Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[O:29]1[CH2:34][CH2:33][CH:32]([C:35](Cl)=O)[CH2:31][CH2:30]1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[C:35]([CH:32]5[CH2:33][CH2:34][O:29][CH2:30][CH2:31]5)=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: O=C(Cl)C1CCOCC1
Reactant: COc1cc2c(NCc3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(C3CCOCC3)n(Cc3ccccn3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
To a solution of 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-N4-(2-pyridinylmethyl)-3,4-quinolinediamine (for a preparation see Intermediate 38, 0.5 g, 1.33 mmol) in DCM (20 ml) was added tetrahydro-2H-pyran-4-carbonyl chloride (1.1 eq., 1.46 mmol, 0.15 g, Apollo Scientific) at 0° C., the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was hydrolysed with saturated aqueous Sodium hydrogen carbonate and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated to give the crude product which was used in the next step without purification. AcOH (5 ml) was added to the crude product and the mixture was stirred at 100° C. overnight. The reaction mixture was concentrated under reduce pressure, hydrolised with sodium hydroxide 1N and extracted with DCM. The organic phase was dried over over Na2SO4, evaporated under reduce pressure. The residue was purified by flash chromatography on silica gel (DCM/MeOH, 95:5) and the compound was re-crystallised from acetonitrile to give the title compound as an off-white powder (0.13 g, 21%)
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N+:11]([O-])=O>[Pd].C(O)C>[NH2:11][C:5]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[C:3]([N:2]([CH3:15])[CH3:1])=[O:14]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)N(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(N)c(C(=O)N(C)C)c1
Reaction time: 18 h
Yield: 85 %

Procedure:
A mixture of N,N,5-trimethyl-2-nitrobenzamide (11 g, 52.8 mmol) and 5% palladium on carbon (1 g) in 100 mL of ethanol was stirred under a hydrogen atmosphere for 18 hours. Additional 5% palladium on carbon (1 g) was added and the mixture was stirred for approximately 8 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified on silica gel by flash chromatography eluting with 4% ethanol/methylene chloride to give 2-amino-N,N,5-trimethylbenzamide (8 g, 44.9 mmol), m.p. 98°-99° C.
Reaction SMILES: [CH2:1]([C:4]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH2:1]([C:4]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]([C:28]3[CH:27]=[CH:26][C:25]([F:24])=[CH:30][C:29]=3[F:31])[CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: C=CCC1(c2ccccc2)CCN(c2cccc(Br)c2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=CCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Yield: 18.4 %

Procedure:
To a solution of 6-allyl-3-(3-bromophenyl)-6-phenyl-1,3-oxazinan-2-one (50 mg, 0.134 mmol) and 2,4-difluorophenylboronic acid (40 mg, 0.215 mmol), K2CO3 (0.5 mL, 2 M) in 1,4-dioxane (1.5 ml) was slowly added Pd(Ph3)2Cl2 (10 mg, 20%) at 0° C. under N2. The mixture was refluxed overnight. The mixture was concentrated to give the crude product, which was purified by TLC and preparative HPLC to afford 6-allyl-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 18%). 1H NMR (400 MHz, CDCl3): δ=2.40 (m, 2H), 2.55-2.72 (m, 2H), 3.26 (m, 1H), 3.47 (m, 1H), 5.05 (m, 2H), 5.76 (m, 1H), 6.76-6.90 (m, 2H), 7.04 (m, 1H), 7.28 (m, 4H), 7.36 (m, 2H).
Reaction SMILES: CON(C)[C:4]([C@:6]1([CH3:13])[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[O:7]1)=[O:5].CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:11][C:8]1([CH3:12])[O:7][C@:6]([CH3:13])([CH:4]=[O:5])[CH2:10][O:9]1
Reactant: CON(C)C(=O)[C@]1(C)COC(C)(C)O1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC1(C)OC[C@@](C)(C=O)O1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
(S)-N-methoxy-N,2,2,4-tetramethyl-1,3-dioxolane-4-carboxamide (23.1 g, 114 mmol) was dissolved in THF (600 mL) and cooled to −78° C. DIBAL-H (1M in toluene, 125 ml, 125 mmol) was added slowly through an addition funnel over about 15 minutes. The reaction was stirred for an additional 30 minutes at −78° C. and then quenched with saturated aqueous NH4Cl. The mixture was partitioned between EtOAc and water. The two layers were filtered through a silica plug and separated. The organic layer was dried over sodium sulfate, filtered and concentrated to afford (S)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde (16.4 g, 114 mmol, 100% yield).
Reaction SMILES: [OH2:1].Br[CH2:3][C:4]1[C:12]2[C:7](=[N:8][C:9]([Cl:13])=[CH:10][CH:11]=2)[S:6][N:5]=1>CS(C)=O>[Cl:13][C:9]1[N:8]=[C:7]2[S:6][N:5]=[C:4]([CH2:3][OH:1])[C:12]2=[CH:11][CH:10]=1
Reactant: O
Reactant: Clc1ccc2c(CBr)nsc2n1
Solvent: CS(C)=O
Product: OCc1nsc2nc(Cl)ccc12
Temperature: 80 °C

