Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[Cl:16][C:17]1[CH:25]=[C:24]([C:26]#[C:27][CH2:28][O:29][CH3:30])[C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH2:31].Cl[C:33]1[C:42]2[C:37](=[CH:38][C:39]([O:50][CH2:51][CH2:52][CH2:53][N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[CH:40][C:41]=2[O:43][CH:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[N:36]=[CH:35][N:34]=1>CN(C=O)C>[Cl:16][C:17]1[CH:25]=[C:24]([C:26]#[C:27][CH2:28][O:29][CH3:30])[C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH:31][C:33]1[C:42]2[C:37](=[CH:38][C:39]([O:50][CH2:51][CH2:52][CH2:53][N:54]3[CH2:55][CH2:56][O:57][CH2:58][CH2:59]3)=[CH:40][C:41]=2[O:43][CH:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)[N:36]=[CH:35][N:34]=1
Reactant: COCC#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: Clc1ncnc2cc(OCCCN3CCOCC3)cc(OC3CCOCC3)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)cc(OC4CCOCC4)c23)c2c1OCO2
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 36.2 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide (1.28 ml) in tetrahydrofuran (1.0M, 1.28 mmol) was added to a suspension of 5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (0.153 g) and 4-chloro-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinazoline (0.260 g) in DMF (4 ml) that had been cooled to −10° C. and the mixture was stirred for 90 minutes. A further portion of sodium bis(trimethylsilyl)amide (0.64 ml) in tetrahydrofuran (1.0M, 0.64 mmol) was added and the reaction was allowed to warm to room temperature and then stirred for a further 2 hours. The reaction mixture was quenched into water and saturated ammonium chloride solution was added. This was then extracted into dichloromethane and the organic portion was then washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol as eluent. The product material gathered after chromatography as a foam was triturated with diethyl ether giving an off-white solid. This was then re-dissolved into dichloromethane and then evaporated under reduced pressure. The resulting solid was triturated with diethyl ether and air-dried. There was thus obtained the title compound (0.141 g) as a white solid; NMR Spectrum: (CDCl3) 2.00 (m, 4H), 2.23 (m, 2H), 2.48 (m, 4H), 2.54 (t, 2H), 3.46 (s, 3H), 3.63 (dq, 2H), 3.73 (t, 4H), 4.02 (dt, 2H), 4.16 (t, 2H), 4.35 (s, 2H), 4.76 (tt, 1H), 6.11 (s, 2H), 6.51 (d, 1H), 6.85 (d, 1H), 7.06 (s, 1H), 8.52 (s, 1H), 9.26 (s, 1H); Mass Spectrum: M+H+ 611/613.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:15])[CH3:14])[CH2:9][CH2:8]1)=[O:5].CCN(C(C)C)C(C)C>C(Cl)Cl.CS(C)=O>[C:13]([C@H:10]1[CH2:11][CH2:12][C@H:7]([NH:6][C:4](=[O:5])[C:3]2[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:2]=2[Cl:1])[CH2:8][CH2:9]1)(=[O:15])[CH3:14]
Reactant: C[C@H](O)[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of Trans-2-chloro-N-(-4-((S)-1-hydroxyethyl)-cyclohexyl)-5-(trifluoromethyl)benzamide (1.00 g, 2.86 mmol) in DCM (20 mL) is added DIPEA (1.48 g, 11.4 mmol) of DIPEA. The reaction mixture is cooled to 0° C. and then a solution of sulfur trioxide-pyridine complex (1.82 g, 11.4 mmol) in DMSO (5 mL) is added. The reaction mixture is stirred at 0° C. for 10 min and then partitioned between DCM and water. The organic phase was washed with water and brine, dried over MgSO4, filtered and the solvent was removed in vacuo. Purification by chromatography on a pre-packed 40 g silica gel column using 0-100% EtOAc in isohexane (gradient elution) gave the desired product as a colourless solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([O:9]C(C)C)=[O:8])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].CCCCCC.C(OCC)(=O)C.Cl>CS(C)=O>[CH:1]([O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([OH:9])=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1ccccc1OC(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CC(C)Oc1ccccc1C(=O)O
Temperature: 70 °C
Yield: 17.6 %

Procedure:
To a stirred solution of Isopropyl 2-isopropoxy-benzoate (10 g, 240 mmol) in dimethyl sulfoxide (40 mL) was added potassium tert-butoxide (10 g, 890 mmol) in portions. The solution was heated to 70° C. on a water bath for 2 h, and the progress of the reaction was monitored by TLC using a hexane-ethyl acetate (8:2) solvent system. The reaction mass was cooled to 10° C., poured into ice water, and then acidified with 5% dilute hydrochloric acid. The precipitated solid was filtered and washed thoroughly with distilled water, and the crude mass was recrystallized in hexane (50 mL) to yield an off-white solid of 2-Isopropoxy-benzoic Acid (7.6 g, 80%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:3]=1.[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O>[N:26]([C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=2)[N:3]=1)=[N+:27]=[N-:28]
Reactant: N#Cc1ccc(Nc2nc(Cl)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)nc(N=[N+]=[N-])n2)cc1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
A solution of intermediate (27) in dimethylsulfoxide was treated with NaN3 in one portion and was stirred at RT for 28 hours. The reaction mixture was poured into ice and then filtered. The precipitate was washed with cold water and was recrystallized from ACN, yielding 0.46 g of 4-[[4-azido-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]amino]benzonitrile (compound 68).
