Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=O)[CH:3]=1.C(O)C.[NH3:13].C(Cl)(Cl)Cl>CCOCC>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:13][C:4](=[O:5])[CH:3]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: N
Solvent: CCO
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)cc(=O)[nH]1
Temperature: 25 °C
Yield: 88 %

Procedure:
4-Hydroxy-6-methyl-2H-pyran-2-one (11.1 g, 88.0 mmol) was suspended into ethanol (5.0 mL), added with 28% aqueous ammonia (55 mL), and the resultant mixture was stirred at 100° C. for 1 hour. The reaction solution was cooled down to room temperature, added with chloroform (25 mL) and ether (25 mL) to extract solid substance which was then washed sequentially with chloroform (10 mL), ether (10 mL) and tetrahydrofuran (30 mL), and concentrated in vacuo. Then, the obtained residue was further washed sequentially with chloroform (10 mL), ether (10 mL) and tetrahydrofuran (30 mL). 4-Hydroxy-6-methylpyridin-2(1H)-one (9.70 g, yield 88%) was obtained as a pale yellow crystal.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(O)=O)C3C=C(F)C([F:66])=CC=3N=2)=CC=1.NC1C=CC(C(OC)=O)=CC=1F>CN(C)C1C=CN=CC=1>[CH3:1][O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[C:7]([F:66])[CH:6]=1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: CN(C)c1ccncc1
Agent: COC(=O)c1ccc(N)c(F)c1
Product: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
This compound was prepared in analogy to example 22, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid, methyl 4-amino-3-fluorobenzoate and using 4-(dimethylamino)pyridine as base.
Reaction SMILES: CON(C)[C:4](=[O:38])[CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C:12]([C:13]3[CH2:14][CH2:15][C@@H:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C@H:18]([O:28][Si](C(C)(C)C)(C)C)[C:17]4([CH3:37])[CH3:36])=[CH:11][CH2:10]1)[CH3:8].[CH3:40][CH2:41][CH:42]([Mg]Br)[CH2:43][CH3:44].C(O)C.Cl>>[OH:28][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C:13]3[C:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:5][C:4]([CH:42]([CH2:43][CH3:44])[CH2:41][CH3:40])=[O:38])[CH2:10][CH:11]=4)[C:17]1([CH3:37])[CH3:36]
Reactant: CCC(CC)[Mg]Br
Reactant: CON(C)C(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Agent: Cl
Solvent: CCO
Product: CCC(CC)C(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid-N-methoxy-N-methyl amide (0.57 g) is reacted with 3-pentylmagnesiumbromide and hydrolysed with ethanol/HCl following the procedure outlined in example 6 to give the title compound (13 mg). 1H-NMR (CDCl3, 300 MHz): δ=5.35 (1H, s); 3.23 (1H, m). MS: Calculated: 454.7. Found: 454.3.
Reaction SMILES: [N:1]1([S:7]Cl)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:16][C:17]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])[CH:21]=[CH:20][C:18]=1[NH2:19]>C(OCC)C>[Cl:35][C:26]1[CH:27]=[C:28]([C:31]([F:32])([F:34])[F:33])[CH:29]=[CH:30][C:25]=1[O:24][C:22]1[CH:21]=[CH:20][C:18]([NH:19][S:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[C:17]([F:16])[CH:23]=1
Reactant: ClSN1CCOCC1
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Fc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1NSN1CCOCC1
Reaction time: 0.33 h
Yield: 59.3 %

