Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.C([Sn](=O)CCCC)CCC.[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)#[N:19].C(OCC)(=O)C>C1(C)C=CC=CC=1>[NH:5]1[C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)=[N:19][N:7]=[N:6]1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2nnn[nH]2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Trimethylsilyl azide (25 g) and dibutyltin oxide (8.8 g) were added to a solution of 4-cyanobenzaldehyde (13 g) in toluene (200 ml). The reaction was stirred with warming to 50° C. over 1 hr, and then warmed to 96° C. over 30 minutes and maintained at that temperature for 3 hours. The solvent was evaporated in vacuo to afford an orange oil which was purified by column chromatography over silica gel (ethyl acetate). The crude product was dissolved in refluxing toluene and allowed to cool with stirring overnight. The resulting slurry was granulated in an ice-bath for 1 hour, filtered and washed with cold toluene. The filtrate was evaporated in vacuo to afford a solid. The solid was dissolved in refluxing ethyl acetate (250 ml) and concentrated to 60 ml by rotary evaporation. The solution was cooled to room temperature and then granulated in an ice bath. The thick slurry was collected by filtration, washed and dried, with warming, in a vacuum oven to afford the title compound, 12 g.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[CH:11]([NH2:34])[C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[C:14]([O:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:13]=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:35](Cl)(=[O:37])[CH3:36].C(N(CC)CC)C>ClCCl>[CH:1]1([NH:7][C:8]([C:10]2[CH:11]([NH:34][C:35](=[O:37])[CH3:36])[C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[C:14]([O:25][CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[CH:13]=3)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1C(C(=O)NC2CCCCC2)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1C(C(=O)NC2CCCCC2)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Temperature: 0 °C
Reaction time: 24 h
Yield: 19.9 %

Procedure:
1-Amino-6-(2-morpholine-4-yl-ethoxy)-3-phenyl-1H-indene-2-carboxylic acid cyclohexylamide (14 mg, 0.03 mmol) prepared in Example 22 was dissolved in dichloromethane (10 mL), acetyl chloride (24 mg, 0.3 mmol) and triethylamine (30 mg, 0.3 mmol) were added thereto in order at 0° C., and stirred for 24 hrs at RT. The resulting mixture washed with saturated saline and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 3 mg of the titled compound (yield: 20%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:29])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[N:17]1[C:21]([CH2:22]O)=[C:20]([CH3:24])[N:19]=[C:18]1[CH2:25][N:26]([CH3:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]1(=[O:59])[NH:53][C:52](=[O:54])[C:51]2=[CH:55][CH:56]=[CH:57][CH:58]=[C:50]12.N(C(OCC)=O)=NC(OCC)=O>>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([N:17]2[C:21]([CH2:22][N:53]3[C:49](=[O:59])[C:50]4=[CH:58][CH:57]=[CH:56][CH:55]=[C:51]4[C:52]3=[O:54])=[C:20]([CH3:24])[N:19]=[C:18]2[CH2:25][N:26]([CH3:28])[CH3:27])=[C:10]([C:9](=[O:29])[C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2c(F)cccc2F)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2c(F)cccc2F)c1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 3, 2',6'-difluoro-5-chloro-2-[2-[(dimethylamino)methyl]-4-methyl-5-hydroxymethylimidazol-1-yl]benzophenone, triphenylphosphine, phthalimide and thereafter diethyl azodicarboxylate are reacted together to give N-[[1-[4-chloro-2-(2,6-difluorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[C:9]3[OH:17])[CH2:3][CH2:2]1.Br[CH2:19][CH2:20][O:21]C(=O)C.IC>>[CH:1]1([C:4]2[N:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[C:9]3[O:17][CH2:19][CH2:20][OH:21])[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(O)c2ccnc(C3CC3)c2n1
Reactant: CC(=O)OCCBr
Solvent: CI
Product: O=C(O)c1cc(OCCO)c2ccnc(C3CC3)c2n1

