Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([CH3:35])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)=[CH:20][N:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:35][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:28][CH:29]=3)=[CH:20][N:19]=2)[N:14]=1)([CH3:8])[C:6]([OH:36])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCOc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.1 %

Procedure:
2-Methyl-2-({4-[2-({5-[4-(trifluoromethoxy)phenyl]pyrimidin-2-yl}oxy)ethyl]-1,3-thiazol-2-yl}thio)propionic acid tert-butyl ester (600 mg) obtained in Example 110-2 was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (350 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][CH:24]=1)[CH2:8][N:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)=[O:4].ClCCl.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[N:9]1([CH2:8][C:7]2[CH:6]=[C:5]([CH:24]=[CH:23][CH:22]=2)[C:3]([O:2][CH3:1])=[O:4])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: COC(=O)c1cccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(CN2CCNCC2)c1

Procedure:
Tert-butyl 4-(3-(methoxycarbonyl)benzyl)piperazine-1-carboxylate (1.25 g, 3.74 mmol) was stirred with a 4/1 solution of dichloromethane/trifluoroacetic acid (20 mL) for 1 hour at room temperature. The solution was then concentrated under vacuum to afford the title compound (1.73 g). MS (ESI) m/z 235.1 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[O:22]([CH2:29][CH2:30][CH2:31]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:22]([CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCCCOc1ccccc1
Reactant: COc1ccc(S(=O)(=O)N2CCc3ccccc32)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2CCc3ccccc32)cc1OCCCOc1ccccc1
Temperature: 75 °C
Yield: 86.8 %

Procedure:
A solution of N-(3-hydroxy-4-methoxybenzenesulphonyl)- 1,2-dihydroindole (0.2 g) and 3-phenoxypropylbromide (0.15 g) in N,N-dimethylformamide (20 ml) was treated with cesium carbonate (0.3 g) and heated at 75° C. overnight. The solvent was removed in vacuo and the residue partitioned between dichloromethane (30 ml) and water (15 ml). The organic phase was washed with brine (15 ml) then dried over magnesium sulphate and concentrated in vacuo. The residue was purified using column chromatography eluting with dichloromethane to yield the title compound as a white solid (0.25 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 70 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 70%). 1H NMR (300 MHz, CDCl3): δ 2.43-2.49 (m, 3H), 3.13-3.21 (m, 4H), 3.77 (s, 3H), 4.11-4.13 (m, 4H), 6.88-6.99 (m, 4H), 7.13 (m, 1H), 7.25 (m, 1H), 7.48-7.65 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:29]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of 11e, and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.68 (d, 1H), 7.97 (d, 1H), 7.87 (m, 2H), 7.79 (d, 2H), 7.47 (m, 1H), 7.33 (d, 1H), 7.18 (d, 2H), 7.12 (m, 1H), 7.02 (d, 1H), 6.94 (d, 1H), 6.90 (s, 1H), 4.52 (s, 2H), 4.47 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.50 (t, 2H); MS 508 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Clc1ccc(Br)nc1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 436 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18](O)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:23]=4[OH:22])[CH2:28]3)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: Cc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(C)cc3)nc3ccccc13)C2
Yield: 36 %

Procedure:
Reaction of 2-(4-methylphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 12 (36% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.41 (s, 3H), 2.63 and 2.90 (2t, 2H), 3.47 and 4.03 (2t, 2H), 3.74 and 3.80 (2s, 3H), 4.38 and 4.92 (2s, 2H), 6.32 and 6.77 (2d, 1H), 6.70 and 6.91 (2d, 1H), 7.36-7.41 (m, 2H), 7.67-7.77 (m, 1H), 7.84-7.95 (2d, 1H), 8.04-8.15 (m, 2H), 8.39-8.45 (m, 2H), 8.68 and 8.72 (2s, 1H); MS (ESI) m/z 426 ([M+H]+).
Reaction SMILES: Br[CH:2]([C:4]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)[CH3:3].Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:28][NH2:29])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][CH:25]([F:27])[F:26]>>[Cl:14][C:13]1[C:4]2[CH:2]([CH3:3])[N:29]([CH2:28][C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][CH:25]([F:26])[F:27])=[C:17]([Cl:16])[CH:18]=3)[C:6](=[O:8])[C:5]=2[CH:10]=[CH:11][N:12]=1
Reactant: NCc1cnc(OCC(F)F)c(Cl)c1
Reactant: COC(=O)c1ccnc(Cl)c1C(C)Br
Agent: Cl
Product: CC1c2c(ccnc2Cl)C(=O)N1Cc1cnc(OCC(F)F)c(Cl)c1
Yield: 16 %

