([C:27]34[CH2:36][CH:31]5[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]5)[CH2:28]3)[CH2:34]4)Cl)[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.CCOCC>C1COCC1.CCCCC>[C:15]12([P:25]([C:27]34[CH2:28][CH:29]5[CH2:30][CH:31]([CH2:32][CH:33]([CH2:35]5)[CH2:34]3)[CH2:36]4)[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:16][CH:17]3[CH2:23][CH:21]([CH2:20][CH:19]([CH2:18]3)[CH2:24]1)[CH2:22]2
Reactant: ClP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Reactant: Brc1ccccc1-c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: c1ccc(-c2ccccc2P(C23CC4CC(CC(C4)C2)C3)C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 5.8 %

Procedure:
An oven dried Schlenk tube was charged with magnesium turnings (240 mg, 9.89 mmol), 2-bromo-biphenyl (1.55 mL, 7.5 mmol). The tube was evacuated and backfilled with argon two times. To the above mixture THF (15 mL) was added through a rubber septum and the reaction mixture was heated to a mild reflux for 3 hours. The reaction mixture was then temporarily cooled to room temperature for the addition of cuprous chloride (930 mg, 9.45 mmol) followed by a solution of the di-1-adamantylchlorophosphine in 5 mL THF. Heating was resumed for an additional 3 hours. The reaction mixture was cooled to room temperature, and ether (50 mL) and pentane (50 mL) were added. The resulting suspension was stirred for 10 minutes, during which time a heavy dark-brown precipitate formed. The suspension was filtered and the solid was collected on a fritted funnel. The solid was partitioned between ethyl acetate-ether (100 mL 1:1) and 38% ammonium hydroxide-water (100 mL 1:1). The mixture was vigorously shaken several times over 30 minutes. The aqueos layer washed twice with ether-ethyl acetate (1:1, 100 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous magnesium sulfate, decanted, and concentrated in vacuo. The product was crystallized from toluene/methanol to afford 450 mg (5.8%) product as a white solid.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6]1)=[O:4].O.[OH-].[Li+:14]>CO.O>[CH3:10][C:7]1([CH3:11])[O:6][C@@H:5]([C:3]([O-:4])=[O:2])[CH2:9][O:8]1.[Li+:14]
Reactant: COC(=O)[C@H]1COC(C)(C)O1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)OC[C@H](C(=O)[O-])O1
Yield: 96.6 %

Procedure:
To a solution of (R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid methyl ester (5.0 g, 31.25 mmol) in MeOH (32.0 mL) at room temperature was added a solution of lithium hydroxide monohydrate (1.31 g, 31.25 mmol) in water (10.0 mL). The resulting mixture was stirred for thirty min before it was concentrated. The resulting white solid was further dried under vacuum to give the title compound (4.59 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.O[C@H:32]1[CH2:37][CH2:36][O:35][C:33]1=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1(C)C=CC=CC=1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:25]=[C:26]([O:30][C@@H:32]2[CH2:37][CH2:36][O:35][C:33]2=[O:34])[CH:27]=[CH:28][CH:29]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(OCCCN(Cc2cccc(O)c2)c2nc3ccccc3o2)cc1
Reactant: O=C1OCC[C@@H]1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(OCCCN(Cc2cccc(O[C@@H]3CCOC3=O)c2)c2nc3ccccc3o2)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
In an argon atmosphere, N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)-3-hydroxybenzylamine (2.0 g), (S)-2-hydroxybutyrolactone (1.0 g), and triphenylphosphine (2.6 g) were dissolved in toluene (30 mL), and a solution of di-tert-butyl azodicarboxylate (2.3 g) in toluene (10 mL) was dropwise to the solution at 0° C., followed by stirring for 24 hours at 40° C. Subsequently, triphenylphosphine (1.3 g) and di-tert-butyl azodicarboxylate (1.1 g) were added to the mixture at 40° C., followed by stirring for 24 hours at the same temperature. The reaction mixture was returned to room temperature. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine. The washed mixture was dried over sodium sulfate anhydrate. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane/ethyl acetate=1/1), to thereby yield a colorless oil (2.2 g, 92%, 98% ee).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.C([O-])(=O)C.[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c(CN(O)C(=O)CCC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Yield: 44 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine is reacted with 1.0 eq of succinic anhydride in dioxane/water (2:1) in the presence of sodium acetate (2.5 eq). The reaction mixture is diluted with ethyl acetate and is washed with dilute aqueous HCl and then with water. The crude product is purified by recrystallization from methylene chloride. The compound is dissolved in a minimal amount of methanol, diluted with water and lyophylized to give pure 4-[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]--4-oxo-butanoic acid (44%); mp 134°-136° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:19])[NH2:18])[S:14][CH:15]=2)[N:10]=1.[C:20](Cl)(=[O:22])[CH3:21].C(N(CC)CC)C>CN(C)C=O>[C:20]([NH:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:19])[NH2:18])[S:14][CH:15]=2)[N:10]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: NCCc1nc(-c2csc(N=C(N)N)n2)cs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NCCc1nc(-c2csc(N=C(N)N)n2)cs1
Yield: 36.3 %

