Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[CH2:22]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[CH2:30]([N:29]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (44 mg), dibenzylamine (32 mg), 1H-1,2,3-benzotriazol-1-ol (31 mg) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (39 mg) at 4° C., and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with diethyl ether to give the title compound (53 mg, yield 78%) as pale-brown crystals. melting point 198-199° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)[C:9]2=[O:12])=[CH:4][CH:3]=1.CI.[CH3:21]C(C)([O-])C.[K+]>[Cl-].[Na+].O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:17][CH2:16][CH:15]([O:18][CH3:21])[CH2:14][CH2:13]3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1c2cc(Br)ccc2CCC12CCC(O)CC2
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC1CCC2(CCc3ccc(Br)cc3C2=O)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
7′-Bromo-4-hydroxy-3′,4′-dihydro-1′H-spiro[cyclohexane-1,2′-naphthalen]-1′-one (Intermediate 8, 1.78 g, 5.76 mmol) was dissolved in 2-methyl THF (15 mL) under an inert atmosphere and the solution was cooled to 0° C. Methyl iodide (0.720 mL, 11.5 mmol) was added followed by portion wise addition of potassium tert-butoxide (1.29 g, 11.5 mmol). The resulting mixture was stirred at r.t. overnight. Potassium tert-butoxide (0.323 g, 2.88 mmol) and methyl iodide (0.717 mL, 11.5 mmol) were added. The mixture was stirred for 1.5 h. Potassium tert-butoxide (0.194 g, 1.73 mmol) was added and the mixture was stirred for an additional 2 h. Brine was added and the phases were separated. The aqueous phase was extracted with EtOAc and to the combined organics were added activated charcoal. The mixture was filtered through a pad of diatomaceous earth and rinsed with EtOAc. The organic phase was concentrated in vacuo to give the title compound (1.41 g, 76% yield): MS (ES+) m/z 323 [M+H]+.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH2:8]([C:10]1[CH:38]=[CH:37][C:13]([C:14]([N:16]2[CH2:21][CH2:20][C:19]3([O:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[N:23]4[C:31](/[CH:34]=[N:35]\O)=[CH:32][CH:33]=[C:22]34)[CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[O:39][CH3:40])[CH3:9].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:8]([C:10]1[CH:38]=[CH:37][C:13]([C:14]([N:16]2[CH2:17][CH2:18][C:19]3([O:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[N:23]4[C:31]([C:34]#[N:35])=[CH:32][CH:33]=[C:22]34)[CH2:20][CH2:21]2)=[O:15])=[CH:12][C:11]=1[O:39][CH3:40])[CH3:9]
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(/C=N\O)ccc23)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(C#N)ccc23)cc1OC
Temperature: 140 °C
Yield: 116.1 %

Procedure:
Acetic anhydride (4.0 mL, 42 mmol) was added to (Z)-1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde oxime (847 mg from previous step). The reaction mixture was heated at 140° C. for 3.5 h then cooled to room temperature and poured onto ice. Dichloromethane (30 mL) was added followed by sodium bicarbonate (0.7 g). The organic phase was then separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried, filtered, and concentrated to give a yellow oil. The crude material was purified by column chromatography (silica gel: 5-45% EtOAc in hexanes) to give 1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile (944 mg, 69%). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=8.0 Hz, 1H), 7.22-7.16 (m, 1H), 7.15-7.08 (m, J=7.6 Hz, 3H), 7.00 (d, J=4.0 Hz, 1H), 6.93-6.87 (m, 2H), 6.08 (d, J=4.0 Hz, 1H), 4.64 (s, 1H), 3.83 (s, 3H), 3.65-3.14 (m, 3H), 2.62 (q, J=7.5 Hz, 2H), 2.27-1.67 (m, 4H), 1.16 (t, J=7.5 Hz, 3H). ESI-MS m/z calc. 427.5. found 428.5 (M+1)+; Retention time: 2.08 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][NH:5][C:6](=[O:13])[C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][OH:10].[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1)[CH3:19]>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[O:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]([NH:5][CH2:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[Cl:1])=[O:13])=[CH:22][CH:21]=1)[CH3:19]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: CC(C)(CCO)C(=O)NCc1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCc1ccc(NC(=O)OCCC(C)(C)C(=O)NCc2ccccc2Cl)cc1
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a solution of N-(2-chlorobenzyl)-4-hydroxy-2,2-dimethylbutanamide (400 mg, 1.6 mmol) in THF (25 mL) were added 4-ethylphenylisocyanate (276 μL, 1.92 mmol, 1.2 equiv.) and DMAP (293 mg, 2.4 mmol, 1.5 equiv.). The reaction mixture was stirred overnight. The reaction mixture was concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O, and further purified by flash column chromatography using a mixture of hexanes and EtOAc to give 4-(2-chlorobenzylamino)-3,3-dimethyl-4-oxobutyl 4-ethylphenylcarbamate (160 mg, 25%). LRMS (M+H+) m/z 403.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=2)[NH:32][C:33](=[O:35])[CH3:34])O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([C:29]4[CH:30]=[C:31]([NH:32][C:33](=[O:35])[CH3:34])[CH:36]=[CH:37][CH:38]=4)[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: CC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1cccc(-c2cc(-c3cccc4[nH]ncc34)nc3c2cnn3C)c1
Temperature: 130 °C

