Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:13]=[C:14]([N:21]4[CH2:31][CH2:30][C:24]5([O:28]C(=O)[NH:26][CH2:25]5)[CH2:23][CH2:22]4)[C:15]4[O:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.ClC1N=C(Cl)C2OC=CC=2N=1.O1C2(CCNCC2)CNC1=O.[OH-].[Na+]>CO>[NH2:26][CH2:25][C:24]1([OH:28])[CH2:23][CH2:22][N:21]([C:14]2[C:15]3[O:20][CH:19]=[CH:18][C:16]=3[N:17]=[C:12]([NH:11][C:7]3[CH:6]=[C:5]4[C:10]([C:2]([CH3:1])=[N:3][NH:4]4)=[CH:9][CH:8]=3)[N:13]=2)[CH2:31][CH2:30]1
Reactant: Cc1n[nH]c2cc(Nc3nc(N4CCC5(CC4)CNC(=O)O5)c4occc4n3)ccc12
Agent: Clc1nc(Cl)c2occc2n1
Agent: O=C1NCC2(CCNCC2)O1
Agent: [Na+]
Solvent: CO
Product: Cc1n[nH]c2cc(Nc3nc(N4CCC(O)(CN)CC4)c4occc4n3)ccc12
Temperature: 100 °C
Yield: 75 %

Procedure:
To a vial was added 8-(2-(3-methyl-1H-indazol-6-ylamino)furo[3,2-d]pyrimidin-4-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one (0.100 g, 0.238 mmol, prepared using A from 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] with 1-oxa-3,8-diazaspiro[4.5]decan-2-one [Chembridge], B with Example #3, Step B and C) in MeOH (3 mL). Then aqueous NaOH (5 M, 0.715 mL, 3.58 mmol) was added. The mixture was heated in a microwave at about 100° C. for about 30 min (300 psi maximum pressure, 2 min ramp, 250 max watts). Aqueous NaOH (5 M, 0.350 mL, 1.75 mmol) was added. The mixture was heated in a microwave at about 120° C. for about 40 min (300 psi maximum pressure, 2 min ramp, 250 max watts). The mixture was filtered and the filtrate was cooled on ice and the precipitate formed was collected via filtration and dried in a vacuum oven at about 75° C. for about 15 h to give 4-(aminomethyl)-1-(2-(3-methyl-1H-indazol-6-ylamino)furo[3,2-d]pyrimidin-yl)piperidin-4-ol (0.07 g, 75%): LC/MS (Table 2, Method c) Rt=1.44 min.; MS m/z: 394 (M+H)+. Syk IC50=A
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH2:16]([O:18][C:19](=[O:27])[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH3:17].[Cl:28][C:29]1[N:34]=[C:33]([Cl:35])[C:32]([CH2:36]I)=[CH:31][N:30]=1>O1CCCC1.C(OCC)(=O)C>[CH2:16]([O:18][C:19](=[O:27])[CH:20]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:36][C:32]1[C:33]([Cl:35])=[N:34][C:29]([Cl:28])=[N:30][CH:31]=1)[CH3:17]
Reactant: CCOC(=O)Cc1cccnc1
Reactant: Clc1ncc(CI)c(Cl)n1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cnc(Cl)nc1Cl)c1cccnc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-isopropylcyclohexylamine (1.44 g, 10.0 mmol) (Aldrich) in dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) (Aldrich) at −78° C. under argon. After 10 minutes, a solution of 2-pyridin-3-yl-acetic acid ethyl ester (1.65 g, 10.0 mmol) (Acros) in tetrahydrofuran (5 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 10 minutes. To the reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (1.45 g, 5.0 mmol) (from Example 1c supra) in tetrahydrofuran (5 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 2 hours then slowly allowed to warm up to −20° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (100 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 3-(2,4-dichloro-pyrimidin-5-yl)-2-pyridin-3-yl-propionic acid ethyl ester as a brown oil. (Yield 1.10 g, 68.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:19])[CH2:17][CH3:18])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using propionyl chloride (48 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]propanamide (0.012 g).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.[CH2:29](I)[CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:29]([N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12)[CH3:30]
Reactant: CCI
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), ethyl iodide (0.38 mL), potassium carbonate (0.13 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.55 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:25]([C:22]3[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=3)(=[O:26])=[O:27])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.8 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 4-nitro benzenesulfonyl chloride (292 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12g as a solid (120 mg, 33.3%). HPLC: 97% (Rt=7.76 min).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]([F:43])([F:42])[C:27]1[CH:28]=[C:29]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH:30]=[CH:31][C:32](O)=[O:33].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]([F:42])([F:43])[C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][C:32]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:33])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1
Reactant: O=C(O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 45.6 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 3,5-bis(trifluoromethyl)cinnamic acid (4.0 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (2.6 g, 64%) as crystals.