Procedure:
A suspension of 4-[2-(2-aminoethyl)thiazol-4-yl]-2-(diaminomethyleneamino)thiazole dihydrochloride (1.0 g), acetyl chloride (230 mg) and triethylamine (1.0 g) in N,N-dimethylformamide (30 ml) was stirred with cooling on an ice-water bath for 1 hour. The solvent was removed under reduced pressure. The residue was suspended in water (30 ml). The mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution and then was extracted with ethyl acetate. The extract was dried with magnesium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column eluting with chloroform:methanol =10:11. Recrystallization from a mixture of methanol, ethyl acetate and diisopropyl ether afforded 4-[2-(2-acetylaminoethyl)thiazol-4-yl]-2-(diaminomethyleneamino)thiazole (0.33 g).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[CH:6]1[C:20]([C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=1)=[O:21].Cl>C(O)C.[OH-].[Na+]>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([CH2:4][C:3]([OH:29])=[O:2])=[C:6]([C:20]([C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=3)=[O:21])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)N1c2cc(Cl)ccc2C(CC(=O)OC)C1C(=O)c1cc(C)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Temperature: 25 °C
Yield: 16.6 %

Procedure:
A stirred solution of methyl[6-chloro-1-ethoxycarbonyl-2-(4-methylpyridine-2-carbonyl)indolin-3-yl]acetate (step 2, 930 mg, 2.2 mmol) in ethanol (20 ml) and 2N aqueous NaOH (10 ml) was heated at reflux temperature for 72 h. After cooling to room temperature, the resulting mixture was neutralized with 2N aqueous HCl (10 ml) and concentrated. The residue was diluted in dichloromethane/mehanol (10:1, 300 ml) and dried (MgSO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with dichloromethane/methanol (20:1) and then washed with i-PrOH (ca.20 ml) to give 120 mg (17%) of the title compound as a yellow powder.
Reaction SMILES: Br[CH2:2][C:3](=[O:6])[CH2:4][CH3:5].[C:7]([O-:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Na+].CN(C)C=O>C(OCC)C>[C:7]([O:15][CH2:2][C:3](=[O:6])[CH2:4][CH3:5])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])c1ccccc1
Reactant: CCC(=O)CBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC(=O)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 1-bromobutan-2-one (7.2 g, 47.7 mmol), sodium benzoate (7.56 g, 52.4 mmol), and N,N-dimethylformamide (72 ml) was stirred at room temperature for 3 hours and 45 minutes. Diethyl ether was added to the reaction mixture and the mixture was washed with water and a saturated saline solution, dried over magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure to obtain the title compound (9.5 g, quantitatively) as a light brown oil.
Reaction SMILES: Cl.[F:2][C:3]([F:28])([O:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:10][CH:9]=1)[CH:4]([F:6])[F:5]>O1CCOCC1>[F:28][C:3]([F:2])([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:26][CH:27]=1)[CH:4]([F:6])[F:5]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OC(F)(F)C(F)F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)C(F)(F)Oc1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4M HCl in dioxane (30 mL) was added to tert-butyl 4-[4-(1,1,2,2-tetrafluoroethoxy)phenoxy]piperidine-1-carboxylate (3.3 g). The mixture was stirred at ambient temperature for 30 minutes. The mixture was then concentrated at reduced pressure and triturated with diethyl ether. The resulting precipitate was filtered, washed with diethyl ether and dried under vacuum to give 4-[4-(1,1,2,2-tetrafluoroethoxy)phenoxy]piperidine as the hydrochloride salt (2.76 g); NMR Spectrum: (DMSOd6) 1.75-1.91 (m, 2H), 2.02-2.17 (m, 2H), 2.95-3.12 (m, 2H), 3.13-3.29 (m, 2H), 4.57-4.69 (m, 1H), 6.75 (tt, 1H), 7.06 (d, 2H), 7.19 (d, 2H), 8.95 (bs, 2H); Mass Spectrum: M+H+ 294.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13]CC2C=CC=CC=2)[CH2:10][CH:9]1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CC(OCc2ccccc2)CN1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CC1CC(O)CN1C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
The 4-benzyloxy-2-methyl-pyrrolidine-1-carboxylic acid t-butyl ester (168.57 mg, 0.58 mmol) was taken up in ethyl acetate in a Paar vessel. The solution was flushed with argon and Pd/C (100.00 mg) was added to the vessel. The argon atmosphere was replaced by hydrogen at 50 psi. The vessel was shaken for 12 h. The hydrogen atmosphere was replaced by argon and the solution was filtered through a celite pad. The pad was washed twice with ethyl acetate. The solvent was removed under reduced pressure. The product was used without further purification. Yield 110.89 mg. C10H19NO3 MS m/e=202.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH3:33][N:34]([CH2:36][C:37]1([OH:43])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH3:35]>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:40]5[CH2:41][CH2:42][C:37]([CH2:36][N:34]([CH3:35])[CH3:33])([OH:43])[CH2:38][CH2:39]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:30])([F:31])[F:32])[CH:3]=1
Reactant: CN(C)CC1(O)CCNCC1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(C)CC1(O)CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-dimethylaminomethyl-4-hydroxy-piperidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-Dimethylaminomethyl-piperidin-4-ol following General Procedure B.