Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH:23][S:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:32])=[O:31])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(=O)(=O)c4ccccc4)cc3CO1)CC2
Yield: 25.8 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (155 mg, 0.50 mmol, HPLC 0.776 min) and benzenesulfonyl chloride (70 ul, 0.55 mmol) according to the procedure described for Example 27. Obtained the title compound as an off-white solid (58 mg, 26%, HPLC 1.576 min), MS (ISP) m/e=450.2 [(M+H)+].
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:9]=[C:8]2[CH:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([N:7]2[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:9]=[C:8]2[CH:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC(N)c1nc2cnccc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2cnccc2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 6.2 %

Procedure:
A mixture of 1-(1-phenyl-1H-imidazo[4,5-c]pyridin-2-yl)ethylamine (184 mg, 0.77 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (256 mg, 1.08 mmol) and DIPEA (0.25 mL, 1.39 mmol) in 1-butanol (2 mL) was stirred at 90° C. in a sealed microwave tube for 16 h. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3/MeOH then concentrated in vacuo. The resulting residue was purified by chromatography (SiO2 0-10% (2M ammonia in methanol) in DCM), then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 60 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 236 as a white solid (0.017 g, 6%). LCMS (method K): Rt 2.04 min, [M+H]+ 357. 1H NMR (DMSO-d6): δ 12.89 (1H, s), 8.94 (1H, s), 8.30 (1H, d, J=5.54 Hz), 8.09-8.00 (2H, m), 7.65-7.50 (5H, m), 7.12 (1H, d, J=5.57 Hz), 5.53 (1H, s), 1.58 (4H, d, J=7.36 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]([F:15])([F:16])[F:17])[CH:3]=1
Reactant: [H][H]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(Cl)cc1C(F)(F)F
Yield: 99.2 %

Procedure:
A mixture of (E)-methyl 3-(4-chloro-2-(trifluoromethyl)phenyl)acrylate (5 g) and palladium on charcoal (10%, dry, 2 g) in ethyl acetate (50 ml) was stirred under balloon hydrogen pressure for 3 hours. After filtration, filtrate was concentrated to give methyl 3-(4-chloro-2-(trifluoromethyl)-phenyl)propanoate (5 g).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1O.[C:18](#[N:21])[CH:19]=[CH2:20]>CO.[Pd]>[NH2:21][CH2:18][CH2:19][CH2:20][C:16]1[C:14](=[O:15])[NH:13][C:11](=[O:12])[N:10]([CH:17]=1)[C@@H:1]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:2]1
Reactant: C=CC#N
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [Pd]
Solvent: CO
Product: NCCCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
Uridine is reacted with mercuric chloride (5 mmol) at pH 5.0. The 5-mercurichloride-dU so produced is reacted with acrylonitrile and lithium tetrachloro-palladiate in methanol yielding 5-(2-cyanoethenyl) dU which is reduced by hydrogenation at 3 atmospheres in the presence of 10% palladium on charcoal in methanol.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccc([N+](=O)[O-])cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, yellow solid (16 mg, 19%), MS (ISN) m/z=333.4 [(M+H)+], mp 369.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-nitro-phenylboronic acid (54.3 mg, 0.325 mmol).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH2:15][NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH:12]=[CH:11][C:10]=2[Cl:25])=[O:7])=[CH:4][N:3]=1.[CH3:28][NH:29][CH3:30]>C1COCC1>[Cl:25][C:10]1[CH:11]=[CH:12][C:13]([CH2:15][NH:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:14][C:9]=1[NH:8][C:6](=[O:7])[C:5]1[CH:26]=[CH:27][C:2]([N:29]([CH3:30])[CH3:28])=[N:3][CH:4]=1
Reactant: CNC
Reactant: C[C@@H](NCc1ccc(Cl)c(NC(=O)c2ccc(Cl)nc2)c1)c1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](NCc1ccc(Cl)c(NC(=O)c2ccc(N(C)C)nc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.6 %

