Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH:8]([C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:14]([CH:18]=2)[C:15](O)=[O:16])[CH:6]=1.Cl.[CH3:34][O:35][C:36](=[O:43])[C@H:37]([CH2:39][CH2:40][S:41][CH3:42])[NH2:38].C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH:8]([C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:14]([CH:18]=2)[C:15]([NH:38][C@@H:37]([CH2:39][CH2:40][S:41][CH3:42])[C:36]([O:35][CH3:34])=[O:43])=[O:16])[CH:6]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: Cc1cn(CC(Oc2ccc(CCc3ccc(F)cc3)c(C(=O)O)c2)c2nccs2)cn1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1cc(OC(Cn2cnc(C)c2)c2nccs2)ccc1CCc1ccc(F)cc1
Reaction time: 18 h
Yield: 88.9 %

Procedure:
A mixture of 5-[2-(4-methylimidazol-1-yl)-1-(thiazol-2-yl)ethoxy]-2-(4-fluorophenethyl)benzoic acid (0.4 g; 0.89 mM), L-methionine methyl ester hydrochloride (0.27 g, 1.35 mM) and DMAP (0.54 g, 4.43 mM) was stirred until solution and EDC (0.026 g, 1.35 mM) in dichloromethane was added and the mixture stirred for 18 hours. It was purified on silica using dichloromethane then methanol/dichloromethane (5:95) as eluant to give the title product (0.47 g, 89%) as a foam.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]([C:9](=[O:31])[CH2:10][CH2:11][N:12]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19]3[C:14]([N:15]([CH3:30])[C:16](=[O:29])[N:17]([CH3:28])[C:18]3=[O:27])=[CH:13]2)[S:7][CH:8]=1>CO>[Cl:3][C:4]1[N:5]=[C:6]([CH:9]([OH:31])[CH2:10][CH2:11][N:12]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19]3[C:14]([N:15]([CH3:30])[C:16](=[O:29])[N:17]([CH3:28])[C:18]3=[O:27])=[CH:13]2)[S:7][CH:8]=1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCC(=O)c3nc(Cl)cs3)cc2n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCC(O)c3nc(Cl)cs3)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium borohydride (415 mg, 10.96 mmol) was added to a suspension of 6-(3-(4-chlorothiazol-2-yl)-3-oxopropyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (470 mg, 1.096 mmol) in methanol (20 mL). The mixture was stirred at room temperature for 15 mins. The reaction was quenched with saturated NH4Cl(aq) and extracted with chloroform (3×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[CH:4]([CH3:17])[N:5]1[CH:9]=[C:8]([CH3:10])[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1.[CH2:20](I)C>>[CH3:19][N:2]([CH3:1])[C:3]([C:4]1([N:5]2[CH:9]=[C:8]([CH3:10])[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:6]2)[CH2:20][CH2:17]1)=[O:18]
Reactant: Cc1cn(C(C)C(=O)N(C)C)nc1-c1ccccc1
Reactant: CCI
Product: Cc1cn(C2(C(=O)N(C)C)CC2)nc1-c1ccccc1

Procedure:
Following the procedure of Example 95, but substituting α-(2-chloroethyl)-N,N,4-trimethyl-3-phenylpyrazole-1-acetamide (prepared in Example 45) for N,N,α,4-tetramethyl-3-phenylpyrazole-1-acetamide and without addition of ethyl iodide there was obtained N,N-dimethyl-1-(4-methyl-3-phenylpyrazole-1-yl)cyclopropanecarboxamide, m.p. 52°-55° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH:16]=[CH2:17])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)=[O:7])(C)(C)[CH3:2].C(OC(C1(C(=O)C)COC(C)(C)OC1)=O)C>>[CH2:1]([O:5][C:6]([C:8]1([CH:16]=[CH2:17])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)=[O:7])[CH3:2]
Reactant: C=CC1(C(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: CCOC(=O)C1(C(C)=O)COC(C)(C)OC1
Product: C=CC1(C(=O)OCC)COC(C)(C)OC1
Yield: 50 %