Reaction SMILES: [C@@H:1]1([C:9]([O:11]CC)=[O:10])[CH2:3][C@H:2]1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[OH-].[Na+].Cl>C(O)C>[CH2:7]([O:6][C:4]([C@@H:2]1[CH2:3][C@H:1]1[C:9]([OH:11])=[O:10])=[O:5])[CH3:8]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of diethyl trans-1,2-cyclopropanedicarboxylate (110 mg, 0.59 mmol) in ethanol (3 mL) is added aqueous 1M NaOH (0.65 mL, 0.65 mmol) and the mixture is stirred at room temperature for 48 hours. To this mixture is added 0.65 mL of aqueous 1M HCl and the solvent is removed under reduced pressure to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:56]=[CH:55][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C@@H:16]4[O:45][C@H:44]([CH2:46][O:47]CC5C=CC=CC=5)[C@@H:35]([O:36]CC5C=CC=CC=5)[C@H:26]([O:27]CC5C=CC=CC=5)[C@H:17]4[O:18]CC4C=CC=CC=4)[CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1>O1CCCC1.CO.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C@@H:16]4[O:45][C@H:44]([CH2:46][OH:47])[C@@H:35]([OH:36])[C@H:26]([OH:27])[C@H:17]4[OH:18])[CH:14]=3)[CH:9]=[CH:8]2)=[CH:55][CH:56]=1
Reactant: Cc1ccc(Cn2ccc3ccc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)cc32)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(Cn2ccc3ccc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)cc32)cc1

Procedure:
A solution of 1-[1-(4-methylbenzyl)-1H-indol-6-yl]-1-deoxy-2,3,4,6-tetra-O-benzyl-β-D-glucopyranose and 10% palladium-carbon powder (0.12 g) in tetrahydrofuran (3 mL) and methanol (3 mL) was stirred at room temperature for 1 hour under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (0.035 g).
Reaction SMILES: [C:1]([C@@:4]1([OH:23])[C@@H:8]([CH:9]([C:11](=[O:13])[CH3:12])[OH:10])[O:7][C@@H:6]([N:14]2[CH:21]=[C:20]([Br:22])[C:18](=O)[NH:17][C:15]2=[O:16])[CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.C1(C)C=C(C)C=C(C)C=1S(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1.[NH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[OH:62]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:22][C:20]1[C:18]([NH:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[OH:62])=[N:17][C:15](=[O:16])[N:14]([CH:21]=1)[C@@H:6]1[O:7][C@H:8]([CH:9]([C:11](=[O:13])[CH3:12])[OH:10])[C@@:4]([C:1](=[O:3])[CH3:2])([OH:23])[CH2:5]1
Reactant: Nc1ccccc1O
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2cc(Br)c(=O)[nH]c2=O)C[C@@]1(O)C(C)=O
Agent: CN(C)c1ccncc1
Agent: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(=O)C(O)[C@H]1O[C@@H](n2cc(Br)c(Nc3ccccc3O)nc2=O)C[C@@]1(O)C(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3′,5′-diacetyl-5-bromo-2′-deoxyuridine (8.5 g; 21.7 mmol), methylene chloride (100 ml), triethylamine (8.8 g; 87 mmol) and DMAP (0.13 g) was added 2-mesitylsulfonyl chloride (9.5 g; 43.4 mmol). After stirring at room temperature for 18 h. DBU (6.6 g; 43.5 mmol) and 2-aminophenol (9.5 g; 87 mmol) were added and the solution was stirred for 1 hr. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate aq. solution. The organic layer was purified by flash column chromatography on silica gel to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([Cl:15])=[C:13]([Cl:16])[N:12]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([Cl:15])=[C:13]([Cl:16])[N:12]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]2=[C:10]([Br:23])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2c(c1O)c(Cl)c(Cl)n2CCC(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(Cl)c(Cl)n2CCC(C)C
Yield: 49.6 %

Procedure:
A suspension of 2,3-dichloro-4-hydroxy-1-(3-methyl-butyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (2.23 g, 6.46 mmol), N-bromosuccinimide (1.38 g, 7.75 mmol), and benzoyl peroxide (156 mg, 0.646 mmol) in 50 mL of benzene was heated at reflux temperature for 5 hours. The reaction mixture was washed successively with saturated sodium bicarbonate, brine, saturated ammonium chloride solution, and brine. The organic solution was dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-2% ethyl acetate in hexanes to produce 1.36 g of a white solid. MS: (+) m/z 423.1 (M+1).