Procedure:
To a solution of (R)-6-chloro-N-(2-chloro-5-((1-phenylethylamino)methyl)phenyl)nicotinamide 48 (0.175 g, 0.44 mmol) in THF (3 mL) at 0° C. was added dimethylamine (5.0 mL, 153 mmol). The reaction mixture was warmed to room temperature, stirred for 20 h, quenched with saturated NaHCO3, and diluted with EtOAc. The organic phase was washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 50% to 100% EtOAc in hexanes) gave (R)—N-(2-chloro-5-((1-phenylethylamino)methyl)phenyl)-6-(dimethylamino)nicotinamide 49 (0.118 g, 66% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.37 (d, J=6.5 Hz, 3H), 3.19 (s, 6H), 3.60 (d, J=13.5 Hz, 1H), 3.66 (d, J=13.5 Hz, 1H), 3.81 (q, J=6.6 Hz, 3H), 6.57 (d, J=8.6 Hz, 1H), 7.00 (dd, J=8.2, 2.2 Hz, 1H), 7.25-7.37 (m, 7H), 8.00 (dd, J=9.0, 2.5 Hz, 1H), 8.27 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.2 Hz, 1H). Mass spectrum: calculated for C23H25ClN4O 408.2. found 409.2 (M++1).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16](Cl)=[C:11]2[C:10]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>O1CCOCC1.[H][H].[OH-].[OH-].[Pd+2]>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][CH:16]=[C:11]2[C:10]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2c1c(-c1ccco1)nn2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: c1ccc(Cn2nc(-c3ccco3)c3cncnc32)cc1

Procedure:
5.81g of 1-benzyl-4-chloro-3-(2-furyl)pyrazolo[3,4-d]pyrimidine are dissolved in 450 ml of dioxane and hydrogenated in the Parr apparatus at a hydrogen pressure of 3 bar for 5 h using 4 g of 20% Pd(OH)2 on carbon after addition of 2.61 ml of triethylamine. After filtration through kieselguhr, evaporation and chromatography, 2.26 g of yellowish crystals are obtained (m.p.=106° C., Rf=0.2 toluene/ethyl acetate=4:1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[O:9](C(OC(C)(C)C)=O)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=O>O1CCCC1>[OH:4][CH2:3][C@@H:2]([NH:1][C:10](=[O:9])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)C[C@H](N)CO
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
To a stirred solution of (S)-2-amino-4-methylpentan-1-ol (5 g, 42.7 mmol) in tetrahydrofuran (100 mL) at rt was added BOC2O (9.91 mL, 42.7 mmol) dropwise and the reaction was stirred at rt for 5 h. After the completion of reaction, solvent was removed under reduced pressure to yield (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (6.3 g, 29.0 mmol, 68% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 6.42 (d, J=8.8 Hz, 1H), 4.55 (m, 1H), 3.32 (m, 1H), 3.27 (m, 1H), 3.17 (m, 1H), 1.47 (m, 1H), 1.37 (s, 9H), 1.22 (m, 2H), 0.85 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:10][C:11]([F:16])([F:15])[C@H:12]([OH:14])[CH3:13]>>[F:10][C:11]([F:16])([F:15])[C@H:12]([O:14][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)[CH3:13]
Reactant: C[C@@H](O)C(F)(F)F
Reactant: N#Cc1ccc(Cl)nc1
Product: C[C@@H](Oc1ccc(C#N)cn1)C(F)(F)F
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (592 mg, colorless oil) from 6-chloronicotinonitrile (500 mg, 3.61 mmol) and (R)-1,1,1-trifluoropropan-2-ol instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24]C(C)(C)C)=[O:23])[CH2:10]/[CH:11]=[C:12](/[CH2:18][CH2:19][CH2:20][F:21])\[C:13]([O:15]CC)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C(O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10]/[CH:11]=[C:12](/[CH2:18][CH2:19][CH2:20][F:21])\[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C(=C\C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCF
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](C/C=C(/CCCF)C(=O)O)C(=O)O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-tert-Butyl 1-ethyl (Z)—(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioate (50.0 mg, 0.12 mmol) and lithium hydroxide (29.7 mg, 1.24 mmol) in ethanol (0.5 mL) and water (0.5 mL) was stirred at r.t. for 24 h, 30 min at 60° C. (microwave irradiation), and 14 h at 40° C. (oil bath). The mixture was cooled down to r.t. and acidified to pH 2 by addition of 2 N aqueous hydrochloric acid. The ethanol was then removed under reduced pressure and the aqueous solution extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over sodium sulphate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (XBridge C18, 5 μm 150×19 mm, acetonitrile/water (0.1% TFA) gradient, 21 mL/min). Yield: 10.0 mg, 0.03 mmol, 25%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[NH3:17]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH2:17])=[O:15]
Reactant: COCCCCCCCCCCCC(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: COCCCCCCCCCCCC(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the title product from Example 11 (1.1 g, 4.3 mmol) in 70 mL of anhydrous tetrahydrofuran was added 20 mL of freshly distilled liquid ammonia in a Parr shaker which was sealed and shaken at room temperature for 16 hours. After filtering and concentration, the crude residue was dissolved in anhydrous methanol and passed through a basic ion exchange resin and eluted with anhydrous methanol. Concentration afforded the title compound (780 mg) as a white solid, m.p. 83.9-85.6° C. (DSC). The structure was supported by NMR, infrared spectroscopy, elemental analysis, and mass spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][CH:3]=1.[CH3:11][CH:12]([C:18]([CH3:20])=O)[C:13](OCC)=[O:14]>C(O)C>[CH3:11][C:12]1[C:13](=[O:14])[NH:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)=[N:8][C:18]=1[CH3:20]
Reactant: Cc1ccc(C(=N)N)cc1
Reactant: CCOC(=O)C(C)C(C)=O
Solvent: CCO
Product: Cc1ccc(-c2nc(C)c(C)c(=O)[nH]2)cc1
Temperature: 0 °C
Yield: 85.4 %

