Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=[O:15])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[N:37][NH:38]3)O1>>[NH:38]1[C:39]2[C:35](=[C:34]([C:2]3[N:3]=[C:4]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=5)[C:14]([OH:16])=[O:15])=[CH:8][C:6]=4[N:7]=3)[CH:42]=[CH:41][CH:40]=2)[CH:36]=[N:37]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: O=C(O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: O=C(O)c1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (100 mg) via General Procedure A to yield 7.6 mg of 338. MS (Q1) 458.1 (M)+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]O)[CH2:10][CH:9]1[C:18](=[O:35])[NH:19][CH:20]([CH:24]1[CH:29]([OH:30])[CH:28]([OH:31])[CH:27]([OH:32])[CH:26]([S:33][CH3:34])[O:25]1)[CH:21]([CH3:23])[CH3:22])=O)(C)(C)C.[CH2:36]([S-:38])[CH3:37].[Na+]>>[CH3:22][CH:21]([CH3:23])[CH:20]([NH:19][C:18]([CH:9]1[CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][S:38][CH2:36][CH3:37])[CH2:12][CH2:13][NH:8]1)=[O:35])[CH:24]1[CH:29]([OH:30])[CH:28]([OH:31])[CH:27]([OH:32])[CH:26]([S:33][CH3:34])[O:25]1
Reactant: CC[S-]
Reactant: CSC1OC(C(NC(=O)C2CC(CCCO)CCN2C(=O)OC(C)(C)C)C(C)C)C(O)C(O)C1O
Agent: [Na+]
Product: CCSCCCC1CCNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1

Procedure:
The title compound of example 22 was prepared from protected tosylate intermediate prepared in example 19, according to the procedure used in examples 19-21, using sodium ethanethiolate in the displacement step; MS (ESPOS): 465.3 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[C:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][C:26]1[C:30]([S:31](Cl)(=[O:33])=[O:32])=[C:29]([CH3:35])[O:28][N:27]=1.C(N(CC)CC)C>>[CH3:25][C:26]1[C:30]([S:31]([N:22]2[CH2:21][CH2:20][CH:19]([C:10]3[C:9]4[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][CH:11]=3)[CH2:24][CH2:23]2)(=[O:33])=[O:32])=[C:29]([CH3:35])[O:28][N:27]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3=CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1

Procedure:
Following the general procedure in example 267, 5-phenyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole-7-carboxamide (32 mg, 0.1 mmol), 3,5-dimethyl-4-isoxazolesulfonyl chloride (22.9 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (11 mg, 23%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O[C@H:16]([CH3:26])[CH2:17][NH:18]C(=O)OC(C)(C)C>>[NH2:18][CH2:17][C@H:16]([N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1)[CH3:26]
Reactant: N#Cc1ccc(-c2cc[nH]n2)cc1Cl
Reactant: C[C@@H](O)CNC(=O)OC(C)(C)C
Product: C[C@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1

