Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10].[OH-].[Na+].[N:22]1([CH2:28][CH2:29]Cl)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1C=CC=CC=1.C(#N)C>[N:22]1([CH2:28][CH2:29][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9]([C:11]2[C:12]3[CH:13]=[CH:14][NH:15][C:16]=3[CH:17]=[CH:18][CH:19]=2)=[O:10])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCN1CCCCC1
Reactant: O=C(Nc1ccccc1O)c1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1OCCN1CCCCC1)c1cccc2[nH]ccc12
Yield: 83.3 %

Procedure:
3 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide in 50 ml of benzene, 25 ml of acetonitrile and 50 ml of a 5N aqueous solution of sodium hydroxide were heated to 60° C. for 3 hours with stirring under an inert atmosphere with 0.4 g of 2-tetrabutylammonium hydrogenosulfate and 2.2 g of 2-piperidino-1-chloroethane. After cooling, decanting, extracting with ethyl acetate and purifying by chromatography over silica (eluent: ethyl acetate-triethylamine, 9-1), 3.6 g of N-[2-[2-(1-piperdinyl)ethoxy]phenyl]-1H-indol-4-carboxamide were obtained.
Reaction SMILES: COP([CH2:7][C:8](=[O:23])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)(=O)OC.[CH:24]([C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[N:30][CH:31]=1)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:32][C:29]1[N:30]=[CH:31][C:26]([CH:24]=[CH:7][C:8](=[O:23])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][NH:16][C:15]=3[N:14]=2)=[CH:27][N:28]=1
Reactant: COP(=O)(CC(=O)CCCCc1ccc2c(n1)NCCC2)OC
Reactant: Cc1ncc(C=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(C=CC(=O)CCCCc2ccc3c(n2)NCCC3)cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-6 (5.5 g, 16.2 mmol), 5-formyl-2-methylpyrimidine (1-6a, 1.8 g, 14.7 mmol; for preparation, see J. Heterocyclic Chem., 28, 1281 (1991)) in 40 mL DMF was added K2CO3(4.07 g, 32 mmol). The mixture was stirred at ambient temperature for 15 hr, and concentrated to a paste. The residue was diluted with water, extracted with ethyl acetate, and dried over magnesium sulfate. Following concentration, the residue was chromatographed on silica gel (70 chloroform/25 ethyl acetate/5 methanol) to give 1-7 as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:29][CH:30]1[CH2:33][NH:32][CH2:31]1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:32]3[CH2:33][CH:30]([OH:29])[CH2:31]3)=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: OC1CNC1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(CN2CC(O)C2)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-benzyloxy-1-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 1d, 72 mg, 0.17 mmol) in DMF (2 mL) is added 3-hydroxyazetidine hydrochloride (56 mg, 0.51 mmol). The reaction mixture is stirred for 30 min at room temperature. The mixture is purified via reverse phase HPLC chromatography (Gilson, Xbridge C18 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][O:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[Br:18]Br>O.CC(O)=O>[NH2:1][C:2]1[C:3]([C:8]([NH:10][O:11][CH3:12])=[O:9])=[N:4][C:5]([Br:18])=[CH:6][CH:7]=1
Reactant: CONC(=O)c1ncccc1N
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CONC(=O)c1nc(Br)ccc1N
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
A suspension of 3-amino-N-methoxypyridine-2-carboxamide (Compound 46E, 0.275 g, 1.64 mmol) in H2O (4.5 mL) was treated with a drop of Sulfuric acid and 0.6 mL of AcOH. After about 10 min of vigorous stirring, a solution of Bromine (84.7 uL, 1.64 mmol) in 0.4 mL of AcOH was cautiously added. After an additional 15-20 min of stirring the texture of the reaction mixture/suspension changed to become a more coarse orange ppt. This material was collected by filtration and dried to afford 240 mg of the title compound as an orange solid (59%). 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 6.91 (br. s., 2H), 3.66 (s, 3H); MS (ESI): m/z=245.98, 247.98 [M+H]+; UPLC: tR=0.67 min (UPLC-TOF: polar—2 min)
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:51][O:52][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:51][OH:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Solvent: CC(=O)Cl
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Reaction time: 1 h
Yield: 83.6 %

