Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:18][OH:19])[CH:7]=[C:8]([O:15][CH2:16][CH3:17])[C:9]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH3:2]>C1(C)C=CC=CC=1.O=[Mn]=O>[CH2:16]([O:15][C:8]1[CH:7]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH:18]=[O:19])[CH3:17]
Reactant: CCOc1cc(CO)cc(OCC)c1-n1cccc1
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Yield: 89.1 %

Procedure:
To a solution of 3,5-diethoxy-4-pyrrol-1-yl-benzoic acid ethyl ester (1.51 g, 4.98 mmol, 1.0 equiv) in toluene (5 mL) was added slowly over a time period of 15 min under slight cooling to 20° C. a solution of diisobutylaluminium hydride (8.9 mL, 12.45 mmol, 2.5 equiv; 20% solution in toluene). After 1 h, the excess hydride was quenched by cautious addition of water (10 mL) and a 28% solution of NaOH (2 mL). The mixture was stirred for 30 min and the organic phase filtered over Hyflo Super Cel. The aqueous layer was extracted with toluene (2×50 mL), the combined organic phases washed with a sat. solution of NaCl (2×50 mL) and concentrated by evaporation under reduced pressure to afford 1.30 g (100%) of (3,5-diethoxy-4-pyrrol-1-yl-phenyl)-methanol. The crude alcohol (1.30 g, 4.98 mmol, 1.0 equiv) was dissolved in toluene (20 mL) and activated MnO2 (7.79 g, 89.5 mmol, 18.0 equiv) was added. The reaction mixture was heated to reflux for 7 h, after which time the reaction mixture was filtered through Hyflo Super Cel and concentrated yielding 1.15 g (89% yield) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.17 (t, J=7.0 Hz, 6H), 4.02 (q, J=7.0 Hz, 4H), 6.08-6.09 (m, 2H), 6.75-6.76 (m, 2H), 7.25 (s, 2H), 9.89 (s, 1H). MS (ISP): 260.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[C:8]([C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)=[CH:7][N:6]=1.Cl[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[NH:20]1[CH:21]=[CH:22][N:23]=[C:19]1[C:8]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[N:10][C:5]([NH:4][CH2:3][CH2:2][NH:1][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[N:6][CH:7]=1
Reactant: N#Cc1ccc(-c2nc(NCCN)ncc2-c2ncc[nH]2)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2nc(NCCNc3ccc(C(F)(F)F)cn3)ncc2-c2ncc[nH]2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 5 %

