Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][OH:15])=[C:12]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>ClCCl>[CH3:23][S:24]([O:15][CH2:14][C:13]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)=[N:10][S:11][C:12]=1[C:16]([F:22])([F:21])[C:17]([F:18])([F:19])[F:20])(=[O:26])=[O:25]
Reactant: CCc1ccc(-c2nsc(C(F)(F)C(F)(F)F)c2CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(-c2nsc(C(F)(F)C(F)(F)F)c2COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed [3-(4-ethylphenyl)-5-(pentafluoroethyl)-1,2-thiazol-4-yl]methanol (108 mg, 0.32 mmol, 1.00 equiv), dichloromethane (10 mL). The solution was cooled to 0 degree C. MsCl (73 mg, 0.64 mmol, 2.00 equiv) and triethylamine (0.097 g, 0.96 mmol, 3.00 equiv) were added dropwise. The resulting solution was stirred for 2 h at 25° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 5 mL of water. Organic phase was separated and the aqueous phase was extracted with 3×10 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.150 g (crude) of [3-(4-ethylphenyl)-5-(pentafluoroethyl)-1,2-thiazol-4-yl]methyl methanesulfonate as a white solid. And it could been used for the next step directly. Mass spectrum (ESI, m/z): Calcd. for C15H14F5NO3S2, 416.4 (M+H). found 416.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH2:33][C:34]2[CH:39]=[CH:38][C:37](Br)=[CH:36][CH:35]=2)[NH:23][S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[Cl:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1>>[C:1]([O:5][C:6](=[O:41])[CH2:7][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:46]3[CH:47]=[CH:48][C:43]([Cl:42])=[CH:44][CH:45]=3)=[CH:36][CH:35]=2)[NH:23][S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[N:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(Br)cc2)NS(=O)(=O)c2cccnc2)n1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-c3ccc(Cl)cc3)cc2)NS(=O)(=O)c2cccnc2)n1
Yield: 84.6 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 9-(b) except for using tert-butyl({6-[(4-bromobenzyl)(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}tert-butoxycarbonylamino)acetate (187 mg, 0.289 mmol) obtained in Example 9-(a), and using 4-chlorophenylboronic acid (70.6 mg, 0.452 mmol) in place of 4-fluorophenylboronic acid to afford the title compound (166 mg) as a colorless oil. (Yield: 84%)
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:11]=[C:12]1[NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[NH:15][CH2:14][C@@H:13]1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>C1COCC1.CCOC(C)=O>[CH3:36][O:35][C:33](=[O:34])[CH2:32][N:18]1[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[NH:15][CH2:14][C@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:12]1=[O:11]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A 1.0 M solution of lithium bis(trimethylsilyl)amide (3.4 ml, 3.4 mmol) in THF was added dropwise to a −78° C. solution of (3S)-2-oxo-3-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.94 g, 3.38 mmol) in 20 ml of anhydrous THF and stirred for 30 min. Methyl bromoacetate (0.44 ml, 4 mmol) was added dropwise to the reaction mixture then warmed to RT. The reaction was diluted with 100 ml of EtOAc and washed with 0.3N KHSO4 (50 ml), H2O (2×50 ml, and brine. The combined organics were dried over anhydrous Na2SO4, filtered, and evaporated to afforded a gum that was purified by flash chromatography eluting with 3:7 EtOAc/Hex. to give 0.98 g (83%) of the title compound as a white solid. 1H NMR (CDCl3) δ7.15-7.07 (2H, m), 6.98-6.94 (1H, m), 6.88-6.84 (1H, d), 5.62-5.55 (1H, d), 4.71-4.65 (1H, d), 4.65-4.6 (1H, m), 4.33-4.27 (1H, d), 3.96-3.90 (1H, m), 3.78 (3H, s), 3.44-3.37 (1H, m), 1.4 (9H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH:14]([CH3:16])[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:23]=[C:24](Br)[CH:25]=[CH:26][C:10]2=1)=[O:5])[CH3:2].[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C(#N)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH:14]([CH3:16])[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:23]=[C:24]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:25]=[CH:26][C:10]2=1)=[O:5])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1)c1cc(Br)ccc1-2
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1)c1cc(C#C[Si](C)(C)C)ccc1-2
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A mixture of ester 112 (3.0 g, 7.07 mmol) and bis(triphenylphosphine)palladium (II) acetate (0.42 g, 0.57 mmol) was dissolved in a mixed solvent system of acetonitrile (80 mL) and TEA (120 mL). The mixture was degassed under vacuum and argon gas was added, after which trimethylsilylacetylene (2 mL, 14.14 mmol) was added into the mixture. The mixture was degassed again under vacuum (argon) and heated to reflux. The mixture was heated at reflux until analysis by TLC (EtOAc) indicated that all of the starting material 112 had been consumed. The mixture was cooled to rt and the precipitate which formed was removed by filtration through celite. The filtrate was concentrated under reduced pressure and partitioned between H2O and EtOAc. The combined layers of EtOAc were washed with brine and dried (Na2SO4), after which the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, EtOAc:hexane 1:1). Conditions for TLC were EtOAc. A white solid 113 (2.60 g, 83.3%) was obtained. mp 160-162° C.; IR (KBr, cm−1) 3365, 2925, 1706, 1616, 1553, 1498; 1H NMR (CDCl3) δ 7.89 (s, 1 H), 7.73 (dd, J=1.73 Hz, 1 H), 7.51-7.36 (m, 7 H), 6.66 (q, J=7.30, 1 H), 4.45-4.30 (m, 2 H), 1.40 (t, J=7.11, 3 H), 1.25 (d, J=7.38 Hz, 3 H), 0.15 (s, 9 H). MS (EI) m/e (relative intensity) 441 (M+, 15), 369 (25), 323 (55), 295 (100), 267 (15).
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([C@@H:23]([F:27])[CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].C(Cl)CCl.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)(C)C>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([C@@H:23]([F:27])[CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[CH2:18][CH2:19]2)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@@]21C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@@]21C