Procedure:
Compound 99b was prepared in the same manner as 2,2-dimethyl-5-vinyl-[1,3]dioxane-5-carboxylic acid tert-butyl ester using 5-acetyl-2,2-dimethyl-[1,3]dioxane-5-carboxylic acid ethyl ester instead of 5-acetyl-2,2-dimethyl-[1,3]dioxane-5-carboxylic acid tert-butyl ester in 50% yield over 2 steps. 1H NMR (300 MHz, CDCl3) δ 1.31 (t, J=7.1 Hz, 3H), 1.41 (s, 3H), 1.46 (s, 3H), 4.10 (ABq, ΔδAB=0.44, JAB=11.9 Hz, 4H), 4.26 (q, J=7.1 Hz, 2H), 5.24 (d, J=17.4 Hz, 1H), 5.28 (d, J=10.9 Hz, 1H), 5.24 (dd, J=17.4, 10.9 Hz, 1H). LCMS (m/z) 237.0 [M+Na], Tr=2.14 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([O:22]C)=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:10].[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:10]
Reactant: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.4 %

Procedure:
To a stirred solution of methyl 3-chloro-4-[N′-(2-chlorophenyl)ureido]phenylacetate (1.35 g, 3.82 mmol) in THF (30 ml) was added 0.25 N NaOH (30 ml). After stirring at room temperature for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried at 60° C. for 2 days under a reduced pressure to give 3-chloro-4-[N′-(2-chlorophenyl) ureido]phenylacetic acid (1.12 g, 86%) as colorless powder. 1H-NMR (DMSO-d6) δ 3.52 (s, 2H), 7.05 (m, 1H), 7.17 (d, J=8.5 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.37 (s, 1H), 7.46 (dd, J=8.0, 1.5 Hz, 1H), 7.95 (dd, J=8.3, 1.2 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 9.00 (d, J=8.0 Hz, 2H); MS (FAB) m/z 339 (M++1), 341 (M++3), 343 (M++5).
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:29])[C@@H:8]([NH:15][C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C>[CH:1]1([O:6][C:7](=[O:29])[C@@H:8]([NH:15][C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)=[O:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)N[C@H](C(=O)OC1CCCC1)c1ccccc1
Solvent: CCO
Product: Nc1cccc(CNC(=O)N[C@H](C(=O)OC2CCCC2)c2ccccc2)c1
Reaction time: 18 h
Yield: 70.8 %

Procedure:
(S)-[3-(3-Nitro-benzyl)-ureido]-phenyl-acetic acid cyclopentyl ester (3.6 g, 9.0 mmol) was dissolved in ethanol (50 ml) Pd/C (10% wet) catalyst (100 mg) was added and the mixture was stirred under H2 atmosphere (balloon pressure) for 18 h. The reaction mixture was filtered through a celite plug and evaporated to dryness to give a purple oil (2.34 g, 71% yield). LCMS purity 90%, m/z 368 [M++H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH:12][C:21]([NH:20][CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:26])[F:25])=[CH:24][CH:23]=1)=[O:22])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2c(N)cccc2cn1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc2cn1

Procedure:
Prepared from 3-methylisoquinolin-5-amine (Description 45) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 360 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][O:15]C)[CH2:6]2.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][OH:15])[CH2:6]2
Reactant: COCCN1Cc2cc(OC)ccc2C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C1c2ccc(O)cc2CN1CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
A mixture of 5-methoxy-2-(2-methoxy-ethyl)-2,3-dihydro-isoindol-1-one (150 mg, 0.68 mmol) and boron tribromide (1 M in CH2Cl2, 1.4 mL, 1.36 mmol) in CH2Cl2 (8 mL) at −78° C. was stirred for 16 h at RT. The mixture was then cooled to −78° C. and MeOH (25 mL) was added. After 1 h at −78° C. the mixture was evaporated and the residue purified by chromatography (SiO2, CH2Cl2:2N NH3-MeOH 98:2 to 90:10) to afford the title product (42 mg, 32%) as a light orange solid. MS m/e=193.3 (M+).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:14]3[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[N:16]([CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[CH:24]=4)[C:15]3=[O:30])[CH:12]=2)[C:7]([CH3:32])([CH3:31])[CH2:6]1)=[O:4].[CH:33]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:29][C:25]1[CH:24]=[C:23]([CH2:22][N:16]2[C:17]([CH3:20])([CH3:21])[C:18](=[O:19])[N:14]([C:11]3[CH:12]=[C:13]4[C:8]([C:7]([CH3:32])([CH3:31])[CH2:6][N:5]4[C:3](=[O:4])[CH2:2][NH:38][CH:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:9][CH:10]=3)[C:15]2=[O:30])[CH:28]=[CH:27][N:26]=1
Reactant: CC1(C)CN(C(=O)CCl)c2cc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)ccc21
Reactant: NC1CCCC1
Product: CC1(C)CN(C(=O)CNC2CCCC2)c2cc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)ccc21

