Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Se].O.[C]=O.[O:13]1CCC[CH2:14]1>C(N(CC)CC)C>[N:7]1[C:14](=[O:13])[N:8]=[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=12
Reactant: Nc1ccccc1N
Reactant: C1CCOC1
Agent: [C]=O
Agent: [Se]
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1N=c2ccccc2=N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
o-Phenylenediamine 1.35 g (12.5 m moles), selenium powder 0.99 g (12.5 m moles), water 1.6 ml (89 m moles), triethylamine 5 g (50 m moles) and tetrahydrofuran 100 ml were placed in a 200-ml capacity autoclave, and the atmosphere therein was replaced by carbon monoxide of 20 Kg/cm2. The contents in the autoclave were heated to 80° C. and held at the temperature for 3 hours with stirring. Thereafter the reaction mixture was cooled to room temperature, and carbon monoxide was removed from the autoclave. The reaction mixture was taken out of the autoclave and worked up in the same manner as in EXAMPLE 1 to provide benzimidazolone 1.66 g (99.0% yield) of 95.6% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[F-:13].[K+].C1OCCOCCOCCOCCOCCOC1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([F:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [F-]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(F)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the commercially available 3-chloro-4-fluorobenzenesulfonyl chloride (7 g, 30 mmol) in CH3CN (40 mL) was added KF (7 g, 120 mmol) and 18-crown-6 (0.5 g), then the mixture was stirred at room temperature overnight. The mixture was quenched with aqueous water and extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give the crude product which was purified by column to give the reagent R-12a (4.2 g, 95.5%) as a pale yellow solid. ESI-MS (M+1): 213.2 calc. for C6H3CIF2O2S
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>C(#N)C>[Br:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:11]1[C:10](=[O:13])[N:9]([CH:14]2[CH2:16][CH2:15]2)[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:12]1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Reactant: BrCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1n(Cc2ccccc2Br)nc(-c2ccc(Cl)cc2)n1C1CC1

Procedure:
1.04 g (4.41 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one [preparation according to WO 2007/134862 Example 36A] and 2.16 g (6.62 mmol) of cesium carbonate were suspended in 35 ml of acetonitrile, and 1.32 g (5.30 mmol) of 2-bromobenzyl bromide were added. The mixture was stirred under reflux for 18 h. The precipitated solid was then filtered off and the filtrate was concentrated under reduced pressure. The solid that remained was stirred in about 50 ml of diethyl ether and then filtered off and washed with a little diethyl ether. Drying under reduced pressure gave 1.05 g (59% of theory) of the target compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:17][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=2)=[N:3][CH:4]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:17][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:23](=[O:24])[C:22]4[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=4[C:20]3=[O:25])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: OCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: Nc1ccc(OCc2ccc(Cl)cc2)nc1
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(OCc2ccc(Cl)cc2)nc1

Procedure:
The compound, 5-amino-2-(4-chlorobenzyloxy)pyridine is prepared from 2-chloro-5-nitropyridine and 4-chlorobenzyl alcohol and then reacted with 3,4,5,6-tetrahydrophthalic anhydride using the procedure of Example 1 to yield N-[2-(4-chlorobenzyloxy)-5-pyridyl]-3,4,5,6-tetrahydrophthalimide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][N:5]=1)([O-:3])=[O:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.[OH-].[Li+].CN(C=O)C>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)=[CH:6][N:5]=1)([O-:3])=[O:2]
Reactant: Sc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Sc2ccc(Cl)cc2)cn1

Procedure:
2-Nitro-5-chloropyridine (9.5 grams), 4-chlorothiophenol (8.7 grams), and lithium hydroxide (4 grams) were mixed in 100 ml. of DMF and the reaction mixture was stirred overnight (about 18 hours) at room temperature. The reaction mixture was then poured into water and the product separated by filtration and crystallized from ethanol-hexanes, yield, 10.0 grams, m.p., 96°-98° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:1]1([NH:6][C:7]2[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Clc1cc(Cl)nc(NC2CCCC2)n1
Reactant: C1CCNC1
Product: Clc1cc(N2CCCC2)nc(NC2CCCC2)n1
Yield: 72.4 %

