Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:13]=[N:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:3]([CH2:13][NH:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1
Reactant: COCCCc1cc(C=NC2CC2)c(Cl)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCCc1cc(CNC2CC2)c(Cl)cn1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-2-(3-methoxy-propyl)-pyridine-4-carbaldehyde (21.0 g, 98.2 mmol) and cyclopropylamine (13.8 mL, 196 mmol) in MeOH (450 mL) was stirred at rt overnight. NaBH4 (4.83 g, 128 mmol) was added at 0° C., and the mixture was stirred at rt overnight. Ice was added, and the mixture was concentrated under reduced pressure. The crude product was dissolved in EtOAc, and this mixture was washed with aq. 1 M NaOH. The aq. layer was extracted back with EtOAc. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:5→1:4→1:3→1:1→3:1→EtOAc) yielded the title compound (11.8 g) and [5-chloro-2-(3-methoxy-propyl)-pyridin-4-ylmethylene]-cyclopropyl-amine (10.7 g). This unreacted imine was dissolved in MeOH (20 mL), and this sol. was cooled to 0° C. NaBH4 (3.20 g, 84.6 mmol) was added, and the mixture was stirred at rt overnight. NaBH4 (3.20 g, 84.6 mmol) was added again, and the mixture was stirred for 3 days. Ice was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The crude product was dissolved in EtOAc and the resulting mixture was washed with aq. 1M NaOH. The aq. phase was extracted back with EtOAc. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:3→1:2→1:1→EtOAc) yielded the title compound (9.4 g). The fractions of the title compound were mixed together (21.2 g, 85%). LC-MS: tR=0.55 min; ES+: 296.16.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][NH:28]3)=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([N:38]5[CH2:39][CH2:40][CH:41]([OH:44])[CH2:42][CH2:43]5)=[CH:34][CH:33]=4)[N:3]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: Nc1ccc(N2CCC(O)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Nc4ccc(N5CCC(O)CC5)cc4)nc32)cc1
Temperature: 116 °C
Yield: 13.2 %

Procedure:
A mixture of 2-chloro-N-(1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (61 mg, 0.14 mmol), 1-(4-aminophenyl)piperidin-4-ol (61 mg, 0.32 mmol) and trimethylsilyl chloride (TMSCl) (0.060 mL, 0.48 mmol) in n-butyl alcohol (2 mL) was heated at 116° C. for 96 h. The mixture was then purified by HPLC to give 1-(4-(4-(1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperidin-4-ol (11 mg).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH2:30]O)[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Br)(Br)(Br)[Br:36].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH2:30][Br:36])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1CBr
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(hydroxymethyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (210 mg, 0.419 mmol) in CH2Cl2 (4 mL) was added CBr4 (292 mg, 0.880 mmol) and a solution of PPh3 (220 mg, 0.838 mmol) in CH2Cl2 (4 mL). The mixture was allowed to warm to room temperature, and, after 90 minutes had elapsed, it was concentrated on to silica gel. Purification of the residue by flash chromatography on silica gel (10 to 50% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(bromomethyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.10 (50% EtOAc/hexanes). LCMS=564.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 1H), 7.78 (s, 2H), 7.63-7.57 (m, 2H), 7.52 (s, 1H), 5.79 (d, J=8.0 Hz, 1H), 5.09 (d, J=15.8 Hz, 1H), 4.61 (dd, J=13.8, 10.5 Hz, 2H), 4.27 (d, J=15.8 Hz, 1H), 4.06-1.00 (m, 1H), 0.82 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][C:23]=4[CH3:30])[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].OO.FC(F)(F)C([OH:40])C(F)(F)F>ClCCl>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:29])=[O:40])=[CH:24][C:23]=4[CH3:30])[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: CSc1ccc(-c2ccc3c(c2)CC(C2CCN(C(=O)OC(C)C)CC2)O3)c(C)c1
Agent: OO
Solvent: ClCCl
Product: Cc1cc(S(C)=O)ccc1-c1ccc2c(c1)CC(C1CCN(C(=O)OC(C)C)CC1)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[5-(2-methyl-4-methylsulfanyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester (20 mg), aqueous hydrogen peroxide solution (35%; 3.5 μL) and 1,1,1,3,3,3-hexafluoro-2-propanol (200 μL) is stirred at room temperature for 2 h. The reaction mixture is diluted with dichloromethane and extracted with sodium thiosulfate solution (10%; 2 mL). The organic phase is washed with brine, dried over MgSO4 and the solvent is evaporated. The residue is chromatographed on silica gel (dichloromethane/methanol 95:5) to give the title compound. Yield: 9 mg (43% of theory); LC (method 2): tR=1.45 min; Mass spectrum (ESI+): m/z=442 [M+H]+.
Reaction SMILES: CCCCCCCCCCCCCCCC(OC[C@@H](OC(CCCCCCCCCCCCCCC)=O)COC(CCC(O)=O)=O)=[O:17].ON1C(=O)CCC1=O.CN(C1C=CC=CN=1)C.[CH:65]1([N:71]=[C:72]=[N:73][CH:74]2[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]2)[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]1>C(#N)C>[C:72]([NH:71][CH:65]1[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70]1)([NH:73][CH:74]1[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]1)=[O:17]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H](COC(=O)CCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Agent: CN(C)c1ccccn1
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 5 h