Procedure:
The compound prepared in Example 5 (3.4 g) was dissolved in diethyl ether (10 ml). The solution was added to a solution of triethylamine (2.2 g) and the compound prepared in Example 1 (6.1 g) in diethyl ether (50 ml) at 15°-20° C. The solution was stirred for 20 minutes, diethyl ether was added (20 ml), the solution was washed with water, and dried. The solvent was removed by evaporation. Column chromatography on silica using 50:50 (v/v) diethyl ether-dichloromethane as eluant yielded the title compound as a brown oil (5 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]=2[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=1)=[O:4].[OH-].[Na+].Cl>CO.O>[C:14]([C:12]1[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2[CH:7]=[CH:8][N:9]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:10]=2[CH:11]=1)#[N:15]
Reactant: COC(=O)c1cc(C#N)cc2c1ccn2-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1cc(C(=O)O)c2ccn(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 6-cyano-1-(4-fluorophenyl)-1H-indole-4-carboxylic acid methyl ester (0.34 g, 1.2 mmol) in a mixture of MeOH—H2O (20 mL:5 mL) is added 2 N aqueous NaOH (40 mL) and the mixture is warmed at reflux. After 1 hour, the reaction is cooled to room temperature. The solution is acidified with 2 N aqueous HCl (pH=3). The solid is collected by filtration, washed with CH2Cl2 and dried to afford the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][CH2:19]OS(C3C=CC(C)=CC=3)(=O)=O)[C:13]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:8][CH:7]=1.O>CS(C)=O>[N:1]([CH2:19][CH2:18][CH2:17][N:14]1[CH:15]=[CH:16][C:12]([C:9]2[CH:8]=[CH:7][C:6]([F:5])=[CH:11][CH:10]=2)=[C:13]1[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCCn2ccc(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCCn1ccc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 10.5 %

Procedure:
0.38 g (5.90 mmol) of sodium azide were added to a solution of 1.33 g (2.95 mmol) of 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1-[3-(p-toluenesulfonyloxy)propyl]-1H-pyrrole [prepared as described in step 22(iii) above] in 13 ml of dimethylsulfoxide. The resulting mixture was stirred at 70° C. for 1 hour. At the end of this time water was added to the reaction mixture and then this was extracted with dichloromethane. The organic extract was washed with water and then concentrated under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 1:1 by volume mixture of hexane and ethylacetate as the eluant to afford 100 mg (yield 11%) of the title compound as a pale brown powder.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO.C1COCC1.C(Cl)Cl>[F:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: FC(F)(F)/C=C/c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Oc1ccc(CCC(F)(F)F)cc1
Yield: 72.5 %

Procedure:
A solution of (E)-1-(benzyloxy)-4-(3,3,3-trifluoroprop-1-enyl)benzene (305 mg, 1.096 mmol) and palladium on carbon (305 mg, 10 wt. %, wet, Aldrich) in MeOH (15 mL) and THF (5 mL) was placed under hydrogen (1 Atm) for 4 hrs. The resulting mixture was diluted with CH2Cl2 and filtered through a pad of CELITE® 545 filter aid. The filtrate was evaporated under reduced pressure and then purified by flash chromatography on silica gel (0 to 30% EtOAc/hexanes) to yield the title compound (151 mg, 72%) as a colorless oil. MS (ESI) 189 (M−H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:23])[CH2:11][N:10]([C:12]3[NH:13][C:14](=[O:22])[C:15]4[CH:20]=[CH:19][N:18]([CH3:21])[C:16]=4[N:17]=3)[CH2:9]2)=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:21][N:18]1[C:16]2[N:17]=[C:12]([N:10]3[CH2:9][C:8]([CH3:23])([C:5]4[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=4)[CH2:11]3)[NH:13][C:14](=[O:22])[C:15]=2[CH:20]=[CH:19]1
Reactant: Cn1ccc2c(=O)[nH]c(N3CC(C)(c4ccc(Br)cc4)C3)nc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1ccc2c(=O)[nH]c(N3CC(C)(c4ccccc4)C3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A mixture of 2-(3-(4-bromophenyl)-3-methylazetidin-1-yl)-7-methyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (100.3 mg, 269 μmol) in ethyl acetate (2.7 mL) and methanol (2.8 mL) was treated with 10% palladium on carbon (9.2 mg, ˜10% weight of starting material used). The flask was capped with a rubber septum and a hydrogen balloon was attached. The reaction was stirred at room temperature overnight. At this time, the reaction was concentrated in vacuo onto Celite®. Flash chromatography (24 g silica gel column, 20-100% ethyl acetate/hexanes) afforded 7-methyl-2-(3-methyl-3-phenyl-azetidin-1-yl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as an off-white solid (43.2 mg, 54.6%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61 (s, 3H) 3.53 (s, 3H) 4.10 (d, J=8.67 Hz, 2H) 4.24 (d, J=8.29 Hz, 2H) 6.23 (d, J=3.01 Hz, 1H) 6.73 (d, J=3.20 Hz, 1H) 7.13-7.50 (m, 5H) 10.90 (s, 1H). LC-MS calcd. for C17H19N4O [(M+H)+] 295, obsd. 295.1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:33])[CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].COCCOC>[CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:33])[CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc(C#CCCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a degassed solution of {4-[4-(3-tert-butoxycarbonylaminopropionylamino)phenyl]-but-3-ynyl}carbamic acid benzyl ester 320 (1.91 g, 4.1 mmol) and 1,2-dimethoxyethane (DME, 35 mL) was added 10% palladium on activated carbon (0.5 g, 50% wet). The mixture was hydrogenated overnight at 50 psi pressure. The catalyst was filtered through a pad of Celite and the solvent was evaporated in vacuo to provide 330 (1.78 g, 99%). 1H NMR (300 MHz, CDCl3) δ 1.42 (s, 9H), 1.58 (m, 4H), 2.59 (t, 4H), 3.17 (q, 2H), 3.47 (q, 2H), 5.18 (m, 3H), 5.58 (m, 1H), 5.70 (m, 1H), 7.07 (d, 2H), 7.33 (m, 5H), 7.49 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:15][C:5]2[S:6][CH2:7][CH:8]([CH2:11][C:12]([OH:14])=O)[C:9](=O)[C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:12](=[O:14])[CH2:11][CH:8]3[CH2:7][S:6][C:5]4[S:15][C:2]([CH3:1])=[CH:3][C:4]=4[C:9]3=[N:24]2)=[CH:19][CH:18]=1
Reactant: Cc1cc2c(s1)SCC(CC(=O)O)C2=O
Reactant: NNc1ccc(Cl)cc1
Solvent: CCO
Product: Cc1cc2c(s1)SCC1CC(=O)N(c3ccc(Cl)cc3)N=C21
Yield: 46.3 %

