Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][N:67]([CH2:70][CH2:71][O:72][Si:73]([C:76]([CH3:79])([CH3:78])[CH3:77])([CH3:75])[CH3:74])[C:66](=[O:80])[CH:65]=1>>[C:76]([Si:73]([CH3:74])([CH3:75])[O:72][CH2:71][CH2:70][N:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][C:66]1=[O:80])([CH3:77])([CH3:79])[CH3:78]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)cc1=O
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)c(=O)c2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.5 g, 0.86 mmol), was reacted with diisopropylethylamine (0.89 g, 6.9 mmol), diphenylphosphinic chloride (0.82 g, 3.5 mmol), then reacted with 4-amino-1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyridin-2-one (0.23 g, 0.86 mmol) at 60° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl}-amide as a off white foam (Yield 0.2 g, 32%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+:2]=[N-:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:37]([C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1)([O-:39])=[O:38].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.O>[N:1]([CH2:4][C@@H:5]1[C@@H:9]([O:10][C:44]([C:43]2[CH:42]=[CH:41][C:40]([N+:37]([O-:39])=[O:38])=[CH:48][CH:47]=2)=[O:45])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+:2]=[N-:3]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CN=[N+]=[N-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To a solution of the compound 3 (1.30 g) in tetrahydrofuran (25 mL), triphenylphosphine (3.10 g), 4-nitrobenzoic acid (2.24 g) and 2.2 mol/L of a solution (5.4 mL) of diethyl azodicarboxylate in toluene were added at 0° C. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was added water and extracted with ethyl acetate. The extract was washed with aqueous saturated sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→4:1) to obtain the title compound (1.22 g) having the following physical properties.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:41]=[C:35]5[CH2:36][N:37]([CH3:40])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:42])[N:27]([CH3:43])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:41]=[C:35]5[CH2:36][N:37]([CH3:40])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:42])[N:27]([CH3:43])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)cc2C1
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a solution of 128e (158 mg, 0.27 mmol) in methanol/dichloromethane (5/5 mL) was added NaBH4 (31 mg, 0.82 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was complete. The reaction was quenched with water (10 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 128 (95 mg, 60%) as a white solid. MS-ESI: [M+H]+ 585.3. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=5.0 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.00 (d, J=2.5 Hz, 1H), 7.58-7.54 (m, overlap, 4H), 7.44 (s, 1H), 5.70 (s, 1H), 4.52-4.39 (m, 2H), 4.10-4.09 (m, 3H), 3.70 (s, 3H), 3.59 (s, 2H), 2.88-2.86 (m, 2H), 2.47 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[CH2:29]([O:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[C:39]([N+:44]([O-:46])=[O:45])[CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.C(OCC)(=O)C>[CH2:29]([O:36][C:37]1[CH:43]=[CH:42][C:40]([NH:41][C:11](=[O:13])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])=[C:39]([N+:44]([O-:46])=[O:45])[CH:38]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-D,L-alanine (3.49 g, 18.4 mmol) and triethylamine (2.56 mL, 18.4 mmol) in THF (100 mL) was added 2-methylpropyl chlorocarbonate (2.39 mL, 18.4 mmol) under ice-cooling, and the mixture was stirred for 30 min. To this solution was added 4-(benzyloxy)-2-nitroaniline (3.00 g, 12.3 mmol), and the mixture was heated under reflux at 90° C. for 16 hr under a nitrogen atmosphere. After being allowed to cool to room temperature, the reaction mixture was diluted with ethyl acetate, and the mixture was washed with 0.5N hydrochloric acid, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. This solution was applied to basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure to give tert-butyl (2-{[4-(benzyloxy)-2-nitrophenyl]amino}-1-methyl-2-oxoethyl)carbamate (5.10 g) as a crude product. To a solution (66 mL) of the obtained oil (5.10 g, 12.3 mmol) in 90% aqueous acetic acid was slowly added zinc powder (8.03 g, 123 mmol) under ice-cooling, and the mixture was stirred for 30 min. The reaction mixture was filtered through celite, and the filtrate was stirred under heating at 70° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The obtained residue was diluted with ethyl acetate, and the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was applied to basic silica gel column chromatography (ethyl acetate), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate), and triturated with diisopropyl ether to give the title compound (663 mg, yield in 3 steps 15%).
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=2[F:15])[C:6](=[O:16])[N:5]([CH:17]2[CH2:19][CH2:18]2)[C:4](=[O:20])[CH:3]=1.[CH3:21][NH2:22]>CO>[CH:17]1([N:5]2[C:4](=[O:20])[CH:3]=[C:2]([NH:22][CH3:21])[N:7]([C:8]3[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=3[F:15])[C:6]2=[O:16])[CH2:19][CH2:18]1
Reactant: CN
Reactant: O=c1cc(Cl)n(-c2ccc(I)cc2F)c(=O)n1C1CC1
Solvent: CO
Product: CNc1cc(=O)n(C2CC2)c(=O)n1-c1ccc(I)cc1F

