Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]([OH:28])=O)[N:25]=1)[CH3:20])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][C@@H:30]([CH3:46])[CH2:31][N:32]1[CH:36]=[CH:35][C:34]([C:37]2[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[C:39]([Cl:45])[CH:38]=2)=[N:33]1>>[Si:1]([O:18][CH:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]([NH:29][C@@H:30]([CH3:46])[CH2:31][N:32]2[CH:36]=[CH:35][C:34]([C:37]3[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[C:39]([Cl:45])[CH:38]=3)=[N:33]2)=[O:28])[N:25]=1)[CH3:20])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1nc(C(=O)O)cs1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-4-carboxylic acid (326 mg, 0.792 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (105 mg, 0.403 mmol). After extraction, based on the LC-MS data, the product was estimated to be pure enough for the next step. LC-MS: [M+1]=655.30.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:16]2[CH:25]=[C:24]([O:26][CH2:27][CH2:28][F:29])[CH:23]=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:16]2[CH:25]=[C:24]([O:26][CH2:27][CH2:28][F:29])[CH:23]=[CH:22][C:17]=2[C:18]([OH:20])=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OCCF)cc1OCC1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(COc2cc(OCCF)ccc2C(=O)O)C1

Procedure:
Using a procedure similar to that of Example 26-C, the ester is hydrolyzed using LiOH.H2O (1.50 g, 2.2 equivalents), water (20 mL) and THF (60 mL) to afford the acid (2.93 g, 59% for the two steps).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36]>CN(C=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[S:23][CH:24]=[C:20]([CH2:19][S:18][C:4]3[N:3]=[C:2]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:7]([C:8]#[N:9])=[C:6]([N:10]4[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]4)[C:5]=3[C:16]#[N:17])[N:21]=2)=[CH:26][CH:27]=1
Reactant: NCCC(=O)O
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Solvent: CN(C)C=O
Product: N#Cc1c(NCCC(=O)O)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 70 mg (0.14 mmol) of the compound from Example 4A and 27 mg (0.30 mmol) of beta-alanine in 2 ml of DMF is stirred at RT for 8 h. The mixture is then stirred at +90° C. for 2 h. After cooling to RT the reaction mixture is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([C:9]1[CH:38]=[CH:37][C:12]2[N:13]([C:20]3[CH:25]=[N:24][C:23]([NH:26][C:27](=[O:36])[C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=4[F:35])=[CH:22][N:21]=3)[C:14]([C:16]([F:19])([F:18])[F:17])=[N:15][C:11]=2[CH:10]=1)=[O:8])C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CCOC(C)=O>CS(O)(=O)=O>[F:34][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([F:35])[C:28]=1[C:27]([NH:26][C:23]1[CH:22]=[N:21][C:20]([N:13]2[C:12]3[CH:37]=[CH:38][C:9]([C:7]4[O:8][CH:4]=[CH:5][N:6]=4)=[CH:10][C:11]=3[N:15]=[C:14]2[C:16]([F:19])([F:18])[F:17])=[CH:25][N:24]=1)=[O:36]
Reactant: CCOC(CNC(=O)c1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1)OCC
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOC(C)=O
Product: O=C(Nc1cnc(-n2c(C(F)(F)F)nc3cc(-c4ncco4)ccc32)cn1)c1c(F)cccc1F
Temperature: 130 °C
Reaction time: 3 h
Yield: 11.4 %

Procedure:
Into a 50 mL roundbottom flask, was placed a solution of 1-[5-(2,6-difluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid (2,2-diethoxy-ethyl)-amide (xiv) (50 mg, 0.09 mmol, 1.00 equiv) in CH3SO3H (3 g). To the mixture was added P2O5 (80 mg, 0.56 mmol, 5.00 equiv). The resulting solution was allowed to stir at 130° C. for 3 h, then was diluted with ice water and extracted three times with 150 mL of EtOAc. The organic layers were combined and dried over Na2SO4. After removal of the solvent and volatile components, the residue was purified by eluting through a silica gel column with first a 1:3 and then 1:2 EtOAc/PE solvent system to provide 2,6-difluoro-N-[5-(5-oxazol-2-yl-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide (5 mg, 12% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1
Reactant: CN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(C(O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 4-chlorophenyl 1-methylpiperidin-4-yl methanone 1.19 g (5 mmol) in 30 ml methanol was added in small portions sodium borohydride 0.378 g (10 mmol). The reaction mixture was stirred at room temperature for two hours, concentrated, added water and extracted with methylene chloride 2×50 ml. The combined organic solution was dried over sodium sulfate and concentrated to give 1.2 g of desired product in 98% yield.
Reaction SMILES: [O:1]1[CH:6]([C:7]([O-:9])=[O:8])[CH:2]1[C:3]([O-:5])=[O:4].[Ca+2]>P(OCCCCCCCC)(OCCCCCCCC)(OCCCCCCCC)=O>[O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C([O-])C1OC1C(=O)[O-]
Agent: CCCCCCCCOP(=O)(OCCCCCCCC)OCCCCCCCC
Agent: [Ca+2]
Product: O=C(O)C1OC1C(=O)O

