Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:12][C:13]1[N:14]=[CH:15][N:16]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[CH:17]=1
Reactant: Cc1c[nH]cn1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-n2cnc(C)c2)cc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 9.8 %

Procedure:
A mixture of methyl 4-fluorobenzoate (1.00 g, 6.49 mmol), 4-methylimidazole (559 mg, 6.81 mmol), potassium carbonate (941 mg, 6.81 mmol) and DMF (30 ml) was stirred at 110° C. for 24 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was subjected to column chromatography using basic silica gel and eluted with ethyl acetate-methanol (1:0-1:1, v/v) to give the title compound (137 mg, 10%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[C:5]([CH3:17])[C:4]([C:18]([OH:20])=O)=[CH:3]1.C(Cl)(=O)C(Cl)=O.[CH3:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1>[CH3:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([NH:35][C:18]([C:4]2[C:5]([CH3:17])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]([F:16])([F:14])[F:15])[N:2]([CH3:1])[CH:3]=2)=[O:20])=[CH:33][CH:32]=1)(=[O:29])=[O:30]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1c(C(=O)O)cn(C)c1-c1ccccc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cn(C)c1-c1ccccc1C(F)(F)F
Reaction time: 0.5 h
Yield: 27.5 %

Procedure:
To a solution of 1,4-dimethyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid (56 mg, 0.20 mmol) in DCM (4 mL) was added oxalyl chloride (22 pt, 0.25 mmol). After stirring 30 min, solvent was removed in vacuo to give an oil, which was re-dissolved in anhyd THF (4 mL). To this solution were added 4-methanesulfonyl-aniline (68 mg, 0.40 mmol) and DIEA (140 μL, 0.8 mmol) and the mixture was stirred at 60° C. overnight. After cooling, solvent was removed in vacuo to give a crude residue, which was purified by column chromatography on silica gel, eluted with EtOAc-hexane (0:100 to 25:75) to give the title compound (24 mg, 28%). 1H-NMR (CDCl3): δ 7.89-7.91 (m, 2H), 7.80 (m, 3H), 7.57-7.66 (m, 3H), 7.33 (d, 1H), 7.30 (s, 1H), 3.32 (s, 3H), 3.05 (s, 3H), 2.12 (s, 3H). MS (ES): 437 (MH+). E. In a manner similar to that described for Example 16D, the following compounds were prepared from the appropriate anilines:
Reaction SMILES: [CH2:1]([C:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[CH:7][C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].COS([O-])(=O)=O.[CH3:27][S:28][C:29](=[S+]C)[S:30][CH3:31]>O1CCOCC1>[CH3:27][S:28][C:29]([S:30][CH3:31])=[C:7]1[C:6](=[O:16])[C:5]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:1][CH2:2][CH2:3][CH3:4])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:15]
Reactant: CSC(SC)=[S+]C
Reactant: CCCCC1(CCCC)C(=O)C=C(O)c2ccccc21
Agent: COS(=O)(=O)[O-]
Solvent: C1COCCO1
Product: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of the product of Example 5B (25 mg, 0.092 mmol) in dioxane (4 mL) was treated with the product of Example 5A (71 mg, 0.27 mmol) and stirred at 100° C. for 2 hours, cooled to 25° C., diluted with ice water and extracted with ethyl acetate (3×). The combined organic layers were washed with water (3×) and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound. 1H NMR (300 MHz, DMSO-d6): δ 8.05 (m, 1 H), 7.66 (m, 1 H), 7.56 (d, J=7.72 Hz, 1 H), 7.43 (t, J=6.80 Hz, 1 H), 2.51 (m, 6 H), 2.10 (m, 2 H), 1.82 (m, 2 H), 1.09 (m, 4 H), 0.69 (m, 10 H).
Reaction SMILES: [I-].[K+].[SH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9](=[O:15])[CH2:8][CH2:7]2.Cl[C:17]1[S:18][C:19]([C:22]2([O:30][CH3:31])[CH2:27][CH2:26][O:25][C:24]([CH3:29])([CH3:28])[CH2:23]2)=[CH:20][N:21]=1>>[CH3:31][O:30][C:22]1([C:19]2[S:18][C:17]([S:3][C:4]3[CH:5]=[C:6]4[C:11](=[CH:12][CH:13]=3)[N:10]([CH3:14])[C:9](=[O:15])[CH2:8][CH2:7]4)=[N:21][CH:20]=2)[CH2:27][CH2:26][O:25][C:24]([CH3:29])([CH3:28])[CH2:23]1
Reactant: COC1(c2cnc(Cl)s2)CCOC(C)(C)C1
Reactant: CN1C(=O)CCc2cc(S)ccc21
Agent: [I-]
Agent: [K+]
Product: COC1(c2cnc(Sc3ccc4c(c3)CCC(=O)N4C)s2)CCOC(C)(C)C1
Yield: 80 %

