Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CB(O)O.[C:5]([O-])([O-])=O.[K+].[K+].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([N+:32]([O-:34])=[O:33])[C:23]=1OS(C(F)(F)F)(=O)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1.O.CCOC(C)=O.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH3:5][C:23]1[C:22]([N+:32]([O-:34])=[O:33])=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][C:13]=1[O:12][CH3:11]
Reactant: CCOC(=O)c1cc(OC)c(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB(O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(OC)c(C)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a stirred solution of 4.92 g of MeB(OH)2, 33.9 g of K2CO3, 25.6 g of ethyl 3-methoxy-5-nitro-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate in 500 ml of THF and 50 ml of water was added 5.03 g of PdCl2 dppf and the mixture was stirred under argon atmosphere at 80° C. overnight. The mixture was diluted with AcOEt and water, filtered through Celite and the filtrate was extracted with AcOEt. The extract was washed successively with saturated NaCO3aq and saturated brine, dried over Na2SO4, and concentrated. The residue was purified on SiO2 column chromatography and the fractions containing the intended compound were concentrated. The resulting solid was washed with n-hexane and dried to give 12.9 g of the intended compound as a yellow solid.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:8]([CH:12]=O)=[N:9][NH:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH2:24])[C:19]([NH2:23])=[CH:20][C:21]=1[CH3:22]>ClCCl.CO>[CH:1]([NH:4][C:5]([C:7]1[C:8]([C:12]2[NH:23][C:19]3[CH:20]=[C:21]([CH3:22])[C:16]([O:15][CH3:14])=[CH:17][C:18]=3[N:24]=2)=[N:9][NH:10][CH:11]=1)=[O:6])([CH3:2])[CH3:3]
Reactant: COc1cc(N)c(N)cc1C
Reactant: CC(C)NC(=O)c1c[nH]nc1C=O
Solvent: CO
Solvent: ClCCl
Product: COc1cc2nc(-c3n[nH]cc3C(=O)NC(C)C)[nH]c2cc1C

Procedure:
By proceeding in a manner similar to Example 235(a) above but using 3-formyl-pyrazole-4-carboxylic acid-isopropylamide [198 mg, Reference Example 60)] and 4-methoxy-5-methyl-benzene-1,2-diamine [166 mg, Reference Example 29(b)] and subjecting the reaction product to flash chromatography on silica eluting with dichloromethane/methanol (95:5) followed by recrystallisation from a mixture of ethyl acetate and n-pentane there was prepared 3-(5-methoxy-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide (145 mg) as a white solid. LC-MS (Method H): RT=2.09 minutes, 314.27 (M+H)+, 312.29 (M−H)−.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O>CN(C=O)C>[S:14]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3cccnc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde (16.7 g, 114 mmol) in DMF (150 mL) was added to a chilled (0° C.) mixture of dry DMF (300 mL) and sodium hydride (4.88 g, 122 mmol, 60% dispersion in mineral oil). This was stirred at 0° C. for 30 minutes, and a DMF solution (100 mL) of tosyl chloride (21.8 g, 114 mmol) was then added slowly over a ten minute period. The mixture was then allowed to warm to room temperature and stirred for 3 hours. Water (500 mL) was then added, and the solids were collected to give 1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (29.7 g, 87%). 1H NMR (400 MHz, d6-DMSO) δ 10.07 (s, 1H), 8.43-8.49 (m, 2H), 8.08-8.13 (m, 2H), 7.44-7.50 (m, 3H), 2.37 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>ClCCl>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3ccccc3C2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2ccccc2CN1C1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.58 mmol) in dichloromethane (15 mL) was added trifluoro-acetic acid (3.0 mL) and the reaction mixture stirred at ambient temperature during 4 h. The solvent was removed under reduced pressure and the crude product (0.710 g) used in the consecutive step without further purification assuming quantitative deprotection and formation of the trifluoroacetate salt. MS (ISP): 217.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:17]([O-])=O)[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:17])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1Cc2ccc(N)cc2C1
Reaction time: 2 h

Procedure:
A solution of (5-nitro-indan-2-yl)-carbamic acid tert-butyl ester (3.52 g, 12.6 mmol) in ethanol (100 mL) is degassed and 10% palladium on carbon added. The reaction is evacuated and placed under 1 atm H2(g) for 2 h. Filtration of the reaction mixture through Celite is followed by concentration of the filtrate under reduced pressure to give (5-amino-indan-2-yl)-carbamic acid tert-butyl ester as an oil which is used directly without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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>[Br:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Brc1cncc(Br)n1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Brc1cncc(-c2ccccc2)n1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 2,6-dibromo-pyrazine and phenylboronic acid. Additionally, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:6]=1
Reactant: OCCCC#Cc1ccc(-c2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: OCCCCCc1ccc(-c2ccccc2)cc1
Reaction time: 4 h
Yield: 88 %