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (80 mg, 0.28 mmol) and 3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acetanilide (1.4 equiv.) were suspended in 2 ml acetonitrile. Sodium carbonate (3 equiv., 92 mg) and bis(triphenylphosphine)palladium(II) chloride (0.05 equiv.) were added as a solution in water (0.5 ml). The reaction mixture was heated in microwave at 130° C. for 20 min. Water was added to the mixture, and the precipitated product was filtered and purified by column chromatography to yield 112. NMR (CDCl3): 2.27 (3H, s), 4.33 (3H, s), 7.34 (1H, br), 7.52-7.68 (5H, m), 7.84 (1H, d), 7.85 (1H, s), 8.10 (1H, s), 8.26 (1H, s), 8.96 (1H, s). MS: MH+ 383.12 (100%)
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([C:21]#[N:22])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1.Cl.[OH-].[Na+]>C1COCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:21](=[NH:22])[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18]=2[CH:19]=[CH:20][C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)=[N:12]3)=[CH:26][CH:25]=1
Reactant: N#Cc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N=C(c1ccc(F)cc1)c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Temperature: 0 °C
Yield: 55.1 %

Procedure:
To a cooled (ice bath) and stirred suspension of 2-((R)-indan-1-ylamino)-quinoline-5-carbonitrile (example 80, step A) (285 mg, 1.0 mmol) in THF (5 ml) was added drop wise a 1M solution of 4-fluorophenyl-magnesium bromide (6 ml, 6.0 mmol), the reaction mixture was heated under reflux conditions for 92 h and poured into ice-water (20 ml). 2N HCl (5 ml) was added, the mixture was stirred at room temperature for 10 min, 3 N NaOH (5 ml) was added and the mixture was extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with brine (2×50 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as light red foam (210 mg, 55%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2I)=[O:5])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([C:29]#[CH:30])[CH:26]=[CH:27][CH:28]=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.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[C:30]#[C:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=1)=[O:5])[CH3:2]
Reactant: C#Cc1cccc(F)c1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C#Cc3cccc(F)c3)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To 0.502 g (1.161 mmole) of ethyl-6-chloro-8-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 67 mg (0.060 mmole) tetrakis(triphenylphosphine)palladium(0), 22 mg (0.116 mmole) copper (I) iodide, 10 mL degassed toluene, 0.484 mL (3.48 mmole) degassed TEA, and 0.199 mL (1.74 mmole) 3-fluorophenylacetylene. The mixture was stirred overnight at room temperature. The mixture was concd and the resulting oil was purified using reverse phase chromatography to afford 0.440 g (89%) of a crystalline solid: 1H NMR (CDCl3/400 MHz) 1.35 (t,3H, J=6.8 Hz), 4.28-4.37 (m, 2H), 5.83 (q, 1H, J=6.8 Hz), 7.04-7.09 (m, 1H), 7.18 (d, 1H, J=2.4 Hz), 7.20-7.23 (m, 1H), 7.30-7.33 (m, 2H), 7.44 (d, 1H, J=2.8 Hz), 7.63 (s, 1H); MS (ES+) 425 (M+1, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][CH:15]([CH2:18]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14][C:13]=3[CH:12]=[C:11]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:36][NH2:37]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH:37][CH3:36])[CH2:14][C:13]=3[CH:12]=[C:11]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CN
Reactant: COc1ccc(-c2cc(-c3ccccc3)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)cc1
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3ccc(OC)cc3)c2O1

