Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.CO[C:19]1C=CC(C(C2C=CC(OC)=CC=2)=O)=C[CH:20]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)([OH:7])[C:19]#[CH:20])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Product: C#CC(O)(c1ccc(C)cc1)c1ccc(C)cc1

Procedure:
The procedure of Step 1 of Example 1 was followed except that 4,4'-dimethylbenzophenone was used n place of 4,4'-dimethoxybenzophenone to produce 1,1-bis(4-methylphenyl)-2-propyn-1-ol.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:10]([CH3:49])=[C:11]([NH:15][C:16]([C:18]2[C:26]3[N:25]=[C:24]([NH:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[NH:23][C:22]=3[CH:21]=[C:20]([NH:36][C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]([F:48])([F:47])[F:46])=[O:38])[CH:19]=2)=[O:17])[CH:12]=[CH:13][CH:14]=1>C(Cl)Cl>[Cl:8][C:9]1[C:10]([CH3:49])=[C:11]([NH:15][C:16]([C:18]2[C:26]3[N:25]=[C:24]([NH:27][CH2:28][C:29]([OH:31])=[O:30])[NH:23][C:22]=3[CH:21]=[C:20]([NH:36][C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]([F:46])([F:47])[F:48])=[O:38])[CH:19]=2)=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(NCC(=O)OC(C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(NCC(=O)O)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl N-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoro methyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}glycinate (95 mg) in methylene chloride (2 mL), and the mixture was stirred for 1 hour at room temperature, and concentrated. The residue was neutralized with 1N aqueous NaOH under ice-cooling and extracted with EtOAc. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified on column chromatography to obtain N-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoro methyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}glycine (50 mg) as white powder. N-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoro methyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}glycine (16 mg) was suspended in MeOH. To the suspension was added 2N hydrogen chloride/EtOH solution (1 Eq) to obtain a homogeneous solution. The solvent was removed under reduced pressure. The residue was triturated in diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (12 mg) as white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:19]([CH3:20])=[N:9][C:3]=2[CH:4]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Product: Cc1nc2cc(Br)ccc2n1-c1ccccc1
Yield: 60.6 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 2,5-Dibromonitrobenzene (140 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as a yellow solid (87 mg, 61%). 1H NMR (DMSO) δ 2.52 (s, 3 H), 7.18 (d, J=8.8 Hz, 1 H), 7.43 (d, J=8.8 Hz, 1 H), 7.58-7.68 (m, 5 H), 7.98 (br s, 1 H); 13C NMR δ 13.5, 112.5, 115.5, 119.5, 126.4, 126.9, 129.6, 130.1, 134.0, 139.0, 154.2, 156.8.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[N:21]([CH3:46])[C:22]4[C:27]([N:28]=3)=[C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:25]=[C:24]([N:35]3[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]=[C:36]3[CH2:44][CH3:45])[N:23]=4)[CH2:15][CH2:14]2)=[O:12])[CH2:10][CH2:9]1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1([C:11]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][C:20]3[N:21]([CH3:46])[C:22]4[C:27]([N:28]=3)=[C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:25]=[C:24]([N:35]3[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]=[C:36]3[CH2:44][CH3:45])[N:23]=4)[CH2:17][CH2:18]2)=[O:12])[CH2:9][CH2:10]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)C4(NC(=O)OC(C)(C)C)CC4)CC3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)C4(N)CC4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
A mixture of (1-{4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]piperazine-1-carbonyl}cyclopropyl)carbamic acid tert-butyl ester (0.123 g, 0.19 mmol) in DCM/TFA (5 mL/5 mL) was stirred for 4 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The eluent was concnentrated in vacuo and the residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 10:90) to give 432 as a white solid (0.066 g, 64%). LCMS (Method I): RT=2.47 min, [M+H]+ 462.3. 1H NMR (400 MHz, DMSO-d): δ 8.04-8.00 (m, 1 H); 7.66-7.61 (m, 1 H); 7.28-7.21 (m, 2 H); 4.18-4.22 (m, 4 H); 3.85 (s, 3 H); 3.82 (s, 2 H); 3.78 (t, J=4.6 Hz, 4 H); 3.58-3.53 (m, 4 H); 3.27 (q, J=7.4 Hz, 2 H); 2.55-2.45 (m, 4 H); 1.34 (t, J=7.4 Hz, 3 H); 0.92-0.87 (m, 2 H); 0.82-0.75 (m, 2 H)
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:23][CH3:24])=[CH:6][C:7]2[O:12][C:11](=[O:13])[C:10]([CH2:14][CH2:15]OS(C)(=O)=O)=[C:9]([CH3:21])[C:8]=2[CH:22]=1)[CH3:2].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)(C)C>[CH2:1]([O:3][C:4]1[C:5]([O:23][CH3:24])=[CH:6][C:7]2[O:12][C:11](=[O:13])[C:10]([CH2:14][CH2:15][N:34]3[CH2:35][CH2:36][N:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:32][CH2:33]3)=[C:9]([CH3:21])[C:8]=2[CH:22]=1)[CH3:2]
Reactant: CCOc1cc2c(C)c(CCOS(C)(=O)=O)c(=O)oc2cc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CC(C)O
Product: CCOc1cc2c(C)c(CCN3CCN(c4ccccc4)CC3)c(=O)oc2cc1OC
Yield: 70 %

