Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]([O:14][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OC1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a round bottom flask, benzhydrol (1.84 g, 10 mmol, 1.0 eq.), 4-hydroxypiperidine (1.01 g, 10 mmol, 1.0 eq.), and p-toluenesulfonic acid monohydrate (2.09 g, 1.1 eq.) were suspended in toluene (400 ml). The mixture was refluxed with a Dean-Stark condenser for 3-4 hours. After cooling to room temperature, the solution was washed with 5% NaOH solution (2×20 ml), then with water (2×20 ml). The solution was then dried over anhydrous Na2SO4. The solvent was then removed under vacuum. The crude product, 4-benzhydryloxy-piperidine was obtained (2.46 g, 92.0% yield). 1H-NMR (CDCl3, ppm): 7.10-7.25 (m, 10H), 5.41 (s, 1H), 3.48 (m, 1H), 3.13 (m, 2H), 2.78 (m, 2), 1.86 (m, 2H), 1.66 (m, 2H). ESMS 268.1 (M+1), 290.1 (M+23).
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>O1CCCC1>[C:13]([CH2:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1)([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: Cn1nnnc1S
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Cn1nnnc1S
Reaction time: 0.67 h
Yield: 80.1 %

Procedure:
A solution of 1-methyl-1H-tetrazole-5-thiol (23 g) in dry tetrahydrofuran (80 ml) was added over 20 minutes with stirring under dry nitrogen atmosphere to a n-butyllithium (250 ml, 15% in hexane) solution in dry tetrahydrofuran (250 ml) precooled to -15° to -10° C. After stirring at the same temperature for 40 minutes, the mixture was cooled to -60°±5° C. and thereto was added dropwise a solution of diethyl oxalate (28.95 g) in dry tetrahydrofuran (80 ml) over 30 min. The reaction mixture was stirred at -60°±5° C. for 1.5 hours. 10% Aqueous hydrochloric acid (72 ml) was added with stirring and the separated aqueous layer (pH 7.5) was adjusted to pH 2.5 with 10% hydrochloric acid and extracted with ethyl acetate (200 ml×3). The combined extracts were dried over magnesium sulfate and evaporated to give oily residue of 1-ethoxalylmethyl-1H-tetrazole-5-thiol (34.3 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.O.[CH2:17](O)[CH3:18]>C1C=CC=CC=1>[OH:1][C:2]1[C:3]([C:8]([O:10][CH2:17][CH3:18])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1ncccc1O

Procedure:
3-Hydroxypicolinic acid (12.5 g, 900 mmol) was suspended in a mixture of ethanol (300 ml) and benzene (100 ml). Sulfuric acid (5 ml) was added and the reaction mixture was heated at reflux with azeotropic removal of water via Dean Stark trap. After the reaction was complete, the organics were removed in vacuo. The residue was dissolved in water, basified with sodium carbonate and extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, concentrated in vacuo to give ethyl 3-hydroxypicolinate (15 g).
Reaction SMILES: [CH:1]([O:3][CH2:4][F:5])=[O:2].[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7]>>[CH2:6]([N:8]([CH2:9][CH3:10])[C:1](=[O:2])[O:3][CH2:4][F:5])[CH3:7]
Reactant: O=COCF
Reactant: CCNCC
Product: CCN(CC)C(=O)OCF
Reaction time: 1 h

Procedure:
In a 100 mL PFA-flask, fluoromethyl formate (27.0 g, 245 mmol) is given. Diethylamine (50.5 mL; 0.490 mmol) is added dropwise at about 0° C. The mixture is stirred for 1 hour. Solids are filtered off, and the resulting liquid is subjected to a distillation to isolate pure fluoromethyl N,N-diethylcarbamate.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][CH:8]([NH:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:12])[CH:7]([OH:18])[CH2:6]1)=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[O:32])=[CH:22][C:21]=1[F:33]>>[F:33][C:21]1[CH:22]=[C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[O:32])[CH:24]=[CH:25][C:20]=1[NH:19][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:12])[C@@H:7]([OH:18])[CH2:6]1)=[O:4]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: COC(=O)C1CC(O)C(NC(=O)c2cccs2)C1
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1O)c1cccs1

Procedure:
In analogy to example 1C, 1R,3S,4S)-3-hydroxy-4-[(thiophene-2-carbonyl)-amino]-cyclo-pentanecarboxylic acid methyl ester was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) to give thiophene-2-carboxylic acid {(1S,2S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-hydroxy-cyclopentyl}-amide. Light yellow solid. MS: 442.1 ([M+H]+).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[OH:27])=[O:12])(=O)C.[OH-].[Na+].Cl>>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[OH:27])=[O:12]
Reactant: CC(=O)Oc1ccccc1C(=O)N[C@H]1CCN(Cc2ccccc2)C[C@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@H]1CCN(Cc2ccccc2)C[C@H]1O)c1ccccc1O
Temperature: 60 °C
Yield: 27 %

