Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH2:29]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH3:30]>C1COCC1>[CH2:29]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][C:2]([OH:4])=[O:3])=[CH:34][CH:33]=1)[CH3:30]
Reactant: CCOc1ccc(C=O)cc1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOc1ccc(CCCCC=CC(=O)O)cc1
Yield: 64 %

Procedure:
This compound was synthesized from 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) and p-ethoxybenzaldehyde (3.00 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (hexanes-ethyl acetate) afforded the product (3.18 g, 64%) as white crystals (mp 62-63° C.), IR: 3450-2500, 1720 cm-1 ; 1H-NMR: 1.40 (t, 3 H), 1.50 (m, 2 H), 1.70 (m, 2 H), 2.38 (m, 4 H), 4.00 (q, 2 H), 5.72+6.05 (m, 1 H), 6.32 (t, 1 H), 7.05 (q, 4 H), 10.10 (bs, 1 H). Anal. Calcd. for C15H20O3 : C, 72.55, H, 8.12% Found: C, 72.53, H, 8.15%. Z:E=45:55.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>C(=O)(OC)OC>[CH3:21][S:22]([O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:24])=[O:23]
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(=O)OC
Solvent: CCN(CC)CC
Product: COc1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 75.8 %

Procedure:
15.0 g (83.2 mmol) of 4-hydroxy-3-tert-butylanisole and 10.5 g (104 mmol) of triethylamine were dissolved in 250 ml of dimethyl carbonate (solvent), and 11.9 g (104 mmol) of methanesulfonyl chloride was dropwise added thereto, taking 25 minutes and controlling the inner temperature at 5° C. or lower. After the addition, this was stirred at 25° C. for 1.5 hours, the reaction mixture was poured into an aqueous saturated sodium bicarbonate solution, the aqueous layer was separated, the organic layer was washed twice with water, and then the organic layer was separated and concentrated. The concentrate was purified through distillation (139° C./32 pa) to give 16.3 g of 2-tert-butyl-4-methoxyphenyl methanesulfonate (yield, 76%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]3)[CH2:10][CH:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([Cl:34])[CH:33]=1>>[Cl:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:3]=[C:4]3[C@@:11]4([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]4)[CH2:10][CH:9]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:31]=[C:32]([Cl:34])[CH:33]=1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)COC1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(-c4cc(Cl)cc(Cl)c4)cc32)C(F)(F)COC1
Yield: 8 %

Procedure:
The cross coupling reaction of (2RS,4R)-6-bromo-6′,6′-difluoro-2-phenyl-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepin]-3′-amine (intermediate C3.4) with 3,5-dichlorophenylboronic acid yielded the title compound (8% yield) as a white solid. MS (ISP): m/z=489.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[N:15]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cccnc1Nc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
A mixture of N2-(3-chlorophenyl)pyridine-2,3-diamine (29 mg, 0.13 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (27 mg, 0.15 mmol), HOAt (20 mg, 0.15 mmol), 4-methylmorpholine (32 μL, 0.29 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol) in DCM (5 mL) was stirred at RT for 1 h then left standing at RT for 64 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The organic fraction was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting {(S)-1-[2-(3-chlorophenylamino)pyridin-3-ylcarbamoyl]ethyl}carbamic acid tert-butyl ester, as a brown oil (44 mg), was dissolved in AcOH (3 mL) and heated at 70° C. for 4 h. After cooling to RT, the volatiles were removed in vacuo. The resulting residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic fraction was washed water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting brown oil was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford the title compound as an orange/brown oil (35 mg, 72% over two steps). LCMS (Method C): RT 3.34 min [M+H]+ 373.2.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH2:11][C:12]([NH:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=1[CH:17]=[CH:18]O[C:20]3=[O:25])=[O:13])[CH2:8]2.[NH3:26]>C(O)C>[CH:3]12[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]([CH2:10]3)[CH:2]1[CH2:11][C:12]([NH:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=1[CH:17]=[CH:18][NH:26][C:20]3=[O:25])=[O:13])[CH2:9]2
Reactant: O=C(CC1C2CC3CC(C2)CC1C3)Nc1cccc2c(=O)occc12
Reactant: N
Solvent: CCO
Product: O=C(CC1C2CC3CC(C2)CC1C3)Nc1cccc2c(=O)[nH]ccc12
Temperature: 115 °C
Yield: 45 %