Procedure:
A mixture of 3.0 g of 2-methyl-4-oxo-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-acetic acid and 2.0 g of 4-chlorophenylhydrazine in 50 ml of ethanol is refluxed under heating for 9 hours. After cooling, the mixture is concentrated under reduced pressure, the residue is subjected to column chromatography on silica gel and eluted with chloroform. The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 2.0 g of 2-(4-chlorophenyl)-8-methyl-4a,5-dihydro-2H-thieno[2',3':2,3]thiopyrano[4,5-c]pyridazin-3(4H)-one as pale brown crystals, melting at 142°-144° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:19]=[C:6]2[O:7][C:8]3[CH2:9][N:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:12][C:13]=3[N:5]2[N:4]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[CH:19]=[C:6]2[O:7][C:8]3[CH2:9][N:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:12][C:13]=3[N:5]2[N:4]=1)=[O:1]
Reactant: CCOC(=O)N1CCc2c(oc3cc(CO)nn23)C1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCc2c(oc3cc(C=O)nn23)C1
Yield: 82.3 %

Procedure:
To the stirred solution of ethyl 2-(hydroxymethyl)-7,8-dihydropyrazolo[5′,1′:2,3][1,3]oxazolo[5,4-c]pyridine-6(5H)-carboxylate (1.76 g, 6.6 mmol) in 60 ml of CHCl3 was added 10 g of MnO2. Th suspension was refluxed for 1.5 hour under a nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated to give yellow solid. The product was purified by chromatography. 1.43 g of the product was obtained (82%); M.pt: 97-99° C. (M+H) 264.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](N)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.ClC1C=CC(C(Cl)=O)=CN=1.[Cl:22][C:23]1[CH:39]=[CH:38][C:26]([C:27]([NH:29]C2C=CC(I)=C(C)C=2)=[O:28])=[CH:25][N:24]=1>>[Cl:22][C:23]1[CH:39]=[CH:38][C:26]([C:27]([NH:29][C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][N:2]3[CH3:1])=[CH:6][CH:7]=2)=[O:28])=[CH:25][N:24]=1
Reactant: Cn1ccc2cc(N)ccc21
Reactant: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Agent: O=C(Cl)c1ccc(Cl)nc1
Product: Cn1ccc2ccc(NC(=O)c3ccc(Cl)nc3)cc21

