Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].O.[OH-].[Na+]>CCOCC>[CH2:6]([N:8]([CH2:9][CH3:10])[CH2:1][CH:3]1[O:5][CH2:4]1)[CH3:7]
Reactant: CCNCC
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCN(CC)CC1CO1
Yield: 59.6 %

Procedure:
In a three neck flask was placed 102 g (1.1 mols) of epichlorohydrin and while stirring vigorously, 73 g (1 mol) of diethylamine was added dropwise to epichlorohydrin together with a small amount (1/10 mol of the amine) of water at temperatures below 25° C. Thereafter, the mixture was stirred for 5 hours at 30° to 35° C. Then, an aqueous 35 to 40% solution of 1.7 mols of sodium hydroxide was added dropwise to the mixture at 25° to 30° C. followed by stirring vigorously. Thereafter, the mixture was further stirred for 3 hours at the same temperature as above. Then, after cooling the mixture, 200 ml of water was added to the reaction mixture to dissolve the salts formed and after further adding 300 ml of ether to the mixture and shaking them, the resultant mixture was allowed to stand, thereby the reaction mixture was separated into two phases. The organic phase thus formed was collected and dried with the addition of granular potassium hydroxide. Then, ether was distilled away and the residue was distilled under reduced pressure in N2 stream to provide 77 g of diethylglycidylamine having a boiling point of 50° to 52° C./13 mmHg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH3:12].[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(N(CC)CC)C>ClCCl>[CH2:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[CH3:12])[CH2:17][CH2:16]1)[CH3:14]
Reactant: Cc1cc([N+](=O)[O-])ccc1CBr
Reactant: CCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CCN(Cc2ccc([N+](=O)[O-])cc2C)CC1

Procedure:
A solution of 1 g (3.78 mmol) 1-bromomethyl-2-methyl-4-nitro-benzene, 0.539 ml (4.16 mmol) 1-ethylpiperazine and 0.63 ml (4.54 mmol) triethylamine in 15 ml dichloromethane is stirred at room temperature for 0.5 h. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, 100% EtOAc=>EtOAc:MeOH=7:3) to afford the title compound as a solid.
Reaction SMILES: [F:1]C1C=CC([N+]([O-])=O)=C(C)C=1.F[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([N+:22]([O-:24])=[O:23])[CH:14]=1>>[F:1][C:21]1[CH:13]=[CH:14][C:15]([N+:22]([O-:24])=[O:23])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Product: O=C(O)c1cc(F)ccc1[N+](=O)[O-]

Procedure:
The starting 5-fluoro-2-nitrobenzoic acid is prepared from 5-fluoro-2-nitrotoluene using a procedure similar to that for the preparation of 4-fluoro-2-nitrobenzoic acid which follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:23])=[O:14])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A suspension of 4-benzyloxy-3-nitro-benzoic acid (36 g, 132 mmol) in toluene (1000 mL) and dimethylformamide (3 mL) was treated with thionyl chloride (47 g, 28.7 mL, 395 mmol) and stirred at 90° C. for 18 hours. The volatiles were evaporated completely and the residue dried under high vacuum. 4-Benzyloxy-3-nitro-benzoyl chloride thus obtained (37.5 g, 97%) was used crude in the following reaction.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[Cl:30])[NH2:26]>>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[C:3]3[C:10]4[CH2:11][NH:12][CH2:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: CC(C)(C)OC(=O)N1CCc2sc3ncnc(Cl)c3c2C1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: Clc1ccc(Nc2ncnc3sc4c(c23)CNCC4)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 12A from tert-butyl 4-chloro-7,8-dihydropyrido[3′,4′:4,5]thieno[2,3-d]pyrimidine-6(5H)-carboxylate from Example 75A (122 mg, 0.37 mmol) and 3,4-dichloroaniline (64 mg, 0.39 mmol) to yield 127 mg (91%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:38])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2[C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)[CH:5]=[CH:6][CH:7]=1.OO.C([O-])([O-])=[O:42].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:3]([F:38])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2[C:28]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([NH2:36])=[O:42])=[CH:31][CH:30]=2)=[O:37])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)CC1CN(C(=O)c2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)C[C@@H]1CN(C(=O)c2ccc(C(N)=O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 56.7 %