Procedure:
Using an analogous procedure to that described in Example 1 except that a catalytic amount (0.01 g) of potassium iodide was added, 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with 4-(2-chlorothiazol-5-yl)-4-methoxy-2,2-dimethyltetrahydropyran to give 4-methoxy-2,2-dimethyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thiazol-5-yl]tetrahydropyran in 80% yield as a foam;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)([O-])=O.[CH3:25][N:26]([CH3:44])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])=[CH:29][CH:28]=1>>[CH3:16][N:15]([CH3:17])[C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:7][C:6]2[CH:19]=[CH:20][C:21]3[NH:22][C:40]([C:39]4[CH:38]=[CH:37][C:36]([C:34](=[O:35])[NH:33][C:30]5[CH:31]=[CH:32][C:27]([N:26]([CH3:44])[CH3:25])=[CH:28][CH:29]=5)=[CH:43][CH:42]=4)=[N:1][C:4]=3[CH:5]=2)=[O:18])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(NC(=O)c2ccc(C=O)cc2)cc1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Product: CN(C)c1ccc(NC(=O)c2ccc(-c3nc4cc(NC(=O)c5ccc(N(C)C)cc5)ccc4[nH]3)cc2)cc1

Procedure:
Compound 193 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-dimethylaminobenzoyl)aniline and 4-(4-dimethylaminophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C31H30N6O2: 519.24; found: 519.04.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:35]1[N:36]=[C:37]([NH:40]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:38][CH:39]=1)\[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:18])=[C:12]([CH2:15]I)[CH2:13][S:14][C@H:9]12)=[O:6].[CH3:60][O:61][C:62]([NH:64][C:65]1[S:66][C:67]2[CH:72]=[CH:71][N:70]=[CH:69][C:68]=2[N:73]=1)=[O:63].C(O)(C(F)(F)F)=O>CS(C)=O.CCOCC.C1(OC)C=CC=CC=1>[NH2:40][C:37]1[S:38][CH:39]=[C:35](/[C:4](=[N:3]/[O:2][CH3:1])/[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O-:19])=[O:18])=[C:12]([CH2:15][N+:70]4[CH:71]=[CH:72][C:67]5[S:66][C:65]([NH:64][C:62]([O:61][CH3:60])=[O:63])=[N:73][C:68]=5[CH:69]=4)[CH2:13][S:14][C@H:9]23)=[O:6])[N:36]=1
Reactant: COC(=O)Nc1nc2cnccc2s1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: CS(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc4sc(NC(=O)OC)nc4c3)CS[C@H]12)c1csc(N)n1
Reaction time: 1 h

Procedure:
A solution of diphenylmethyl 7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VIIa] (419 mg, 0.45 mmole) and 2-methoxycarbonylaminothiazolo[4,5-c]pyridine (94 mg, 0.45 mmole) in 2 ml of dry DMSO was allowed to stand at room temperature for 1 hour and diluted with ether to give 514 mg of crude quaternary salt, which was treated with 5 ml of TFA and 3 drops of anisole at room temperature for 30 minutes. The mixture was evaporated in vacuo and triturated with ether to afford 338 mg of crude Is which was purified on a column of HP-20 resin (40 ml) using 30% aqueous CH3OH as an eluant to give 95 mg (35%) of Is. Mp. 156°~184° C. (dec.). Estimated purity by HPLC: 40%.
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.F[C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12]>CS(C)=O>[N:3]1([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: N#Cc1ccccc1F
Reactant: c1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1ccccc1-n1ccnc1
Reaction time: 1 h

Procedure:
To a stirred solution of KOH (5.81 g) in DMSO (15 mL) was added imidazole (5.0 g, 73.4 mmol). The mixture was stirred for 1 hour, then 2-fluorobenzonitrile (8.76 mL) in DMSO (10 mL) was added dropwise over 20 minutes. The reaction mixture was stirred at room temperature overnight and the product was collected by filtration and washed with water to afford 10.91 g of 2-(1-imidazolyl)benzonitrile as a white solid.
Reaction SMILES: O1CCCC1.Cl[Si:7]([CH2:10][Cl:11])([CH3:9])[CH3:8].[CH2:12]([Mg]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CCCCCC>[CH2:12]([Si:7]([CH2:10][Cl:11])([CH3:9])[CH3:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Si](C)(Cl)CCl
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(CCl)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 109.5 %

