Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Cl:3])=[CH2:2].S(OOS([O-])(=O)=O)([O-])(=O)=[O:5].[K+:14].[K+].[CH2:16]([O:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[Na:38]>O>[CH:1]([Cl:3])=[CH2:2].[CH2:16]([O:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[Na:38].[C:16]([O-:28])(=[O:5])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[K+:14]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: C=CCl
Agent: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: [K+]
Solvent: O
Product: CCCCCCCCCCCC(=O)[O-]
Temperature: 66 °C

Procedure:
A 2.5-L autoclave was charged with 830 g of deionized water, 750 g of vinyl chloride monomer, 6.8 g of 3 wt % potassium persulfate, and 75 g of an aqueous sodium dodecylbenzenesulfonate solution having a concentration of 5 wt % (0.50 parts by weight based on the monomer), and by raising the temperature to 66° C., emulsion polymerization was initiated. The temperature was kept at 66° C. and when 60 minutes passed after the initiation of polymerization, 270 g of an aqueous sodium dodecylbenzenesulfonate solution having a concentration of 5 wt % (1.80 parts by weight based on the monomer) was continuously added over 360 minutes. After the pressure in the autoclave at 66° C. was reduced to 0.7 MPa, unreacted vinyl chloride monomer was recovered and to the residue, 45 g of an aqueous potassium laurate solution having a concentration of 5 wt % (0.30 parts by weight based on the monomer) was additionally added to obtain a vinyl chloride resin latex (amounts of sodium dodecylbenzenesulfonate and potassium laurate, per 100 parts by weight of vinyl chloride homopolymer: 2.56 parts by weight and 0.33 parts by weight, respectively). The average particle diameter was measured and found to be 0.1 μm.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C@H:12]([NH:14][C:15]1[C:16]2[N:17]=[CH:18][N:19]([C:29]=2[N:30]=[C:31](Br)[N:32]=1)[C@@H:20]1[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:21]1[OH:22])[CH3:13].[CH2:34]([NH2:36])[CH3:35]>O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C@H:12]([NH:14][C:15]1[C:16]2[N:17]=[CH:18][N:19]([C:29]=2[N:30]=[C:31]([NH:36][CH2:34][CH3:35])[N:32]=1)[C@@H:20]1[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:21]1[OH:22])[CH3:13]
Reactant: C[C@H](CSc1nc2ccccc2s1)Nc1nc(Br)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CCN
Solvent: C1COCCO1
Product: CCNc1nc(N[C@H](C)CSc2nc3ccccc3s2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
The title compound was prepared according to general method B by reaction of N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-bromoadenosine (Example 7) (0.24 g, 0.35 mmol) with 70% w/w aqueous ethylamine (0.23 g) in dioxan (10ml) in a sealed vessel at 100° C. to provide the desired N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-(ethylamino)adenosine as a foam (following column chromatography), 1H NMR (DMSO-d6) δ 1.04 (3H, br t, --NCH2CH3), 1.42 (3H, d, --CHCH3), 3.20 (3H, br m, --NCH2CH3), 3.55-3.80 (4H, m, H-5'a and H-5'b and --CH2 --), 3.95 (1H, q H-4'), 4.15 (1H, q, H-3'), 5.16, 5.41 (2H, 2d, 2'- and 3'-OH), 5.79 (1H, d, H-1'), 6.22 (1H, t, --NHCH2CH3), 7.43, 7.54 (2H, 2 t, Ar-H), 7.98 (1H, s, H-8). HPLC retention time 17.0 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.[I:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[N:24][C:25]=2[NH:27]C(=O)OC(C)(C)C)[N:20]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][CH3:42])=[CH:37][N:36]=2)[N:19]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[NH2:27][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:20]([C:35]3[N:36]=[CH:37][C:38]([N:41]([CH3:42])[C:7](=[O:8])/[CH:6]=[CH:5]/[CH2:4][N:3]([CH3:10])[CH3:2])=[CH:39][CH:40]=3)[N:19]=[C:18]([I:17])[C:26]=12
Reactant: CN(C)C/C=C/C(=O)O
Reactant: CNc1ccc(-n2nc(I)c3c(NC(=O)OC(C)(C)C)ncnc32)nc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C/C=C/C(=O)N(C)c1ccc(-n2nc(I)c3c(N)ncnc32)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a suspension of (E)-4-(dimethylamino)but-2-enoic acid (5) (185 mg, 1.12 mmol) and a drop of DMF in dry DCM (3 mL) was added oxalyl dichloride (427 mg, 3.36 mmol) slowly. The mixture was stirred at room temperature for 2 h and the solvent was removed in vacuo. The freshly generated acid chloride was dissolved in dry DCM (5 mL) and was added dropwise into a solution of tert-butyl 3-iodo-1-(5-(methylamino)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (64) (400 mg, 0.86 mmol) in DCM (8 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 h. TFA (2 mL) was introduced and the reaction mixture was stirred for 5 h. The solvent was removed and the residue was purified by column chromatography (silica gel, 0 to 7% methanol in dichloromethane) to provide (E)-N-(6-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridin-3-yl)-4-(dimethylamino)-N-methylbut-2-enamide (65) (300 mg, 73%) as a white solid. LC-MS (ESI): m/z (M+1) 479.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH:20][S:32]([CH3:31])(=[O:34])=[O:33])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(N)c3)c2)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(NS(C)(=O)=O)c3)c2)n1
Yield: 29.4 %

