Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH2:4][OH:5]>CC(C)=O.[O-2].[Mn+4].[O-2]>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: OCc1cc(I)ccc1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: O=Cc1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
To a stirred solution of 2-hydroxy-5-iodobenzyl alcohol (43.5 g, 174.0 mmol) in acetone (700 mL) was added 85% activated manganese(IV) oxide (5 micron, 50 g, 494.0 mmol) and the solution stirred at room temperature for 16 hours. The manganese oxide was removed by filtration through diatomaceous earth and the filtrate concentrated in vacuo. The product was purified by flash silica chromatography (0-20% ethyl acetate in hexanes) The 2-hydroxy-5-iodobenzaldehyde was obtained as a greenish-yellow solid (24.3 g, 58%). A small amount of the 2-hydroxy-5-iodobenzaldehyde was recrystallized from methanol/water to afford an analytical sample and the remainder of the compound was used without further purification: mp 99-101° C. 1H NMR (CDCl3/300 MHz) 9.83 (s, 1H), 7.79 (d, 1H, J=2.2 Hz), 7.77 (dd, 1H, J=8.7 Hz, J=2.2 Hz), 6.81 (d, 1H, J=8.7 Hz). ESHRMS 246.9229 (M−H Calc'd 246.9256).
Reaction SMILES: [H-].[Na+].[CH:3]1([N:9]2[C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:15][CH2:14]3)[C:12](=[O:29])[NH:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CN(C)C=O.O>[C:38]([O:37][C:35]([C:34]1[CH:33]=[C:32]([CH:44]=[CH:43][CH:42]=1)[CH2:31][N:11]1[C:12](=[O:29])[C:13]2([CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:15][CH2:14]2)[N:9]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:10]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)c1cccc(CBr)c1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
Sodium hydride (0.0699 g, 2.91 mol) was added portionwise at 0° C. to benzyl 1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.03 g, 2.77 mmol) in N,N-dimethylformamide (5 mL) and stirred at 0° C. for 10 minutes. tert-Butyl 3-(bromomethyl)benzoate (0.75 g, 2.77 mmol) was added dropwise at 0° C., the mixture allowed to warm to room temperature, and stirred overnight. The reaction was diluted with water and extracted with ethyl acetate. The extracts were washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by PTLC (50% ethyl acetate/hexanes) to give product as an oil (1.37 g, 88%); 1H NMR (DMSO-d6); δ0.97 (m, 1H); 1.20 (m, 4H); 1.53 (s, 9H); 1.53-1.69 (m, 9H); 2.60 (m, 1H); 3.59 (m, 2H); 3.73 (m, 2H); 4.47 (s, 2H); 5.09 (s, 2H); 7.30-7.39 (m, 5H); 7.45-7.50 (m, 2H); 7.73 (m, 1H); 7.81 (m, 1H); MS for C33H43N3O5 m/z 562 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[C:28]([NH2:35])[N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:24][CH:23]=[CH:22][N:21]=2)=[CH:8][N:7]=[C:6]([CH2:5][NH:4][CH2:3][CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[C:28]([NH2:35])[N:27]=2)[N:11]=1
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Product: Nc1nc(NCCNCc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
Using the procedure described above, reaction of (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methylamine and 2-chloro-5-nitro-6-amino-pyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methyl {2-[(5-nitro-6-amino(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.[F:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[C:23]([F:25])[CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([NH:1][N:2]2[C:7](=[O:8])[C:6]3[S:9][CH:10]=[CH:11][C:5]=3[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:3]2)=[O:28])[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: Nn1nc(-c2ccccc2)c2ccsc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2ccccc2)c2ccsc2c1=O

Procedure:
The product from Example 29B and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.79 (s, 2H) 6.94-7.36 (m, 3H) 7.51-7.64 (m, 4H) 7.61-7.84 (m, 2H) 8.37 (d, J=5.19 Hz, 1H) 11.87 (s, 1H); MS (ESI) m/z 398 (M+H)+.