Procedure:
The targeted formulation disclosed in Example 11 of commonly owned U.S. application Ser. No. 08/851,780, filed May 6, 1997 (the disclosure of which is incorporated herein by reference), was prepared in the following manner: to a cooled (0 to 5° C.) solution of 1,2-dipalmitoyl-sn-glycero-3-succinate 66.8 mg, N-hydroxy-succinimide 11.5 mg, dimethylaminopyridine (DMAP) 2 mg and acetonitrile 40 mL in a 100 mL round bottom flask was added dropwise to a solution of dicyclohexyl carbodiimide (DCC) 20.6 mg in acetonitrile 10 mL. The resulting mixture was stirred for 5 hours. The solid material which formed during the reaction (dicyclohexylurea) was removed by filtration, and the filtrate was concentrated in vacuo to yield 78 mg of a white product of N-DPGS-succinimide.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[Br:16][C:17]1[S:21][C:20](N)=[N:19][CH:18]=1>ClCCCl>[Br:16][C:17]1[S:21][C:20]([N:14]=[C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:19][CH:18]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Nc1ncc(Br)s1
Agent: Br
Solvent: ClCCCl
Product: Brc1cnc(N=C(c2ccccc2)c2ccccc2)s1
Yield: 82.9 %

Procedure:
26 g of benzophenone imine are added to 34 g of 5-bromo-1,3-thiazol-2-amine hydrobromide, in suspension in 300 ml of 1,2-dichloroethane. The mixture is kept under reflux for 18 hours. The precipitate formed is filtered and the filtrate is concentrated to give 37.2 g of solid.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][N:21](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:2]=[O:3].C(N(CC)C(C)C)(C)C.[CH2:51]([N:53]1[CH2:57][CH2:56][CH:55]([OH:58])[CH2:54]1)[CH3:52]>C(Cl)Cl>[CH2:51]([N:53]1[CH2:57][CH2:56][CH:55]([O:58][C:2](=[O:3])[NH:1][C:4]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]4[C:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[O:30][CH3:31])=[CH:22][NH:21][C:18]4=[N:19][CH:20]=3)=[CH:11][C:5]=2[C:6](=[O:7])[N:8]([CH3:9])[CH3:10])[CH2:54]1)[CH3:52]
Reactant: CCN1CCC(O)C1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N=C=O)c(C(=O)N(C)C)c3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN1CCC(OC(=O)Nc2ccc(-c3cnc4[nH]cc(-c5ccccc5OC)c4c3)cc2C(=O)N(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.4 %