Procedure:
The intended compound was produced according to the procedures described in reference examples 35 and 36 but using 8-cyclopropyl-4-hydroxy-[1,7]naphthyridine-2-carboxylic acid and acetic acid 2-bromoethyl ester in place of 1-Cyclopropyl-5-hydroxy-isoquinoline-7-carboxylic acid methyl ester and iodomethane.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]>O>[CH2:1]([OH:23])[C@H:2]1[O:7][CH:6]([OH:8])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[OH2:7]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Product: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
29 parts of liquid saccharose and 49 parts of water were mixed at 60° C. 0.2 parts of stabiliser formed by carrageenans and xanthan gum and 3.5 parts of glucose syrup were then added. 15.5 parts of apple puree, colouring agent and finally 2.1 parts of citric acid were then added thereto. After pasteurisation of the mixture at 86° C. for 23 seconds, the composition was cooled to 4° C. and left to rest for 4 hours at this temperature. It was brought to 100 parts by the addition of cola aroma.
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[C:26]([O:30][C:31]([C:33]1[CH:44]=[C:43]([OH:45])[C:36]2[CH2:37][C:38]([CH2:41][OH:42])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].[N:46]1([C:50]([C:52]2[CH:57]=[CH:56][C:55](F)=[CH:54][C:53]=2[F:59])=[O:51])[CH2:49][CH2:48][CH2:47]1>>[C:26]([O:30][C:31]([C:33]1[CH:44]=[C:43]([O:45][C:55]2[CH:56]=[CH:57][C:52]([C:50]([N:46]3[CH2:49][CH2:48][CH2:47]3)=[O:51])=[C:53]([F:59])[CH:54]=2)[C:36]2[CH2:37][C:38]([CH2:41][OH:42])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:27])([CH3:28])[CH3:29]
Reactant: O=C(c1ccc(F)cc1F)N1CCC1
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(C)(CO)C2
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)c(F)c2)c2c(c1)OC(C)(CO)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227c) and azetidin-1-yl-(2,4-difluoro-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 7.48-7.56 (m, 1 H) 7.24 (s, 1 H) 7.20 (d, J=1.26 Hz, 1 H) 6.77 (dd, J=8.59, 2.53 Hz, 1 H) 6.66 (dd, J=11.24, 2.40 Hz, 1 H) 4.21 (t, J=7.83 Hz, 2 H) 4.11-4.17 (m, 2 H) 3.65-3.74 (m, 1 H) 3.55-3.63 (m, 1 H) 3.13 (d, J=16.67 Hz, 1 H) 2.76 (d, J=16.67 Hz, 1 H) 2.34 (dt, J=15.60, 7.74 Hz, 2 H) 1.89-1.97 (m, 1 H) 1.56 (s, 9 H) 1.44 (s, 3 H); LCMS for C25H28FNO6 m/z 458.20 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Br:16]Br.O>FC(F)(F)C(O)=O.ClCCl>[Br:16][C:7]1[C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[C:9]([S:11][C:12]([F:15])([F:13])[F:14])[CH:8]=1
Reactant: BrBr
Reactant: Nc1ccc(SC(F)(F)F)cc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Nc1c(Br)cc(SC(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
24 g of finely pulverulent 2-nitro-4-trifluoromethylmercaptoaniline were dissolved in 50 ml of tri-fluoroacetic acid, and 18 g of bromine were metered in at 20° C. Stirring was then continued for 3 hours at 20° C. and for a further 30 minutes at 40° C. The mixture poured into water and the product taken up in dichloromethane. After the solvent had been removed, 31 g of 6-bromo-2-nitro-4-trifluoromethylmercaptoaniline were obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=O.S(O)(O)(=O)=O.[NH2:16][OH:17].[OH-].[NH4+]>O>[CH3:1][C:2]([NH:16][OH:17])=[C:4]1[CH:5]=[CH:6][C:7](=[O:10])[CH:8]=[CH:9]1
Reactant: NO
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(NO)=C1C=CC(=O)C=C1
Yield: 173.7 %

Procedure:
A solution was prepared by adding 20.4 g (0.15 mol) of 4-hydroxyacetophenone and 13.0 g (0.08 mol) of hydroxylamine sulfate to 100 mL of water at 70° C. To the solution was added 16.3 mL of 30% ammonium hydroxide which was then heated at reflux for 0.5 h. White crystals formed upon cooling yielding 21.0 g (92.6%) of 4-hydroxyacetophenone oxime.
Reaction SMILES: C(OC(=O)/C=C/C1([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:36][CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:25][CH2:26][C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][CH:28]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])C=CNC1)(C)(C)C.[C:47]([OH:53])([C:49](F)(F)F)=[O:48]>ClCCl>[C:42]([Si:39]([CH3:40])([CH3:41])[O:38][CH2:37][CH2:36][N:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([N:29]2[CH:30]=[CH:35][C:27](/[CH:26]=[CH:49]/[C:47]([OH:53])=[O:48])=[CH:28]2)(=[O:16])=[O:15])=[CH:22][CH:21]=1)[CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)([CH3:44])([CH3:43])[CH3:45]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)/C=C/C1(S(=O)(=O)c2ccc(CN(CCO[Si](C)(C)C(C)(C)C)CCc3c[nH]c4ccccc34)cc2)C=CNC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Reaction time: 26 h

