Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[S:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[N:20]=2)=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[NH2:21][CH2:22][CH2:23][N:24]1[C:28]([CH3:30])([CH3:29])[C:27](=[O:31])[NH:26][C:25]1=[O:32].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([C:12]2[S:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[N:20]=2)=[N:4][C:5]([NH:21][CH2:22][CH2:23][N:24]2[C:28]([CH3:29])([CH3:30])[C:27](=[O:31])[NH:26][C:25]2=[O:32])=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Reactant: CS(=O)(=O)c1ncc(Br)c(-c2nc3ccncc3s2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2nc3ccncc3s2)n1
Temperature: 160 °C
Yield: 4.5 %

Procedure:
A microwave tube was charged with 2-(5-bromo-2-(methylsulfonyl)pyrimidin-4-yl)thiazolo[5,4-c]pyridine (300 mg, 0.81 mmol), 1-(2-Aminoethyl)-5,5-dimethyl-imidazolidine-2,4-dione (138 mg, 0.81 mmol), isopropanol (3 mL) and N,N-diisopropylethylamine (0.21 mL, 1.21 mmol). The vessel was sealed and heated in a microwave reactor at 160° C. for 1000 seconds. The resulting solid was filtered off and washed with methanol (4×10 mL). The solid was then dissolved in dimethylsulfoxide (4 mL) and purified by reverse phase HPLC. Product fractions were combined and loaded onto an SCX cartridge, washed with methanol (4 mL), then free based and eluted with 2 M ammonia in methanol (4 mL). The solvent was evaporated in vacuo to yield 1-(2-(5-bromo-4-(thiazolo[5,4-c]pyridin-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (17 mg, 5%) as a yellow amorphous solid. 1H NMR δ (d6-DMSO, 400 MHz) 1.50 (s, 6H), 3.67 (br. s., 2H), 3.75 (br. s., 2H), 4.32 (br. s., 1H), 6.89 (s, 1H), 7.49 (s, 1H), 8.33 (d, J=5.5 Hz, 1H), 8.91 (d, J=5.1 Hz, 1H), 9.71 (s, 1H): HRMS (M+H)+ Calcd. C17H16BrN7O2S 462.0348. found 462.0339.
Reaction SMILES: S(=O)(=O)=O.[CH3:5][S:6]([CH3:8])=O.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>ClCCl>[CH3:5][S:6]([CH3:8])=[N:15][C:14]1[CH:16]=[CH:17][C:11]([C:10]([F:9])([F:18])[F:19])=[CH:12][CH:13]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CS(C)=O
Agent: O=S(=O)=O
Solvent: ClCCl
Product: CS(C)=Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
Sulfur trioxide (4.84 g, 60.5 mmol) in dichloromethane (10 mL) was added to dimethyl sulfoxide (4.84 g, 62.0 mmol) in dichloromethane (10 mL) at −5 to 0° C. When the addition was complete 4-(trifluoromethyl)aniline (5.00 g, 31.0 mmol) was added dropwise. The mixture was allowed to warm to ambient temperature. After about 1 h the mixture was diluted with dichloromethane (80 mL) and washed with sodium hydroxide (1 N, 100 mL), dried and evaporated to give the title product as a solid (6.58 g, 96% yield).