Procedure:
A mixture of 4-{2-[(2-aminoethyl)amino]-5-imidazolylpyrimidin-4-yl}benzenecarbonitrile (30 mg, 0.098 mmol), 2-chloro-5-(trifluoromethyl)pyridine (18 mg, 0.098 mmol), and Hünig's base (70 uL, 0.4 mmol) in DMA (500 uL) were heated to 80° C. After stirring for 12 hours, the reaction was diluted with ethyl acetate (10 ml) and extracted with sat. aq. NaHCO3 (2×5 ml), water (3×5 ml), brine (5 ml), dried with Na2SO4, filtered, and concentrated. The product was purified by preparative HPLC using a reverse phase column and a water/acetonitrile gradient. The product 4-{5-imidazolyl-2-[(2-{[5-(trifluoromethyl)(2-pyridyl)]amino}ethyl)amino]pyrimidin-4-yl}benzenecarbonitrile was obtained as a off-white solid in 5% yield.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[F:26][C:27]([F:39])([F:38])[S:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:36]([NH:35][C:32]4[CH:33]=[CH:34][C:29]([S:28][C:27]([F:38])([F:26])[F:39])=[CH:30][CH:31]=4)=[O:37])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: O=C=Nc1ccc(SC(F)(F)F)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(SC(F)(F)F)cc4)ccc3C2=O)C(=O)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
TEA (0.28 g, 2.8 mmol) was added to a mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) and 4-(trifluoromethylthio)phenyl isocyanate (0.31 g, 1.4 mmol) in acetonitrile (30 mL) at 0° C. The reaction was stirred at 0° C. for 2 h and then 4% aqueous HCl (30 mL) was added. The solid precipitate was filtered and dried in vacuo providing 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(4-trifluoromethylsulfanyl-phenyl)-urea as a white solid (0.34 g, 51% yield); mp 218-220° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 3.18 (97.19%); 1H NMR (DMSO-d6) δ 1.97-2.02 (m, 1H), 2.31-2.46 (m, 1H), 2.57-2.63 (m, 1H), 2.87-2.98 (m, 1H), 4.28-4.48 (m, 4H), 5.11 (dd, 1H, J=13.2 Hz, J=5.1 Hz), 6.92 (t, 1H, J=6.0 Hz), 7.45 (d, 1H, J=8.1 Hz), 7.52-7.64 (m, 5H), 7.70 (d, 1H, J=7.8 Hz), 9.08 (s, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.8, 47.1, 51.5, 113.0, 118.4, 121.9, 122.9, 126.9, 129.6 (q, J=306 Hz), 130.3, 137.3, 142.4, 143.6, 144.5, 154.8, 167.9, 171.0, 172.8; LCMS: MH=493; Anal. Calcd for C22H19F3N4O4S+0.2H2O: C, 53.27; H, 3.94; N, 11.29. Found: C, 53.06; H, 3.59; N, 11.12.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][OH:28])[CH2:22]2)[NH:12][C:11]([C:29]2[N:33]=[CH:32][NH:31][N:30]=2)=[N:10]1.[C:34](O)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][O:28][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:22]2)[NH:12][C:11]([C:29]2[N:33]=[CH:32][NH:31][N:30]=2)=[N:10]1
Reactant: CC(C)(C)C(=O)O
Reactant: CCOC(=O)C1=C(CN2CCO[C@@H](CO)C2)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCO[C@@H](COC(=O)C(C)(C)C)C2)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Yield: 42.9 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((R)-2-(hydroxymethyl)morpholino)methyl)-2-(1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (2 g, 3.8 mmol) was reacted with pivalic acid (0.51 g, 5 mmol) according to the procedure as described in Example 49 to give the title compound as yellow oil (0.99 g, 43%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:6]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:7]=2[S:8][CH:9]=1.[F:16][C:17]([F:35])([F:34])[C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(C#N)(C)=O.CCOCC>[F:16][C:17]([F:34])([F:35])[C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][O:14][C:11]3[CH:12]=[CH:13][C:6]4[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[CH:9][S:8][C:7]=4[CH:10]=3)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1csc2cc(O)ccc12
Reactant: FC(F)(F)c1ccc(COc2ccc(CCl)cc2)cc1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Product: O=C(O)Cc1csc2cc(OCc3ccc(OCc4ccc(C(F)(F)F)cc4)cc3)ccc12
Yield: 62 %

Procedure:
Compounds 5C, 5E and cesium carbonate in 10 mL AcCN stirred at 60° C. for 18 hours. The reaction was then cooled, diluted with Et2O and filtered through Celite®. The filtrate was collected and concentrated in vacuo. Recrystalisation from CHCl3/Hexanes gave 340 mg (62%) of the title compound. MS m/z 487 (M+1).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=O)[C:11](=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH2:22][C:23]([NH2:25])=[NH:24].C[O-].[Na+]>CO>[NH2:24][C:23]1[N:25]=[C:11]2[CH2:10][N:9]([CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:14][CH2:13][CH:12]2[C:15](=[O:17])[N:22]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC1=NC(=O)C2CCN(Cc3ccccc3)CC2=N1
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A suspension of ethyl N-benzyl-3-oxo-4-piperidine-carboxylate hydrochloride (2.98 g, 10 mmol) and guanidine hydrochloride (1.15 g, 12 mmol) in a solution of sodium methoxide in methanol (11.5 mL, 25% wt) was stirred at 100° C. in a sealed tube overnight before solvent was removed in vacuo. Residue was dissolved in water (10 mL) and was extracted by CHCl3 and i-PrOH (3:1, 5×80 mL), dried over sodium sulfate. Solvent was removed in vacuo, and the product was obtained as a light yellow powder (2.45 g).
Reaction SMILES: [F:1][CH:2]([F:24])[S:3][CH2:4][C@@H:5]1[CH2:9][C@@H:8](O)[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:56]([SH:64])(=[O:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>O1CCCC1>[C:56]([S:64][C@@H:8]1[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:5]([CH2:4][S:3][CH:2]([F:24])[F:1])[CH2:9]1)(=[O:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1CSC(F)F
Reactant: O=C(S)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(S[C@H]1C[C@@H](CSC(F)F)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1

