Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.Br.Br[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>CN(C=O)C>[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[N:13]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1
Reactant: BrCc1cccnc1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccnc1
Reaction time: 0.17 h

Procedure:
Sodium hydride (13 mg, 0.32 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (20 mg, 0.1 mmol, from Example 2, Step 5) in DMF (3.0 mL). After stirring for 10 minutes, a solution of 3-(bromomethyl)pyridine hydrobromide (0.027 g, 0.11 mmol, Aldrich) in DMF (0.3 mL) was added. The mixture was stirred for 45 minutes and then quenched by the addition of water, diluted to 5 mL with MeCN, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (8 mg, 30%).
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:18](O)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:28]>C1(C)C=CC=CC=1>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:18]([Cl:28])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(=C(O)c2ccccc2)c2ccccc2N1C(=O)c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1C(=C(Cl)c2ccccc2)c2ccccc2N1C(=O)c1ccccc1

Procedure:
Prepared analogously to Example 2b from 1-benzoyl-3-(1-hydroxy-1-phenyl-methylidene)-2-indolinone and phosphorus pentachloride in toluene.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:11])[S:4]([NH:7][CH2:8][CH2:9][NH2:10])(=[O:6])=[O:5].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1C=CC=CC=1>[ClH:1].[CH:12](=[N:10][CH2:9][CH2:8][NH:7][S:4]([N:3]([CH3:11])[CH3:2])(=[O:6])=[O:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CN(C)S(=O)(=O)NCCN
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)NCCN=Cc1ccccc1
Yield: 41.1 %

Procedure:
A mixture of 4.0 g (0.02 mole) of 2-[N-[(dimethylamino)sulfonyl]-amino]ethylamine hydrochloride and 2.0 g (0.02 mole) of benzaldehyde was stirred and treated immediately with 2.0 g (0.02 mole) of triethylamine, followed by the addition of 200 ml of dry benzene. The solution was heated to reflux employing a Dean-Stark apparatus. After 2 hr at reflux, the benzene solution was cooled and washed twice with 100 ml portions of water. The organic phase was separated, dried over magnesium sulfate, and concentrated under reduced pressure to an oil, which was dissolved in ether and treated with HCl gas to precipitate a yellowish solid. The product was collected by filtration, washed with ether and air dried to provide 2.4 g (50%) of product. The NMR spectrum was consistent with the assigned structure and the solid was used without additional purification.
Reaction SMILES: [N:1]1([C:7](=[O:15])[CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:16].[CH3:17][O:18][C:19]1[C:27]2[O:26][C:25](C)(C)C[C:23]=2[C:22]([C:30]2[C@@H:39]3[C@@H:34]([CH2:35][CH:36]=[CH:37][CH2:38]3)[C:33](=[O:40])[N:32]([C:41]3[CH:46]=[CH:45][C:44]([C:47](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:48])=[CH:43][CH:42]=3)[N:31]=2)=[CH:21][CH:20]=1>>[ClH:16].[CH3:25][O:26][C:27]1[CH:23]=[C:22]([C:30]2[C@@H:39]3[C@@H:34]([CH2:35][CH:36]=[CH:37][CH2:38]3)[C:33](=[O:40])[N:32]([C:41]3[CH:42]=[CH:43][C:44]([C:47]([N:12]4[CH2:11][CH2:10][N:9]([CH2:8][C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[O:15])[CH2:14][CH2:13]4)=[O:48])=[CH:45][CH:46]=3)[N:31]=2)[CH:21]=[CH:20][C:19]=1[O:18][CH3:17]
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(CC(=O)N5CCOCC5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from intermediate product A6 and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone as described for compound 8. M.p. 168–169° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:20][CH2:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]=3[CH:9]2[C:21]2[CH:22]=[CH:23][C:24]3[O:28][CH2:27][CH2:26][C:25]=3[CH:29]=2)=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)CCC>O1CCOCC1.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>[N:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:20][CH2:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]=3[CH:9]2[C:21]2[CH:22]=[CH:23][C:24]3[O:28][CH2:27][CH2:26][C:25]=3[CH:29]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Brc1ccc(N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)CCO3)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: c1ccc(-c2ccc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)CCO4)nc2)nc1

