Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11]C(N)=[CH:9][C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].CI.O.[CH3:23][N:24]([CH:26]=O)[CH3:25]>>[CH2:7]([NH:6][C:4](=[O:5])[C:3]1[CH:9]=[C:26]([N:24]([CH3:23])[CH3:25])[CH:11]=[CH:12][C:2]=1[Cl:1])[CH3:8]
Reactant: CCNC(=O)c1cc(N)ccc1Cl
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CCNC(=O)c1cc(N(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
A mixture of the above amine (3 g, 0.015 mol), potassium carbonate (3.8 g, 0.028 mol) and MeI (1.4 mL, 0.022 mol) in DMF stirred at RT overnight. The reaction mixture was poured into water and extracted with ether. The ether layer was washed with water and brine, dried (MgSO4) and concentrated to give an oil. Purification by flash chromatography (0-50% ethyl acetate/hexanes) gave N-ethyl 2-chloro-5-(dimethylamino)benzamide as a yellow solid in 29% yield.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH:9]([C:12]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)=[O:13])[CH2:10][CH3:11])(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:1].[NH2:8][CH:9]([CH2:10][CH3:11])[C:12]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)=[O:13]
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)c1nc2ccccc2o1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC(N)C(=O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Hydrogen chloride in dioxane (1M, 1 ml) was added to a solution of, 1-(Benzooxazole-2-carbonyl)-propyl]-carbamic acid tert-butyl ester (2a) in dry methylene chloride (3 ml) and stirred at room temperature for 4 hrs. Concentration under reduced pressure gave the title compound as white solid (65 mg); 1H NMR (CDCl3) δ 0.99 (t, J=7.5 Hz, 3H), 2.20–2.05 (m, 2H), 4.96 (m, 1H), 7.58 (t, J=7.4 Hz, 1H), 7.69 (t, J=7.4 Hz, 1H), 7.94 (d, J=8.2 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H), 8.75 (m, 3H); MS: 207(MH+).
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][OH:9])[CH2:2][CH:3]([CH3:5])[CH3:4].[C:10]([N:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]1[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)(=[O:13])[CH:11]=[CH2:12]>CC(O)C>[CH:24]1([CH:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22][CH2:23][N:14]2[C:10](=[O:13])[CH2:11][CH2:12][N:6]([CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:7][CH2:8][OH:9])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: C=CC(=O)N1CCc2ccccc2C1C1CCCCC1
Reactant: CC(C)CCNCCO
Solvent: CC(C)O
Product: CC(C)CCN(CCO)CCC(=O)N1CCc2ccccc2C1C1CCCCC1
Temperature: 90 °C
Reaction time: 10 h
Yield: 28.8 %

Procedure:
2-(isopentylamino)-ethanol (26 mg) was added to a solution of 2-acryloyl-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (7 mg) in iPrOH (0.1 mL), followed by stirring at 90° C. for 10 hours. Thereafter, the reaction liquid was purified by preparative HPLC to obtain 2-[[3-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl](3-methylbutyl)amino]ethanol (3 mg).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[CH:10]([NH2:19])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1>C1COCC1>[NH2:19][CH:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)[CH2:9][OH:8]
Reactant: COC(=O)C(N)c1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(CO)c1ccc(F)c(F)c1
Temperature: 0 °C

Procedure:
To a well stirred suspension of LiAlH4 (4.7 g, 0.125 mol) in THF (120 mL) in a 3-necked round bottom flask fitted with a condenser and a dropping funnel, was added a solution of amino-(3,4-difluorophenyl)-acetic acid methyl ester (10.0 g, 0.05 mol) in THF (100 mL) dropwise at 0° C. The resulting greenish brown suspension was then heated to reflux for 2 h. The reaction mixture was cooled to 0° C. and then carefully quenched sequentially with 5 mL of water, 5 mL of 3N NaOH followed by 15 mL of water. The resulting suspension was filtered through a fritted glass funnel. To the residue was added 100 mL Et2O and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgSO4, filtered and the solvent was removed in vacuo. 2-amino-2-(3,4-difluorophenyl)-ethanol was obtained as a yellow glassy syrup (8.6 g, 99%) which was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][CH:10]=[C:9]([CH:12]=O)[CH:8]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][CH:10]=[C:9](/[CH:12]=[CH:22]/[CH:23]=[O:24])[CH:8]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1csc(-c2ccccn2)c1
Product: O=C/C=C/c1csc(-c2ccccn2)c1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 5-(2-pyridinyl)-3-thiophenecarboxaldehyde (prepared as described in Reference Example 94) or the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 216 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][O:13][C:14]2[C:22]([F:23])=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([F:24])[CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(N(C(C)C)C(C)C)C.[CH3:34][N:35]([CH3:40])[S:36]([NH2:39])(=[O:38])=[O:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][O:13][C:14]2[C:22]([F:23])=[CH:21][C:17]([C:18]([NH:39][S:36]([N:35]([CH3:40])[CH3:34])(=[O:38])=[O:37])=[O:19])=[C:16]([F:24])[CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CN(C)S(N)(=O)=O
Reactant: CC(C)Oc1ncc(COc2cc(F)c(C(=O)O)cc2F)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Oc1ncc(COc2cc(F)c(C(=O)NS(=O)(=O)N(C)C)cc2F)cc1Cl
Reaction time: 18 h

