Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O>C(O)(=O)C>[C:13]1([N:11]=[N:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=Nc1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(N=Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
9.18 g (0.067 mol) of 4-aminobenzoic acid (Merck, purum) was placed in a 250 mL one-necked round flask with a magnetic stirring bar and 100 mL of glacial acetic acid was added causing a light yellow solution. After 20 minutes 7.21 g (0.067 mol) of nitrosobenzene (Fluka, purum) was added in one portion immediately forming a green solution with particles. Stirring at room temperature was continued for 16 h. The formed metal shining precipitate was filtered off and washed once with 50 mL of cold glacial acetic acid and twice with 100 mL of cold water. The orange precipitate was dissolve in a hot mixture of 200 mL of ethanol and 20 mL of water. After cooling, filtration and 15 h drying under vacuum at 60° C. 10.96 g (72% yield) of [4-(phenylazo)phenyl]-methanoic acid was obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[CH:8](OC(=O)C)[O:7][C@@H:6]1[C:18]1[CH:22]=[C:21]([CH2:23][CH3:24])[O:20][N:19]=1)(=[O:3])[CH3:2].[Cl:25][C:26]1[N:34]=[C:33]2[C:29]([NH:30][CH:31]=[N:32]2)=[C:28]([Cl:35])[N:27]=1.N12CCCN=C1CCCCC2.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C>[C:11]([O:10][C@@H:9]1[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:6]([C:18]2[CH:22]=[C:21]([CH2:23][CH3:24])[O:20][N:19]=2)[O:7][C@H:8]1[N:32]1[CH:31]=[N:30][C:29]2[C:33]1=[N:34][C:26]([Cl:25])=[N:27][C:28]=2[Cl:35])(=[O:13])[CH3:12]
Reactant: CCc1cc([C@H]2OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1cc([C@H]2O[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Temperature: 60 °C
Reaction time: 21 h

Procedure:
(2R,3 R,4R)-4,5-bis(acetyloxy)-2-(5-ethyl isoxazol-3-yl)tetrahydrofuran-3-yl acetate isomer 1 (193 mg) was dissolved in acetonitrile (5 ml) and treated sequentially with 2,6-dichloropurine (213 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.186 ml) and trimethylsilyl trifluoromethanesulphonate (TMSOTf) (0.225 ml) via a syringe over 5 min. The clear yellow solution was stirred at 22° C. for 40 h, at 60° C. for 21 h, and at 80° C. for 6 h. The mixture was cooled to room temperature and more DBU (0.186 ml) and TMSOTf (0.225 ml) were added. After stirring at 22° C. for 36 h the yellow mixture was heated at 60° C. overnight and at 80° C. for 6 h. The solvents were removed in vacuo and the resultant brown oily solid taken up in ethyl acetate and washed with water (20 ml, 3:1). The aqueous layer was extracted with ethyl acetate and the combined organic layers dried (MgSO4) and evaporated in vacuo to afford a brown oily solid. The residue was triturated with dichloromethane and a white solid removed by filtration. Evaporation of the filtrate afforded a tan solid. Purification by flash chromatography on silica gel eluting with ether:cyclohexane (1:1) afforded the title compound as a white solid (161 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([C:22]3[CH:23]=[N:24][C:25](SC)=[N:26][CH:27]=3)[N:6]=[C:5]2[C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH2:3][CH2:2]1>CCO.[Ni]>[CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:18][CH2:19][CH2:20][CH2:21]4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([C:22]3[CH:23]=[N:24][CH:25]=[N:26][CH:27]=3)[N:6]=[C:5]2[C:30]2[CH:31]=[CH:32][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=2)[CH2:3][CH2:2]1
Reactant: CSc1ncc(-c2nc(-c3ccc(OC(F)(F)F)cc3)n(C3CC3)c2C(=O)N2CCC(N3CCCC3)CC2)cn1
Agent: [Ni]
Solvent: CCO
Product: O=C(c1c(-c2cncnc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1)N1CCC(N2CCCC2)CC1
Reaction time: 0.25 h
Yield: 40.7 %

Procedure:
To a solution of 0.08 g (0.14 mmol) of [3-cyclopropyl-5-(2-methylsulfanyl-pyrimidin-5-yl)-2-(4-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 88) in 1 ml of EtOH was added a generous spatula of Rainey nickel. The mixture was stirred for 15 minutes after which time the reaction was filtered over Hyflo and concentrated. Purification by flash column chromatography [CH2Cl2/MeOH 8:2] afforded 0.03 g (38%) of the title compound as a colorless amorphous solid. MS: 527.2 (MH+)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.[CH3:35][S:36]([NH:39][C:40]1[CH:41]=[CH:42][C:43]2[O:48][CH2:47][CH:46]([CH2:49][NH2:50])[O:45][C:44]=2[CH:51]=1)(=[O:38])=[O:37]>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][NH:50][CH2:49][CH:46]2[CH2:47][O:48][C:43]3[CH:42]=[CH:41][C:40]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:51][C:44]=3[O:45]2)=[CH:2]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OC(CN)CO2