Procedure:
(E)-3-{3-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylic acid tert-butyl ester (compound D5) is dissolved in dichloromethane (50 ml). Then it is added TFA and the mixture is stirred for 26 hours. After evaporation, the residue is washed with toluene.
Reaction SMILES: CC1(C)[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][NH:14][C:15]=3[CH3:16])[S:10][C:5]=2[C:4](=[O:17])[NH:3]1.Cl>CO>[NH2:7][C:6]1[CH:8]=[C:9]([C:11]2[CH:12]=[N:13][NH:14][C:15]=2[CH3:16])[S:10][C:5]=1[C:4]([NH2:3])=[O:17]
Reactant: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(C)N2
Agent: Cl
Solvent: CO
Product: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Yield: 71.9 %

Procedure:
A mixture of 2,2-dimethyl-6-(5-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (1.97 g, 7.51 mmol), 1 M aqueous HCl. (38 mL) and MeOH (38 mL) was stirred at 50° C. for 4 h. After removal of the solvent at reduced pressure, the organic materials were extracted with EtOAc/THF. The combined extracts were dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, EtOAc to 90:10 EtOAc/MeOH) to give the title compound (1.20 g, 72%) as a green solid:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([CH2:19][OH:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([CH:19]=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
To a solution of (2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)methanol (E13, 26 mg) in chloroform (2 mL), manganese dioxide (41 mg) was added at room temperature, and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was cooled to room temperature, then the insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 70 to 40% hexane in ethyl acetate) to obtain 2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidine-5-carbaldehyde (E14, 26 mg).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([F:19])=[C:12]([CH2:20][OH:21])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[NH:1]([C:8]1[N:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]2[N:11]=[C:12]([CH:20]=[O:21])[C:13]([F:19])=[CH:14][C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(CO)c(F)cc12
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1nc2c(cc1F)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 70 °C
Yield: 15.1 %

Procedure:
2-anilino-6-fluoro-7-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.277 mmol) was dissolved in 4.5 mL CHCl3. MnO2(311 mg, 3.05 mmol) was added and the reaction was heated to 70° C. under argon for 3 d. The reaction mixture was filtered through celite and concentrated in vacuo. Purification by silica gel flash chromatography eluting with 3:1 to 100:0 EtOAc:Hex provided 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carbaldehyde (15 mg, 15%) as a white solid: LCMS RT: 2.18 min, MW: 360.2.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16]([NH:18][CH3:19])=[O:17].[F:20][CH:21]([CH3:25])[C:22](O)=[O:23].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[F:20][CH:21]([CH3:25])[C:22]([NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16]([NH:18][CH3:19])=[O:17])=[O:23]
Reactant: CC(F)C(=O)O
Reactant: CNC(=O)c1[nH]c2ccc(OC)cc2c1CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNC(=O)c1[nH]c2ccc(OC)cc2c1CCNC(=O)C(C)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-aminoethyl)-5-methoxy-N-methyl-1H-indole-2-carboxamide hydrochloride (90.0 mg) and acetonitrile (5.00 mL) were added 2-fluoropropionic acid (0.0495 mL), diisopropylethylamine (0.272 mL), and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (181 mg), followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:0 to 10:1). The obtained residue was solidified with a mixed solvent of hexane:ethyl acetate=2:1 to obtain 3-{2-[(2-fluoropropanoyl)amino]ethyl}-5-methoxy-N-methyl-1H-indole-2-carboxamide (70.0 mg) as a white solid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[O:20][CH2:21][C:22](O)=[O:23]>>[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[O:20][CH2:21][C:22]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:23]
Reactant: O=C(O)COc1nc2ccccc2s1
Reactant: c1ccc2c(c1)CCCN2
Product: O=C(COc1nc2ccccc2s1)N1CCCc2ccccc21
Yield: 28 %