Procedure:
To a stirred and cooled solution of 3-[6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl-2′-yl]-phenylamine (example 307) (0.200 g, 0.493 mmol) in EtOAc (2 mL) and sat. NaHCO3-sol. (1 mL) was added methanesulfonyl chloride (1.0 mL, 13.6 mmol) and the mixture was stirred at 23° C. for 2 h. Diluted with EtOAc, washed with sat. NaHCO3-sol. and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with EtOAc, followed by trituration with diethyl ether to give the title compound as a white solid (0.070 g, 29%). MS (ISP) 484.4 [(M+H)+]; mp 196° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(N(CC)CC)C.[C:25]([N:29]=[C:30]=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:30]([NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(C)N=C=O
Reactant: Brc1cnc2ccc(NC[C@@H]3CCCN3)nn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CCC[C@H]1CNc1ccc2ncc(Br)n2n1
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of (S)-3-bromo-N-(pyrrolidin-2-ylmethyl)imidazo[1,2-b]pyridazin-6-amine (400 mg, 1.2 mmol) and triethylamine (0.5 mL, 3.5 mmol) in DCM (10 mL) was added t-butyl isocyanate (0.2 mL, 1.75 mmol) dropwise. After stirring at it for 2 h, the reaction mixture was concentrated and purified by ISCO column chromatography (10% MeOH/DCM) to give (S)-2-(((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)methyl)-N-(tert-butyl)pyrrolidine-1-carboxamide (360 mg, 76% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.58 (d, J=9.60 Hz, 1H), 7.42 (s, 1H), 6.72 (d, J=9.85 Hz, 1H), 5.07 (s, 1H), 4.26 (dd, J=6.57, 1.77 Hz, 1H), 3.35-3.48 (m, 4H), 2.09-2.20 (m, 1H), 1.90-2.05 (m, 3H), 1.26 (s, 9H); LRMS (ESI) m/e 395.2 [(M+H)+, calcd for C16H24BrN6O 396.3].
Reaction SMILES: [Na].[Na].[Na].S(C1C=C(P(C2C=CC=C(S(O)(=O)=O)C=2)C2C=CC=C(S(O)(=O)=O)C=2)C=CC=1)(O)(=O)=O.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[C:45]([F:48])([F:47])[F:46].Br[C:50]1[CH:51]=[CH:52][C:53]([CH2:68][CH3:69])=[C:54]([CH:56]2[C:61](=[O:62])[C:60]([CH3:64])([CH3:63])[O:59][C:58]([CH3:66])([CH3:65])[C:57]2=[O:67])[CH:55]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:50]2[CH:51]=[CH:52][C:53]([CH2:68][CH3:69])=[C:54]([CH:56]3[C:61](=[O:62])[C:60]([CH3:64])([CH3:63])[O:59][C:58]([CH3:66])([CH3:65])[C:57]3=[O:67])[CH:55]=2)=[CH:38][C:37]=1[C:45]([F:48])([F:47])[F:46]
Reactant: CCc1ccc(Br)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 160 °C
Reaction time: 0.08 h
Yield: 53.5 %