Procedure:
To a solution of 4-methylbenzamidine (4.4 g) in 30 ml of ethanol was added ethyl 2-methylacetoacetate (6.1 g), and the mixture refluxed for 4 hours, giving a precipitate. The mixture was cooled to 0° C., the solid filtered off, washed with ethanol, and dried under reduced pressure, yielding 6 g of 5,6-dimethyl-2-(4-methylphenyl)-3H-pyrimidin-4-one, m.p. 250° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[C:5]([O:15][CH3:16])=[CH:4][N:3]=1.[F-:17].[Cs+]>CS(C)=O.O>[F:17][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[C:5]([O:15][CH3:16])=[CH:4][N:3]=1
Reactant: COc1cc2c(OC)cnc(Cl)c2cc1F
Reactant: [F-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(OC)cnc(F)c2cc1F
Temperature: 145 °C
Yield: 25.5 %

Procedure:
To a solution of 1-chloro-7-fluoro-4,6-dimethoxyisoquinoline (2 g, 8.28 mmol) in DMSO (5 ml) was added cesium fluoride (2.51 g, 16.55 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (475 mg, 25.5%) as white solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.69-7.67 (d, J=8 Hz, 1H), 7.53-7.51 (d, J=8 Hz, 1H), 7.45-7.44 (m, 1H), 4.05 (s, 3H), 4.03 (s, 3H); 19F NMR: δ ppm −129.58 (1F), −79.2 (1F); MS: MS m/z 226.0 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](B2OC(C)(C)C(C)(C)O2)=[N:24]1>>[NH:23]1[C:31]2[C:26](=[C:27]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=4)[N:3]=3)[CH:28]=[CH:29][CH:30]=2)[CH:25]=[N:24]1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Reactant: CC(=O)Nc1ccc(Nc2nc(Cl)nc3c2cnn3C)cc1
Product: CC(=O)Nc1ccc(Nc2nc(-c3cccc4[nH]ncc34)nc3c2cnn3C)cc1

Procedure:
N-[4-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-phenyl]-acetamide was reacted with indazole boronic acid pinacol ester in General Procedure A. Purification on silica and trituration yielded 157. NMR: (CDCl3): 2.08 (s, 3H, CH3), 4.17 (s, 3H, CH3), 7.51 (t, H, ArH, J=7.77 Hz), 7.69 (m, 3H, 3×ArH), 7.78 (m, 2H, 2×ArH), 8.28 (d, H, ArH, J=7.26 Hz), 8.17 (sbr, H, NH), 8.93 (s, H, ArH), 9.98 (s, H, ArH), 10.07 (s, H, ArH), 13.18 (s, H, ArH). MS: (ESI+) MH+=399.13
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[C:35](=[O:36])[N:34]([CH3:37])[C:27]4[N:28]=[C:29](SC)[N:30]=[CH:31][C:26]=4[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:38])=[O:16])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][NH2:40].C1COCC1>>[C:1]([N:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[C:35](=[O:36])[N:34]([CH3:37])[C:27]4[N:28]=[C:29]([NH:40][CH3:39])[N:30]=[CH:31][C:26]=4[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:38])=[O:16])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cnn(C(C)(C)C)c4C(F)(F)F)c3)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cnn(C(C)(C)C)c4C(F)(F)F)c3)c(=O)n(C)c2n1
Yield: 63 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (247 mg, 0.449 mmol) and 2.0N methylamine in THF (2.25 mL, 4.49 mmol) were combined to afford 1-(1-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (152 mg, 63% yield). 1H NMR (300 MHz, acetone-d6) δ 1.64 (s, 9H), 2.82 (s, 3H), 3.06 (m, 3H), 6.80-6.95 (m, 1H), 7.14-7.19 (m, 1H), 7.38-7.42 (m, 1H), 7.85 (s, 1H), 8.06 (s, 1H), 8.11 (br. s, 1H), 8.50 (br. s, 1H), 8.57-8.59 (m, 1H), 8.60-8.63 (m, 1H); MS (ESI) m/z: 533.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CC(C)=O>[CH3:23][O:22][C:20](=[O:21])[CH2:19][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[CH3:11]
Reactant: Cc1cc2cc(F)ccc2[nH]1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)Cn1c(C)cc2cc(F)ccc21