Procedure:
[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethylsilane 4h (10.52 g, 12.5 mmol) was dissolved in 50 mL methanol, followed by dropwise addition of acetyl chloride (0.13 mL, 1.9 mmol). The reaction mixture was stirred for 1 hour. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 4i (7.6 g, yellow grease), yield: 83.6%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:18]Br.C(OCC)(=O)C>C(O)(=O)C>[BrH:18].[Br:18][CH:10]([C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)[C:9]([C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:17]
Reactant: BrBr
Reactant: Cc1cc(C)cc(C(=O)Cc2ccncc2)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Br
Product: Cc1cc(C)cc(C(=O)C(Br)c2ccncc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 268.1 %

Procedure:
1-(3,5-Dimethylphenyl)-2-(4-pyridyl)ethanone (7.0 g, 31 mmol) was dissolved in acetic acid (35 mL) and bromine (1.6 mL, 31 mmol) was added. The mixture was stirred at 80° C. for 3 h. Ethyl acetate was added to the residue and the precipitated crude crystals were collected by filtration. The crude crystals were washed with ethyl acetate to give the title compound (16 g, yield 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].N1C=CC=CC=1.[F:19][C:20]1[CH:21]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[F:26].Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][S:27]([C:22]1[CH:23]=[CH:24][C:25]([F:26])=[C:20]([F:19])[CH:21]=1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: COc1ccc(CN)c(OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CNS(=O)(=O)c2ccc(F)c(F)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 2,4-dimethoxybenzylamine (3.35 mL, 22.3 mmol) and pyridine (9.02 mL, 111.5 mmol) in dichloromethane (75 mL), 3,4-difluorobenzenesulfonyl chloride (3.04 mL, 22.3 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 16 hours. To the reaction solution, 2 M hydrochloric acid (100 mL) was added, and an organic layer was extracted. The thus obtained organic layer was dried over anhydrous sodium sulfate and vacuum concentrated to yield the title compound (7.66 g, 99%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=[O:14].S(Cl)(Cl)=O.CO.N1C=CC=C[CH:31]=1>C(Cl)CCl>[CH3:31][O:14][C:13]1([C:3]2[CH:4]=[CH:5][C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:7][C:2]=2[CH3:1])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=[O:19])[O:18]1
Reactant: c1ccncc1
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Solvent: CO
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: CCN(CC)c1ccc(C2(OC)OC(=O)c3ccccc32)c(C)c1

Procedure:
Proceeding in a manner similar to that described in Example 1 above, 5.2 g of 2-(2-methyl-4-diethylaminophenyl)carbonylbenzoic acid, 1.2 ml of thionyl chloride and 5.0 ml of methyl alcohol were interacted in 30.0 ml of ethylene dichloride in the presence of 1.3 ml of pyridine to obtain 2.5 g of 3-methoxy-3-(2-methyl-4-diethylaminophenyl)phthalide (Formula II: R0 =R=R1 =R2 =H; R4 =R4' =C2H5 ; R5 =Y=CH3 ; X=O), a yellow-colored oil. A significant infrared maximum appeared at 1770 cm-1 (C=O; s). The nuclear magnetic resonance spectrum was concordant with the assigned structure. Analysis by mass spectrum showed m/e peaks at 325 (M+) and 294 (M+ -OCH3). A toluene solution of the product spotted on an acidic clay-coated paper developed a yellow-colored image.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].[F:14][C:15]([Si](C)(C)C)([F:17])[F:16]>O1CCCC1.CN(C)C=O>[F:14][C:15]([F:17])([F:16])[CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[OH:7]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OC(c1cccs1)C(F)(F)F
Yield: 77.7 %