Procedure:
To 4-((5-chloro-6-isopropoxypyridin-3-yl)methoxy)-2,5-difluorobenzoic acid (Preparation 9, 0.05 g, 0.14 mmol) in solution in DCM (5 mL) is added WSCDI (0.04 g, 0.21 mmol), DMAP (0.026 g, 0.21 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.09 mL, 0.42 mmol). After 10 minutes was added N,N-dimethylsulfamide (0.026 g, 0.21 mmol) and the reaction was left at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and purified using reverse phase preparative HPLC to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[CH:28]=[CH:29][C:30]=3[CH3:31])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36]
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)(=O)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: NCCC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCC(=O)O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Temperature: 100 °C
Yield: 42.9 %

Procedure:
To 3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (100 mg, 0.2 mmol) in DMF (1 mL) was added β-alanine (35.6 mg, 0.4 mmol) and triethylamine (56.2 uL, 0.4 mmol). The mixture was heated with microwave at 100° C. for 2 hrs. The mixture was separated by HPLC to afford the title compound (45 mg, 43%). LC-MS m/z 525 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.C([O-])([O-])=O.[Ca+2].[CH3:12][Si:13](F)([CH3:15])[CH3:14].C(O)=O.[OH2:20]>>[CH3:12][Si:13]([CH3:15])([CH3:14])[O:20][Si:13]([CH3:15])([CH3:14])[CH3:12]
Reactant: C[Si](C)(C)F
Reactant: O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O=CO
Solvent: c1ccncc1
Product: C[Si](C)(C)O[Si](C)(C)C
Temperature: 0 °C

Procedure:
Working up of the HF/pyridine reaction solution takes place suitably with a suspension of excess finely powdered CaCO3 in ice water with vigorous stirring and filtration of the resultant calcium fluoride. Further, excess hexamethyldisiloxane can be added to the crude reaction mixture with vigorous stirring, so that the phases are at least somewhat mixed, and the volatile trimethylsilyl fluoride (boiling point 17° C.) and water format temperatures between -20° C. and 24° C. The trimethylsilyl fluoride can be cleaved in a receiver with alkaline solution to form alkali fluorides and hexamethyldisiloxane. The working up with hexamethyldisiloxane is particularly suitable for the reaction of the 5'-phosphates.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:8]2[O:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:8]2[O:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3cccnc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(3-methylfuro[3,2-b]pyridin-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (383 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (315 mg, 88%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][N:14]1[C:21](=[O:31])[C:22]([OH:30])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=[C:13]21)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>CN(C=O)C>[CH2:38]([O:30][C:22]1[C:21](=[O:31])[N:14]2[CH2:15][CH:16]3[CH2:17][CH2:18][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])([C:13]2=[N:24][C:23]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]3)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Yield: 42 %