Reaction SMILES: S(=O)(=O)(O)O.[Si]([O:13][C:14]1[CH:15]=[C:16]([CH:28]=[CH:29][C:30]2[CH:31]=[C:32]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([CH3:50])([CH3:49])[O:42]C3CCCCO3)[CH:33]=[CH:34][CH:35]=2)[CH:17]=[CH:18][C:19]=1[O:20][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C>C1COCC1.O>[OH:42][C:41]([CH3:50])([CH3:49])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][C:32]1[CH:31]=[C:30]([CH:29]=[CH:28][C:16]2[CH:15]=[C:14]([OH:13])[C:19]([OH:20])=[CH:18][CH:17]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(CCCCCc1cccc(C=Cc2ccc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c2)c1)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)CCCCCc1cccc(C=Cc2ccc(O)c(O)c2)c1

Procedure:
In a manner similar to Example 25(d), by reacting 0.118 ml of concentrated sulphuric acid with 1.38 g (2.11 mmol) of 2-[6-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxy)phenyl]vinyl}phenyl)-1,1-dimethylhexyloxy]tetrahydropyran in 20 ml of THF and 10 ml of water, after purification on a silica column (ethyl acetate 45-heptane 55), a solid having a cottony appearance (m=522 mg; Y=77%) is obtained.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].Cl.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41](Cl)=[O:42]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=3)=[O:42])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)c1ccccn1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccccn4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 55.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.98 g, 6.48 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, picolinoyl chloride hydrochloride (0.41 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCL (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:CH3OH 97.5:2.5) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-pyridylcarboxamide (0.40 g, 55%) as a white solid: mp 155-157° C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 9.50 (t, J=6.2 Hz, 1H), 8.70 (d, J=4.6 Hz, 1H), 8.08-7.98 (m, 2H), 7.82-7.62 (m, 4H), 5.21-5.14 (dd, J=5.4 and 12.6 Hz, 1H), 4.97 (d, J=6.3 Hz, 2H), 2.99-2.84 (m, 1H), 2.65-2.50 (m, 2H), 2.10-2.06 (m, 1H); 13C NMR (DMSO-d6) δ 172.77, 169.85, 167.59, 166.99, 164.38, 149.59, 148.56, 139.02, 137.87, 134.79, 132.95, 131.57, 127.16, 126.76, 122.05, 121.87, 48.87, 38.37, 30.94, 21.97; Anal. Calcd. For C20H16N4O5+0.08H2O: C, 61.08; H, 4.13; N, 14.25. Found: C, 61.48; H, 4.22; N, 13.87.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:17])[CH2:14][O:15][CH3:16])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1F.CCO>CN(C=O)C.Cl>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:17][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][O:15][CH3:16]
Reactant: COC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COC[C@H](Oc1ccc(Cl)cc1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-1-Hydroxy-2-methoxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10.0 mg, 40.8 μmol) was dissolved in DMF (0.1 mL). NaH (1.5 mg, 61.1 μmol) was slowly added and the mixture was stirred at room temperature for 15 minutes. Then, 2,4-dichloro-1-fluorobenzene (20.2 mg, 122 μmol) was added. The mixture was stirred at 100° C. for 1 hour, then cooled to room temperature. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) and stirred overnight at room temperature. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (12.8 mg, 99% purity). MS m/z: [M+H] calcd for C13H17Cl2NO2, 290.06. found 290.0.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[Cl:14])[NH2:10].[CH:15]([S:17]([F:20])(=[O:19])=[O:18])=[CH2:16]>O>[Cl:6][C:7]1[CH:8]=[C:9]([NH:10][CH:16]=[CH:15][S:17]([F:20])(=[O:19])=[O:18])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: C=CS(=O)(=O)F
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(F)C=CNc1ccc(Cl)c(Cl)c1

Procedure:
A N,N-dimethylformamide solution (DMF, 100ml) of 3,4-dichloroaniline (6.48 g, 40 mmol) and ethenesulfonyl fluoride (6.7 g, 57.9 mmol) was warmed to 110° C. for three hours. The cooled dark solution was diluted to 400 ml with water and the resulting dark oily precipate was decanted from the supernatant layer. This layer was extracted with ether (4×50 ml). The combined ether extracts were added to the oily precipitate and this dark solution was washed with brine and dried over MgSO4. The organic solution was evaporated to give the crude 2-[(3,4-dichlorophenyl)amino]ethenesulfonyl fluoride as a dark liquid in quantitative yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]1)[NH:20][C:19]2=[O:29]
Reactant: OB(O)c1ccccc1F