Procedure:
2-Isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (125 mg, 0.22 mmol), N,N-diisopropylethylamine (0.06 mL, 0.34 mmol), 1-ethyl-pyrrolidin-3-ol (253 mg, 2.2 mmol), and methylene chloride (3 mL) were combined and stirred at room temperature for 18 hours. The reaction was concentrated to dryness in vacuo. The crude material was dissolved in a solution of tetrahydrofuran (4 mL) and methanol (1 mL). To the mixture was added 0.2 mL 50% w/v aqueous potassium hydroxide and the combined mixture stirred for 30 minutes. The reaction was quenched with saturated sodium bicarbonate, and the mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate and concentrated to dryness in vacuo. The crude material was purified by preparative HPLC to give 25 mg (47 μmol, 22%) of {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-carbamic acid 1-ethyl-pyrrolidin-3-yl ester. 1H-NMR (250 MHz, CDCl3) δ 11.93 (s, 1H), 9.10 (s, 1H), 8.64 (d, J=1.9 Hz, 1H), 8.16 (d, J=2.1 Hz, 1H), 7.75-7.54 (m, 5H), 7.30 (t, J=7.1 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 5.10-5.02 (m, 1H), 3.82 (s, 3H), 2.97 (s, 3H), 2.93 (s, 3H), 2.77-2.24 (m, 7H), 1.80-1.72 (m, 1H), 1.03 (t, J=7.2 Hz, 3H); MS: m/z 528.3 (M+H+).
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C:5]([N:7]1[CH:11]=[N:10][C:9]([S:12][CH2:13][CH2:14][CH3:15])=[N:8]1)=[O:6])[CH2:2][CH3:3].[OH:19]O>C(O)(=O)C>[CH2:16]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([N:7]1[CH:11]=[N:10][C:9]([S:12]([CH2:13][CH2:14][CH3:15])=[O:19])=[N:8]1)=[O:6])[CH2:17][CH3:18]
Reactant: OO
Reactant: CCCSc1ncn(C(=O)N(CCC)CCC)n1
Solvent: CC(=O)O
Product: CCCN(CCC)C(=O)n1cnc(S(=O)CCC)n1

Procedure:
A solution of 13.5 g. 1-dipropylcarbamoyl-3-propylthio-1,2,4-triazole and 100 vol. hydrogen peroxide solution (5.7 ml., 1.0 molecular proportion) in 450 ml. glacial acetic acid was kept at room temperature for 14 days. The resulting solution was evaporated to dryness under reduced pressure and the residual oil was dissolved in methylene dichloride. The resulting solution was washed successively with 0.5N sodium hydroxide solution, and 0.5N hydrochloric acid. Solvent was removed from the solution by distillation under reduced pressure to give a residual oil which solidified on cooling. The solid product was recrystallized from benzene/petroleum ether, b.p. 40° - 60° C. to give 1-dipropylcarbamoyl-3-propylsulphinyl-1,2,4-triazole, m.p. 51° - 52.5° C. Elemental analysis satisfactory.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].Cl.CN.[CH2:18]([N:20](CC)CC)C.Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH:20][CH3:18])(=[O:13])=[O:12]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(F)c(S(=O)(=O)Cl)c1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
A solution of 2-fluoro-5-nitrobenzenesulfonyl chloride (3.2 g, 12.6 mmol) in THF (30 mL) at −45° C. was treated with methylamine hydrochloride (1.0 g, 15.1 mmol) and triethylamine (2.1 mL, 15.1 mmol) and stirred for 30 minutes. The mixture was then treated with 6M aqueous HCl to adjust the pH to 3 and warmed to room temperature before being diluted with water and extracted with EtOAc. The organic extract was dried (sodium sulfate), concentrated, and subjected to flash chromatography (5-20% EtOAc-petroleum ether) to give 2-fluoro-N-methyl-5-nitrobenzenesulfonamide as a yellow solid (3.0 g, 93%). MS (m/z) 235.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCCC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (266 mg, 1.0 mmol) was treated with cyclohexylamine following general procedure B to afford 4-cyclohexylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (286 mg). Thus obtained amino-ester (33 mg, 0.1 mmol) was subjected to reaction with ethyl isocyanate according to general procedure C to furnish 3-ethyl-7-methoxy-1-(3-pyrrolidin-1-yl-propyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (15 mg). LCMS: m/z 354 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.58 (s, 1H), 7.58 (m, 1H), 7.50 (m, 1H), 7.41 (m, 1H), 7.24 (m, 1H), 7.06-7.14 (m, 2H), 6.48 (m, 1H), 4.92 (m, 1H), 4.08 (s, 3H), 2.46 (m, 2H), 1.64-1.92 (m, 5H), 1.42 (m, 2H), 1.28 (m, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([F:1])[CH:3]=1)[CH3:18]
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(O)c(F)c1
Temperature: 0 °C