Procedure:
5-(1,1′-biphenyl-4-yl)-4-pentyn-1-ol (3.89 g, 16.46 mmol) was dissolved in methanol (30 mL), and 10% Pd/C (2.5% w/w) was added. The resulting mixture was hydrogenated on a Parr hydrogenation apparatus (45 psi) for 4 hrs. The catalyst was removed by filtration through a Celite pad. The filter cake was rinsed with methanol, and the combined organic liquors were concentrated under reduced pressure. The crude product was purified by column chromatography (hexanes:ethyl acetate 1:1) to afford 3.48 g of the title compound. Yield: 88%. 1H NMR (300 MHz, CDCl3) δ 1.35-1.48 (m, 3H), 1.55-1.74 (m, 4H), 2.66 (t, J=7.5 Hz, 2H), 3.64 (t, J=6.6 Hz, 2H), 7.21-7.60 (m, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ 25.7, 31.5, 32.9, 35.8, 63.1, 127.08, 127.13, 128.8, 128.9, 138.7, 141.2, 141.8 ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][C:23]1[CH:27]=[CH:26][O:25][CH:24]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccoc1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Product: CCOC(=O)N1CCC(c2cn(Cc3ccoc3)c3ncccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 24, part C, starting with 3 g (11 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1 carboxylic acid ethyl ester and 20 ml of a 0.6M solution of 3-bromomethylfuran freshly prepared. After standard work-up, 4.44 g of 4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][OH:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C1([Se](O)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH:17]=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc2c(c1)ncn2-c1cccc(Br)c1
Agent: O=[Se](O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Temperature: 70 °C

Procedure:
A mixture of 27 from Example 6 (3.9 g, 12.9 mmol) and benzeneseleninic acid (3.04 g, 16.1 mmol) in toluene is stirred at 70° C. over night. The product precipitates upon cooling. The precipitate is filtered off, washed with petroleum ether and dried. Subsequent washings with aqueous sodium carbonate and water affords pure 28. Yield: 2.99 g (77%). Mp 179-181° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[NH2:8][OH:9]>>[OH:9]/[N:8]=[C:6](\[NH2:7])/[CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: NO
Reactant: COCCCC#N
Product: COCCC/C(N)=N/O

Procedure:
In analogy to the procedure described for example D28 4-methoxybutanenitrile (3.1 g) and hydroxylamine (2.07 g, 50 wt % in water) yield the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:21]3[C:20](=[O:28])[N:19]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:18](=[O:37])[N:17](COC(=O)C(C)(C)C)[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>O1CCCC1.CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[C:25]([CH3:26])[CH3:27])[C:21]3[C:20](=[O:28])[N:19]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:18](=[O:37])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
4-[1,3-Bis(2,2-dimethylpropionyloxymethyl)-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (277 mg) was dissolved in a solvent mixture of tetrahydrofuran (3 ml) and methanol (6 ml), sodium hydride (21 mg) was added to the solution, and the mixture was stirred at room temperature for 1 hour and 10 minutes. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation from the organic layer to give 214 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:10](=[O:27])[C:11]3[CH:16]=[N:15][N:14]([C:17]4[CH:18]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH3:35][C:36](=O)[CH2:37][CH2:38][C:39](=O)[CH3:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:10](=[O:27])[C:11]3[CH:16]=[N:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([N:26]5[C:39]([CH3:40])=[CH:38][CH:37]=[C:36]5[CH3:35])(=[O:24])=[O:25])[CH:18]=4)[C:12]=3[N:13]=2)=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C)n1S(=O)(=O)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1