Procedure:
According to Reference Example 8-2, by use of thiophene-2-carbaldehyde (300 mg, 2.67 mmol) dissolved in tetrahydrofuran (4.5 mL) and N,N-dimethylformamide (1.5 mL), potassium carbonate (74 mg, 0.53 mmol) and (trifluoromethyl)trimethylsilane (0.772 mL, 5.34 mmol), the mixture was stirred and reacted at room temperature for 16 hours. Then, purification by extraction gave 2,2,2-trifluoro-1-(thiophen-2-yl)ethanol (Compound DN) (378 mg, yield: 78%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:41](O)=[O:42])=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:75][C:76]1[CH:81]=[CH:80][C:79]([CH2:82][NH2:83])=[CH:78][CH:77]=1>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[C:10]([C:41]([NH:83][CH2:82][C:79]2[CH:80]=[CH:81][C:76]([F:75])=[CH:77][CH:78]=2)=[O:42])=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)O)n3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)NCc4ccc(F)cc4)n3)cc12
Reaction time: 3 h
Yield: 95.9 %

Procedure:
A mixture of 3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinic acid (200 mg, 0.33 mmol), HATU (252 mg, 0.66 mmol) and Et3N (111 mg, 1 mmol) was stirred in DMF (5 mL) at RT for 1 h, and then (4-fluorophenyl)methanamine (124 mg, 1 mmol) was added. After being stirred for 3 h, the mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated and purified by column chromatography (DCM:MeOH=100:1 to 50:1) to get the product of 3-(benzyloxy)-N-(4-fluorobenzyl)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinamide (225 mg, yield: 96%). 1H-NMR (Methanol-d4, 400 MHz) δ 7.90˜7.94 (m, 2H), 7.83 (s, 1H), 7.76 (s, 1H), 7.65˜7.72 (m, 2H), 7.43˜7.45 (m, 2H), 7.28˜7.34 (m, 5H), 7.22 (t, J=8.6 Hz, 2H), 6.91 (t, J=8.6 Hz, 2H), 5.20 (s, 2H), 4.50 (s, 2H), 3.14 (s, 3H), 2.89 (s, 3H), 2.87 (s, 3H). MS (M+H)+: 711.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N.Cl[Sn](Cl)(Cl)Cl.[C:18]1([OH:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.CO>O>[CH3:18][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[OH:11].[CH3:1][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([OH:28])=[CH:19][CH:20]=1
Reactant: Oc1cccc2ccccc12
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: N
Solvent: O
Solvent: CO
Product: Cc1ccc(O)c2ccccc12
Product: Cc1ccc2ccccc2c1O
Reaction time: 3 h

Procedure:
Tasaka et al (JP 50047958) disclose the following reaction scheme: methylation of alpha-naphthol at position 2 was effected by vapor phase methylation of 1-naphthol at elevated temperature in the presence of catalyst comprising CeO2 and Sb2O3, GeO2, SnO2 or MgO. Aqueous ammonia (28%) was added to a mixture of SnCl4 and Ce(NO3)4 -2NH4NO3 2H2O in water at 50° C. The resulting precipitate was dried, calcinated for 3 hours at 600° C., and crushed to form a catalyst. 1-Naphthol/methanol mixture (1:6 molar) was passed over the catalyst at 425° C. and 1000 hr-1 space velocity to give 72.5 wt. % 2-methyl-1-naphthol, 2.6 wt. % 4-methyl-naphthol and 2.2 wt. % of other material.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:14]([NH2:16])[CH3:15].CN>>[CH2:14]([NH:16][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3])[CH3:15]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN
Agent: CN
Product: CCNS(=O)(=O)c1ccc(C(=O)O)cc1
Yield: 64 %