Procedure:
Process B; starting materials: 6-ethoxy-3-[2-(methanesulphonyloxy)ethyl]-7-methoxy-4-methyl -2H-1-benzopyran-2-one (Example 29) and 1-phenylpiperazine; yield 70%; m.p. 164°-165° C. (from isopropanol).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([CH:15]=[O:16])=[C:12]([CH2:17][CH3:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][OH:16])=[C:12]([CH2:17][CH3:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1CO
Yield: 94 %

Procedure:
To a solution of 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethylthiophene-2-carboxaldehyde that was obtained in Example 10 (10b) (1.5 g, 5.8 mmol) in methanol (10 mL) were slowly added sodium borohydride (0.22 g, 5.8 mmol) at 0° C. with stirring, and the resulting mixture was stirred for 30 minutes. After stirring, the solvent was evaporated in vacuo. Subsequently, a solution of the residue obtained in ether was poured into water (20 mL) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:4 to 3:7) as the eluent to afford the pure title compound (1.4 g) in a yield of 94% as a colourless oily product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C([O-])([O-])=O.[K+].[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
N-(tert-butoxycarbonyl)-isonipecotic acid (5.73 g, 25 mmol), as prepared in the preceding step, was dissolved in tetrahydrofuran (50 mL) and cooled to 0° C. (ice-bath). Borane-tetrahydrofuran complex (1M, 25 mL, 25 mmol) was added slowly over 30 min. The reaction mixture was stirred at 0° C. overnight and then warmed up to room temperature for 6 h. Water (10 mL) was added slowly and then K2CO3 (5 g in 50 mL water) was added. The reaction mixture was extracted into ethyl acetate (3×50 mL). The organic phase was washed with saturated NaHCO3 (2×50 mL), brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (1:1 hexane:ethyl acetate) to give the title compound as white crystals (4.55 g, 84%). 1H-NMR (300 MHz, CDCl3) δ 1.13 (m, 2H), 1.42 (s, 9H), 1.67 (m, 4H), 2.67 (t, 2H), 3.46 (d, 2H), 4.09 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O)(=O)C.[N:21]([O-])=[O:22].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:16])[C:12](=[N:21][OH:22])[C:13](=[O:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=N[O-]
Reactant: COc1ccc(C(=O)CC(C)=O)cc1OC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)C(=NO)C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 g of 1-(3,4-dimethoxyphenyl)butane-1,3-dione (41) were initially introduced into 25 ml of acetic acid, and 1.71 g of sodium nitrite, dissolved in 5 ml of water, were then added dropwise at 15° C. The reaction solution was stirred at RT for 1 h and then remained standing for 2 h. 50 g of ice were added to the solution and the whole was then stored at 0° C. for 12 h, in connection with which the product precipitated out. The product was subsequently filtered off with suction and dried at 50° C. in a drying oven. The following was obtained: 42 C12H13NO5 (251.24); MS (ESI) 252 (M+H)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13](=[O:26])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[H][H]>C1(C)C=CC=CC=1>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH:13]([OH:26])[CH2:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1)([O:24][CH3:25])=[O:23]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C=CC(=O)C=Cc2ccc(C(=O)OC)cc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCC(O)CCc2ccc(C(=O)OC)cc2)cc1
Temperature: 180 °C
Yield: 79.7 %