Procedure:
A mixture of 5 parts of cis-2-[3-hydroxy-1-(phenylmethyl)-4-piperidinylaminocarbonyl]phenol acetate (ester) and 30 parts of sodium hydroxide solution 1N was stirred and heated for four hours at 60° C. The reaction mixture was cooled to room temperature and neutralized with a hydrochloric acid solution 1N. The product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (85:15 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue solidified on triturating in 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.21 parts (27%) of cis-2-hydroxy-N-[3-hydroxy-1-(phenylmethyl)-4-piperidinyl]benzamide; mp. 127.1° C. (compound 235).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[NH:25][C:24]([C:26]([F:29])([F:28])[F:27])=[N:23][C:20]4=3)[O:15][CH2:14]2)(=O)=O)=CC=1.[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[C:34]2[C:40]1[CH2:41][CH2:42][NH:43][CH2:44][CH:45]=1>CS(C)=O.C(OCC)(=O)C>[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[C:34]2[C:40]1[CH2:41][CH2:42][N:43]([CH2:12][CH:13]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[NH:25][C:24]([C:26]([F:29])([F:28])[F:27])=[N:23][C:20]4=3)[O:15][CH2:14]2)[CH2:44][CH:45]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6[nH]c(C(F)(F)F)nc6c5O4)CC3)c2c1
Temperature: 85 °C
Yield: 79.4 %

Procedure:
A mixture of 0.50 g (1.2 mmole) of [(8R)-2-trifluoromethyl-7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl]methyl 4-methylbenzenesulfonate and 1.0 g (4.6 mmole) of 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 5.0 mL of DMSO was heated at 85° C. under nitrogen for 6 hours. The reaction was allowed to come to room temperature, diluted to 250 mL with ethyl acetate, washed with 250 mL portions of saturated aqueous sodium bicarbonate and water, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 1% methanol in chloroform as eluant and the product fractions concentrated in vacuum to give 0.45 g of the desired compound as the free base. Recrystallization from ethanol with the addition of 0.11 g of fumaric acid gave 0.25 g of the (S)-enantiomer of the title compound as a yellow solid hemifumarate, m.p. 236-238° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([N:40]2[CH2:39][CH2:38][N:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=3)[CH2:42][CH2:41]2)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: Cc1onc(-c2ccccc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4ccccc4F)noc3C)CC2)c1
Yield: 85.3 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(2-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (622 mg, 1.57 mmol, 86%) was obtained.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][NH:9][CH:10]=2)[CH2:5][CH2:4]1.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1>CN(C)C=O.[Cl-].[Na+].O>[CH:3]1([C:6]2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][N:9]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH2:4][CH2:5]1
Reactant: Clc1ccnc2ccccc12
Reactant: COC(=O)c1c[nH]cc1C1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)cc1C1CC1
Temperature: 40 °C
Reaction time: 0.3 h

Procedure:
0.208 g (6.5 mmol) of sodium hydride at 75% by weight in liquid petroleum jelly is added to a solution of 1.07 g (6.5 mmol) of 4-cyclopropyl-3-methoxycarbonyl-1H-pyrrole in 20 mL of dimethylformamide at a temperature in the region of 20° C. under an argon atmosphere. After the reaction mixture has been stirred at a temperature in the region of 40° C. for 0.3 hour, 1.07 g (6.5 mmol) of 4-chloroquinoline and 10 mL of dimethylformamide are added. After stirring for 6 hours at a temperature in the region of 120° C., the reaction mixture is poured into 200 mL of brine and then extracted with 100 mL and then 50 mL of ethyl acetate. The organic extracts are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The oily residue is purified by chromatography on silica gel [eluent: dichloromethane/ethyl acetate (75/25 by volume)]. After the fractions containing the expected product have been concentrated to dryness under reduced pressure (2.7 kPa), 1.2 g of 4-cyclopropyl-3-methoxycarbonyl-1-(quinolin-4-yl)-1H-pyrrole are obtained in the form of a thick clear oil, which is used directly in the following step.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([F:18])=[C:4](F)[C:3]=1F.[CH2:21]([C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH3:31])[C:24]=1[NH2:25])[CH3:22]>>[CH2:21]([C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH3:31])[C:24]=1[NH:25][C:4]1[C:3]([NH:25][C:24]2[C:26]([CH2:30][CH3:31])=[CH:27][CH:28]=[CH:29][C:23]=2[CH2:21][CH3:22])=[C:2]([F:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]=1[F:18])[CH3:22]
Reactant: CCc1cccc(CC)c1N
Reactant: O=C1c2ccccc2C(=O)c2c(F)c(F)c(F)c(F)c21
Product: CCc1cccc(CC)c1Nc1c(F)c2c(c(F)c1Nc1c(CC)cccc1CC)C(=O)c1ccccc1C2=O
Reaction time: 8 h
Yield: 74.6 %

