Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][CH:7]([F:40])[C:8]1[N:12]([C:13]2[N:14]=[C:15]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:16]3[N:21]=[N:20][N:19]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[C:17]=3[N:18]=2)[C:11]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:10]=2[N:9]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[F:40][CH:7]([F:6])[C:8]1[N:12]([C:13]2[N:14]=[C:15]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[C:16]3[N:21]=[N:20][N:19]([CH:22]4[CH2:23][CH2:24][N:25]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:26][CH2:27]4)[C:17]=3[N:18]=2)[C:11]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:10]=2[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2nnn(C3CCNCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2nnn(C3CCN(S(C)(=O)=O)CC3)c2n1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 87.1 %

Procedure:
Methanesulfonyl chloride (0.09 mL, 1.16 mmol) was added dropwise to a mixture of the above amine (107 mg, 0.220 mmol) and powdered K2CO3 (274 mg, 1.98 mmol) in CH2Cl2 (10 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred for 16.5 hrs. Water was added, the phases were separated, and the aqueous phase was extracted with CH2Cl2 (1×). The combined organic extracts were dried (Na2SO4) and the solvent removed under vacuum. Recrystallization from CH2Cl2/MeOH gave 5-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-3-[1-(methylsulfonyl)-4-piperidinyl]-7-(4-morpholinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (108 mg, 87%): mp 258-259° C.; 1H NMR (CDCl3) δ 7.81 (dd, J=8.4, 0.5 Hz, 1H), 7.41 (t, JHF=53.5 Hz, 1H), 7.39 (t, J=8.2 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 4.93 (tt, J=10.5, 4.2 Hz, 1H), 4.79 (br s, 2H), 4.16 (br s, 2H), 4.07 (s, 3H), 4.01-3.90 (m, 6H), 3.14 (m, 2H), 2.89 (s, 3H), 2.60 (m, 2H), 2.35 (m, 2H); Anal. Calcd. for C23H27F2N9O4S: C, 49.0; H, 4.8; N, 22.4. Found: C, 48.9; H, 4.8; N, 22.2%.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16]Br>>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16][N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: Clc1cccc(Cl)c1CBr
Product: O=C1CNc2ncc(I)cc2N1Cc1c(Cl)cccc1Cl

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (500 mg) was treated with 2,6-dichlorobenzyl bromide as in General Procedure 1 to give the title compound as an off-white solid. M.p.>200° C., LCMS: m/z=434.37 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 3.30 (2H, s), 5.29 (2H, s), 7.31 (1H, d, J=8.6 Hz), 7.34 (1H, d, J=7.6 Hz), 7.45 (1H, s), 7.47 (1H, s), 7.76 (1H, d, J=1.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[C:12]([OH:14])=[O:13].[H-].[Na+].[CH:17]1([CH2:23]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O>CN(C)C=O>[CH:17]1([CH2:23][N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[C:8]([C:12]([OH:14])=[O:13])=[CH:9]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: BrCC1CCCCC1
Reactant: COc1cccc2c(C(=O)O)c[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c(C(=O)O)cn(CC3CCCCC3)c12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
The damp solid was suspended in 4 M aqueous sodium hydroxide (1700 ml) and heated to reflux with stirring for 2 h. The mixture was cooled and washed with diethyl ether (2×400 ml). The aqueous phase was then acidified to pH 1 using 5 M hydrochloric acid and the resulting fine precipitate filtered off, washed with water to neutrality and dried to afford 7-methoxy-1H-indole-3-carboxylic acid as a pink solid (42.7 g). To a solution of 7-methoxy-1H-indole-3-carboxylic acid (42.7 g, 224 mmol) in di-methylformamide (1250 ml) at 10° C. under nitrogen was added sodium hydride (60% dispersion in mineral oil, 23.0 g, 575 mmol) portionwise over 20 minutes, maintaining the temperature below 15° C. The cooling bath was removed and the suspension stirred for 90 minutes. Cyclohexylmethyl bromide (64.7 ml, 464 mmol) was added. The mixture was heated at 60° C. with stirring for 3 h. The mixture was cooled to 10° C. and poured into water (3600 ml). The emulsion was washed with diethyl ether (3×500 ml). The aqueous phase was acidified to pH 1 using 5 M hydrochloric acid and the precipitate filtered off, washed