Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[NH:4][C:5]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Na+].Cl[C:18]1[N:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[N:19]=1.O>CN(C=O)C>[F:14][CH:2]([F:1])[C:3]1[N:7]([C:18]2[N:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[N:19]=2)[C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=2[N:4]=1
Reactant: COc1cccc2nc(C(F)F)[nH]c12
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)cc(Cl)n1
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
2-Difluoromethyl-4-methoxybenzimidazole (9.03 g, 45.6 mmol) was dissolved in DMF (100 ml), 60% NaH (1.82 g, 45.6 mmol) was added, and stirred for 30 minutes. The reaction mixture was added to a solution obtained by dissolving 2,4,6-trichloropyrimidine (15.7 g, 92.1 mmol) into DMF (100 ml) while cooling with ice, and stirred on an ice bath for 30 minutes and further at room temperature for 2 hours. Water was added to the reaction mixture, precipitated crystals were filtered, and washed well with hexane and ether, then air-dried to afford 2-(2-difluoromethyl-4-methoxybenzimidazol-1-yl)-4,6-dichloropyrimidine (12.3 g, yield 78%).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH:11]([CH3:13])[O:10][CH:9]([CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:14][CH:9]1[O:10][CH:11]([CH3:13])[CH2:12][N:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]([F:29])([F:28])[F:17])=[CH:3][CH:4]=2)[CH2:8]1
Reactant: CC1CN(Cc2ccc(Br)cc2)CC(C)O1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1CN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CC(C)O1
Temperature: 120 °C

Procedure:
100 mg of 4-(4-Bromo-benzyl)-2,6-dimethyl-morpholine was combined with 100 mg of 2-(Trifluoromethyl)phenyl boronic acid, 20 mg of tetrakis(triphenylphosphine)palladium(0), 1.179 mL of 2M sodium carbonate solution, 3.2 mL toluene and 1.6 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by reverse phase HPLC. ES MS (+) m/z 350.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:16])[C:3]=1[N:17]1[C:21](=[O:22])[NH:20][C:19]([C:23]2[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=2)=[N:18]1.[C:30]([CH:32]1[CH2:34][CH2:33]1)#[CH:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CS(C)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:16])[C:3]=1[N:17]1[C:21](=[O:22])[NH:20][C:19]([C:23]2[CH:28]=[CH:27][C:26]([C:31]#[C:30][CH:32]3[CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[N:18]1
Reactant: C#CC1CC1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c1F
Yield: 41 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 by using N-(4-chloro-2-fluoro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide (Intermediate-68, 0.050 g, 0.094 mmol), ethynylcyclopropane (0.009 g, 0.142 mmol), TBAF (0.074 g, 0.283 mmol), bis(triphenylphosphine)palladium(11) chloride (0.003 g, 0.003 mmol) and DMSO (3.0 mL) to afford 0.018 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 0.75 (m, 2H), 0.77-0.91 (m, 2H), 1.36 (s, 9H), 1.53-1.59 (m, 2H), 7.38 (t, J=5.9 Hz, 1H), 7.46-7.52 (m, 3H), 8.79 (d, J=4.4 Hz, 2H), 8.19 (t, J=4.3 Hz, 1H); MS (m/z): 467.15 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[OH2:9]>C(O)C>[CH:7]1[CH:6]=[N:5][CH:4]=[C:3]([C:1]([NH2:2])=[O:9])[CH:8]=1
Reactant: N#Cc1cccnc1
Reactant: O
Solvent: CCO
Product: NC(=O)c1cccnc1
Temperature: 87.5 °C
Yield: 95.7 %