Procedure:
The title compound is prepared in 16% yield (45 mg, colorless oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-6, racemate) and (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanamine hydrochloride (223 mg, 0.86 mmol, Amine-12) in a similar manner to Intermediate-2.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[C:16]([CH3:28])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:36]([CH3:38])[CH3:37].O>CN(C)C=O>[C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH:25]4[CH2:27][CH2:26]4)=[CH:23][CH:24]=3)=[C:16]([CH3:28])[N:15]([CH:36]([CH3:38])[CH3:37])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CC(C)I
Reactant: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cc2ccc(C3CC3)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(C)C
Reaction time: 0.58 h

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-5-methyl-4-[(4-cyclopropylphenyl)methyl]-1H-pyrazole (56 mg) and cesium carbonate (23 mg) in N,N-dimethylformamide (1.5 mL) was added 2-iodopropane (0.043 mL) at 8° C., and the mixture was stirred for 35 minutes. To the reaction mixture was added water, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol). The obtained crude product was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloromethane/methanol=7/1) to give 3-(β-D-glucopyranosyloxy)-5-methyl-1-isopropyl-4-[(4-cyclopropylphenyl)methyl]-1H-pyrazole (45 mg).
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:7]=1[CH:8]([O:14][CH3:15])[O:9]2.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[F:21][CH:2]([F:1])[O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6]1[CH:19]=[CH:18][C:17]([NH:20][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:16][C:7]=1[CH:8]([O:14][CH3:15])[O:9]2
Reactant: CS(=O)(=O)Cl
Reactant: COC1Oc2cccc(OC(F)F)c2-c2ccc(N)cc21
Solvent: c1ccncc1
Product: COC1Oc2cccc(OC(F)F)c2-c2ccc(NS(C)(=O)=O)cc21
Reaction time: 15 h

Procedure:
To a solution of Example 96B (3.9 g, 13 mmol) in pyridine (40ml) at 0° C. was added methylsulfonylchloride (1.5 g, 13 mmol). The mixture was stirred for 15 hour, concentrated under reduced pressure. The residue was dissolved in 10% HCl solution (50 mL) and extracted with ethyl acetate (3×30 mL). The combined extract were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate in hexanes to provide the titled compound. MS (ESI(−)Q1MS) m/z 370 (M−H)−.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.ClCCl.[F:26][C:27]1[CH:28]=[C:29]([C:34](=[O:62])[C:35](=[C:53]2[NH:57][C:56]3[CH:58]=[CH:59][CH:60]=[CH:61][C:55]=3[NH:54]2)[C:36]([C:38]2[CH:39]=[C:40]([S:44]([NH:47][C:48](=[NH:52])[CH:49]([OH:51])[CH3:50])(=[O:46])=[O:45])[CH:41]=[CH:42][CH:43]=2)=[O:37])[CH:30]=[C:31]([F:33])[CH:32]=1>C(OCC)(=O)C>[F:26][C:27]1[CH:28]=[C:29]([C:34](=[O:62])[C:35](=[C:53]2[NH:54][C:55]3[CH:61]=[CH:60][CH:59]=[CH:58][C:56]=3[NH:57]2)[C:36]([C:38]2[CH:39]=[C:40]([S:44]([NH:47][C:48](=[NH:52])[C:49](=[O:51])[CH3:50])(=[O:45])=[O:46])[CH:41]=[CH:42][CH:43]=2)=[O:37])[CH:30]=[C:31]([F:33])[CH:32]=1
Reactant: CC(O)C(=N)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)C(=N)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.6 %

Procedure:
Dess-Martin reagent (15 wt. % dichloromethane solution, 0.73 mL) was added to a dichloromethane (2 mL) solution of N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxypropanimidamide (90 mg), followed by stirring at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture, washed with water, dried over anhydrous magnesium sulfate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-2-oxopropanimidamide (57 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:31]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2ccc(Cl)cc2Cl)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]malonate and 2,4-dichlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:10])[N:5]([CH2:7][CH2:8][NH2:9])[CH:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][CH:22]=O)[CH:15]=[C:16]([F:19])[C:17]=1[CH3:18]>>[F:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][CH:22]2[NH:9][CH2:8][CH2:7][N:5]3[C:4]([CH3:10])=[N:3][C:2]([I:1])=[C:6]23)[CH:15]=[C:16]([F:19])[C:17]=1[CH3:18]
Reactant: Cc1c(F)cc(CCC=O)cc1F
Reactant: Cc1nc(I)cn1CCN
Product: Cc1c(F)cc(CCC2NCCn3c(C)nc(I)c32)cc1F