Procedure:
A mixture of 5-fluoro-2-methylindole (2.4 g), cesium carbonate (16.6 g) and methyl bromoacetate (5.4 ml) in acetone 240 ml was stirred and heated under reflux for 16 h. The solvent was removed, water and ethyl acetate were added and the organic phase separated. The aqueous phase was re-extraced with ethyl acetate and the combined organic solution dried and concentrated to a solid. Purification by flash chromaography using dichloromethane:ethylacetate gave the subtitle compound as a solid (2.9 g)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH3:37])[CH:25]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)COc1ccc(CN(CCOC)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Reaction time: 3 h
Yield: 52.8 %

Procedure:
To a solution of N-(2-methoxyethyl)-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (0.1 g, 0.34 mmol) in anhydrous acetonitrile (10 mL) was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (0.097 g, 0.34 mmol) and N,N-diisopropylethylamine (0.059 mL, 0.34 mmol). The resulting mixture was heated to reflux and stirred under nitrogen for 3 h. The reaction mixture was concentrated in vacuo and the residue partitioned between water (20 mL) and CH2Cl2 (40 mL), the organic extract was separated by hydrophobic frit and the solvents removed in vacuo. Purification by Biotage™ chromatography (Silica, 12 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a colourless oil (90 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14](=O)[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:12][N:13]=1
Reactant: COc1ccc2c(-c3ccc(OC)c(OC)c3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(-c3ccc(OC)c(OC)c3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(3,4-dimethoxyphenyl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:8]=[C:7]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:6]1.[N:29]#[C:30]Br.C(N(CC)CC)C>C(Cl)Cl>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:7]1[S:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:30]#[N:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:8]=1
Reactant: N#CBr
Reactant: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCNC#N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one (33 mg, 0.0817867 mmol) was weighed into a 10 ml flask and dissolved in 1.0 mL of CH2Cl2, followed by addition of cyanogen bromide (11.2618 mg, 0.106323 mmol) and dropwise addition of triethylamine (0.0398980 mL, 0.286253 mmol). The reaction was then stirred at ambient temperature for 1 hour. The reaction was then concentrated in vacuo and the resulting tan foam was used in the next step without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].Cl>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)OCc1ccccc1)(NC(=O)OCc1ccccc1)C(=O)OCC
Yield: 98.9 %

Procedure:
A solution of diethyl 2-benzyloxycarbonylaminomalonate (30 g) in anhydrous DMF (100 mL) was added portionwise with sodium hydride (60%, 4.27 g) with ice cooling and stirring, then the mixture was stirred at room temperature for 30 minutes, and then added with benzyl 2-bromoacetate (28.9 g), and the mixture was stirred overnight. The reaction mixture was poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, and then purification was performed with n-hexane/ethyl acetate (4:1), to obtain the title compound (43.9 g, yield: 99%) as colorless oil.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:39]2[N:40]([CH3:44])[N:41]=[N:42][CH:43]=2)[OH:38])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:39]2[N:40]([CH3:44])[N:41]=[N:42][CH:43]=2)=[O:38])=[CH:33][CH:32]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cn1nncc1C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cn1nncc1C(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Dess-Martin periodinane (8 g, 19 mmol) was added to a solution of 73.2 (˜15.5 mmol) in DCM (80 mL). After 1 hour, the reaction mixture was concentrated with silica gel and chromatographed (silica gel, 1:2 EtOAc/hexane) to obtain compound 73.3 (4.3 g, 14.7 mmol). MS ESI (pos.) m/e: 294.1 (M+H).