Procedure:
The title compound was prepared (0.081 g, 99%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(4-methoxyphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp >250° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:9]([CH3:10])[C:8]2[S:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:10][N:9]1[C:5]([CH2:3][NH:2][CH3:1])=[CH:6][C:7]2[CH:13]=[CH:12][S:11][C:8]1=2
Reactant: CNC(=O)c1cc2ccsc2n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCc1cc2ccsc2n1C
Temperature: 25 °C
Yield: 114.2 %

Procedure:
To a solution of N,6-dimethyl-6H-thieno[2,3-b]pyrrole-5-carboxamide (134 mg, 0.69 mmole) in dry THF (5 mL) was added a solution of LiAlH4 in THF (1.0 M, 1.38 mL, 1.38 mmole) slowly at RT. After gas evolution had ceased the mixture was heated to a gentle reflux. After 2 hr the mixture was cooled to RT and quenched by dropwise addition of 2M NaOH until a white solid had formed. The mixture was dried (MgSO4), filtered, and concentrated to give the title compound as a brown oil (142 mg, 100%) which was sufficiently pure for use in the next step: 1H NMR (400 MHz, CDCl3) δ 6.95 (d, J=5.2 Hz, 1 H), 6.78 (d, J=5.2 Hz,1H), 6.27 (s,1H), 3.78 (s, 2H), 3.72 (s, 3H), 2.47 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Li].[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][OH:27]>>[OH:27][CH2:26][C@@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:8][CH:7]=2)=[CH:14][CH:13]=1)=[O:16]
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: OC[C@@H]1CCCN1
Agent: [Li]
Product: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@H]1CO

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B′ from 4′-trifluoromethyl-biphenyl-4-carboxylic acid, lithium salt using (S)-2-pyrrolidine methanol as the amine. MS (ES+) 350.2
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC.[OH-].[Na+]>[CH3:22][C:19]1[CH:18]=[CH:17][C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:8]([C:3]3([CH:2]=[O:1])[CH2:4][CH2:5][CH2:6][CH2:7]3)=[O:9])[CH2:15][CH2:14]2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(N2CCN(C(=O)C3(CO)CCCC3)CC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(N2CCN(C(=O)C3(C=O)CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 105 %

Procedure:
(1-Hydroxymethyl-cyclopentyl)-(4-(4-methylphenyl)piperazin-1-yl)-methanone from the previous step (1.57 g, 5.22 mmol) was dissolved in DCM (40 mL). Dess-Martin periodinane (3.06 g, 7.22 mmol) was added and the reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture diluted with Et2O (100 mL) and 1M aq NaOH solution (50 mL) was added. The reaction mixture was stirred for 20 minutes and then the organic layer was separated and washed with 1M aq NaOH solution (50 mL), water (50 mL), dried (MgSO4) and concentrated in vacuo to give 1-(4-(4-methylphenyl)-piperazine-1-carbonyl)-cyclopentanecarbaldehyde (1.64 g, 105%) as a brown oil which was used without further purification.
Reaction SMILES: C([O:8][N:9]([C:13]1([CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([OH:23])=[C:15]([C:24]2[NH:29][C:28]3[CH:30]=[CH:31][C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][C:27]=3[S:26](=[O:40])(=[O:39])[N:25]=2)[C:14]1=[O:41])[C:10](=[O:12])[CH3:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]([C:13]1([CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([OH:23])=[C:15]([C:24]2[NH:29][C:28]3[CH:30]=[CH:31][C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][C:27]=3[S:26](=[O:40])(=[O:39])[N:25]=2)[C:14]1=[O:41])[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)N(OCc1ccccc1)C1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(=O)N(O)C1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 57.8 %

