Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([CH2:10][S:11](/[CH:14]=[CH:15]/[C:16]2[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])(=[O:13])=[O:12])=[CH:5][N:4]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[C:8]([NH:9][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:7][C:6]([CH2:10][S:11](/[CH:14]=[CH:15]/[C:16]2[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])(=[O:13])=[O:12])=[CH:5][N:4]=1
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2cnc(OC)c(N)c2)c(OC)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNc1cc(CS(=O)(=O)/C=C/c2c(OC)cc(OC)cc2OC)cnc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of (E)-2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-amine (28 mg, 0.072 mmol) in DMF (5 mL), ethyl bromoacetate (0.110 mL, 1 mmol) and potassium carbonate (138 mg, 1 mmol) were added. The mixture was stirred at 60° C. overnight. The mixture was diluted with H2O (20 mL) and extracted (2×20 mL ethyl acetate). The combined extracts were washed with brine, dried on MgSO4, and filtered. The residue was further purified by silica gel chromatography, eluting with PE/EtOAc (2:3, v/v) to afford pure product as a white solid (24.2 mg, 70%). 1H-NMR (CDCl3): δ 3.85 (s, 6H, 2×OCH3), 3.87 (s, 3H, OCH3), 3.90 (d, 2H, J=2.8 Hz, CH2), 4.00 (s, 3H, OCH3), 4.15 (s, 2H, CH2), 4.27 (q, 2H, CH2), 6.10 (s, 2H, Ph-H), 6.74 (d, 1H, J=2.0 Hz, Py-H), 7.04 (d, 1H, J=15.6 Hz, CH), 7.44 (d, 1H, J=2.0 Hz, Py-H), 7.811 (d, 1H, J=15.6 Hz, CH); HR-MS (ESI+) m/z: 481.1364 [M+H]+; C22H28N2O8S requires 480.1566,
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][N:12]=2)[NH:7][N:6]=1.Cl[C:19]1[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][N:12]=2)[N:7]([C:19]2[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=2)[N:6]=1
Reactant: Fc1ccccc1Cc1n[nH]c2nccnc12
Reactant: Nc1nc(N)nc(Cl)n1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1nc(N)nc(-n2nc(Cc3ccccc3F)c3nccnc32)n1

Procedure:
A solution of 144 mg (0.63 mmol) of 3-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyrazine from example 14A, 92 mg (0.63 mmol) of 6-chloro-1,3,5-triazine-2,4-diamine, 12 mg (0.013 mmol) of tris(di-benzylideneacetone)dipalladium, 18 mg (0.038 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPHOS) and 287 mg (0.88 mmol) of cesium carbonate in 4 ml of degassed toluene is heated at 90° C. for 20 h. It is then diluted with ethyl acetate and a little methanol and filtered with suction. The solid is again stirred with methanol and filtered off with suction once again. The filtrates are then combined and concentrated, and the residue is purified by preparative HPLC. The product fraction obtained is concentrated, again stirred with methanol and filtered off with suction. 13 mg (6% of theory) of the desired product are obtained in this way.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33])=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: Cc1ccccc1N=C=O
Product: COc1cccc2c1ncc1c(=O)n(-c3ccccc3C)c(=O)n(C3CCCC3)c12
Yield: 59.8 %

Procedure:
1-Cyclopentyl-7-methoxy-3-o-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (24 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanato-2-methyl-benzene (0.5 mmol) following general procedure C. LCMS: m/z 402 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Br:17])[CH:11]=2)=O)=[N:4][S:5][N:6]=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:27]2)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:7](=[S:27])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Br:17])[CH:11]=2)=[N:4][S:5][N:6]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Nc1nsnc1C(=O)Nc1ccc(F)c(Br)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1nsnc1C(=S)Nc1ccc(F)c(Br)c1
Yield: 55.7 %