Procedure:
A mixture of 3-fluoro-4-hydroxybenzoic acid (5.0 g), ethanol (100 ml) and concentrated sulfuric acid (1 ml) was refluxed for 1 day. The reaction mixture was poured into ice water, the crystal that was precipitated was filtered, then dried to provide the title compound (24.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C@@H:4]([C:6]([S:9][CH3:10])([CH3:8])[CH3:7])[NH2:5].C(N(C(C)C)CC)(C)C.[O:21]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C@@H:4]([C:6]([S:9][CH3:10])([CH3:8])[CH3:7])[NH:5][S:34]([C:31]1[CH:30]=[CH:29][C:28]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:33][CH:32]=1)(=[O:36])=[O:35]
Reactant: COC(=O)[C@H](N)C(C)(C)SC
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](NS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(C)(C)SC
Reaction time: 2.5 h
Yield: 87 %

Procedure:
To a solution of S-methyl-D-penicillamine methyl ester (0.160 g., 0.904 mmol) and diisopropylethylamine (0.172 mL, 0.99 mmol) in dichloromethane (3 mL) was added 4-phenoxybenzenesulfonyl chloride (0.304 g, 1.13 mmol) via solid addition funnel. After 2.5 hours at room temperature, the solution was concentrated and the residue was purified on silica, eluting with 20% ethyl acetate in hexane, to give S-methyl--N--[4-(phenoxy)benzenesulfonyl]-D-penicillamine methyl ester as a white solid in 87% yield: 1H NMR (CDCl3) δ 1.31 (s, 3H), 1.37 (s, 3H), 1.96 (s,3H), 3.48 (s, 3H), 3.79 (d, 1H, J=9 Hz), 5.34 (d, 1H, J=10 Hz), 6.99-7.79 (m, 9H); FAB HRMS: expected (M+Na)=432.0915, found (M+Na)=432.0907.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=O.[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:3](=[O:5])[C:2]([CH3:1])([CH3:9])[CH2:6][CH2:7][CH3:8])[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: CCCC(C)(C)C(=O)O
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: CCCC(C)(C)C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2,2-dimethylpentanoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (61% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.96, 6.98, 3.85-3.72, 3.56, 1.64-1.45, 1.23, 0.96, 0.82-0.62, 0.49-0.45, 0.12-0.07. MS (ES+) m/z 388.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](C(CC)(CC)C([O-])([O-])[O-])[CH3:13]>>[CH3:12][C:13]1[O:11][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[N:1]=1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Product: Cc1nc2c([N+](=O)[O-])cccc2o1
Temperature: 100 °C
Yield: 95.1 %

Procedure:
To 2-amino-3-nitrophenol (6.17 g, 40.0 mmol) was added triethylorthoacetate (25.96 g, 160.0 mmol) and the mixture was heated at 100° C. for 12 h to give a dark red solution. Cooling to room temperature produced a crystalline mass which was filtered and washed with hexane to give compound 474A (6.78 g, 95%) as light maroon needles. HPLC: 98.1% at 1.86 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 179.08 [M+H]+.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:46])[N:25]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37](C)(C)[O:38][SiH2]C(C)(C)C)[CH:31]=1)[CH2:26][CH3:27])([CH3:22])([CH3:21])[CH3:20].CCOC(C)=O>C1COCC1>[C:19]([O:23][C:24](=[O:46])[N:25]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([CH2:37][OH:38])[CH:31]=1)[CH2:26][CH3:27])([CH3:20])([CH3:21])[CH3:22]
Reactant: CCN(CCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CCc1ccc(Cl)c(CO)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
TBAF (1M in THF, 1.39 mL, 1.39 mmol) was added to a sol. of {2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethyl}-ethyl-carbamic acid tert-butyl ester (298 mg, 0.696 mmol) in THF (6.82 mL) at 0° C. The mixture was stirred for 1 h while warming up to rt. EtOAc was added, and the mixture was washed with aq. sat. NH4Cl and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 19:1) yielded the title compound (110 mg, 50%). LC-MS: tR=0.97 min; ES+: 314.11.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[CH:15]([C:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]>>[CH:15]([C:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:2][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]4)[CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Reactant: O=CC1(c2cccc(O)c2)CCOCC1
Product: Cn1c(=O)ccc2cc(COc3cccc(C4(C=O)CCOCC4)c3)ccc21
Yield: 45 %