Procedure:
The yield in the reaction effected in trioctyl phosphate amounted to 96%. From 2 moles of acid calcium epoxysuccinate, 507 g. of free epoxysuccinic acid in aqueous solution were obtained.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl:11][C:12]1[N:16]([CH3:17])[N:15]=[C:14]([CH3:18])[C:13]=1[S:19](Cl)(=[O:21])=[O:20].O1CCCC1>C(OCC)C.C(=O)(O)[O-].[Na+]>[Cl:11][C:12]1[N:16]([CH3:17])[N:15]=[C:14]([CH3:18])[C:13]=1[S:19]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:20])=[O:21]
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2c(C)nn(C)c2Cl)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
A mixture of orcinol monohydrate (650 mg, 4.58 mmol) and 1.03 g (4.50 mmol) of 5-chloro-1,3-dimethylpyrazole-4-sulfonyl chloride in diethyl ether (20 mL) and saturated aqueous sodium bicarbonate (20 mL) was stirred overnight. To the reaction mixture was added 15 mL of tetrahydrofuran, and the reaction mixture was heated to 50° C. for 1 h and at 70° C. for 1 h. The reaction mixture was cooled to room temperature, extracted into ethyl acetate, dried (MgSO4), and purified by flash chromatography (dichloromethane/diethyl ether (100:0 to 95:5 to 93:7)) to give the title compound (558 mg, 37% yield) as an oil. 1H-NMR (300 MHz, CDCl3) δ 6.91-6.92 (m, 1H), 6.57-6.61 (m, 1H), 6.41-6.50 (m, 1H), 5.93 (s, 1H), 3.82 (s, 3H), 2.29 (s, 3H), 2.25 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C12H13ClN2O4S: 316.9 (M+H). Found: 317.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[C:7]2[S:8][C:9]([B:11]([OH:16])[OH:12])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2ccsc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OB(O)c1cc2cccc(Cl)c2s1
Temperature: -30 °C
Yield: 96.2 %

Procedure:
To a solution of 7-chlorobenzo[b]thiophene (1.0 g, 5.92 mmol) in THF (25 mL) at −78° C. was added nbutyllithium (7.41 mL, 11.8 mmol, 1.6 M solution). The reaction was allowed to warm to −30° C. then was cooled back to −78° C. and triisopropyl borate (2.23 g, 11.8 mmol) was added. The mixture was allowed to warm to 0° C., saturated ammonium chloride added and the organic phase separated off and concentrated in vacua. To the residue was added aqueous sodium hydroxide (10 mL, 2N solution) followed by water (30 mL) and the mixture was washed with DCM. The aqueous phase was acidified with 2N sulfuric acid, and the resulting precipitate isolated by filtration and dried under vacuum to yield 7-chlorobenzo[b]thiophene-2-boronic acid (1.21 g, 96%) as white solid. 1H NMR (400 MHz, CDCl3) δ=7.41 (t, J=7.70 Hz, 1H), 7.50 (d, J=7.70 Hz, 1H), 7.91 (d, J=7.70 Hz, 1H), 8.03 (s, 1H), 8.63 (s, 2H); MS (ES+): m/z 211.86 [M+].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C@H:38]([NH2:40])[CH3:39].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C@H:38]([NH:40][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH:19]=1)=[O:23])[CH3:39]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@@H](N)c1ccco1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (300 mg, 0.68 mmol) and (R)-1-furan-2-yl-ethylamine hydrochloride (416 mg, 1.55 mmol). DMF (3.5 ml) was added followed by N,N-diisopropylethylamine (0.85 ml, 4.87 mmol) and HATU (284 mg, 0.75 mmol). The reaction was stirred at room temperature overnight then water and petroleum ether were added. The resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 338 mg (88%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-furan-2-yl-ethyl)-amide as a light brown powder.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]3=[O:17])[CH2:7][CH2:6]2)[O:4]CC1.Cl.C(=O)(O)[O-].[Na+]>CC(C)=O>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[O:17])[CH2:7][CH2:6]1
Reactant: O=c1ccccn1C1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CCC(n2ccccc2=O)CC1