Procedure:
A solution of 4-amino-N-(3-bromo-4-fluorophenyl)-1,2,5-thiadiazole-3-carboxamide (225 mg, 0.7 mmol) and 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (570 mg, 1.4 mmol) in toluene (6.8 mL) was stirred at 95° C. for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL) and the insoluble salts were filtered. The filtrate was concentrated to a crude residue which was purified on silica gel to give the desired product (130 mg, 55%). LCMS for C9H7BrFN4S2 (M+H)+: m/z=332.8, 334.9.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH2:16][CH2:17]O)=[N:8]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][C:29]2[C:30](=[O:36])[NH:31][CH:32]=[CH:33][C:34]=2[CH3:35])[CH:27]=1)[C:23]#[N:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][C:29]2[C:30](=[O:36])[N:31]([CH2:17][CH2:16][C:9]3[C:10]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:32]=[CH:33][C:34]=2[CH3:35])[CH:27]=1)[C:23]#[N:24]
Reactant: OCCc1nn(C2CCCCO2)c2ncccc12
Reactant: Cc1cc[nH]c(=O)c1Oc1cc(Cl)cc(C#N)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccn(CCc2nn(C3CCCCO3)c3ncccc23)c(=O)c1Oc1cc(Cl)cc(C#N)c1
Reaction time: 0.08 h

Procedure:
To a solution of 2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]ethanol (14.6 mg, 0.059 mmol) in CH2Cl2 (400 ul) was added 3-chloro-5-[(4-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy]benzonitrile (15.4 mg, 0.059 mmol), and the resulting mixture was stirred over an ice bath for 5 minutes. The mixture was then treated with triphenylphosphine (30.9 mg, 0.118 mmol) and then diisopropylyazodicarboxylate (13 ul, 0.068 mmol) and stirred over an ice bath for 10 minutes and then at 25° C. for 30 minutes. LC-MS showed the reaction was not complete, and so the mixture was re-cooled over an ice bath and treated with additional diisopropylazodicarboxylate (10 μL, 0.052 mmol). This mixture was stirred over an ice bath for 5 minutes and then stirred at 25° C. for 20 minutes to give a 3:2 mixture of 0 to N alkylation. After this time, the reaction was quenched with MeOH (1 mL) and purified on Gilson LC using a Luna reverse phase column (10μ, C18, 250×21.2 mm) and eluting with a gradient of 5-95% ACN/water (0.5% TFA). The desired fractions were combined and evap in vacuo to give the title compound. LRMS (M+1): 489.9/405.9.
Reaction SMILES: [Cl-].[NH4+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[C@:13]12[CH2:22][C@@H:21]([O:23][CH3:24])[CH2:20][CH2:19][C@H:18]1[CH2:17][S:16][C:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:14]2>[Fe].C(O)C>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([F:3])=[C:5]([C@:13]23[CH2:22][C@@H:21]([O:23][CH3:24])[CH2:20][CH2:19][C@H:18]2[CH2:17][S:16][C:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[N:14]3)[CH:6]=1
Reactant: CO[C@H]1CC[C@H]2CSC(NC(=O)OC(C)(C)C)=N[C@@]2(c2cc([N+](=O)[O-])ccc2F)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CO[C@H]1CC[C@H]2CSC(NC(=O)OC(C)(C)C)=N[C@@]2(c2cc(N)ccc2F)C1
Temperature: 25 °C

Procedure:
Ethanol (5 mL), a saturated ammonium chloride solution (0.5 mL) and iron powder (175 mg) were added to tert-butyl (±)-[(4aR*,7S*,8aS*)-8a-(2-fluoro-5-nitrophenyl)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in Preparation Example 57-(9) (138 mg), and the mixture was stirred with heating under reflux for 30 minutes. The reaction solution was cooled to room temperature, and then the solid was removed by filtration through celite. The filtrate was concentrated under reduced pressure. Then, the residue was suspended in dichloromethane, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain the title compound (98 mg).
Reaction SMILES: C([NH:8][C@H:9]([C:14]([NH:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:23](=[O:27])[O:24]2)=[CH:19][CH:18]=1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])(OC(C)(C)C)=O.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[NH2:8][C@H:9]([C:14]([NH:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:23](=[O:27])[O:24]2)=[CH:19][CH:18]=1)=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2cc(-c3ccccc3)c(=O)oc2c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)C(=O)Nc1ccc2cc(-c3ccccc3)c(=O)oc2c1
Reaction time: 2 h

