Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C(O)C.[OH-].[Na+].[CH2:10]([O:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]=[O:24])=[CH:17][CH:16]=1)=[O:14])[CH3:11]>C(OCC)(=O)C>[N+:1]([CH2:4][CH:23]([OH:24])[CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])=[CH:16][CH:17]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1ccc(CCC=O)cc1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(CCC(O)C[N+](=O)[O-])cc1
Temperature: 38 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
To a stirred mixture of 2.25 (37 mmol) of nitromethane, 1.2 mL of ethanol and 0.06 mL of 10N aqueous sodium hydroxide solution was added 7.18 g (37 mmol) of 3-(4-ethoxycarbonylphenyl)-1-propanal at room temperature. After addition of the aldehyde, 0.06 mL of 10N aqueous sodium hydroxide and 0.23 mL of ethanol were added, and the resulting mixture was stirred at 38° C. for 48 hours and then poured into a mixture of ethyl acetate (100 mL) and hexanes (100 mL). The resulting solution was washed with water (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual solid was purified by column chromatography on silica gel, eluting with 1:4 ethyl acetate:hexanes, to afford 4.1 g (72%) of 1-nitro-4-(4-ethoxycarbonylphenyl)-2-butanol as a white solid, IR (KBr) 3439, 2929, 1700, 1619, 1553, 1362, 1289, 1180, 1137, 1105, 1019, 882, 739 cm-1. 1H NMR (CDCl3) δ 7.98 (2H, d, J=8.5 Hz), 7.28 (2H, d, J=8.0 Hz), 4.42 (2H, d, J=5.5 Hz), 4.38 (2H, q, J=7.0 Hz), 4.34-4.29 (1H, m), 3.03 (1H, br s), 2.96-2.90 (1H, m), 2.84-2.78 (1H, m), 1.92-1.78 (2H, m), 1.40 (3H, t, J=7.0 Hz); 13C NMR (CDCl3) 8166.86, 146.36, 130.05, 128.70, 128.61, 80.76, 67.85, 61.15, 34.99, 31.50, 14.46; EIMS m/z 267 (M+), 265, 252, 249, 232, 222, 206, 177, 161, 149, 133, 105, 91, 77; HRMS calc'd for C13H17NO5 267.1107, found 267.1095.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[H-].[Na+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1>CN(C)C=O.C(OCC)(=O)C>[N+:16]([C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[N:7]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:25][CH:24]=1)[C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])([O-:18])=[O:17]
Reactant: CCCCC(=O)Nc1ccc(OC)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1)c1ccc(OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
2.5 g (0.01 mol) of 2-pentanoylamino-5-methoxy-nitrobenzene are dissolved in 30 ml of dimethylformamide, treated with 550 mg (0.11 mol) of sodium hydride (50% in oil) and stirred for 30 minutes at 80° C. 3.5 g (0.01 mol) of tert.butyl 4'-bromomethyl-biphenyl-2-carboxylate are then added and stirred for a further 2 hours at 80° C. The solvent is distilled off in vacuum, the oily residue obtained is dissolved in ethyl acetate, washed with water and evaporated in vacuum after drying over sodium sulphate. A yellowish oil is obtained after column chromatography (silica gel: 0.06-0.2 mm, eluting agent: methylene chloride).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([NH:15][C:16]2[NH:17][CH2:18][CH:19]([OH:22])[CH2:20][N:21]=2)[CH:14]=1)[C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6].Cl.[CH2:24]([O:26][C:27](=[O:46])[CH2:28][C@H:29]([NH2:45])[C:30]1[CH:35]=[C:34]([C:36]2([C:42]#[N:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH:33]=[C:32]([Cl:44])[CH:31]=1)[CH3:25].O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[Cl:44][C:32]1[CH:31]=[C:30]([C@@H:29]([NH:45][C:9](=[O:11])[CH2:8][NH:7][C:5](=[O:6])[C:4]2[CH:12]=[C:13]([NH:15][C:16]3[NH:17][CH2:18][CH:19]([OH:22])[CH2:20][N:21]=3)[CH:14]=[C:2]([OH:1])[CH:3]=2)[CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:46])[CH:35]=[C:34]([C:36]2([C:42]#[N:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH:33]=1