Procedure:
In a 2 L 3-necked flask equipped with a nitrogen inlet, a 500 ml dropping funnel and a thermometer, was placed 500 ml of tetrahydrofuran. Chloro(chloromethyl)-dimethylsilane (100 ml, 0.744 mol) was added by syringe and the colorless solution cooled to 0° C. in an ice/acetone bath. Then benzylmagnesium chloride (2.0 M solution, 400 ml, 0.8 mol) was transferred to the dropping funnel by syringe and added dropwise over 2 hours. A slightly exothermic reaction was observed and the temperature was maintained below 10° C. After addition of the benzylmagnesium chloride was complete, the ice bath was allowed to warm up to room temperature without heating, and the reaction mixture was stirred overnight. Thereafter hexane (300 ml) was added and the reaction mixture was worked up by dropwise addition of saturated aqueous ammonium chloride (300 ml) and transferred to a 2 L separatory funnel with additional hexane (300 ml). After partitioning, the organic layer was washed with saturated aqueous ammonium chloride (200 ml) and saturated aqueous sodium chloride (200 ml). The combined aqueous layers were backwashed with hexane (2×500 ml). The combined organic layers were dried over magnesium sulfate, evaporated on a rotary evaporator, and finally evaporated with an oil pump to give a colorless oil 162.0 g (109.5% yield). A quantitative yield was assumed with a purity of the crude product as 91.3%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14]([CH3:16])=[C:13]([CH3:17])[N:12]=[C:11]([NH2:18])[C:10]=2[N:9]=[C:8]1[CH2:19][CH3:20].[C:21]([N:29]=[C:30]=[O:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:18][C:11]1[C:10]2[N:9]=[C:8]([CH2:19][CH3:20])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][C:21](=[O:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:31])[C:15]=2[C:14]([CH3:16])=[C:13]([CH3:17])[N:12]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CCc1nc2c(N)nc(C)c(C)c2n1CCOCCN
Product: CCc1nc2c(N)nc(C)c(C)c2n1CCOCCNC(=O)NC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A solution of 1-[2-(2-aminoethoxy)ethyl]-2-ethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (1.60 g, 5.77 mmol) was treated with benzoyl isocyanate (0.98 g, 6.6 mmol) using the method described in Example 105. The crude product was purified by column chromatography on silica gel (150 mL, eluting with 90:10 dichloromethane:methanol) and recrystallized from acetonitrile (75 mL/g). The crystals were subsequently recrystallized twice from 2-propanol (40–44 mL/g) and then stirred in water for 30 minutes and isolated by filtration. The solid was dried for three days under high vacuum to provide 0.54 g of N-{2-[2-(4-amino-2-ethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethyl}-N′-benzoylurea as a white solid, mp 185–187° C. 1HNMR (300 MHz, CDCl3) δ 8.98 (br s, 1H), 8.87 (br t, 1H), 7.93–7.87 (m, 2H), 7.63–7.56 (m, 1H), 7.52–7.44 (m, 2H), 4.84 (s, 2H), 4.45 (t, J=5.8 Hz, 2H), 3.76 (t, J=5.8, 2H), 3.57–3.46 (m, 4H), 2.91 (q, J=7.5, 2H), 2.42 (s, 6H), 1.41 (t, J=7.5, 3H); MS (APCI) m/z 425 (M+H)+; Anal. Calcd for C22H28N6O3.0.25 H2O: C, 61.59; H, 6.70; N, 19.59. Found: C, 61.25; H, 6.90; N, 19.72.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[N:30][OH:31])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[N:30][OH:31])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OC2Cc3ccccc3C2=NO)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: ON=C1c2ccccc2CC1Oc1ccc(Cl)cc1OC1CNC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The title compound from Step B was dissolved in CH2Cl2 (20 mL), and CF3COOH (3 mL) was added. The mixture was stirred at 25° C. for 4 h. After concentration and purification via PTLC, the title compound was obtained (91 mg). MS (ESI): mass calcd. for C18H17ClN2O3, 344.1; m/z found, 345.0 [M+H]+. 1H NMR (MeOD): 8.40 (d, J=8.0 Hz, 1H), 7.50-6.80 (m, 6H), 5.48-5.46 (m, 1H), 5.18-5.10 (m, 1H), 4.45-4.32 (m, 2H), 4.18-4.08 (m, 2H), 3.62-3.52 (m, 1H), 3.16-3.08 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])(=[O:13])[CH:11]=[CH2:12].C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrC1C=CC=CC=1OC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:11][C:10]([O:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:13])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: C=CC(=O)OCC(CC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccccc1Br
Product: CCCCC(CC)COC(=O)C=Cc1ccc(OC)cc1
Temperature: 170 °C
Yield: 82 %