Reaction SMILES: Br[C:2]1[N:3]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]2[CH2:15][O:16][CH2:17][C:18]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.[CH:45]1(B(O)O)[CH2:47][CH2:46]1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:45]1([C:2]2[N:3]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:4]=[C:5]3[C:10]=2[CH:9]=[C:8]([C:11]([F:12])([F:14])[F:13])[CH:7]=[C:6]3[CH2:15][O:16][CH2:17][C:18]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:19]2)[CH2:47][CH2:46]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3c(Br)n(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3c(C4CC4)n(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Temperature: 100 °C

Procedure:
tert-Butyl 4-(((3-bromo-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (36 mg, 0.05 mmol), cyclopropylboronic acid (13 mg, 0.16 mmol), and tetrakis(triphenylphosphine) palladium(0) (6 mg, 0.005 mmol) were combined in dry tetrahydrofran (2 mL) in a microwave tube and sealed. The mixture was flushed with nitrogen then 180 μL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 100° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water (2×), then brine (2×), dried over sodium sulfate, and concentrated. Flash chromatography on silica gel (15% ethyl acetate/hexanes) gave 18 mg (53%). 1H-NMR (CDCl3, 500 MHz) δ 7.99 (s, 1H), 7.37 (s, 1H), 7.15-7.21 (m, 5H), 5.30 (s, 2H), 4.68 (s, 2H), 3.68 (m, 2H), 3.43 (s, 2H), 3.35-3.38 (m, 2H), 2.98-3.02 (m, 2H), 2.10-2.19 (m, 3H), 1.74-1.79 (m, 2H), 1.41 (s, 9H), 1.03-1.06 (m, 4H), 0.73-0.76 (m, 2H), 0.11 (s, 9H). Mass spec.: 660.31 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:17][C:13]=1[C:14](O)=O.Cl>P(Cl)(Cl)(Cl)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:14]([C:13]3[CH:17]=[CH:18][C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:12]=3[O:11][CH3:10])[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(O)cc1N
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2ccc(O)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Quantities of 1.6 gm (10 mmol) of 4-hydroxy-1,2-phenylenediamine and 4.9 gm (20 mmol) of 2-methoxy-4-methanesulfonylamino-benzoic acid were refluxed for 1.5 hours, under stirring, in 80 ml of phosphorus oxychloride. The resulting dark solution was then decanted off to eliminate any undissolved components, the phosphorus oxychloride was distilled off in vacuo, and the residue was carefully mixed with 10 gm of crushed ice. Ten milliliters of 4N sodium hydroxide were added to the suspension thus obtained, and the resulting mixture was stirred for one hour at ambient temperature. It was then neutralized with concentrated hydrochloric acid, while being cooled, the solution was evaporated in vacuo to about 3 to 4 ml, the crude product precipitate was subjected to suction filtration, and the resultant crude product was purified by chromatography (250 gm of silica gel, eluant: methylene chloride with 5% ethanol).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.O[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][O:8][N:11]2[C:12](=[O:21])[C:13]3=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]3[C:15]2=[O:16])[CH2:4][O:3]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](CON2C(=O)c3ccccc3C2=O)O1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of (R)-2,2-dimethyl-1,3-dioxolane-4-methanol (7.3 g, 0.05 mol), N-hydroxyphthalimide (8.15 g, 0.05 mol) and triphenylphosphine (13.11 g, 0.05 mol) in tetrahydrofuran (200 ml) was cooled to 0° C. and stirred during the addition of diethyl azodicarboxylate (9.57 g, 0.066 mol). The dark red solution was stirred at 25° C. for 18 h when the colour had turned to pale yellow, and the solution was evaporated to dryness. The residue was extracted once with ether (200 ml) and the ether removed under reduced pressure. The residue was chromatographed in chloroform-hexane 10:1 affording (S)-N-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)phthalimide (10.5 g, 69%) as a white solid; m.p. 99°-100° C., [α]D25 -14.6° (0.4 in MeOH); υmax (KBr) [α]D25 1790, 1730 and 1610 cm-1 ; δH (CDCl3) 1.35(3H,S,CH3), 1.4 (3H,S,CH3), 3.99(1H,q,J5.5,8.8 Hz,CH2ON/CH2OCMe2), 4.17(2H,m,1H of CH2ON+1H of CH2OCMe2), 4.32(1H,q,J5.7,10.1 Hz,CH2ON/CH2OCMe2), 4.50(1H,m,CH) and 7.75-7.87(4H,m,aromatic). Found: C, 60.53; H, 5.46; N, 5.03%. C14H15NO5 requires C, 60.64; H, 5.45; N, 5.05%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:16]([CH3:17])=[N:15][N:14]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1.C(O[K])(C)(C)C>C(O)(C)(C)C.O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:14]2[C:11]3=[N:12][CH:13]=[C:8]([C:4]4[CH:3]=[C:2]([NH:34][CH:31]5[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]5)[CH:7]=[CH:6][CH:5]=4)[CH:9]=[C:10]3[C:16]([CH3:17])=[N:15]2)=[CH:20][CH:21]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4cccc(Cl)c4)cnc32)cc1