Procedure:
6-Chloro-N-(1-methyl-1H-indol-6-yl)-nicotinamide was prepared from 1-methyl-1H-indol-5-ylamine (prepared as described in J. Med. Chem. 2007, 5509) and 6-chloronicotinoyl chloride in a manner similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after purification with a silica gel column and 0.0-30% EtOAc in hexanes gradient. H1 NMR (300 MHz, chloroform-d) d ppm 3.79 (s, 3H), 6.44 (d, J=3.0 Hz, 1H), 6.94 (dd, J=10.2, 8.4 Hz 1H), 7.04 (d, J=3.0, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.89 (s, 1H), 8.05 (s, 1H), 8.16 (dd, J=10.2, 8.4 Hz, 1H), 8.87 (apparent s, 1H)
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[S:16])=[CH:10][CH:9]=1.[BH4-].[Na+].S(=O)(=O)(O)O>O1CCCC1>[OH:1][CH:2]1[CH2:6][S:5][CH2:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[S:16])=[CH:10][CH:9]=1
Reactant: CC(C(O)=S)c1ccc(CC2CSCC2=O)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C(O)=S)c1ccc(CC2CSCC2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.9 %

Procedure:
2-[4-(4-Oxothiolan-3-ylmethyl)phenyl]thiopropionic acid (100 mg) obtained in Example 11 was dissolved in tetrahydrofuran (5.0 ml), and to the solution was added sodium borohydride (16.2 mg) under ice cooling, and then the reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, to the reaction mixture was added 0.5 M aqueous sulfuric acid, and the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the compounds of Example 12-A (pale brown oil, 16 mg, 15.9%) and Example 12-B (colorless oil, 12 mg, 11.9%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[N:23]1[C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=[CH:25][C:24]=1[C:32]([OH:34])=[O:33].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:29]([C:28]3[N:23]=[C:24]([C:32]([OH:34])=[O:33])[CH:25]=[CH:26][CH:27]=3)=[O:30])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: O=C(O)c1cccc(C(=O)O)n1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1