Procedure:
To a solution of (2S,4R)-2-(difluoromethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.01 g) and triphenylphosphine (1.1 g) in tetrahydrofuran (20 ml) was added dropwise a solution of diethyl azodicarboxylate (0.66 ml) in tetrahydrofuran (3 ml) at -10° C. to -5° C. with stirring. The mixture was stirred at the same temperature for 30 minutes. To the solution was added thiobenzoic S-acid (0.49 ml) at the same temperature and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (60 ml). The solution was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of n-hexane and ethyl acetate (3:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-benzoylthio-2-(difluoromethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.01 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][N:8]=[CH:9][C:10](=[O:12])[CH3:11].[CH:13]([CH:15]=O)=[O:14]>O.CO.CCOC(C)=O>[OH:12][C:10]1[C:9]([C:13](=[O:14])[CH3:15])=[N:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:11]=1
Reactant: O=CC=O
Reactant: CC(=O)C=NNc1ccccn1
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)c1nn(-c2ccccn2)cc1O
Temperature: 25 °C
Yield: 2.6 %

Procedure:
A solution of 2-oxopropanal pyridin-2-ylhydrazone (6.12 g, 37.5 mmol) and glyoxal (16.3 g, 12.9 mL, 113 mmol) in water (50 mL) and methanol (10 mL) was heated at reflux overnight. The mixture was cooled to room temperature, diluted with EtOAc and sequentially washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The crude material was passed over a plug of silica gel, eluting with heptane/EtOAc (1:2, 300 mL) to afford 1-(4-hydroxy-1-pyridin-2-yl-1H-pyrazol-3-yl)ethanone (199 mg, 2.6%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:42]([OH:44])=O)=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[C:6]=1[CH3:7].C(Cl)(=O)C(Cl)=O.[CH2:51]([NH:55][C:56]1[CH:61]=[CH:60][C:59]([CH2:62][CH2:63][C:64]([O:66][CH3:67])=[O:65])=[CH:58][CH:57]=1)[CH2:52][CH2:53][CH3:54].C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C=O)C>[CH2:51]([N:55]([C:56]1[CH:57]=[CH:58][C:59]([CH2:62][CH2:63][C:64]([O:66][CH3:67])=[O:65])=[CH:60][CH:61]=1)[C:42]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:17])=[O:18])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[N:4]=1)=[O:44])[CH2:52][CH2:53][CH3:54]
Reactant: Cc1c(Cl)c(C(=O)O)nn1-c1ccc(C(=O)NS(=O)(=O)c2ccc3ccccc3c2)cc1C(=O)N1CCc2ccccc2C1
Reactant: CCCCNc1ccc(CCC(=O)OC)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl)c1ccc(CCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a solution of 4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxylic acid (116 mg, 0.18 mmol) in CH2Cl2 (1.0 mL) was added oxalyl chloride (48 μL, 0.55 mmol) followed by 1 drop of DMF. The resulting reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was dissolved in CH2Cl2 (1.0 mL), and methyl 3-(4-(butylamino)phenyl)propanoate (Intermediate 122A, 17 mg, 0.074 mmol) and i-Pr2EtN (32 μL, 0.18 mmol) were added. The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The crude oil was purified by preparative HPLC to give the title compound (30 mg, 57%). 