Procedure:
One gram of 17-acetoxy-11β-fluoro-4-pregnene-3,20-dione is combined in a solvent mixture of 6 ml. of ethylene chloride and 10 ml. of tert.-butanol with 1.5 g. of chloranil and 10 mg. of p-toluenesulfonic acid. The mixture is heated for 6 hours under reflux. Then, the mixture is filtered off from the chloranil and the precipitate washed with ethyl acetate and ether. The filtrate is diluted with ether and combined repeatedly with 2N NaOH solution. The solution is then washed neutral with water and dried. After chromatography of the crude product on silica gel with 14- 17% acetone/hexane, 344 mg. of 17-acetoxy-11β-fluoro-4,6-pregnadiene-3,20-dione is obtained; m.p. 220°-222° C. from acetone/hexane. UV: ε280 = 26,500.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:19]1([CH:26]=[CH:25][CH:24]=[C:22]([OH:23])[CH:21]=1)[OH:20].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([C:24]1[CH:25]=[CH:26][C:19]([OH:20])=[CH:21][C:22]=1[OH:23])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: Oc1cccc(O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)(C)c1cc(C(=O)c2ccc(O)cc2O)cc(C(C)(C)C)c1O
Temperature: 50 °C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
107.5 g of 3,5-di-tert-butyl-4-hydroxybenzoyl chloride and 48.4 g of resorcinol are suspended in 400 ml of nitrobenzene and warmed to 50° C. The brown solution is cooled to 0° C. 58.7 g of aluminium chloride are added in portions over the course of 45 minutes with vigorous stirring. The reaction mixture is slowly warmed to 20° C. over the course of 18 hours. The mixture is subsequently stirred at 50° C. for a further 4 hours, then cooled to room temperature and poured into 500 ml of hydrochloric acid/ice. The thick yellow suspension is extracted with ether, the ether phase is extracted with 500 ml of sodium hydroxide (15%), and the basic solution is washed three times with 250 ml of ether in each case, acidified to a pH of 1-2 using 15% hydrochloric acid and extracted with ether. The ether extracts are combined, dried and evaporated under reduced pressure, giving 124.4 g of 3,5-di-tert-butyl-2',4,4'-trihydroxybenzophenone, which, after recrystallisation from methanol, has a melting point of 192°-193° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([OH:18])=O)[CH3:15])=[N:9]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:21]1C=CN=C1)=O.[OH-].[NH4+]>>[NH2:21][C:16]([CH:14]([O:13][C:10]1[N:11]=[CH:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[N:9]=1)[CH3:15])=[O:18]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(Oc1ncn(-c2ccc(Br)cc2)n1)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CC(Oc1ncn(-c2ccc(Br)cc2)n1)C(N)=O
Yield: 53.5 %