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Nc1ccc2c(c1)OC(CNCCCc1c[nH]c3ccccc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
3-Indolepropionic acid (0.77 g, 4.1 mmole), 1-hydroxybenzotriazole hydrate (0.66 g, 4.9 mmole) and 1,3-diisopropylcarbodiimide (0.77 ml, 4.9 mmole) were combined in 75 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methylsulfonylamino-2,3-dihydro-1,4-benzodioxin-2-methanamine (1.0 g, 4.1 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using 10% hexane in ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.1 g (61%) of the desired product, (S)-(7-methylsulfonyl-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-propanamide, as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.[H-].[K+].C([Li])(C)(C)C.[CH2:20]([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:20]([N:27]1[CH2:32][CH2:31][C:30]([OH:33])([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=3)[CH:3]=2)[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Oc1ccc2cc(C3(O)CCN(Cc4ccccc4)CC3)ccc2c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 15.2 %

Procedure:
A solution of 10.0 gm (44.8 mMol) 2-bromo-6-hydroxynaphthalene in tetrahydrofuran was added dropwise to a suspension of 9.42 gm (47.1 mMol) potassium hydride (20% suspension) in 180 mL tetrahydrofuran at 0° C. After stirring at this temperature for 2 hours the reaction mixture was cooled further to -78° C. and to it was added dropwise 58 mL (98.6 mMol) tert-butyllithium (1.7M in tetrahydrofuran). The mixture was stirred for 20 minutes at this temperature and then a solution of 8.73 mL (47.1 mMol) 1-benzyl-4-piperidone in 30 mL tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm gradually to room temperature and was stirred at this temperature for 18 hours. The reaction mixture was then partitioned between ethyl acetate and dilute ammonium hydroxide. The phases were separated and the aqueous phase was extracted well with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with 5% methanol in dichloromethane. Fractions containing product were combined and concentrated under reduced pressure to provide 2.27 gm (15%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:29])[C:12]3[CH:26]=[C:25]([CH2:27]Cl)[S:24][C:13]=3[N:14]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:32][CH:33]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:34]1[CH2:38][CH2:37][CH2:36][NH:35]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:29])[C:12]3[CH:26]=[C:25]([CH2:27][N:35]4[CH2:36][CH2:37][CH2:38][C@@H:34]4[C@@H:33]([OH:32])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[S:24][C:13]=3[N:14]([CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH:15]=2)=[O:9])=[CH:30][CH:31]=1
Reactant: OC(c1ccccc1)C1CCCN1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCOCC2)c2sc(CCl)cc2c1=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCOCC2)c2sc(CN3CCC[C@@H]3[C@@H](O)c3ccccc3)cc2c1=O

Procedure:
Analogous to the procedures described in Example 2, N-(4-chlorobenzyl)-2-(chloromethyl)-7-(2-morpholin-4-ylethyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 23) is treated with 2-(hydroxy(phenyl)methyl)pyrrolidine (Preparation 2) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:26][Li]>>[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=2[C:7](=[O:8])[CH3:26])=[CH:17][CH:16]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1cc(Cl)ccc1Nc1ccc(OCc2ccccc2)cc1
Reactant: [Li]C
Product: CC(=O)c1cc(Cl)ccc1Nc1ccc(OCc2ccccc2)cc1
Yield: 80 %

Procedure:
[II; R=5-Cl, R' and R"=H, OR°=4-OCH2C6H5, Alk=CH3 ] was prepared from 5-chloro-2-(4-benzyloxyphenylamino)benzoic acid and methyllithium according to the procedure of Example 1, part (a), and obtained in about 80% yield as a yellow solid, m.p. 74°-75° C. when recrystallized from cyclohexane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[N:22][C:21]([CH:24]2[CH2:27][CH2:26][CH2:25]2)=[C:20]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:30][CH:29]=2)[CH:19]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[N:23]=[N:22][C:21]([CH:24]3[CH2:25][CH2:26][CH2:27]3)=[C:20]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:32][CH:33]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CCC2)nn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCC3)nn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.66 mmol, 0.13 