Procedure:
2 g of 1,2,3,4-Tetrafluoroanthraquinone and 25 g of 2,6-diethylaniline were charged in a 50 cc, four necked flask and the reaction was carried out at 160° C. for about 8 hours. After completion of reaction, 2,6-diethylaniline was distilled out from the reaction solution and then a column purification using a column with a silica gel was effected to give rise to 2.87 g of 2,3-bis(2,6-diethylanilino)-1,4-difluoroanthraquinone (Dye 23') (yield 74.6 mol %). The physical properties of Dye 23' and analytical values defining the compound are tabulated in table 24.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:18]([C:20](=[O:22])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.N12CCN(CC1)CC2.O>ClCCl>[CH3:1][C:2]1[N:3]([CH:18]([CH:20]([O:22][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC(C)C(C)n2c(C)c(C(=O)OC(C)(C)C)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a mixture of tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H-indole-3-carboxylate (1.1 g, 3.6 mmol) in dichloromethane (4 mL) were added 4-methylbenzene-1-sulfonyl chloride (1.3 g, 7.2 mmol), and 1,4-diazabicyclo[2.2.2]octane (1.2 g, 10.8 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was added to water (30 mL). The aqueous layers was extracted with dichloromethane (10 mL×3). The combined organic layers was dried over sodium sulfate and concentrate to afford tert-butyl 2-methyl-1-(3-(tosyloxy)butan-2-yl)-1H-indole-3-carboxylate (1.6 g, yield: 96%) as a yellow oil. LRMS (M+H+) m/z: calcd 457.19. found 458.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].[H][H].CCCCCCC>C(O)(=O)C.[Ni]>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[CH:23]1[CH:14]([CH2:15][C:16]2[C:21]([NH:22]1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11]
Reactant: [H][H]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: [Ni]
Solvent: CCCCCCC
Solvent: CC(=O)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CC2Cc3ccccc3NC12
Temperature: 110 °C
Yield: 95.7 %

Procedure:
In a 350 mL high pressure autoclave, 6 g (17.2 mmol) of camptothecin was suspended in 60 mL of acetic acid, and into which 2.4 g of stabilized nickel catalyst (N113) was added. After substituting the atmosphere in the autoclave with hydrogen, the suspension was heated at 110° C. under 2.0 MPa for 3 hours with stirring, whereat the starting material disappeared. The reaction liquid was cooled off to room temperature, filtered on 3 g of Celite and washed with 30 mL of acetic acid. The filtrate was washed with heptane (once with 80 mL and twice with 60 mL each), extracted with 60 mL of chloroform, and the organic layer was washed successively with 30 mL of water and 30 mL of saturated saline. The organic layer was dried over 2 g of magnesium sulfate, filtered and concentrated. To the resulting orange colored oil, 10 mL of chloroform was added and heated at 35° C. to form a homogeneous solution. Upon adding thereto 10 mL of heptane, a precipitate was formed. Distilling the solvent off under reduced pressure and drying the residue, 5.8 g of 1,2,6,7-tetrahydrocamptothecin was obtained as an orange colored powder (yield: 96.8%, in which the diastereoisomeric ratio* was 21:76).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH:10][C:27]([C:24]2([C:22]3[CH:21]=[CH:20][C:19]4[O:15][CH2:16][O:17][C:18]=4[CH:23]=3)[CH2:26][CH2:25]2)=[O:28])=[N:7][CH:6]=1
Reactant: Nc1ncc(Cc2ccccc2Cl)s1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 16 h
Yield: 9.8 %

Procedure:
5-(2-Chloro-benzyl)-thiazol-2-ylamine (22 mg, 0.10 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (22 mg, 0.10 mmol) were dissolved in acetonitrile (1.5 mL) containing triethylamine (42 L, 0.30 mmol). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 49 mg, 0.11 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography to yield the pure product (4.1 mg, 0.0098 mmol, 9.8%). ESI-MS m/z calc. 412.1. found; 413.3 (M+1)+ Retention time 3.12 minutes.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:19])([F:18])[C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:28](#[N:32])[CH2:29][C:30]#[N:31].Cl>CS(C)=O>[F:18][C:8]([F:19])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:7][C:29]([CH2:7][C:8]([F:18])([F:19])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:12])[F:13])([C:28]#[N:32])[C:30]#[N:31]
Reactant: N#CCC#N
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CC(F)(F)C(F)(F)C(F)(F)C(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 1.3 %