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 110° C.; 5 bars; 10 min.) between 2-(4-iodo-2-methyl-imidazol-1-yl)-ethylamine (696 mg; 2.774 mmol) and 3-(3,5-difluoro-4-methyl-phenyl)-propionaldehyde (510 mg; 2.774 mmol) afforded 8-[2-(3,5-difluoro-4-methyl-phenyl)-ethyl]-1-iodo-3-methyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by FC (DCM/MeOH=25/1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:19])=[N:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:20][N:21]=[C:22]=[O:23]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([NH:19][C:22]([NH:21][CH3:20])=[O:23])=[N:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Nc1n[nH]c(-c2ccncc2)c1-c1ccc(F)cc1
Reactant: CN=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CNC(=O)Nc1n[nH]c(-c2ccncc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine prepared as set forth in Example 2 (100 mg, 0.38 mmol), methyl isocyanate (22 mg, 0.39 mmol) and 4-dimethylaminopyridine (2.5 mg) in methylene chloride (10 ml) was stirred at room temperature for 30 minutes. The reaction was stripped in vacuo. The residue was triturated with hexane and the solid filtered to give pure N-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]-N′-methylurea, m. p. 212-213° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH3:14][O:15][C:16](=[O:23])[C@@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([NH:18][C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([O:15][CH3:14])=[O:23])=[O:7]
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: COc1cc(SC)ccc1C(=O)O
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1ccc(SC)cc1OC

Procedure:
Prepared in a similar manner to example 4 using 2-methoxy-4-(methylthio)benzoic acid and D-leucine methyl ester. MS (M+H, 326).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[C:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:28]4[CH:29]=[CH:30][C:25]([C:22](=[O:24])[CH3:23])=[CH:26][CH:27]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: COc1ccc(-c2nc3cc(-c4ccc(C(C)=O)cc4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 4-acetylphenylboronic acid (139 mg, 0.85 mmol) the subtitle compound was obtained (119 mg, 36%). 1H NMR (DMSO) δ 8.64(d, 1H), 8.46(dd, 1H), 8.16(d, 1H), 8.06(d, 2H), 7.93–7.90(m, 3H), 7.81(dd, 1H), 7.63(d, 1H), 4.05(s, 3H), 2.63(s, 3H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[N+]([C:7]1[C:12]([CH3:13])=[CH:11][N+:10]([O-:14])=[C:9]([CH3:15])[C:8]=1[CH3:16])([O-])=O>CO>[CH3:1][O:2][C:7]1[C:12]([CH3:13])=[CH:11][N+:10]([O-:14])=[C:9]([CH3:15])[C:8]=1[CH3:16]
Reactant: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C)c[n+]([O-])c(C)c1C
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of sodium methoxide, prepared from Na (8.62 g, 0.375 mol) and MeOH (500 ml), was added 4-nitro-2,3,5-trimethylpyridine-N-oxide (45.5 g, 0.25 mol). The reaction mixture was refluxed for 5 h, cooled to rt and most of the solvent removed in vacuo. The slurry was diluted with water (100 ml) and extracted with CH2Cl2 (3×100 ml). The extracts were combined, washed with sat. NaCl solution, dried (MgSO4) and the solvent removed in vacuo to give 4-methoxy-2,3,5-trimethylpyridine-N-oxide as a semi-solid (37.5 g, 90%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:17])=[C:11]2[CH3:18])=[O:7])[CH3:4].[C:19](Cl)(=[O:21])[CH3:20].O>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:19](=[O:21])[CH3:20])[C:12]([CH3:17])=[C:11]2[CH3:18])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.2 %

