Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C[Sn](C)(C)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O1CCOCC1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Reactant: C[Sn](C)(C)c1ccccn1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1-c1ccccn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
In a 25 mL pear shaped flask was placed 5-iodo-2′-deoxycytidine (0.425 g, 1.2 mmol), 2-trimethylstannylpyridine (1.4 g, 5.8 mmol), Bis(triphenylphosphine)-palladium (II) chloride (0.084 g, 0.12 mmol), and anhydrous 1,4-dioxane (15 mL). The reaction was heated at 60° C. for 15 hrs then at 90° C. for 1 h. The solvent was evaporated and the residue purified by silica gel chromatography (10% CH3OH in CH2Cl2 (1% NH3)) to yield 0.173 g (47%) of the title compound as a white solid m.p. 197-198° C.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][O:25][C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29](B(O)O)=[CH:28][N:27]=1.O>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.C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>[CH3:24][O:25][C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29]([C:2]2[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=2)=[CH:28][N:27]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: COc1ncc(-c2ccc(CCNC(=O)OC(C)(C)C)cc2)c(OC)n1
Temperature: 90 °C

Procedure:
Industrial methylated spirits (IMS; 15 mL) and water (5 mL) were degassed thoroughly. tert-butyl 4-bromophenethylcarbamate (1.08 g, 3.63 mmol), sodium carbonate (1.54 g, 14.52 mmol), palladium tetrakis (0.42 g, 0.36 mmol) and 2,4-dimethoxy-5-pyrimidinylboronic acid (1.00 g, 5.44 mmol) were added and the reaction mixture heated to 90° C. for 18 hours. No starting material was observed by LCMS. Water (100 ml) and ethyl acetate (300 ml) were added and the organic layer separated. The organic layer was washed with water (100 ml), dried (MgSO4) and concentrated to give a yellow oil. The crude residue was subject to column chromatography (20 to 60% ethyl acetate/hexane) to give a yellow oil, tert-butyl 4-(2,4-dimethoxypyrimidin-5-yl)phenethylcarbamate, which crystallized on standing (1.18 g, 3.28 mmol, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[CH:6]=[C:5]2[C:20](=[O:22])[CH3:21].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.[OH:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[OH:27][CH:28]1[CH2:29][CH2:30][N:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:12]=[CH:13][C:14]([C:15](=[O:17])[NH:26][CH:23]5[CH2:25][CH2:24]5)=[CH:18][CH:19]=3)[CH:6]=[C:5]4[C:20](=[O:22])[CH3:21])=[O:39])=[CH:36][CH:35]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)c1cn(-c2ccc(C(=O)O)cc2)c2ccc(N)cc12
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Product: CC(=O)c1cn(-c2ccc(C(=O)NC3CC3)cc2)c2ccc(NC(=O)c3ccc(N4CCC(O)CC4)cc3)cc12

Procedure:
Compound 984 was prepared according to the procedure described in Scheme IV from 4-(5-amino-3-acetyl-1H-indol-1-yl)benzoic acid, cyclopropaneamine, and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C32H32N4O4: 537.24; found: 537.06.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].[N+](C1C=C[C:20]([O:23]C(Cl)=O)=CC=1)([O-])=O.CCN(CC)CC.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([CH2:53][C:54]2([C:59]([OH:61])=[O:60])[CH2:58][CH2:57][CH2:56][CH2:55]2)[CH2:49][CH2:48]1>C(Cl)Cl>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:20]([NH:45][CH2:46][CH:47]2[CH2:52][CH2:51][N:50]([CH2:53][C:54]3([C:59]([OH:61])=[O:60])[CH2:58][CH2:57][CH2:56][CH2:55]3)[CH2:49][CH2:48]2)=[O:23])[C:5]1=[O:13])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Reactant: NCC1CCN(CC2(C(=O)O)CCCC2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1c(=O)n(C(=O)NCC2CCN(CC3(C(=O)O)CCCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