Procedure:
The product of Example I, above, (191.5 mg, 0.43 mmol) was dissolved at room temperature in 2 mL of trifluoroacetic acid. After 2 hr, the excess trifluoroacetic acid was removed at 1.6 kPa and room temperature, and the residue was dried at 0.1 Pa overnight. The yield of pale yellow glass was quantitative. It was purified by dissolving in 1 mL of methanol and reprecipitating by adding 30 mL of ether; mp=155.6°; NMR (2/1 CDCl3 /CD3OD) δ(LeuCH3)=1.02 D (6), J=5 Hz, δ(LeuCH2)=1.87 D (2), δ(LeuCH)=4.2 M (1), δ(ArH)=7.6 M (9).
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl.[CH2:14](O)[CH3:15]>>[CH2:14]([O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH:6]=[CH:7][CH2:8][P:9]([OH:12])([OH:11])=[O:10])[CH3:15]
Reactant: CCO
Reactant: NC(/C=C/CP(=O)(O)O)C(=O)O
Agent: Cl
Product: CCOC(=O)C(N)C=CCP(=O)(O)O

Procedure:
2.0 g of E-2-amino-5-phosphono-3-pentenoic acid are placed in 50 ml of ethanol and the whole is saturated with hydrogen chloride gas for 21/2 hours at 50°. After concentration, the residue is dissolved in 18 ml of ethanol, 18 ml of propylene oxide are added and the precipitate is filtered off. Recrystallisation from water/ethanol 1:3 yields 2-amino-5-phosphono-3-pentenoic acid ethyl ester, m.p. 167°-168°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:17]([C:6]1([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1C1CCCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1ccccc1)C1CCCC1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-cyclopentyl-1,3-dihydro-indol-2-one (0.24 g, 1 mmol) (from Example 3b, supra), benzyl bromide (0.21 g, 1.2 mmol), potassium iodide (0.20 g, 1.2 mmol) and potassium carbonate (0.3 g, 2.2 mmol) in acetone (6 mL) was heated at 60° C. for 13 days in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloromethane, then 3% ethyl acetate in dichloromethane as solvent) to give two products. Lower Rf sample was recrystallized from dichloromethane-hexanes to give rac-3-benzyl-6-chloro-3-cyclopentyl-1,3-dihydro-indol-2-one as white prisms. (Yield 0.13 g, 39.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[C:16](Cl)(Cl)=[S:17]>O1CCOCC1.O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[C:2]([N:1]=[C:16]=[S:17])=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2ccccc2N)cc1
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccccc2N=C=S)cc1