Procedure:
In a four neck round bottom flask fitted with thermowell, agitator and reflux condenser, 3-cyanopyridine (500 g), de-mineralized water (560 g; pH 7.5), ethyl alcohol (56 g) and 40 g of fresh catalyst prepared in Example 1 were charged. The mixture was heated up to 85-90° C. for 4-6 hrs. The completion of reaction was monitored by HPLC. After the completion of reaction the crude product was cooled to 50-60° C. and filtered to separate niacinamide from the catalyst bed. The catalyst bed was washed with de-mineralized water to make catalyst free from hydrolyzed mass of 3-cyanopyridine. The wet catalyst obtained was recycled back for next batch of hydrolysis. The colorless mother liquor was concentrated and dried to get 561.5 g niacinamide. Purity: 99.6% (w/w); niacin content<0.23%; Melting Point: 128-131° C. The water layer recovered containing 3-cyanopyridine and alcohol was recycled back for next hydrolysis batch.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)[CH3:2].[H-].[Na+].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH:20]=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:14])[CH:5]=[CH:20][C:19]1[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:18]=1[Cl:17])[CH3:2]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1c(F)cccc1Cl
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A solution of (diethoxyphosphoryl)-acetic acid ethyl ester (87 g, 0.39 mol) in tetrahydrofuran (100 mL) was slowly added to a suspension of sodium hydride (60% in mineral oil, 15 g, 0.39 mol) in tetrahydrofuran (200 mL) at 0° C. After stirring for 20 minutes, a solution of 2-chloro-6-fluoro-benzaldehyde (40 g, 0.26 mol) in tetrahydrofuran (100 mL) while maintaining the temperature at 0° C. The mixture was heated to 50° C. for 1 hour and then cooled to room temperature. The reaction was quenched by addition of a saturated aqueous solution of ammonium chloride (300 mL). The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness to give 3-(2-chloro-6-fluoro-phenyl)-acrylic acid ethyl ester, which was used directly in the next step. 1H NMR (CDCl3) δ: 7.89 (d, 1H, J=16.4 Hz), 7.26-7.06 (m, 2H), 7.06-7.02 (m, 1H), 6.72 (d, 1H, J=16.4 Hz), 4.28 (q, 2H, J=7.6 Hz), 1.34 (t, 3H, J=7.6 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[C:10](OCC)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CCCCCC>[OH:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:3][CH2:2][N:1]=[C:21]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CCCCCCCCCCCC(=O)OCC
Reactant: NCCNCCCCO
Solvent: CCCCCC
Product: CCCCCCCCCCCC1=NCCN1CCCCO
Yield: 54.2 %

Procedure:
8 g (60.6 mmoles) of 4-(2-aminoethylamino)butanol and 12.5 g of ethyl dodecanoate were treated as under Example 25. The resulting 10.8 g of an oil (66.7%) was dissolved in 100 ml of hexane and kept in the freezer to give 8.8 g of pure product, m.p. 58°-60° C.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([NH:33][C:34]([NH2:36])=[O:35])=[C:12]([CH2:31][CH3:32])[N:13]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(C)(C)C>CO.O1CCCC1>[CH2:31]([C:12]1[N:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:14]2[C:10]([C:11]=1[NH:33][C:34]([NH2:36])=[O:35])=[C:9]([O:8][CH2:7][C:6]([OH:37])=[O:5])[CH:17]=[CH:16][CH:15]=2)[CH3:32]
Reactant: CCc1c(NC(N)=O)c2c(OCC(=O)OC(C)(C)C)cccc2n1Cc1ccccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: CCc1c(NC(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 53.6 %

Procedure:
[[2-Ethyl-1-(2-phenyl-phenylmethyl)-3-ureido-1H-indol-4-yl]oxy]acetic acid tert-butyl ester (0.206 g) was treated with 5 mL of a 7:1 mixture of methanol/tetrahydrofuran at room temperature overnight. After concentrating to dryness and adding 1 mL of 1N HCl, stirring was continued at room temperature for an hour. The resulting solid was filtered off and vacuum dried to provide 0.098 g of [[2-ethyl-1-(2-phenyl-phenylmethyl)-3-ureido-1H-indol-4-yl]oxy]acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33]C(OC(C)(C)C)=O)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1>CCOC(C)=O>[NH2:33][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]([CH2:29][CH:30]2[CH2:31][CH2:32]2)[S:25]([CH3:28])(=[O:26])=[O:27])[CH2:16][CH2:17]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1

Procedure:
(2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(cyclopropylmethyl) (methylsulfonyl)amino]phenyl}piperazinyl)propan-1-one was prepared according to the procedure for Preparation XVI using N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}-piperazinyl)-2-oxoethyl](tert-butoxy)carboxamide (Step 2) (560 mg, 0.95 mmol). The resulting crude material was diluted with EtOAc and washed with satd NaHCO3 soln. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to afford 449 mg. MS (ESI, pos. ion) m/z: 491 (M+H), (ESI, neg. ion) m/z: 489 (M−H). Calc'd for C24H31ClN4O3S: 491.05.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8](O)=[O:9])[C:4](=[O:11])[O:3]1.C(N(S(F)(F)[F:19])CC)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8]([F:19])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)O)O1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC1(C)OC(=O)[C@@H](CC(=O)F)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of [(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (100 mg, 0.6 mmol) in CH2Cl2 (2 mL) was added (diethylamino)sulfur trifluoride (DAST) (111 mg, 0.7 mmol) at 0° C. and the resulting solution was stirred at 0° C. for 1 h. More CH2Cl2 (10 mL) was added. The whole mixture was washed with cold water twice, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to afford the title compound. 1H NMR (400 MHz, CDCl3): δ4.68-4.71 (m, 1H), 3.11-3.17 (m, 1H), 2.98-3.04 (m, 1H), 1.64 (s, 3H), 1.58 (s, 3H).
Reaction SMILES: C(=O)=O.[O:4]=[CH:5][C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7]>O>[OH:4][CH2:5][C:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])=[O:7]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C=O
Solvent: O
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 2525 %