Procedure:
A solution of 3.423 g of 3-[1-(chloroacetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage j) below in 42 mL of cyclopentylamine is heated at 70° C. for 4 hours. The reaction mixture is then concentrated under reduced pressure and the residue is taken up in 100 mL of water and extracted with three times 60 mL of ethyl acetate. The combined organic phases are then washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (95/5 by volume) to give 3.5 g of 1-[(2-chloropyridin-4-yl)methyl]-3-[1-(N-cyclopentylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethylimidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[C:14]([NH2:27])[CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[C:14]([NH:27][C:34](=[O:36])[CH3:35])[CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(C(=O)NC2CN3CCC2CC3)c2nc(-c3ccccc3)oc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(C(=O)NC2CN3CCC2CC3)c2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
To a solution of N-(1-azabicyclo[2.2.2]oct-3-yl)-6-amino-2-phenylbenzoxazole-4-carboxamide (35 mg, 0.09 mmol) in methylene chloride (1 mL) was added pyridine (11 μL, 0.14 mmol) and acetic anhydride (11 μL, 0.10 mmol) at 0° C. and stirred for 30 min, then allowed to warm to room temperature for 1 h. The reaction mixture was quenched with saturated solution of sodium bicarbonate and concentrated under reduced pressure. The crude was purified by semi-preparative HPLC to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-6-acetylamino-2-phenylbenzoxazole-4-carboxamide (13 mg, 44%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.58 (d, J=7.4 Hz, 1H), 8.73 (d, J=1.9 Hz, 1H), 8.20 (d, J=6.8 Hz, 1H), 8.13 (s, 1H), 7.81 (d, J=1.7 Hz, 1H), 7.55-7.50 (m, 4H), 4.35-4.27 (m, 1H), 3.57-3.48 (m, 1H), 3.16-3.03 (m, 2H), 2.97-2.82 (m, 2H), 2.27 (s, 3H), 2.17-2.05 (m, 2H), 1.85-1.60 (m, 3H); MS (ESI+) m/z 405 (M+H); HPLC>99% (AUC), tR=23.81 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(C(c3ccccc3)c3ccccc3)C2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)O)cn1)[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.9 %

Procedure:
To a stirred solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (205 mg) in methanol (5 mL) was added 1N-NaOH solution (0.8 mL). The mixture was stirred at ambient temperature for 12 hours. Methanol was evaporated in vacuo and the aqueous layer was washed with diisopropyl ether. The aqueous layer was acidified by hydrochloric acid to pH 4, and the precipitate was collected and washed with water to give (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (161 mg) as a white powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.[N-:22]=[N+:23]=[N-:24].[Li+]>CS(C)=O>[N:22]([CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C(Oc1ccc(CBr)cc1)c1ccccc1Cl
Agent: [Li+]
Solvent: CS(C)=O
Product: COC(=O)C(Oc1ccc(CN=[N+]=[N-])cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A concentrated stirred solution of the product of Step D in anhydrous dimethylsulfoxide (DMSO) is treated at ambient temperature with lithium azide (25% excess) portionwise. The mixture is then stirred at ambient temperature under protection from moisture for about 1 hour, or until TLC indicates complete reaction. The mixture is then partitioned between ether (or ethyl acetate) and water. The organic phase is washed repeatedly with H2O, then dried over MgSO4, filtered, and concentrated. The residue may be purified by chromatography on silica gel.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C@@H:17]2[CH2:22][CH2:21][CH2:20][C@H:19]([N:23]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:18]2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:34].[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1B(O)O.C(N(CC)CC)C>CCO.C1(C)C=CC=CC=1>[NH2:23][C@H:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH:10][C:8](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([F:34])=[C:2]([C:37]3[C:36]([F:35])=[CH:41][CH:40]=[CH:39][C:38]=3[F:42])[N:7]=2)[CH2:18]1
Reactant: OB(O)c1c(F)cccc1F
Reactant: O=C(Nc1cnccc1[C@@H]1CCC[C@H](N2C(=O)c3ccccc3C2=O)C1)c1ccc(F)c(Br)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCO
Product: N[C@H]1CCC[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C1