Procedure:
90 mg (0.27 mmol) of 2-adamantyl-N-(1-oxo-1H-isochromen-5-yl)acetamide (1) was treated with 10 mL (20 mmol) of a 2 M ammonia solution in ethanol at room temperature in a resealable tube. The reaction vessel was sealed and heated at 115° C. for 48 h. After the reaction mixture was cooled down to room temperature, the solvent was evaporated and residue obtained was purified by prep. HPLC to yield 2-adamantyl-N-(1-oxo-1,2-dihydroisoquinolin-5-yl)acetamide (2a) (41 mg, 0.122 mmol, 45%) as an off-white powder. HPLC ret. time 2.07 min, 10-100% CH3CN, 3.5 min gradient; ESI-MS m/z 337.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]2[N:6](COC)[C:7]([C:9]3[N:10]([CH3:26])[C:11]4[C:16]([CH:17]=3)=[CH:15][C:14]([CH:18]=[C:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:13][CH:12]=4)=[N:8][C:4]=2[CH:3]=1.Cl.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]2[N:6]=[C:7]([C:9]3[N:10]([CH3:26])[C:11]4[C:16]([CH:17]=3)=[CH:15][C:14]([CH:18]=[C:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:13][CH:12]=4)[NH:8][C:4]=2[CH:3]=1
Reactant: COCn1c(-c2cc3cc(C=C4SC(=O)NC4=O)ccc3n2C)nc2cc(Cl)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1c(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc2cc(C=C3SC(=O)NC3=O)ccc21
Yield: 51.1 %

Procedure:
To a solution of 5,6-dichloro-2-[5-[(2,4-dioxothiazolidin-5-ylidene)methyl]-1-methylindol-2-yl]-1-(methoxymethyl)benzimidazole obtained in Example 48 (26 mg, 0.053 mmol) in 1,4-dioxane (5 mL) was added concentrated hydrochloric acid (0.5 mL), and the mixture was heated to reflux for 1 h. The pH was adjusted to 7 by 2 mol/L sodium hydroxide and the precipitated products were collected by filtration to afford 5,6-dichloro-2-[5-[(2,4-dioxothiazolidin-5-ylidene)methyl]-1-methylindol-2-yl]benzimidazole (12 mg, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:8]([CH:12]=O)[CH2:9]2)=[CH:5][CH:4]=1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20]>ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:12]/[C:8]1[CH2:9][C:10]2[C:6]([C:7]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCC1=C(C=O)Cc2cc(OC)ccc21
Solvent: ClCCl
Product: CCCCCC1=C(/C=C/C(=O)OC)Cc2cc(OC)ccc21
Yield: 61.2 %