Procedure:
A reaction mixture of 18.7 g of 4-bromoanisole, 20.3 g of 2-ethylhexyl acrylate, 6.36 g of sodium carbonate, 0.0025 g of palladium(II) acetate, 0.21 g of triphenylphosphane and 5.0 g of polyethylene glycol 1000 was heated to 170° C. under nitrogen. The conversion of bromoanisole, determined by gas chromatography, was 100% after 2 hours. After vacuum distillation, an 82% yield of 2-ethylhexyl 4-methoxycinnamate, based on the 4-bromoanisole reacted, was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])C)=[O:7])([CH3:4])([CH3:3])C.[F:17][C:18]([F:35])([F:34])[C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][C@@H:28]3[C@@H:30]([NH2:33])[CH2:31][CH2:32][C@@H:27]3[CH2:26]2)=[N:23][CH:24]=1.C(N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[O:16]=[C:14]([NH:33][C@@H:30]1[C@@H:28]2[C@@H:27]([CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:35])([F:34])[F:17])=[CH:24][N:23]=3)[CH2:29]2)[CH2:32][CH2:31]1)[C@@H:9]([NH:8][C:6](=[O:7])[O:5][CH:1]([CH3:3])[CH3:4])[CH2:10][CH2:11][CH3:13]
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CCC[C@H](NC(=O)OC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (S)-2-(isopropoxycarbonylamino)pentanoic acid from Step A for N-(tert-butoxycarbonyl)-L-leucine and (3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Step B of Example 262 for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.52 (d, J=1.0, 1H), 7.94 (dd, J=4.3, 2.4, 1H), 7.60 (dd, J=8.9, 2.5, 1H), 7.07 (d, J=7.0, 1H), 6.35 (d, J=8.9, 1H), 5.03 (dt, J=12.5, 6.2, 1H), 4.49 (dd, J=13.9, 8.0, 1H), 4.35-4.19 (m, 1H), 3.73 (dd, J=11.3, 3.6, 1H), 3.66 (dd, J=11.3, 7.6, 1H), 3.57 (dd, J=11.0, 8.0, 1H), 3.32 (dd, J=11.2, 3.9, 1H), 2.81-2.66 (m, 2H), 2.10 (dt, J=12.4, 7.0, 1H), 2.04-1.88 (m, 2H), 1.86-1.75 (m, 1H), 1.72-1.60 (m, 1H), 1.57-1.46 (m, 2H), 1.45-1.33 (m, 1H), 1.21 (d, J=6.2, 3H), 1.18 (d, J=6.2, 3H), 0.87 (t, J=7.4, 3H); MS (ESI+) m/z 457 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([CH3:14])([CH3:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][N:9]1[C:8]([CH3:14])([CH3:13])[C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=2[S:10]1(=[O:12])=[O:11])[CH3:16]
Reactant: CCOC(CBr)OCC
Reactant: CC1(C)NS(=O)(=O)c2cccc(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CN1C(C)(C)c2c(Cl)cccc2S1(=O)=O)OCC
Temperature: 120 °C
Reaction time: 5 h
Yield: 65.3 %

Procedure:
7.7 g (33 mmol) of 4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide, 8.25 ml (55 mmol) of bromoacetaldehyde diethyl acetal and 7.0 g of potassium carbonate were taken up in 100 ml of dry DMF and stirred at 120° C. for 5 h. The reaction mixture was poured into ice-water and then extracted with ethyl acetate, and the organic phase was washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure, the crude product was purified by column chromatography. 7.5 g (65%) of the product were obtained as an oil in this way.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:27](=[O:28])[C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[C:42]5[NH:46][C:45](=[O:47])[O:44][N:43]=5)=[CH:32][CH:31]=4)=[C:25]([CH2:48][CH2:49][CH3:50])[N:24]=[C:23]3[CH3:51])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>O1CCCC1>[OH:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[C:27](=[O:28])[C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[C:42]5[NH:46][C:45](=[O:47])[O:44][N:43]=5)=[CH:32][CH:31]=4)=[C:25]([CH2:48][CH2:49][CH3:50])[N:24]=[C:23]3[CH3:51])=[CH:20][CH:21]=2)[CH2:11][CH2:10]1
Reactant: CCCc1nc(C)n(-c2ccc(OC3CCC(O[Si](C)(C)C(C)(C)C)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC3CCC(O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 67.9 %