Procedure:
Water (8 mL) was added to a solution of 3-(bromomethyl)-6-chloroisothiazolo[5,4-b]pyridine (19.0 mmol) in dimethylsulfoxide (40 mL) and the reaction mixture was heated at 80° C. for 1.5 h. The reaction mixture was then quenched with water (50 mL) and the resulting solution was extracted with ethyl acetate (3×40 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the crude (6-chloroisothiazolo[5,4-b]pyridin-3-yl) methanol as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH3:12])=[C:7]([Cl:13])[C:6]=1[OH:14])(=O)[CH3:2].C([O-])(=O)C.[Na+]>>[CH3:2][C:1]1[O:14][C:6]2[C:7]([Cl:13])=[C:8]([CH3:12])[C:9]([Cl:11])=[CH:10][C:5]=2[N:4]=1
Reactant: CC(=O)Nc1cc(Cl)c(C)c(Cl)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1nc2cc(Cl)c(C)c(Cl)c2o1

Procedure:
A mixture of 79 g. of 2-acetylamino-5-methyl-4,6-di-chloro-phenol and 3.6 g. of anhydrous sodium acetate was heated at 180° C. for some minutes. The liquid obtained was distilled under vacuum, collecting the fraction passed from 140° C. to 145° C. at 1.2 mm. Hg. The distilled oil became a mass of crystals which was purified by crystallization from ligroin. 36 g. of pure base were obtained. M.P. = 80°-82° C.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(N(C(C)C)CC)(C)C.[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[C:30](Br)[CH:29]=[CH:28][C:27]=1[F:33].[C:35]([C:37]1[CH:38]=[N:39][CH:40]=[C:41]([CH:44]=1)[C:42]#[N:43])#[CH:36]>O1CCOCC1.[Cu]I>[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[C:30]([C:36]#[C:35][C:37]2[CH:38]=[N:39][CH:40]=[C:41]([C:42]#[N:43])[CH:44]=2)[CH:29]=[CH:28][C:27]=1[F:33]
Reactant: COC(=O)c1cc(Br)ccc1F
Reactant: C#Cc1cncc(C#N)c1
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C#Cc2cncc(C#N)c2)ccc1F
Reaction time: 2 h
Yield: 44.1 %

