Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.Br[C:19]1C=CC(C(O)=O)=CC=1OC1CCCCO1.C(=O)([O-])[O-].[Cs+].[Cs+].IC>CC(C)=O.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[CH:4][C:3]=1[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: O=C(O)c1ccc(Br)c(OC2CCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(Br)c(OC2CCCCO2)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
To flask containing 26.1 (2.15 g, 7.14 mmol) and cesium carbonate (3.95 g, 12.1 mmol) in acetone (50 mL), was added iodomethane (0.667 mL, 10.7 mmol). The resulting mixture was stirred overnight. The reaction was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and then purified by combiflash (0 to 20% EtOAc/Hexanes) to provide methyl 26.2 (2.25 g, 99% yield).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38])=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1ccccc1C(=O)CCCCCBr
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1ccccc1C(=O)CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(2-methoxyphenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(2-methoxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: S(O)(O)(=O)=O.NC(=N)[NH:8][CH2:9][CH2:10]CCN.[C:15](Cl)(=O)[CH:16]=[CH2:17].C([O-])([O-])=O.[K+].[K+].[CH3:26][C:27]([CH3:29])=O>O>[CH3:10][CH2:9][N:8]([CH:27]([CH3:29])[CH3:26])[CH:16]([CH3:17])[CH3:15]
Reactant: CC(C)=O
Reactant: N=C(N)NCCCCN
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCN(C(C)C)C(C)C
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Agmatine sulphate (2.28 g, 10 mmol) was dissolved in distilled water (10 ml) in a round-bottom flask (50 ml) equipped with a magnetic stirrer. Diisopropylethyldiamine (DIPEA) (3.88 g, 5.23 ml, 20 mmol) was added to the round-bottom flask together with acetone (10 ml). The reaction mixture was cooled down on an ice-bath and the mixture was stirred for 10 minutes at 5° C. Acryloyl chloride (1.81 g, 1.625 ml, 20 mmol), dissolved in acetone (5 ml), was added drop wise to the flask using a Pasteur-pipette. The reaction was allowed to proceed at 5° C. for 1 h. The stirring was then stopped. K2CO3 was added to the round-bottom flask until the pH was settled to 12. The volume of the aqueous phase was then 75 ml. The aqueous phase was then extracted with MIBK (2 times 150 ml) to remove DIPEA. The pH of the aqueous phase was then fixed to pH 2.3 by addition of concentrated sulphuric acid. The aqueous phase was then extracted with MIBK (3 times 150 ml) to remove excess acrylic acid formed during the reaction. The pH of the aqueous phase was then fixed to pH 7 by addition of K2CO3. The yield was at least 95%.
Reaction SMILES: CO.[C@@H]1([O:14][C:15]2[C:16]([O:18][C@H:19]([C@H:22]([CH2:24][OH:25])[OH:23])[C:20]=2[OH:21])=[O:17])O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.O=[C:27]1[O:33][C@H:32]([C@H:34]([CH2:36][OH:37])[OH:35])[C:30]([OH:31])=[C:28]1[OH:29]>C([O-])(=O)C.C(O)[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O>[C@@H:27]1([C@:19]2([C@H:22]([CH2:24][OH:25])[OH:23])[O:18][C:16](=[O:17])[C:15]([OH:14])=[C:20]2[OH:21])[O:33][C@H:32]([CH2:30][OH:31])[C@@H:34]([OH:35])[C@H:36]([OH:37])[C@H:28]1[OH:29]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: CC(=O)[O-]
Agent: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CO
Product: O=C1O[C@]([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)([C@@H](O)CO)C(O)=C1O
Temperature: 100 °C