Procedure:
(R)-4-[1-(1-Aminopropan-2-yl)-1H-pyrazol-3-yl]-2-chlorobenzonitrile was prepared using the method of Example 34(c) starting from 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile and (R)-tert-butyl 2-hydroxypropylcarbamate. 1H NMR (400 MHz, CDCl3): 1.24 (21-1, broad s), 1.54 (3H, d), 3.05 (1H, distorted dd), 3.17 (1H, distorted dd), 4.34 (1H, m), 6.61 (1H, d), 7.52 (1H, d), 7.66 (1H, d), 7.78 (1H, dd), 7.98 (1H, d).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[O:24])[C@H:4]([CH2:25][CH2:26][CH3:27])[CH2:3]1.[CH3:28][C:29]([CH3:31])=O.[C:32]([BH3-])#N.[Na+].C=O>CO>[CH:29]([N:1]([CH3:32])[C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:9]2=[O:24])[C@H:4]([CH2:25][CH2:26][CH3:27])[CH2:3]1)([CH3:31])[CH3:28]
Reactant: [BH3-]C#N
Reactant: CCC[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The entirety of benzyl (S)-1-[(1S,2R,4R)-4-amino-2-propylcyclohexyl]-2-oxopyrrolidin-3-ylcarbamate prepared in Step 1 (assumed 8.2 mmol) was dissolved in methanol (40 mL). The resultant solution was charged with acetone (6 mL, 82 mmol) and stirred at RT for 10 min before sodium cyanoborohydride (2.6 g, 41 mmol) was added in one portion. The reaction was stirred at RT for 10 h and then charged successively with formaldehyde (3.0 mL of 37 wt % aq soln, 41 mmol) and sodium cyanoborohydride (0.52 g, 8.2 mmol). The reaction was stirred for another 9 h at RT and then quenched with sat. NaHCO3 (150 mL). The aqueous mixture was extracted with EtOAc (200 mL, then 2×75 mL). The organic extracts were combined, washed with brine (30 mL), dried (MgSO4), filtered, and concentrated in vacuo. After the resulting oil stood, some paraformaldehyde-related products solidified; these were removed by dissolving the mixture in a minimal volume of EtOAc and filtering. Subsequent concentration provided benzyl (S)-1-[(1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl]-2-oxopyrrolidin-3-ylcarbamate. MS found: (M+H)+=430.5.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[N:24]1([CH:30]=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[CH:30]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:26][CH2:25]1)=[O:31]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: O=CN1CCNCC1
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCN(C=O)CC3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and piperazine-1-carbaldehyde (34 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 20-45% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (35 mg, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6 H) 3.59-3.82 (m, 8 H) 6.39 (d, J=2.02 Hz, 1 H) 7.43 (s, 1 H) 7.60 (d, J=8.59 Hz, 2 H) 8.00 (d, J=8.34 Hz, 2 H) 8.08-8.15 (m, 2 H) 10.94 (s, 1 H). ESI-MS: m/z 409.2 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([C:15](=[O:18])[CH2:16][Cl:17])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].Cl>ClCCl.CO>[ClH:17].[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([C:15](=[O:18])[CH2:16][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(=O)N1CCc2ccc(C(=O)CCl)cc2CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(C(=O)CN3CCCCC3)cc2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 10 ml of dichloromethane was dissolved 1.50 g of 1-(3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-2-chloro-1-ethanone obtained in Reference Example 2. To the solution was added 1.7 ml of piperidine, and the mixture was stirred for one hour at room temperature. The reaction mixture was poured into an aqueous solution of potassium carbonate, which was subjected to extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate, from which was distilled off the solvent to leave an oily residue. To the residue was dissolved in 5 ml of methanol, to which was added 1.7 ml of 4N methanolic hydrochloric acid. Then the solvent was distilled off to leave 1.50 g of the title compound as colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]#[N:12])=[CH:5][CH:4]=1.O.[NH2:15][NH2:16]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:16][N:15]=[C:11]([NH2:12])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CC#N)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(N)n[nH]2)cc1
Temperature: 60 °C
Yield: 88 %

Procedure:
A suspension of 3-(4-methoxyphenyl)-3-oxopropanenitrile in ethanol was heated to 60° C. Hydrazine hydrate was added dropwise over a minimum of 30 min at 60° C. The resulting solution was held at 60° C. until reaction completion, generally 15-18 hr. The reaction mixture was quenched with water. Ethanol was removed by distillation to about 5 volumes. The product was isolated by filtration, washed with water and dried in a vacuum oven. The yield was 88-95%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:19][OH:20])[C:8]([CH3:26])=[CH:7][C:5]=2[N:6]=1.[O-:27]S([O-])=O.[Na+].[Na+]>C(#N)C.O.CCOC(C)=O>[NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)=[C:9]([C@H:18]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:19]([OH:27])=[O:20])[C:8]([CH3:26])=[CH:7][C:5]=2[N:6]=1
Reactant: O=S([O-])[O-]
Reactant: Cc1cc2nc(N)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc2nc(N)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethanol (1.95 g, 5.00 mmol) in acetonitrile (25 mL) and water (1 mL) was added H5IO6 (1.37 g, 6.00 mmol) and CrO3 (1.00 g, 10.0 mmol). The mixture was stirred at rt for 1 h and was diluted with EtOAc (50 mL) and a saturated solution of Na2SO3 (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc. The crude material was taken on without further purification. 1H-NMR: 400 MHz, (CDCl3) δ: 7.42-7.61 (m, 4H), 7.20 (s, 1H), 5.11 (s, 1H), 2.47 (s, 3H), 0.93 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:16])=[C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[NH:9][N:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:16])=[C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[N:9]([CH2:24][C:25]([N:27]2[CH2:28][CH2:29][N:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:31][CH2:32]2)=[O:26])[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]c(-c2cccs2)c1Cl
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c(-c2cccs2)c1Cl

Procedure:
Protocol T was followed using 4-Chloro-3-Thiophen-2-yl-2H-pyrazole-5-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1.5/1: Rf=0.62) afforded the title compound. 1H NMR (400 MHz, CDCl3): 7.06-7.36 (m, 1H), 6.96-7.2 (m, 3H), 6.84-6.92 (m, 3H), 54.46 (s, 2H), 4.3-4.4 (q, 2H), 3.6-3.82 (m, 4H), 3.05-3.25 (m, 4H), 1.3-1.42 (m, 3H).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].CS(O[C@H:11]([CH3:27])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(=O)=O>>[C:1]([O:4][C@@H:11]([CH3:27])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](COc1ccc(Oc2ccccc2)cc1)OS(C)(=O)=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)O[C@@H](C)COc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 70.7 %