Reaction SMILES: ClC1C=C(C=CC=1)C(O)=[O:6].[Br:11][C:12]1[CH:20]=[CH:19][N:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2>C(Cl)(Cl)Cl>[Br:11][C:12]1[CH:20]=[CH:19][N+:18]([O-:6])=[C:17]2[NH:16][CH:15]=[CH:14][C:13]=12
Reactant: Brc1ccnc2[nH]ccc12
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(Br)c2cc[nH]c21
Reaction time: 0.5 h
Yield: 132 %

Procedure:
m-Chlorobenzoic acid (1.0 g) was added to a chloroform (19 ml) solution containing 4-bromo-7-azaindole (760 mg) under ice cooling, followed by stirring for 30 minutes. Then, chloroform (10 ml) was distilled away under reduced pressure, diisopropylether was added, an insoluble precipitate was collected by filtration, and a white solid of 4-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (1.085 g) was thus obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([O:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:15]([O-:17])=[O:16])=[C:7]([O:11][C:12](=[O:14])[CH3:13])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cccc(OC(C)=O)c1
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(OC(C)=O)c1
Temperature: -10 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
Acetic acid 3-acetylamino-phenyl ester (21.7 g, 112.4 mmol) was added portionwise, at −15° C., to fuming nitric acid (109 mL) maintaining the temperature below −10° C. The reaction mixture was stirred at −10° C. for 3 hours and then was poured into ice. The resulting mixture was extracted 3 times with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, 1/1) to afford 20.608 g (77% yield) of acetic acid 5-acetylamino-2-nitro-phenyl ester as a cream colored solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][CH2:30][CH2:31][C:32]#[C:33][CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[CH3:11][C:10]1([CH3:12])[S:9][CH2:8][CH2:7][N:6]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:34][C:33]#[C:32][CH2:31][CH2:30][O:29][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:5]1[C:3]([O:2][CH3:1])=[O:4]
Reactant: OCC#CCCOC1CCCCO1
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)CCSC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
To a solution of 3.31 g (9.6 mmol) of of 4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and 2.12 g (11.5nmmol) of 5-(tetrahydro-2H-pyran-2-yloxy)-2-pentyn-1-ol in 15 mL of THF was added 3.0 g (11.5 mmol) of triphenylphosphine, followed by dropwise addition of 1.8 mL (11.5 mmol) of diethyl azodicarboxylate. The resulting solution was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate:hexanes (1:9) to provide 3.03 g (62%) of methyl 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylate as a colorless oil. Electrospray Mass Spec: 534.4 (M+Na)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[CH:14]=[O:15])[C:5]#[N:6].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C@:24]([OH:39])([C@H:31]([S:33][CH:34]([CH2:37]O)[CH2:35][OH:36])[CH3:32])[CH2:25][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[C:5]([C:4]1[CH:7]=[CH:8][C:9](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C@H:14]2[O:36][CH2:35][C@H:34]([S:33][C@H:31]([CH3:32])[C@:24]([C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[F:16])([OH:39])[CH2:25][N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)[CH2:37][O:15]2)=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(/C=C/C=C/C=O)c(F)c1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A mixture of 4.63 g (23.0 mmol) of 3-fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]benzonitrile [produced as described in Step 1(II) above], 8.73 g (24.3 mmol of (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [produced as described in Japanese Patent Application (Kokai) Hei 8-333350)], 5.07 g (26.7 mmol) of p-toluenesulfonic acid monohydrate and 200 ml of anhydrous tetrahydrofuran was allowed to stand at ambient temperature for 30 minutes. At the end of this time, the reaction mixture was concentrated using a rotary evaporator and dried in vacuo. The resulting residue was dissolved in 150 ml of anhydrous tetrahydrofuran and the resulting mixture was then evaporated to dryness in vacuo using a rotary evaporator. This procedure was repeated twice more. A solution of the resulting residue in 150 ml of anhydrous tetrahydrofuran was poured into a saturated aqueous sodium hydrogen carbonate solution with stirring. The product was then extracted with ethyl acetate and the organic layer was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residual oil was purified by chromatocraphy on a silica gel (500 g) column using a 2:1 mixture of ethyl acetate and hexane as the eluant to give 9.35 g (yield 74%) of the title compound as a yellow amorphous solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([N:30]([CH:34]([CH3:37])[C:35]#[CH:36])[CH2:31][CH2:32][OH:33])[CH3:29]>>[CH2:28]([N:30]([CH:34]([CH3:37])[C:35]#[C:36][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:27])([F:1])[F:26])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:31][CH2:32][OH:33])[CH3:29]
Reactant: C#CC(C)N(CC)CCO
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Product: CCN(CCO)C(C)C#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and 2-[Ethyl-(1-methyl-prop-2-ynyl)-amino]-ethanol were converted to yield 2-(Ethyl-{1-methyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amino)-ethanol as brown oil, MS: 419 (MH+).