1H NMR (CD3OD, 1:1 mixture of amide rotamers) δ 8.73 (s, 1H), 8.10 (d, J=9.0 Hz, 1H), 8.07-8.06 (m, 1H), 8.04-8.00 (m, 2H), 7.94-7.91 (m, 1H), 7.74-7.66 (m, 2H), 7.48 (br s, 1H), 7.39 (br s, 1H), 7.21-7.19 (m, 3.5H), 7.03 (br s, 1H), 6.98-6.96 (m, 0.5H), 6.90 (br s, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.43 (br s, 1H), 4.73 (br s, 1H), 4.44 (br s, 1H), 4.26 (br s, 1H), 4.10 (br s, 1H), 3.90 (br s, 1H), 3.60-3.56 (m, 3H), 3.48 (br s, 2H), 2.94 (br s, 1H), 2.79-2.71 (m, 2H), 2.54-2.46 (m, 2H), 2.12 (s, 3H), 1.43-1.24 (m, 4H), 0.89-0.83 (m, 3H); MS (ESI+) m/z 847.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[S:18](=[O:20])(=[O:19])[NH:17][C:16](=[O:21])[CH2:15]2)=[C:10]([OH:22])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:15][C:16](=[O:21])[NH:17][S:18]2(=[O:20])=[O:19])=[C:10]([O:22][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(c2ccc(Cc3ccccc3)cc2O)S(=O)(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN(c2ccc(Cc3ccccc3)cc2OC(=O)c2ccccc2)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-(4-benzyl-2-hydroxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (45 mg, 0.141 mmol) in DMF (0.2 mL) is added KOtBu (1.0 M in THF, 0.17 mL, 0.17 mmol). After it is stirred at ambient temperature for 5 min., benzoyl chloride (35 mg, 0.254 mmol) is added. After it is stirred at ambient temperature for 10 min., the reaction is quenched with 1N HCl solution. The residue is then purified by prep. HPLC using CH3CN (0.1% TFA)/water (5-70%) to give the title compound: MS (M−H)−=421.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=3[CH3:34])[C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl.N1C=CC=CC=1>[Si:17]([O:16][C@H:14]([CH3:15])[C@H:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:37])[CH3:36])=[CH:7][CH:6]=2)=[N:9][N:10]=1)[NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34])([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(N)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@@H](C)O[Si](C)(C)C(C)(C)C)o2)cc1
Yield: 100 %

Procedure:
To a solution of 4-((1R,2R)-1-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-3-methylbenzonitrile (intermediate 69d) (311 mg, 0.62 mmol) in CH2Cl2 (10 mL) and pyridine (1.5 mL) was added acetylchloride (62 μL, 0.87 mmol) at room temperature. The resultant solution stirred for 89 hours and quenched with 2N aq. HCl (15 mL). The mixture was further partitioned between H2O (40 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (35 mL). The combined organic extracts were washed with sat. aq. NaHCO3 (2×45 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a colourless oil (335 mg, 100%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.49 (s 1H), 7.93 (dm, J=8.8 Hz, 2H), 7.83 (dm, J=8.8 Hz, 2H), 7.50 (d, J=8.6 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 5.74 (d, J=9.0 Hz, 1H), 5.03 (dd, J=6.4, 9.0 Hz, 1H), 4.65 (pentet, J=6.4 Hz, 1H), 2.34 (s, 3H), 2.12 (s, 3H), 1.44 (d, J=6.1 Hz, 3H), 0.81 (s, 9H), 0.09 (s, 3H), −0.02 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:32]=O)[CH:27]=[N:28][C:29]=1[CH2:30][OH:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCl.CO>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:32][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[CH:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)[CH:27]=[N:28][C:29]=1[CH2:30][OH:31]
Reactant: O=Cc1cnc(CO)c(Cl)c1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cnc(CO)c(Cl)c4)CC3)c2c1
Reaction time: 3 h
Yield: 29.7 %

