Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][CH:16]([NH:18][CH3:19])[CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:36][C:37]([OH:39])=O>>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][CH:8]([C:11]([N:13]3[CH2:14][CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH:16]([N:18]([CH3:19])[C:37](=[O:39])[CH2:36][C:30]4[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=4[F:28])[CH2:17]3)=[O:12])[CH2:9][CH2:10]2)[CH2:3][CH2:2]1
Reactant: O=C(O)Cc1cccc(F)c1F
Reactant: CNC1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Cc1cccc(F)c1F)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(2,3-difluoro-phenyl)-N-methyl-acetamide was prepared from (1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 2,3-difluorophenylacetic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a colorless semi-solid. MS m/e: 564.4 [M]+.
Reaction SMILES: S(N[C@H](C([O:16][C:17]1[C:26]2[O:25][CH2:24][C@H:23]([O:27][N+:28]([O-:30])=[O:29])[CH2:22][C:21]=2[CH:20]=[CH:19][CH:18]=1)=O)CC1C=CC=CC=1)(C)(=O)=O.CO.[OH-].[Na+].Cl>O1CCCC1>[O:27]([C@@H:23]1[CH2:22][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:16])[C:26]=2[O:25][CH2:24]1)[N+:28]([O-:30])=[O:29]
Reactant: CS(=O)(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1cccc2c1OC[C@H](O[N+](=O)[O-])C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])O[C@H]1COc2c(O)cccc2C1
Reaction time: 1 h
Yield: 38 %

Procedure:
21.6 g of the ester obtained in (A) was dissolved in 200 ml of tetrahydrofuran, and at room temperature, 100 ml of methanol and then 40 ml of a 10% aqueous solution of sodium hydroxide were added. The mixture was stirred for 1 hour. The reaction mixture was adjusted to a pH of about 4 with cold hydrochloric acid, and concentrated. To the residue were added 300 ml of chloroform and dilute hydrochloric acid. The aqueous layer was adjusted to pH 2, and the chloroform layer was separated. The chloroform layer was washed with an aqueous solution of sodium hydrogen carbonate and also with water, and the solvent was evaporated. Recrystallization of the residue from ethyl acetate-hexane gave 9.2 g (yield 38.0%) of the desired product as colorless prisms having a melting point of 129.0° to 130.5° C.
Reaction SMILES: N[C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[OH:18][C:19]([C:26](=[O:34])[NH:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])([CH2:23][CH2:24][CH3:25])[C:20]([OH:22])=O.O.O[N:37]1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[OH:18][C:19]([CH2:23][CH2:24][CH3:25])([C:20]([NH2:37])=[O:22])[C:26]([N:27]([C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)[CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[O:34]
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: CCCC(O)(C(=O)O)C(=O)NCCC(F)(F)F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(O)(C(N)=O)C(=O)N(CCC(F)(F)F)[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 8 h

Procedure:
A solution of 135 mg (0.60 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one, and 154 mg (0.60 mmol) (S or R )-2-hydroxy-2-(3,3,3-trifluoro-propylcarbamoyl)-pentanoic acid, entity B, in 10 ml tetrahydrofuran were cooled to 0° C. and 93.8 mg (0.60 mmol) 1-hydroxy-benzotriazole hydrate, 210 μl (1.20 mmol) diisopropylethylamine and 117 mg (0.60 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight. Removal of the solvent by distillation and chromatography on silicagel with ethylacetate/heptane (gradient 10:90 to 100:0) yielded 221 mg (80%) (S or R)-2-hydroxy-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-propyl-N-(3,3,3-trifluoro-propyl)-malonamide, entity B: MS (m/e): 462.0 (M−H)−.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[NH2:15])[C:9]([OH:11])=[O:10].[CH3:16]O>>[CH3:16][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([NH2:15])=[C:6]([NH2:5])[CH:7]=1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (13.0 ml, 180 mmol) was slowly added dropwise at 0° C. to a solution of 3,4-diaminobenzoic acid (25.0 g, 164 mmol) in methanol (164 ml). After stirring the mixture at room temperature overnight, it was further stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, and the precipitated solid was filtered out and washed with methanol. The filtrate was concentrated under reduced pressure and the obtained solid was filtered out and washed with methanol. All of the obtained solid was dried under reduced pressure at 60° C. to obtain 3,4-diaminobenzoic acid methyl ester. The compound was identified by NMR.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl.[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:35]([C:34]3[CH:38]=[CH:39][C:31]([C:30]([O:29][CH3:28])=[O:40])=[CH:32][CH:33]=3)=[O:36])=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(=O)n1nc(-c2ccccc2)c2cc(N)ccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)c(-c2ccccc2)nn3C(C)=O)cc1
Reaction time: 18 h
Yield: 74.2 %