Procedure:
The product from step A above (0.4 g, 0.896 mmol), 2-tributylstannanyl-pyridine (0.8 g, 2.17 mmol) and Pd(PPh3)4 (0.12 g, 0.104 mmol) were stirred in 1,4-dioxane (5 mL) at 88° C. for 24 h. The reaction mixture was filtered through a plug of Celite with CH2Cl2 and then concentrated to a small volume. Preparative TLC (3:7 ethyl acetate/heaxne; then 5% CH3OH/CH2Cl2) yielded the product as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26](Cl)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([N:34]3[CH:38]=[C:37]([CH3:39])[CH:36]=[N:35]3)[C@@H:31]([OH:40])[C@H:30]2[OH:41])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH:42]#[C:43][CH2:44][CH2:45][CH2:46][CH3:47].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26]([C:42]#[C:43][CH2:44][CH2:45][CH2:46][CH3:47])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([N:34]3[CH:38]=[C:37]([CH3:39])[CH:36]=[N:35]3)[C@@H:31]([OH:40])[C@H:30]2[OH:41])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(Nc2nc(Cl)nc3c2ncn3[C@@H]2C[C@H](n3cc(C)cn3)[C@@H](O)[C@H]2O)c2ccc(OC)cc2)cc1
Reactant: C#CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCCCC#Cc1nc(NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c2ncn([C@@H]3C[C@H](n4cc(C)cn4)[C@@H](O)[C@H]3O)c2n1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
(1R,2S,3R,5S)-3-(6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-5-(4-methyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BB1) (0.1 g, 0.17 mmol), 1-hexyne (0.42 g, 1.70 mmol), copper (I) iodide (0.008 g, 43 μmol), dichlorobis(triphenylphosphine)palladium(II) (0.031 g, 43 μmol), triphenylphosphine (0.023 g, 86 μmol), diethylamine (1 mL) and DMF (0.5 mL) are placed in a 0.5-2.5 mL microwave vial. The reaction mixture is heated to 120° C. using microwave radiation. The reaction is shown to be complete by LCMS after 1 hour. The reaction mixture is partitioned between dichloromethane (20 mL) and 2M HCl (20 mL). The organic layer is washed with sat. NaHCO3 (20 mL), water (20 ml) and brine (20 ml), dried over MgSO4, filtered and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, dichloromethane/methanol 25:1). MS (ES+) m/e 622 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH:9]2[C:14](=O)[CH:13]3[CH2:16][CH2:17][N:10]2[CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].NN.C(O)COCCO>O>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:16][CH2:17][N:10]2[CH2:11][CH2:12]3)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C2CCN(CC2)C1CC(c1ccccc1)c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: c1ccc(C(CC2CC3CCN2CC3)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.75 h