g) in anhydrous THF (0.5 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (0.88 mmol, 0.035 g) and continued stirring for 10 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 6-chloro-3-cyclobutyl-4-(4-cyclohexyloxy-phenyl)-pyridazine (0.44 mmol, 0.15 g) in THF (0.5 mL). After completion of addition, the reaction mixture was warmed to 65° C. and stirred for 1 hour. After cooling the reaction to room temperature, the reaction was quenched with water (1 mL) and extracted with ethyl acetate (1×3 mL). The ethyl acetate layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 4 g SiO2 cartridge eluting with a 10-30% ethyl acetate/hexanes gradient to give 4-[6-cyclobutyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.18 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH:29]([CH3:31])[CH3:30]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:22][CH2:23]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Reactant: CC(C)CI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(CC(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 1-iodo-2-methylpropane.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.I[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[CH3:20])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1NCCc2ccc(Cl)cc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc(Cl)cc2C1=O
Yield: 31.1 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-chloro-3,4-dihydro-2H-isoquinolin-1-one (I-1d: 150 mg, 0.824 mmol) was reacted with 3-iodo-4-methyl-pyridine (216 mg, 0.989 mmol), 1,4-dioxane (10 mL), copper iodide (15.69 mg, 0.0824 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (35.10 mg, 0.2472 mmol) and potassium phosphate (524 mg, 2.472 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 70 mg of the product (31.25% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C=O)cc4)c4ccccc43)cn12
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CN5CCOCC5)cc4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of Intermediate 176b (0.10 mmol) and morpholine (17.4 mg, 0.200 mmol) in DCM (3 mL) was added sodium triacetoxyborohydride (31.8 mg, 0.15 mmol) and the resulting yellow solution stirred at RT for 1 h. Water (3 mL) was added and the mixture shaken. The aqueous was extracted with DCM (3 mL), then the combined organics passed through a hydrophobic frit and concentrated in vacuo to leave a vivid yellow gum. Flash chromatography (silica 12 g, 3.5-4.5% (2M NH3 in MeOH) in DCM) gave a vivid yellow gum (70 mg). Prep HPLC (Gemini C18, 25-75% MeCN in water, 0.1% HCO2H, 20 min) and concentration of the desired fractions removed the MeCN. The aqueous was extracted with DCM (3×15 mL), then the combined organics passed through a hydrophobic frit and concentrated in vacuo to leave a glassy orange solid (43.7 mg). Prep HPLC (Gemini C18, 25-50% MeCN in water, 20 min) and concentration of the desired fractions removed the MeCN. The aqueous was extracted with DCM (3×5 mL), then the combined organics passed through a hydrophobic fit and concentrated in vacuo to leave the title compound as a white solid (25.4 mg, 35%). LCMS (Method 5): Rt 3.61 min, m/z 718.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.27 (9H, s), 1.47-1.55 (2H, m), 1.63-1.71 (2H, m), 1.76-1.95 (4H, m), 2.00-2.16 (2H, m), 2.37 (4H, t, J=4.3 Hz), 2.90 (1H, ddd, J=12.1, 9.0, 3.9 Hz), 3.16 (1H, dt, J=12.2, 4.3 Hz), 3.29-3.34 (1H, m, obscured by water signal), 3.50 (2H, s), 3.56 (4H, t, J=4.5 Hz), 4.81 (1H, td, J=8.6, 5.6 Hz), 5.51 (1H, t, J=4.3 Hz), 6.34 (1H, s), 7.09 (1H, d, J=8.6 Hz), 7.19 (1H, dd, J=9.9, 2.2 Hz), 7.25-7.37 (4H, m), 7.43 (2H, d, J=8.7 Hz), 7.45 (2H, d, J=8.7 Hz), 7.64 (1H, dd, J=9.8, 0.8 Hz), 7.69 (1H, dd, J=2.2, 0.9 Hz), 8.08 (1H, s).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[C:11]([Cu])#[N:12].CN1C(=O)CCC1>O>[NH2:6][C:5]1[C:7]([F:9])=[CH:8][C:2]([C:11]#[N:12])=[CH:3][C:4]=1[F:10]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cc(F)c(N)c(F)c1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
340 g (1.63 mol) of 4-bromo-2,6-difluoroaniline, 223 g (2.5 mol) of CuCN and 800 cm3 of NMP were refluxed for 1.5 hours on a mantle heater. The reaction solution was cooled to room temperature, and after adding 300 cm3 of EDA, it was poured into 2,000 cm3 of water, extracted with hexane, and washed with an aqueous EDA solution and ice. The hexane was removed, and the residue was distilled under reduced pressure (b. p. 143° C./6mmHg) to obtain 108 g (0.7 mol) of 4-amino-3,5-difluorobenzonitrile.
