Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH:23]1[CH2:25][CH2:24]1)[C:15](O)=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]2[O:10][C:4]3[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=3[N:2]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH:23]1[CH2:24][CH2:25]1
Reactant: O=C(O)c1ccc(OCC2CC2)c(Cl)c1
Reactant: Nc1ccc(O)cc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 11.3 %

Procedure:
To a solution of 4-aminoresorcinol hydrochloride (5.00 g), 3-chloro-4-(cyclopropylmethoxy)benzoic acid (6.38 g) and diisopropylethylamine (7.37 mL) in DMF (50 mL) was added HATU (11.8 g), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a suspension of the obtained residue, hexachloroethane (16.7 g) and triphenylphosphine (18.5 g) in acetonitrile (50 mL) was added triethylamine (11.8 mL), and the mixture was stirred at room temperature for 15 min, and then with heating at 80° C. for 2 hr. The reaction mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.00 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C(C([O-])=O)=NN=N1)C1C=CC=CC=1.[K+].[CH3:32][C:33]1[CH:38]=[C:37]([C:39]([CH3:41])=[O:40])[C:36]([OH:42])=[C:35]([NH2:43])[CH:34]=1.N1C=CC=CC=1>C(Cl)Cl>[C:39]([C:37]1[C:36]([OH:42])=[C:35]([CH:34]=[C:33]([CH3:32])[CH:38]=1)[NH:43][C:13]([C:12]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[N:10][N:11]=1)=[O:14])(=[O:40])[CH3:41]
Reactant: O=C(Cl)c1nnnn1Cc1ccccc1
Reactant: CC(=O)c1cc(C)cc(N)c1O
Agent: O=C([O-])c1nnnn1Cc1ccccc1
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1cc(C)cc(NC(=O)c2nnnn2Cc2ccccc2)c1O
Reaction time: 8 h

Procedure:
A solution of crude 1-benzyl-1H-tetrazole-5-carbonyl chloride (prepared from 0.73 g of potassium 1-benzyl-1H-tetrazole-5-carboxylate in the manner hereinbefore described in Reference Example 3) in dry methylene chloride (14 ml) was added to a stirred mixture of 3-amino-2-hydroxy-5-methylacetophenone (0.5 g) and pyridine (0.27 g) in dry methylene chloride (12 ml) at between 5° and 10° C. Stirring was maintained for 2 hours, allowing the temperature to rise to room temperature, and then the mixture was left to stand overnight. A further portion of methylene chloride (20 ml) was then added and the mixture was washed with water. The organic phase was dried over magnesium sulphate, and evaporated in vacuo to give a solid, which was recrystallised from ethanol, to give 3'-acetyl-1-benzyl-2'-hydroxy-5'-methyl-1H-tetrazole-5-carboxanilide (1.0 g), m.p. 183°-184° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]([N+:28]([O-])=O)=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:14][C@H:13]1[O:31][CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C.C1COCC1>[NH2:28][C:21]1[CH:20]=[CH:19][C:18]([N:15]2[CH2:16][CH2:17][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[C@H:13]([O:31][CH3:32])[CH2:14]2)=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1N
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Methyl cis(±)-5-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-2-nitrobenzoate obtained in Example (185a) was dissolved in ethanol (20 ml) and THF (20 ml). Tin (II) chloride dihydrate (4.4 g, 19.6 mmol) was added, and the mixture was stirred at 75° C. overnight. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with aqueous sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, 900 mg of the title compound was obtained as an oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([Cl:13])[C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[C:5]2[Cl:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:31]2[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=2)=[O:30])=[CH:25][CH:24]=1.[Li]CCCC>>[Cl:13][C:7]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:5]([Cl:21])[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:2]([C:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)([C:31]3[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=3)[OH:30])[CH:3]=2)[N:8]=1
Reactant: Cc1cc(Br)cc2c(Cl)c(-c3cccc(F)c3)c(Cl)nc12
Reactant: Cn1cncc1C(=O)c1ccc(F)cc1
Agent: [Li]CCCC
Product: Cc1cc(C(O)(c2ccc(F)cc2)c2cncn2C)cc2c(Cl)c(-c3cccc(F)c3)c(Cl)nc12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A round bottom flask was charged with 6-bromo-2,4-dichloro-3-(3-fluorophenyl)-8-methylquinoline (1.00 g, 2.60 mmol, Intermediate 50, step c) and (4-fluorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (583 mg, 2.86 mmol, Intermediate 49, step b) and was evacuated and re-filled with argon (three times). THF (20 mL) was added, and the solution was cooled in a dry ice acetone bath for 2 minutes. At this point the mixture began to turn cloudy and n-BuLi (1.6 M in hexane, 2.11 mL, 3.38 mmol), was added over about 1 minute. The mixture was stirred at −78° C. for 10 minutes, then in an ice water bath for 1 hour. The reaction was quenched by addition of saturated aqueous NH4Cl, diluted with water and extracted with EtOAc (3×). The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 30-60% acetone-DCM) to afford slightly impure title compound as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (s, 1H), 7.60 (s, 1H), 7.44-7.55 (m, 1H), 7.30-7.39 (m, 3H), 7.15-7.23 (m, 1H), 7.01-7.12 (m, 4H), 6.40 (s, 1H), 4.00 (br. s., 1H), 3.40 (s, 3H), 2.74 (s, 3H). MS m/e 510.1 [M+H]+.
Reaction SMILES: [OH:1][N:2]1C2C=CC=CC=2N=N1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C@H:30]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C:31]([OH:33])=O)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Si](ON)(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C@H:30]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C:31]([NH:2][OH:1])=[O:33])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCCCC1
Agent: CC(C)(C)[Si](C)(C)ON
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NO)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCCCC1
Reaction time: 0.33 h
Yield: 34.6 %