Procedure:
Using, as an index, a retention time of 5.2 minutes in LC system manufactured by GILSON (master pump 305 type, UV detector 116 type), column: INERTSIL® ODS-3 (manufactured by GL Science, 4.6×150 mm, 5 μm) , mobile phase: 20% MeOH-20 mM phosphoric acid-5 mM tetra-n-amylammonium bromide, flow rate: 0.5 ml/min, detection wavelength: 254 nm) of a chemically synthesized product of 2-O-(β-D-glucopyranosyl)ascorbic acid, commercially available cellulase, (β-glucosidase, and β-glucanase enzyme preparations were searched. An enzyme reaction system was obtained by being dissolved in a 10 mM acetate buffer (pH 5.0) to 1 ml so that cellobiose became to be 0.3 M and ascorbic acid became to be 0.2 M. After addition of 50 μl of an enzyme solution, the reaction was initiated at 37° C. The reaction was stopped by heating at 100° C. for 5 minutes, and β-D-glucopyranosylascorbic acid produced was analyzed by high performance liquid chromatography. As a result, it was found that cellulase (manufactured by Sigma), β-glucosidase (Toyobo Co., Ltd., Nakarai Tesque), CELLULOSIN T2 (Hankyu Kyoei Bussan), cellulase “ONOZUKA” RS, “ONOZUKA” FA and PANCELLASE BR (Yakult Pharmaceutical Ind. Co., Ltd.) have (β-glucosyltransferase activity. Free ascorbic acid appeared a position of 4.0 minutes, while peaks were recognized at positions of 3.6 minutes and 5.2 minutes before and after that position, and they were designated as substance X and substance Y. A conversion rate of the substance X indicated 15.7%, and a conversion rate of the substance Y indicated 0.8%. By cochromatography analysis of this substance X and substance Y with chemically synthesized products, a retention time of the substance X was consistent with that of 6-O-(β-D-glucopyranosyl)ascorbic acid, and a retention time of the substance Y was consistent with that of 2-O-(β-D-glucopyranosyl)ascorbic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].C(Cl)Cl.[CH3:15][CH2:16][O:17]C(C)=O>>[O:11]1[CH2:15][CH2:16][O:17][CH:10]1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc([N+](=O)[O-])cn1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C2OCCO2)nc1

Procedure:
2-(1,3-Dioxolanyl)-5-nitropyridine was prepared from 5-nitropyridine-2-carboxaldehyde by the procedure employed for the synthesis of Example III. Yield: 2.0 g (84%); mp 104°-105° C.; TLC Rf 0.73 (CH2Cl2 /EtOAc, 1:1, v/v); 1H NMR (90 MHz, CDCl3) δ 4.10 (s, 4H, CH2CH2), 5.92 (s, 1H, 2-CH), 7.72 (d, 1H, 3-H, J3,4 =8 Hz), 8.50 (dd, 1H, 4-H, J3,4 =8 Hz, J4,6 =2 Hz), 9.42 (d, 1H, 6-H, J4,6 =2 Hz). Anal.(C8H8N2O4) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:24]3[CH2:32][CH2:31][NH:30][CH2:29][C:25]=3[N:26]=[CH:27][N:28]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:1].[C:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:24]3[CH2:32][CH2:31][N:30]([C:2]4[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=4)[CH2:29][C:25]=3[N:26]=[CH:27][N:28]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: CC(C)(C)c1ccc(Nc2ncnc3c2CCNC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CCN(c2ncccc2C(F)(F)F)C3)cc1
Product: Cl

Procedure:
The title compound was prepared using the general procedure set forth in Example 3, above, by heating a mixture of 2-chloro-3-(trifluoromethyl)pyridine (0.108 g, 0.59 mmol), N-(4-tert-butylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (Example 3.A) (0.112 g, 0.40 mmol) and potassium carbonate (0.16 g, 1.19 mmol) in DMF (2 mL) for 1 h.
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH2:18]=O.[CH3:20][NH:21][CH3:22]>C(O)C>[Br:5][C:6]1[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]2[C:7]=1[C:8]([CH2:20][N:21]([CH3:18])[CH3:22])=[CH:9][NH:10]2
Reactant: CNC
Reactant: NC(=O)c1ccc(Br)c2cc[nH]c12
Reactant: C=O
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)Cc1c[nH]c2c(C(N)=O)ccc(Br)c12
Temperature: 80 °C
Reaction time: 2 h
Yield: 109.8 %

Procedure:
Acetic acid (1.15 mL, 20.08 mmol) was added to a suspension of 4-bromo-1H-indole-7-carboxamide (3 g, 12.55 mmol), paraformaldehyde (0.603 g, 20.08 mmol) and dimethylamine (2 M in methanol, 10 mL, 20.08 mmol) in ethanol (50 mL). The mixture was heated to 80° C. After 2 h, the ethanol was removed under vacuum. The residue was partitioned between NaHCO3 (aq) and EtOAc. The organic phase was washed with brine (15 mL), dried and concentrated to afford the crude desired product as a light brown solid (4.08 g). LCMS (M+H)+ m/z 295.8, 297.8.
Reaction SMILES: Cl.[S:2]([N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7]1)(=[O:5])(=[O:4])[NH2:3].[C:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21].CCN(CC)CC>>[C:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:11]2[CH2:12][CH2:13][C:8]3([C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:6]([S:2](=[O:4])(=[O:5])[NH2:3])[CH2:7]3)[CH2:9][CH2:10]2)=[O:31])=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(NC(=O)N2CCC3(CC2)CN(S(N)(=O)=O)c2ccccc23)cc1
Temperature: 25 °C
Yield: 33.2 %