Procedure:
A mixture of anhydrous sodium acetate (82 mg, 1.0 mmol), (R)-1-methyl-2-(4-phenoxyphenoxy)ethyl methanesulfonate (250 mg, 0.78 mmol; ee.: 99.4%) and dimethylformide (5 ml) was stirred at an inner temperature of 100° to 110° C. for 5 hours. After allowed to cool, ice-water was added thereto, and the reaction mixture was extracted with toluene three times. The toluene layer was dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by thin layer chromatography using silica gel to give (S)-(-)-1-methyl-2-(4-phenoxyphenoxy)ethyl acetate (158 mg). [α]D23 =-30.6° (CHCl3, c=1). ee.: 88.8%.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:19]=[C:18]([CH2:20][C:21]2[C:26](=[O:27])[N:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=3)[C:24]([CH3:38])=[N:23][C:22]=2[CH2:39][CH2:40][CH3:41])[CH:17]=[CH:16][C:15]=1[C:42]1[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=1>C(OCC)(=O)C>[F:13][C:14]1[CH:19]=[C:18]([CH2:20][C:21]2[C:26](=[O:27])[N:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH:35]([CH3:36])[CH3:37])=[CH:32][CH:33]=3)[C:24]([CH3:38])=[N:23][C:22]=2[CH2:39][CH2:40][CH3:41])[CH:17]=[CH:16][C:15]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:48]1[NH:3][C:4](=[O:7])[O:5][N:49]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)c(F)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)c(F)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
A mixture of hydroxylammonium chloride (1.12 g), sodium hydrogen carbonate (1.6 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 2′-fluoro-4′-{[1-(4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.94 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-carbonyldiimidazole (0.4 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.53 g, 50%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[NH:24])[NH:22][OH:23])=[CH:17][CH:16]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47](Cl)=O)=[CH:43][CH:42]=2)=[CH:37][CH:36]=1>CC(=O)OCC>[C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:24]=[C:34]([C:35]3[CH:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=4)=[CH:37][CH:36]=3)[O:23][N:22]=2)=[CH:17][CH:16]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN(Cc1ccc(C(=N)NO)cc1)C(=O)OC(C)(C)C
Reactant: Cc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)CN(Cc1ccc(-c2noc(-c3ccc(-c4ccc(C)cc4)cc3)n2)cc1)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 43 %

Procedure:
Prepared using General Procedure 20. To a stirring solution of methyl 2-((tert-butoxycarbonyl)(4-(N-hydroxycarbamimidoyl)benzyl)amino)acetate INT-75 (786 mg, 2.33 mmol) and DIEA (448 μL, 2.56 mmol) in dioxanes (15 mL) was added 4′-methyl-[1,1′-biphenyl]-4-carbonyl chloride (591 mg, 2.56 mmol), at room temperature. After 30 min the reaction mixture was heated to 120° C. for 3 h. The reaction mixture was diluted with EA (150 mL) and washed with brine (100 mL). The organics were concentrated in vacuo and the crude product purified by chromatography (MeCN/DCM) to afford 518 mg (43%) of methyl 2-((tert-butoxycarbonyl)(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)amino)acetate INT-76 as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=2)[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:23]([CH3:26])([CH3:25])[CH3:24].[C:27]1(C)[CH:32]=CC(S(O)(=O)=O)=[CH:29][CH:28]=1.O>C(O)CCC.C1(C)C=CC=CC=1>[CH2:32]([O:10][C:9](=[O:11])[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]([CH3:20])([CH3:22])[CH3:21])[CH:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:4]=1)[CH2:27][CH2:28][CH3:29]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)c1cc(C(C(=O)O)c2ccc(O)c(C(C)(C)C)c2)ccc1O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCO
Product: CCCCOC(=O)C(c1ccc(O)c(C(C)(C)C)c1)c1ccc(O)c(C(C)(C)C)c1