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4ccccc4F)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 2-fluorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11FN4O3, 350.1; m/z found, 351.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.02 (br s, 1H), 12.95 (br s, 1H), 8.99 (s, 1H), 8.28 (s, 2H), 8.05 (d, J=8.5 Hz, 1H), 7.81 (s, 1H), 7.67 (t, J=7.9, 1H), 7.49 (tdd, J=7.1, 5.1, 1.7, 1H), 7.40-7.34 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13](O)=[O:14])=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:13]([C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:5][C:6]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:7][C:8]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:34])(=[O:35])[NH2:36]
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.29) and 3-amino-benzenesulfonamide according to general procedure II. Pale-yellow solid. MS (ISP) 502.3 [(M+H)+]; mp 249-250° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:28])[C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([OH:27])[CH:20]=3)[CH2:13][CH2:12]2)[CH:7]=[C:6]([O:29][CH2:30][CH3:31])[C:5]=1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH3:2].[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:19]3[CH:20]=[C:21]([O:27][S:40]([CH3:39])(=[O:42])=[O:41])[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=3)=[O:28])[CH2:13][CH2:12]2)[CH:7]=[C:6]([O:29][CH2:30][CH3:31])[C:5]=1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH3:2]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1-c1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OS(C)(=O)=O)c3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
In analogy to the procedure described in example 72a), N-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-3-hydroxy-5-methoxy-benzamide (example 259) was reacted with methanesulfonyl chloride, N-ethyl-diisopropylamine in CH2Cl2 at rt to yield the title compound as colorless solid. MS: 601.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[CH3:15][O:16][C:17](=[O:27])[C@@H:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][O:16][C:17](=[O:27])[C@@H:18]([NH:26][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH2:19][C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: COC(=O)[C@@H](N)Cc1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccncc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 185 mg, 0.94 mmol) in DMF (7 mL) was added 2-(S)-amino-3-pyridin-4-yl propionic acid methyl ester hydrochloride (Preparation 93, 204 mg, 0.94 mmol) followed by TBTU (333 mg, 1.04 mmol) and DIPEA (740 μL, 4.24 mmol), and the reaction stirred at rt for 16 h. Solvent was removed in vacuo and the residue partitioned between ethyl acetate (30 mL) and water (30 mL). The organic layer was washed with water (2×30 mL), NaHCO3 solution (3×40 mL) then brine (3×50 mL), dried (MgSO4) and the solvent removed in vacuo. Purification by chromatography (SiO2, EtOAc) gave the title compound as a pink powder. m/z (ES+)=359.11 [M+H]+; RT=2.42 min.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)=[CH:9][C:8]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:30](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[CH:17]1([C:15]2[NH:14][N:13]=[C:12]([N:11]3[C:10]4[CH:9]=[C:8]([NH:20][C@H:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[CH3:22])[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2]=4[N:1]=[CH:30]3)[CH:16]=2)[CH2:19][CH2:18]1
Reactant: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c(N)c(C(N)=O)c1)c1ccc(F)cc1
Reactant: CC(=O)O
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H](Nc1cc(C(N)=O)c2ncn(-c3cc(C4CC4)[nH]n3)c2c1)c1ccc(F)cc1
Yield: 11.1 %

Procedure:
The mixture of (S)-2-amino-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(1-(4-fluorophenyl)ethylamino)benzamide (Method 100, 3.95 g, 10 mmol) and formamidine acetate (2.2 g, 21 mmol) in EtOH (50 ml) was heated at reflux for 36 hours. After cooling, the reaction mixture was treated with saturated sodium bicarbonate solution (30 ml) and EtOAc (80 ml). The organic layer was separated, washed with brine (30 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc-MeOH=30:1) to give the title compound as an off-white solid (0.45 g, 11%). 1H NMR (400 MHz) 12.79 (s, 1H), 9.00 (d, J=2.8 Hz, 1H), 8.42 (s, 1H), 7.67 (d, J=2.8 Hz, 1H), 7.43 (m, 2H), 7.38 (d, J=2.0 Hz, 1H), 7.09 (m, 3H), 6.59 (d, J=6.4 Hz, 1H), 6.16 (d, J=1.6 Hz, 1H), 4.54 (m, 1H), 1.97 (m, 1H), 1.43 (d, J=6.4 Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 404; Found: [M+H]+ 405.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:12]=[N:11][C:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([N:24]4[CH2:28][N:27]=[C:26]([C:29]([F:32])([F:31])[F:30])[O:25]4)=[CH:19][C:18]=3[CH3:33])=[CH:9][CH:8]=2)OCC[O:3]1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>O>[C:2]([C:7]1[N:12]=[N:11][C:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([N:24]3[CH2:28][N:27]=[C:26]([C:29]([F:32])([F:31])[F:30])[O:25]3)=[CH:19][C:18]=2[CH3:33])=[CH:9][CH:8]=1)(=[O:3])[CH3:1]