Procedure:
The reaction of 2-cyclopentylamino-4,6-dichloropyrimidine with pyrrolidine as described in Example 13 gives the title compound as an oily product in a yield of 72.4%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH:10]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[N:11]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].O.NN>C1COCC1.CO>[C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH:10]([NH2:11])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC(c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(N)c1cccc(Cl)c1
Temperature: 55 °C

Procedure:
To a stirred solution of [3-(3-chloro-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-carbamic acid tert-butyl ester (0.15 g, 0.36 mmol) in THF (2 mL) and methanol (2 mL) was added hydrazine hydrate (0.18 g, 3.6 mmol). The mixture was heated at 55° C. for 2 hours. Then the reaction mixture was concentrated and extracted with ethyl acetate (10 mL). The organic mixture was washed with water (3×1 mL), brine (1 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (methanol:dichloromethane, 1:100) to afford [3-amino-3-(3-chloro-phenyl)-propyl]-carbamic acid tert-butyl ester. (Yield 0.061 g, 60%). LC-MS: [M+H]+ 285.
Reaction SMILES: CSC.B.[Si]([O:12][CH2:13][CH2:14][S:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=[O:20])(C(C)(C)C)(C)C.Cl>C1COCC1>[OH:20][CH2:19][C:18]1[CH:17]=[C:16]([S:15][CH2:14][CH2:13][OH:12])[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)OCCSc1cccc(C(=O)O)c1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: OCCSc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Borane dimethyl sulfide complex (2M in THF, 17.3 mL) was added dropwise to an ice cold solution of 3-(2-(tert-butyldimethylsilyloxy)ethylthio)benzoic acid [Aromatic Intermediate 16, step a] (2.16 g) in THF (50 mL). The reaction was allowed to warm to RT, then heated at reflux for 2 h. The reaction was cooled in an ice bath and aqueous HCl solution (2M, 50 mL) was added dropwise. The resulting mixture was stirred overnight. The reaction was concentrated to half its original volume and the resulting aqueous extracted with DCM (3×100 mL). The combined organics were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 4:1 isohexane:ethyl acetate to 100% ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 0.77 g.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:18](O)[CH2:19][OH:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CCOCC>[O:20]1[C:2]2([CH2:3][CH2:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:7]2)[O:1][CH2:18][CH2:19]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C1(C(=O)OCC)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
The procedure described in Pearson at al., J. Org. Chem., 1997, 62, 5284 was followed with a minor modification. A mixture of diethyl 4-oxocyclohexane-1,1-dicarboxylate, Intermediate 2, (120.6 g, 463 mmol), ethane-1,2-diol (110 mL, 1973 mmol), and para-toluene sulfonic acid mono hydrate (1.0 g, 5.26 mmol) in Benzene (250 mL) was stirred at room temp under N2 for 2 days. The mixture was diluted with Et2O (1 L) and washed with water (300 mL×3), sat'd NaHCO3 (100 mL) and then with brine, dried (MgSO4), and concentrated to dryness to provide the title compound (132.7 g, 463 mmol, 100% yield) as an amber oil HPLC: 2.38 min (AP 70% at 220 nm). LCMS: m/z 287 (M+H). 1H NMR (500 MHz, CDCl3) δ ppm 1.17 (6H, t, J=7.2 Hz, 9,12-CH3), 1.60 (4H, t, J=6.4 Hz, 2,6-CH2), 2.09 (4H, t, J=6.4 Hz, 3,5-CH2), 3.86 (4H, s, 13,14-OCH2), 4.11 (4H, q, J=7.2 Hz, 8,11-OCH2). 13C NMR (126 MHz, CDCl3) δ ppm 14.1 (9,12-CH3), 29.0 (3,5-CH2), 31.6 (2,6-CH2), 53.9 (4-C), 61.3 (8,11-OCH2), 64.3 (13,14-OCH2), 107.7 (1-OCO), 171.2 (7,10-OC═O).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[N-:39]=[N+:40]=[N-].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.CCOCC>[N:1]([C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:31][CH2:32][CH2:33][CH2:34]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[N+:39]=[N-:40]
Reactant: Nc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: [N-]=[N+]=Nc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
This reaction was performed in a dark environment. To a cold (0–5° C.) solution of 2-(3-aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine (46 mg, 0.10 mmol) in acetic acid (3 mL) was added sodium nitrite (0.31 mL of a 25 mg/mL aqueous stock solution, 7.7 mg, 0.11 mmol). The mixture turned dark and was stirred for 20 minutes at 0° C. Sodium azide was then added and the mixture was stirred for 20 minutes, allowed to warm to room temperature and stirred for an additional 10 minutes. Ether was added and the mixture was neutralized with sodium bicarbonate. Aqueous workup was followed by drying over sodium sulfate. Filtration and concentration followed by flash chromatography (4:1 to 2:1 hexanes-ethyl acetate) provided 2-(3-azidophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine (25 mg, 52%) as a yellow solid. 1H NMR (CDCl3): δ 8.05 (d, 1 H), 7.75 (d, 1 H), 7.45–7.42 (m, 3 H), 7.36 (t, 1 H), 7.13 (m, 1 H), 6.33 (d, 1 H), 6.10–6.03 (m, 2 H), 5.10 (d, 1 H), 4.36 (m, 1 H), 4.05 (m, 1 H), 2.20–1.54 (m, 16 H); MS m/z 480 (M+1); IR 2109 cm−1.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([CH:11]([NH:13]C(=O)OC(C)(C)C)[CH3:12])[CH:9]=[CH:10][C:5]=2[C:4]([CH3:22])([CH3:21])[O:3]1.[ClH:23].O>CO>[ClH:23].[NH2:13][CH:11]([C:8]1[CH:9]=[CH:10][C:5]2[C:4]([CH3:21])([CH3:22])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)[CH3:12]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc2c(c1)B(O)OC2(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(N)c1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)ethyl-carbamate (0.93 mmol) in MeOH (10 mL) was added 6N HCl (10 mL). The mixture was stirred at rt overnight. The mixture was poured into water and washed with EA (50 mL×2). The water layer was lyophilized to give crude 6-(1-aminoethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride. It was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:36][CH:37]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 10.9 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (120 mg) and 1,1-dimethylethyl 4-aminobenzoate (158 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[4-(1,1-dimethylethyloxycarbonyl)phenyl]amino]carbonylbicyclo[2.2.2]oc t-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (20.1 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:18][CH2:17][CH2:16][CH2:15][CH:13]2[O:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:14]2)[CH2:31][CH2:30]1
Reactant: O=CCCCC1CC(c2cccc([N+](=O)[O-])c2)=NO1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCN(CCCCC2CC(c3cccc([N+](=O)[O-])c3)=NO2)CC1
Yield: 48 %