A mixture of 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (10 g, 56.8 mmol) and chloroformic acid 4-nitrophenyl ester (11.4 g, 56.8 mmol) in CH2Cl2 (150 mL) was stirred at room temperature for 5 min. To this mixture, Et3N (17.4 mL, 125 mmol) was added slowly and the resulting mixture was added to a mixture of 1-{[4-(aminomethyl)piperidin-1-yl]methyl}cyclopentanecarboxylic acid 4-methylbenzene sulfonate (23.4 g, 56.8 mmol, Step 8) in CH2Cl2 (75 mL) at room temperature. After stirring for 10 min, Et3N (7.9 mL, 56.8 mmol) was added and the resulting mixture was stirred at room temperature for 2 hr. This mixture was washed with 1 N HCl aq (100 mL). Organic layer was concentrated at 50° C. until ca 5 vol and it was replaced by acetone (50 mL×3) at 80° C. until ca 5 vol. To this mixture, H2O (100 mL) was added at 80° C. and the resulting mixture was concentrated at 100° C. After cooling down to 50° C., 20% N,N-dimethylaminoethanol aqueous solution (100 mL) was added to this mixture and the solid was observed. The resulting mixture was cooled in ice cold bath and it was stirred for 18 hrs at that temperature. This mixture was filtered and the obtained solid was washed with H2O (100 mL), dried at 50° C. under vacuum to afford 17.9 g (71%) of the titled compound as white solid.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].CO>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(F)c1F
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(F)c(F)c(CO)c1

Procedure:
To a stirring solution of 2,3-difluoro-5-nitrobenzoic acid (Butt Park Ltd.; 9.00 g; 44.3 mmol) in THF at 0° C. was added a 1M solution of borane-tetrahydrofuran complex in THF (177.3 mL; 177.3 mmol). The mixture was allowed to react at RT overnight. Then, MeOH was cautiously added to the stirred mixture while cooling with an ice bath. The batch was diluted with ethyl acetate and washed with aqueous sodium hydroxide solution (1N) and saturated aqueous sodium chloride solution. The organic phase was dried (sodium sulfate), filtered and concentrated. The residue was purified by chromatography (hexane to hexane/ethyl acetate 1:2) to give the pure product (8.20 g; 43.4 mmol).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:23])[CH:7]([O:20][CH2:21][CH3:22])[CH2:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12]([OH:19])=[CH:11][CH:10]=1)[CH3:4].Cl[CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31].C(C1C=CC(C=O)=CC=1)(C)C.O=P(Cl)(Cl)Cl>CN(C)C=O.O>[CH2:3]([O:5][C:6](=[O:23])[CH:7]([O:20][CH2:21][CH3:22])[CH2:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12]([O:19][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:33]=[CH:34][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:37]=3)[O:29][C:30]=2[CH3:31])=[CH:11][CH:10]=1)[CH3:4]
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1CCCC2)OCC
Agent: CC(C)c1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(C(C)C)cc3)oc2C)c2c1CCCC2)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
0.037 g (1.54 mmol) Sodium hydride was added in small portions below 30° C. and under argon to a solution of 0.30 g (1.03 mmol) [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester in 5.0 ml N,N-dimethylformamide. After 10 minutes, 0.384 g (1.54 mmol) 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole (prepared from 4-isopropyl-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 21 a] and b]) were added and the reaction mixture then stirred for 16 hours at ambient temperature. It was then diluted with water and extracted with ether. The combined organic phases were dried