Reactant: Cc1cc(N2CN=C(C(F)(F)F)O2)cc(C)c1OCCCc1ccc(C2(C)OCCO2)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(CCCOc2c(C)cc(N3CN=C(C(F)(F)F)O3)cc2C)nn1
Yield: 65.8 %

Procedure:
A mixture of 0.5 g (1.08 mmol) of 6-(2-methyl-1,3-dioxolan-2-yl)-3-[3-[2,6-dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-2-yl)-phenoxy]-propyl]-pyridazine from example 8f, 8 mL of acetic acid, and 2 mL of water was heated to reflux. After adding acid solution, the reaction mixture was refluxed for 5 h. Upon cooling, the above reaction mixture was added to a freshly prepared sodium bicarbonate solution with stirring. The product was isolated and purified by chromatography on MPLC eluting with 30-50% ethyl acetate/hexane and recrystallized from hexane to afford 0.30 g (66%) of 6-acetyl-3-[3-[2,6-dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-2-yl)-phenoxy]-propyl]-pyridazine (R1, R2 =3,5-dimethyl, R3 =6-acetyl, R4 =hydrogen, R5 =5-trifluoromethyl-1,2,4-oxadiazolyl, Y=1,3-propylene), as a crystalline solid, m.p. 86°-87° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:12]2[N:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:14][N:13]=2)[CH:7]=[C:8]([Br:11])[C:9]=1[OH:10].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([C:12]2[N:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:14][N:13]=2)[CH:7]=[C:8]([Br:11])[C:9]=1[O:10][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1nc(-c2cc(Br)c(O)c(Br)c2)no1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2cc(Br)c(OCc3ccc(OC)cc3)c(Br)c2)no1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
Sodium hydride (100 mg of a 60% suspension in oil, 2.5 mmol) was added to a stirred solution of ethyl 3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylate (980 mg, 2.5 mmol) in dry dimethylformamide (5 mL) under nitrogen and the mixture was stirred at room temperature for 15 minutes. 4-Methoxybenzyl chloride (470 mg, 3.0 mmol) was added and the resulting solution was stirred at 50° C. for 20 h. The cooled mixture was treated with water (10 mL) to give a colourless solid that was filtered, washed with water and dried. Crystallization from di-isopropyl ether gave the title compound (840 mg, 65%) as a colourless powder. 1H NMR δ (ppm) (DMSO-d6): 1.41 (3 H, t), 3.52 (3 H, s), 4.49 (2 H, t), 5.06 (2 H, s), 7.01 (2 H, d), 7.53 (2H, d), 8.30 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C(=O)([O-])O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl>O1CCCC1.O>[F:9][C:4]1[CH:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(O)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(O)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
To a suspension of 4-amino-2-fluorophenol (60 g, 472 mmol) in tetrahydrofuran/water (=1/1, 600 mL) was added sodium hydrogen carbonate (43.6 g, 519 mmol), and benzyl chloroformate (74.1 mL, 519 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature for 16 hr, 2N hydrochloric acid (150 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, the residue was washed with hexane/diethyl ether (=1/1) and collected by filtration to give the title compound (82.5 g, 67%). The solvent of the filtrate was evaporated under reduced pressure, and the residue was washed with hexane/diethyl ether (=1/1) and collected by filtration to give the title compound (17.7 g, 14%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]([NH:14]C(OCC1C=CC=CC=1)=O)=[CH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1.C(OCC)(=O)C>[Pd].CO>[CH3:1][O:2][C:3](=[O:25])[CH:4]([NH2:14])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1
Reactant: COC(=O)C(=Cc1ccc(OC)nc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(N)Cc1ccc(OC)nc1
Reaction time: 8 h

Procedure:
A flask containing 2-benzyloxycarbonylamino-3-(6-methoxy-pyridin-3-yl)-acrylic acid methyl ester (620 mg), palladium on charcoal (10%, 100 mg), ethyl acetate (10 mL) and methanol (20 mL) was flushed with nitrogen, then hydrogen, before finally affixing a balloon of hydrogen. The reaction was allowed to stir overnight. The flask was flushed with nitrogen, filtered through celite, and concentrated to give 390 mg (quant.) which was used without purification. Mass spec.: 211.11 (MH)+.