Procedure:
A solution of 6-bromo-N-(4-((1R,3S)-3-(1,3-dioxoisoindolin-2-yl)-cyclohexyl)pyridin-3-yl)-5-fluoropicolinamide (1.0 equiv), 2,6-difluorophenyl boronic acid (3.0 equiv.), tetrakistriphenylphosphine (0.2 equiv.) and triethylamine (3.0 equiv.) in 1:1 EtOH/toluene (0.1 M) was heated at 120° C. with microwave irradiation for 1200 seconds. Upon cooling, removal of the volatiles in vacuo, the Suzuki product was directly purified by reverse phase HPLC. The product fraction was lyophilized and the resulting phthalimide group was deprotected as described in Method 9 yielding, after RP HPLC purification and lyophilization, N-(4-((1R,3S)-3-aminocyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide as the TFA salt. LCMS (m/z): 427.2 (MH+); LC Rt=2.26 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)=[N:8][CH:7]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:56][C@@H:57]([CH2:71][C:72]1[CH:77]=[C:76]([F:78])[CH:75]=[C:74]([F:79])[CH:73]=1)[C@H:58]([OH:70])[CH2:59][NH:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([CH2:68][CH3:69])[CH:63]=1>C(Cl)Cl.CN(C=O)C>[F:78][C:76]1[CH:77]=[C:72]([CH:73]=[C:74]([F:79])[CH:75]=1)[CH2:71][C@H:57]([NH:56][C:14]([C:13]1[CH:12]=[C:11]([C:9]2[O:10][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:20])=[CH:7][N:8]=2)[CH:19]=[CH:18][CH:17]=1)=[O:16])[C@H:58]([OH:70])[CH2:59][NH:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([CH2:68][CH3:69])[CH:63]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: COC(=O)CCc1cnc(-c2cccc(C(=O)O)c2)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(-c3ncc(CCC(=O)OC)o3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[5-(3-Methoxy-3-oxopropyl)-1,3-oxazol-2-yl]benzoic acid (285 mg, 1.0 mmol) is dissolved in methylene chloride (5 mL) and DMF (5 mL), and diisopropylethylamine (695 μL, 4.0 mmol), HATU (472 g, 1.2 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method of Example SP-272 (448 mg, 1.1 mmol) are added. The reaction stirred at room temperature 1 h. The reaction is partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) provides the title compound. ESI MS m/z 591.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:17]1([C:28]2[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][C:18]1=[O:19].O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:32]([C:31]2[CH:30]=[CH:29][C:28]([N:17]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][C:18]3=[O:19])=[CH:36][CH:35]=2)=[O:33])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(N2C(=O)CCc3ccccc32)cc1
Reactant: COc1ccc(N)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2ccc(N3C(=O)CCc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of p-anisidine (0.11 g) in chloroform (5 ml) is added triethylamine (0.15 g) and thereto is added with stirring a solution of 4-(3,4-dihydrocarbostyril-1-yl)benzoic acid chloride obtained above in chloroform (2 ml) under ice cooling. The mixture is stirred at room temperature overnight. Water is added to the reaction mixture and the mixture is extracted with dichloromethane, washed with water and dried with magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is crystallized from diethyl ether and further recrystallized from ethanol/diethyl ether/n-hexane to give 1-[4-(4-methoxyanilinocarbonyl)phenyl]-3,4-dihydrocarbostyril (240 mg) as white powder, m.p.: 254°-255° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=3[CH:12]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[S:28]([CH3:31])(=[O:30])=[O:29])[NH:11][C:10]2=[O:32])[CH:6]=[CH:7][CH:8]=1.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([CH:12]2[C:13]3[C:14](=[O:19])[CH2:15][CH2:16][CH2:17][C:18]=3[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:4]=3)[C:10](=[O:32])[N:11]2[C:36]([O:38][C:39]2[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=2)=[O:37])=[C:21]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:22]=1)#[N:25]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 150 °C