with water to neutrality and dried to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid (55 g) as a white solid. Oxalyl chloride (12.4 g, 97.4 mmol) was added dropwise to a mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid (7.0 g, 24.4 mmol) and dichloromethane (150 ml) under ice-water cooling and the resulting mixture was stirred at room temperate for 18 h. Dichloromethane and excess oxalyl chloride were removed by evaporation and the obtained residue was mixed with dichloromethane (150 ml). Ammonia gas was bubbled into the resulting mixture for 30 min under ice-water bath cooling. The reaction mixture was concentrated in vacuo, then the obtained solid was triturated sequentially with 0.5 M hydrochloric acid, 5% aqueous sodium carbonate, and water, and dried under reduced pressure to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid amide (5.1 g) as a brown solid.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:18](OC)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.CCCCCC>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([CH:18]=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@H](C=O)CCCCNC(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 102.1 %

Procedure:
To a solution of 0.975 g of Boc-Lys(Cbz)-OMe in 25 ml of dichloromethane at −78° C. under a nitrogen atmosphere was added 6 ml of a 1M diisobutylaluminiumhydride solution in hexane. After 15 min the reaction was completed, the reaction mixture poured into 150 ml of 2% citric acid solution and filtered. The organic layer was separated, washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was coevaporated with toluene to give 0.92 g of Boc-Lys(Cbz)-H. This aldehyde (0.89 g) was dissolved in 1.4 ml of toluene and 0.90 g of 2-(trimethylsilyl)oxazole (prepared according to: Edwards, P. D., Wolanin, D. J., Andisik D. W., and Davis W., J. Med. Chem. 38, 76 (1995)) was added and heated at 80° C. After 60 h the reaction mixture was concentrated, the residue dissolved in 5 ml of tetrahydrofuran, treated with 3 ml of a 3M tetrabutylammonium fluoride in tetrahydrofuran solution and stirred at room temperature for 2 h. The mixture was concentrated dissolved in ethyl acetate, washed with 3% aqueous sodium hydrogencarbonate solution and brine, dried (magnesium sulfate) and evaporated. Purification by column chromatography on silica gel eluting with a gradient of ethyl acetate/dichloromethane=2/1 (v/v) to ethyl acetate afforded an oil that was rechromatographed on silica gel eluting with a gradient of ethyl acetate/heptane=1/1 (v/v) to ethyl acetate/heptane=1/3 (v/v) to give 0.22 g of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[CH:4]([CH2:21][OH:22])[NH:5][C:6](=[O:20])[C:7]1[C:12]([I:13])=[C:11]([NH2:14])[C:10]([I:15])=[C:9]([C:16]([OH:18])=[O:17])[C:8]=1[I:19].[CH3:24][C:25](N(C)C)=[O:26].C(Cl)(=O)C>O>[CH3:1][NH:2][C:3](=[O:23])[CH:4]([CH2:21][OH:22])[NH:5][C:6](=[O:20])[C:7]1[C:12]([I:13])=[C:11]([NH:14][C:25](=[O:26])[CH3:24])[C:10]([I:15])=[C:9]([C:16]([OH:18])=[O:17])[C:8]=1[I:19]
Reactant: CC(=O)N(C)C
Reactant: CNC(=O)C(CO)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: O
Solvent: CC(=O)Cl
Product: CNC(=O)C(CO)NC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)O)c1I
Reaction time: 20 h

Procedure:
82.4 g. (0.125 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-DL-serine methylamide (IVb), m.p. 259°-260° C. (decomposition), is dissolved in 200 ml. of dimethylacetamide; under agitation, 33.4 ml. of acetyl chloride is added dropwise thereto. The reaction mixture is agitated for 20 hours, mixed with 40 ml. of water, and, after another 30 minutes of agitation, concentrated under vacuum. The residue is stirred overnight with 150 ml. of water, the precipitate is vacuum-filtered, stirred in 150 ml. of 1 N sodium hydroxide solution with the addition of 15 ml. of 37% strength sodium hydroxide solution and activated carbon for 2 hours, the activated carbon is removed, and the filtrate is brought to pH 1 with concentrated hydrochloric acid. After allowing the reaction mixture to stand overnight at 0° C., the precipitate is vacuum-filtered, washed with ice water, and dried under vacuum at 70° C.
