Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]=O.[NH2:9][C:10]1[C:15]2=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=4[F:40])=[O:28])=[CH:22][CH:21]=3)[C:17]([CH3:19])=[CH:18][N:14]2[N:13]=[CH:12][N:11]=1>C(O)(=O)C>[NH2:9][C:10]1[C:15]2=[C:16]([C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][C:31]=4[F:40])=[O:28])=[CH:24][CH:25]=3)[C:17]([CH3:19])=[C:18]([CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:14]2[N:13]=[CH:12][N:11]=1
Reactant: C1COCCN1
Reactant: C=O
Reactant: Cc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Solvent: CC(=O)O
Product: Cc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1CN1CCOCC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 0.2 %

Procedure:
A mixture of morpholine (35 mg, 41 mmol) and 100 uL acetic acid were sonicated until homogeneous, then treated with 37% aqueous formaldehyde (30 uL, 33 mg, 41 mmol) and the mixture added to a solution of N-[4-(4-amino-6-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea (150 mg, 34 mmol) in 1 mL acetic acid. This mixture was stirred for 16 h at 60° C. and then concentrated in vacuo. The residue was dissolved in methanol with 5 drops of trifluoroacetic acid and purified by RP-HPLC to provide the title compound as a white solid (32.3 mg, 17.1% yield). 1H-NMR (DMSO-d6) δ 9.34 (d, J=9.6 Hz, 1H), 8.94 (bs, 1H), 8.62 (d, J=7.2 Hz, 1H), 7.92 (s, 1H), 7.85 (s, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.47 to 7.53 (m, m1H), 7.33 to 7.41 (m, 1H), 7.31 (d, J=8.7 Hz, 2H), 3.80 (s, 2H), 3.48 to 3.55 (m, 4H), 2.34 to 2.44 (m, 4H); MS [M+H]+=544.1; LCMS RT=2.70.
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH:13](/B(O)O)=[CH:14]\[CH2:15][CH2:16][CH2:17][CH3:18]>C(O)C>[O:10]1[CH2:11][CH2:12][N:7]([CH:3](/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][CH3:18])[C:2]([OH:6])=[O:5])[CH2:8][CH2:9]1
Reactant: C1COCCN1
Reactant: CCCC/C=C/B(O)O
Reactant: O=CC(=O)O
Solvent: CCO
Solvent: O
Product: CCCC/C=C/C(C(=O)O)N1CCOCC1
Temperature: 50 °C
Yield: 95 %