Procedure:
150 mg (1.1 mmol) of 1-hydroxybenzotriazole and 210 mg (1.1 mmol) of 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride are added to a solution of 420 mg (1.0 mmol) of (S)-3-(4-benzyloxybenzenesulfonylamino)-2-piperidin-1-ylpropanoic acid in 15 ml of dimethylformamide. The reaction medium is stirred for 20 min and then a solution of 160 mg (1.1 mmol) of O-tert-butyldimethylsilylhydroxylamine in 3 ml of dimethylformamide is added. The reaction medium is then stirred at ambient temperature for 18 h and then hydrolyzed with 2 ml of a saturated aqueous solution of sodium hydrogen carbonate and 2 ml of water. After stirring for 20 min in order to complete the deprotection of the hydroxamate, the product is extracted with ethyl acetate. The organic phases are washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue obtained is crystallized from isopropyl ether under hot conditions, and then filtered off. The resulting solid is recrystallized from a 1/1 heptane/ethyl acetate mixture, filtered and then oven-dried under vacuum for 4 h. 150 mg of (S)-3-(4-benzyloxybenzenesulfonylamino)-N-hydroxy-2-piperidin-1-ylpropionamide are obtained in the form of a beige solid with a melting point of 126° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([OH:18])=[CH:4][CH:3]=1.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:25]([O:18][C:5]1[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: Oc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc2[nH]c(-c3nc(Cl)ccc3OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
A mixture of 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol (100 mg, 0.38 mmol, prepared using similar method described in Example 1), BnBr (97 mg, 0.572 mmol) and K2CO3 (158 mg, 1.146 mmol) in DMF (1 mL) was stirred at room temperature overnight. The mixture was then concentrated in vacuo. The resulting resulting residue was diluted with water (15 mL) and extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using Prep-TLC (petroleum ether:EA=3:1) to provide 2-(3-(benzyloxy)-6-chloropyridin-2-yl)-4-fluoro-1H-indole (100 mg, yield: 74.6%). 1H-NMR (CDCl3, 400 MHz) δ 9.64 (s, 1H), 7.12˜7.48 (m, 10H), 6.76 (t, J=8.8 Hz, 1H), 5.33 (s, 2H). MS (M+H)+: 353/355.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:15]([OH:17])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl.[NH2:29][C@H:30]([C:38]([NH:40][C@H:41]([C:49]([OH:51])=[O:50])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N1CCOCC1)C>CN(C)C=O>[NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:15]([NH:29][C@H:30]([C:38]([NH:40][C@H:41]([C:49]([OH:51])=[O:50])[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 24 h