Reaction SMILES: [F:1][C:2]([F:18])([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].N1C=CC=CC=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.Cl>O>[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:18])([F:1])[C:11]([F:16])([F:17])[C:12]([F:14])([F:15])[F:13])(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCOCC(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOCCOCC(F)(F)C(F)(F)C(F)(F)F)cc1
Reaction time: 3 h
Yield: 103.2 %

Procedure:
5.0 g (17.3 mM) of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecanol and 4.8 ml of pyridine were stirred under cooling on an ice bath. To the mixture, 4.0 g (20.8 mM) of p-toluenesulfonyl chloride was added, followed by stirring for 3 hours. The reaction mixture was poured into water and acidified by hydrochloric acid, followed by extraction with ethylacetate, washing with water, drying with anhydrous sodium sulfate and distilling-off of the solvent to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=10/1) to obtain 7.92 g of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecyl p-toluenesulfonate (Yield: 99.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](O)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][C:12]=1[CH3:23]>FC(F)(F)C(O)=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:6]2[CH:5]=[C:4]([CH3:8])[C:3]([OH:9])=[C:2]([CH3:1])[CH:7]=2)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][C:12]=1[CH3:23]
Reactant: Cc1cccc(C)c1O
Reactant: CCC(O)(CC)c1ccc(Br)c(C)c1
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(Br)c(C)c1)c1cc(C)c(O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
2,6-Dimethylphenol (950 mg, 7.78 mmol) was added to a solution of 3-(4-bromo-3-methyl-phenyl)-pentan-3-ol (Example 38-(1); 2.0 g, 7.78 mmol) in trifluoroacetic acid (20 mL), and the mixture was stirred at room temperature for two hours. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50) to give the target compound as a colorless oil (2.62 g, 93%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[C:13](O)=[C:12]([N+:21]([O-:23])=[O:22])[C:11]1=[O:24])[CH2:7][CH2:8][CH3:9]>>[CH2:6]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[C:13]([Cl:3])=[C:12]([N+:21]([O-:23])=[O:22])[C:11]1=[O:24])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCn1c(=O)c([N+](=O)[O-])c(O)c2cccnc21
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCn1c(=O)c([N+](=O)[O-])c(Cl)c2cccnc21
Temperature: 25 °C
Yield: 56.1 %

Procedure:
Phosphorus oxychloride (20 ml, 0.21 mol) was added to 2.0 g (7.6 mmol) of 1-n-butyl-4-hydroxy-3-nitro-1,8-naphthyridin-2(1H)-one [J. Heterocyclic Chem., 22, 193 (1985)], and the mixture was heated to reflux for 30 minutes. After cooling to room temperature, the solvent was distilled off under reduced pressure and ice water was added to the resulting residue. The mixture was neutralized with 4N aqueous solution of sodium hydroxide, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then filtered. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol=20/1) to give 1.2 g (yield 56%) of Compound d as colorless crystals.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:31]=[N:30][C:12]3[N:13]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4[CH:19]=[N:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=4[C:11]=3[CH:10]=2)O1.Br[C:34]1[CH:49]=[CH:48][C:37]([CH2:38][N:39]2[CH:44]3[CH2:45][CH2:46][CH:40]2[CH2:41][CH:42]([OH:47])[CH2:43]3)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC.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>[OH:47][CH:42]1[CH2:41][CH:40]2[N:39]([CH2:38][C:37]3[CH:36]=[CH:35][C:34]([C:9]4[CH:31]=[N:30][C:12]5[N:13]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C:14]6[CH:19]=[N:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=6[C:11]=5[CH:10]=4)=[CH:49][CH:48]=3)[CH:44]([CH2:45][CH2:46]2)[CH2:43]1