Procedure:
To a flask containing 1-acetyl-5-amino-3-phenyl-1H-indazole (300 mg, 1.2 mmol) was added dichloromethane (10 mL), 4-(dimethylamino)pyridine (75 mg, 0.6 mmol) and triethylamine (180 mg, 1.8 mmol). The mixture was allowed to stir for ten minutes. Terephthalic acid monomethyl ester hydrochloride (285 mg, 1.44 mmol) was then added and stirring continued for 18 hours. The mixture was quenched with 5% sodium bicarbonate and extracted with dichloromethane. The extracts were dried using sodium sulfate, filtered and condensed to give a solid. The solid was recrystallized in ethanol to give the title compound (368 mg, 75%/; yield). ES-MS (m/z) 414 [M+1]+.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Br:7][C:8]1[C:9](=[O:31])[C:10]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:11]([C:19]([O:21][CH3:22])=[O:20])[N:12]([CH2:14][CH:15]([OH:18])CO)[CH:13]=1>O>[Br:7][C:8]1[C:9](=[O:31])[C:10]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:11]([C:19]([O:21][CH3:22])=[O:20])[N:12]([CH2:14][CH:15]([OH:2])[OH:18])[CH:13]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(Br)cn1CC(O)CO
Agent: [Na+]
Solvent: O
Product: COC(=O)c1c(OCc2ccccc2)c(=O)c(Br)cn1CC(O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
A reactor was charged with sodium periodate (1.67 kg, 7.8 mol) and 44 L of deionized water. To the agitated mixture was added 8.5 kg of ice. This was stirred until all the ice melted and the mixture temperature was 1.4° C. To this was added methyl 5-bromo-1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 19 (2.73 kg, 6.62 mol) via a powder addition funnel. The mixture was allowed to warm to rt and the slurry was stirred for 16 h. A sample was monitored by 1H NMR and showed the disappearance of starting material. The mixture was filtered and the cake washed with 20 kg of deionized water. This was repeated until a negative starch/iodide paper result was obtained (4×20 L washes). The solids were dried in a vacuum oven at 45-55° C. to provide methyl 5-bromo-1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 20 (2.176 kg, 88%) as a mixture with the corresponding aldehyde form 21. Purity was determined to be 99.5% by HPLC. 1H NMR (300 MHz, acetone-d6) δ 8.12 (s, 1H), 7.49-7.30°(m, 5H), 5.56 (dd, J=6.0, 2.4 Hz, 1H), 5.23 (m, 1H), 5.20 (s, 2H), 3.97 (d, J=5.1 Hz, 2H), 3.87 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][C:8]2=[O:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C1COCC1>[C:15]1([CH2:14][NH:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][NH:7][C:8]3=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cccc2c1CCNC2=O
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1NCCc2c(NCc3ccccc3)cccc21
Temperature: 0 °C
Yield: 19.3 %