Procedure:
4.19 g of Z-Lys(Boc)-OPc and 2.47 g of HCl.H-Phe-Phe-OH are taken up in 50 ml of dimethylformamide, 0.84 ml of N-ethylmorpholine are added and the whole is left to stand for 24 hours at 20°. The reaction mixture is concentrated by evaporation and the residue is triturated with water and dried over phosphorus pentoxide. Recrystallisation from ether yields crystals having a melting point of 154° to 156°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]=O.[C:9](O)(=O)[CH2:10][C:11]([OH:13])=[O:12]>O1CCOCC1>[N:1]1([CH2:7][C:10](=[CH2:9])[C:11]([OH:13])=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(O)CC(=O)O
Reactant: C=O
Solvent: C1COCCO1
Product: C=C(CN1CCOCC1)C(=O)O
Yield: 32 %

Procedure:
In a manner described by Krawczyk [Henryk Krawczyk, Synthetic Communications, 25 641-650, (1995)] an 8.8 mL (8.8 g; 0.1 mole) portion of morpholine was added to 6.6 g (0.22 eq) of paraformaldehyde and 10.4 g (0.1 mole) of malonic acid in 100 mL of dioxane. After heating in an oil bath at 70 deg for 1 {fraction (1/12)} hours, the solvents were removed in vacuo. The residue was dissolved in acetone, some insoluble material being filtered. The filtrate was taken to an oil in vacuo. This oil was chromatographed on silica gel. Elution of the product with 1:19 methanol methylene chloride gave 5.51 g (32%) of the product, which melted at 121-125° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[CH3:5][O-].[Na+].[CH2:8]1[O:12]C[CH2:10][CH2:9]1>CC(CC(C)=O)C>[OH:4][CH2:3][CH2:2][S:1][CH2:5][CH:8]([OH:12])[CH2:9][CH3:10]
Reactant: C1CCOC1
Reactant: OCCS
Reactant: C[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CCC(O)CSCCO
Temperature: 50 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
In a reaction vessel equipped with a stirrer, a cooling tube, a nitrogen introducing tube and a thermometer, 78.1 parts of 2-mercaptoethanol was charged, and 2-mercaptoethanol was diluted with 159.6 parts of MIBK. Then, 1.48 parts of sodium methoxide (28% solution in methanol) was added, and after heating to 50° C., 82.9 parts of butylene oxide was added dropwise with stirring over 3 hours in a dry nitrogen atmosphere. The reaction vessel was cooled and maintained at 50° C. 3 Hours after dropping, it was confirmed that an absorption of --SH (2540 cm-1) and an absorption of a glycidyl group (910 cm-1) are disappeared by the measurement of infrared spectra. Further, the reaction product had no mercapto-like odor. Thereafter, MIBK was removed under reduced pressure to give 1-(2-hydroxyethylthio)-2-butanol as a viscous liquid. Yield was 95% of the charge weight.
Reaction SMILES: C(NC(C1C=C(S(OC[C@](O)(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](CC2C=CC=CC=2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC2C=CC=CC=2)NC(=O)CN2CCOCC2)(=O)=O)C=CC=1)=O)C#C.[CH3:69][O:70][C:71]1[CH:76]=[C:75]([O:77][CH3:78])[CH:74]=[C:73]([O:79][CH2:80][C:81]#[CH:82])[C:72]=1[S:83](Cl)(=[O:85])=[O:84].[OH:87][CH2:88][C@:89]([OH:139])([CH3:138])[C:90](=[O:137])[C@@H:91]([NH:96][C:97](=[O:136])[C@@H:98]([NH:106][C:107](=[O:135])[C@@H:108]([NH:113][C:114](=[O:134])[C@@H:115]([NH:124][C:125](=[O:133])[CH2:126][N:127]1[CH2:132][CH2:131][O:130][CH2:129][CH2:128]1)[CH2:116][CH2:117][C:118]1[CH:123]=[CH:122][CH:121]=[CH:120][CH:119]=1)[CH2:109][CH:110]([CH3:112])[CH3:111])[CH2:99][C:100]1[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=1)[CH2:92][CH:93]([CH3:95])[CH3:94]>>[CH3:69][O:70][C:71]1[CH:76]=[C:75]([O:77][CH3:78])[CH:74]=[C:73]([O:79][CH2:80][C:81]#[CH:82])[C:72]=1[S:83]([O:87][CH2:88][C:89]([OH:139])([CH3:138])[C:90](=[O:137])[C@H:91]([CH2:92][CH:93]([CH3:94])[CH3:95])[NH:96][C:97](=[O:136])[C@H:98]([CH2:99][C:100]1[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=1)[NH:106][C:107](=[O:135])[C@H:108]([CH2:109][CH:110]([CH3:112])[CH3:111])[NH:113][C:114](=[O:134])[C@H:115]([CH2:116][CH2:117][C:118]1[CH:119]=[CH:120][CH:121]=[CH:122][CH:123]=1)[NH:124][C:125](=[O:133])[CH2:126][N:127]1[CH2:132][CH2:131][O:130][CH2:129][CH2:128]1)(=[O:84])=[O:85]
Reactant: C#CCOc1cc(OC)cc(OC)c1S(=O)(=O)Cl
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)CO
Agent: C#CCNC(=O)c1cccc(S(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)c1
Product: C#CCOc1cc(OC)cc(OC)c1S(=O)(=O)OCC(C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1