Procedure:
To a microwave vial is added palladium(II) acetate (3.3 mg, 0.015 mmol), tris(3-sulfophenyl)phosphine trisodium salt (22 mg, 0.038 mmol), 4-chloro-3-trifluoromethylphenyl boronic acid (0.200 g, 0.89 mmol), 4-(5-bromo-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.208 g, 0.59 mmol) and potassium phosphate (0.625 g, 2.95 mmol). A degassed mixed solution of acetonitrile/distilled water (1.5 ml, 1:1 ratio) is next added (washing-down any solids from the slides of the vial), followed by stirring for 5 minutes and flushing with argon. This mixture is then heated at 160° C. under microwave irradiation for 15 minutes. After cooling to room temperature the reaction mixture is diluted with ethyl acetate (3 ml) and acidified to pH2 with dilute aqueous hydrochloric acid. The organic phase is separated and the aqueous phase is further extracted with ethyl acetate (2×3 ml). All organics are then combined, filtered through a silica plug and evaporated to give a crude product which is dissolved in N,N-dimethylformamide (2.5 ml) and purified by preparative reverse phase HPLC to afford 4-(4′-chloro-4-ethyl-3′-trifluoromethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.143 g) as a white powder.
Reaction SMILES: [OH-].[Na+].[CH:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O.CC(C)=O>[CH2:12]([O:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[CH:3]=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1ccccc1OCc1ccccc1
Yield: 132.9 %

Procedure:
Sodium hydroxide (20.0 gms.; 0.5 mole) was dissolved in 150 ml H2O and salicylaldehyde (53.2 ml; 0.5 mole) dissolved in 200 ml acetone was added, followed by benzyl bromide (65.4 ml; 0.55 mole) dissolved in 200 ml acetone. The reaction mixture was refluxed for a period of 24 hours and allowed to cool. The acetone was evaporated in vacuum and the two phase residue extracted with 300 ml CH2Cl2. The CH2Cl2 layer was washed with 150 ml H2O and dried over anhydrous Na2SO4. The Na2SO4 was filtered off and the solvent removed from the filtrate to yield 141 grams of the crude product.
Reaction SMILES: [CH3:1][C:2]([C:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH3:18])([CH3:7])[CH2:3][C:4]([OH:6])=O.ClC(OCC(C)C)=O.[NH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][OH:33])=[CH:30][CH:29]=1>C1COCC1>[OH:33][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([NH:27][C:4](=[O:6])[CH2:3][C:2]([CH3:1])([C:8]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=2[CH3:18])[CH3:7])=[CH:29][CH:30]=1
Reactant: Nc1ccc(CO)cc1
Reactant: CC1=C(C)C(=O)C(C(C)(C)CC(=O)O)=C(C)C1=O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CC1=C(C)C(=O)C(C(C)(C)CC(=O)Nc2ccc(CO)cc2)=C(C)C1=O
Yield: 74 %

Procedure:
To a solution of 3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)butanoic acid (1.75 g, 7.46 mmol) and isobutyl chloroformate (1.11 g, 8.12 mmol) in 20 ml of dry THF, N-methyl morphorline (0.82 ml) was added at 0° C. The resultant mixture was stirred for 30 minutes at 0° C., 4-aminobenzylalcohol (1.38 g, 11.2 mmol) added, and the resultant mixture stirred overnight. After removal of the solid by filtration, the compound was directly purified with silica chromatography using heptane and ethyl acetate as eluent to give a yield of 74%. 1H NMR (300 MHz, CD2Cl2) δ 7.40 (d, J=9, 2H), 7.28 (d, J=9, 2H), 7.19 (s, br, 1H, NH), 4.61 (s, 2H, CH2O), 2.99 (s, 2H, CH2), 2.14 (s, 3H, CH3), 1.97 (s, 6H, CH3), 1.55 (s, 3H, CH3), 1.48 (s, 3H, CH3). MS (m/e): 356 (M+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[C:11]([C:35]([F:38])([F:37])[F:36])=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]([N:22]([C:31]([O:33][CH3:34])=[O:32])[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])=[CH:15][CH:14]=[CH:13]2>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[C:11]([C:35]([F:36])([F:38])[F:37])=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]([N:22]([C:31]([O:33][CH3:34])=[O:32])[CH2:23][C:24]([OH:26])=[O:25])=[O:21])=[CH:15][CH:14]=[CH:13]2
Reactant: COC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1cccc2c(C(F)(F)F)c(OC)ccc12
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N(CC(=O)O)C(=O)c1cccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 20 °C
Yield: 106.6 %