Procedure:
A mixture of 175 g (0.50 moles) of 1,5-bis-(4'-carbomethoxyphenyl)1,4-pentadien-3-one, 1.75 g copperchromite, and 1750 mL of toluene were placed in a stainless steel autoclave. The autoclave was pressurized to 250 psi with hydrogen and then heated to 180° C. Upon reaching the desired temperature the pressure was adjusted to 1000 psig with hydrogen. The temperature and pressure were maintained at these levels for 5 h. The autoclave was then cooled and vented. The mixture was removed from the autoclave and transferred to a 2 L Erlenmeyer flask where the mixture was heated to >90° C. and then filtered through a steam jacketed Buchner funnel using a pad of Celite Filter-Aid to assist in catalyst removal. The solution was allowed to cool to room temperature and was filtered to give 142.1 g of 1,5-bis-(4'-carbomethoxyphenyl)-3-pentanol as a fluffy, white crystalline product. The volume of the mother liquor was reduced in vacuo to a level of 500-600 mL, heated to dissolve any solids, and crystallized to give an additional 13.9 g. Reducing the volume to 250 mL yielded an additional 5.2 g. All three batches of crystals were indistinguishable by chromatography and were combined to give a total of 161.2 g (0.453 moles, 91% yield) of 1,5-bis-(4'-carbomethoxyphenyl)-3-pentanol. 270 MHz 1H NMR (CDCl3) δ=1.81 (t,4H), 2.77 (m,4H), 3.61 (m,1H), 3.88 (s,6H), 7.21 (d,4H), 7.91 (d,4H). IR (KBr): 1720, 1290 cm1 ; (mull) 3460 cm1. FDMS (M+/e): 356. Elemental Analysis: Calc. for C21H24O5 : C,70.77; H,6.79. Found: C,71.09; H,6.68. m.p. 129°-130° C.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12.[CH2:18]([OH:21])[C:19]#[CH:20]>C(NCC)C.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.[Cu]I>[OH:21][CH2:18][C:19]#[C:20][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12
Reactant: C#CCO
Reactant: CN1Cc2c(I)ncn2-c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#CCO)ncn2-c2ccccc2C1=O

Procedure:
3.90 g (11.5 mmol) of 4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 5 hours with 0.67 g (12 mmol) of propargyl alcohol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The solvent was then evaporated, the residue was taken up in methylene chloride, the solid was filtered off and rinsed with ethyl acetate. After drying there was obtained 4,5-dihydro-3-(3-hydroxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 240°-241°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.N1C=CN=C1.[CH3:27][O:28][C:29](=[O:37])[CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35]O>C(Cl)Cl>[CH3:27][O:28][C:29](=[O:37])[CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][Br:20]
Reactant: COC(=O)COCCCCO
Reactant: BrBr
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)COCCCCBr
Reaction time: 1 h
Yield: 50.4 %