Procedure:
To a 1:2 mixture (62.9 g) of 6-chloro-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 50 and 6-chloro-1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 51 obtained in Step 3 were added methanol (189 ml) and a solution (126 ml) of 40% methylamine in methanol, and the mixture was stirred at room temperature for 2 hrs. The precipitated crystals were filtered off and the filtrate was concentrated under reduced pressure. The residue was extracted with chloroform (200 ml) and water (200 ml), and the organic layer was washed with brine (200 ml) and dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give a 2:1 mixture (34.55 g) of 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6-methylamino-1H-pyrimidine-2,4-dione 52 and 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-6-methylamino-1H-pyrimidine-2,4-dione 53 as yellow crystals, which were used for the next step without purification.
Reaction SMILES: C[N:2]1[C:8](=O)[O:7][C:5](=O)[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1>O1CCOCC1>[CH3:8][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([NH:22][CH2:21][CH2:20][CH2:19][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:7]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: NCCCn1ccnc1
Solvent: C1COCCO1
Product: CNc1ccccc1C(=O)NCCCn1ccnc1
Reaction time: 0.67 h
Yield: 69.8 %

Procedure:
N-Methylisatoic anhydride (17.7 g) was added in portions to a stirred solution of 3-imidazol-1-ylpropylamine (12.5 g) in dioxan (150 ml) over a period of 15 minutes. Stirring was continued for 40 minutes before the solution was evaporated in vacuo to give 2-methylamino-N-(3-imidazol-1-ylpropyl)benzamide (18.0 g), in the form of a buff coloured solid, m.p. 138°-141° C., after recrystallisation from isopropanol.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:29])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[O:14][C:15]([C:18]3[S:19][CH:20]=[C:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:22]=3[CH3:23])=[N:16][N:17]=2)=[CH:8][C:7]=1[CH3:28].[C:30](O)(=[O:33])[CH2:31][OH:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:33][CH2:30][C:31]([NH:1][CH2:2][CH:3]([OH:29])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[O:14][C:15]([C:18]3[S:19][CH:20]=[C:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:22]=3[CH3:23])=[N:16][N:17]=2)=[CH:8][C:7]=1[CH3:28])=[O:32]
Reactant: O=C(O)CO
Reactant: Cc1cc(-c2nnc(-c3scc(CC(C)C)c3C)o2)cc(C)c1OCC(O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nnc(-c3scc(CC(C)C)c3C)o2)cc(C)c1OCC(O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 1.7 %

Procedure:
To a solution of crude 1-amino-3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl phenoxy}-propan-2-ol (0.22 mmol) in DMF (1 mL) are added glycolic acid (25 mg), DIPEA (0.1 mL) and finally TBTU (60 mg). The mixture is stirred for 15 h at rt, evaporated and the residue purified by TLC (SiO2, EA) to give 2-hydroxy-N-(2-hydroxy-3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propyl)-acetamide (1.8 mg); LC-MS: tR=0.97 min, [M+1]+=474.26.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=1[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18].FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:37](=[O:52])[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([S:48]([CH3:51])(=[O:50])=[O:49])[CH:39]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=1[N:15]([CH2:16][C:17]([F:20])([F:18])[F:19])[C:37](=[O:52])[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:41]=[C:40]([S:48]([CH3:51])(=[O:50])=[O:49])[CH:39]=1
Reactant: Cc1cc(-c2ccccc2Cl)c(NCC(F)(F)F)cn1
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccccc2Cl)c(N(CC(F)(F)F)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(2-chlorophenyl)-6-methyl-N-(2,2,2-trifluoroethyl)pyridin-3-amine (0.066 g, 219 μmol) and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (66.1 mg, 230 μmol, example 223, intermediate d) in CH2Cl2 (1 mL) was added DIPEA (56.7 mg, 76.7 μL, 439 μmol) and the clear yellow solution was stirred at room temperature for 4 hours. Another batch of 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (66.1 mg, 230 μmol, example 223, intermediate d) and DIPEA (56.7 mg, 76.7 μL, 439 μmol) were added and stirring was continued for another 48 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (ISCO) system eluting with EtOAc (isocratic). The product was further purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Light brown solid (5%). MS (ESI): m/z=551.06 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:20][C:21]4[N:22]([C:24]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)=[C:25]([Br:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[Br:27][C:25]1[N:26]=[C:21]2[CH:20]=[C:19]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:11][CH2:10][CH2:9]4)=[CH:17][CH:16]=3)=[N:23][N:22]2[C:24]=1[C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nn4c(-c5ccc(F)cc5)c(Br)nc4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3nn4c(-c5ccc(F)cc5)c(Br)nc4cc3-c3ccccc3)cc2)CCC1