Procedure:
The process was carried out as was Example 45, starting with 3 g of the compound of Example 37, 2.6 g of carbonyldiimidazole and 0.7 g of ammonium hydroxide. The product was recrystallized from ethanol to obtain 1.6 g of the desired product, m.p. 179°-181°.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:20])[CH2:7][CH2:8][C:9]1([CH3:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)C>O.C(O)C>[CH3:19][C:9]1([CH2:8][CH2:7][C:6]([OH:20])=[O:5])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)CCC1(C)CCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(CCC(=O)O)CCCc2ccccc21
Reaction time: 2 h

Procedure:
A solution of 14 g NaOH in 60 ml of water was added to a solution of 21 g of 5 in 600 ml ethanol. The mixture was stirred for 2 hours. The bulk of the ethanol was then evaporated and the residue poured into 1 liter of water. The mixture was acidified with 2N HCl and the product extracted with ether. The organic layer was dried and evaporated. This yielded 17.5 g of carboxylic acid 6 in the form of an oil; Rf =0.47 (toluene/ethyl acetate/ethanol/acetic acid 8/2/1/0 1).
Reaction SMILES: [F:1][C:2]1([CH2:18]OS(C)(=O)=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[N:24]([CH2:18][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1)=[N+:25]=[N-:26]
Reactant: CS(=O)(=O)OCC1(F)CCN(C(=O)OCc2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1(F)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 110 °C
Reaction time: 60 h

Procedure:
To a solution of benzyl 4-fluoro-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (1.3 g, 3.7 mmol) in DMF (10 mL) at RT was added NaN3 (2.4 g, 37.0 mmol). The reaction mixture was heated to 110° C. and stirred for 60 h, cooled and partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4, filtered, concentrated and purified on silica gel (10:1 to 1:2 hexanes:EtOAc) to give benzyl 4-(azidomethyl)-4-fluoropiperidine-1-carboxylate.
Reaction SMILES: N1(C2N=CC(C[C:13](O)=[O:14])=CC=2)C=NN=N1.[N:16]1([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[N:25][CH:26]=2)[CH:20]=[N:19][N:18]=[N:17]1.ClC1C(OC)=CC([N+]([O-])=O)=CN=1>>[CH3:13][O:14][C:23]1[C:24]([CH2:27][C:28]([OH:30])=[O:29])=[N:25][CH:26]=[C:21]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[CH:22]=1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)nc1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cn1
Agent: COc1cc([N+](=O)[O-])cnc1Cl
Product: COc1cc(-n2cnnn2)cnc1CC(=O)O

Procedure:
The title compound was prepared in an analagous fashion to that described for the syntheses of [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid (Method 1, Steps B-F and [5-(1H-tetrazol-1-yl)pyridin-2-yl]acetic acid (Steps A-E) starting from 2-chloro-3-methoxy-5-nitropyridine. LC/MS: [(M+1-28)]+=208.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccc(F)cc2)cnc1N
Yield: 93.9 %