Procedure:
To a solution of 2.0 g (12.3 mmol) of 5-amino-3,4-dihydro-1(2H)-isoquinolinone, monohydrochloride in 10 ml of THF was added 2.6 g (14.76 mmol) of benzylbromide and 2 ml of triethylamine. The mixture was heated under reflux for six hours and then poured into ice water and extracted with ether. The ether extracts were washed with water, dried (MgSO4), and concentrated. The residue was chromatographed (SiO2, ether to 10:1 ether/methanol) to provide 0.6 g of the dibenzylated product and 0.95 g (31%) of the desired monobenzylated product after crystallization from ethanol; mp. 142°-144°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH:30]5[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]5)(=[O:29])=[O:28])=[CH:23][CH:22]=4)[N:19]=3)[N:14](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=1)[CH2:7]2.C([SiH](CC)CC)C.[C:69]([OH:75])([C:71]([F:74])([F:73])[F:72])=[O:70]>C(Cl)Cl>[OH:75][C:69]([C:71]([F:74])([F:73])[F:72])=[O:70].[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([S:27]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)(=[O:28])=[O:29])=[CH:25][CH:26]=4)[N:19]=3)[NH:14][CH:13]=1)[CH2:7]2
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(-c3cnc4c(n3)c(N3Cc5cccc(Cl)c5C3=O)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2c(Cl)cccc2CN1c1c[nH]c2ncc(-c3ccc(S(=O)(=O)C4CCNCC4)cc3)nc12
Reaction time: 8 h
Yield: 59 %

Procedure:
tert-butyl 4-[4-[7-(7-chloro-1-oxo-isoindolin-2-yl)-5-trityl-pyrrolo[2,3-b]pyrazin-2-yl]phenyl]sulfonylpiperidine-1-carboxylate (186 mg, 0.2187 mmol) dissolved in DCM (2 mL) and triethylsilane (175 μL, 1.094 mmol) then TFA (0.3 mL) added under N2. Reaction mixture stirred overnight and residue azeotroped with DCM (×2) then purified by hplc. Product isolated as the TFA salt (80 mg, 59%); 1H NMR (400 MHz, DMSO) δ 1.72 (2H, brdq), 2.08 (2H, brd), 2.89 (2H, brq), 3.37 (2H, partly obsc brd), 3.63-3.70 (1H, partly obsc m), 5.49 (2H, s), 7.59 (1H, d), 7.70 (1H, t), 7.74 (1H, t), 7.99 (2H, d), 8.10-8.26 (1H, m), 8.55-8.58 (4H, m), 9.11 (1H, s), 12.42 (1H, d) ppm; MS (ES+) 508.0.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:12])[CH3:11])[N:5]=1)(=[O:3])[CH3:2].CCOCC.N(CCO)CCO>C1COCC1>[C:1]([C:4]1[N:5]=[C:6]([C@H:10]([CH3:11])[OH:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: OCCNCCO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cccc([C@H](C)O)n1
Temperature: -18 °C
Reaction time: 24 h

Procedure:
(-)-DIP-Cl (about 70% in hexane, about 22 mmol) was evaporated under reduced pressure to remove hexane. The resulting oil was dissolved in THF (15 ml) and added over 5 minutes into the solution of 2,6-diacetylpyridine (Example 23, 1.0 g, 6.13 mmol) in THF (20 ml) which had been cooled to -18° C. with ice-salt bath. The resulting orange solution was stirred at -18° C. to room temperature for 24 hours. Ether (60 ml) was added. The solution was cooled to 0° C. and then (HOCH2 CH2)2NH (5 ml, 52 mmol) was added. The resulting suspension was stirred at 0° C. to room temperature for 6 hours and filtered through Celite. The filtrate was evaporated to dryness. The residue was taken into ether/hexane, and filtered again. This operation was repeated a few times until there was little solid left when the residue was treated with ether/hexane. The final residue was subjected to chromatography on silica gel column, eluted consecutively with hexane/AcOEt (8:1) hexane/AcOEt (1:4). The crude product obtained was subjected to chromatography on a silica gel column again, and eluted consecutively with hexane/AcOEt (8:1), hexane/AcOEt/Et3N (800:600;14), hexane/AcOEt (1;3). From hexane/AcOEt/Et3N (800:600;14) eluant, (S)-(-)-6-acetyl-a-methyl-2-pyridinemethanol was obtained. From hexane/AcOEt (1:3) eluant monitored by chiral GC column (fused silica capillary column, SUPLECO β-DEX# 120, 30 m×0.25 mm, 150° C.), (S,S)-(-)-α,α'-dimethyl-2,6-pyridinedimethanol pyridinedimethanol was obtained. Yield: 0.41 g (40%). EE: 98%, containing 0.5% meso-isomer. 1H-NMR (CDCl3): dH=7.68 (t, 3J(HH)=7.7 Hz, 1 H, H-gpy), 7.20 (d, 3 j(HH)=7.7 Hz, 2 H, H-bpy), 4.88 (q, 3J(HH)=6.6 Hz, 2 H, CH), 3.94 (s, broad, 2 H, OH), 1.49 (d, J(HH)=6.6 Hz, 6 H, CH3). 13C-NMR (CDCl3): dC=162.06 (C2,6), 137.64 (C4), 118.26 (C3,5), 69.18 (CHOH), 24.07 (CH3).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])=[CH:20][CH:21]=2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(CCN(C)C)cc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(CCN(C)C)cc1
Yield: 31.4 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{4-[2-(dimethylamino)ethyl]phenylamino}-1,5-naphthyridin-3-yl)ethanone (40 mg, 0.11 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.15 mmol) followed by formation of the dihydrochloride salt to afford the desired product (13 mg, 22%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.29 (s, 1H), 8.42 (d, J=9.1 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.41-7.35 (m, 3H), 7.11 (br s, 1H), 3.43-3.36 (m, 2H), 3.23-3.13 (m, 2H), 2.98 (s, 6H), 2.80 (s, 3H); ESI MS m/z 479 [M+H]+; HPLC>99% (AUC), tR=9.67 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[S:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2)(=[O:26])=[O:24]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CCN(Cc2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 24.6 %