Procedure:
9.3 Parts 3-(2,2-diphenylethyl-1-azabicyclo[2.2.2]-octan-3-one, 1.30 parts potassium hydroxide, 3.6 parts by volume of an 85% solution of hydrazine in water, and 59 parts diethylene glycol are combined and refluxed, with stirring, under nitrogen for 2.75 hours. Stirring and heating are then discontinued and the reaction mixture is allowed to stand for 16 hours at which time the mixture is heated to distill until a head temperature of 235° C. is reached. After cooling to room temperature, the mixture is partitioned between 900 parts by volume of a 5% sodium chloride solution and two 430 parts portions of ether. The ethereal extracts are combined, washed with water, dried over anhydrous sodium sulfate and stripped in vacuo to give an oil which solidifies upon standing. This solid is crystallized from n-pentane to afford, as a white solid, 2-(2,2-diphenylethyl)-1-azabicyclo[2.2.2]-octane, melting at about 87.5°-89.0° C. This compound is represented by the following structural formula. ##STR10##
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])([O-:3])=[O:2].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:36]O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:36])=[O:27])([O-:3])=[O:2]
Reactant: O=C(O)CCCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)CCCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
8 g of N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]-4-amino-n-butyric acid are dissolved in 50 ml of methanol and then 10 ml of concentrated sulfuric acid are slowly added. The reaction mixture is left to stand for some hours, then poured onto ice, made alkaline with sodium hydroxide solution and extracted with toluene. The toluene extract is washed with water until neutral and substantially concentrated in vacuo. The residue is crystallised from hexane, affording 6 g of methyl N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]-4-amino-n-butyrate with a melting point of 60°-62° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16](=[O:18])[CH3:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Solvent: c1ccncc1
Product: CC(=O)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 6 h

Procedure:
To 10.0 g (41.3 mmol) of 4-benzyloxyphenylacetic acid (31) was added, 20 mL of acetic anhydride and 20 mL of pyridine, which was heated to reflux with stirring under argon atmosphere for 6 hours. Solvents were evaporated and residue dissolved in CHCl3 (50 mL) and washed with 1N NaOH (2×50 mL). Dried organic layer (MgSO4), filtered, and evaporated to 11.8 g of an amber oil. Vacuum distillation at 0.1 mm Hg in an oil-bath set to 170° C. followed by silica gel chromatography eluting with 8/2 CH2Cl2-hexanes gave 2.68 g (27%). 1H NMR (CDCl3) □δ□ 2.14 (s, 3H), 3.63 (s, 2H), 5.05 (s, 2H), 6.94 (d, 2H, J=8.7 Hz), 7.10 (d, 2H, J=8.7 Hz), 7.26-7.47 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:41])=[C:37]([CH:40]=1)[CH2:38]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH2:38][C:37]2[CH:40]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=2[CH3:41])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3ccccc23)CC1
Reactant: Cc1ccc(F)cc1CBr
Product: Cc1ccc(F)cc1Cc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1-c1ccccc1

Procedure:
From the compound of example 16, step 1, (150 mg, 341 μmol) the title compound was prepared analogously as described in example 17, step 1, using 5-fluoro-2-methylbenzyl bromide. Yield: 9 mg.
Reaction SMILES: COCOC1C=C([C@@H](N2CC[C@H](OCOC)C2)CO)C=CC=1.[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([C@H:33](O)[CH2:34][N:35]2[CH2:39][CH2:38][C@H:37]([O:40][CH2:41][O:42][CH3:43])[CH2:36]2)[CH:30]=[CH:31][CH:32]=1.[CH3:45][NH:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=1>>[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([C@H:33]([N:46]([C:47]2[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=2)[CH3:45])[CH2:34][N:35]2[CH2:39][CH2:38][C@H:37]([O:40][CH2:41][O:42][CH3:43])[CH2:36]2)[CH:30]=[CH:31][CH:32]=1
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: COCOc1cccc([C@H](O)CN2CC[C@H](OCOC)C2)c1
Agent: COCOc1cccc([C@H](CO)N2CC[C@H](OCOC)C2)c1
Product: COCOc1cccc([C@@H](CN2CC[C@H](OCOC)C2)N(C)c2ccc(C(=O)OC)cc2)c1
Yield: 60 %