Procedure:
To a stirred solution of glyoxylic acid monohydrate (80 mg, 0.87 mmol) in ethanol (6 mL) was added morpholine (76 mg, 0.87 mmol) in one portion. After 5 min (E)-1-hexenyl boronic acid (121 mg, 0.82 mmol) was added. The reaction mixture was heated at 50° C. for 36 hours, after which time precipitate was isolated by filtration, washed with cold ethanol (10 mL) and dried under vacuum to give (E)-2-morpholino-3-octenoic acid (177 mg,78% yield). 1H-NMR (360 MHz, d6-DMSO) δ 5.65 (dt, J=16.1 Hz, 7.0 Hz, 1H), 5.28 (dd, J=16.1 Hz, 9.1 Hz, 1H), 4.81 (d, J=9.1 Hz, 1H), 2.50 (m, 2H), 1.1 (m, 4H), 0.7 (t, J=7.1 Hz, 3H). 13C-NMR (90 MHz, d6-DMSO) δ 171.1, 136.7, 127.4, 68.8, 62.5, 56.7, 31.7, 30.2, 22.1, 13.9. HRMS-CI (M++1) Calcd for C12H21NO3: 228.1521, Found: 228.1513.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH2:19][F:20])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:21][N:22](COCC[Si](C)(C)C)[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)=[C:11]2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O.N>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH2:19][F:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:32])=[O:33])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(CF)ccc32)c1NC1CCN(S(C)(=O)=O)CC1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(CF)ccc23)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 30 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 87 mg of [5-(2,6-difluorophenyl)-7-(fluoromethyl)-N-[1-(methylsulphonyl)piperidin-4-yl]-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-amine in 7 ml of DCM. After cooling to 0° C. using an ice bath, 0.85 ml of TFA is added and the mixture is stirred at RT for 3 h. The mixture is concentrated under RP and the solid obtained is taken up in 24 ml of water and 1.1 ml of 0.75M aqueous ammonia solution. It is extracted with ethyl acetate, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/MeOH mixture (95/05 by vol.). This gives 27 mg of [5-(2,6-difluorophenyl)-7-(fluoromethyl)-N-[1-(methylsulphonyl)piperidin-4-yl]-1H-pyrazolo[4,3-c]isoquinolin-3-amine (yellow solid). 1H NMR; 1.67 (m, 2 H) 2.11 (m, 2 H) 2.87 (s, 3 H) 2.90 (m, 2 H) 3.56 (m, 2 H) 3.80 (broad m, 1 H) 5.58 (d, J=47.2 Hz, 2 H) 6.05 (broad d, J=8.0 Hz, 1 H) 7.33 (t, J=77 Hz, 2 H) 7.57-7.73 (m, 2 H) 7.95 (broad d, J=8.3 Hz, 1 H) 8.45 (d, J=8.3 Hz, 1 H) 12.81 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.O[N:15]1[C:19]2[CH:20]=CC=[CH:23][C:18]=2[N:17]=N1.Cl.CN(C)CCCN=C=NCC.CN(C)C=[O:39]>>[NH2:17][C@@H:18]1[CH2:23][O:39][CH2:20][C@@H:19]1[NH:15][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13]
Reactant: On1nnc2ccccc21
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: N[C@@H]1COC[C@@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of the compound obtained in Referential Example 171 (0.5 g) in N,N-dimethylformamide (10 mL) were sequentially added 5-chloroindole-2-carboxylic acid (0.29 g), 1-hydroxybenzotriazole (0.2 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g) at room temperature, followed by stirring at 50° C. for 1 day. The reaction mixture was concentrated, and the residue was diluted with a solvent mixture comprising chloroform and methanol (9:1). The diluted mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, and the organic layer was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=95:5), to thereby give the title compound (0.2 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:7]2Cl)(=[O:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:30]1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>C(O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:30])=[O:19])[CH:8]=[C:7]2[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCCc1c(O)c(C(C)=O)cc2c(Nc3ccccc3)cc(C(=O)OCC)nc12

Procedure:
Methyl 6-acetyl-4-chloro-7-hydroxy-8-propyl-quinoline-2-carboxylate (1.5 g) was treated with aniline (20 ml) at 175° C. in an autoclave in the presence of p-toluene sulphonic acid (0.1 g) for 72 hours. On cooling the aniline was removed and the residue was heated on a steambath for 12 hours with 70% sulphuric acid. The reaction mixture was poured onto crushed ice and neutralised with ammonia solution to pH 7. Extraction with ethyl acetate followed by drying and evaporation afforded a gum which was taken up in dry ethanol and saturated with hydrogen chloride gas while refluxing for 1 hour. Evaporation of the solvent and trituration with ether afforded the sub-title compound (0.37 g) identified by NMR and mass spectroscopy.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:17][NH2:18])[CH:14]=[CH:15][CH:16]=1>>[OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:18][CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=1)=[O:6]
Reactant: CC(C)(CO)C(=O)O
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNC(=O)C(C)(C)CO)c1

Procedure:
Prepared as in Example 24a from 3-hydroxy-2,2-dimethylpropanoic acid and (3-methoxyphenyl)methanamine as an orange oil (41%). MS 238 (MH+).
Reaction SMILES: [O:1]=[C:2](Cl)[O:3][C:4](Cl)(Cl)Cl.[NH2:9][C@@H:10]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)CO.CCN(CC)CC.C>C1COCC1>[CH:13]1([C@H:10]2[CH2:4][O:3][C:2](=[O:1])[NH:9]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: N[C@H](CO)C1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1N[C@@H](C2CCCCC2)CO1
Temperature: 50 °C
Yield: 87.9 %