Reaction SMILES: [O-]CCCC.[K+].C1COCC1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]1[CH:24]=[CH:23][N:22]([CH2:25][C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[N:21]=1.[Cl:32][C:33]1[N:37]([CH3:38])[N:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[C:34]=1[C:43](Cl)=[O:44]>O>[F:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[C:14]=1[C:20]1[CH:24]=[CH:23][N:22]([C:25](=[C:43]([C:34]2[C:35]([C:39]([F:42])([F:41])[F:40])=[N:36][N:37]([CH3:38])[C:33]=2[Cl:32])[OH:44])[C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[N:21]=1
Reactant: Cn1nc(C(F)(F)F)c(C(=O)Cl)c1Cl
Reactant: C=CCOC(=O)Cn1ccc(-c2c(F)cccc2F)n1
Agent: CCCC[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)C(=C(O)c1c(C(F)(F)F)nn(C)c1Cl)n1ccc(-c2c(F)cccc2F)n1
Reaction time: 0.08 h

Procedure:
Potassium butoxide (0.5 g) was added to a THF (10 mL) solution of allyl 2-{3-(2,6-difluorophenyl)pyrazol-1-yl}acetate (0.5 g) and 5-chloro-1-methyl-3-trifluoromethylpyrazole-4-carbonyl chloride (0.44 g) at 0° C., and stirred for 5 minutes. Water (5 ml) was added thereto, and then extracted with diluted hydrochloric acid and ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, and then concentrated, and the resulting concentrate was purified through silica gel column chromatography (chloroform) to obtain the intended product, Compound No. I-133 (0.89 g).
Reaction SMILES: S1C=CC=C1C([Cl:8])=O.[CH3:9][N:10]([CH2:12][CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH2:23])[CH3:11]>>[ClH:8].[CH3:11][N:10]([CH2:12][CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH2:23])[CH3:9]
Reactant: O=C(Cl)c1cccs1
Agent: CN(C)CCn1c(N)nc2ccccc21
Product: Cl

Procedure:
1-(N,N-Dimethylaminoethyl)-2-aminobenzimidazole hydrochloride was prepared by the method of Example 1 using thiophenecarbonyl chloride and 1-(N,N-dimethylaminoethyl)-2-aminobenzimidazole. MS 314 (M +1). 1H NMR (DMSO): δ 2.95 (s, 311), 2.97 (s, 3H), 3.57 (m, 2H), 4.70 (m, 2H), 6.08-7.89 (m, 7H), 10.66 (broad s, NH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([OH:26])[C:12]3[CH:13]=[C:14]([NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH:15]=[CH:16][C:17]=3[F:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:12]3[CH:13]=[C:14]([NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH:15]=[CH:16][C:17]=3[F:18])=[O:26])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Br)cc23)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To propane-1-sulfonic acid 3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-4-fluoro-phenyl-amide (673, 55.0 mg, 0.12 mmol) in tetrahydrofuran (8.0 mL) was added Dess-Martin periodinane (70.0 mg, 0.17 mmol). The reaction was stirred at room temperature for 5 minutes. The reaction was concentrated with silica gel and purified with silica gel column chromatography eluting with 25% ethyl acetate in hexane to give an off-white solid (P-1403, 26.2 mg, 47%). MS (ESI) [M+H+]+=437.9, 439.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[CH2:22][O:21][C:20](=[O:24])[NH:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:23]3[CH2:22][O:21][C:20](=[O:24])[N:19]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2COC(=O)N3)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2COC(=O)N3Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.9 %

Procedure:
To a solution of 4-(2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (43 mg, 0.13 mmol) in 2 ml anhydrous dimethylformamide was added sodium hydride (8 mg of a 60% suspension in mineral oil, 0.2 mmol) portion-wise at 0° C. The solution was stirred with a magnetic stirrer at 0° C. for 20 minutes, at which time the initial off-gassing ended. Benzyl bromide (0.02 ml, 0.17 mmol) was added in one portion and the reaction mixture was stirred at 0° C. for an hour. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by prep TLC to give 33 mg of 4-(1-benzyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester as a white solid (60%). MS: 424 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]3[C:30]4[C:25](=[N:26][CH:27]=[CH:28][N:29]=4)[N:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[O:31]C)[CH:6]=1)([F:4])[CH3:3].B(Br)(Br)Br.CCCCCC>C(Cl)Cl>[F:4][C:2]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]3[C:30]4[C:25](=[N:26][CH:27]=[CH:28][N:29]=4)[N:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[OH:31])[CH:6]=1)([F:1])[CH3:3]
Reactant: COc1cc(CCNc2ncnc3nccnc23)ccc1Oc1cc(C(C)(F)F)ccn1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(F)(F)c1ccnc(Oc2ccc(CCNc3ncnc4nccnc34)cc2O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a solution of (2-{4-[4-(1,1-difluoroethyl)-pyridin-2-yloxy]-3-methoxyphenyl}-ethyl)-pteridin-4-yl-amine (1.37 g, 3.13 mmol) in CH2Cl2 (15 mL) cooled to 0° C., was added 1M BBr3/hexane (9.4 mL, 9.4 mmol). The solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched with methanol and concentrated in vacuo. The residue was dissolved in small amount of methanol and poured into aqueous NaHCO3. The hydroxyaryl product precipitated and was collected by suction filtration and washed with H2O. The filter cake was air dried on the filter to yield 2-[4-(1,1-difluoroethyl)-pyridin-2-yloxy]-5-[2-(pteridin-4-ylamino)-ethyl]-phenol (0.76 g), as a light brown solid: 1H NMR (300 MHz, d6-DMSO) δ 9.53 (br s, 1H), 9.45 (s, 1H), 9.12 (s, 1H), 8.91 (d, J=1.5 Hz, 1H), 8.78 (br, 1H), 8.20 (d, J=5.3 Hz, 1H), 7.22 (d, J=5.3 Hz, 1H), 7.08 (s, 1H), 6.98 (d, J=8.1 Hz, 1H), 6.85 (d, J=1.8 Hz, 1H), 6.72 (dd, J=8.1, 1.8 Hz, 1H), 3.84 (dd, J=14.7, 7.4 Hz, 2H), 2.93 (t, J=7.4 Hz, 2H), 1.98 (t, J=19.2 Hz, 3H); ESIMS m/z 425 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][Br:9].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[Br-:9].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][P+:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Clc1ccccc1CBr
Solvent: Cc1ccccc1
Product: Clc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 99.5 %

Procedure:
Under a nitrogen atmosphere, a solution of 10.0 grams (0.049 mole) of 2-chlorophenylmethyl bromide and 13.0 grams (0.050 mole) of triphenylphosphine in about 100 mL of toluene was heated at reflux for about 18 hours. The reaction mixture was cooled, and a solid was collected by filtration. The solid was washed with toluene and dried under vacuum, yielding 22.8 grams of 2-chlorophenylmethyltriphenylphosphonium bromide, mp>250° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH:11]([OH:13])[C:10]2[CH:14]=[C:15](S(N)(=O)=O)[S:16][C:9]=2[S:8]1(=O)=O)[CH3:2].CC(C)(C)C([O-])([O-])[O-]>C(#N)C>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH:11]([OH:13])[C:10]2[CH:14]=[CH:15][S:16][C:9]=2[S:8]1)[CH3:2]
Reactant: CCOCCCN1CC(O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: CC(C)(C)C([O-])([O-])[O-]
Solvent: CC#N
Product: CCOCCCN1CC(O)c2ccsc2S1
Yield: 167.8 %

Procedure:
The product from Step D (1.6 g, 4.32 mmol) was dissolved in dry acetonitrile (20 mL) and trimethylorthoacetate (11 mL) was added. The mixture was heated at reflux temperature for 18 hr and then evaporated to provide an oil (1.88 g, 100%) which was used without further purification.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH:15]=2)[CH:11]=[C:10]([CH3:29])[N:9]=1.[CH3:30][C:31]([CH3:33])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[NH3:2].[CH:31]([N:5]1[CH2:6][CH:1]2[CH2:7][CH:4]1[CH2:3][N:2]2[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH:15]=2)[CH:11]=[C:10]([CH3:29])[N:9]=1)([CH3:33])[CH3:30]