Procedure:
Compound 62 was synthesized according to General Procedure B using compound 3 and compound 61 to yield 62 (183 mg, 28%): MS (APCI): m/z 325 [M+H]+. Anal. Calcd. for C18H16N2O2S: C, 66.64; H, 4.97; N, 8.64. Found: C, 66.88; H, 4.94; N, 8.60.
Reaction SMILES: C[C:2]([O-:5])(C)C.[K+].[F:7][C:8]([F:20])([F:19])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[Li]CCCC.C=O.Cl>C1COCC1>[F:7][C:8]([F:19])([F:20])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:10]=1[CH2:2][OH:5]
Reactant: CC(C)(C)[O-]
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: OCc1c(C(F)(F)F)cccc1C(F)(F)F
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
A mixture of 80 mL of THF and t-BuOK (7.0 g, 62.5 mmol) is added to a 250 mL four-neck flask equipped with a mechanical stirrer, a thermometer, a gas inlet tube and a 100 mL dropping funnel with a gas outlet tube. Cool down to −70° C. and 2,6-bis(trifluoromethyl)benzene (8.0 mL, 10.7 g, 50.0 mmol) is added dropwise and keep agitating ˜−70° C. for 30 min. Add n-BuLi (0.10 mol, 2.87 M in hexanes 35.0 mL, 100.0 mmol) dropwise over 30 min with agitation at ˜−70° C. for 60 min. Paraformaldehyde (6.0 g, 0.20 mol) is added and keep agitating ˜70° C. for 30 min, then gradually warm to room temperature for 3 h. Pour mixture into conc HCl (10 mL) and ice water (300 mL), and stir for 1 h. Extract with hexanes (3×50 mL). Wash the combined organic layers with 50 mL of brine, dry over anhydrous Na2SO4, filter and concentrate. The crude product is vacuum distilled (72-76° C. at 4-5 mm Hg) to give the desired compound (5 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C@@:21]([NH:30]C(OC(C)(C)C)=O)([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])[CH3:22])=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].Cl>O1CCOCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C@@:21]([NH2:30])([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])[CH3:22])=[CH:20][C:13]=3[N:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc([C@@](C)(NC(=O)OC(C)(C)C)C(=O)N3CCCC3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc([C@@](C)(N)C(=O)N3CCCC3)ccc21

Procedure:
Prepared analogously to Example 6i from (R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-tert.butyloxycarbonylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and 6N hydrochloric acid in dioxane.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:21](COCC[Si](C)(C)C)[C:20]4[C:19](=[O:30])[N:18]([CH2:31][CH2:32][CH3:33])[C:17](=[O:34])[N:16]([CH2:35][CH2:36][CH3:37])[C:15]=4[N:14]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][N:3]1[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=1.Cl>C(O)C>[O:1]=[C:2]1[CH:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[NH:21][C:20]4[C:19](=[O:30])[N:18]([CH2:31][CH2:32][CH3:33])[C:17](=[O:34])[N:16]([CH2:35][CH2:36][CH3:37])[C:15]=4[N:14]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][N:3]1[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=1
Reactant: CCCn1c(=O)c2c(nc(-c3cnn(CC4CCN(c5cccc(C(F)(F)F)c5)C4=O)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: Cl
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC4CCN(c5cccc(C(F)(F)F)c5)C4=O)c3)nc2n(CCC)c1=O
Temperature: 85 °C
Yield: 83.3 %

Procedure:
A mixture of 8-{1-[2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione obtained in step 5 (0.1 g, 0.148 mmol), 2 N HCl (3 ml), ethanol (2 ml) was heated at 85° C. for 3 hours. The mixture was cooled to 10-15° C. The solid obtained was filtered and washed with water, diethyl ether to obtain the title compound as a white solid (0.067 g, 83%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](Cl)=[O:22]>CN(C)C=O.CN(C)C1C=CN=CC=1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([C:21]([C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)=[O:22])[C:7]1=[O:15]
Reactant: O=C1Cc2ccccc2N1c1nccs1
Reactant: O=C(Cl)c1ccco1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: O=C(c1ccco1)C1C(=O)N(c2nccs2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 64 %