Procedure:
Trifluoroacetic acid (20.0 mL, 260 mmol) was added to a solution of N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(methoxycarbonyl)glycine, 1,1-dimethylethyl ester (1.5 g, 3.41 mmol) in chloroform (25 mL) at 20° C. and the mixture refluxed for 1.5 hours. The solution was cooled to 20° C. and the solvent evaporated under reduced pressure. The residual solid was recrystallized from acetone-water and dried at 70° C./0.1 m.m. Hg to yield the pure product as a white solid (1.4 g, 100%), m.p. 148°-150° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6])[CH3:2].[C:17]([O-:20])([O-])=[O:18].[Cs+].[Cs+]>>[CH2:1]([O:3][C:4](=[O:16])[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:11][CH2:10][NH:9][C:17]([O:20][C:7]([CH3:15])([CH3:8])[CH3:5])=[O:18])[CH:8]=1)=[O:6])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Agent: [Cs+]
Product: CCOC(=O)C(=O)c1cn(CCNC(=O)OC(C)(C)C)c2ccccc12
Yield: 135.9 %

Procedure:
The general procedure 1 was then followed using the above product (6.68 mmol, 1.54 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (6.68 mmol, 1.45 g) and Cs2CO3 (9.82 mmol, 3.20 g). The purification was achieved by column chromatography (petro-lether:ethylacetate:diethylamine 5:4:1) to yield ethyl-2-(1-{2-[(tert.-butoxycarbonyl)-amino]ethyl}-1H-indol-3-yl)-2-oxoacetate (4.54 mmol, 68%) as white crystals. Mp=114-115° C. IR {tilde over (ν)} [cm−1]=3357; 2977; 1727; 1686; 1638; 1518. EI-MS (m/z)=360 (7.59%; M+•.). 1H NMR (300 MHz, CDCl3) 8.44 (m; 1H; indole-H); 8.34 (s; 1H; indole-H); 7.42 (m; 1H; indole-H); 7.35 (m; 1H; indole-H); 4.63 (bs; 1H; NH); 4.37 (m; 4H; OCH2CH3; indole-CH2); 3.54 (q; 3J=6.2 Hz; 2H; CH2—N); 1.43 (t; 3H; 3J=7.1 Hz; OCH2CH3); 1.43 (s; 9H; C(CH3)3).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)#[N:15].O>C1COCC1>[C:14]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:1][CH2:2][CH:3]([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])(=[O:24])=[O:23])=[CH:20][CH:21]=1)#[N:15]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(CN)CNC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(CNC(=O)OC(C)(C)C)CNS(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
To a solution of tert-butyl (3-amino-2-methylpropyl)carbamate (200 mg, 1.06 mmol) and TEA (0.444 mL, 3.19 mmol) in THF (5 mL) was added 4-cyanobenzene-1-sulfonyl chloride (214 mg, 1.06 mmol), and the mixture was stirred at room temperature for 16 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give tert-butyl (3-(4-cyanophenylsulfonamido)-2-methylpropyl)carbamate (273 mg, 0.772 mmol, 72.7%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(CO)ccc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.6 %

Procedure:
To a stirred solution of (4-fluoro-3-nitro-phenyl)-methanol (750 g, 4.4 mmol) in DCM (40 mL) at 0° C. was added Dess-Martin Reagent (3.0 g, 7 mmol). The solution was stirred at room temperature for 4 hours. TLC showed disappearance of starting material. The reaction was quenched with 10% NaHCO3 and 10% Na2S2O3 aqueous solution and DCM layer separated and washed with water (100 mL) and brine (50 mL). The reaction was concentrated, and the residue was purified by flash chromatography on silica to obtain the title compound (570 mg, yield: 75%). 1H-NMR (400 MHz, DMSO-d6) δ 10.09 (d, 1H), 8.36 (t, 1H), 8.06 (dd, 1H), 7.97 (m, 1H).
Reaction SMILES: S(=O)(=O)(O)O.O.[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][OH:12].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH:11]=[O:12]
Reactant: OCc1ccc(F)c(Br)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(F)c(Br)c1
Reaction time: 2 h
Yield: 80.3 %

Procedure:
A mixture of 29.4 g (0.3 mol) of sulphuric acid, 50 ml of water and 2 ml of Aliquat 336 (tricapryl-methylammonium chloride) was added to a solution of 20.5 g (0.1 mol) of 3-bromo-4-fluoro-benzyl alcohol in 250 ml of methylene chloride at room temperature. Thereafter, 9.7 g (0.033 mol) of potassium dichromate were added to the reaction mixture and the temperature was kept at about 25° C. for 2 hours by cooling slightly. After adding 100 ml of water, the organic phase was separated off and the aqueous phase was extracted once more with 100 ml of methylene chloride. The organic phases were washed twice with 100 ml of water each time, then once with 100 ml of saturated sodium bicarbonate solution and once more with 100 ml of water, dried over sodium sulphate and evaporated in vacuo. The residue was distilled. 16.3 g (81% of theory) of 3-bromo-4-fluoro-benzaldehyde were obtained in this manner as a colorless oil with a boiling point of 65° C./0.3 mm Hg.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][N:14]=1)=[O:12].[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][N:14]=2)=[O:12])=[O:29])[N:27]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: O=C(NC[C@H]1NC[C@@H]2CCC[C@@H]21)c1noc2ccccc12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2noc3ccccc23)c1