Procedure:
To a suspension of 1-sulfamoylspiro[indoline-3,4′-piperidine] hydrochloride 3-1 (100 mg, 0.33 mmol) and phenyl 4-acetylphenylcarbamate 3-2 (92 mg, 0.36 mmol) in CHCL3 (3 mL) was added Et3N (0.23 mL, 1.65 mmol) at room temperature. The reaction mixture was heated to reflux for 1 h. The resulting suspension was cooled to room temperature. The resulting suspension was filtered and the filter cake was washed with CHCl3 to give 300 (47 mg, 33%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[CH3:33][C:34]([CH3:45])([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:35](Cl)=[O:36].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:36])[C:34]([CH3:33])([CH3:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: CC(C)(Cc1ccccc1)C(=O)Cl
Reactant: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)C(C)(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.23 mmol) in pyridine (2.5 mL) was treated with 2,2-dimethyl-3-phenylpropanoyl chloride (0.120 g, 0.61 mmol). The reaction mixture was stirred for 2 h at room temperature under a nitrogen atmosphere. Saturated sodium bicarbonate solution (10 mL) was added, and the reaction mixture was stirred for 20 min. Solvent was removed under reduced pressure. Dichloromethane and saturated sodium bicarbonate solution was added to the residue. The layers were separated using an Empore extraction cartridge. The organic solvent was removed under reduced pressure. The crude compound was purified by flash chromatography on silica gel, using 10% methanol in dichloromethane as eluent to give 0.085 g (62%) cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2,2-dimethyl-3-phenylpropanamide. 1H NMR (CDCl3, 400 MHz) δ 8.595-8.574 (m, 1H), 8.372 (s, 1H), 7.985 (s, 1H), 7.292-7.158 (m, 7H), 4.923 (m, 1H), 3.891 (s, 3H), 3.050-3.013 (m, 1H), 2.965 (s, 2H), 2.65-2.55 (m, 5H), 2.440-2.346 (m, 4H), 2.244-2.166 (m, 4H), 1.854-1.823 (m, 3H), 1.688 (m, 3H), 1.334 (s, 6H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.517 min (100%/).
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:12].C([Li])CCC.CN([CH:21]=[O:22])C.Cl>C1COCC1>[CH:21]([C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:12])=[O:22]
Reactant: CN(C)C=O
Reactant: Cc1cc(C(=O)O)cc(C)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(C)c1C=O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-3,5-dimethylbenzoic acid (0.92 g, 4 mmol) in THF (10 mL) was cooled down to −100° C. with N2(I)-Et2O bath and added n-butyllithium (1.6 M in hexanes, 5 mL, 8 mmol) slowly. After completion of addition, the reaction mixture was warmed to −78° C. and DMF (0.74 mL, 8 mmol) was added dropwise. The resulting mixture was stirred at −78° C. for 1.5 h and allowed to warm to −20° C., followed by the addition of 2N aqueous HCl (30 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc, the combined organic phases were dried over MgSO4. The solvent was removed and the resulting residue was purified by flash column chromatography (eluent: EtOAc-hexanes-1:1) to yield 4-formyl-3,5-dimethyl-benzoic acid (10c).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[CH:37][C:36]=1[N+:43]([O-:45])=[O:44]>CN(C=O)C>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH:42][C:6]([C:3]2([C:2]([F:10])([F:9])[F:1])[CH2:5][CH2:4]2)=[O:7])=[CH:37][C:36]=1[N+:43]([O-:45])=[O:44]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: NCc1ccc(Cl)c([N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)c([N+](=O)[O-])c1)C1(C(F)(F)F)CC1
Reaction time: 1 h