Procedure:
Reaction of 2-amino-4'-methoxybiphenyl (10 g) with thiophosgene (8.7 g) in dioxane (25 ml) and water (80 ml) at 0° C. for 3 hours gave 4'-methoxy-2-biphenylylisothiocyanate as a pale yellow oil.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:11]2[CH:21]=[CH:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[CH3:29])[C:12]=2[C:13](=[O:18])[N:14]([CH2:16][CH3:17])[N:15]=1>CN(C=O)C.O>[CH3:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[N:19]1[C:12]2[C:13](=[O:18])[N:14]([CH2:16][CH3:17])[N:15]=[C:10]([O:6][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[C:11]=2[CH:21]=[CH:20]1
Reactant: CCn1nc(Cl)c2ccn(-c3ccc(C)cc3C)c2c1=O
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)Oc1nn(CC)c(=O)c2c1ccn2-c1ccc(C)cc1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
To a solution of 3-pentanol (0.079 ml, 0.73 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 29 mg, 0.73 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-(2,4-dimethylphenyl)-6-ethyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (55 mg, 0.18 mmol). The mixture was stirred at 60° C. for 4 hours, then diluted with water (30 ml) and extracted with ethyl acetate (50 ml). The extract were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (10:1) to give 48 mg (48%) of the title compound as an oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([Sn](C)(C)C)[CH:15]=[C:14]([NH2:23])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][N:29]2[S:35]([C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)(=[O:37])=[O:36]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:34][C:32]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][N:29]2[S:35]([C:38]2[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=2)(=[O:36])=[O:37])=[C:25]([C:16]2[CH:15]=[C:14]([NH2:23])[C:13]3[CH:12]=[N:11][N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[C:18]=3[CH:17]=2)[CH:33]=1
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)n2ccc3c(Br)cc(F)cc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1cc(-c2cc(F)cc3c2ccn3S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (0.8 g), 4-bromo-6-fluoro-1-[(4-nitrophenyl)sulfonyl]-1H-indole (0.879 g) and Pd(PPh3)4 (0.212 g) in DMF (5 ml) was heated at 120° C. for 18 h. The solvent was removed in vacuo and the residue purified by silica cartridge (100 g) using a gradient of cyclohexane and ethyl acetate to give the title compound as an orange solid, 0.42 g.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[Cl:22][C:23]1[S:27][C:26]([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.[K+].[Br-]>CCO>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:33][CH2:34][N:29]([CH2:28][C:26]4[S:27][C:23]([Cl:22])=[CH:24][CH:25]=4)[CH2:30][CH2:31]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Clc1ccc(CN2CCNCC2)s1
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(Cc2ccc(Cl)s2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(5-chloro-thiophen-2-ylmethyl)-piperazine, yield 48%. White crystals, m.p. 225–226° C. (from EtOH); 1H NMR (DMSO-d6): δ 12.00 (br, 1H), 8.60–8.55 (1H), 8.27–8.21 (dd-like, 1H), 7.33–7.20 (m, 6H), 7.20–7.15 (d, 1H), 4.55 (br s, 2H), 4.40–4.00 (br, 2H), 3.74–3.27 (br, 4H+H2O); 3.27–2.97 (br, 2H); IR (KBr): ν 1723 (C═O) cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O=[C:10]([CH2:16][CH3:17])[CH2:11][C:12]([O:14][CH3:15])=[O:13]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]([CH2:16][CH3:17])=[CH:11][C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: Nc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(=CC(=O)OC)Nc1ccc(Cl)cc1
Reaction time: 2.5 h
Yield: 70.5 %

Procedure:
In a 300 ml-flask were placed 4-chloroaniline (25.0 g, 196 mmol), methyl 3-oxopentanoate (28.1 g, 216 mmol) and toluene (100 ml). To this solution was added p-toluenesulfonic acid monohydrate (0.19 g, 0.98 mmol), and the resulting mixture was heated in a bath kept at 100° C. under a reduced pressure of 23 kPa for 2.5 hours, while removing the water formed by refluxing by using a Dean-Stark trap. The heating was then discontinued, nitrogen leaked in, and the reaction mixture cooled. The solvent was evaporated off by using a rotary evaporator, and the residue was distilled under reduced pressure to give 33.1 g of the title compound. The yield was 70.5%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:14])[N:3]=1.[NH:15]1[CH:19]=[C:18]([CH2:20][CH2:21][OH:22])[CH:17]=[N:16]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[NH:15]1[CH:19]=[C:18]([CH2:20][CH2:21][O:22][C:2]2[C:11]3[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=3[CH:5]=[C:4]([Cl:14])[N:3]=2)[CH:17]=[N:16]1
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Reactant: OCCc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cnc2cc(Cl)nc(OCCc3cn[nH]c3)c2c1=O
Temperature: 80 °C