Procedure:
prepared by reaction of benzo[d]isoxazole-3-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](O)(=[O:30])[C:27]([CH3:29])=[CH2:28].C(N(CC)CC)C.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:30])[C:27]([CH3:29])=[CH2:28]
Reactant: C=C(C)C(=O)O
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1c(Cc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Reaction time: 1 h
Yield: 94 %

Procedure:
To the same flask as used in Example 1 were added 340.51 g (1.0 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 86.41 g (1.0 mole) of 98.5% methacrylic acid, 500 g of toluene and 242.86 g (2.4 moles) of triethylamine. After replacing the air in the container with nitrogen, 229.14 g (1.2 moles) of o-toluenesulfonyl chloride was added dropwise with stirring. After completion of the dropwise addition, the reaction solution was kept at 90° C. for 1 hour. Thereafter, the organic layer was washed with water until it became neutral, and toluene was removed under reduced pressure. The residue was recrystallized from n-hexane to obtain 384.1 g of a white crystalline 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monomethacrylate having a melting point of 144° to 146° C. Yield, 94%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][CH:14]=[C:13]([C:16](=[N:18][NH:19][C:20]([NH:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([Cl:33])[CH:24]=3)=[S:21])[CH3:17])[C:12]=2[OH:34])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)(C)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][CH:14]=[C:13]([C:16](=[N:18][NH:19][C:20]([NH:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([Cl:33])[CH:24]=3)=[S:21])[CH3:17])[C:12]=2[OH:34])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(NC(=S)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
Methyl 4-{[(2-{1-[5-(4-t-butylphenyl)-4-hydroxy-3-thienyl]ethylidene}hydrazino)carbonothioyl]amino}-2-chlorobenzoate (100 mg, 0.19 mmol) synthesized in Synthetic Example 100 was dissolved in isopropyl alcohol (1.9 ml), and 0.2 M sodium hydroxide aqueous solution (2.1 ml, 0.42 mmol) was added thereto, following by stirring overnight at room temperature, then at 45° C. for 1 day. Then 0.2 M sodium hydroxide aqueous solution (1.1 ml, 0.22 mmol) was added thereto, following by stirring at 45° C. for 5.5 hours. After completion of the stirring, 1 M hydrochloric acid (0.64 ml, 0.64 mmol) was added. The precipitated solid was filtered, and purified with a silica gel plate (chloroform/methanol=9/1) to obtain the desired product as a yellow solid (24 mg, yield 25%).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[C:14]([NH:37][C:38]([C:40]4[O:41][CH:42]=[CH:43][CH:44]=4)=[O:39])[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]5[N:25](S(C6C=CC=CC=6)(=O)=O)[CH:26]=[CH:27][C:20]=45)[CH:17]=3)[CH:12]=[N:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].Cl>CC(O)C>[NH:25]1[C:21]2=[N:22][CH:23]=[CH:24][C:19]([C:16]3[CH:17]=[C:18]4[C:13]([CH:12]=[N:11][NH:10]4)=[C:14]([NH:37][C:38]([C:40]4[O:41][CH:42]=[CH:43][CH:44]=4)=[O:39])[CH:15]=3)=[C:20]2[CH:27]=[CH:26]1
Reactant: O=C(Nc1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)cc2c1cnn2S(=O)(=O)c1ccccc1)c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(Nc1cc(-c2ccnc3[nH]ccc23)cc2[nH]ncc12)c1ccco1
Temperature: 70 °C

Procedure:
A solution of N-{1-(phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-indazol-4-yl}-2-furancarboxamide (80 mg) and 2M sodium hydroxide (2 ml) in IPA (4 ml) was stirred for 18 h at RT. The solution was heated at 70° C. for 1.5 h. The solution was cooled, neutralized with 2M HCl (aq) (2 ml) and purged with nitrogen to remove the IPA. The resulting solid was collected by filtration and dried in vacuo at 50° C. to give title compound, 30 mg.