Procedure:
36 mg (0.06 mmol) (1-{4-[2-Bromo-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester in 2.7 mL 4M hydrogen chloride in dioxane were stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in methanol and given on a ForaPak Rxn CX column. The column was washed with 100 mL methanol and the product was eluted with methanol/NH3 yielding 29 mg (91.5%) of the title compound.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([C:9]2[N:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][CH:10]=2)[CH2:6]1)(=O)[CH2:2][CH3:3]>C1COCC1>[CH2:1]([N:5]1[CH2:8][CH:7]([C:9]2[N:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:28])([F:29])[F:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][CH:10]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCC(=O)N1CC(c2ccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cn2)C1
Solvent: C1CCOC1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cn2)C1
Yield: 60.2 %

Procedure:
Following the same procedure as described in Example 46.6, N-[6-(1-propionyl-azetidin-3-yl)-pyridin-3-yl]-4-trifluoromethoxy-benzenesulfonamide (130 mg, 0.30 mmol) in THF (15 ml) was treated with 1M BH3. THF (3 ml). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 95:5) provides the title compound (75 mg, 60%) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([CH3:16])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8].[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>C(O)(=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2[C:5]([CH3:16])=[C:4]([CH3:17])[S:3][C:2]=2[N:1]2[C:21](=[O:22])[C:20]3[C:19](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]2=[O:23])=[O:8])=[CH:10][CH:11]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1sc(N)c(C(=O)c2ccc(Cl)cc2)c1C
Solvent: CC(=O)O
Product: Cc1sc(N2C(=O)c3ccccc3C2=O)c(C(=O)c2ccc(Cl)cc2)c1C
Reaction time: 1 h

Procedure:
To a solution of (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (532 mg, 2 mmol; prepared as described in U.S. Pat. No. 6,323,214) in acetic acid (15 mL) is added phthalic anhydride (360 mg, 2.4 mmol) and the mixture is heated to reflux for 15 h. The solvent is evaporated in vacuo and the residual material is dissolved in ethyl acetate (20 mL). The organic solution is washed with a saturated aqueous solution of NaHCO3 (5 mL), water (5 mL), then brine (5 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude product is stirred for 1 h in petroleum ether (20 mL), then filtered, affording (2-[3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl]isoindoline-1,3-dione as a yellow powder. 1H NMR (CDCl3) δ: 2.10 (s, 3H), 2.43 (s, 3H), 7.24 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.78 (m, 4H).
Reaction SMILES: [CH2:1]1[C@@H:14]2[C@@:5]([C:15]([OH:17])=[O:16])([C:6]3[C:11]([CH2:12][CH2:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH:3]=[CH:2]1>CO.[Pd]>[CH2:1]1[C@@H:14]2[C@@:5]([C:15]([OH:17])=[O:16])([C:6]3[C:11]([CH2:12][CH2:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@]12CC=CC[C@H]1CCc1ccccc12
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@]12CCCC[C@H]1CCc1ccccc12
Yield: 87.9 %

Procedure:
A solution of the product from Example 4 (27.4 g, 0.120 mol) in methanol was hydrogenated over 5% palladium on carbon (2.5 g). The reaction mixture was concentrated to give the title compound (24.3 g, 88%) as a white solid mp 142°-144° C.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]([O:19][C:20]([N:22]1[CH:27]([C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH2:26][O:25][C@@H:24]([O:41][CH2:42][CH3:43])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCCC1.C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH:27]([C@@H:28]([OH:40])[C@@H:29]([NH:39][C:8](=[O:10])[CH3:9])[CH2:30][C:31]2[CH:32]=[C:33]([F:38])[CH:34]=[C:35]([F:37])[CH:36]=2)[CH2:26][O:25][C@@H:24]([O:41][CH2:42][CH3:43])[CH2:23]1)=[O:21])([CH3:17])([CH3:18])[CH3:16]
Reactant: CCO[C@H]1CN(C(=O)OC(C)(C)C)C([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCO[C@H]1CN(C(=O)OC(C)(C)C)C([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(C)=O)CO1
Reaction time: 4 h