Procedure:
Sequentially add tri-tert-butylphosphine (88 mg, 0.437 mmol) in anhydrous 1,4-dioxane (1 mL), diisopropylethylamine (1.5 mL, 8.74 mmol), 5-bromo-2-fluorobenzoic acid methyl ester, (prepared as described in PREPARATION 42), (1.69 g, 7.28 mmol) and a solution of 5-ethynylnicotinonitrile, (prepared as described in PREPARATION 4), (0.93 g, 7.28 mmol) in anhydrous 1,4-dioxane (4 mL), to a stirring mixture of dichloro(benzonitrile)palladium (II) (84 mg, 0.218 mmol) and copper (I) iodide (28 mg, 0.146 mmol) in anhydrous 1,4-dioxane (1 mL) under nitrogen. Stir for 2 h and concentrate. Purify the residue twice by silica gel chromatography, eluting with 10:90 ethyl acetate:hexanes, to give the title compound as a white solid (0.9 g, 44%).
Reaction SMILES: [N+:1]([C:4]12S[CH:9]1[CH:8]=[CH:7][CH:6]1[S:11][CH:5]21)([O-:3])=[O:2].[BH4-].[Na+].Cl>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([SH:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])C12SC1C=CC1SC12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(S)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 164.8 %

Procedure:
(Cashman, J. R. et al. Chem. Res. Toxicol., 1989, 2:392-399). To a solution of m-nitrobenzene disulfide (300 mg, 0.97 mmol) in anhydrous THF (2 mL) was added solid NaBH4 (140 mg, 3.4 mmol) in small portions. The resulting mixture was stirred at room temperature under an inert atmosphere. After 2 hr, the reaction mixture was cooled in an ice bath, and then about 5 mL of ice water was added to the mixture. The resulting mixture was acidified with HCl (1 M), then extracted with CH2Cl2 (10 mL). The organic layer was then washed with water (10 mL), then brine (10 mL), dried over MgSO4, and concentrated in vacuo to give 43 (248 mg, 83%) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz): δ 8.10 (d, J=2.0 Hz, 1H); 7.97 (dd, J=8.0, 2.0 Hz, 1H); 7.54 (d, J=8.0 Hz, 1H); 7.38 (t, J=8.0 Hz, 1H); 3.68 (s, 1H); 13C NMR (CDCl3, 100 MHz): δ 134.9, 130.0=, 123.9, 120.7.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:11][C:12](=[O:34])[CH:13]([C:23](=[O:33])[N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:25])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(#N)C>FC(F)(F)C(O)=O.ClCCl>[CH2:26]([N:24]([CH3:25])[C:23]([CH:13]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=1)[C:12]([NH:11][C@@H:4]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:3]([OH:35])=[O:2])=[O:34])=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C#N)cc1)C(=O)N(C)Cc1ccccc1)C1CCCCC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)C(Cc1ccc(C#N)cc1)C(=O)N[C@H](C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 240 h
Yield: 63 %

Procedure:
1.5 g (3.15 mmol) of the above [2-(R,S)-(Benzyl-methyl-carbamoyl)-3-(4-cyano-phenyl)-propionylamino]-(S)-cyclohexyl-acetic acid methyl ester was suspended in water/concentrated hydrochloric acid (1/1, 40 ml) and acetonitrile (40 ml) was added to give a solution. The reaction mixture was stirred at room temperature for 10 days. The reaction mixture was concentrated in vacuo and the residue lyophilized to give the desired product in 63% yield.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([C:13]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C:9](F)=[N:10][CH:11]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([C:13]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C:9]([NH:29][C:30]2[CH:35]=[N:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[N:10][CH:11]=1
Reactant: COc1ccc(N)cn1
Reactant: Cc1nc(-c2cc(C3OCCO3)cnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(C3OCCO3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 77.8 %