Reactant: O=C(O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1
Reactant: CCOC(=O)C[C@H](N)c1cc(Cl)cc(C2(C#N)CCOCC2)c1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Cl)cc(C2(C#N)CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetic acid (Example B) (264.7 mg, 0.859 mmol), (S)-ethyl-3-amino-3-(3-chloro-5-(4-cyanotetrahydro-2H-pyran-4-yl)phenyl)propanoate hydrochloride salt (from step 1 above) (314.3 mg, 0.842 mmol) and 1-hydroxybenzotriazole hydrate (27.4 mg, 0.179 mmol) was dissolved in a mixture of DMF/DCM (1:1) (8 mL) and stirred at room temperature under nitrogen atmosphere for 10 min to give a cream suspension. Neat N,N′-diisopropylcarbodiimide (175 μL, 1.13 mmol) was added to the above suspension and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The solvent was evaporated in vacuo to give a pale yellow-cream gummy residue. LC-MS analysis of the crude residue shows the desired product: (3S)-ethyl 3-(3-chloro-5-(4-cyanotetrahydro-2H-pyran-4-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate's mass: m/z 627 (35ClM+H) and m/z 629 (37ClM+H); Calcd for C30H35ClN6O7: 627.09. The crude residue is used as such for the saponification with lithium hydroxide monohydrate (Step 3).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:13])[N:8]([CH3:14])[C:7]2=[O:15].C([Sn](CCCC)(CCCC)[C:21]([O:23]CC)=[CH2:22])CCC>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:21]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:13])[N:8]([CH3:14])[C:7]2=[O:15])(=[O:23])[CH3:22]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CSc1nc2c(Br)cccc2c(=O)n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CSc1nc2c(C(C)=O)cccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.5 %

Procedure:
A solution of 8-bromo-3-methyl-2-(methylthio)quinazolin-4(3H)-one (500 mg, 1.753 mmol), tributyl(1-ethoxyvinyl)stannane (Synthonix, Wake Forest, N.C.; 0.652 mL, 1.929 mmol), and Pd(PPh3)4 (81 mg, 0.070 mmol) in toluene (9.0 mL) was stirred under argon at 100° C. for 19 h, then at 110° C. for 1 d. The reaction was cooled to 25° C. and concentrated onto silica gel. Chromatographic purification (silica gel, 0-50% EtOAc/Hexanes) furnished 8-acetyl-3-methyl-2-(methylthio)quinazolin-4(3H)-one (128.7 mg, 0.518 mmol, 30% yield) as a white solid: m/z (ESI, +ve) 249.2 (M+H)+. 8-(1-ethoxyvinyl)-3-methyl-2-(methylthio)quinazolin-4(3H)-one (35.5 mg, 0.128 mmol, 7% yield) as a colorless oil: m/z (ESI, +ve) 277.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[O:9][C:8]([NH:10][C@H:11]([C:15]([O:17]C)=[O:16])[CH:12]([CH3:14])[CH3:13])=[N:7][N:6]=1)[CH2:2][CH:3]=[CH2:4].[Li+].[OH-].Cl>O.C1COCC1>[CH2:1]([C:5]1[O:9][C:8]([NH:10][C@H:11]([C:15]([OH:17])=[O:16])[CH:12]([CH3:14])[CH3:13])=[N:7][N:6]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCc1nnc(N[C@H](C(=O)OC)C(C)C)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCc1nnc(N[C@H](C(=O)O)C(C)C)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0.18 M solution of methyl N-(5-but-3-en-1-yl-1,3,4-oxadiazol-2-yl)-L-valinate (from Step 4) in H2O/THF (1/1 v/v), LiOH (2 eq.) was added at RT. The resulting reaction mixture was stirred for 1 h at RT and then treated with HCl 1N until pH=2 was reached. The aqueous phase was extracted with EtOAc and the organic layer dried over Na2SO4 to obtain a pale yellow solid. MS (ES+) C11H17N3O3 requires: 239 found: 240 (M+H+).