Procedure:
In a manner similar to the method described in Example 19, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-1-(4-cyano-benzoyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (27.6 mg, 0.05 mmol) was reacted with 30% H2O2 (1.0 mL, excess), K2CO3 (excess) in DMSO (2 mL) at rt overnight to give rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-benzamide (15.3 mg, 56.7%). HRMS (ES+) m/z Calcd for C30H27Cl2F2N3O2+H [(M+H)+]: 570.1521, found: 570.1523.
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][CH2:8][CH2:9][OH:10]>O>[OH:10][CH2:9][CH2:8][N:7]1[CH2:1][CH2:2][CH2:3][C:4]1=[O:5]
Reactant: NCCO
Reactant: O=C1CCCO1
Solvent: O
Product: O=C1CCCN1CCO

Procedure:
A reactor was charged with γ-butyrolactone, 2-aminoethanol and water, to produce N-(2-hydroxyethyl)-2-pyrrolidone. The molar ratio of the 2-aminoethanol/γ-butyrolactone was 1.0, and that of the γ-butyrolactone/water was 1.1. The reaction temperature was 250° C. and the reaction time was 2 hours.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][C@@H:13]([CH3:17])[C:14]#[C:15][CH3:16])[CH:3]=1.ClC(OCC)=O.[NH2:24][CH:25]1[CH:30]2[CH2:31][N:32]([CH3:34])[CH2:33][CH:26]1[CH2:27][N:28]([CH3:35])[CH2:29]2.[OH-].[Na+]>ClCCl.O.C(N(CC)CC)C>[CH3:34][N:32]1[CH2:33][CH:26]2[CH:25]([NH:24][C:6](=[O:8])[C:5]3[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=3[O:12][C@@H:13]([CH3:17])[C:14]#[C:15][CH3:16])[CH:30]([CH2:29][N:28]([CH3:35])[CH2:27]2)[CH2:31]1
Reactant: CC#C[C@H](C)Oc1cc(N)c(Cl)cc1C(=O)O
Reactant: CN1CC2CN(C)CC(C1)C2N
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC#C[C@H](C)Oc1cc(N)c(Cl)cc1C(=O)NC1C2CN(C)CC1CN(C)C2
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
A solution of 546 mg of (S)-4-amino-5-chloro-2-[(1-methyl-2-butynyl)oxy]benzoic acid and 0.9 ml of triethylamine in 10 ml of dichloromethane was cooled with ice. followed by the addition thereto of 0.225 ml of ethyl chloroformate. The obtained mixture was stirred for 10 minutes, while the temperature was brought to room temperature. 400 mg of 9-amino-3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane was added to the resulting mixture at room temperature. The obtained mixture was stirred for 30 minutes, followed by the addition thereto of 200 mg of 9-amino-3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane at room temperature. The obtained mixture was stirred for one hour, followed by the addition thereto of dichloromethane and water. The pH of the aqueous layer was adjusted to 10 or above with a 2.5N aqueous solution of sodium hydroxide. The organic phase was recovered, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The residue was purified by silica gel column chromatography (with 0 to 10 to 20% methanol/chloroform and then with chloroform/methanol/aqueous ammonia (75/25/1.5) to give 650 mg of the title compound.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]1[N:10]=[C:9]([C:11]2[S:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=[O:17])[N:16]=2)[CH:8]=[CH:7][CH:6]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[CH2:1]([S:3]([CH2:4][C:5]1[N:10]=[C:9]([C:11]2[S:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=[O:17])[N:16]=2)[CH:8]=[CH:7][CH:6]=1)=[O:30])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: ClC(Cl)Cl
Product: CCS(=O)Cc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
2-[6-[(Ethylthio)methyl]-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.10 g, 0.32 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.071 g, 0.32 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.095 g, 91%) as pale yellow crystals.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[N+](=[CH2:20])=[N-]>>[CH3:20][O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12]
Reactant: C=[N+]=[N-]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Yield: 58 %