Procedure:
Using a similar procedure to that described in Example 14, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with 4-formyl-4-(3-hydroxyphenyl)tetrahydropyran to give 4-formyl-4-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran in 45% yield as a glassy solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[N:28]=[CH:27][C:26]([C@@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][C:23]2[N:28]=[CH:27][C:26]([C@@H:29]([NH:31][C:2]3[N:7]=[C:6]([N:8]4[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]4=[O:16])[CH:5]=[CH:4][N:3]=3)[CH3:30])=[CH:25][CH:24]=2)=[CH:32][CH:33]=1
Reactant: C[C@H](N)c1ccc(Oc2ccc(F)cc2)nc1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(Oc3ccc(F)cc3)nc2)n1
Temperature: 107.5 °C
Yield: 14 %

Procedure:
To (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (28 mg, 0.116 mmol) was added (S)-1-(6-(4-fluorophenoxy)pyridin-3-yl)ethanamine (46.7 mg, 0.174 mmol), DMSO (0.6 ml) and Hunig's Base (0.071 ml, 0.406 mmol). The reaction was heated at 105-110° C. for 24 hours or until done by LCMS. The reaction was let cool, 0.5 ml of DMSO was added, filtered, purified by prep LC and lyophilized to give 7.1 mg of (S)-3-(2-((S)-1-(6-(4-fluorophenoxy)pyridin-3-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one as the TFA Salt. LCMS m/z 438.2 (M+H)+, Rt 0.82 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].Br[CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].[OH-].[Na+]>CN(C)C=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16]
Reactant: O=C(CCBr)c1ccccc1
Reactant: Sc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CCSc1ccc2ccccc2c1)c1ccccc1
Yield: 22.1 %

Procedure:
A mixture of 2-naphthalenethiol (12.94 g), 3-bromopropiophenone (17.35 g), cuprous oxide (5.83 g), sodium hydroxide (3.24 g) and dimethylformamide (130 ml) was heated to reflux for 18 hours. The mixture was concentrated and the residue was partitioned between diethyl ether and water. The organic phase was dried (MgSO4) and evaporated. The residue was dissolved in a mixture of ethyl acetate and hexane and treated with charcoal. The solution was filtered and evaporated. The residue was recrystallised from a mixture of methanol and water to give 3-(naphth-2-ylthio)propiophenone (5.23 g, 22%), m.p. 90°-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4](Cl)[CH3:5].[CH:12]1[CH:13]=[CH:14][N+:15]([O-:19])=[C:16]([S-:18])[CH:17]=1.[Na+]>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4]([S:18][C:16]1[CH:17]=[CH:12][CH:13]=[CH:14][N+:15]=1[O-:19])[CH3:5]
Reactant: [O-][n+]1ccccc1[S-]
Reactant: CC(Cl)c1c(F)cccc1Cl
Agent: [Na+]
Solvent: CCO
Product: CC(Sc1cccc[n+]1[O-])c1c(F)cccc1Cl
Temperature: 75 °C
Reaction time: 2 h

Procedure:
2-chloro-6-fluoro-alpha-methylbenzyl chloride (46.2, 0.24 mol is dissolved in ethanol (120 Ml) and warmed to 75° C. A 40 percent solution of sodium omadine (98.1 g, 0.26 mol) is added dropwise over a period of 30 minutes maintaining a reaction temperature of 75° C. throughout. Once the addition is complete, the reaction mixture is kept at 75° C. for 2 hours and then stirred at room temperature for 16 hours. Thereafter the mixture is quenched in ice-water and crude product is filtered off. After recrystallization with ethyl acetate pure title product (27.7 g, 40.8%) is obtained; Melting Point 142°-144° C.