Procedure:
A solution of 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-1H-pyridin-2-one (as prepared in the previous step, ˜300 mg, 1.28 mmol)) in acetone (10 mL) was treated with 1N HCl (2 mL) at room temperature for 4 hours. The reaction was worked up with saturated sodium bicarbonate to adjust the pH to neutral. The solvent was removed in vacuo and residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated to afford the title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1.Cl>[CH2:22]([O:21][C:19]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)=[O:20])[CH3:23]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)n1ccc2cc(N)ccc21
Temperature: 0 °C
Yield: 112.2 %

Procedure:
To a solution of 4.27 gm (32.3 mMol) 5-amino-1H-indole in 50 mL tetrahydrofuran were added 5.4 ML (38.8 mMol) triethylamine and the reaction mixture was then cooled to 0° C. To this solution were then added dropwise 3.4 mL (35.5 mMol) ethyl chloroformate. After 4 hours the reaction mixture was diluted with 1N HCl and was then extracted with ethyl acetate. The organic phase was washed sequentially with 1N HCl, water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure to give 7.4 gm of a dark oil. This oil was purified by flash chromatography, eluting with a gradient of dichloromethane containing 0-2.5% methanol, to give 4.95 gm (75%) of the title compound as a tan solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[BrH:12].[Br:13]CC(C1C=C(C)C=CN=1)=O>>[BrH:13].[Br:12][CH2:2][C:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: Cc1ccnc(C(=O)CBr)c1
Reactant: COc1ccnc(C(C)=O)c1
Agent: Br
Product: COc1ccnc(C(=O)CBr)c1

Procedure:
* 2-Bromoacetyl-4-methoxypyridine hydrobromide was prepared from 2-acetyl-4-methoxypyridine (B. Case et al., J. Org. Chem., 1961, 26, 4415) according to the procedure for preparing 2-bromoacetyl-4-methylpyridine hydrobromide described in step 2 of Example 31.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:19]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:3]=1
Reactant: Clc1ccccc1C(c1ccccc1)c1ccccc1
Reactant: Fc1cnc2[nH]nc(Br)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cnc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-5-fluoro-1H-pyrazolo[3,4-b]pyridine, 4, (0.97 g, 4.49 mmol) and K2CO3 (1.86 g, 13.47 mmol) in DMF (9.7 mL) was cooled to 0° C. Chlorodiphenylmethylbenzene (1.38 g, 4.94 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was diluted with 40 mL of ethyl acetate and washed with 30 mL of water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (40% ethyl acetate/hexanes) to afford 1.68 g of the desired product as a white solid: 1H NMR (300 MHz, d6-DMSO) δ 8.45-8.38 (m, 1H), 8.04 (dd, J=8.0, 2.7 Hz, 1H), 7.35-7.16 (m, 15H); LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, Retention Time=3.03 min, (M+H) 459.46.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13]([CH:16]=[N:17][O:18][CH2:19][CH2:20][OH:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].C(N(CC)C(C)C)(C)C.[CH3:40][Si:41]([C:44]#[CH:45])([CH3:43])[CH3:42]>O1CCCC1.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.[Cu](I)I>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:45]#[C:44][Si:41]([CH3:43])([CH3:42])[CH3:40])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][CH2:20][OH:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1cc(C=NOCCO)c(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(Nc2c(C(=O)NOCCO)cc(/C=N/OCCO)c(F)c2F)c(F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyimino)-methyl]-benzamide (334 mg, 0.620 mmol) prepared in Example 1 was dissolved in anhydrous tetrahydrofuran (10 mL). (PPh3)2PdCl2 (20,867-1, Sigma-Aldrich Inc.) (21 mg, 0.031 mmol), copper iodide (11 mg, 0.0062 mmol), N,N-diisopropylethylamine (130 μL, 0.774 mmol), and trimethylsilylacetylene (1 mL) were then added thereto at room temperature. The mixture was stirred at 50° C. for two hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]([C:13]([O:15][CH2:16]C)=[O:14])[CH2:6][CH2:5]2.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([O:12][C:11]1[CH:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH:7]([C:13]([O:15][CH3:16])=[O:14])[O:8]2)=[CH:3][C:2]=1[Cl:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCc2cc(Cl)c(O)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CCc2cc(Cl)c(OCc3ccccc3)cc2O1
Reaction time: 0.33 h
Yield: 6.9 %