Procedure:
Robins et al., 1974 J. Org. Chem. 39, 1891, describe the treatment of a methanolic solution of uridine with diazomethane (in glyme) in the presence of stannous chloride dihydrate (in methanol) to synthesize 2′-O-methyluridine (58% yield). This reaction also yielded a significant fraction (28%) of 3′-O-methyluridine which is purified away from the 2′-O-methyl form by chromatography.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10]C)[C:3](=[O:6])[CH2:4][Br:5].C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][N:2]([CH2:7][CH:8]1[O:9][CH2:10][CH2:14][CH2:13][O:12]1)[C:3](=[O:6])[CH2:4][Br:5]
Reactant: CCOC(CN(C)C(=O)CBr)OCC
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(CC1OCCCO1)C(=O)CBr

Procedure:
N-Methyl-N-(2,2-diethoxyethyl)-α-bromoacetamide (10 grams), propandiol-1,3 (3 ml) and trace amounts of toluenesulfonic acid are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated until no more ethanol is given off. After this time sodium carbonate (1 gram) is added to the mixture with stirring and the resulting mixture is distilled to yield the desired product N-methyl-N-(1,3-dioxan-2-ylmethyl)-α-bromoacetamide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[OH:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([O:20][C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH:24]=[CH:25][CH:26]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2nc(Cl)nc3c2ccn3COCC[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1470 mg, 4.62 mmol) in acetonitrile (10 mL) was added tert-butyl (3-hydroxyphenyl)carbamate (966 mg, 4.62 mmol) and K2CO3 (1280 mg, 9.24 mmol) and the mixture heated at 80° C. with stirring overnight. The reaction was then cooled to rt, EtOAc (20 mL) added, washed with water (50 mL), the aqueous layer extracted with EtOAc (three×20 mL), dried with MgSO4, filtered and stripped to a light oil. Upon standing, the light oil solidified to give the title compound (2052 mg, 90% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.38-9.83 (m, 1H) 7.73 (d, J=3.78 Hz, 1H) 7.41-7.46 (m, 2H) 7.51 (s, 1H) 6.97 (dt, J=5.98, 2.68 Hz, 1H) 6.58 (d, J=3.78 Hz, 1H) 5.64 (s, 2H) 3.54-3.67 (m, 2H) 1.54 (s, 9H) 0.91-0.96 (m, 2H) 0.00 (s, 9H). LCMS (ESI, pos): m/z (ESI+) for C23H31ClN4O4Si 491.20 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[CH:15](O)([CH3:17])[CH3:16]>>[CH:15]([O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([I:5])=[CH:7][CH:8]=1)([CH3:17])[CH3:16]
Reactant: CC(C)O
Reactant: O=C(O)c1ccc(I)cc1
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)c1ccc(I)cc1
Temperature: 50 °C

Procedure:
Thionyl chloride (1.4 ml) was added to a solution of 4-iodobenzoic acid (3.72 g) in isopropanol (25 ml) and the reaction mixture heated at 50° C. for several hours. The reaction mixture was cooled to ambient temperature and evaporated. Methylene chloride was added to the residue and the mixture filtered. The filtrate was washed with saturated sodium bicarbonate solution, water, saturated brine, dried (MgSO4) and evaporated to give isopropyl-4-iodo-benzoate as an oil (1.5 g); NMR: 1.28-137(6H,d), 5.04-5.21(1H,m), 7.65-7.74(2H,d), 7.88-7.95(2H,d); m/z 291(M+H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:9])[CH3:8])=[N:2]1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[N+:10]([C:4]1[C:3]([NH:6][C:7](=[O:9])[CH3:8])=[N:2][NH:1][CH:5]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc[nH]n1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1n[nH]cc1[N+](=O)[O-]
Yield: 64.7 %