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1.S(=O)(=O)(O)O>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([O:11][CH:3]([C:2]([Cl:1])([Cl:12])[Cl:13])[C:4]2[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=2)=[CH:17][CH:16]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: OC(c1ccc(Cl)cc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Product: Clc1ccc(OC(c2ccc(Cl)cc2)C(Cl)(Cl)Cl)cc1
Reaction time: 2 h

Procedure:
α-trichloromethyl-p-chlorobenzyl alcohol, 5.0g, was stirred with p-chlorophenol, 2.6g, and sulfuric acid, 35 ml, was added dropwise. After 2 hrs. of stirring, the mixture was poured onto ice and extracted with ether. After drying with sodium sulfate, the ether was removed under vacuum and the residue was recrystallized from ethanol to give α-trichloromethyl-p-chlorobenzyl p-chlorophenyl ether, mp 101°C. This method of synthesis is referred to in Table I as method A.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:26][C:25](=[O:27])[C:24]4[C:23]5[C:18](=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:17]=[CH:16][C:15]=4[N:14]=3)=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:32](#[N:34])C.O.CN>[Cl-].[Na+].O>[CH3:32][NH:34][C:25]([C:24]1[C:23]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16][C:15]=1[NH:14][C:13]([C:12]1[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=[C:10]([C:28]([F:30])([F:31])[F:29])[CH:11]=1)=[O:26])=[O:27]
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3ncccc3c12
Reactant: CC#N
Agent: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CNC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2ncccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
To a suspension of 150 mg (0.30 mmol) of the above 2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-3-oxa-1,8-diaza-phenanthren-4-one in 6 mL of a mixture acetonitrile: H2O 4:1 (v/v) is added 79 μL (0.91 mmol) of methylamine (solution 40% in water). The reaction mixture is stirred for 6 hours at ambient temperature. Brine is then added to the mixture and the product is extracted with ethyl acetate (3 times). The regrouped organic phases are dried on Na2SO4, filtrated and evaporated. The purification of the residue by flash chromatography (SiO2, heptane/ethyl acetate 1:1) affords 110 mg (76%) of a white solid; LC/MS:475/477 (M+H)+, m.p.: 210-211° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Cl:29])[CH:23]=4)[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][CH:65]=1>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:31])=[CH:65][CH:66]=1)#[N:69]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 87 (0.4 g, 0.71 mmol), was reacted with diisopropylethylamine (0.82 g, 6.4 mmol), diphenylphosphinic chloride (0.67 g, 2.8 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.34 g, 2.8 mmol) to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a white solid (Yield, 0.14 g, 55%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[N:6][CH:7]=1.[C:12]([C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][C:40]=1[CH3:41])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:21]=1)=[O:18])#[CH:13]>>[NH2:11][C:9](=[O:10])[CH2:8][C:5]1[N:6]=[CH:7][C:2]([C:13]#[C:12][C:14]2[CH:15]=[C:16]([CH:38]=[CH:39][C:40]=2[CH3:41])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]3)=[C:22]([C:34]([F:35])([F:37])[F:36])[CH:21]=2)=[O:18])=[N:3][CH:4]=1
Reactant: NC(=O)Cc1cnc(Br)cn1
Reactant: C#Cc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)ccc1C
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc(CC(N)=O)cn1

Procedure:
The title compound can be prepared as for example 1 using 2-(5-bromopyrazin-2-yl)acetamide and 3-ethynyl-4-methyl-N-{4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl}-benzamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:35])[C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([S:19][C:20]3[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:44])C=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:35])[C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([S:19]([C:20]3[CH:25]=[C:24]([C:26]([CH3:27])([CH3:28])[CH3:29])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=3)=[O:44])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)n1C