Procedure:
Prepared in a similar manner to compound 13, except from 2,4-dimethoxy-6-(prop-2-yn-1-yloxy)benzene-1-sulfonyl chloride and (S)—N—((S)-1-(((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide.
Reaction SMILES: Cl[Si:2]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11]C1)([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].[CH:15]1([Mg]Cl)[CH2:19][CH2:18]CC1.[Cl-].[NH4+].[CH2:24](OCC)C>>[CH:9]1([Si:2]([CH2:24][CH:19]([CH3:18])[CH3:15])([O:3][CH2:4][CH3:5])[O:6][CH2:7][CH3:8])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCO[Si](Cl)(OCC)C1CCCCC1
Reactant: Cl[Mg]C1CCCC1
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Product: CCO[Si](CC(C)C)(OCC)C1CCCC1
Reaction time: 6 h

Procedure:
60 ml of dry diethyl ether and 14.0 gram (0.063 mole) of chlorocyclohexyldiethoxysilane (d) were charged in a 250 ml flask equipped with a reflux condenser and a stirring apparatus in an atmosphere of nitrogen and the above prepared solution of cyclopentyl magnesium chloride (2nd Grignard reagent) was slowly added while keeping the internal temperature below 10° C. After completion of addition stirring was carried out at room temperature for 6 hours and at reflux temperature for 5 hours. To the resulting reaction mass 10-20 ml of saturated aqueous ammonium chloride solution was added drop wise to dissolve magnesium salt. The organic layer was separated from the aqueous phase, dried and evaporated to give crude cyclopentylisobutyldiethoxysilane. This crude was purified by fractional distillation under reduced pressure, yielding 12 gram (75%) of pure cyclopentylisobutyldiethoxysilane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][NH:11][C:10](=[O:15])[C:9]=2[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:7]=1)=[O:5])[CH3:2].[C:24]([O:28][C:29](=[O:41])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:37]3[CH:38]=[CH:39][C:34]([C:31]4([CH2:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:41])[CH2:32][CH2:33]4)=[CH:35][CH:36]=3)[C:10](=[O:15])[C:9]=2[N:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCNC2=O
Reactant: CC(C)(C)OC(=O)CC1(c2ccc(I)cc2)CC1
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(C3(CC(=O)OC(C)(C)C)CC3)cc1)C2=O
Yield: 86 %