Procedure:
A solution of 2.59 g of 2-amino-5-(4-fluorophenyl)-3-nitro-pyridine (compound G1) in 36 ml ethanol is treated with 12.9 g of SnCl2.2H2O at 90° C. for 24 h under a nitrogen atmosphere. Thereafter, the solution is concentrated to dryness. The residue is dissolved in 600 ml H2O and adjusted to pH 8 using a 1.0 M solution of aqueous sodium hydroxide. Subsequently, the aqueous layer is extracted six times each with 50 ml of ethyl acetate. The combined organic phases are extracted once with 100 ml of brine, dried using magnesium sulfate, filtered with suction, and evaporated to dryness to yield 2.12 g of the pure title compound of m.p. 261° C. MS: 204.3 (MH+). TLC: Rf=0.50 (dichloromethane/methanol 5:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28]([NH:19][C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)=[C:2]([Cl:1])[CH:3]=1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1cnc(Oc2ccc3ncccc3c2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2ccc3ncccc3c2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-6-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 3) and 2,4-dichlorobenzene-1-sulfonyl chloride.
Reaction SMILES: O[C:2]1([OH:20])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:19].[Se]=O.CC(O)=O.[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)([CH3:29])[CH3:28]>O1CCOCC1>[OH:20][C:2]1([C:33]2[CH:34]=[CH:35][C:30]([CH:27]([CH3:29])[CH3:28])=[CH:31][C:32]=2[O:36][CH3:37])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:19]
Reactant: CC(=O)Nc1c([N+](=O)[O-])ccc2c1C(=O)C(O)(O)C2=O
Reactant: COc1cccc(C(C)C)c1
Agent: O=[Se]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1cc(C(C)C)ccc1C1(O)C(=O)c2ccc([N+](=O)[O-])c(NC(C)=O)c2C1=O
Reaction time: 12 h
Yield: 14 %

Procedure:
N-(2,2-dihydroxy-5-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (2.60 g, 11.1 mmol) was completely dissolved in anhydrous dioxane (20 ml). This solution was added with selenium oxide (2.70 g, 24.4 mmol) and AcOH (1.5 ml). The reaction mixture was heated for 7 hrs under reflux. After filtration at high temperature, the filtrate was concentrated to afford 1.79 g (100%). Trifluoroacetic solution of the resulting product was added with isopropyl-3-methoxybenzene (1.66 g, 11.1 mmol), followed by stirring for 12 hrs. The remainder was extracted with ethyl acetate, and concentrated organic layer was purified using column chromatography (ethylacetate 100%) to afford the title compound (0.64 g, 14%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]#[N:22])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([NH:15][CH2:16][CH3:17])=[O:14].[S:23](Cl)(=[O:26])(=[O:25])[NH2:24]>CC(N(C)C)=O>[C:21]([C:3]1[C:2]([NH:1][S:23](=[O:26])(=[O:25])[NH2:24])=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([NH:15][CH2:16][CH3:17])=[O:14])#[N:22]
Reactant: CCNC(=O)N1CCCCC1COc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Product: CCNC(=O)N1CCCCC1COc1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.7 %

Procedure:
To a solution of 2-((3-amino-2-cyanophenoxy)methyl)-N-ethylpiperidine-1-carboxamide (Example 26b. 0.407 g, 1.35 mmol) in DMA (5 mL) was added sulfamoyl chloride (0.234 mg, 2.02 mmol) and the reaction mixture was stirred vigorously at r.t. for 2 h, then extracted with H2O/EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by Biotage purification system (120 g Silicycle column, DCM:THF=4:1 as eluent) to provide the desired product (0.606 g, 90%). MS 382 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][N:6]=[C:5]([OH:8])[CH:4]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[OH:1][CH2:2][C:3]1[NH:7][N:6]=[C:5]([O:8][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:4]=1
Reactant: OCc1cc(O)n[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2cc(CO)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.2 %