Procedure:
4-[3-(3-Nitrophenyl)-4,5-dihydroisoxazol-5-yl]butanal (25.2 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.6 mg, 0.312 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 18.3 mg (44.6%) of the target compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[OH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C1CCN2C(=NCCC2)CC1.O>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]([C:9]#[N:10])=[C:6]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:7]=1
Reactant: OCc1ccccn1
Reactant: CSc1nc(N)nc(Br)c1C#N
Solvent: O
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1nc(N)nc(OCc2ccccn2)c1C#N
Reaction time: 16 h
Yield: 16.1 %

Procedure:
To a stirred suspension of 1.00 g (4.08 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 10 ml DME were added 0.33 ml (4.08 mmol) 2-(hydroxymethyl)pyridine and 0.62 ml (4.08 mmol) DBU and stirring continued for 16 hours at room temperature. 50 ml water was then added and the resulting crystals collected by filtration. Chromatography (ethyl acetate) followed by trituration in ether afforded 180 mg (16%) 2-amino-4-methylsulfanyl-6-(pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 273 (M+, 100), 258 (89), 108 (63), 92 (95), 65 (70), 39 (36).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([CH3:29])[CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[C:21]([CH3:29])[CH:20]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: Cc1cc(COC(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(COC(=O)N2CCC(N)CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3-methyl-5-(trifluoromethyl)benzyl 4-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (237 mg, 0.569 mmol) in DCM (5 ml) at RT under nitrogen was added 4M HCl in Dioxane (1.423 ml, 5.69 mmol) and the reaction mixture stirred at RT for 3 hours. The reaction mixture was concentrated under reduced pressure to afford the title product as the hydrochloride salt;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].[CH3:36]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH3:36])[CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1cc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Solvent: ClCCl
Solvent: CI
Product: Cn1cc(Cc2cn(C)c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To the solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-[(1-methyl-1H-pyrazol-4-yl)methyl]-4(1H)-pyrimidinone (71 mg, 0.109 mmol) in DCM (1.5 mL) was added DIPEA (0.038 mL, 0.217 mmol) and MeI (10.18 μL, 0.163 mmol). The mixture was stirred at room temp overnight. Purification via MDAP then afforded the title compound (34 mg, 60.3% yield). LCMS: rt=3.35 min, [M+H+]=519
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:28][C@@H:29]([N:36]=[C:37]=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:37]([NH:36][C@@H:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH3:28])=[O:38])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C[C@@H](N=C=O)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)N[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (R)-(+)-α-methylbenzyl isocyanate.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.[CH2:17]1C[O:20][CH2:19][CH2:18]1>BrCCCO>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:10]3)=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Agent: OCCCBr
Product: OCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C