Procedure:
As in Example 111, 6-methoxy-3-pentyl-1H-2-indenecarboxaldehyde (8.5 g) and (carbomethoxymethylene)triphenylphosphorane (18.8 g) in dichloromethane (75 mL) was stirred at room temperature for 42 hours. The crude reaction product from the normal work up was purified by HPLC (diethyl ether-hexane; 1:3) to provide 6.4 g of (E)-3-(6-methoxy-3-pentyl-1H-inden-2-yl)-2-propenoic acid methyl ester as an oil.
Reaction SMILES: NC1C2C=CN(C(OCC3C=CC=CC=3)=O)C=2C=CN=1.C(N(CC)CC)C.C1(C(Cl)=O)CC1.[CH:34]1([C:37]([N:39](C(C2CC2)=O)[C:40]2[C:45]3[CH:46]=[CH:47][N:48](C(OCC4C=CC=CC=4)=O)[C:44]=3[CH:43]=[CH:42][N:41]=2)=[O:38])[CH2:36][CH2:35]1.C1(C(NC2C3C=CN(C(OCC4C=CC=CC=4)=O)C=3C=CN=2)=O)CC1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO>[NH:48]1[C:44]2[CH:43]=[CH:42][N:41]=[C:40]([NH:39][C:37]([CH:34]3[CH2:35][CH2:36]3)=[O:38])[C:45]=2[CH:46]=[CH:47]1
Reactant: O=C(C1CC1)N(C(=O)C1CC1)c1nccc2c1ccn2C(=O)OCc1ccccc1
Agent: Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Agent: O=C(Cl)C1CC1
Agent: O=C(Nc1nccc2c1ccn2C(=O)OCc1ccccc1)C1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1nccc2[nH]ccc12)C1CC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a stirred solution of benzyl 4-amino-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (1 g, 3.5 mmol) in tetrahydrofuran was added triethylamine (1 mL, 7 mmol). The mixture was cooled to −10° C. and cyclopropanecarbonyl chloride (0.53 mL, 5.3 mmol) was added drop wise. The reaction mixture was stirred at room temperature for 1 hour, followed by concentration under vacuum to remove tetrahydrofuran. The residue was dissolved in ethyl acetate and organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to give the crude mixture of benzyl 4-[bis(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridine-1-carboxylate and benzyl 4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridine-1-carboxylate. The mixture was treated with a saturated potassium carbonate solution in methanol and stirred at room temperature followed by removal of methanol under vacuum at the same temperature. The residue was treated drop wise with saturated aqueous sodium bicarbonate solution and the precipitated solid was filtered, washed with water and dried to yield N-(1H-pyrrolo[3,2-c]pyridin-4-yl)cyclopropanecarboxamide (0.5 g, 69%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[N:6][CH:7]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Brc1ccc(NCCN2CCCC2)nc1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(NCCN4CCCC4)nc3)nc2)cc1

Procedure:
The product is obtained analogously to Example 3.16b is from 90 mg (0.33 mmol) (5-bromo-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine and 88 mg (0.41 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:18][C@H:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C@@H:20]([NH2:22])[CH3:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:18][C@H:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C@@H:20]([NH:22][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cccc([C@@H](Oc2cc3cnn(-c4ccc(F)cc4)c3cc2C)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2cc3cnn(-c4ccc(F)cc4)c3cc2C)[C@H](C)NC(=O)C(C)(C)C)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (73 mg, 0.18 mmol) and pivaloyl chloride (0.088 ml, 0.72 mmol). Yield 75 mg (85%).
Reaction SMILES: [N:1]1[N:2]([CH2:10][C:11](=[O:13])[CH3:12])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.ClCC(=O)C.C(=O)([O-])[O-].[K+].[K+].[NH:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[N:26]1.[NH2:34]C1C(C)=NC=CC=1>>[NH2:34][C:11]([CH3:12])([CH2:10][N:2]1[CH:3]=[C:4]2[N:5]=[CH:6][CH:7]=[CH:8][C:9]2=[N:1]1)[C:33]#[N:25].[N:1]1[N:2]([CH2:10][C:11](=[O:13])[CH3:12])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.[NH:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[N:26]1
Reactant: Cc1ncccc1N
Agent: CC(=O)CCl
Agent: CC(=O)Cn1cc2ncccc2n1
Agent: O=C([O-])[O-]
Product: CC(N)(C#N)Cn1cc2ncccc2n1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(2H-pyrazolo[4,3-b]pyridin-2-yl)-propionitrile (27 mg), the title compound was isolated as a white solid (8 mg). MS (ES): M/Z [M+H]=390. 1H NMR: (400 MHz, CHLOROFORM-d): 1.94 (s, 3H), 4.87 (d, J=14.1 Hz, 1H), 5.04 (d, J=14.1 Hz, 1H), 7.31 (d, J=7.6 Hz, 3H), 7.90 (d, J=8.8 Hz, 2H), 8.05 (d, J=8.8 Hz, 1H), 8.30 (s, 1H), 8.43 (s, 1H) and 8.65 (d, J=2.9 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F). 2-Amino-2-methyl-3-(2H-pyrazolo[4,3-b]pyridin-2-yl)-propionitrile (37 mg) was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (37 mg). 1-(2H-Pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (37 mg, 6.6%; MS (ES): M/Z [M+H]=176) was prepared using a procedure similar to that described in Example 182 part g using chloroacetone and potassium carbonate except starting from 1H-pyrazolo[4,3-b]pyridine (380 mg). 1H-pyrazolo[4,3-b]pyridine (380 mg, 34%) was prepared using a procedure similar to that described in Example 182 part f except starting from 3-amino-2-methylpyridine (1 g).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:13][CH:14]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:13][CH:14]=1
Reactant: COC(=O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(O)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred solution of methyl 2-(5-((tert-butyldimethylsilyl)oxy)pyridin-2-yl)acetate (1 g, 3.5 mmol) in THF was added TBAF (1M, 3.5 ml) at room temperature. The whole mixture was stirred at room temperature overnight. It was evaporated and extracted with EtOAc, the organic layer was washed with water, evaporated and purified by a standard method.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH:7]1[CH3:14].[ClH:15].Cl.[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.[Na+].[I-]>C(#N)C>[ClH:15].[ClH:15].[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([N:32]3[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]4[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH:7]4[CH3:14])[CH2:34][CH2:33]3)=[CH:24]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(-n2cc(N3CCNCC3)c3ccccc32)cc1
Reactant: CC1SC(C)(C)C(=O)N1CCCCBr
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1SC(C)(C)C(=O)N1CCCCN1CCN(c2cn(-c3ccccc3)c3ccccc23)CC1
Temperature: 75 °C
Yield: 45.8 %