Procedure:
A mixture of 3-[6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzene sulfonamide (prepared as described in example 6, 10.00 g, 17.95 mmol), hexane-2,5-dione (6.14 g, 53.9 mmol), and p-toluenesulfonic acid monohydrate (1.000 g, 5.257 mmol) in dry toluene (250 mL) is heated to reflux in a Dean-Stark apparatus for 18 h. The reaction mixture is concentrated and the residue obtained is stirred in ethyl acetate and filtered. About 7.1 g of starting material is recovered. Concentration of the filtrate afforded the crude product. It is then purified by column chromatography (silica gel, 60-120 mesh) to afford the 6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-1-[3-(2,5-dimethyl-pyrrole-1-sulfonyl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:5](=N/S(C2SC=CC=2)(=O)=O)/[CH:4]=[C:3]1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].ClC1C(=O)C2C(=CC=CC=2)/C(=N/S(C2SC=CC=2)(=O)=O)/C=1.CCOC(C)=O.[N+:55]([C:58]1[CH:63]=[CH:62][C:61]([S:64]([NH2:67])(=[O:66])=[O:65])=[CH:60][CH:59]=1)([O-:57])=[O:56]>ClCCCl>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:67][S:64]([C:61]2[CH:60]=[CH:59][C:58]([N+:55]([O-:57])=[O:56])=[CH:63][CH:62]=2)(=[O:65])=[O:66])=[CH:4][C:3]=1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CSC1=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc2C1=O
Agent: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CSc1cc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2c1O

Procedure:
5.2.25 Ethyl 2-(1-hydroxy-4-(4-nitrophenylsulfonamido)naphthalen-2-ylthio)acetate (9e) was prepared according to the procedure for 8a except using 4-nitrobenzenesulfonamide, 1,2-dichloroethane as solvent and applying 100° C. to the reaction. The reaction was worked up according to the procedure for 12a and the title compound was isolated from the product mixture by flash chromatography (EtOAc/Hex) affording 48 mg (10.4%) as a brown solid, m.p.: 143-145° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]/[C:14](=[C:21]2\[C:22](=[O:40])[NH:23][C:24]3[C:29]\2=[CH:28][C:27]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[CH:26][CH:25]=3)/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=[O:5])C.[OH-].[Na+]>CO.ClCCl>[C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]/[C:14](=[C:21]2\[C:22](=[O:40])[NH:23][C:24]3[C:29]\2=[CH:28][C:27]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[CH:26][CH:25]=3)/[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][CH:8]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)Cc1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
720 mg (1.3 mmol) of (Z)-3-[1-(4-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone are dissolved in a mixture of 20 ml of methanol and 20 ml of dichloromethane. 4 ml of 1 N sodium hydroxide solution are added and the mixture is stirred for 18 hours at ambient temperature and for another 1 hour at 40° C. The reaction solution is evaporated down to half the volume and the pH is adjusted to 4-5 with 1 N hydrochloric acid. The precipitate formed is suction filtered, washed with water, a little isopropanol and ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:22][OH:23])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH3:10]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH3:10])[CH:22]=[O:23]
Reactant: CCCN(CCC)CCCCN(C)Cc1ccc(CO)cc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)CCCCN(C)Cc1ccc(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 22 h
Yield: 88.7 %

Procedure:
The compound (290.8 mg) obtained in Example 77-4 was dissolved in chloroform (6 ml). The reaction solution was added with manganese dioxide (1.4331 g) and the whole was stirred at room temperature for 22 hours. The catalyst was filtrated out through Celite. The filtrate was concentrated under reduced pressure, thereby obtaining the subject compound (256.4 mg) as a colorless oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][C:9]([CH:12]=O)=[CH:10][N:11]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][C:9]([CH2:12][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]2)=[CH:10][N:11]=1
Reactant: OCC1CCNCC1
Reactant: O=Cc1cnc(-c2ccccn2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: OCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
The compound prepared in Example 139 (0.569 g), piperidin-4-ylmethanol (0.689 g) and sodium triacetoxyborohydride (1.902 g) were suspended in 1,2-dichloroethane (15 mL) and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution, ammonium chloride solution and brine. The organics were then dried over magnesium sulfate, filtered and concentrated under reduced pressure and to afford the crude material, which was purified by flash column chromatography (eluant: 10% (9:1 methanol/concentrated ammonium hydroxide)/ethyl acetate) to furnish the title compound (0.571 g) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:9](O)=[O:10])=[N:6][C:7]=1[CH3:8].S(Cl)(Cl)=O>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:9][OH:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C(=O)O)cnc1Cl
Solvent: O=S(Cl)Cl
Product: Cc1nc(CO)cnc1Cl
Reaction time: 3 h
Yield: 67.1 %