Procedure:
6-(5-(1,3-Dioxolan-2-yl)-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (4.557 g, 11.82 mmol) and 5-amino-2-methoxypyridine (1.507 g, 12.14 mmol) were dissolved in tetrahydrofuran (80 mL) and cooled in an ice water bath. Then, LiHMDS (Aldrich 1.0 M in THF, 36.0 mL, 36.0 mmol) was added via syringe over about 10 minutes. The reaction was stirred under nitrogen at 0° C. for 40 minutes, and then the reaction was treated with water (100 mL) and warmed to room temperature. The layers were separated, and the aqueous phase was extracted with DCM. The aqueous phase was diluted with brine and extraction with DCM was continued. The combined organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (600 mL fritted filter, about 3 inches of silica gel, 80:1 DCM/2 N ammonia in MeOH to 50:1 DCM/2 N ammonia in MeOH) to give 5-(1,3-dioxolan-2-yl)-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (4.500 grams, 71% purity, 52% yield over two steps). MS MS (ESI pos. ion) m/z 446. Calculated exact mass for C23H23N7O3: 445 (M+—C2H4O). 1H NMR (CDCl3, 400 MHz) δ 12.69 (s, 1H), 9.91 (s, 1H), 8.44 (d, J=2.74 Hz, 1H), 8.41 (d, J=2.15 Hz, 1H), 8.29 (s, 1H), 8.23 (dd, J=8.80 Hz, 2.74 Hz, 1H), 6.79 (d, J=8.80 Hz, 1H), 5.94 (s, 1H), 5.87 (dd, J=10.56 Hz, 2.15 Hz, 1H), 4.24-4.17 (m, 3H), 4.12-4.05 (m, 2H), 3.96 (s, 3H), 3.88-3.79 (m, 1H), 2.91 (s, 3H), 2.19-2.00 (m, 3H), 1.93-1.77 (m, 3H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:33](Br)[CH:34]=[CH2:35]>O1CCCC1>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH:15]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH2:35][CH:34]=[CH2:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CC1CCCCC1)N1C(=O)OCC1Cc1ccccc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)N1C(=O)OCC1Cc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-benzyl-3-(2-cyclohexyl-acetyl)-oxazolidin-2-one (16.0 g, 53 mmol) in anhydrous tetrahydrofuran at −78° C. was added a 1.0 M solution of sodium bis(trimethylsilyl)-amide (79.0 mL, 79 mmol), and the reaction mixture was stirred for 1 h. To the reaction mixture was then added allyl bromide (18.4 mL, 213 mmol), and the temperature was raised to −45° C. The reaction mixture was stirred at this temperature for 3 h. The reaction was quenched with aqueous saturated NH4Cl solution, and the resulting mixture was warmed to room temperature. The reaction mixture was extracted with ethyl acetate, and the combined extracts were washed with brine. The organic layers were dried (MgSO4) and concentrated in vacuo to yield a residue that was purified by silica gel column chromatography (5:1 hexanes:ethyl acetate) to yield (4-benzyl-3-(2-cyclohexyl-pent-4-enoyl)-oxazolidin-2-one) as a thick liquid that became a solid upon storage.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C:4]1[C:14]2[O:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.C(OCC)(=O)C.[ClH:29]>C(OCC)(=O)C>[ClH:29].[CH3:1][CH:2]([CH3:22])[CH2:3][C:4]1[C:14]2[O:13][CH2:12][CH2:11][NH:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)Cc1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cc1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A mixture of tert-butyl 9-(2-methylpropyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (260 mg, 0.937 mmol), ethyl acetate (2 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (192 mg, 93.7%) as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[C:9]([O:11]C)=O.[NH2:13][C:14]1[NH:18][N:17]=[CH:16][CH:15]=1>C(O)(=O)C>[Cl:8][C:6]1[N:5]=[CH:4][C:3]2[C:9](=[O:11])[N:18]3[N:17]=[CH:16][CH:15]=[C:14]3[NH:13][C:2]=2[CH:7]=1
Reactant: Nc1ccn[nH]1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Solvent: CC(=O)O
Product: O=c1c2cnc(Cl)cc2[nH]c2ccnn12

Procedure:
205 g. of 4,6-dichloropyridine-3-carboxylic acid, methyl ester and 166 g. of 5-aminopyrazole are refluxed together in 300 ml. of acetic acid for 10 hours with stirring. The crystalline 6-chloropyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one is filtered off, washed with water and recrystallized from dimethylformamide, yield: 185 g. (84%); m.p. > 300°.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[NH2:34][C:35]1([CH2:40][OH:41])[CH2:39][CH2:38][CH2:37][CH2:36]1>CS(C)=O>[OH:41][CH2:40][C:35]1([NH:34][C:7]2[C:8]3[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[O:24][CH:23]=[N:22][CH:21]=4)=[CH:18][CH:19]=3)[N:12]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: NC1(CO)CCCC1
Solvent: CS(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NC3(CO)CCCC3)c2C1
Reaction time: 8 h
Yield: 27.1 %