Procedure:
Diphosgene (0.704 mL, 6.05 mmol) was added dropwise to a stirred suspension of (S)-2-amino-2-cyclohexylethanol (1.02 g, 7.12 mmol), Et3N (6.95 mL, 49.9 mmol) and activated charcoal (40 mg) in THF (20 mL) at 0° C. under N2. The reaction mixture was heated at 50° C. overnight. After cooling, the suspension was filtered through Celite. To the filtrate was added sat. aq. NaHCO3 solution. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by silica gel flash column chromatography (1:1 hexane/EtOAc) to give (S)-4-cyclohexyloxazolidin-2-one (0.900 g, 75%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[F:21][C:22]1[CH:39]=[CH:38][C:25]2[CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[O:28][C:24]=2[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[F:21][C:22]1[CH:39]=[CH:38][C:25]2[CH:26]=[C:27]([C:2]3[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=4)[N:3]=3)[O:28][C:24]=2[CH:23]=1
Reactant: CC1(C)OB(c2cc3ccc(F)cc3o2)OC1(C)C
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cc4ccc(F)cc4o3)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 0.67 h
Yield: 41.1 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (100 mg, 0.34 mmol) in dioxane (2 mL) was added 2-(6-fluoro-1-benzofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (600 mg, crude), Pd(PPh3)4 (20 mg, 0.02 mmol), K3PO4 (140 mg, 0.66 mmol) under nitrogen atmosphere. After stirring 40 min at 95° C., the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 2% ethyl acetate in petroleum ether to afford methyl 2-(6-fluoro-1-benzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a light yellow solid (55 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9].[CH:29]1([NH2:32])[CH2:31][CH2:30]1.COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC(C)(C)C(NC)=O>>[CH:29]1([NH:32][C:8](=[O:9])[C:7]([CH3:11])([CH3:12])[CH2:6][O:5][C:4]2[C:13]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH2:22][C:23]4=[O:28])=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:3]=2[O:2][CH3:1])[CH2:31][CH2:30]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)(C)C(=O)O)c1OC
Reactant: NC1CC1
Agent: CNC(=O)C(C)(C)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)(C)C(=O)NC2CC2)c1OC

Procedure:
From 3-[2,3-Dimethoxy-6-(1-oxo-indan-4-yl)-phenoxy]-2,2-dimethyl-propionic acid (Compound 199) and cyclopropylamine following the procedure for the preparation of Compound 200. Purification by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) afforded the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH2:13][CH2:14][C:15]23[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]4)[CH2:16]2)[CH2:22]3)=[C:11](C(O)=O)[N:10]=[C:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:35]=[C:36]=[O:37].[CH2:38]([OH:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:1]([O:5][C:6]([N:8]1[C:12]([CH2:13][CH2:14][C:15]23[CH2:22][CH:21]4[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]4)[CH2:16]2)[CH2:24]3)=[C:11]([NH:35][C:36]([O:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:37])[N:10]=[C:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1-c1nc(C(=O)O)c(CCC23CC4CC(CC(C4)C2)C3)n1C(=O)OC(C)(C)C
Reactant: [N-]=C=O
Reactant: OCc1ccccc1
Product: Cc1ccccc1-c1nc(NC(=O)OCc2ccccc2)c(CCC23CC4CC(CC(C4)C2)C3)n1C(=O)OC(C)(C)C

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-o-tolyl-imidazole-1,4-dicarboxylic acid 1-tert-butyl ester (Example 75, step c) was converted to the isocyanate and reacted with benzyl alcohol according to the procedure of Example 75, step d using benzyl alcohol in place of 3-amino-benzoic acid benzyl ester. The crude reaction mixture was purified by flash column chromatography (silica, hexane/ethyl acetate 3:2) to give the product. 1H NMR (300 MHz, CDCl3) 7.39-7.19 (9H, m), 6.10 (1H, br s), 5.20 (2H, s), 2.79 (2H, m), 2.18 (3H, s), 1.96 (3H, s), 1.68 (6H, m), 1.50 (6H, s), 1.31 (2H, m), 1.19 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](F)(F)F.[Al+3].[Cl-:13].[Cl-:14].[Cl-].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])([Cl:14])[Cl:13])=[CH:19][CH:18]=1
Reactant: [Cl-]
Reactant: FC(F)(F)c1ccccc1Cl
Reactant: Fc1ccccc1
Agent: [Al+3]
Product: Fc1ccc(C(Cl)(Cl)c2ccccc2Cl)cc1