Reaction SMILES: [Mg].II.Cl[CH:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.[CH3:12][CH:13]1[CH2:22][C:18]2[S:19][CH:20]=[CH:21][C:17]=2[C:16](=[O:23])[C:15]2[CH:24]=[CH:25][CH:26]=[CH:27][C:14]1=2.[Cl-].[NH4+]>O1CCCC1>[CH3:12][CH:13]1[CH2:22][C:18]2[S:19][CH:20]=[CH:21][C:17]=2[C:16]([CH:5]2[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]2)([OH:23])[C:15]2[CH:24]=[CH:25][CH:26]=[CH:27][C:14]1=2
Reactant: CC1Cc2sccc2C(=O)c2ccccc21
Reactant: CN1CCC(Cl)CC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1Cc2sccc2C(O)(C2CCN(C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.4 g of magnesium previously activated with iodine were reacted with 12.0 g of 4-chloro-1-methylpiperidine in 100 ml of anhydrous tetrahydrofuran over 2 hours at reflux temperature. The reaction mixture was cooled to 10°, and reacted with a solution of 9,10-dihydro-9-methyl4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one in 70 ml of anhydrous tetrahydrofuran. After 1 hour of stirring at room temperature and 1 hour at reflux temperature the reaction mixture was cooled and treated with 150 ml of 20% w/v of aqueous ammonium chloride. The organic phase was separated off and worked up to give as a thick oil 9,10-dihydro-9-methyl-4-(1-methyl-4-piperidyl)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol which was further reacted as such.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[NH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][NH:24][CH2:25]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][N:24]([C:10]1[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15])[CH2:25]2
Reactant: Nc1cccc2c1CNC2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4cccc(N)c4C3)c(F)c21
Yield: 41.4 %

Procedure:
136 mg of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 100 mg of 4-aminoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 80 mg of the target compound.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[NH2:15][CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:15][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CO
Product: N#CNC(=NC(c1ccccc1)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and aminodiphenylmethane (0.54 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 40 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure to give N-cyano-N'-diphenylmethyl-3-pyridinecarboximidamide (0.48 g, 1.5 mmol, yield: 58%) as colorless syrup. Next, to this syrup was added a solution of 5% hydrogen chloride in methanol (2 ml) to form a solution. The solution was further crystallized from methanol-diethyl ether to give N-cyano-N'-diphenylmethyl-3-pyridinecarboximidamide hydrochloride as colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([CH2:14][OH:15])[CH:10]=1.C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=1
Reactant: OCc1c[nH]c(-c2c(F)cccc2F)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1c[nH]c(-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution (26 mL) of [5-(2,6-difluorophenyl)-1H-pyrrol-3-yl]methanol (2.56 g) in acetonitrile were added tetra-n-propylammonium perruthenate (430 mg), N-methylmorpholine N-oxide (2.15 g) and molecular sieves 4A powder (5 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (60 mL) and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as pale-red crystals (yield 1.94 g, 77%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:11][C:12]1[C:13]([C:21]([NH2:23])=[O:22])=[N:14][C:15]([CH2:19][CH3:20])=[C:16](Cl)[N:17]=1.C(N(C(C)C)CC)(C)C.O1CCOCC1>O>[Cl:11][C:12]1[C:13]([C:21]([NH2:23])=[O:22])=[N:14][C:15]([CH2:19][CH3:20])=[C:16]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:17]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1nc(C(N)=O)c(Cl)nc1Oc1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A mixture of 3-nitrophenol (1 g), 3,5-dichloro-6-ethylpyrazine-2-carboxamide (1.74 g), diisopropylethylamine (2.63 mL), and dioxane (10 mL) was stirred