Reaction SMILES: [F:1][CH:2]([C@H:7]1[C@H:12]([OH:13])[CH2:11][C@H:10]2[C@@H:8]1[O:9]2)[C:3]([O:5][CH3:6])=[O:4].N1C=CN=C1.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C@H:7]1[C@H:12]([O:13][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24])[CH2:11][C@H:10]2[C@@H:8]1[O:9]2)[F:1]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C(F)[C@@H]1[C@H]2O[C@H]2C[C@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)C(F)[C@@H]1[C@H]2O[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a solution of epoxy alcohol 3 (1.60 kg, 8.40 mol) and DMF (3.40 L) was added imidazole (1.26 kg, 18.5 mol) at 10° C. TBSCl (1.52 kg, 10.1 mol) was added to the reaction mixture while maintaining the batch temperature below 8° C. The resulting solution was stirred at 5° C. for 10 min, then allowed to warm to 20° C. over 30 min and stirred for 2 h at the same temperature. The consumption of the starting alcohol was monitored by GC, and the reaction mixture was diluted with cold toluene (17.0 L, 5° C.). The resulting mixture was washed with H2O (5.67 L), saturated aqueous NaHCO3 (5.67 L), H2O (5.67 L×2), and brine (5.67 L). Assay of the organic solution indicated 4. Concentration of the solution gave 4 as yellow liquid, which was used for the next step without further purification. Analytically pure sample was obtained by flash silica gel column chromatography (hexanes/MTBE) as colorless crystals: mp 28-30° C.; 1H NMR (400 MHz, CDCl3) δ 5.00 (dd, J=48.2, 3.5 Hz, 1H), 4.45 (m, 1H), 3.85 (s, 3H), 3.51 (m, 1H), 3.42 (m, 1H), 2.64-2.52 (dm, J=34.5 Hz, 1H), 2.14 (m, 1H), 1.91 (m, 1H), 0.88 (s, 9H), 0.054 (s, 3H), and 0.051 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.8 (d, J=24.1 Hz), 88.3 (d, J=186.1 Hz), 75.4 (d, J=1.6 Hz), 58.3, 57.2 (d, J=7.2 Hz), 52.8 (d, J=19.3 Hz), 52.7, 38.3, 25.9, 18.0, −4.5, and −4.7; 19F NMR (376 MHz, CDCl3) δ −199.9 (dd, J=48.2, 34.5 Hz); LRMS m/z 305 (M+1), 121 (base peak); [α]D25=−27 (c 1.0, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[C:18](=[O:19])[CH2:17][N:16]([S:20]([C:23]4[S:27][C:26]5[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:25]=5[CH:24]=4)(=[O:22])=[O:21])[CH2:15][CH:14]3[C:33](O)=[O:34])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C[N:37]1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.N>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[C:18](=[O:19])[CH2:17][N:16]([S:20]([C:23]4[S:27][C:26]5[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:25]=5[CH:24]=4)(=[O:21])=[O:22])[CH2:15][CH:14]3[C:33]([NH2:37])=[O:34])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnc2cc(CN3C(=O)CN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3C(=O)O)ccc12
Reactant: CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To a mixture containing (±)-1-(4-amino-quinazolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-carboxylic acid (45 mg, 0.08 mmol), EXAMPLE 800, N-methylmorpholine (18 mg, 0.18 mmol), and HATU (35 mg, 0.09 mmol) in anhydrous DMF (1 mL) is added NH3 (7N in MeOH, 2 drops, approx. 0.5 mmol). The heterogeneous mixture is stirred 16 h at ambient temprature and then concentrated to dryness. The residue is dissolved in water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 25 mg (46%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.63 (d, J=16.0 Hz, 1H), 4.01 (m, 4H), 5.17 (d, J=16.6 Hz, 1H), 7.58 (m, 3H), 8.08 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 8.26 (d, J=8.6 Hz, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.74 (s, 1H), 9.63 (br s, 2H) ppm; MS (ISP loop): m/z 531 (M+H).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][CH:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7][S:6]1(=[O:21])=[O:20])=[N+]=[N-].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][S:10][CH:8]2[CH2:7][S:6](=[O:21])(=[O:20])[CH:5]([CH2:4][NH2:1])[CH2:9]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(CSC2CC(CN=[N+]=[N-])S(=O)(=O)C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CSC2CC(CN)S(=O)(=O)C2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
A 0° C. solution, under argon, of 1.4 g of product from Example 179 in 14 ml of dry methylene chloride is treated with 1.19 ml of triethylamine. Hydrogen sulfide gas is slowly bubbled through the cold solution for 20 minutes (the excess gas is trapped in a flask containing an aqueous solutin of 5.25% sodium hypochlorite). The mixture is stirred at 0° C. for 2 hours, the flask flushed for 20 minutes with argon and the reaction is concentrated in vacuo. The residue is purified by chromatography (silica gel: 10-100% ethyl acetate/hexane, 5% methyl alcohol/ethyl acetate) to give 0.757 g of the desired product (mixture of isomers).