Procedure:
To a solution of ethyl 10-(((benzyloxy)carbonyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (prepared according to the procedure in WO2009117540) (500 mg, 1.170 mmol) in DMF (20 mL) was added K2CO3 (323 mg, 2.339 mmol) followed by benzyl bromide (0.208 mL, 1.755 mmol) and the resulting mixture was heated at 50° C. for 16 h. After cooling to room temp, water was added and the mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography (20-100% ethyl acetate/hexane to afford the title compound (250 mg, 42% yield) as a light yellow liquid. 1H NMR (500 MHz, CDCl3) δ: 7.47 (d, 2H, J=7.02 Hz), 7.32-7.39 (m, 8H), 7.19 (brs, 1H), 5.26 (s, 2H), 5.08 (s, 2H), 4.31 (q, 2H, J=7.02 Hz), 4.13 (d, 2H, J=3.97 Hz), 2.87-2.96 (m, 2H), 2.46 (brs, 1H), 1.94-2.03 (m, 2H), 1.80-1.89 (m, 2H), 1.65-1.75 (m, 2H), 1.29 (t, 3H, J=7.32 Hz). LCMS (M+H)=518.28.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH2:21][CH2:22][CH:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[OH:24])[C:10]2=[O:32])=[CH:5][CH:4]=1.[S:33]([CH2:37][C:38](O)=[O:39])([OH:36])(=[O:35])=[O:34].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH:23]([OH:24])[CH2:22][CH2:21][CH:11]2[C:10](=[O:32])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:38]([CH2:37][S:33]([OH:36])(=[O:35])=[O:34])=[O:39])=[CH:4][CH:5]=3)[CH:12]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CN)cc2)cc1
Reactant: O=C(O)CS(=O)(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CNC(=O)CS(=O)(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 60 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one (5) in 1 ml of dimethylformamide was added to a solution of 20 mg of sulfoacetic acid, 55 μl of diisopropylcarbodiimide, 38 mg of hydroxybenzotriazole in 1 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20->10/90). This gave the product of molecular weight 556.61 (C28H29F1N2O7S1); MS (ESI) 539.05 (M+H+—H2O)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][OH:25])[CH2:20][CH2:19]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:33][S:34]([O:25][CH2:24][C@H:21]1[CH2:22][CH2:23][C@H:18]([NH:17][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:19][CH2:20]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CO)CC1)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reaction time: 2 h

Procedure:
To a suspension of (6-bromo-4-((trans-4-(hydroxymethyl)cyclohexyl)amino)quinolin-3-yl) (cyclopropyl)methanone (1.23 g, 3.05 mmol) in dichloromethane (60 mL) was added triethylamine (2.09 mL, 15 mmol) and methanesulfonyl chloride (0.35 mL, 4.5 mmol) was added dropwise. The reaction mixture was stirred for 2 h. The solution was then diluted with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, ethyl acteate/hexanes) afforded the desired product (0.98 g, 67%) as a white solid. ESI MS m/z 481 [C21H25BrN2O4S+H]+
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][P:23]([C:26]1[N:27]=[C:28]([O:33][CH3:34])[C:29]([NH2:32])=[N:30][CH:31]=1)([CH3:25])=[O:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:32][C:29]2[C:28]([O:33][CH3:34])=[N:27][C:26]([P:23]([CH3:22])([CH3:25])=[O:24])=[CH:31][N:30]=2)=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: COc1nc(P(C)(C)=O)cnc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1nc(P(C)(C)=O)cnc1Nc1nnc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[C:11]([NH2:13])=[O:12].[Cl:14][CH2:15][C:16]([CH2:18]Cl)=O>>[Cl:14][CH2:15][C:16]1[N:13]=[C:11]([C:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[O:12][CH:18]=1
Reactant: NC(=O)C1=Cc2ccccc2CC1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(C2=Cc3ccccc3CC2)n1
Yield: 60 %

Procedure:
In substantially the same manner as in Reference Example 31, 3,4-dihydro-2-naphthalenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(3,4-dihydro-2-naphthyl)oxazole. The yield was 60%. Recrystallization from isopropyl ether gave colorless prisms, mp 73-74° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:13])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4].[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:13][Br:14])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)c1c(C)cc(Cl)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1c(C)cc(Cl)nc1CBr