Reactant: CN1CCC(N)CC1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: COc1ccc(Cn2nc(C)c3cc(-c4cccc(NC5CCN(C)CC5)c4)cnc32)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a stirred solution of 5-(3-chlorophenyl)-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine (96) (50 mg, 0.137 mmol) in tert-BuOH (4 mL), 1,4 dioxane (6 mL) was added 1-methylpiperidin-4-amine (16) (14 mg, 0.23 mmol, 0.9 eq) and tert-BuOK (38 mg, 0.344 mmol, 2.5 eq). The resulting reaction mixture was degassed, purged with N2 for 10 min and Pd2(dba)3 (5 mg, 0.00549 mmol, 0.04 eq) and tertButyl X-phos (0.08 eq) was added, the mixture was degassed and purged with nitrogen for 15 min. The reaction mixture was stirred overnight at 80° C. under sealed condition for 16 h. After completion of the reaction the reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and solvent completely distilled off to get the crude. The crude was passed through 100-200 mesh silica gel. Eluting the pure compound at 5% MeOH/CHCl3 gave 25 mg of N-(3-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-1-methylpiperidin-4-amine 97.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:22]([F:25])([F:24])[F:23])=[C:12]([N:15]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]3[CH3:21])[CH:13]=2)[NH:8][C:7](=[O:26])[C:6]1=[O:27])(O)=[O:2].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.O>[CH2:28]([NH:35][C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:22]([F:23])([F:25])[F:24])=[C:12]([N:15]3[C:16]([CH3:21])=[CH:17][CH:18]=[C:19]3[CH3:20])[CH:13]=2)[NH:8][C:7](=[O:26])[C:6]1=[O:27])=[O:2])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(C)n1-c1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2CC(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(C)n1-c1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2CC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.7 %

Procedure:
1.6 g (4.2 mmol) of the compound of Example 72 and 0.5 ml (4.6 mmol) of benzylamine were dissolved in 50 ml of anhydrous dimethylformamide under a nitrogen atmosphere. At 0° C., 1 ml (4.6 mmol) of diphenylphosphoryl azide dissolved in 10 ml of anhydrous dimethylformamide, and 1.3 ml (9.2 mmol) of triethylamine were successively added dropwise. The mixture was then stirred at room temperature for 16 h and subsequently diluted with water, acidified and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was recrystallized from ethanol to yield 1.1 g (56%) of the product. Melting point >250° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[C:16]4[C:20](=[C:21]([C:23](O)=[O:24])[CH:22]=3)[NH:19][N:18]=[CH:17]4)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1.CCN(CC)CC>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[C:16]4[C:20](=[C:21]([C:23]([N:51]5[CH2:56][CH2:55][O:54][CH2:53][CH2:52]5)=[O:24])[CH:22]=3)[NH:19][N:18]=[CH:17]4)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:26]
Reactant: C1COCCN1
Reactant: Cc1cc(-c2ncccc2-c2cc(C(=O)O)c3[nH]ncc3c2)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(-c2ncccc2-c2cc(C(=O)N3CCOCC3)c3[nH]ncc3c2)ccc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A capped vial containing a stir-bar, was charged with 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-7-carboxylic acid (100 mg, 0.28 mmol), HBTU (140 mg, 0.36 mmol), morpholine (29 mg, 0.03 mL, 0.34 mmol), NEt3 (57 mg, 0.08 mL, 0.57 mmol) and acetonitrile (3 ml) successively and stirred the contents at room temperature. After 12 h, the reaction mixture was concentrated and diluted with EtOAc (15 mL)/H2O (5 mL). Organic layer was separated, washed with brine, dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC. Product fractions were concentrated, diluted with water and neutralized with aq. Na2CO3 solution. The resulting white precipitate was filtered and dried to obtain (5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-7-yl)(morpholino)methanone. 1H NMR (DMSO-d6): δ 13.27 (s, 1H), 8.66 (d, 1H, J=4.7 Hz), 8.17 (s, 1H), 7.97-7.92 (m, 2H), 7.48 (dd, 1H, J=4.9 and 7.6 Hz), 7.33 (d, 1H, J=7.8 Hz), 6.97-6.88 (m, 3H), 3.62-3.42 (m, 8H), 2.10 (s, 3H).19F NMR (DMSO-d6): δ −118.69 (s).LCMS: rt 4.45 min (A), purity 97%, MS (m/e) 417 (MH+)