Procedure:
A solution of ethyl 6-chloro-7-hydroxychroman-2-carboxylate (3.0 g, 11.7 mmol) in THF is treated with NaH (3.0 equiv, 35 mmol) at 0° C., stirred for 20 minutes, treated with benzylbromide (3.0 g, 17.5 mmol), stirred for 16 hr, concentrated and diluted with water and EtOAc. The aqueous phase is separated, acidified to pH 1-2 with 2N HCl and extracted with EtOAc. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is dissolved in methanol, treated with a catalytic amount of p-toluenesulfonic acid, heated at reflux temperature for 18 hr, cooled and concentrated in vacuo. This resultant residue is triturated under EtOAc/hexanes and filtered. The filtercake is further purified by short-column chromatography (silica gel, 5:1 hexane:EtOAc as eluent) to afford the title product as a light yellow solid, 2.7 g (6.9% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:12]1([CH2:15][N:16]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH2:14][CH2:13]1
Reactant: NCC1CC1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CC1CC1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
N-Cyclopropylmethylphthalimide is prepared as described in Example 2, starting with 4 g of phthalic anhydride, 2.3 cm3 of cyclopropylmethylamine and a catalytic amount of para-toluenesulfonic acid in 40 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 140° C. for 2 hours and is then cooled to a temperature in the region of 20° C. and stirred for 16 hours. The reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The organic phase is separated out after settling of the phases, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 4.3 g of N-cyclopropylmethylphthalimide are thus obtained in the form of a cottony white solid (Rf=0.46, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (40/60 by volume)).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:16]#[N:17])[S:6][C:7]=1[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH3:2].[NH2:18][OH:19]>>[CH2:1]([C:3]1[CH:4]=[C:5]([C:16](=[N:18][OH:19])[NH2:17])[S:6][C:7]=1[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH3:2]
Reactant: CCc1cc(C#N)sc1COC1CCCCO1
Reactant: NO
Product: CCc1cc(C(N)=NO)sc1COC1CCCCO1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1d) using 4-ethyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]thiophene-2-carbonitrile (0.86 g, 3.4 mmol) that was obtained in Example 22 (22c) and a 50% aqueous solution of hydroxylamine (0.5 mL). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3 to 5:5) as the eluent to afford the title compound (0.96 g) in a yield of 98% as a colourless oily product.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[NH:20]1[CH2:23][CH:22]([N:24]2[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]2)[CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:20]3[CH2:23][CH:22]([N:24]4[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]4)[CH2:21]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: O=S1(=O)CCN(C2CNC2)CC1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CC(N3CCS(=O)(=O)CC3)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 40 h
Yield: 90.7 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (400 mg, 1.42 mmol), 4-azetidin-3-ylthiomorpholine-1,1-dioxide (324 mg, 1.70 mmol) and 4 Å powdered molecular sieves (900 mg) in DCE (20 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (602 mg, 2.84 mmol). The reaction mixture was stirred for 40 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%) affording 2-Chloro-8-[3-(1,1-Dioxo-1-thiomorpholin-4-yl)azetidin-1-ylmethyl]-9-methyl-6-morpholin-4-yl-9H-purine as a cream solid (587 mg, 91%). LCMS (Method H): RT 2.25 min [M+H]+ 456.3
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([C:26]([NH:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]C)=[O:23])[CH:17]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].[OH-]>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([C:26]([NH:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(Cc2cccc(C(=O)OC)c2)C(=O)Nc2ccc3ccccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)C(Cc2cccc(C(=O)O)c2)C(=O)Nc2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of 2-[(1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(3-(methoxycarbonyl)phenyl)ethyl)carbonyl]aminonaphthalene (110 mg, 0.2 mmol) in THF (8 mL) was added a solution of LiOH (27 mg, 0.6 mmol) in water (6 mL). The reaction mixture was stirred at ambient temperature. After 5 hours, the reaction mixture was acidified to pH 2-3 by 2N NaHSO4,then extracted with ethyl acetate (3×10 mL). The organic layer was dried over Na2SO4 and evaporated in vacuo to afford 2-[(1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(3-carboxyphenyl)ethyl)carbonyl]aminonaphthalene (90 mg, 0.18 mmol); NMR (DMSO-d6) 1.25 (t, 3), 3.10-3.30 (m, 6), 3.40-3.60 (m, 4), 3.97 (q, 2), 4.14 (t, 1), 7.35-7.55 (m, 5), 7.70-7.87 (m, 5), 8.14 (s, 1), 10.12 (s, 1) ppm.