Procedure:
14.6 g of 2,2,3,3,4,4,5,5-octafluoropentyl trifluoromethanesulfonate was dissolved in 30 ml of dimethyl sulfoxide, and 5.5 g of potassium carbonate was added. Further, 2.6 g of malononitrile dissolved in 10 ml of dimethyl sulfoxide was added dropwise, and the mixture was stirred at room temperature for 3 hours. Further, 7.0 g of 2,2,3,3,4,4,5,5-octafluoropentyl trifluoromethanesulfonate and 2.7 g of potassium carbonate were added, and the mixture was stirred for 1 hour. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. The resulting fraction was concentrated and washed with chloroform to obtain 0.13 g of 2,2-bis(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (49)).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:33])[O:5][C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[C:15]1([NH:29][C:30](=[O:32])[CH3:31])[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[N+:25]([O-])=O)[C:16]1=[O:28])[CH3:2].Cl>C(O)C.O.[Fe]>[CH2:1]([NH:3][C:4](=[O:33])[O:5][C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[C:15]1([NH:29][C:30](=[O:32])[CH3:31])[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH2:25])[C:16]1=[O:28])[CH3:2]
Reactant: CCNC(=O)Oc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCNC(=O)Oc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2cccc(N)c2C1=O
Yield: 36 %

Procedure:
2-(2-acetamido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl ethylcarbamate (0.27 g, 0.59 mmol) was dissolved in Ethanol (10 ml) and water (1 ml). This solution was added with iron (0.24 g, 4.3 mmol) and conc. HCl (0.03 ml). The reaction mixture was heated for 2 hrs under reflux. After filtrating and washing with MeOH, the remainder was concentrated in a vacuum and purified using column chromatography (ethylacetate:hexane=1:1) to afford the title compound (90 mg, 36%).
Reaction SMILES: [C:1]([C:4]1[C:5](F)=[C:6]([F:22])[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=O)[CH3:2].[NH2:24][NH2:25]>CN(C=O)C>[CH3:12][O:11][C:9]([C:8]1[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:6]([F:22])[C:5]2[C:4](=[C:1]([CH3:2])[NH:24][N:25]=2)[CH:13]=1)=[O:10]
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1F
Reactant: NN
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(C)[nH]nc2c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 150.5 %

Procedure:
To a solution of methyl 5-acetyl-2-(2-fluorophenylamino)-3,4-difluorobenzoate (500 mg, 1.55 mmol, from step D in example 3) in DMF (10 ml) was added hydrazine (0.06 mL, 185 mmol). After stirring at room temperature for 16 h, the reaction was quenched with NH4Cl solution and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford 740 mg (75%) of the title compound.
Reaction SMILES: [OH:1][C:2]([CH2:4][C:5]1([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14])=[O:3].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[Na+]>CS(C)=O>[CH2:28]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][C:2]([OH:1])=[O:3])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:6]1=[O:14])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1ccc(NC(=O)NC2(CC(=O)O)C(=O)Nc3ccccc32)cc1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)NC2(CC(=O)O)C(=O)N(Cc3ccccc3)c3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 0.404 g of (RS)-3-(hydroxycarbonylmethyl)-3-(N′-(4-methylphenyl)ureido)indolin-2-one in 20 ml of dry dimethyl sulfoxide was added 2.5 ml of a 1M solution of sodium hydride in dry dimethyl sulfoxide at room temperature under a nitrogen atmosphere. After stirring the mixture for 15 minutes, 0.19 ml of benzyl bromide was added thereto, followed by stirring at the same temperature for 30 minutes. The reaction mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl ether. The ethyl ether layer was dried over anhydrous magnesium sulfate and concentrated to give (RS)-1-benzyl-3-(hydroxycarbonylmethyl)-3-(N′-(4-methylphenyl)ureido)indolin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.I[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:25]([N:17]1[C:18]2=[N:19][CH:20]=[N:21][C:22]([NH2:24])=[C:23]2[C:15]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=2[O:2][CH3:1])=[N:16]1)([CH3:27])[CH3:26]
Reactant: COc1cccc(B(O)O)c1OC
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1cccc(-c2nn(C(C)C)c3ncnc(N)c23)c1OC
Temperature: 80 °C
Yield: 87.4 %

Procedure:
A solution 2,3-dimethoxyphenylboronic acid (105 mg, 0.58 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (70 mg, 0.23 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by silica gel column chromatography [MeOH—CH2Cl2, 2:98] to yield BA65 (63 mg, 88% yield). ESI-MS (M+H)+ m/z calcd 314.1, found 314.1.