Reactant: CC(C)=O
Reactant: Cc1cc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)nc(N2CC3CC2CN3)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)nc(N2CC3CC2CN3C(C)C)n1
Product: N
Temperature: 70 °C
Reaction time: 2 h
Yield: 1 %

Procedure:
A solution of 4-(2-(2,5-diaza-bicyclo[2.2.1]heptan-2-yl)-6-methylpyrimidin-4-yl)-N-((S)-1-phenylethyl)pyridin-2-amine (0.23 g, 0.60 mmol) in chloroform (5 mL) were added acetone (1 mL) and sodium triacetoxyborohydride (0.45 g, 2.14 mmol) and stirred at 70° C. for 2 h. Upon cooling to room temperature, the reaction was diluted with methylene chloride and washed with saturated sodium bicarbonate, brine, and dried over anhydrous K2CO3. Flash chromatography of the crude product with 1% 2M NH3 in MeOH/CHCl3 afforded the title compound as a pale yellow solid. MS (ES+): 429[M+H]+,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([N:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:18])=[O:16])[CH2:10][C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:12])[CH2:14][C:15]([N:17]([CH3:18])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(Cc1ccccc1)C(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(Cc1ccccc1)C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
3,4-Dichloro-beta-[2-[(phenylmethyl)methylamino]-2-oxoethyl]benzenepropanoic acid (6.9 g) in EtOAc (150 mL) was treated with carbonyldiimidazole (4.4 g) and N,N-dimethylaminopyridine (0.22 g). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for 1 hour. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (4.46 g) in H2O (75 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was then diluted with EtOAc (250 mL) and washed with 1N HCl (250 mL), H2O (250 mL) and dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound (6.29 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C1CCN2C(=NCCC2)CC1>CN(C=O)C.C(OCC)(=O)C>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[S:13]([NH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:3][CH:4]=1)(=[O:15])=[O:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=S(=O)(Nc1ccc(O)c2ccccc12)c1cccs1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(NS(=O)(=O)c2cccs2)c2ccccc12
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
61.1 mg 3 was dissolved in 1 ml DMF, to which was added 60 μl tert-butyl bromoacetate followed by 0.4 ml DBU solution (1M in NMP) and catalytic amount of KI. The mixture was heated with microwave initiator (biotage) to 90° C. and reacted for 20 min. TLC indicated the reaction didn't go complete. Additional 13.5 eq. of tert-butyl bromoacetate was added. The mixture was continued at 90° C. for 30 min. The mixture was diluted with ethyl acetate to 40 ml and washed with 0.5 M NaHSO4, H2O and brine. Dried over Na2SO4, the organic phase was concentrated and the residue was purified via flash chromatography (5 g silica gel, Hex/EtOAc) affording 43 mg (51.3%) solid. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=7.8 Hz, 1H), 7.80 (dd, J=8.1, 1.2 Hz, 1H), 7.61 (dd, J=5.0, 1.3 Hz, 1H), 7.56 (dd, J=3.8, 1.3 Hz, 1H), 7.46-7.36 (m, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.99 (dd, J=5.0, 3.8 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 3.92 (s, 2H), 1.52 (s, 9H).; LRMS (ES+) 420 (M+H)+; HRMS (ES+) m/z calculated for C20H22NO5S2 (M+H)+ 420.0934, found 420.0932.