Procedure:
The recovered crystals were suspended into chilled water, and the suspension was neutralized until below pH 10 by introducing carbon dioxide gas at 0° C. The precipitates of calcium carbonate were filtered, and the filtrate of which pH was about 8.5 was concentrated to 420 g. The concentrated solution contained 202 g fructose (Yield; 66.7%) and 8 g glucose. The concentrated solution was passed through two columns, one was packed with strongly acidic cation exchange resin and the other was packed with weakly basic anion exchange resin, and accordingly the solution was desalted and partially decolorized. The effluent was further treated with activated carbon, concentrated, and colorless solution (fructose concentration; 70%) was obtained.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:20][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[C:17]([F:19])[CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(F)cc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cc(F)cc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 97 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 83b (1.2 g, 2.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.3 g, 97%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][C:8]([OH:10])=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:34][C:35]1([C:41]2[CH:42]=[C:43]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:44]=[CH:45][CH:46]=2)[CH:40]2[CH:36]1[CH2:37][NH:38][CH2:39]2.C(=O)([O-])O.[Na+]>CN(C)C=O.CO>[CH3:34][C:35]1([C:41]2[CH:42]=[C:43]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:44]=[CH:45][CH:46]=2)[CH:40]2[CH:36]1[CH2:37][N:38]([C:8](=[O:10])[CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH2:39]2
Reactant: O=C(O)CCc1ccsc1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCc3ccsc3)CC21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a solution of 3-(3-thienyl)propanoic acid (200 mg, 1.2 mmol) in N,N-dimethylformamide (25 ml) was added 1-hydroxybenzotriazole monohydrate (200 mg, 1.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (340 mg, 1.77 mmol). After stirring at room temperature for 10 min the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 400 mg, 1.3 mmol) and sodium hydrogen carbonate (220 mg, 2.6 mmol). The reaction mixture was stirred at room temperature for 72 h before concentrating in vacuo. Water (15 ml) was added and the reaction mixture was extracted with ethyl acetate (1×20 ml and 2×15 ml). The combined organic extracts were washed with water (15 ml) and saturated brine (15 ml), dried (MgSO4), and concentrated in vacuo to give a buff solid. The crude product was sonicated in methanol (5 ml) to afford the title compound as an off-white solid (330 mg, 63%, m.p. 179.7° C.).
Reaction SMILES: [CH2:1]([N:3]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[CH2:8][C@H:4]1[C:5]([OH:7])=O)[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[CH2:44][NH2:45].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[CH2:44][NH:45][C:5](=[O:7])[C@@H:4]1[CH2:8][C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:3]1[CH2:1][CH3:2]
Reactant: CCN1C(=O)C(C)(C)C[C@H]1C(=O)O
Reactant: NCc1ccc(F)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C(=O)C(C)(C)C[C@H]1C(=O)NCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
1-ethyl-4,4-dimethyl-5-oxoproline (0.130 g, 0.702 mmol, prepared as described below), 1-Hydroxybenzotriazole (0.161 g, 1.053 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.202 g, 1.053 mmol) were dissolved in dichloromethane (5 ml) and stirred for 15 minutes at room temperature. [(2-chloro-4-fluorophenyl)methyl]amine (0.134 g, 0.842 mmol) and diisopropylethylamine (0.184 ml, 1.053 mmol) were then added to the mixture and stirring continued overnight at room temperature. The mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate and water and extracted with ethyl acetate. The combined organic layers were washed sequentially with 3N citric acid, water, saturated aqueous sodium carbonate, water (×3), and then brine and dried over anhydrous sodium sulfate. Concentration gave a crude solid which was subsequently purified by mass-directed automated HPLC to give N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-4,4-dimethyl-5-oxoprolinamide (0.146 g) as a solid. LC/MS [M+H]+=327/329, retention time=2.35 minutes.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(CC(OCC)=O)[C:14]([O:16]CC)=[O:15]>Cl.CC(O)=O>[NH2:3][CH2:12][CH:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)CC(Cc1ccccc1)(CN1C(=O)c2ccccc2C1=O)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: NCC(Cc1ccccc1)C(=O)O
Temperature: 120 °C