Reactant: OC1CC2CCC(C1)N2Cc1ccc(Br)cc1
Reactant: CC1(C)OB(c2cnc3c(c2)c2cc(C#N)ncc2n3COCC[Si](C)(C)C)OC1(C)C
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(-c3ccc(CN4C5CCC4CC(O)C5)cc3)cnc21
Temperature: 100 °C
Yield: 59.8 %

Procedure:
A degassed mixture of 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (217 mg, 0.48 mmol), 8-(4-bromobenzyl)-8-aza-bicyclo[3.2.1]octan-3-ol (157 mg, 0.53 mmol), tetrakis(triphenylphosphine)palladium(0) (33 mg, 5 mol %) and cesium carbonate (157 mg, 0.48 mmol) in a mixture of DME (5 mL), IMS (2 mL) and water (1.3 mL) was heated under microwave irradiation at 100° C. for 30 minutes. The cooled reaction mixture was purified by flash chromatography (silica, 50 g column, Biotage, 0-5% (2N ammonia in MeOH) in DCM) to afford the title compound as an off-white solid (155 mg, 60%). 1H NMR (CDCl3, 300 MHz): 9.21-9.17 (m, 1H), 8.95 (d, J=2.1 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H), 8.43 (s, 1H), 7.67-7.53 (m, 4H), 6.04 (s, 2H), 3.70-3.58 (m, 4H), 3.35-3.15 (m, 2H), 2.20-1.60 (m, 10H), 0.95 (t, J=8.2 Hz, 2H), 0.00 (s, 9H). LCMS (Method B): RT=2.92 min, M+H+=540.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[Cl:17][CH2:18][C:19](=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(O)C>[Cl:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[N:1]=[C:19]([CH2:18][Cl:17])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: CCOC(=O)c1c(CCl)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
To a yellow solution of 2-amino-5-chlorobenzophenone (6.93 g, 30.0 mmol) in ethanol (150 ml) was added ethyl 4-chloroacetoacetate (5.3 ml, 39.0 mmol) followed by ytterbium triflate (1.6 g, 3.0 mmol). The mixture was stirred at room temperature for 48 hours, at which time a voluminous white suspension was noted. The mixture was filtered, and the precipitate washed with ethanol, then diethyl ether, to provide ethyl 6-chloro-2-(chloromethyl)-4-phenylquinoline-3-carboxylate as a white powder (93%). 1H NMR (CDCl3; 400 MHz) δ 8.08 (d, 1H, J=8.9 Hz); 7.71 (dd, 1H, J=8.9, 2.3 Hz); 7.59 (d, 1H, J=1.95 Hz); 7.54 (m, 3H); 7.38-7.30 (m, 2H); 5.0 (s, 2H); 4.05 (q, 2H, J=7.0 Hz); 0.92 (t, 3H, J=7.0 Hz). LC MS (CI) shows M+H 360.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:52])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([O:42][Si](C(C)(C)C)(C)C)[C:38]([CH3:41])([CH3:40])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])[CH:17]=1>ClCCl>[CH3:8][O:9][C:10](=[O:52])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:27][CH3:28])([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([OH:42])[C:38]([CH3:40])([CH3:41])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])[CH:17]=1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Trifluoroacetic acid (0.18 mL) was added to a solution of {5-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester (Example 62-(1); 23.3 mg, 0.0370 mmol) in dichloromethane (0.9 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 8 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=1/1 to 2/1) to give the title compound (17.0 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:17][C:18]([CH3:22])([CH3:21])[CH:19]=O)[C:15]#[CH:16].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[SH:13][C:10]([CH3:11])([CH3:12])[CH2:9][NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:19][C:18]([S:17][CH2:14][C:15]#[CH:16])([CH3:22])[CH3:21]
Reactant: CC(C)(S)CNc1ccccc1N
Reactant: C#CCSC(C)(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C#CCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Temperature: 21 °C
Reaction time: 17 h