Reaction SMILES: [ClH:1].[NH2:2][OH:3].[CH3:4][CH2:5][CH2:6][C:7](=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)C>[ClH:1].[CH3:4][CH2:5][CH2:6][C:7](=[N:2][OH:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NO
Reactant: CCCCCC(=O)CCC
Agent: Cl
Solvent: CCO
Product: CCCCCC(CCC)=NO
Temperature: 25 °C
Yield: 75.3 %

Procedure:
Hydroxylamine hydrochloride (2.1 g) was added to a solution of 1-azabicyclo[3.2.2.]nonan-4-one (2.77 g) in ethanol (30 ml) and the mixture was heated under reflux for 2 h. On cooling the reaction mixture to room temperature, the white solid was collected by filtration and dried in vacuo to give the title compound (2.84 g, 75%).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC>ClCCl>[Cl:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: ClCCCNCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)N(CCCCl)CCc1ccccc1
Reaction time: 0.03 h

Procedure:
To a solution of valeryl chloride (342 mg, 338 μl, 2.83 mmol) in dichloromethane (6 ml) and cooled to 0° C. is added a solution of (3-chloro-propyl)-phenethyl-amine (Starting material Q-01e, 560 mg, 2.83 mmol). The colourless solution turns yellow and after 2 min, a solid crystallizes out. Upon dropwise addition of Et3N (315 mg, 409 μl, 2.83 mmol) the solution turns colourless again and the solid dissolves instantaneously. The mixture is allowed to stir for 4 h at which time yet again a solid had crystallized out. Saturated aqueous NH4Cl solution is added and the organic phase is washed once with some saturated aqueous NaHCO3 solution and dried over Na2SO4. The solvent is removed in vacuo and the residue is dried under high vacuum, yielding the title compound as an orange oil: tR=2.48 min (LC-2), ESI-MS (pos.): m/z 282.07 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 0.86-0.97 (m, 3H, CH3), 1.23-1.44 (m, 4H, CH2CH3), 1.55 (quint., 1H, CH2CH2CH3), 1.65 (quint., 1H, CH2CH2CH3), 1.95 (quint., 2H, CH2CH2N), 2.03-2.19 (m, 2H, CH2C═O), 2.90 (t, 2H, CH2Ph), 3.35-3.59 (m, 6H), 7.15-7.34 (m, 2Harom).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:19][C:6]2=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[S:8][C:9]([S:10]([CH3:12])=O)=[C:5]2[C:4](=[O:20])[CH2:3]1.[OH-].[Na+].SC[CH2:26][OH:27]>C(O)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:21])[CH2:19][C:6]2=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[S:8][C:9]([S:10][CH2:12][CH2:26][OH:27])=[C:5]2[C:4](=[O:20])[CH2:3]1
Reactant: CS(=O)c1sc(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Reactant: OCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)CC(=O)c2c(SCCO)sc(-c3ccccn3)c2C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
6,6-Dimethyl-3-methanesulphinyl-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (160 mg, 0.5 mmol) was suspended in ethanol (5 mL) and 4M sodium hydroxide solution (138 μL, 0.55 mmol) was added. 2-Mercaptoethanol (43 mg, 0.55 mmol) was added and the suspension was stirred at 20° C. for 2 h. After this time, further 2-mercaptoethanol (10 mg, 0.12 mmol) and 4M sodium hydroxide solution (35 μL, 0.12 mmol) was added and the mixture stirred for a further 2 h. The mixture was then diluted with ethyl acetate and 1M HCL (1 mL) was added. The ethyl acetate layer was washed with water, dried (Na2SO4), then evaporated to dryness. The residue was purified by chromatographed on silica gel, eluting with ethyl acetate, to yield the title compound as a pale yellow solid (58 mg, 36%). mp 175-177° C. Found: C, 61.18; H, 5.62; N, 3.97%. C17H19NO2S2 requires: C, 61.26; H, 5.70; N, 4.20%. 1HNMR (360 MHz, CDCl3)δ 1.08 (6H, s), 2.45 (2H, s), 2.93 (2H, s), 3.33 (2H, t, J=7.2 Hz), 3.98-4.02 (2H, m), 7.16-7.20 (1H, m), 7.46-7.49 (1H, m), 7.72-7.76 (1H, m), 8.64-8.66 (1H, m). MS (ES+) 334 (M+1).