Procedure:
A mixture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone (5.00 g), 1-(1-phenyl-1H-indol-3-yl)piperazine dihydrochloride (7.80 g), N,N-diisopropylethylamine (9.65 g), NaI (350 mg) in acetonitrile (250 ml) was heated at 75° C. for 17 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.80 g of crystals, m.p. 217°-219° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:28]=[N:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH:14]=1)=[O:11].O>CN(C=O)C>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:27]=[CH:28][C:19]=1[C:15]1[CH:14]=[C:13]([NH:12][C:10](=[O:11])[CH2:9][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:18]=[CH:17][CH:16]=1
Reactant: c1nc[nH]n1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1cncn1)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.1 %

Procedure:
To a solution of 1,2,4-triazole (18 mg, 0.258 mmol) in DMF (1 mL), NaH (11.5 mg 60% in mineral oil, 0.282 mmol) was added and the slurry was stirred at room temperature for 5 min. To the slurry, 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (70 mg, 0.235 mmol) in DMF (2 mL) was added at room temperature at stirred for 2 days. Water (5 mL) was added and the reaction mixture was extracted with ethyl acetate (25 mL). The organic phase was dried over MgSO4, the solvent evaporate in vacuo, and the resulting solid was purified by preparative LCMS to afford N-[3-(quinoxalin-2-yl)phenyl]-2-(1H-1,2,4-triazol-1-yl)acetamide (56 mg, 72% yield). LCMS calculated for C18H14N6O (M+H): 331.34. found 331.11. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.65 (1H, br. s), 9.52 (1H, s), 8.58 (1H, s), 8.55 (1H, m), 8.12 (1H, m), 8.10 (1H, d, J=7 Hz), 8.04 (1H, s), 7.98-7.80 (3H, m), 7.58 (1H, m), 5.21 (2H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:14])[N:3]=1.[NH2:15][CH:16]1[CH:20]([F:21])[CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:17]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[F:21][CH:20]1[CH:16]([NH:15][C:2]2[N:3]=[C:4]([CH3:14])[CH:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)[CH2:17][N:18]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:19]1
Reactant: NC1CN(C(=O)OCc2ccccc2)CC1F
Reactant: Cc1cc(N2CCOCC2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCOCC2)nc(NC2CN(C(=O)OCc3ccccc3)CC2F)n1
Yield: 7.1 %