Procedure:
TEA (21.7 mL; 156 mmol) was added to a mixture of 1-(trifluoromethyl)-cyclopropanecarboxylic acid (8.00 g; 51.9 mmol) and TBTU (16.7 g; 52 mmol) in DMF (40 mL). After 1 h at rt, a solution of (4-chloro-3-nitrophenyl)methylamine hydrochloride (11.6 g; 52 mmol) in DMF (70 mL) was added dropwise over 30 min. After 17 h at rt, the mixture was concentrated and the residue partitioned between water and MTBE. The organic layer was washed with water, dried over Na2SO4 and concentrated. The residue was purified by column chromatography to give the sub-title compound. Yield: 13.191 g (78%).
Reaction SMILES: C([O:8][C:9](=[O:28])[CH2:10][CH2:11][NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)C1C=CC=CC=1.[NH2:29][CH2:30][C@@H:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[OH:32]>>[OH:32][C@H:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[CH2:30][NH:29][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([C:13]([NH:12][CH2:11][CH2:10][C:9]([OH:8])=[O:28])=[O:27])=[CH:19][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(C(=O)NCCC(=O)OCc3ccccc3)cc2)CC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C(=O)NCCC(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 3-[4-(4-oxo-piperidine-1-yl)-benzoylamino]-propionic acid benzyl ester (which was obtained in Example 159) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 179 as a white solid; mp >170° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.45 (m, 2H), 1.80-1.95 (m, 2H), 2.43 (t, J=7.0 Hz, 2H), 2.60-2.90 (m, 5H), 2.90 (s, 3H), 3.00-3.40 (m, 2H), 3.70-3.85 (m, 2H), 4.50 (dd, J=8.0, 4.2 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 6.92 (d, J=8.9 Hz, 2H), 7.01 (dd, J=8.3, 1.9 Hz, 1H), 7.18 (d, J=1.9 Hz, 1H), 7.68 (d, J=8.9 Hz, 2H), 8.26 (t, J=5.2 Hz, 1H); MS (ES) m/z: 521.2 (MH+); HRMS Calcd. for C24H33N4O7S(MH+): 521.2064. Found: 521.2056.
Reaction SMILES: C[O:2]C1C=C(CNCCCNCCCCNCCCN)C=CC=1O.O[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]([CH3:44])([CH3:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:34]=2)[CH2:29][CH:28]([CH2:45][CH2:46][NH2:47])[C:27]1([CH3:49])[CH3:48].C(N(CC)CC)C.[C:57]1([CH3:67])[CH:62]=[CH:61][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:59][CH:58]=1>C(Cl)Cl>[OH:2][C:31]1[CH:32]=[C:33]([C:36]([CH3:44])([CH3:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:34]=[C:35]2[C:30]=1[CH2:29][CH:28]([CH2:45][CH2:46][NH:47][S:63]([C:60]1[CH:61]=[CH:62][C:57]([CH3:67])=[CH:58][CH:59]=1)(=[O:65])=[O:64])[C:27]([CH3:49])([CH3:48])[NH:26]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Reactant: CCCCCCC(C)(C)c1ccc2c(c1)N(O)C(C)(C)C(CCN)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)NC(C)(C)C(CCNS(=O)(=O)c1ccc(C)cc1)C2
Temperature: -20 °C

Procedure:
To 20 ml of methylene chloride is added 346 mg (1 mmole) dl-5-hydroxy-3-(2-aminoethyl)-7-(1,1-dimethylheptyl)-2,2-dimethyl-1,2,3,4-tetrahydroquinoline and 0.166 ml (1.2 mmole) triethylamine. The solution is cooled to -20° C. and a solution of ;b 191 mg (1 mmole) p-toluenesulfonyl chloride in 10 ml methylene chloride is added dropwise over ten minutes. The mixture is allowed to warm to 0° C., poured into ice/water and the layers separated. The aqueous layer is extracted with fresh methylene chloride, the combined organic layers washed with water, saturated sodium bicarbonate solution, brine and dried over anhydrous magnesium sulfate. Evaporation of solvent affords the crude product which is purified by chromatography on silica gel.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:16]([O-])=O.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:16][S:24]([C:20]1[S:19][CH:23]=[CH:22][CH:21]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: O=[N+]([O-])c1cccc2cc(-c3ccccn3)[nH]c12
Product: O=S(=O)(Nc1cccc2cc(-c3ccccn3)[nH]c12)c1cccs1