Procedure:
This was prepared from the mixture of 2-(R)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and 1-(S)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and methyl 4-methylaminobenzoate in 60% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([C:19]4[CH:20]=[C:21]5[CH:27]=[N:26][N:25]([S:28]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)(=[O:30])=[O:29])[C:22]5=[N:23][CH:24]=4)[CH:15]=[C:14]([NH2:37])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:44][CH2:45][C:46]1[S:47][CH:48]=[C:49]([C:51](Cl)=[O:52])[N:50]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:44][CH2:45][C:46]1[S:47][CH:48]=[C:49]([C:51]([NH:37][C:14]2[CH:15]=[C:16]([C:19]3[CH:20]=[C:21]4[CH:27]=[N:26][N:25]([S:28]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)(=[O:29])=[O:30])[C:22]4=[N:23][CH:24]=3)[CH:17]=[C:18]3[C:13]=2[CH:12]=[N:11][N:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[O:52])[N:50]=1
Reactant: Nc1cc(-c2cnc3c(cnn3S(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)c1csc(CCl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(-c2cnc3c(cnn3S(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CCl)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 22.4 %

Procedure:
1-(Phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-1H-indazol-4-amine (185 mg, 0.349 mmol) was dissolved in DCM (3 ml) and pyridine (0.034 mL, 0.418 mmol) was added. The mixture was cooled to 0° C. in an ice bath and 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (77 mg, 0.349 mmol) in DCM (3 ml) was added dropwise over 5 mins. The mixture was stirred at 0° C. for 15 mins. A further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (38.4 mg, 0.174 mmol) in DCM (1.5 ml) was added. The mixture was stirred for 2 hours, letting the ice melt over this time. A further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (38.4 mg, 0.174 mmol) in DCM (1.5 ml) was added and stirring continued with monitoring by LCMS. The mixture was diluted with DCM (10 ml), saturated aqueous sodium bicarbonate (10 ml) was added and the mixture stirred vigorously for 10 mins. The organic layer was separated, washed with water (10 ml), passed through a hydrophobic frit and concentrated in vacuo. The residue was dissolved in DMSO and loaded onto a 43 g C18 Reverse Phase RediSep column that was then eluted with 30-85% acetonitrile (+0.1% TFA)/H2O (+0.1% TFA) over 30 mins. The product-containing fractions were combined and concentrated in vacuo to give a cream solid which was then dried on the vacuum line for 1 hour to give the title compound (54 mg).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([NH:12][C:13](=[O:35])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:27][N:26]([CH3:28])[C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[O:23]3)=[C:16]([CH3:33])[C:15]=2[CH3:34])[CH:6]=1.COCCOC.[OH-].[Na+].C(COC)(C)(C)C>CO>[CH3:34][C:15]1[C:16]([CH3:33])=[C:17]([O:20][CH2:21][C@@H:22]2[CH2:27][N:26]([CH3:28])[C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[O:23]2)[CH:18]=[CH:19][C:14]=1[C:13]([NH:12][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:36])=[O:2])[CH:10]=[CH:9][C:8]=1[F:11])=[O:35]
Reactant: COC(=O)Cc1ccc(F)c(NC(=O)c2ccc(OC[C@@H]3CN(C)c4ccccc4O3)c(C)c2C)c1
Agent: COCC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Product: Cc1c(OC[C@@H]2CN(C)c3ccccc3O2)ccc(C(=O)Nc2cc(CC(=O)O)ccc2F)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of the compound (240 mg) prepared in Example 12, 1,2-dimethoxyethane (5.0 mL), and methanol (5.0 mL), 1N sodium hydroxide solution (3.0 mL) was added, and the mixture was stirred for 1 hour at room temperature. Methyl tert-butylmethyl ether was added to the reaction mixture, which was extracted by 1N sodium hydroxide solution. The water layer was neutralized by adding 5N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with water and saturated brine solution, and was dried by anhydrous magnesium sulphate. The compound (208 mg) of the present invention having the following physical data was obtained by allowing the residue obtained by removing the solvent to recrystallize from a mixed solvent of n-hexane, ethyl acetate, and tetrahydrofuran.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][Br:7])=[O:3].Cl.[Cl:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][Cl:15].C(N(CC)CC)C>ClCCl>[Br:7][CH2:6][CH2:5][O:4][C:2]([N:12]([CH2:13][CH2:14][Cl:15])[CH2:11][CH2:10][Cl:9])=[O:3]
Reactant: ClCCNCCCl
Reactant: O=C(Cl)OCCBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCBr)N(CCCl)CCCl
Temperature: 7.5 °C
Reaction time: 18 h