Procedure:
A mixture of 4-(2-chloro-6-methylpyrimidin-4-yl)morpholine (180 mg), benzyl (3RS,4RS)-3-amino-4-fluoropyrrolidine-1-carboxylate (240 mg), Pd(OAc)2 (38 mg), 2-(di-t-butylphosphino)biphenyl (0.10 g), sodium t-butoxide (0.24 g), and toluene (2 mL) was heated to reflux under nitrogen atmosphere for 6 h. The reaction solution was extracted with chloroform and dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=1:2) to obtain benzyl (3RS,4RS)-3-fluoro-4-(4-methyl-6-morpholin-4-ylpyrimidin-2-ylamino)pyrrolidine-1-carboxylate (25 mg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]1([CH2:15][N:16]([CH2:39][CH:40]2[CH2:42][CH2:41]2)[C:17]2[C:18]([S:36]([CH3:38])=[O:37])=[N:19][N:20]3[C:25]([C:26]4[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])=[CH:24][CH:23]=[CH:22][C:21]=23)[CH2:14][CH2:13]1.O.C(OCC)(=O)C>ClCCl>[CH:12]1([CH2:15][N:16]([CH2:39][CH:40]2[CH2:42][CH2:41]2)[C:17]2[C:18]([S:36]([CH3:38])(=[O:9])=[O:37])=[N:19][N:20]3[C:25]([C:26]4[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])=[CH:24][CH:23]=[CH:22][C:21]=23)[CH2:13][CH2:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(S(C)=O)nn12
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(S(C)(=O)=O)nn12
Reaction time: 4 h
Yield: 5.4 %

Procedure:
m-Chloroperbenzoic acid (91 mg) was added to a solution of N,N-dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfinyl)pyrazolo[1,5-a]pyridin-3-yl]amine (162 mg) in dichloromethane (10 mL) at 0° C., and the mixture was stirred for 4 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (10 g), and the title compound (9 mg) was obtained from the n-hexane:ethyl acetate (1:2) fraction as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C(N)(N)=[O:13].OO.C1(=O)OC(=O)C2=CC=CC=C12.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:11])=[N+:4]([O-:13])[CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: NC(N)=O
Reactant: COc1c(C)cnc(C)c1Cl
Agent: O=C1OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1c(C)c[n+]([O-])c(C)c1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.5 %

Procedure:
The above 3-chloro-4-methoxy-2,5-dimethylpyridine (181 mg) was dissolved in 5 ml of dichloromethane, and urea peroxide (169 mg) and phthalic anhydride (219 mg) were then added to the solution. The resulting mixture was stirred at room temperature for 2.5 hours. Thereafter, a saturated aqueous sodium thiosulfate solution was added to the reaction solution under cooling on ice, and the resulting mixture was then diluted with chloroform. The water layer was extracted with chloroform two times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away, so as to obtain the title compound (181 mg) as a solid.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:20]([C:22]3[O:23][C:24](=[O:38])[C:25]4[C:30]([C:31]=3[C:32]3[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:21])[N:10]=[C:11]([C:12]3[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([F:19])[CH:13]=3)[C:4]=12.[CH:39](=O)[C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1.CCN(C(C)C)C(C)C.[O-]S([O-])(=O)=O.[Na+].[Na+].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:20]([C:22]3[O:23][C:24](=[O:38])[C:25]4[C:30]([C:31]=3[C:32]3[CH2:33][CH2:34][N:35]([CH2:39][C:40]5[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=5)[CH2:36][CH:37]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:21])[N:10]=[C:11]([C:12]3[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([F:19])[CH:13]=3)[C:4]=12
Reactant: CC(c1oc(=O)c2ccccc2c1C1=CCNCC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(c1oc(=O)c2ccccc2c1C1=CCN(Cc2ccncc2)CC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one hydrochloride (example 64, 37 mg, 0.064 mmol), isonicotinaldehyde (8.89 mg, 0.083 mmol) and DIEA (11.15 μl, 0.064 mmol) were dissolved in DCM (1.23 ml) followed by a spatula tip of anhydrous Na2SO4, and the mixture stirred rt for 10 min prior to add AcOH (10.97 μl, 0.192 mmol) and NaBH(OAc)3 (27.1 mg, 0.128 mmol). The resulting mixture was stirred for 1 h at rt, then quenched with 2M HClaqueous (1 ml), filtered to remove insoluble materials, and the filtrate purified via reverse phase chromatography using a Biotage C18 60 g SNAP with a gradient of water and acetonitrile to give (prior to drying a small amount of 1M HClaqueous was added) the title compound (10.6 mg, 26.5%) as white solid.