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(S(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (Ex. 4a, 490 mg, 0.94 mmol) in 10 mL of dichloromethane at room temperature under N2 was added m-chloroperbenzoic acid (247 mg, 1.1 mmol) in 5 portions during a period of 30 min. The resulting suspension was stirred for 3 h at room temperature and then the reaction was quenched by pouring the suspension onto ice (20 g). The mixture was extracted with ethyl acetate (2×40 mL) and the combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. Chromatography (3-50% Ethyl acetate/hexanes) gave 5-[4-(3,5-di-tert-butyl-4-hydroxy-benzenesulfinyl)-piperidine-1-sulfonyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester a white solid (480 mg, 95%). ESI/Cl-MS m/z 537 ([M−H]−).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][CH:23]([CH3:26])[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH3:26]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: CC(N)CO
Product: CC(CO)Nc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 71 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-amino-propan-1-ol according to the GPA affording 25 mg (71%) of a red powder. Rt=3.21 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[CH3:13][O:14][C:15](=[O:22])[C@@H:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH2:17]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:17][C@H:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:15]([O:14][CH3:13])=[O:22])=[O:7]
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: COc1ccc(C(=O)O)cc1F
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1ccc(OC)c(F)c1

Procedure:
Prepared in a similar manner to example 4 using 3-fluoro-4-methoxybenzoic acid and D-leucine methyl ester. MS (M+H, 298).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:8]=1)(=O)=O.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:6][C:7]2[N:8]=[C:9]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][CH:12]=2)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(Cc2cccc(NC(=O)OC(C)(C)C)n2)CC1
Reaction time: 16 h

Procedure:
To a solution {6-[(tert-butoxycarbonyl)amino]pyridin-2-yl}methyl methanesulfonate (156 mg, 0.518 mmol) in acetonitrile (2.5 mL) was added N-methyl piperazine (103 mg, 1.03 mmol) and potassium carbonate (214 mg, 1.55 mmol) at room temperature. After 16 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate, partially concentrated under reduced pressure, and then diluted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl {6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}carbamate that was used without further purification. MS ESI calc'd for C16H27N4O2 [M+H]+ 307. found 307.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[N:5][NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([C:20]1[CH:21]=[C:22]([C:32]([O:34][CH3:35])=[O:33])[N:23]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:24]=1)=[O:19]>C(#N)C>[Cl:31][C:30]1[C:25]([N:23]2[CH:24]=[C:20]([C:18](=[O:19])[CH2:17][N:5]3[N:6]=[N:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]3)[CH:21]=[C:22]2[C:32]([O:34][CH3:35])=[O:33])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1cc(C(=O)CBr)cn1-c1ncccc1Cl
Reactant: FC(F)(F)c1nn[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C(=O)Cn2nnc(C(F)(F)F)n2)cn1-c1ncccc1Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
890 mg (1.61 mmol) of 5-(trifluoromethyl)-2H-tetrazole and 297 mg (2.14 mmol) of potassium carbonate were initially charged in 10 ml of acetonitrile and heated at reflux for 15 min. 630 mg (1.07 mmol) of methyl 4-(bromoacetyl)-1-(3-chloropyridin-2-yl)-1H-pyrrole-2-carboxylate, dissolved in 10 ml of acetonitrile, were added, and the reaction mixture was stirred at 70° C. for 1 h. The solvent was distilled off, the residue was taken up in water and the mixture was extracted twice with dichloromethane. The combined organic phases are washed with sodium chloride solution, dried over sodium sulphate and concentrated. The desired product was isolated by chromatographic purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:27][C:28]1[CH:32]=[C:31]([CH2:33]OS(C)(=O)=O)[O:30][N:29]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][C:31]2[O:30][N:29]=[C:28]([CH3:27])[CH:32]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(COS(C)(=O)=O)on1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)on1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with methanesulfonic acid 3-methyl-isoxazol-5-ylmethyl ester (described in Heterocycles, 23(3), 571-83; 1985) gave the title compound. ES-MS m/e (%): 462.2(M+H+).