Procedure:
A solution of N-1H-pyrazol-3-ylacetamide (Liebigs annalen der chemie., 1967, 707, 147; 0.500 g, 4.0 mmol) was stirred in a mixture of nitric acid (d=1.52, 0.2 ml, 4.8 mmol) and sulphuric acid (d=1.83, 2 ml) at 0° C. for 2.5 hours. The mixture was poured onto ice and the resultant precipitate was filtered, washed with water and then a 2:1 mixture of diethyl ether:methanol and then with diethyl ether. The residue was dried in vacuo to give N-(4-nitro-1H-pyrazol-3-yl)acetamide (0.44 g, 65% yield):
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH2:20][NH:19]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.O(C(C)(C)C)[Na]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:17][CH:18]1[NH:19][CH2:20][CH2:21][N:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[S:13][CH:14]=[CH:15][N:16]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:23]1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1
Reactant: CC1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC1CN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CCN1
Yield: 77.4 %

Procedure:
Synthesized according to general procedure 8. The reaction was set up with 4-bromo-N-(thiazol-2-yl)benzenesulfonamide (1.0 g, 3.1 mmol), 2-methylpiperazine (310 mg, 3.1 mmol), Pd2(dba)3 (56 mg, 0.061 mmol), 2-(di-t-butylphosphino)biphenyl (73 mg, 0.25 mmol), NaO-tBu (930 mg, 0.25 mmol), and toluene (7.0 mL) to obtain the desired amine as a tan solid (800 mg, 2.4 mmol, 76% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=339.3; tR=0.68 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[OH:12])[O:8][CH2:7][CH2:6][C:5]2=[O:14].N1C=CN=C1.[CH:20]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>CN(C)C=O.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[O:12][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:20]([CH3:22])[CH3:21])[O:8][CH2:7][CH2:6][C:5]2=[O:14]
Reactant: Cc1cc2c(c(C)c1O)OCCC2=O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(c(C)c1O[Si](C(C)C)(C(C)C)C(C)C)OCCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6,8-dimethyl-7-hydroxychroman-4-one (the compound of Preparation 26, 0.50 g, 2.60 mmol), imidazole (0.35 g, 5.14 mmol), and triisopropylsilyl chloride (0.61 mL, 2.85 mmol) in dimethylformamide (10 mL) was stirred at ambient temperature overnight. The reaction was diluted with water and extracted with ether (2×). The combined organic phase was washed with 1N lithium chloride (2×) and brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (1×4 inches packed in hexane) with elution proceeding as follows: 5% ethyl acetate/hexane (100 mL), nil; 5% ethyl acetate/hexane (100 mL) and 10% ethyl acetate/hexane (150 mL), 0.529 g (58%) of 6,8-dimethyl-7-triisopropylsilyloxychroman-4-one as a waxy lemon yellow solid which had: NMR δ 7.57 (s, 1 H), 4.52 (t, J=6.4 Hz, 2 H), 2.74 (t, J=6.4 Hz, 2 H), 2.21 (s, 3 H), 2.11 (s, 3 H), 1.40-1.26 (m, 3 H), 1.13 (d, J=7.2 Hz, 18 H); 13C NMR δ 191.60, 160.25, 159.93, 125.91, 122.55, 116.15, 115.29, 67.24, 37.52, 17.91, 17.69, 17.38, 14.24, 12.28, 9.97. A small silyl impurity was noted in the proton NMR at 1.06 ppm however, the material was found to be suitable for further transformations without additional purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:6]=1[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:20][C:17]1[CH:18]=[CH:19][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cc1CNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)Oc1ccc(N)cc1CNC(=O)OC(C)(C)C
Yield: 100.8 %