Procedure:
To a solution of 710 mg, (3.6 mmol) 6-chloro-2,4-dimethyl-pyridine-3-carboxylic acid methylester in CCl4 (16 ml) were added 688 mg (3.90 mmol) N-bromosuccinimide, 59 mg (0.36 mmol) AIBN and 210 μl (3.72 mmol) acetic acid. The reaction mixture was irradiated with a 200 W Wolfram lamp at 60° C. for 24 h. The mixture was then filtered through celite, washed with CCl4 and concentrated in vacuo. After CC (hexane/EtOAc 97:3) of the residue a mixture of 6-chloro-2,4-dimethyl-pyridine-3-carboxylic acid methylester, 4-(bromomethyl)-6-chloro-2-methyl-pyridine-3-carboxylic acid methylester and 2-(bromomethyl)-6-chloro-4-methyl-pyridine-3-carboxylic acid methylester was obtained. This mixture was dissolved in dioxane (10 ml) and added at 0° C. to a solution prepared by dissolving 594 mg (25.8 mmol) sodium in MeOH (11 ml) at 0° C. This reaction mixture was stirred at RT for 3 h. Then the reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. After CC (hexane/EtOAc 97:3) of the residue again a mixture of 6-chloro-4-(methoxymethyl)-2-methyl-pyridine-3-carboxylic acid methylester and 6-chloro-2-(methoxymethyl)-4-methyl-pyridine-3-carboxylic acid methylester was obtained. This material was dissolved in NMP (7.8 ml) and 860 μl (9.85 mmol) morpholine and 1.36 g (9.85 mmol) K2CO3 were added followed by heating at 100° C. for 5 h. Then the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 9:1) provided 90 mg (0.32 mmol, 9%) 2-(methoxymethyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid methylester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([CH3:12])[C:8](=[O:13])[CH2:7][C:6]=2[CH:14]=1.[CH3:15][NH:16][C:17]([C:19]1[C:24]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=2)=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:18]>>[CH3:15][NH:16][C:17]([C:19]1[C:24]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[CH2:11][CH2:10][N:9]([CH3:12])[C:8](=[O:13])[CH2:7][C:6]=4[CH:14]=3)[N:27]=2)=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:18]
Reactant: CNC(=O)c1ncccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCc2ccc(N)cc2CC1=O
Product: CNC(=O)c1ncccc1Nc1nc(Nc2ccc3c(c2)CC(=O)N(C)CC3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1742a, 8-amino-3-methyl-1,3,4,5-tetrahydro-benzo[d]azepin-2-one and 3-(2,5-dichloro-pyrimidin-4-ylamino)-pyridine-2-carboxylic acid methylamide were converted to 3-[5-chloro-2-(3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-pyridine-2-carboxylic acid methylamide. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.58 (d, 1H), 8.18 (s, 1H), 7.69 (m, 3H), 7.44 (m, 2H), 7.23 (m, 2H), 6.29 (d, 1H), 4.29 (s, 2H), 3.39 (m, 2H), 3.26 (m, 2H), 3.04 (s, 3H), 2.94 (s, 3H); MS (m/e) 452 (M+1).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[CH3:30][C:31]1[N:36]=[C:35]([CH:37]=[O:38])[CH:34]=[CH:33][CH:32]=1>ClCCl>[CH3:30][C:31]1[N:36]=[C:35]([CH:37]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:6]=2)[OH:38])[CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cccc(C=O)n1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cc1cccc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n1

Procedure:
A mixture of 4-iodo-1-tritylimidazole (commercially available) (5.0 g, 11.5 mmol) in dichloromethane (50 mL) at −10° C. was treated with ethyl magnesium bromide (3.8 mL, 11.5 mmol, 3M in ether) and allowed to react for 90 m. A solution of 6-methyl-pyridine-2-carbaldehyde (Intermediate D1) (commercially available from Aldrich) (0.93 g, 7.7 mmol) in dichloromethane (10 mL) was added via syringe at −10° C. and stirred for 45 m. The mixture was quenched with water (50 mL) and with a saturated solution of ammonium chloride (60 mL). The residue was isolated in an aqueous workup, extracting with CHCl3 and purified by chromatography on silica gel with 5% NH3-MeOH:CH2Cl2 to give (6-Methyl-pyridin-2-yl)-(1-trityl-1H-imidazol-4-yl)-methanol (Intermediate D2) as a solid, 3.3 g (˜99%).
Reaction SMILES: [Cl:1][C:2]1[C:12](I)=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: OB(O)c1ccccc1
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(I)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCNC(=O)c1c([Si](C)(C)C)ccc(-c2ccccc2)c1Cl
Temperature: 90 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
To a solution of the compound of Example 239 (0.191 g, 0.5 mmol) and palladium tetrakistriphenylphosphine (23 mg, 0.02 mmol) in toluene (10 mL) was added 2 M sodium carbonate (0.5 mL) and phenyl boronic acid (73 mg, 0.6 mmol). The mixture was heated at 90° C. for 30 h, additional portions of catalyst (20 mg) and 2 M sodium carbonate (0.5 mL) were added and heating was continued for 24 h. The cool reaction was diluted with CH2Cl2 and washed with 2 M sodium carbonate (50 mL with 5 mL conc NH4OH). The organic layer was dried (MgSO4) and concentrated. The crude product was purified by RC (ethyl acetate/hexanes) and recrystallization from hexanes to afford the title compound as white needles (98 mg, 59%). m.p. 134-135° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:19][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=3)=O)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].Cl.[NH2:37][OH:38].C([O-])(O)=O.[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:19][C:20](=[N:37][OH:38])[C:22]3[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=3)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)c1cccc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cccc(-c2ccc(C(CC(=NO)c3ccnc(C)c3)c3ccccc3C)cc2)c1

Procedure:
In analogy to example 74, step 7, from 4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-3-carboxylic acid ethyl ester and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3.4:1) as a white foam, MS (ESI+): m/z=479.2319 ([M+H]+).