at 80° C. overnight. To the reaction mixture was added water, and the precipitated solid was collected by filtration and then dried under reduced pressure to obtain 3-chloro-6-ethyl-5-(3-nitrophenoxy)pyrazine-2-carboxamide (1.68 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[C:17]([CH2:18]O)=[C:16]3[C:11]([NH:12][C:13]([CH3:23])([CH3:22])[C:14](=[O:21])[N:15]3[CH3:20])=[CH:10][CH:9]=2)[CH:7]=1.C(N(CC)CC)C.CS([Cl:37])(=O)=O.C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[C:17]([CH2:18][Cl:37])=[C:16]3[C:11]([NH:12][C:13]([CH3:22])([CH3:23])[C:14](=[O:21])[N:15]3[CH3:20])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Cl)cc1-c1ccc2c(c1CO)N(C)C(=O)C(C)(C)N2
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1ccc2c(c1CCl)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
7-(5-Chloro-2-methoxyphenyl)-8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 13-1, 1.34 g, 3.71 mmol) was dissolved in anhydrous dichloromethane (19 mL), and triethylamine (621 μL, 4.46 mmol) and methanesulfonyl chloride (316 μL, 4.08 mmol) were added thereto successively. The reaction mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added to the reaction mixture, washed with water (200 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.14 g) as a colorless amorphous product. (Yield 81%)
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:11]=[CH:12][C:13]2[C:17](=[O:18])[CH2:16][O:15][C:14]=2[CH:19]=1.N1C=CN=C1.CCCCCC>CN(C)C=O.CCOCC>[Si:5]([O:9][C:10]1[CH:11]=[CH:12][C:13]2[C:17](=[O:18])[CH2:16][O:15][C:14]=2[CH:19]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1COc2cc(O)ccc21
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCC2=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.4 %

Procedure:
t-butyldimethylchlorosilane (3.6 g, 23.88 mmol) was added to a solution of 6-hydroxy-2,3-dihydrobenzo[b]furan-3-one (3.0 g, 19.98 mmol) and imidazole (2.0 g, 29.38 mmol) in N,N-dimethylformamide (DMF) (30 ml) under cooling with ice. The mixture was warmed to room temperature and stirred for 40 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with water, with diluted hydrochloric acid, with saturated aqueous solution of sodium bicarbonate, and then with saturated brine (aqueous solution of sodium chloride), sequentially, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The oily residue obtained was charged to silica gel column chromatography (hexane:ether=3:1) to obtain a yellow waxy product of 6-t-butyldimethylsilyloxy-2,3- dihydrobenzo[b]furan-3-one (4.3 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O1CCCC1.O.O.O.O.C([O-])(=O)C.[Ni+2].C([O-])(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)nc1)c1ccccc1[N+](=O)[O-]
Agent: [Ni+2]
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ccccc1C(=O)Nc1ccc(Cl)nc1
Yield: 45.6 %

Procedure:
To a stirred solution of N-(6-chloropyridin-3-yl)-2-nitrobenzamide (0.6 g, 2.15 mmol) in methanol (150 mL) and tetrahydrofuran (75 mL) was added nickel acetate tetrahydrate (1.07 g, 4.3 mmol). Sodium borohydride (0.326 g, 8.61 mmol) was then added in small portions. After gas evolution had ceased, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and concentrated ammonium hydroxide, and the layers separated. The organic phase was washed with concentrated ammonium hydroxide and saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated in vacuo. The solid was suspended in ether, sonicated, and filtered to give 0.243 g (46%) of a pink solid.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9](I)=[C:10]([Cl:13])[CH:11]=2)[N:6]=[C:5]1[O:15][C@@H:16]1[CH2:20][O:19][C@@H:18]2[C@H:21]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:22][O:23][C@H:17]12)[CH:2]=[CH2:3].[Br:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O.CCCCCC>O1CCOCC1.O>[CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9]([C:36]3[CH:37]=[CH:38][C:33]([Br:32])=[CH:34][CH:35]=3)=[C:10]([Cl:13])[CH:11]=2)[N:6]=[C:5]1[O:15][C@@H:16]1[CH2:20][O:19][C@@H:18]2[C@H:21]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:22][O:23][C@H:17]12)[CH:2]=[CH2:3]