Procedure:
Part A. Following procedure similar to that of Part C in Example 220 but using 1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester and [1-(4-iodo-phenyl)-cyclopropyl]-acetic acid tert-butyl ester as starting materials, 6-[4-(1-tert-butoxycarbonylmethyl-cyclopropyl)-phenyl]-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester was obtained (406.29 mg, yield: 86%). 1H NMR (CDCl3) δ 7.48 (d, J=8.9 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 6.91 (d, J=8.9 Hz, 2H), 4.47 (q, J=7.1 Hz, 2H), 4.12 (m, 2H), 3.81 (s, 3H), 3.32 (t, J=6.6 Hz, 2H), 2.50 (s, 2H), 1.44 (t, J=7.1 Hz, 3H), 1.38 (s, 9H), 0.90 (s, 4H) ppm. LRMS (ESI) 546.2 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[C:18]([C:19]([NH:21][CH3:22])=[O:20])=[CH:17][N:16]=[C:15](Cl)[N:14]=1)(=[O:4])[CH:2]=[CH2:3].[CH3:24][O:25][C:26]1[CH:32]=[C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:30]=[CH:29][C:27]=1[NH2:28].CO>CC1C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1.C(Cl)Cl>[C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[C:18]([C:19]([NH:21][CH3:22])=[O:20])=[CH:17][N:16]=[C:15]([NH:28][C:27]2[CH:29]=[CH:30][C:31]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:32][C:26]=2[O:25][CH3:24])[N:14]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Nc1ccccc1Nc1nc(Cl)ncc1C(=O)NC
Reactant: COc1cc(N2CCOCC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=CC(=O)Nc1ccccc1Nc1nc(Nc2ccc(N3CCOCC3)cc2OC)ncc1C(=O)NC
Temperature: 100 °C

Procedure:
To a solution of 4-(2-acrylamidophenylamino)-2-chloro-N-methylpyrimidine-5-carboxamide (40 mg, 0.12 mmol) in 0.08M p-TSA/1,4-dioxane (5 mL), 2-methoxy-4-morpholinoaniline (25.13 mg, 0.12 mmol) was added and heated at 100° C. for 1 h. TLC showed completion of starting material (TLC system: 5% methanol in DCM (Rf): 0.3). 1,4 dioxane was evaporated, and the residue was diluted with ethyl acetate (15 mL) and washed with water (2×5 mL). The organic layer was separated, dried over sodium sulphate, and concentrated. Crude compound was purified by column chromatography using silica gel (100-200 mesh) with 2% methanol in DCM to obtain 4-(2-acrylamidophenylamino)-2-(2-methoxy-4-morpholino phenylamino)-N-methylpyrimidine-5-carboxamide as off white solid. Yield: (8 mg, 13%). MS: m/z 504.3 (ES+, M+H).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=C(B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.FC(F)(F)S(O[C:22]1[CH:35]=[C:34]2[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]([NH2:42])=[CH:31][C:32]=3[C@:33]32[CH2:40][CH2:39][O:38][C:37]([NH2:41])=[N:36]3)=[C:24]([F:43])[CH:23]=1)(=O)=O.[C:46](=O)([O-])[O-].[Na+].[Na+]>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:1]1[CH2:6][CH:5]=[C:23]([C:22]2[CH:46]=[C:24]([F:43])[C:25]3[O:26][C:27]4[C:32](=[CH:31][C:30]([NH2:42])=[CH:29][CH:28]=4)[C@@:33]4([CH2:40][CH2:39][O:38][C:37]([NH2:41])=[N:36]4)[C:34]=3[CH:35]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c(F)cc(OS(=O)(=O)C(F)(F)F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Temperature: 85 °C
Reaction time: 4 h
Yield: 27.2 %

Procedure:
In a microwave vial, 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.107 g, 0.509 mmol) and Pd(PPh3)4 (0.053 g, 0.046 mmol) were loaded. A solution of (S)-2,2′-diamino-5′-fluoro-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthen]-7′-yl trifluoromethanesulfonate (0.207 g, 0.463 mmol) in dmf (3.7 mL) was added via cannula. Aqueous 1.5 M sodium carbonate (0.925 mL, 1.388 mmol) was added. Argon was blown through the vessel, which was sealed and heated in an 85° C. oil bath. After 4 h, the reaction was concentrated. The residue was taken up in EtOAc (100 mL) and the organic layer was extracted with quarter-saturated brine (2×8 mL), half-saturated brine (8 mL), and saturated brine (8 mL), dried over MgSO4 and concentrated. The material was purified through silica gel (35 mL) which had been deactivated with Et3N (3.5 mL), using a gradient of 3% to 6% MeOH-dcm with 0.5% v/v Et3N, affording (S)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthene]-2,7′-diamine (48 mg, 0.126 mmol). MS m/z=382 [M+H]1.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCc1ccccn1
Agent: Cl
Product: COc1ccc(N(Cc2cnn(Cc3ccccn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 26.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.94 g) and 2-(chloromethyl)pyridine hydrochloride (0.33 g) as starting materials, 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.28 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-methoxypyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.085 g) was obtained.