Procedure:
2-Pyridin-2-yl-7-nitro-1H-indole prepared in Preparation 9 and 2-thiophenesulfonylchloride were reacted according to the same procedures as Step A of Example 1 and Example 22 sequentially to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]#N)[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.[OH-].[K+].[CH3:25]I.O.C[N:29]([CH3:32])C=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:20]([CH3:21])([CH3:25])[C:32]#[N:29])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1
Reactant: CI
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cc3cc(OC)cc(CC#N)c3o2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2cc3cc(OC)cc(C(C)(C)C#N)c3o2)cc1
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of acetonitrile 18 (0.054 g, 0.184 mmole) in 5 mL dimethylformamide was added pulverized potassium hydroxide (0.024 g, 0.390 mmole) and methyl iodide (0.0552 g, 0.0391 mmole). After stirring; at rt for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 95:5) to afford 0.046 g (78%) of methyl-propionitrile 20 as a yellow solid: Mp=146–148° C., 1H NMR (DMSO-d6) δ 7.87 (d, 2 H, J=8.8 Hz), 7.26 (s, 1 H), ), 7.15 (d, 1 H, J=2.4 Hz), 7.10 (d, 2 H, J=8.9 Hz), 6.86 (d, 1 H, J=2.4 Hz), 3.82 (s, 3 H), 3.81 (s, 3 H), 1.89 (s, 6 H); MS 322 (M+H)+
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([O:15][C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:19]#[N:20])[C:12]([CH:25]([CH3:27])[CH3:26])=[C:11]([O:28]CC2C=CC=CC=2)[N:10]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CCO.[Pd]>[CH:25]([C:12]1[C:11](=[O:28])[NH:10][C:9](=[O:8])[NH:14][C:13]=1[O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:19]#[N:20])([CH3:27])[CH3:26]
Reactant: [H][H]
Reactant: Cc1cc(C#N)cc(Oc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
3-(2,6-Bis-benzyloxy-5-isopropyl-pyrimidin-4-yloxy)-5-methyl-benzonitrile (372 mg, 65% pure, 0.52 mmol) was dissolved in 20 mL of EtOAc and 5 mL of EtOH. 10% Pd/C (75 mg) was added and a hydrogen balloon was applied. The reaction mixture was stirred at room temperature for 1 hour. The Pd/C was filtered through celite, and the filtrate was concentrated and purified using silica gel (EtOAc/hexane) to give a white solid (100 mg, 29%). LC-MS shows 286.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[C:11]([I:12])[C:3]=12.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=[C:11]([I:12])[C:3]=12
Reactant: Fc1cnc2[nH]cc(I)c2c1Cl
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)c(F)cnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 263A (2.8 g, 9.44 mmol) in tetrahydrofuran (200 mL) was cooled to 0° C. and sodium hydride (0.34 g, 14.17 mmol) was added. The mixture was stirred at 0° C. for 30 minutes and (2-(chloromethoxy)ethyl)trimethylsilane (2.5 mL, 14.17 mmol) was added. The mixture was warmed to room temperature, stirred for 2 hours, quenched with brine and extracted with ethyl acetate (twice). The organic phase was concentrated and purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to afford the title compound. MS (ESI+) m/z 427 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:17])[CH2:16]C[CH2:14]1)[N:8]([CH3:18])[C:7]2=[O:19].ClC1N(C)C(=O)C2C(=C(I)C=CC=2)N=1.Cl.[F:35]CC(N)(C)C>>[F:35][CH2:14][C:13]([NH:12][C:9]1[N:8]([CH3:18])[C:7](=[O:19])[C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1)([CH3:17])[CH3:16]
Reactant: Cn1c(NC2(C)CCC2)nc2c(I)cccc2c1=O
Reactant: CC(C)(N)CF
Agent: Cl
Agent: Cn1c(Cl)nc2c(I)cccc2c1=O
Product: Cn1c(NC(C)(C)CF)nc2c(I)cccc2c1=O
Yield: 63 %

Procedure:
This compound (0.71 g, 63% yield) as a yellow crystalline solid was prepared according to the procedure described for intermediate 711, using 2-chloro-8-iodo-3-methylquinazolin-4(3H)-one (700) (0.96 g, mmol), 2-fluoro-1,1-dimethyl-ethylamine hydrochloride (AmfineCom Inc; 0.69 g, 5.40 mmol) (AmfineCom Inc.) and TEA (2.1 mL, 15.10 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (1H, d, J=7.2 Hz), 7.96 (1H, d, J=7.4 Hz), 6.95 (1H, t, J=7.6 Hz), 6.16 (1H, br.), 5.04 (1H, s), 4.92 (1H, s), 3.47 (3H, s), 1.58 (6H, s). m/z (ESI, +ve) 375.8 (M+1-1)′).