Procedure:
Add triethylamine (0.030 g, 0.30 mmol) and acetic anhydride (0.024 g, 0.23 mmol) to (R)-5-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-ethoxymorpholine-4-carboxylic acid tert-butyl ester (0.095 g, 0.228 mmol) in tetrahydrofuran (4 mL) at room temperature. Stir 4 hours and dilute with ethyl acetate. Wash with water and saturated aqueous sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify on silica gel, eluting with 20:80 to 100% ethyl acetate:hexanes to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]1CC[CH2:18][CH2:17]1)=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2].C(N)C.C(O)C>O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[NH:16][CH2:17][CH3:18])=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCCC2)c2ccc(C)nc2n(CC)c1=O
Agent: CCN
Solvent: CCO
Solvent: O
Product: CCNc1c(C(=O)OCC)c(=O)n(CC)c2nc(C)ccc12

Procedure:
A stirred mixture of 5.88 g. (0.02 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (Example 30) and 2.6 g. (0.04 mole) of 70% aqueous ethyl amine in 25 ml. of ethanol was heated under reflux for 5 hours. The solution was cooled and was diluted with water to the cloudy point. The precipitate which formed was collected, air dried, and was recrystallized from heptane to give 1.6 g. of product, m.p. 133°-136° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]([CH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)[CH3:35])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:41](=[O:42])[C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:34]([C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:33])[CH3:35])=[CH:45][CH:44]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Reactant: CN(Cc1ccc(C(=O)O)cc1)C(=O)OC(C)(C)C
Product: CN(Cc1ccc(C(=O)Oc2ccc(S(=O)(=O)CCN3CC[C@H](Cc4ccccc4)[C@H](O)C3)cc2)cc1)C(=O)OC(C)(C)C
Yield: 99 %

Procedure:
The title compound was prepared from (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenol and 4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-benzoic acid in 99% yield as a light brown oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][C:8]=1[Cl:19].CN(C)[CH:22]=[O:23].C(OCC)(=O)C>O1CCCC1>[Cl:19][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:7]=1[CH:22]=[O:23])=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2
Reactant: CN(C)C=O
Reactant: COc1ccc2ncc(Cl)c(Br)c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(Cl)c(C=O)c2c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A solution of n-butyllithium (1.6 M in tetrahydrofuran, 0.46 mL, 0.73 mmol, 1.0 eq) is added at −78° C. to a stirred solution of 4-bromo-3-chloro-6-methoxy-quinoline (200 mg, 0.73 mmol, 1.0 eq) in tetrahydrofuran (10 mL). After 2 hours stirring at −78° C., N,N-dimethylformamide (0.3 mL) is added and the reaction mixture is stirred at 60° C. for two hours. Then solvent is evaporated and the residue is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford 3-chloro-6-methoxy-quinoline-4-carbaldehyde as a light yellow solid (78 mg, 48% yield).
Reaction SMILES: C1(C2C=CC([CH:8]=[O:9])=CC=2)CC1.Br[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16]2.[Li]CCCC.CN(C=O)C>>[CH3:22][C:18]1([CH3:23])[C:19]2[C:15](=[CH:14][C:13]([CH:8]=[O:9])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: CC1(C)CCc2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CC1(C)CCc2cc(C=O)ccc21
Yield: 93 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 5-bromo-1,1-dimethylindan [synthesized in analogy to a procedure described in Org. Prep. Proc. Int. 10:123-131 (1978)] (270 mg, 1.20 mmol), nBuLi (833 μl, 1.6M solution in hexane, 1.33 mmol) and DMF (173 μl, 2.22 mmol). The isolated residue was purified by flash column chromatography (1:9 ether:pentane) to give 1,1-dimethylindan-5-carbaldehyde (195 mg, 93%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 9.96 (s, 1H), 7.71-7.69 (m, 2H), 7.28 (m, 1H), 2.95 (apt t, J=7.0 Hz, 2H), 1.98 (apt t, J=7.0 Hz, 2H), 1.95 (s, 6H).