over MgSO4 and evaporated. The residue formed was purified by flash-chromatography (silica gel; eluent: gradient of hexane and ethyl acetate) to give 0.35 g (67%) of [rac]-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.ClC(Cl)(Cl)C(O[C:31]([CH3:34])([CH3:33])[CH3:32])=O>C1COCC1.C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([O:11][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:10])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: CC(C)(C)OC(=O)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (2.2 g, 6 mmol) in dry THF (20 ml) under nitrogen, added the solution of tert-butyl 2,2,2-trichloroacetate (4.3 ml, 24 mmol) in dry DCM (10 ml), followed by BF3Et2O (0.1 ml, 0.72 mmol). The reaction was stirred at rt overnight. Quenched the reaction with sodium bicarbonate (sat. in water), diluted with EtOAc, washed with 1N HCl, water and brine, dried over anhydrous sodium sulfate. Concentrated, the result was purified by flash chromatography with EtOAc and hexane. Got 650 mg light yellow solid as product. MS calcd for (C19H23BN2O6S): 418.14. MS found (ESI negative): (M−H)−=417.0. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.83 (s, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.40 (d, J=1.6 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 7.09 (dd, J=8 Hz, 1H), 6.39 (d, J=6.8 Hz, 1H), 6.37 (s, 1H), 4.84 (s, 2H), 3.77 (s, 2H), 1.37 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[S:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][N:28]=1>C(O)CCC>[CH3:21][C:16]([CH3:20])([CH2:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:24]3[S:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][N:28]=3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:22])[C:17]([OH:19])=[O:18]
Reactant: CC(C)(CC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)O
Reactant: O=[N+]([O-])c1cnc(Br)s1
Solvent: CCCCO
Product: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3ncc([N+](=O)[O-])s3)cc2)cc1)C(=O)O
Temperature: 90 °C
Yield: 10.5 %

Procedure:
In a 8-mL screw-cap vial, a mixture of 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoic acid (60 mg, 0.20 mmol) and 2-bromo-5-nitro-1,3-thiazole (63.3 mg, 0.30 mmol) in 4 mL n-butanol was heated at 90° C. overnight. The solvent was removed under reduced pressure. The mixture was dissolved in 5 mL 1:4 MeOH/DMF and purified by reverse-phase HPLC to provide 8.9 mg (10%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 11.55 (br s, 1H), 8.50 (s, 11H), 7.70-8.05 (m, 8H), 3.15 (d, 1H), 1.25 (s, 6H); LC-MS m/z 426.2 (MH+), ret. time 3.12 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH3:38])=[O:36])=[CH:31][CH:30]=2)=[C:23]([CH3:39])[CH:22]=1>CC(O)C.Cl>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([C:29]3[CH:34]=[CH:33][C:32]([C:35](=[O:36])[NH:37][CH3:38])=[CH:31][CH:30]=3)=[C:23]([CH3:39])[CH:22]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccc(-c2cc(OC)c(N)cc2C)cc1
Reactant: COC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Product: CNC(=O)c1ccc(-c2cc(OC)c(Nc3ncc(Cl)c(Nc4ccccc4C(=O)OC)n3)cc2C)cc1
Temperature: 120 °C

Procedure:
A mixture of methyl 2-(2,5-dichloropyrimidin-4-ylamino)benzoate (Step 1, 50 mg, 0.16 mmol) and 4′-amino-5′-methoxy-N,2′-dimethylbiphenyl-4-carboxamide (Intermediate 31, 46 mg, 0.16 mmol) in 2-propanol is treated with conc. aqueous HCl (4 drops). The mixture is sealed and heated in a microwave at 120° C. for 20 min. The mixture is concentrated, and the residue is partitioned between ethyl acetate and sodium carbonate aqueous solution. The organic layer is concentrated to afford crude methyl 2-(5-chloro-2-(5-methoxy-2-methyl-4′-(methylcarbamoyl)biphenyl-4-ylamino)pyrimidin-4-ylamino)benzoate