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(I)c(Cl)cc21
Reactant: OB(O)c1ccc(Br)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Temperature: 100 °C

Procedure:
Palladium tetrakistriphenylphosphine (204.6 mg, 0.177 mmol) was added to a stirred suspension of [(3R,3aR,6R,6aS)-3-(1-allyl-6-chloro-5-iodo-imidazo[4,5-b]pyridin-2-yl)oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethyl-silane (1.0083 g, 1.745 mmol), 4-bromophenylboronic acid (385.9 mg, 1.922 mmol), and tripotassium phosphate (1.1412 g, 5.38 mmol) in dioxane (14.0 ml) and water (3.5 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 100° C. for 16 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (150 ml) and water (150 ml). The aqueous layer was extracted with EtOAc (2×75 ml). The organic layers were combined, washed with brine (1×75 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a yellow foam. Flash chromatography of the foam utilizing a 80 g silica RediSep Rf® column and employing a 0-30% EtOAc/hexane gradient followed by 30% EtOAc/hexane afforded the title compound as a yellow foam. LC-MS: calculated for C27H33BrClN3O4Si 605.11, 607.11 observed m/e: 606.20, 608.16 (M+H)+ (Rt 1.47/2 min)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[CH:11][C:7]([CH2:8][OH:9])=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1-c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(CO)cc1-c1ccccc1
Temperature: 0 °C

Procedure:
The resultant acid from Example 16A (1.0 equivalent) is treated with a slight excess of N-methylmorpholine (1.1 equivalent) and isobutylchloroformate (1.0 equivalent) in THF at 0° C. The mixture is then treated with NaBH4 (1.0 equivalent) and aqueous NaHCO3 and stirred at 0° C. until the reaction is judged complete by TLC analysis. The mixture is poured into dilute aqueous acid and extracted into ethyl acetate which is dried and evaporated. The product is purified by chromatography on silica gel.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[CH2:18][N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][CH2:15][N:14]2[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([CH:13]2[CH2:18][N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][CH2:15][N:14]2[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:12])=[CH:8][CH:9]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)C1CN(c2ccccc2)CCN1Cc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1ccc(NC(=O)C2CN(c3ccccc3)CCN2Cc2ccccc2)cc1

Procedure:
In a manner similar to Preparation 20, react N-(4-nitrophenyl)-4-phenyl-1-(phenylmethyl)-2-piperazinecarboxamide (6.85 g, 16.8 mmol) with tin (II) chloride dihydrate (18.5 g, 82 mmol) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12](=[O:18])[C:13]3[S:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:11])[NH:8]2)=[N:4][CH:3]=1.[C:19](=[O:25])=[N:20]S(Cl)(=O)=O.C(#N)C.ClS(NC=O)(=O)=O>CS(C)=O.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12](=[O:18])[C:13]3[S:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:11])[N:8]2[C:19]([NH2:20])=[O:25])=[N:4][CH:3]=1
Reactant: O=C1Nc2cc(F)cnc2C1C(=O)c1cccs1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=CNS(=O)(=O)Cl
Solvent: O
Solvent: CC#N
Solvent: CS(C)=O
Product: NC(=O)N1C(=O)C(C(=O)c2cccs2)c2ncc(F)cc21

Procedure:
The title compound was prepared from 6-fluoro-3-(2-thenoyl)-4-azaoxindole (Example 5) according to the procedure of Example 2C, using 6-fluoro-3-(2-thenoyl)-4-azaoxindole (419 mg, 1.60 mmol), N-chlorosulfonyl isocyanate (0.2 mL, 2.3 mmol), and acetonitrile (8 mL). Reaction time: 3 days. The crude N-chlorosulfonyl carboxamide was hydrolysed by stirring in DMSO in a flask open to the air, diluting with water, and collecting the product by filtration. The product was recrystallized from acetic acid. Yield: 210 mg (43%).