Procedure:
Triphenylphosphine (5.59 g, 21.3 mmol), bromine (1.1 mL, 21.5 mmol) and imidazole (1.41 g, 20.7 mmol) were sequentially added to a solution of (4-hydroxy-butoxy)-acetic acid methyl ester (2.88 g, 17.8 mmol) in CH2Cl2 (15 mL) at 0° C. under nitrogen. After 1 h, the mixture was filtered through basic alumina, rinsing with 5% EtOAc/Hexane (40 mL). The filtrate was concentrated and the residue was purified by flash column chromatography (0%→20% EtOAc/Hexane) to afford 2.02 g (51%) of (4-bromo-butoxy)-acetic acid methyl ester as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[CH:13]=2)[CH:8]=[CH:7]1.[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]Cl)([O-:25])=[O:24]>C(OCC)C>[F:22][C:20]1[CH:19]=[C:4]([CH:3]=[C:2]([F:1])[CH:21]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[CH:13]=2)[C:8]([S:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N+:23]([O-:25])=[O:24])=[CH:7]1
Reactant: O=[N+]([O-])c1ccccc1SCl
Reactant: CC(=O)Nc1ccc2ccn(Cc3cc(F)cc(F)c3)c2c1
Solvent: CCOCC
Product: CC(=O)Nc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of N-[1-(3,5-Difluoro-benzyl)-1H-indol-6-yl]-acetamide (23.3 mg, 0.08 mmol) in diethyl ether (4 mL) was added 2-nitrobenzenesulfenyl chloride (14.7 mg, 0.09 mmol). The resulting yellow solution was stirred overnight at room temperature. The mixture was concentrated in vacuo and purified over a SiO2 column (heptane/ethyl acetate 9:1) to give the title compound as a yellow solid (35.0 mg, yield=96%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7](Cl)=[O:8])=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH:21]=[CH:22][C:23]#[N:24])(=[O:20])=[O:19])=[CH:14][CH:13]=1.N12CCN(CC1)CC2>CC(C)=O>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([S:7]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH:21]=[CH:22][C:23]#[N:24])(=[O:20])=[O:19])=[CH:16][CH:17]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)Nc2ccc(S(=O)(=O)C=CC#N)cc2)cc1
Reaction time: 0.33 h

Procedure:
17.5 g p-toluenesulfinyl chloride (obtained by treating sodium toluenesulfinate.2H2O with thionyl chloride) is dissolved in 100 ml of acetone and this solution is added at room temperature and with stirring to a solution of 20.8 g (0.1 mol) of 2-cyanovinyl 4-aminophenyl sulfone in 250 ml of acetone. Shortly thereafter a solution of 11.2 g (0.1 mol) of 1,4-diazabicyclo[2.2.2]octane in 150 ml of acetone is added over about 10 minutes and the reaction mixture is stirred for another 20 minutes. The reaction mixture is filtered, evaporated in air to about a third of its volume, and then poured into cold water. The precipitate is filtered, washed and dried to give 3-[4-(4-methylbenzenesulfinamido)benzenesulfonyl]acrylonitrile: ##SPC45##
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:12][C:13](O)([CH3:15])[CH3:14].CCN=C=NCCCN(C)C.O>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[C:1]([C:4]1[S:8][C:7]([C:9]([O:11][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)s1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)c1ccc(C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
A solution of 5-acetylthiophene-2-carboxylic acid (7 g, 41 mmol) in DMA (100 mL) was treated with 2-methyl-2-propanol (54 mL, 576 mmol), DMAP (3 g, 25 mmol), and EDCI (9.9 g, 51.5 mmol). The resulting mixture was stirred at 25° C. for 16 h. Water (200 mL) was added and the mixture was extracted with ethyl ether (350 mL). The organic phase was washed with 1 N HCl (100 mL), water (3×100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL); dried (Na2SO4); filtered; and evaporated to afford 6.7 g (72%) of the title compound as a tan solid. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.53 (s, 9H) 2.58 (s, 3H) 7.75 (d, J=3.68 Hz, 1H) 7.92 (d, J=3.68 Hz, 1H); MS (DCI) 227 m/z (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].Cl.[Cl:24][C:25]1[CH:41]=[CH:40][C:28]2[CH2:29][O:30][C:31](=[O:39])[N:32]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:27]=2[CH:26]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:24][C:25]1[CH:41]=[CH:40][C:28]2[CH2:29][O:30][C:31](=[O:39])[N:32]([CH:33]3[CH2:34][CH2:35][N:36]([C:2]4[CH:7]=[CH:6][C:5]([C:8]([C:10]5[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=5[C:12]([O:14][CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=4[N+:20]([O-:22])=[O:21])[CH2:37][CH2:38]3)[C:27]=2[CH:26]=1
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C1OCc2ccc(Cl)cc2N1C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1C(=O)c1ccc(N2CCC(N3C(=O)OCc4ccc(Cl)cc43)CC2)c([N+](=O)[O-])c1