as a brown solid. The obtained crude product is treated with neat cyclopropylamine (0.5 mL). The mixture is heated in a sealed tube at 110° C. overnight. The mixture is concentrated and the residue is applied to RP-HPLC for purification to afford the 4′-(5-chloro-4-(2-(cyclopropylcarbamoyl)phenylamino) pyrimidin-2-ylamino)-5′-methoxy-N,2′-dimethylbiphenyl-4-carboxamide as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.75 (m, 1H), 8.49 (m, 1H), 8.15 (s, 1H), 7.91 (d, 2h0, 7.73-7.71 (m, 1H), 7.60 (m, 1H), 7.46 (d, 2H), 7.30-7.26 (m, 1H), 6.98 (s, 1H), 3.88 (s, 3H), 2.96 (s. 3H), 2.90-2.86 (m, 1H), 2.15 (s, 3H), 0.86-0.83 (m, 2H), 0.67-0.65 (m, 2H); ESMS m/z 557.2 (M+H+).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:25]([CH2:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)[CH2:11]2
Reactant: COc1ccc(CCCN)cc1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1ccc(CCCN2Cc3cccc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.245 g, 0.7 mmol), 3-(4-methoxy-phenyl)-propylamine (0.132 g, 0.8 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-[3-(4-methoxy-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.125 g, 44%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.01 (m, 2H), 2.63 (t, 2H), 3.64 (t, 2H), 3.79 (s, 3H), 4.24 (s, 2H), 6.80 (d, 2H), 7.08-7.44 (m, 4H), 7.90 (d, 1H). GC-MS: m/z 407 (M)+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:40]CC1.O>O=[Os](=O)(=O)=O>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: C=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OCC1Cc1ccccc1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
Dissolve 4-Benzyl-3-[2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one (3.09 g, 5.89 mmol) in 3/1 mix of THF/water (100 ml). Add OsO4 (5.99 g, 0.59 mmol) and NaIO4 (3.82 g, 17.86 mmol). Stir the resulting suspension for 3 hr at room temperature. Quench with 1M solution of sodium thiosulfate (300 ml). Extract in ethyl acetate. Column separation affords 0.885 g (28.5%) of 4-(4-Benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde.
Reaction SMILES: OOS([O-])=O.[K+].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:10].[C:20]([C:23]1[C:24]([CH:61]2[CH2:66][CH2:65][N:64](C(OC(C)(C)C)=O)[CH2:63][CH2:62]2)=[N:25][C:26]2[N:27]([N:46]=[CH:47][C:48]=2[C:49]2[CH:50]=[N:51][C:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:53][CH:54]=2)[C:28]=1[N:29](COCC[Si](C)(C)C)COCC[Si](C)(C)C)(=[O:22])[CH3:21].C1(I)C=CC=CC=1>C(#N)C.O>[NH2:29][C:28]1[N:27]2[N:46]=[CH:47][C:48]([C:49]3[CH:50]=[N:51][C:52]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)=[CH:53][CH:54]=3)=[C:26]2[N:25]=[C:24]([CH:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[C:23]=1[C:20](=[O:22])[CH2:21][OH:10]
Reactant: CC(=O)c1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=S([O-])OO
Agent: [K+]
Solvent: Ic1ccccc1
Solvent: O
Solvent: CC#N
Product: Nc1c(C(=O)CO)c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 15 h
Yield: 19.5 %

Procedure:
A solution of oxone (1.9 g, 3.1 mmol), trifluoroacetic anhydride (1.1 ml, 7.9 mmol) and H2O (5.7 ml) was stirred at 40° C. for 7 h, and then cooled to room temperature. To this a solution of tert-butyl 4-(6-acetyl-7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (0.87 g, 1.13 mmol) and PhI (0.03 ml, 0.23 mmol) in acetonitrile (17 ml) was added. The resulting solution was stirred at 90° C. for 15 h. On cooling, the reaction mixture was filtered and solids were washed with DCM. It was then concentrated in vacuo to give a crude product which was submitted to the analytical group for purification to afford the desired 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyethanone (94.2 mg, 17%).