Procedure:
To a solution ethyl 1-((6-hydroxynaphthalen-2-yl)methyl)piperidine-4-carboxylate (1 g, 3.19 mmol) and TEA (0.64 g, 6.38 mmol, 2 eq) in DCM (20 mL) was added Tf2O (1.8 g, 6.38 mmol, 2 eq) dropwise at 0° C. The mixture was stirred at room temperature for 12 h. The reaction was quenched with water at 0° C., washed with sat.NaHCO3 (10 mL) and brine (5 mL*3). The organic layer was dried over Na2SO4 and concentrated to afford ethyl 1-((6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylate as a brown solid (350 mg, yield: 90%). ESI-MS: 446.1 (M+H)+. 1HNMR (400 MHz, CDCl3) δ: 7.88 (d, J=9.2 Hz, 1H), 7.84-7.82 (m, 2H), 7.79 (s, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.35 (d, J=9.2 Hz, 1H), 4.13 (q, J=7.6 Hz, 2H), 3.66 (s, 2H), 2.89-2.86 (m, 2H), 2.32-2.28 (m, 1H), 2.11-2.07 (m, 2H), 1.88-1.78 (m, 4H), 1.26 (t, J=7.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:17]O>>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: CO
Reactant: Cc1ccc(F)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)ccc1C
Temperature: 25 °C
Yield: 78 %

Procedure:
5-Fluoro-2-methyl-benzoic acid (0.29 g, 1.9 mmol) was dissolved in anhydrous MeOH (7 mL) and c. H2SO4 (0.12 mL, 2.3 mmol) was added, heating to reflux for 16 hours. The solution was cooled to room temperature and partitioned between EtOAc (15 mL) and brine (10 mL). After separating, the aqueous phase was extracted with EtOAc (2×10 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to afford 5-fluoro-2-methyl-benzoic acid methyl ester as a pale brown liquid (0.25 g, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:29])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=[O:5])C.S(=O)(=O)(O)O>CO>[CH3:1][O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:29])[CH:13]([C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[S:9][CH:10]=1)=[O:5]
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)n1
Yield: 55.3 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester (prepared as in Example 39(B)(b), 135 mg, 0.32 mmol) in methanol (10 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was heated under reflux for 68 h. The reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (71.4 mg, 54.8%) as a pale yellow solid: EI-HRMS m/e calcd for C19H21N3O5S (M+) 403.1201, found 403.1188.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH3:27])[C:7](=[C:9]3[S:13][C:12](=[N:14][C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=4[NH:23][CH2:24][CH3:25])[C:18]#[N:19])[NH:11][C:10]3=[O:26])[S:8][C:4]=2[CH:3]=1.[C:30]([O:34][C:35]([NH:37][C:38]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=S)=[O:36])([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.C(Cl)(Cl)Cl.Cl[Hg]Cl>[CH2:18]([N:11]1[C:10](=[O:26])[C:9](=[C:7]2[N:6]([CH3:27])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:38]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:37][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])=[CH:3][C:4]=3[S:8]2)[S:13][C:12]1=[N:14][C:15]1[CH:16]=[C:17]([C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][CH3:25])[C:17]1[CH:20]=[CH:21][CH:22]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: CCNc1ccc(C#N)cc1N=C1NC(=O)C(=C2Sc3cc(N)ccc3N2C)S1
Agent: Cl[Hg]Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)ccc3N2C)C(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 173.1 %