Yield: 74.8 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (5.59 g, 2.85×10-2 mol) and 2-(2-propynylthio)-2-methylpropanal 6.07 g, 4.28×10-2 mol, 150 M %) were mixed, then 125 ml methanol and 5.27 ml (5.7×10-2 mol, 200 M %) acetic acid were added and solids were allowed to dissolve. Sodium cyanoborohydride (5.39 g, 8.56×10-2 mol, 300 M %) was added to the reaction solution in three equal portions. The reaction was stirred at 21° C. for 17 hr, then quenched with 100 ml 0.5M HCl, stirred for 15 min, and then extracted with 2×150 ml ether. The ether layers were combined, washed with 60 ml saturated NaCl solution and dried over Na2SO4. The solvent was removed on the rotary evaporator and the residue was purified by filtration through flash silica in a 600 ml sintered glass funnel 3/4 full of silica, eluting with 500 ml portions of 2 × hexane and 2× 90% hexane/ether to produce 6.88 g (75% yield) 2-(2-mercapto-2-methyl-propylamino)-1-[2-(2-propynylthio)-2methylpropylamino]-benzene.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[C:9]([CH:26]3[CH2:28][CH2:27]3)[C:10]([N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][C:6]=2[O:5][C:4]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)#[N:2].[NH2:36][OH:37]>C(O)C>[CH:26]1([C:9]2[C:10]([N:12]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][C:6]3[O:5][C:4]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)=[C:3]([C:1](=[N:36][OH:37])[NH2:2])[C:7]=3[CH:8]=2)[CH2:28][CH2:27]1
Reactant: NO
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C#N)c3cc2C2CC2)S(C)(=O)=O)cc1
Solvent: CCO
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C(N)=NO)c3cc2C2CC2)S(C)(=O)=O)cc1
Temperature: 140 °C

Procedure:
To a 20 mL microwave tube was added the product from Example 8B (340 mg, 0.693 mmol) and hydroxylamine (50 weight % in water, 6.0 mL, 102 mmol) in ethanol (6 mL). The vial was sealed and heated in a microwave reactor (Personal Chemistry (Biotage), Emrys Creator, 300 W maximum) at 140° C. for 30 minutes. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound which was used without purification (363 mg, quantitative yield). MS (ESI+) m/z 524 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])=[CH:13][CH:14]=2)=[CH:3][C:2]=1[Br:1]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccc(O)c(Br)c2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
A mixture of tert-butyl (3′-bromo-4′-hydroxy[1,1′-biphenyl]-4-yl)methylcarbamate (1.50 g, 3.97 mmol), prepared in the previous step, methyl bromoacetate (376 μL, 3.97 mmol) and potassium carbonate (2.74 g, 19.86 mmol) in 50 mL of DMF was stirred under nitrogen at room temperature for 19 h (overnight). The reaction was partitioned between methylene chloride and water. The organic layer was separated, extracted five times with water, dried (MgSO4) and the solvent removed under reduced pressure to give methyl[(3-bromo-4′-{[(tert-butoxycarbonyl)amino]methyl}[1,1′-biphenyl]-4-yl)oxy]acetate (1.67 g, 93%) as a white solid, mp 96-98° C. Elemental Analysis for C21H24BrNO5. Calc'd: C, 56.01; H, 5.37; N, 3.11. Found: C, 55.47; H, 5.40; N, 3.00
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24]N1C(=O)CCC1=O.C(#N)C>O>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[C:16]([Cl:24])[C:17]([N:19]([CH3:23])[CH:20]([CH3:21])[CH3:22])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CC#N
Product: CC(C)N(C)c1nc2c(nc1Cl)CN(Cc1ccccc1)CCO2
Temperature: 50 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
A mixture of 8-benzyl-N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (500 mg), N-chlorosuccinimide (257 mg) and acetonitrile (10 mL) was stirred at room temperature for 16 hr and at 50° C. for 24 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient: 0→40% ethyl acetate/hexane) to give the title compound (437 mg, 79%) as a yellow oil.