Procedure:
2-Bromoethyl chloroformate (5.6 mL, 50 mmol) was added to a stirred suspension of bis(2-chloroethyl)amine hydrochloride (9.8 g, 55 mmol) in 250 mL of dry dichloromethane at 0-5° C. under argon over 2 min followed by 28 mL (200 mmol) of triethylamine over 20 min. The mixture was stirred at 5-10° C. for 3 h and at room temperature for 18 h, then suction filtered. The filtrate was concentrated in vacuo.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>>[C:18]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Oc1ccc2ncn(-c3ccccc3-c3ccccc3)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and biphenyl-2-ylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=288.0 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(=[CH:29][C:30]([O:32][CH3:33])=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:33][O:32][C:30](=[O:31])/[CH:29]=[CH:8]/[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/Cc1ccccc1
Yield: 80.5 %

Procedure:
To a solution of phenyl acetaldehyde (5.0 g, 41.61 mmol) in toluene (500 mL) was added methyl (triphenylphosphoranylidene)acetate (13.9 g, 41.61 mmol). The reaction mixture was stirred at reflux for 3 h. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was added ether/hexane (=1:1, v/v) at 0° C. then stirred for 30 min. The filtrate was concentrated then purified by a silica gel column to produce the title compound (5.9 g, 70˜90%)
Reaction SMILES: [OH:1][C:2]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O.[C:14]1([S:20]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C>CC(N(C)C)=O>[C:14]1([S:20]([C:23]2[CH:24]=[CH:25][C:26]([NH:27][C:7]([C:2]3([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])=[CH:28][CH:29]=2)(=[O:21])=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C1(O)CCCC1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: C
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(S(=O)(=O)c2ccccc2)cc1)C1(O)CCCC1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 1-hydroxycyclopentanecarboxylic acid (0.76 g, 6.4 mmol) in dry dimethylacetamide (15 ml) was stirred under a nitrogen atmosphere at -10° C. Thionyl chloride (0.76 g, 6.4 mmol) was added and the resulting mixture was allowed to stir at -10° C. for 1 hour. 4-Phenylsulfonylaniline (1.0 g, 4.29 mmol) was then added and the reaction mixture was stirred at -10° C. for a further 15 mins. The solution was then allowed to warm to room temperature where it was stirred overnight. The reaction mixture was poured onto water, extracted with ethyl acetate, and the combined ethyl acetate portions were washed with water, and brine. After drying (Na2SO4) the ethyl acetate was removed by evaporation. Crystallization from ethyl acetate/hexane yielded the title tertiary carbinol (0.70 g, 47%) as a white solid; mp=214.0°-216.0° C. 1H-NMR (300 MHz, d6 -DMSO): 1.73 (m, 6H, CH2), 1.97 (m, 2H, CH2), 5.67 (s, 1H, OH), 7.64 (m, 3H, ArH), 7.94 (m, 6H, ArH), 10.13 (s, 1H, NH). MS (CI, CH4): 346(M+1, 100).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([S:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH3:27].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:25]([S:24][C:5]1[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:3]([CH3:27])[N:4]=1)[CH3:26]
Reactant: CCSc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccccc1
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: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCSc1nc(C)c(-c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 26.5 %

Procedure:
To a solution of 4′-{[5-bromo-2-(ethylthio)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.76 g) and phenylboronic acid (0.32 g) in 1,4-dioxane (10 mL) solution were added 2 M aqueous cesium carbonate solution (2 mL) and tetrakis(triphenylphosphine)palladium (0.1 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.2 g, 26%) as a colorless solid.