Procedure:
To 8E (72 mg, 0.23 mmol) in MeOH (6 mL) was added Pd/C (cat.) and the mixture was hydrogenated at 55 psi overnight. The reaction was filtered and concentrated to provide 8F (65 mg, 99%). LC-MS: 303.22 (M+Na)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][Si](C)(C)C)=[CH:24][C:21]=1[C:22]#[N:23]>O1CCCC1.C(Cl)Cl>[C:28]([C:25]1[CH:26]=[CH:27][C:20]([F:19])=[C:21]([CH:24]=1)[C:22]#[N:23])#[CH:29]
Reactant: C[Si](C)(C)C#Cc1ccc(F)c(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#Cc1ccc(F)c(C#N)c1
Reaction time: 0.33 h

Procedure:
Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 70 mL) was added to a solution of Example 62A (5.05 g, 23.2 mmol) in tetrahydrofuran (50 mL) and allowed to stir for 20 minutes. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.13 (dd, J=6.27, 2.20 Hz, 1H) 7.82-7.95 (m, 1H) 7.56 (t, J=8.99 Hz, 1H) 4.40 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:5])[CH3:4].C(O)(=O)C.[F:10][C:11]([F:27])([F:26])[C@@H:12]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:27][C:11]([F:10])([F:26])[C@@H:12]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH:1][CH2:2][C@H:3]([OH:5])[CH3:4])=[CH:17][CH:18]=1
Reactant: C[C@@H](O)CN
Reactant: CS(=O)(=O)N[C@@H](c1ccc(C=O)cc1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@@H](O)CNCc1ccc([C@H](NS(C)(=O)=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Dissolve (2R)-1-aminopropan-2-ol (0.4 g, 5.33 mmol) in DCM (10.6 mL); then acetic acid (366.2 uL, 6.39 mmol) and N-[(1S)-2,2,2-trifluoro-1-(4-formylphenyl)-ethyl]-methanesulfonamide (1.65 g, 5.86 mmol). Stir the resulting mixture at ambient temperature for 2 hours; then add sodium triacetoxyborohydride (2.82 g, 13.31 mmol); and stir at ambient temperature overnight. Add MeOH (1 mL) and evaporate a portion of the solvent under reduced pressure. Purify via SCX chromatography eluting with 2M NH3/MeOH. Concentrate the appropriate fractions under reduced pressure to give the title compound (1.7 g, 93.8%). MS (m/z): 341 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1C(OC(C)(C)C)=O)#[N:2].[ClH:27]>>[ClH:27].[N+:24]([C:23]1[CH:22]=[CH:21][CH:20]=[C:4]([O:5][CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)[C:3]=1[C:1]#[N:2])([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1COc1cccc([N+](=O)[O-])c1C#N
Agent: Cl
Product: N#Cc1c(OC[C@@H]2CCCCN2)cccc1[N+](=O)[O-]

Procedure:
Prepared as in Example 1d from (S)-tert-butyl 2-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (Example 47e). MS 262 (MH+—HCl).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[C@@H:17]12[C:26](=[O:27])[O:25][C:23](=[O:24])[C@@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22]2>C(OCC)C>[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:26]([C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[C:23]([OH:25])=[O:24])=[O:27])[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[OH:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Solvent: CCOCC
Product: CC(C)(C)c1cc(NC(=O)[C@H]2CCCC[C@H]2C(=O)O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 71.9 %

Procedure:
A solution containing 5.68 g (0.03 mole) of 4-amino-2,6-di-t-butylphenol in 200 ml of diethyl ether was added dropwise to a solution of 4.62 g (0.03 mole) of cis-1,2-cyclohexanedicarboxylic anhydride in 200 ml of diethyl ether. The reaction mixture was stirred at room temperature for about sixteen hours. The resulting precipitate was collected, rinsed with a mixture of diethyl ether and hexane, and dried to give 8.1 g of a solid. This material was recrystallized from a mixture of ethyl acetate and hexane to give 7.3 g of white solid 2-[N-(3,5-di-t-butyl-4-hydroxyphenyl)carbamoyl]-cis-cyclohexanecarboxylic acid, m.p. 181°-184° C. Analysis: Calculated for C22H33NO4 : %C, 70.4, %H, 8.9; %N, 3.7; Found: %C, 70.1; %H, 8.7; %N, 3.6.