Procedure:
35.6 g of bis(4-hydroxy-3-tert.-butyl-phenyl)ethanoic acid (0.1 mol) were dissolved in a mixture of 222 g of n-butanol and 240 g of toluene. As an esterification catalyst, 1 g of p-toluene-sulfonic acid was added. Azeotropic distillation was continued until 1.8 mol of water had separated at the separator. The butanol-toluene phase was washed with 10% sodium bicarbonate solution and then with water. The solvent mixture was distilled off and the residue was dissolved and precipitated in 300 ml of heptane. After distillation of the solvent, 38 g (92 %, calculated on the acid used) of bis(4'-hydroxy-3'-tert-butyl-phenyl)ethanoic acid n-butyl ester were obtained, m.p. 124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](O)=[CH:10]2)=[CH:5][CH:4]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH2:17][OH:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH2:17][O:18][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:10]=1
Reactant: COc1ccc(Br)c(CO)c1
Reactant: COc1ccc2ccc(O)cc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Br)c(COc2ccc3ccc(OC)cc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a solution of 7-methoxy-2-naphthol (26.92 g, 0.15 moles), 2-bromo-5-methoxybenzyl alcohol (33.58 g, 0.15 moles), and triphenylphosphine (39.3 g, 0.15 moles) in anhydrous THF (500 mls) was added a solution of DEAD (26.10 g, 0.15 moles) in THF (100 mL) dropwise over 0.5 hr. The solution was stirred at room temperature overnight and, upon evaporation of half the volume, the product precipitated in good purity. The solid was filtered and rinsed with THF, then dried to yield 32.96 g (59%) of a white solid: mp 156–157° C.; 1H NMR (DMSO-d6): δ 3.77 (3H, s), 3.86 (3H, s), 5.18 (2H, s), 6.92 (1H, dd, J=3.2 Hz, J=8.7 Hz), 7.00 (1H, dd, J=2.4 Hz, J=8.7 Hz), 7.09 (1H, dd, J=2.4 Hz, J=8.9 Hz), 7.22 (1H, d, J=3.2 Hz), 7.25 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.59 (1H, d, J=8.7 Hz), 7.74 (1H, d, J=8.7 Hz), 7.76(1H, d, J=8.7 Hz); MS m/z 373/375 ([M+H]+).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].[CH:29]([C:31]([CH3:33])=[O:32])=[CH2:30]>C(OCC)(=O)C.CC(C)([O-])C.[K+]>[CH2:1]([N:8]([CH2:30][CH2:29][C:31](=[O:32])[CH3:33])[S:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N+:16]([O-:18])=[O:17])(=[O:27])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCc1ccccc1
Reactant: C=CC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of benzylamine (1 ml, 9.16 mmol) in ethyl acetate (10 ml) was added triethylamine (1.252 ml, 9.16 mmol) followed 2-nitrobenzene-1-sulfonyl chloride (2.03 g, 9.16 mmol) at 5-10° C. with stirring. The mixture was stirred for 1 hour (complete by HPLC), stirring continued for 1 hour. The reaction mixture was quenched with water. The organic layer was separated, washed with brine, dried, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (8 ml) and to the resulting solution potassium tert-butoxide (0.051 g, 0.458 mmol) was added followed by methyl vinyl ketone (0.755 ml, 9.16 mmol) with stirring in one portion at 20-25° C. The mixture was stirred for 2 hours at 20-25° C., quenched with brine. The organic phase was separated and the aqueous layer was back extracted with ethyl acetate (5 mL). The combined organic layers were washed with 0.6N HCl (10 mL), concentrated to 3 volumes. The solution was diluted with isopropanol (20 mL), concentrated under reduced pressure until a precipitate appeared. The resulting slurry was then stirred at 20° C. for 4 hours, filtered. The collected solid was then washed with 2-propanol (2×40 mL), dried to give N-benzyl-2-nitro-N-(3-oxobutyl)benzenesulfonamide (2.5 g, 6.87 mmol, 75% yield).
Reaction SMILES: C([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[N:39][C:38]2=[CH:42][C:35]3=[N:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[N:39][C:38]2=[CH:42][C:35]3=[N:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](O)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a solution of methyl (2S)-2-(tert-butoxy)-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15 (20),16,18-decaen-3-yl]acetate (88 mg, 0.134 mmol) in DCM (3 mL) at room temp was added TFA (0.311 mL, 4.03 mmol) and the mixture was stirred at room temp for 16 h. Then, mixture was concentrated and purified by biotage (0-40% EtOAc/hexane) to afford methyl (2S)-2-hydroxy-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15 (20),16,18-decaen-3-yl]acetate (60 mg, 0.100 mmol, 74.6% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 8.53-8.42 (m, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.16-7.11 (m, 2H), 6.96-6.85 (m, 2H), 5.56 (s, 1H), 4.62-4.38 (m, 2H), 4.15 (q, J=7.1 Hz, 1H), 3.89-3.83 (m, 1H), 3.81 (s, 3H), 3.47 (br. s., 1H), 3.41-3.29 (m, 1H), 3.18 (d, J=10.9 Hz, 1H), 2.76 (d, J=11.8 Hz, 1H), 2.66 (s, 2H), 2.36 (s, 3H), 2.05-1.96 (m, 1H), 1.90 (t, J=12.5 Hz, 2H), 1.82-1.72 (m, 2H), 1.68-1.56 (m, 2H), 1.50 (br. s., 2H), 1.29 (t, J=7.1 Hz, 2H), 1.24 (s, 3H), 1.15 (d, J=6.0 Hz, 3H). LCMS (M+H)=599.4.