Reaction SMILES: [OH-].[Na+].[CH3:3][S:4]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)(=[O:6])=[O:5]>CO.O>[CH3:3][S:4]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:6])=[O:5]
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
3.6 g (90 mmol) of NaOH was added to the solution of methyl 4-[(methylsulfonyl)amino]benzoate in 40 mL methanol and 20 mL water and stirred overnight at room temperature. Solvents were then removed and the product purified by ethyl acetate extraction from 1N aqueous hydrochloric acid, providing 1.2 g (yield 74.6%) of the 4-[(methylsulfonyl)amino]benzoic acid. 1H NMR in d-chloroform: 8.03 (2H, d, J=8.7 Hz), 7.34 (2H, d, J=8.7 Hz), 3.09 (3H, s). 13C NMR in d-chloroform: 131.2, 117.9, 38.6.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[N+:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([O-])=O>[Cu]>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([N:42]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=4)[C:45]4[CH:50]=[CH:49][C:48]([C:15]([CH3:18])([CH3:16])[CH3:14])=[CH:47][CH:46]=4)=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CC(C)(C)c1ccc(Nc2ccc(C(C)(C)C)cc2)cc1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)c1ccc(N(c2ccc(-c3ccc(N(c4ccc(C(C)(C)C)cc4)c4ccc(C(C)(C)C)cc4)cc3)cc2)c2ccc(C(C)(C)C)cc2)cc1
Yield: 31.7 %

Procedure:
13.4 g (0.048 mol) of 4,4'-ditertiarybutyl-N,N-diphenylamine, 7.7 g (0.019 mol) of 4,4'-diiodobiphenyl, 7.7 g (0.056 mol) of anhydrous potassium carbonate, 0.53 g (0.008 mol) of copper powder, and 5 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 200° to 215° C. for 4 hours. The reaction product was then extracted with 100 ml of THF. The insoluble contents were removed by filtration. The filtrate was then concentrated to obtain a crystal. The crude crystal thus obtained was then purified by column chromatography (carrier: silica gel; elute: 1/2 mixture of toluene and n-hexane) to obtain 4.3 g (yield: 31.7%) of N,N,N',N'-tetrakis(p-tertiarybutylphenyl)benzidine. The melting point of the product was from 402.0° C. to 403.0° C.
Reaction SMILES: II.C(Br)C.Br[C:7]1[CH:19]=[CH:18][C:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:9][CH:8]=1.[CH3:20][N:21]([CH3:38])[CH2:22][CH2:23][CH2:24][N:25]1[CH:30]=[CH:29][C:28]([C:31](N(OC)C)=[O:32])=[CH:27][C:26]1=[O:37]>C1COCC1>[CH3:38][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][N:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:32])[C:7]2[CH:19]=[CH:18][C:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)=[CH:9][CH:8]=2)=[CH:27][C:26]1=[O:37]
Reactant: CON(C)C(=O)c1ccn(CCCN(C)C)c(=O)c1
Reactant: Brc1ccc(OC2CCCCO2)cc1
Agent: II
Solvent: C1CCOC1
Solvent: CCBr
Product: CN(C)CCCn1ccc(C(=O)c2ccc(OC3CCCCO3)cc2)cc1=O
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
Mg (440 mg, 3.5 eq) was added to a 3-neck round bottom flask containing 50 mL anhydrous THF, and the mixture was heated to 55° C. Iodine chips (2 grains) were added in one lot followed by 0.1 mL ethyl bromide. 2-(4-Bromophenoxy)-tetrahydro-2H-pyran (4.0 g, 3.0 eq) was dissolved in 30 mL anhydrous THF, and 3 mL of this solution was added at once to the Mg-THF suspension. The reaction was initiated after 30 min and reflux started. the remaining solution of 2-(4-bromophenoxy)-tetrahydro-2H-pyran was added dropwise maintaining the reflux temperature over 5 min. After addition, the reaction mixture was further reflux for 2 h., cooled to rt, 1-(3-(dimethylamino)propyl)-N-methoxy-N-methyl-2-oxo-1,2-dihydro-pyridine-4-carboxamide (1.4 g, 1.0 eq) in 20 mL THF was added dropwise at rt, stirred at rt for 30 min., quenched with sat NH4Cl (aq), and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (1.6 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=9.2 Hz, 2H), 7.48 (d, J=6.8 Hz, 1H), 7.11 (d, J=9.2 Hz, 2H), 6.75 (d, J=1.6 Hz, 1H), 6.44 (dd, J=6.8 Hz, 2.0 Hz, 1H), 5.55 (t, J=2.8 Hz, 1H), 4.05 (t, J=7.2 Hz, 2H), 3.82-3.88 (m, 1H), 3.62-3.66 (m, 1H), 2.32 (t, J=6.4 Hz, 2H), 2.24 (s, 6H), 1.88-2.08 (m, 5H), 1.62-1.74 (m, 4H).