Procedure:
A microwave vessel is charged with a mixture of 4-(1-(3-(trifluoromethyl)phenyl)-2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 18, 50 mg, 0.10 mmol), 4-nitrophenyl chloroformate (31 mg, 0.15 mmol) and a tip of a spatula of 4-dimethylaminopyridine in toluene (3 mL). Triethylamine (0.1 mL) is added, and the mixture is heated in a microwave at 150° C. for 10 min. Another portion of 4-nitrophenyl chloroformate (31 mg, 0.15 mmol) is added and the mixture is heated again at 150° C. for 20 min. All volatiles are evaporated and the residue is purified by reversed phase HPLC (Agilent ZORBAX™ SB-C18, gradient of acetonitrile in water, 0.15% formic acid). Yield: 32 mg; ESI mass spectrum M+H]+=655, Retention time HPLC: 1.10 min (Z017_S04).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7][O:8][CH3:9])=[CH:5][CH:6]=1.[O:10]=[S:11]1(=[O:38])[CH2:16][CH2:15][CH:14]([C:17]2[C:25]3[C:20](=[C:21]([C:35]([NH2:37])=[O:36])[CH:22]=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[NH:19][CH:18]=2)[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:38]=[S:11]1(=[O:10])[CH2:16][CH2:15][CH:14]([C:17]2[C:25]3[C:20](=[C:21]([C:35]([NH2:37])=[O:36])[CH:22]=[C:23]([C:2]4[S:3][C:4]([CH2:7][O:8][CH3:9])=[CH:5][CH:6]=4)[CH:24]=3)[NH:19][CH:18]=2)[CH2:13][CH2:12]1
Reactant: COCc1ccc(Br)s1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)s1
Temperature: 100 °C
Yield: 33.5 %

Procedure:
2-Bromo-5-[(methyloxy)methyl]thiophene (35 mg, 0.16 mmol), 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (55 mg, 0.13 mmol) and K2CO3 (83 mg, 0.14 mmol) was taken up in 1,4-dioxane (3 mL) and water (1.5 mL) in a microwave vial. The mixture was degassed by bubbling argon through it for 5 min. PdCl2(dppf) (17 mg, 0.023 mmol) was added, and the reaction was heated in a microwave for 5 min at 100° C. The reaction mixture was concentrated, diluted in DMSO, and purified on a Gilson HPLC (NH4OH buffer), giving 18.2 mg (43%) of the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[C:12]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25]([Si:28]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[N:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1)([CH3:27])[CH3:26].[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.CCO>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:31]4[CH:32]=[CH:33][N:29]([Si:28]([CH:37]([CH3:39])[CH3:38])([CH:40]([CH3:42])[CH3:41])[CH:25]([CH3:26])[CH3:27])[CH:30]=4)[CH:18]=[C:13]3[C:12]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccoc2)c2cc(Br)cnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2cnc3c(c2)c(-c2ccoc2)cn3S(=O)(=O)c2ccccc2)c1
Temperature: 85 °C
Yield: 23.4 %

Procedure:
A mixture of 30 (31.6 mg, 0,078 mmol), 1-triisopropylsilanyl-1H-pyrrole-3-boronic acid (31 mg, 0.12 mmol), PdCl2(PPh3)2 (6 mg, 7.8 μmol), LiCl (10 mg, 0.24 mmol), aqueous 1.0 M Na2CO3 (200 μL, 0.2 mmol), EtOH (0.47 mL) and toluene (0.47 mL) were heated at 85° C. over weekend. After cooling the organic layer was separated and purified by PTLC using AcOEt:hexane=3:7 as eluent to give the product 31 as a colourless oil (15.3 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 1.13 (d, J=7.5 Hz, 18H), 1.49 (septet, J=7.5 Hz, 3H), 6.60 (dd, J=2.7, 1.5 Hz, 1H), 6.71 (dd, J=1.8, 0.79 Hz, 1H), 6.84 (t, J=2.5 Hz, 1H), 7.05 (t, J=1.7 Hz, 1H), 7.48 (t, J=8.0 Hz, 2H), 7.56 (m, 2H), 7.78 (s, 1H), 7.83 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 8.20 (m, 1H), 8.23 (s, 1H), 8.68 (d, J=2.0 Hz, 1H).