Procedure:
From 2-chlorobenzotrifluoride (180 mg, 1 mmol), AlCl3 (400 mg, 3 mmol) and fluorobenzene (96 mg, 1 mmol), light yellow oil (380 mg, 131% crude).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:14][CH:13]([NH:15][C:16]3[N:21]=[CH:20][C:19]([C:22]([CH3:24])=[CH2:23])=[CH:18][N:17]=3)[CH2:12]2)[C:3]1=[O:25]>C(O)C.C(OCC)(=O)C.[Pd]>[CH:22]([C:19]1[CH:18]=[N:17][C:16]([NH:15][C@H:13]2[CH2:14][C@H:11]([N:4]3[C:5]4=[N:6][CH:7]=[CH:8][CH:9]=[C:10]4[C:2]([CH3:1])([CH3:26])[C:3]3=[O:25])[CH2:12]2)=[N:21][CH:20]=1)([CH3:24])[CH3:23]
Reactant: C=C(C)c1cnc(NC2CC(N3C(=O)C(C)(C)c4cccnc43)C2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)c1cnc(N[C@H]2C[C@H](N3C(=O)C(C)(C)c4cccnc43)C2)nc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Palladium (10 wt. % on activated carbon, 3.53 mg, 3.32 μmol) was added to a mixture of 3,3-dimethyl-1-(−3-((5-(prop-1-en-2-yl)pyrimidin-2-yl)amino)cyclobutyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (example 80, 58 mg, 0.166 mmol) in ethanol (1 mL) and ethyl acetate (0.5 mL) under an argon atmosphere. The reaction mixture was placed under a hydrogen atmosphere (balloon) and stirred at room temperature for 6 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated to yield 1-(trans-3-((5-isopropylpyrimidin-2-yl)amino)cyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one as a yellow solid. M+1: 352.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.85 Hz, 6 H) 1.31 (s, 6 H) 2.23-2.39 (m, 2 H) 2.76 (spt, J=6.94 Hz, 1 H) 3.14-3.26 (m, 2 H) 4.47-4.59 (m, 1 H) 5.16 (quin, J=8.51 Hz, 1 H) 7.08 (dd, J=7.24, 5.28 Hz, 1 H) 7.53 (br. d, J=6.50 Hz, 1 H) 7.76 (dd, J=7.24, 1.57 Hz, 1 H) 8.21 (dd, J=5.28, 1.56 Hz, 1 H) 8.24 (s, 2 H)
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([O:12]CC)=[O:11])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[C:17](=[O:35])[CH:18]=[CH:19][C:20]1C=C(C(C)(C)C)[C:23](O)=[C:22]([C:31](C)(C)C)[CH:21]=1.CC1C=CC(C=[S:42])=CC=1>>[OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[C:17](=[O:35])[CH:18]=[CH:19][C:20]1[S:42][CH:23]=[C:22]([CH3:31])[CH:21]=1
Reactant: Cc1ccc(C=S)cc1
Reactant: CCOC(=O)c1c(C)c(C)c(C(=O)C=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(O)c1OC
Product: COc1c(O)c(C(=O)C=Cc2cc(C)cs2)c(C)c(C)c1C(=O)O

Procedure:
This compound was synthesized from 2′-hydroxy-4′-ethyloxycarbonyldimethylmethyloxyacetophenone (starting material 1) and 4-methylthiobenzaldehyde according to general method 2 described earlier.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([O:28][CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[NH:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[CH3:27].C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:44]2[CH2:45][CH2:46][CH:41]([NH:40][C:32]3[N:31]([CH2:30][CH2:29][O:28][CH2:26][CH3:27])[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=3)[CH2:42][CH2:43]2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 1-(t-butoxycarbonyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (25 mmol), (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (30 mmol), and N,N-diisopropylethylamine (18 mL, 101 mmol) in acetonitrile (300 mL). Heat to reflux. After 18 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel to give 1-(t-butoxycarbonyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine.
Reaction SMILES: I[C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O>>[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7]([NH:6][O:5][CH2:4][C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=2[C:28]2[S:27][CH:31]=[CH:30][CH:29]=2)=[O:22])=[CH:17][CH:18]=1
Reactant: OB(O)c1cccs1
Reactant: O=C(NOCc1ccccc1I)c1ccccc1NCc1ccncc1
Product: O=C(NOCc1ccccc1-c1cccs1)c1ccccc1NCc1ccncc1