Procedure:
1H-NMR (300 MHz, DMSO-d6) δ 1.48-1.74 (6H, m), 1.92-2.04 (1H, m), 2.23-2.36 (1H, m), 3.09-3.64(5H, m), 3.89-4.00 (1H, m), 4.52-4.63 (1H, m), 4.88 (1H, brs), 6.23 (1H, d, J=16 Hz), 6.51-6.62 (4H, m), 7.12-7.19 (2H, m), 7.32-7.41 (2H, m), 7.59-7.66 (1H, m), 8.20(1H, brs), 11.1 (1H, brs). MS (ES+) m/z 409 (M+1). Preparation 505 i) A mixture of 5-chloro-6-methyl-2-pyrazinecarboxylic acid (3.83 g) and thionyl chloride (8.09 mL) was stirred for 3 hours at reflux. After cooling, the reaction mixture was evaporated in vacuo. ii) To a suspension of sodium borohydride (2.52 g) in H2O (110 mL) was added above product in dioxane (10 mL) at 10° C. After stirring for 1 hours at 10° C., the reaction mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo to give (5-chloro-6-methyl-2-pyrazinyl)methanol (2.36 g). 1H-NMR (300 MHz, CDCl3) δ 2.67 (3H, s), 2.86-2.95 (1H, m), 4.79 (2H, d, J=3 Hz), 8.25 (1H, s). MS (ES+) m/z 159 (M+1). Preparation 506 1) To a mixture of (5-chloro-6-methyl-2-pyrazinyl)methanol (2.35 g), ethyl acetate (50 mL), and dioxane (25 mL) was added manganese(IV) oxide (12.9 g). After stirring for 2 hours at reflux, a resulting precipitate was filtered and the filtrate was evaporated in vacuo. 2) To a mixture of above product and THF (50 mL) was added (carbethoxymethylene)triphenylphosphorane (6.19 g). The reaction mixture was stirred for 6 hours at room temperature, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-chloro-6-methyl-2-pyrazinyl)acrylate (863 mg). 1H-NMR (300 MHz, CDCl3) δ 1.35 (3H, t, J=7 Hz), 2.68 (3H, s), 4.29 (2H, q, J=7 Hz), 7.01 (1H, d, J=16 Hz), 7.63 (1H, d, J=16 Hz), 8.26 (1H, s). MS (ES+) m/z 227 (M+1). Preparation 507 1) To a mixture of 6-chloro-3-pyridazinecarbaldehyde (300 mg) and THF (6 mL) was added (carbethoxymethylene)triphenylphosphorane (805 mg). The reaction mixture was stirred for 2 hours at room temperature, and evaporated in vacuo. 2) To a mixture of above product and DMF (10 mL) was added (3R)-1-benzyl-3-pyrrolidinamine (556 mg) and Et3N (0.880 mL). After stirring for 5-hours at 100° C., the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridazinyl)acrylate (237 mg). 1H-NMR (300 MHz, CDCl3) δ 1.33 (3H, t, J=7 Hz), 1.60-1.79 (1H, m), 2.25-2.94 (5H, m), 3.63-3.66 (2H, m), 4.27 (2H, q, J=7 Hz), 4.48-4.60 (1H, m), 5.17-5.23 (1H, m), 6.59 (1H, d, J=9 Hz), 6.61 (1H, d, J=16 Hz), 7.25-7.38 (6H, m), 7.78 (1H, d, J=16 Hz). MS (ES+) m/z 353 (M+1). Preparation 508
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[O:19][CH3:20].[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:36])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1>>[CH3:18][O:17][CH:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28](=[O:36])[CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:27]=2)=[C:7]([O:19][CH3:20])[CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: COc1cc(CC(OC)C(=O)O)ccc1OCCCBr
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Product: COc1cc(CC(OC)C(=O)O)ccc1OCCCOc1ccc(C(=O)Cc2ccccc2)cc1

Procedure:
The title compound was prepared from 3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid (Example 175, Step B) and 1-(4-Hydroxy-phenyl)-2-phenyl-ethanone following the Standard Procedure J. MS (ES) for C28H30O7 [M+H]+: 479.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][NH2:12].C=O.[C:15](O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:10][CH2:11][NH:12][CH2:15]2
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cccc(CCN)c1F
Agent: C=O
Solvent: ClCCl
Product: COc1ccc2c(c1F)CCNC2
Temperature: 25 °C

Procedure:
To 1.0 g (5.9 mmol) 2-(2-fluoro-3-methoxy-phenyl)-ethylamine and 0.66 mL (8.9 mmol) formaldehyde (37% solution in water) in 10 mL DCM are added slowly 0.91 mL (12 mmol) TFA and the resulting mixture is stirred at r.t. over night. The reaction mixture is purified by HPLC (ACN/H2O/NH4OH).