Procedure:
A reaction was carried out following the conditions of Example 32 using 4.4 g (20 mmol) of 4-chlorosulfonylbenzoic acid and an ethylamine solution instead of the 40% aqueous solution of methylamine. The reaction product was post-treated to obtain 2.92 g of 4-ethylaminosulfonylbenzoic acid (yield 64%).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:24][CH3:25])=[C:6]([CH:13]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[C:7]([C:11]#[N:12])=[C:8]([CH3:10])[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.C(OCC)(=O)C.O>[C:11]([C:7]1[C:8]([CH3:10])=[CH:9][C:4]([CH:1]([OH:3])[CH3:2])=[C:5]([O:24][CH3:25])[C:6]=1[CH:13]1[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:16]1)#[N:12]
Reactant: COc1c(C(C)=O)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(C(C)O)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
The tert-butyl 3-(3-acetyl-6-cyano-2-methoxy-5-methylphenyl)azetidine-1-carboxylate (2.2 g, 6.4 mmol) was dissolved in methanol (20 mL) and cooled in ice bath. The sodium tetrahydroborate (0.26 g, 7.0 mmol) was added portionwise and the reaction was monitored by LC/MS. After stirring for 1 h the reaction was complete. This was diluted with ethyl acetate and water. The combined organic layer was washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give crude tert-butyl 3-[2-cyano-5-(1-hydroxyethyl)-6-methoxy-3-methylphenyl]azetidine-1-carboxylate as a yellow foam (2.1 g, 99%). LCMS calculated for C15H19N2O4(M+H)+: m/z=291.1; found: 291.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[N:18]=2)=[CH:14][CH:13]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[N:18]=3)=[CH:28][CH:29]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Reaction time: 8 h
Yield: 16.1 %

Procedure:
A solution of 159 mg (1.033 mmol) 4-chlorophenyl isocyanate in 3 ml THF was given at 0° C. to a solution of 269 mg (1.033 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 5 ml THF within 10 min. After stirring overnight the reaction mixture was evaporated and the residue purified by chromatography on silica gel (ethyl acetate). The obtained material was recrystallized from 9 ml methanol to give 69 mg (16%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]([F:44])([F:43])[F:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]([F:43])([F:42])[F:44])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: FC(F)(F)c1ccccc1Sc1ccc(Br)cc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
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: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccccc3C(F)(F)F)cc2)c1C
Yield: 33 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-bromo-4-(2-(trifluoromethyl)-phenylsulfanyl)-benzene (0.279 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. Flash chromatography (0-3% ethyl acetate in hexanes) provided {6-fluoro-3-methyl-4-[4-(2-trifluoromethyl-phenylsulfanyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.088 g, 32%) as a solid. MS calcd. for C27H19F4O2S [(M−H)−] 483, obsd. 483.0.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:36]=[CH:37][C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[O:42]1[C:38]2[CH:37]=[CH:36][C:35]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]5[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]6[CH2:30][CH2:29][O:28][CH2:27][CH2:26]6)=[CH:21][CH:22]=5)=[O:15])=[CH:7][C:6]=4[CH:32]=3)=[CH:43][C:39]=2[CH2:40][CH2:41]1
Reactant: [O-]B([O-])Oc1ccc2c(c1)CCO2
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc5c(c4)CCO5)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 2,3-dihydrobenzofuran-5-yl borate (104 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give pale yellow crystals of 7-(2,3-dihydrobenzofuran-5-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 56) (246 mg).
Reaction SMILES: [O:1]1[CH2:7][CH:6]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[N:9]2)[CH2:5][NH:4][CH2:3][CH2:2]1.[C:31](O)(=[O:35])[CH2:32][CH2:33][CH3:34]>>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH:6]3[CH2:7][O:1][CH2:2][CH2:3][N:4]([C:31](=[O:35])[CH2:32][CH2:33][CH3:34])[CH2:5]3)[N:9]=[C:10]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)[C:11]=12
Reactant: CCCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNCCOC1
Product: CCCC(=O)N1CCOCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1

Procedure:
1-(1,4-oxazepan-6-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine is coupled with butyric acid under basic condition to afford title compound in good yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=N[N:13]2[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[H-].[Na+].[CH2:41]1COCC1>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:41][N:13]2[C:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:19]([O:21][CH3:22])=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(CC(=O)OC(C)(C)C)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-(4-(tert-butoxycarbonylamino)-1H-indazol-1-yl)-2-(4-chlorophenyl)acetate (2 g, 4.83 mmol), as described in Example 2 Step B, and tert-butyl 2-bromoacetate (1.4 g, 7.25 mmol) in THF (10 mL) was added to NaH (290 mg, 7.25 mmol, 60% in oil) dropwise at 0° C. and stirred for 30 min. The mixture was quenched with saturated NH4Cl solution, and extracted with ethyl acetate. The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE:EA=3:1) to afford the title compound. LC/MS m/z=529.2[M+H]+.