Procedure:
A mixture of Example 24B (12 mg, 0.018 mmol) and 10% Pd/C (2 mg) in methanol (1 mL) was hydrogenated at 1 atm for 1 h. The solution was filtered and the filtrate was concentrated in vacuo. Column chromatography on silica (7% methanol/dichloromethane) afforded the title compound (6 mg, 58%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.50-0.62 (m, 1H), 0.67 (dd, J=9.93, 6.62 Hz, 6H), 0.84-1.06 (m, 1H), 1.22-1.33 (m, 1H), 1.96 (s, 3H), 2.01-2.08 (m, 1H), 2.06-2.21 (m, 1H), 3.03 (s, 3H), 7.51 (m, 6H), 8.03 (d, J=8.09 Hz, 1H), 10.04 (s, 1H), 10.22 (s, 1H), 14.45-14.74 (br. s, 1H)); MS m/z 576.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.[ClH:17]>S(Cl)(Cl)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7]([Cl:17])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1

Procedure:
A suspension of 5-nitro-isophtalic acid mono methyl ester (22.52 g, 100.0 mmol) in thionyl chloride (50 ml) was heated to reflux for 6 hours (until the production of SO2 and HCl-gas ceased). The excess of thionyl chloride was removed under reduced pressure, the residue was dissolved in DCM and the product was precipitated by addition of hexane to give a white solid. Yield: 24.10 g (99%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:18])=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-])=O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[C:5]([OH:18])=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(c1ccccc1)c1cccc([N+](=O)[O-])c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc(C(=O)c2ccccc2)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A mixture of 3-nitro-2-hydroxybenzophenone (600 mg, 2.5 mmol) and tin (II) chloride (1.7 g, 7.5 mmol) in ethanol (50 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product (490 mg, 92%). 1H NMR (CD3OD): δ7.65-7.40 (m, 5H), 6.98 (d,1H), 6.86 (d, 1H), 6.67 (t, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:45]=[CH:44][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:19]2=[O:43])=[CH:15][CH:14]=1.C(O)(=O)C>O>[CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:43])=[CH:44][CH:45]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cncnc21
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cncnc21

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 0.24 g of 5-{4-(3-methylimidazo[5,4-d]pyrimidin-2-ylmethoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 51) and 8 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and ethanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 30 mg of the title compound, melting at 245-246° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[Cl:21][CH2:22][CH2:23][C:24](OCC)=[O:25]>C1COCC1>[Cl:21][CH2:22][CH2:23][C:24](=[O:25])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CCCl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisoproply amine (20 mmol, 2.02 g, 3.05 ml) in dry THF (20 ml) at -78° C. was added n-butyllithium (20 mmol), 7.7 ml; 2.6M solution in hexanes. After stirring for 30 minutes, t-butyl acetate (22 mmol, 2.56 g) was added dropwise and the resulting mixture was stirred for 15 minutes. A solution of the lithium enolate of t-butyl acetate was subsequently added by cannula to a solution of ethyl 3-chloropropanoate (10 mmol, 1.37 g) in THF (25 ml) at -78° C. over 15 minutes. After stirring for an additional 15 minutes, the reaction was quenched by addition of glacial acetic acid (10 ml). After heating to room temperature, the reaction mixture was diluted with water (50 ml) and extracted with ether (150 ml). The ethereal extract was washed with 20% aqueous K2CO3 (2×100 ml), the organic phase was dried (MgSO4) and then concentrated in vacuo. Purification of the resulting liquid by gradient flash chromatography (SiO2, 1) 5% Et2O/pentane, 2) 15% Et2O/pentane) afforded t-butyl 5-chloro-3-oxopentanoate as a clear, colorless oil (4.08 g, 99%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:26]([C:23]4[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=4)(=[O:28])=[O:27])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: Nc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC4(CC3)OCCO4)cc2)cc1

Procedure:
The title compound was prepared from 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine (which was obtained in Example 214) and 4-methoxybenzenesulfonyl chloride according to the procedure of Example 215 as a crystalline solid; 1H NMR (300 MHz, DMSO-d6) δ 1.65 (t, J=5.6 Hz, 4H), 3.15 (t, J=5.6 Hz, 4H), 3.79 (s, 3H), 3.88 (s, 4H), 6.79 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 7.02 (d, J=9.0Hz, 2H), 7.60 (d, J=9.0Hz, 2H), 9.63 (s, 1H); MS (ES) m/z: 405.3 (MH+); HRMS Calcd. for C20H24N2O5S(M+): 404.1406. Found: 404.1402. Anal. Calcd. for C20H24N2O5S: C, 59.39; H, 5.98; N, 6.93. Found: C, 59.48; H, 6.03; N, 6.85.