Procedure:
In a third alternate process for preparing the above named compound, 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.1 mmol) and 2,6-pyridinedicarboxylic acid (0.1 mmol) was dissolved in DCM (3 mL), and HOBt was added (1.0 eq, 14.0 mg) along with EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight. The solution was purified by preparative HPLC (Gilson) to yield 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid. This compound was dissolved in 3 mL of DCM along with 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (41.3 mg, 0.1 mmol), followed by the addition of HOBt (1.0 eq, 14.0 mg) and EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight and product was purified by preparative HPLC (Gilson) to give 1,1-dimethylethyl (2S)-4-[(5′-{[({6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate. This compound was then dissolved in 2 mL of dioxane:MeOH (3:1). Three drops of HCl (concentrated) were added to the resultant solution and it was heated at 60° C. for 1 h. The solution was applied to the amine column, rinsed with 10 mL of dioxane:MeOH (3:1) to afford 2.2 mg (2.9%) of the above named product. LC-MS m/z 749 (M+H)+, 1.32 min (ret time).
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([O:9][C:10]1[CH:11]=[C:12](N)[CH:13]=[N:14][CH:15]=1)([CH3:8])[CH3:7].N([O-])=[O:18].[Na+].[OH-].[Na+].[Na+].[Cl-]>O>[CH:6]([O:9][C:10]1[CH:11]=[C:12]([OH:18])[CH:13]=[N:14][CH:15]=1)([CH3:8])[CH3:7]
Reactant: CC(C)Oc1cncc(N)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1cncc(O)c1
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
A mixture of concentrated sulfuric acid (18 M, 2.64 mL), water (3.59 mL) and crushed ice (6.20 g) was added to 5-isopropoxy-3-pyridylamine (1.88 g, 12.38 mmol). The cold mixture (0-5° C.) was stirred for 10 min and a solution of sodium nitrite (0.85 g, 12.38 mmol) in water (2.5 mL) was then added. After stirring for 10 min, a boiling solution of concentrated sulfuric acid (8.0 mL) and water (6.2 mL) was added. The mixture was heated until all solids dissolved. Ice (5.0 g) was added to cool the solution. The pH was adjusted to 8 with 10% NaOH solution. Saturated NaCl solution (100 mL) was added, and the mixture was extracted with ethyl acetate (4×100 mL). The combined ethyl acetate extracts were dried (MgSO4), filtered and concentrated by rotary evaporation to give 1.69 g (89.4%) of a brown oil.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1N.O>CO>[CH2:1]([C:8]1[NH:9][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1ccccc1
Reactant: Nc1ccccc1N
Agent: Cl
Solvent: CO
Solvent: O
Product: c1ccc(Cc2nc3ccccc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1 M solution of benzyl cyanide in anhydrous methanol was treated with hydrogen chloride gas at 0° C. for about thirty minutes. The mixture was stirred for two hours at 0° C. and then a 1 M solution of diaminobenzene was added and the resulting solution was stirred at 0° C. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was then poured into water. The unreacted nitrile was extracted with ethyl acetate. The aqueous layer was neutralized with 1 N sodium hydroxide. The organic fraction was extracted with ethyl acetate and condensed. The desired title product was recrystallized from methanol/water.
Reaction SMILES: N1C=CC=CC=1C.Cl[S:9]([OH:12])(=[O:11])=[O:10].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)=[CH:16][C:15]=1I.C(=O)([O-])[O-].[Na+:34].[Na+]>>[S:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:9](=[O:11])(=[O:10])[O-:12])=[CH:15][CH:16]=1.[Na+:34]
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1I
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccn1
Product: O=S(=O)([O-])Nc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To anhydrous 2-picoline (1.05 g, 11 mmol) was slowly added dropwise chlorsulphonic acid (0.26 g, 2.21 mmol) below 10° C. then 2-(4'-amino-3'-iodophenyl)benzothiazole (0.5 g, 2.21 mmol). The mixture was heated to 50° C. with stirring for 1 hour. After leaving to stand for 2 hours at room temperature, 6 ml of 10% aqueous sodium carbonate was added. The resulting mixture was stirred for 40 minutes at room temperature and concentrated under reduced pressure. The precipitate was filtered off, washed carefully with cold water and treated with hot chlorform. Golden crystals were afforded (0.62 g, 85.5%), m.p. 288-290° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]3[O:25][C:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[N:23][C:22]=3[CH:32]=2)[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12].[C:33](O)(=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[F:8][C:9]1[CH:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]3[O:25][C:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:33](=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:28][CH2:27]4)=[N:23][C:22]=3[CH:32]=2)[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12]
Reactant: CC(C)CC(=O)O
Reactant: NC(=O)c1ccc(-c2ccc3oc(C4CCNCC4)nc3c2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)c(F)c4)ccc3o2)CC1
Yield: 15.2 %

Procedure:
Tert-butyl 4-[5-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate (140 mg, 0.32 mmol) dissolved in DCM (25 ml) and added trifluoroacetic acid (1 ml). This mixture stirred at rt for 3 h. After completion of the reaction, DCM removed on rotavapour and residue was co-distilled with ether to obtain 2-fluoro-4-(2-(piperidin-4-yl)-benzo[d]oxazol-5-yl)-benzamide 2,2,2-trifluoroacetate (140 mg). 2-Fluoro-4-(2-(piperidin-4-yl)-benzo[d]oxazol-5-yl)-benzamide 2,2,2-trifluoroacetate (140 mg, 0.31 mmol) was dissolved in DMF (5 ml) and added isovaleric acid (34.6 mg, 0.34 mmol), EDC.HCl (147 mg, 0.77 mmol), HOBt (50 mg, 0.37 mmol) and TEA (0.4 ml, 2.47 mmol). After completion of the reaction, water added to the reaction mixture to obtain solid. Solid was filtered and washed with ether to obtain the titled compound (20 mg) as a brown solid. M.P.: 186-190° C. MS (m/z): 424.1 [M+H]+.