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])C=[CH:2]1.[CH:9]([Cl:12])(Cl)Cl.S(Cl)([Cl:16])(=O)=O.OS(O)(=O)=O>CCOCC.[Ag]=O>[Cl:16][C:2]1[C:1](=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[C:9]=1[Cl:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: ClC(Cl)Cl
Reactant: O=C1C=CC(=O)C=C1
Agent: O=[Ag]
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: O=C1C=CC(=O)C(Cl)=C1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,4-Benzoquinone (2.01 g, 18.59 mmol) was dissolved in dry ether (50 mL) and dry chloroform (20 mL). The flask was placed under a constant flow of nitrogen and sulfuryl dichloride (5.02 g, 37.2 mmol) added dropwise over 15 minutes at 0° C. After 30 minutes the mixture was warmed to room temperature, stirred for another 30 minutes, returned to the ice-bath and treated with Et2O (25 mL) and conc. H2SO4 (30 mL). After 45 minutes the mixture was poured onto ice-water and extracted with further Et2O (3×75 mL). The combined organics were dried (MgSO4), filtered and concentrated to ca. 125 mL volume, whereupon silver oxide (9.96 g, 43 mmol) was added and the mixture stirred in the abscence of light for 1 hour. The mixture was filtered through celite, washing with ether and chloroform. Evaporation of the filtrate afforded an orange/yellow solid. The mixture was purified by flash chromatography, loading onto silica, eluting with a gradient of 0 to 20% EtOAc/Iso-Hexanes, holding at 9%, then re-purified by flash chromatography, loading onto silica, eluting with a gradient of 5 to 60% EtOAc/Iso-Hexanes, holding at 35%. This afforded compound x (1.15 g, 34.9%) as a bright yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C@:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:32]4[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:26]#[N:27])[CH:14]=3)[O:9][C@H:8]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:32]4[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:26]#[N:27])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3ccc(F)cc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccc(F)cc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Product: CN1C(=O)[C@@]2(C[C@@H](c3ccc(F)cc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 8 %
Yield: 10 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with 2′-amino-6-bromo-2-(4-fluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (40 mg, 0.099 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-cyanophenylboronic acid (29 mg, 0.197 mmol). The mixture was heated under microwave at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 3-((2S,4S)-2′-amino-2-(4-fluorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (19a) (6 mg, 10%), 1H-NMR (MeOD): 2.41 (t, 1H), 2.60 (t, 1H), 3.10 (s, 3H), 5.83 (d, 1H), 7.16 (m, 3H), 7.52 (m, 2H), 7.60 (m, 2H), 7.69 (m, 2H), 7.90 (m, 1H), 7.99 (d, 1H), and 3-(2′-amino-2-(4-fluorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chrom-an-4,4′-imidazole]-6-yl)benzonitrile (19) (4 mg, 8%), 1H-NMR (MeOD): 2.42 (t, 1H), 2.60 (t, 1H), 3.20 (s, 3H), 5.87 (d, 1H), 7.19 (m, 3H), 7.45 (m, 2H), 7.51 (m, 1H), 7.54 (m, 1H), 7.64 (m, 2H), 7.90 (t, 1H), 7.99 (d, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:19][C:20](=[O:22])[CH3:21])=[CH:7][C:8]2[S:13][C:12](=[O:14])[C:11]([C:15](O)=[O:16])=[CH:10][C:9]=2[CH:18]=1)(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([O:19][C:20](=[O:22])[CH3:21])=[CH:7][C:8]2[S:13][C:12](=[O:14])[C:11]([C:15]([Cl:25])=[O:16])=[CH:10][C:9]=2[CH:18]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2cc(C(=O)O)c(=O)sc2cc1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2cc(C(=O)Cl)c(=O)sc2cc1OC(C)=O

Procedure:
A mixture of 6,7-diacetoxy-2-oxo-2H-1-benzothiopyran-3-carboxylic acid (60 mg), thionyl chloride (40 μL), and dimethylformamide (one drop) was heated under reflux for 2 hours in benzene (15 mL), and then the solvent was distilled off. Benzene (15 mL) was added to the residue, and the benzene was distilled off again, followed by vacuum drying to yield 6,7-diacetoxy-2-oxo-2H-1-benzothiopyran-3-carbonyl chloride.