Procedure:
Prepared by a similar procedure as described for preparation of example 363. Starting materials: N-(2-Iodo-benzyloxy)-2-[(pyridin-4-ylmethyl)amino]-benzamide (see example 360) and thiophene-2-boronic acid (Aldrich).
Reaction SMILES: [S:1]1[C:5]([CH:6]=[CH:7][C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.O1CCCC1.C1([Li])C=CC=CC=1.[Br:29][CH2:30][CH2:31][CH2:32]Br>C1CCCCC1>[S:1]1[C:5]([CH:6]=[CH:7][C:8]2[S:9][C:10]([CH2:32][CH2:31][CH2:30][Br:29])=[CH:11][CH:12]=2)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2
Reactant: C(=Cc1cc2ccccc2s1)c1cccs1
Reactant: BrCCCBr
Agent: [Li]c1ccccc1
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: BrCCCc1ccc(C=Cc2cc3ccccc3s2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
To a stirred, chilled (-65° C.) solution of 2-[2-(benzo[b]thiophen-2-yl)-ethenyl]thiophene (8.1 g) and tetrahydrofuran (100 ml) was added over 15 mins phenyl lithium (18 ml of a 2.0M solution in cyclohexane). The mixture was stirred for 1 hr, and 1,3-dibromopropane (40.5 g) was added. The solution was allowed to warm to room temperature, and was refluxed overnight. The reaction mixture was quenched with methanol (30 ml) and water (100 ml). The organic phase was evaporated in vacuo, and the residue was extracted with dichloromethane. The combined, dried over anhydrous sodium sulfate organic phase was concentrated. The residue was purified by high pressure liquid chromatography (silica gel, eluted with 7:1 hexane: dichloromethane). The appropriate fractions were combined and evaporated to yield 2.15 g (18%) of product, mp 109°-111° C.
Reaction SMILES: [C:1]1([S:7]([CH2:9][Cl:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[F:21][C:22]([F:35])([F:34])[S:23]([O:26]S(C(F)(F)F)(=O)=O)(=[O:25])=[O:24]>C(OCC)C>[O-:26][S:23]([C:22]([F:35])([F:34])[F:21])(=[O:25])=[O:24].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S+:7]([CH2:9][Cl:10])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=S(CCl)c1ccccc1
Reactant: CC(C)(C)c1ccccc1
Solvent: CCOCC
Product: CC(C)(C)c1ccc([S+](CCl)c2ccccc2)cc1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C

Procedure:
Chloromethyl phenyl sulfoxide (200 mg, 1.29 mmol) of example 21 was dissolved in dry diethyl ether (7.5 mL) under an argon atmosphere. tert-Butyl benzene (0.191 g, 1.1 eq) was added to the previous solution and then the mixture was cooled to a temperature below −60° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.217 mL, 1 eq) was added slowly maintaining the same temperature. The mixture was stirred until the reaction was complete. The orange precipitated triflate salt was quickly filtered at −60° C. affording 0.487 g as red viscous oil after heating at room temperature, which was a mixture by proton NMR.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([O-:9])=[O:8])=[CH:3][CH:2]=1.[Na+].[CH2:12](N(CC)CC)C.O>CP(OC)(=O)OC>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([CH3:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: CCN(CC)CC
Agent: COP(C)(=O)OC
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(C)(=O)=O)cc1
Temperature: 171 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A suspension of 22.7 g of sodium p-toluenesulphinate in 50 ml of dimethyl methanephosphonate is treated with 12.6 g of triethylamine and the mixture is heated in the course of 45 minutes to 167° C. The temperature is raised further to 171° C. and kept thereat for a further 30 minutes. The cooled solution is poured into 700 ml of water and stired for 1 hour. The precipitated crystalline product is collected by filtration and washed with 350 ml of water. The residue is dried at 25 torr and 50° C., affording 17.2 g (80.9% of theory) of p-tolylmethylsulphone of the formula ##STR14## with a melting point of 85°-96° C. and a purity of 95.8%.