Procedure:
A mixture of 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (115.0 mg, 0.50 mmol), 2-(1H-pyrazol-4-yl)ethanol (112.1 mg, 1.00 mmol) and K2CO3 (138.2 mg, 1.00 mmol) in 1,4-dioxane (5 mL) was heated at 80° C. overnight, cooled down, quenched with H2O (25 mL) and extracted with EtOAc (3×12.5 mL). The combined organic layer was evaporated under reduced pressure and purified by reverse phase HPLC to afford 5-(2-(1H-pyrazol-4-yl)ethoxy)-7-chloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one.
Reaction SMILES: [Si:1]([O:18][C@H:19]1[C:24](=[CH2:25])[C@H:23](O)[CH2:22]/[C:21](=[CH:27]/[C:28]([O:30][CH3:31])=[O:29])/[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:38])CC)C>ClCCl>[Si:1]([O:18][C@H:19]1[C:24](=[CH2:25])[C@@H:23]([F:38])[CH2:22]/[C:21](=[CH:27]/[C:28]([O:30][CH3:31])=[O:29])/[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1[C@H](O)C/C(=C/C(=O)OC)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: C=C1[C@@H](F)C/C(=C/C(=O)OC)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound of Example 18A (600 mg, 0.23 mmol) was dissolved in 2.4 mL of dichloromethane, and the resultant solution was cooled to −78° C. (Diethylamino)sulfur trifluoride (DAST, 0.6 mL) was added; the mixture was stirred for 30 minutes, and then quenched by addition of saturated aqueous sodium bicarbonate solution. The mixture was warmed to ambient temperature; the organic phase was dried over Na2SO4. The solvents were removed in vacuo; the residue was purified by chromatography on an Analogix IntelliFlash 280™, eluting with a gradient of 5% to 7% ethyl acetate in hexanes, to give the titled compound, plus some mixed fractions.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[C:12]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:33][CH2:34][N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]>CN(C=O)C>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[C:12]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH2:33][CH2:34][N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:23][CH:24]=4)[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:6][CH2:7]1
Reactant: CN(CCCl)C(=O)OC(C)(C)C
Reactant: Oc1ccc(-c2cccc3cnc(N[C@H]4CC[C@H](O)CC4)nc23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(CCOc1ccc(-c2cccc3cnc(N[C@H]4CC[C@H](O)CC4)nc23)cc1)C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To the flask were added 4-{2-[(trans-4-hydroxycyclohexyl)amino]quinazolin-8-yl}phenol (110 mg, 0.33 mmol), Cs2CO3 (1345 mg, 4.13 mmol), tert-butyl (2-chloroethyl)methylcarbamate (290 mg, 1.45 mmol) and DMF (5 mL). The mixture was stirred for 3 hours at 85° C. The reaction was completed as judged by TLC. The mixture was concentrated in vacuo to afford crude tert-butyl [2-(4-{2-[(trans-4 hydroxycyclohexyl)amino]quinazolin-8-yl}phenoxy)ethyl]methylcarbamate
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[Na+].[C:11]([O:17][CH2:18]Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].CN(C)C=O>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:18][O:17][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C([O-])c1cnccn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)OCOC(=O)c1cnccn1
Reaction time: 8 h
Yield: 77.9 %

Procedure:
A four-necked flask was charged with 127.5 g (0.873 mole) of sodium pyrazinecarboxylate, 119.3 g (0.792 mole) of chloromethyl pivalate and 146 g of dimethylformamide and the internal temperature was maintained under stirring at 105°-110° C. for 8 hours. The reaction mixture was then cooled and transferred to a separatory funnel. After addition of 500 g of toluene, the mixture was washed with 3 portions, or a total of 900 g, of water. From the toluene layer which separated the toluene was first distilled off and the residue was subjected to distillation under reduced pressure to give 147 g of pivaloyloxymethyl pyrazinecarboxylate. Yield: 78% (based on chloromethyl pivalate).