Procedure:
To a stirred suspension of 5-hydroxymethyl-1H-pyrazol-3-ol (J. Heterocycl. Chem., 1979, 16, 505-508) (1.0245 g, 8.98 mmol) in anhydrous dichloromethane (50 ml), under nitrogen, was added p-toluenesulfonyl chloride (1.8825 g, 9.87 mmol), then dropwise over 5 min, anhydrous triethylamine (1.50 ml, 10.8 mmol). The mixture was stirred at room temperature for 16.5 h under nitrogen, then washed with brine (50 ml). The aqueous layer was further extracted with dichloromethane, and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 5-7% MeOH/CH2Cl2) to afford 1.3067 g (54%) of the title compound as a pale green solid; 1H NMR (360 MHz, d6-DMSO) δ2.42 (3H, s), 4.38 (2H, d, J=5.7 Hz), 5.32 (1H, t, J=5.7 Hz), 5.82 (1H, d, J=2.2 Hz), 7.47 (2H, d, J=8.3 Hz, 7.77 (2H, d, J=8.3 Hz), 12.55 (1H, s).
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9](=[O:10])[C:7]1=[O:8])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Mg]I>C(OCC)C.C1(C)C=CC=CC=1>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:20])([F:21])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9]([OH:10])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[Cl:24])[C:7]1=[O:8])[CH3:23]
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Reactant: Clc1ccccc1[Mg]I
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c1cc(I)cc2C(F)(F)F
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To a solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodoisatin (4 g, 9.09 mmol) in a mixture of diethyl ether (60 mL) and toluene (20 mL) was added dropwise a freshly prepared 0.67 N 2-chlorophenylmagnesium iodide in ether (15 mL, 10.1 mmol) over 20 min at room temperature. The mixture was stirred for 20 min at the same temperature and the reaction was quenched with aqueous NaHCO3. The mixture was extracted with ethyl acetate and the extracts were washed with sat. aqueous NaHCO3, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography with 100:1 to 50:1 chloroform/methanol to give the title compound (2.81 g, 56%).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:22]1([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:35]1([CH:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:29][CH2:30][CH2:31][C:32]([N:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:2]3([CH3:1])[CH2:6][C:5]4[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=4[O:3]3)[CH2:17][CH2:18]2)=[O:33])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)CCCC(c1ccccc1)c1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(C(=O)CCCC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 86 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and 5,5-diphenylvaleric acid, the procedure of Example 10 was otherwise repeated to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH2:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28]Br)[CH3:25]>O>[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28][NH:12][CH:10]([CH3:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:25]
Reactant: COc1cccc(CC(C)N)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CNC(C)Cc1cccc(OC)c1)OCC
Temperature: 130 °C
Yield: 68 %

Procedure:
(+)-2-(3-methoxyphenyl)-1-methylethylamine (472.8 g, 2.86 mol), potassium carbonate (sesquihydrate) (1133.8 g, 6.88 mol) and dimethylformamide (2400 ml) were mixed and heated to 130° C. in a reaction flask fitted with an efficient stirrer and a reflux condenser. Bromoacetaldehyde diethylacetal (630 g, 3.20 mol) was added dropwise over a 45 min period while maintaining the temperature at 130° C. The reaction was mildly exothermic. The temperature was maintained at 130° C. for 1 hr. The reaction mixture was cooled to 45° C., and 325 ml of water was added. After stirring at least 1 hr and after the temperature of the mixture reached 30°, it was filtered from the salts and the solvent evaporated under vacuum on a rotatory evaporator. The residual oil was filtered from some inorganic salts and distilled under vacuum; collected fractions boiling at 115°-130° C. at 0.05 mmHg, yield 68% of (+)-N-(2,2-diethoxyethyl)-2-(3-methoxyphenyl)-1-methylethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Br)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)cccc1Br

Procedure:
The title compound was prepared using 0.30 g of 6-(2-bromo-6-chloro-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 104 and 0.105 mL of tert-butyl isocyanate according to Example 2. The product was purified by MPLC eluting with 1:1CHCl3 :EtOAc; mp 314° C. (dec); MS(CI).