Procedure:
Sodium hydride (0.8 g of 50% dispersion in mineral oil) was added portionwise to a stirred solution of 2,3-dimethylindole-5-carboxylic acid ethyl ester (3.50 g) in dry N,N-dimethylformamide (25 ml) and the mixture was stirred at room temperature for 30 minutes and then cooled to 0°. A solution of acetyl chloride (1.27 g) in dry N,N-dimethylformamide (2.5 ml) was added dropwise with stirring over 2 minutes. The resulting mixture was stirred at room temperature for 3 hours and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed well with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform first gave mineral oil followed by product. Evaporation of the product-containing fractions gave a solid which was crystallised from ethyl acetate/petrol (b.p. 60°-80°) to give 1-acetyl-2,3-dimethylindole-5-carboxylic acid ethyl ester (1.22 g), m.p. 98°-101°.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]1([C:14]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][S:17](=O)[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[C:8]1([C:14]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=[CH:16][S:17][CH2:18][CH2:19]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S1CCC(c2ccccc2)(c2ccccc2)CC1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: C1=CC(c2ccccc2)(c2ccccc2)CCS1
Yield: 83.3 %

Procedure:
3.95 cm3 of acetic anhydride are added to a suspension of 2.7 g of 4,4-diphenyltetrahydrothiapyran 1-oxide in 30 cm3 of anhydrous toluene. The mixture is refluxed for 20 hours and concentrated to dryness at 60° C. under reduced pressure (2.7 kPa and then 0.13 kPa). The oily residue is crystallized from diisopropyl oxide, the crystals are drained and dried. 2.1 g of 3,4-dihydro-4,4-diphenyl-2H-thiapyran are obtained in the form of white crystals; melting point 78° C.
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][CH2:7][C@@H:8]([NH:9][C:10](=[O:25])[C@H:11]([CH2:21][CH:22]([CH3:24])[CH3:23])[N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:13])[C@@H:4]2[CH2:3][NH:2]1.C(N(CC)CC)C.[F:33][C:34]([F:46])([F:45])[C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1>ClCCl>[C:17]([O:16][C:14]([N:12]([CH3:13])[C@H:11]([C:10]([NH:9][C@H:8]1[C@H:4]2[C@H:5]([CH2:1][N:2]([S:41]([C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:33])([F:45])[F:46])[CH:36]=3)(=[O:43])=[O:42])[CH2:3]2)[CH2:6][CH2:7]1)=[O:25])[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:15])([CH3:18])([CH3:19])[CH3:20]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CNC[C@H]21)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N1-[(3aS,4R,6aR)-Octahydrocyclopenta[c]pyrrol-4-yl]-N2-(tert-butyloxycarbonyl)-N2-methyl-L-leucinamide from Step A (220 mg, 0.622 mmol) in dichloromethane (5.0 mL) was added triethylamine (0.130 mL, 0.934 mmol) followed by 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.110 ml, 0.685 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction was reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-24). The title compound was eluted with a gradient of 0% to 10% methanol (2 N ammonia)/dichloromethane over 20 minutes to give N2-(tert-butyloxycarbonyl)-N2-methyl-N1-((3aS,4R,6aR)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydrocyclopenta[c]pyrrol-4-yl)-L-leucinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.32 (bs, 1H), 8.18-8.13 (m, 1H), 8.02-7.95 (m, 1H), 7.90-7.84 (m, 1H), 7.68 (t, J=7.9, 1H), 4.17-4.09 (m, 1H), 3.77-3.69 (m, 1H), 3.20-3.11 (m, 2H), 3.05-2.97 (m, 4H), 2.53-2.47 (m, 2H), 1.98-1.88 (m, 1H), 1.87-1.71 (m, 3H), 1.62-1.48 (m, 3H), 1.46 (s, 9H), 1.32-1.22 (m, 1H), 0.87 (dd, J=6.6, 15.5, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=O)[C:12]([C:16]#[N:17])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:13]1[N:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:11][C:12]=1[C:16]#[N:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(Cl)cc2Cl)cc1
Product: Cc1ccc(-c2cc(C#N)c(Cl)nc2-c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C

Procedure:
To an oven-dried round bottom flask fitted with a condenser was added the product of Step C (0.350 g; 0.986 mmol) and excess phosphorous oxychloride (1 mL). The reaction mixture was heated to reflux for 16 hours. The reaction mixture was allowed to cool to room temperature, and the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3 solution (2×), water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by MPLC (silica gel; 0-10% ethyl acetate:hexane) to afford 0.283 g of the desired product: m/e=375 (M+2) Rt=4.36 min on LCMS.