Procedure:
To a solution of 1-(2-thiazolyl)-2-oxindole (0.6 g, 2.7 mM) in dimethylformamide (8 ml) at 0° C. was added 4-dimethylaminopyridine (0.847 g, 2.2 eq.) and the mixture stirred for 5 minutes. Then, a solution of 2-furoyl chloride (0.31 ml, 3.04 mM, 1.1 eq.) in dimethylformamide (2 ml) was added dropwise and the mixture stirred for 15 minutes at 0° C. and then at room temperature for 2 hours. The reaction was poured onto about 100 ml of ice/2N HCl, and the resulting yellow precipitate recovered by filtration, washed with water and air-dried. Recrystallization from toluene-hexane (1:1) afforded 0.585 g (64%) of title product as yellow needles; m.p. 156°-157° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:19]([O:21]C(=O)C)[CH3:20].O>CN(C=O)C>[O:21]=[C:19]1[NH:10][C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=2[O:1][CH2:20]1
Reactant: CCOC(C)=O
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
24 mmol of 4-Hydroxy-3-nitrobenzonitrile were dissolved in DMF. 1.1 eq of Cs2CO3 were added and the reaction stirred at rt for 15 min. 1.5 eq of ethylbromo acetate were added and the reaction mixture heated to 50° C. for 2 h. The intermediate was isolated via extraction from ethylacetate/water. The organic layer was separated and dried over Na2SO4. After evaporation the resulting solid was redissolved in MeOH and sat. NH4Cl (1:1). 8 g of Zn powder were added and the suspension stirred at rt for 2 h. The solid was filtered off and the organic layer evaporated. Ethylacetate was added and the organic layer washed with sat. NaHCO3. The organic layer was separated again, dried over Na2SO4 and reduced resulting in a light brown solid. MS(ISO): 175.2 (MH+)
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH3:17])=[C:6]([CH:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([CH3:3])[CH3:2].[OH-].[K+].O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Zn+2:33]>CO>[CH:1]([C:4]1[C:5]([O:16][CH3:17])=[C:6]([CH:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=1)[C:7]([O-:9])=[O:8])([CH3:3])[CH3:2].[Zn+2:33].[CH:1]([C:4]1[C:5]([O:16][CH3:17])=[C:6]([CH:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=1)[C:7]([O-:9])=[O:8])([CH3:3])[CH3:2]
Reactant: COc1c(C(=O)O)cc(C(C)C)cc1C(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C(=O)[O-])cc(C(C)C)cc1C(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Five parts of 3,5-diisopropyl-2-methoxybenzoic acid was dissolved in 80 parts of methyl alcohol, followed by the addition of an aqueous solution of 1.3 parts of 96% potassium hydroxide in 10 parts of water. The resulting mixture was heated to 60° C. An aqueous solution of 3.2 parts of zinc sulfate heptahydrate in 10 parts of water was dropped into the resulting mixture over a period of 15 minutes. After the completion of the dropping, the obtained mixture was stirred at that temperature for 2 hours, cooled to a room temperature and filtered to recover a white crystalline precipitate. This precipitate was dispersed in 60 parts of water, washed therewith and filtered. The obtained filter cake was dried to give 4.8 parts of a white crystal. The melting point thereof was 104 to 107° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[Br:31]NC(=O)CCC(N)=O>C1COCC1.C(OCC)(=O)C>[Br:31][CH2:14][C:13]([C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8][CH:9]=1)=[O:15]
Reactant: NC(=O)CCC(=O)NBr
Reactant: CC(=O)c1ccc(N2CCCCC2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(N2CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
4′-Piperidinoacetophenone (203 mg, 1.00 mmol) was dissolved in THF (5 mL) and treated with lithium bis(trimethylsilyl)amide (1.10 mL, 11.0M in THF, 1.10 mmol). The solution was stirred for 30 minutes prior to the addition of chlorotrimethylsilane (140 μL, 1.10 mmol). After stirring for an additional 30 minutes N-bromosuccinamide (300 mg, 1.73 mmol) was added and the mixture was refluxed from 4 hours. Standard aqueous/ethyl acetate workup provided a yellow solid which was further purified by silica gel chromatography, eluting with 3:1 hexane/ethyl acetate, to provide 2-bromo-4′-piperidinoacetophenone as an off white solid (209 mg, 74%). 1H NMR (200 MHz, CDCl3) δ 8.75 (d, 2H), 6.84 (d, 2H), 4.61 (s, 2H), 3.40 (m, 4H), 1.68 (m, 6H).