Procedure:
To a solution of 3-{4-[(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (1.74 g) in tetrahydrofuran (6 mL) was added tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 3.7 mL), and the mixture was stirred at 60° C. for 12 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.99 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([N:25]4[CH2:30][CH2:29][S:28][CH2:27][CH2:26]4)=[O:23])=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: C1CSCCN1
Product: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)N1CCSCC1
Yield: 37 %

Procedure:
As described for example 31b, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.20 mmol) was converted, using thiomorpholine instead of 4-aminotetrahydropyran, to the title compound (32 mg, 37%) which was obtained as a colourless gum after purification by chromatography (silica, heptane:ethyl acetate 1:0 to 0:1 then dichloromethane:methanol 1:0 to 95:5). MS: m/e=433.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][Si:48]([C:51]#[CH:52])([CH3:50])[CH3:49]>CN(C=O)C.[Cu]I>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([C:52]#[C:51][Si:48]([CH3:50])([CH3:49])[CH3:47])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:7]=1
Reactant: CCC(CC)COc1ccc(Br)cc1Cn1nc(CCC(=O)OC)cc1C
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCC(CC)COc1ccc(C#C[Si](C)(C)C)cc1Cn1nc(CCC(=O)OC)cc1C
Temperature: 120 °C
Yield: 48.4 %

Procedure:
A mixture of 3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.0774 g, 0.18 mmol), [PdCl2(PPh3)]2 (0.007 g, 0.01 mmol), PPh3 (0.0094 g, 0.018 mmol) mmol), CuI (2 mg, 0.01 mmol), trimethylsilylacetylene (0.0196 g, 0.2 mmol), Et2N (0.07314 g, 2.72 mmol in DMF (1 ml) heated at 120° C. in a microwave reactor under a N2 atmosphere for 50 min. The mixture was partitioned between 0.1 M HCl and EtOAc. The organic layer was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by MPLC (20 g SiO2 cartridge, eluent 90% iso-hexane-10% EtOAc) yielding 3-{1-[5-trimethylsilanylethynyl-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.0396 g). This was dissolved in THF (20 ml), MeOH (20 ml), glacial acetic acid (8 ml) and Bu4NF solution (24 ml, 1M) was added. The mixture was stirred at RT overnight then heated at 60° C. for 3 hours, thereafter cooled to RT and partitioned between sat. NH4Cl solution and EtOAc, the organic layer was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by MPLC (20 g SiO2 cartridge, eluent 85% iso-hexane-15% EtOAc) yielding 3-{1-[5-Ethynyl-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.0078 g) which was converted to the title compound following the method in Example 1, Step 8.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[C:9]2[N:10]([CH:14]=[CH:15][N:16]=2)[N:11]=[CH:12][CH:13]=1.[I:17]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[I:17][C:14]1[N:10]2[N:11]=[CH:12][CH:13]=[C:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[N:16][CH:15]=1
Reactant: Cc1ccncc1-c1ccnn2ccnc12
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccncc1-c1ccnn2c(I)cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8-(4-methylpyridin-3-yl)imidazo[1,2-b]pyridazine, (480 mg, 1.48 mmol) in CHCl3 (15 mL) were added N-iodo succinimide (400 mg, 1.776 mmol) and TFA (0.34 g, 2.96 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO3 and extracted with CH2Cl2. The combined organic layer was washed with water and brine, and dried over Na2SO4. The crude product was purified by BIOTAGE® (20-40% EtOAc/CH2Cl2; 1.2 L). 1H NMR (400 MHz, CDCl3) δ ppm 8.50-8.70 (3H, m), 7.90 (1H, s), 7.22-7.39 (4H, m), 7.06 (1H, d, J=4.53 Hz), 2.32 (3H, s); LC/MS: Rt=1.13 min. LC/MS (Condition A): 336.97.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([C:8]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=1[C:10](O)=[O:11])=O.O.[NH2:25][NH2:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:8]3[C:9](=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:10](=[O:11])[NH:26][N:25]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(-c3ccc(OC)c(OC)c3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 2-(3,4-dimethoxybenzoyl)-5-methoxybenzoic acid with hydrazine hydrate.