Procedure:
To a solution of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (Prep4, 151 mg) in dry THF (3.3 mL), TEA (0.112 mL) and 3-bromo-1-propanol (0.073 mL) were added and the resulting mixture was heated at reflux for 4 hours. After cooling at room temperature it was diluted with EtAcO (20 mL), washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by a silica SPE cartridge (10 g) eluting with DCM/MeOH from 99/1 to 96/4 to give the title compound as a colourless oil (143 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:18]=[C:17]([CH:19]=O)[C:16]([O:21][CH3:22])=[CH:15][C:14]=1[O:23][CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)(=[O:27])[CH3:26]>>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:18]=[C:17](/[CH:19]=[CH:26]/[C:25]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[O:27])[C:16]([O:21][CH3:22])=[CH:15][C:14]=1[O:23][CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2cccn2C(=O)OC(C)(C)C)cc1C=O
Product: COc1cc(OC)c(-c2cccn2C(=O)OC(C)(C)C)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 6 %

Procedure:
The title compound was prepared by condensing 2-(5-formyl-2,4-dimethoxy-phenyl)-pyrrole-1-carboxylic acid tert-butyl ester (Ex-57A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 205–207° C., 6% yield. 1H-NMR (DMSO-d6) δ 8.19 (d, J=5 Hz, 2H), 8.00–8.10 (m, 3H), 7.87 (s, 1H), 7.80 (d, J=16 Hz, 1H), 7.27–7.28 (m, 1H), 6.71 (s, 1H), 6.22–6.23 (m, 1H), 6.14–6.16 (m, 1H), 3.96 (s, 3H), 3.79 (s, 3H), 1.29 (s, 9H). MS m/z=476 ([M−H]+). HMRS (EI) calcd. for C27H27NO7: 477.1788; found: 477.1793.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([CH3:41])[C@@:38]([OH:43])([CH3:42])[C@H:37]([NH:44]C(=O)OC(C)(C)C)[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([CH3:41])[C@@:38]([OH:43])([CH3:42])[C@H:37]([NH2:44])[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@]1(C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnc3c2CCO3)C[C@@H](N)[C@@]1(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a mixture of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (75 mg, 0.21 mmol), tert-butyl [(3R,4S,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (62 mg, 0.16 mmol) and HATU (196 mg, 0.515 mmol) in DMF (2.0 mL), DIPEA (123 mg, 0.952 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. DCM (2.0 mL) was added to the resulting residue followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (25 mg, 29%). LCMS calc. for C24H27F2N6O3S (M+H)+: m/z=517.2. found 517.0. 1H NMR (500 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.78 (s, 1H), 7.64-7.46 (m, 3H), 7.24 (t, J=8.6 Hz, 2H), 4.47 (t, J=9.1 Hz, 2H), 3.97 (s, 1H), 3.37 (t, J=8.5 Hz, 2H), 2.87-2.79 (m, 2H), 2.79-2.72 (m, 1H), 2.63 (dd, J=10.8, 4.6 Hz, 1H), 2.60-2.55 (m, 1H), 1.85-1.76 (m, 1H), 1.39 (br, 2H), 0.98 (s, 3H), 0.73 (d, J=6.8 Hz, 3H) ppm.