Procedure:
Methyl 2-[(4-chloro-3-nitrophenyl)carbonyl]benzoate (0.5 g), the product from step (ii) (0.47 g) and triethylamine (0.5 ml) in N,N-dimethylformamide (2.5 ml) were heated at 60° C. overnight. The mixture was evaporated under reduced pressure and the residue purified by chromatography eluting with 25% ethyl acetate/toluene. Yield 0.7 g of a solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11]1[CH:28]=[CH:27][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:26])[CH2:24][NH2:25])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1.C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[C:1]([NH:25][CH2:24][C:23]([NH:22][CH:19]1[CH2:18][CH2:17][N:16]([CH2:15][C:14]2[CH:13]=[CH:12][CH:11]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)=[O:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(=O)NC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1ccccc1)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of benzoyl chloride (0.060 mmol) in chloroform (0.4 mL) was added to a solution of 1-(4-chlorobenzyl)-4-(glycylamino)piperidine (0.050 mmol) and triethylamine (0.070 mmol) in chloroform (1.0 mL). After the reaction mixture was agitated at room temperature for 2.5 h, (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was added and the mixture was agitated at room temperature for 12 h. The reaction mixture was filtered and the resin was washed with dichloromethane (0.5 mL). The filtrate and washing were combined, dichloromethane (4 mL) was added, and the solution was washed with 2 N aqueous NaOH solution (0.5 mL) to give 4-(N-benzoylglycyl)amino-1-benzylpiperidine (compound No. 386) (11.3 mg, 64%): The purity was determined by RPLC/MS (94%); ESI/MS m/e 352.0 (M++H, C21H25N3O2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]1[CH2:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH:11]2[CH:10]([CH:27]3[CH2:26][CH:25]2[CH:24]=[CH:23]3)[CH:9]1[C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(=O)C=CC1C(C)(C)O[SiH2]C(C)(C)C
Reactant: C1=CCC=C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(=O)C2C3C=CC(C3)C2C1C(C)(C)O[SiH2]C(C)(C)C
Yield: 67 %

Procedure:
2-(tert-Butyl-dimethyl-silanyloxymethyl)-5-oxo-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (27) (4 g; 12.2 mmol) and freshly distilled cyclopentadiene (8 mL; 12 eq.) were heated in a sealed tube in toluene for 6 h at 110° C. Concentration and purification by flash chromatography (10% EtOAc/90% hexanes) afforded 3.23 g (67%) of the desired product 28. 1H NMR (CDCl3) □ 6.1 (bs, 1H), 6.0 (bs, 1H), 3.8 (dd, 1H), 3.6 (d, 1H), 3.5 (s, 1H), 3.3 (s, 1H), 3.1 (dd, 1H), 2.9 (s, 1H), 2.6 (bs, 1H), 1.6 (d, 2H), 1.5 (s, 9H), 1.3 (d, 1H), 0.9 (s, 9H), 0.15 (s, 3H), 0.1 (s, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:36][C:35]=1[C:46]1[N:51]=[CH:50][N:49]=[C:48]([NH:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([CH3:60])[CH:55]=2)[CH:47]=1>ClCCl.CN(C)C1C=CN=CC=1>[N:40]1([C:37]2[CH:38]=[CH:39][C:34]([NH:33][C:14]([C:13]3[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=3)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])=[O:16])=[C:35]([C:46]3[CH:47]=[C:48]([NH:52][CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[C:56]([CH3:60])[CH:55]=4)[N:49]=[CH:50][N:51]=3)[CH:36]=2)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3N)ncn2)c1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (143 mg, 0.48 mmol, 1.00 equiv) in dichloromethane (10 mL), EDC.HCl (139 mg, 0.72 mmol, 1.50 equiv), 4-dimethylaminopyridine (89 mg, 0.69 mmol, 1.50 equiv), and 6-(2-amino-5-(piperidin-1-yl)phenyl)-N-(3-methylbenzyl) pyrimidin-4-amine (180 mg, 0.48 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (5:1). This resulted in 200 mg (57%) of product as yellow oil.