Procedure:
A solution of diethyl 2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-(phenylmethyl)butanedioate (13 g, 31.8 mmole) in conc. HCl (125 mL) and HOAc (30 mL) was sealed in a 1 L screwcap reaction vessel and the contents heated to 120° C. for 48 h. The reaction solution was concentrated under vacuum and the resulting solids washed with Et2O affording the title compound (quant.) as a white solid: LCMS (ES) m/z 181(M+H)+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:32][CH:33]1[CH2:36][CH2:35][CH2:34]1>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:32][CH:33]3[CH2:36][CH2:35][CH2:34]3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: BrCC1CCC1
Product: Cc1nc2c(ccn2CC2CCC2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and (bromomethyl)cyclobutane. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.43 (m, 1 H), 7.21-7.13 (m, 2 H), 6.99-6.93 (m, 1 H), 6.34 (dd, J=3.5, 7.8 Hz, 1 H), 5.51 (d, J=3.9 Hz, 1 H), 4.54-4.37 (m, 2 H), 4.30 (t, J=5.2 Hz, 2 H), 2.96-2.80 (m, 6H), 2.17-2.05 (m, 4 H), 1.99-1.79 (m, 4 H), 0.99-0.90 (s, 9 H); LC/MS (m/z) ES+=463.37 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:11][O:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15]>C(O)C.C(OCC)(=O)C>[OH:16][C:14]([CH3:17])([CH3:15])[CH2:13][O:12][N:11]=[CH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1
Reactant: CC(C)(O)CON
Reactant: O=Cc1cccc(Br)n1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(O)CON=Cc1cccc(Br)n1
Temperature: 25 °C

Procedure:
A solution of 6-bromopyridine-2-carbaldehyde (334 mg, 1.80 mmol) and 1-(aminooxy)-2-methylpropan-2-ol hydrochloride salt (254.6 mg, 1.80 mmol) were stirred in ethanol (5 ml) for one hour at 10° C. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Column chromatography from 100% hexanes to 30% ethyl acetate afforded the title compound as E/Z mixture.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[NH2:11][C@@H:12]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[N:2]1([CH2:7][C:8]([NH:11][C@@H:12]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)=[O:14])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Cn1cncn1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccccc2)cc1
Yield: 82 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1,2,4)-triazol-1-ylacetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-phenoxyphenyl)propanamide, gave Compound 146, (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-3-(benzyloxy)-N-(4-phenoxyphenyl)propanamide (106 mg, 82%). 1H-NMR (400 MHz, CDCl3): σ 8.69 (s, 1H), 8.41 (br s, 1H), 7.64 (d, 1H), 7.58 (d, 1H), 7.44 (d, 2H), 7.39-7.25 (m, 6H), 7.10-7.06 (m, 2H), 6.99-6.97 (m, 4), 5.03-4.99 (m, 1H), 4.76 (d, 1H), 4.65 (d, 1H), 4.25 (dd, 1H), 3.78 (dd, 1H). MS (EI) for C26H25N5O4. found 472.1 (MH+).
Reaction SMILES: [C:1]([NH:4][S:5]([C:8]1[CH:37]=[CH:36][C:11]([CH2:12][N:13]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=2)[CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2].[ClH:38]>CCOC(C)=O>[ClH:38].[Br:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][CH2:27][N:13]([CH2:12][C:11]2[CH:36]=[CH:37][C:8]([S:5]([NH:4][C:1](=[O:3])[CH3:2])(=[O:7])=[O:6])=[CH:9][CH:10]=2)[CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:30][CH:31]=1
Reactant: CC(=O)NS(=O)(=O)c1ccc(CN(CCc2ccc(Br)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)NS(=O)(=O)c1ccc(CN(CCc2ccc(Br)cc2)C2CCNCC2)cc1

Procedure:
tert-Butyl 4-((4-(N-acetylsulfamoyl)benzyl)(4-bromophenethyl)amino)piperidine-1-carboxylate obtained in Step 1 was subjected to the deprotection reaction as described in Procedure 2 (4 N HCl in EtOAc). The crude product was carried on to the next step without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.BrB(Br)Br>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(N2CCN(S(C)(=O)=O)CC2)cc1
Agent: BrB(Br)Br
Product: CS(=O)(=O)N1CCN(c2ccc(-c3c(O)ccc4[nH]c(=O)c5sccc5c34)cc2)CC1
Yield: 16.8 %

Procedure:
Following General Procedure F, 8-methoxy-9-{4-[4-(methylsulfonyl)piperazin-1-yl]phenyl}thieno[2,3-c]quinolin-4(5H)-one (32 mg, 0.068 mmol) was reacted with tribromoborane (1.0 mL) to afford the desired product (5.2 mg, 17%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 7.58 (d, J=5.4 Hz, 1H), 7.37 (d, J=8.9 Hz, 1H), 7.20 (s, 4H), 7.15 (d, J=8.9 Hz, 1H), 6.16 (d, J=5.4 Hz, 1H), 3.44-3.43 (m, 8H), 2.92 (s, 3H); ESI MS m/z 456[C22H21N3O4S2+H]+; HPLC >99%, tR=10.47 min.