Procedure:
1-[2-(4-amino-1-piperidinyl)ethyl]-7-(methyloxy)-1,5-naphthyridin-2(1H)-one (Intermediate 29: 100 mg, 0.331 mmol) was dissolved in a mixture of Dichloromethane (DCM) (4 mL) and Methanol (0.444 mL). Aldehyde 5-chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde (Intermediate 39: 56.7 mg, 0.331 mmol) was added and the mixture was left at room temp. for 3 hours. Then sodium triacetoxy borohydride (210 mg, 0.992 mmol) was added and after 2 hours 2 more eq. of triacetoxy borohydride were added leaving the reaction under stirring overnight. LCMS overnight showed still imine remaining so 3 eq more of sodium triacetoxy borohydride were added and 2 eq more after 3 hours leaving the reaction overnight. Next morning 2 more eq. of sodium triacetoxy borohydride were added and after 3H reaction was stopped. Volatiles were removed under vacuum and the corresponding crude was diluted with DCM and washed with NaHCO3 several times. Organic layers were dried over Na2SO4, filtered and volatiles removed under vacuum. Corresponding crude was purified by flash master chromatography. Si II, 5 g. DCM/MeOH (0-30%), to obtain a solid which was left in the oven overnight to afford 45 mg of the final compound as a pale yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([O:13]CC)=O.[H-].[K+]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[O:13])[CH2:7][CH2:6][CH:5]1[CH2:4][CH2:3][CH2:2][NH:1][CH2:10]1
Reactant: CCOC(=O)c1ccc2ccccc2n1
Agent: [H-]
Agent: [K+]
Product: O=C(CCC1CCCNC1)c1ccc2ccccc2n1
Yield: 79.3 %

Procedure:
The operation is as in Example 1, starting from 14 g of ethyl quinoline-2-carboxylate, 17.4 g of ethyl 3-[3-(N-benzoyl)piperidyl]propionate and 36 ml of a 20% suspension of potassium hydride in oil. 7.4 g of 1-(2-quinolyl)-3-(3-piperidyl)-1-propanone are obtained, which is converted into its monohydrochloride. This monohydrochloride is recrystallized from ethanol. Its melting point, after recrystallization from ethanol, is 198° C.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH:10]([N:23]1[CH2:26][CH:25](O)[CH2:24]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH:10]([N:23]1[CH2:26][CH:25]([F:7])[CH2:24]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
DAST (26.46 g, 0.164 mol) was added to a solution of Compound 19-2 (13.1 g, 0.0547 mol) in dry DCM (200 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. The end of the reaction was monitored with TLC (petroleum ether/ethyl acetate=5:1). The reaction mixture was poured into ice water, extracted with DCM, washed with saturated brine, dried over anhydrous Na2SO4, and the organic layer was concentrated under reduced pressure, the resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate=150:1) to give Compound 19-3 (4.0 g, 30% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](O)[CH3:12]>>[CH2:11]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=1)[CH3:12]
Reactant: CCO
Reactant: Nc1ccc(C(=O)O)cc1
Product: CCOC(=O)c1ccc(N)cc1
Temperature: 25 °C

Procedure:
4-Aminobenzoic acid (5.0 g, 36.46 mmol) in 500 mL 3-neck round bottomed flask, fitted with a condenser, thermometer, addition funnel, stir bar, and nitrogen atmosphere, was dissolved in ethanol (100 mL). Next ethanol/HCl saturate (from bubbling concentrated HCl through ethanol) was added dropwise, by addition funnel. Then stirred at reflux for 1 h, cooled to room temperature, and stirred an additional 104 hours. Reaction mixture was then concentrated under reduced vacuum, and dissolved in ethyl acetate, and washed with water (2×50 mL), dried (K2CO3), filtered and concentrated under reduced vacuum, yielding 3.56 g of an off-white solid. This material was purified by silica gel chromatography, using a Waters HPLC Prep 2000, over one Prep-Pak, in a 1:1 hexanes:ethyl acetate solvent system, yielding the title compound as 2.35 g (39%) as a white solid.