Procedure:
To a stirred mixture of the product of Example 272 (77 mg, 0.15 mmol), N,N′-di-(tert-butoxycarbonyl)thiourea (50 mg, 0.18 mmol) and TEA (70 μL, 0.5 mmol) in anhydrous DMF (1.5 mL) at 0° C. was added HgCl2 (49 mg, 0.18 mmol). The resulting mixture was stirred at 0° C. for 30 min, then at ambient temperature overnight. The mixture was diluted with CHCl3, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with MeOH-DCM (0:100 to 20:80) to afford the title compound (98 mg, 87%). 1H-NMR (CDCl3): δ 11.62 (1H, br s), 10.43 (1H, br s), 8.02 (2H, m), 7.45-7.20 (7H, m), 7.02 (1H, d), 6.49 (1H, t), 5.16 (2H, s), 3.82 (3H, s), 3.04-2.96 (2H, m), 1.43 (9H, s), 1.35 (9H, s), 1.02 (3H, t); MS(ESI): 756 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:15]([NH2:20])[CH2:16][CH2:17][CH2:18][CH3:19]>O1CCOCC1>[CH2:15]([NH:20][C:8]([C:5]1[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:10])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCN
Reactant: O=C(O)c1ccc(Cl)nn1
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CCCCCNC(=O)c1ccc(Cl)nn1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
To a flask containing 6-chloropyridazine-3-carboxylic acid (375 mg, 2.37 mmol) in dioxane (5 mL) was added thionyl chloride (420 mg, 0.26 mL, 3.56 mmol). The brown mixture was refluxed for 6 hours under nitrogen with stirring. After cooling to ambient temperature, the solvent was removed by rotary evaporator. The gummy black material was diluted with dioxane (5 mL) and the resulting solution was cooled in an ice-water bath. To the cooled solution was added amyl amine (410 mg, 0.55 mL, 4.74 mmol). The resulting black reaction solution was stirred at ambient temperature for 16 hours under nitrogen. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (25 mL). The solution was washed with water (2×10 mL) and the organic layer was dried over MgSO4, filtered-off the solid and concentrated to afford a gummy material which was purified by column chromatography eluted with dichloromethane to yield 310 mg (57%) of the product as a colourless solid. m.p. 98-101° C. 1H NMR (300 MHz, CDCl3) δ 8.28, 8.05, 7.68, 3.51, 169-1.63, 0.90. MS (ES+) m/z 228 (M+1).
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:26](C=O)=[C:25]([Cl:29])[N:24]=[C:23]3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])C.Cl.C(O)C>O>[Cl:29][C:25]1[N:24]=[C:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:22]([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:10]3[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:20][CH:19]=2)[CH:26]=1
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccccc1-c1ccc(Cn2cc(Cl)nc2-c2ccccc2)cc1
Yield: 0.5 %

Procedure:
9.2 g of 4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonic acid dimethylaminomethylenamide (Example 11a), 95 ml of a saturated aqueous HCl solution and 95 ml of ethanol are refluxed for 2 h. After cooling, the mixture is diluted with 500 ml of water and extracted twice using 500 ml of EA each time and the organic phase is washed twice using 100 ml of a saturated aqueous NaCl solution each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. The product mixture is recrystallized from 200 ml of EA and 6.2 g of 4′-(4-chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl)biphenyl-2-sulfonamide (compare Example 11b) are obtained. The solvent of the mother liquor is removed in vacuo and the residue is chromatographed on silica gel using MTB/DIP 1:1. 40 mg of a colorless oil are obtained.