Procedure:
6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol, Example 26a) in DMSO (1 mL) dispensed in a library plate. (1-aminocyclopentyl)methanol (8.06 mg, 0.07 mmol) was added and it was left to shake overnight at 80° C. before filtered and purified by preparative HPLC to yield 1-(4-(1-(hydroxymethyl)cyclopentylamino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (8.5 mg, 26%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.[N:13]1([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24]([C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[O:25])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[O:1]1[C:2]2=[CH:3][CH:4]=[CH:9][C:8]2=[CH:7][CH:6]=[C:5]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:24]([N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[CH2:18][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:25]
Reactant: O=C(c1ccc(Br)cc1)N1CCCC1CN1CCCC1
Reactant: OB(O)c1cc2ccccc2o1
Product: O=C(c1ccccc1-c1ccc2cccc-2o1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure Q starting from 2-Benzofuran boronic acid and 4-(2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl bromide to give 52 mg (47%). MS (ES+) 375.2
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])=[C:4]([CH3:16])[C:3]=1[CH3:17].[CH3:18][C@@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:16][C:4]1[C:3]([CH3:17])=[C:2]([N:23]2[CH2:22][CH2:21][NH:20][C@H:19]([CH3:18])[CH2:24]2)[N:7]=[N:6][C:5]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9]
Reactant: Cc1c(Cl)nnc(C(=O)c2ccccn2)c1C
Reactant: C[C@@H]1CNCCN1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)c2ccccn2)nnc(N2CCN[C@H](C)C2)c1C
Yield: 97.1 %

Procedure:
(6-Chloro-4,5-dimethyl-pyridazin-3-yl)-pyridin-2-yl-methanone (550 mg, 2.22 mmol), (R)-2-methyl-piperazine (320 mg, 3.20 mmol) are added into a microwave vial followed by NMP (6 mL) and triethylamine (0.92 mL, 6.66 mmol). The vial is sealed and irradiated in the microwave at 180° C. for 1 h. The crude material is directly purified via flash chromatography on silica gel (20-70% methanol in CH2Cl2) to afford the title compound (671 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][NH:13][CH3:14].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:13]([CH2:12][CH2:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:14])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CNCCc1c(Cl)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(C)CCc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
A solution of [2-(2-chloro-6-nitro-phenyl)-ethyl]-methylamine (11.0 g, 0.051 mole) and ethyl bromoacetate (8.56 g, 0.051 mole) in acetonitrile (200 mL) containing potassium carbonate (3.54 g, 0.026 mole) was stirred at room temperature overnight. The mixture was evaporated in vacuo, water was added to the residue, this mixture was made basic with sodium carbonate and then extracted with dichloromethane (2×300 mL), the combined organic layers were washed with saturated sodium chloride (300 mL), dried and concentrated. Purification by flash column chromatography (silica gel, methylene chloride:hexanes 1:1) provided 9.0 g of the title compound as a light brown oil. 1H NMR (CDCl3): 7.70 δ (d, 1H); 7.60 δ (d, 1H); 7.35 δ (t, 1H); 4.20 δ (m, 2H); 3.35 δ (s, 2H); 3.15 δ (t, 2H); 2.90 δ (t, 2H); 2.50 δ (s, 3H); 1.30 δ (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(O)C>[CH2:13]([NH:20][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: Clc1cc(Cl)c2ccccc2n1
Solvent: O
Solvent: CCO
Product: Clc1cc(NCc2ccccc2)c2ccccc2n1
Yield: 34.8 %

Procedure:
2,4-Dichloroquinoline (0.70 g, 3.53 mmole) and benzylamine (3.79 g, 35.3 mmole) in ethanol (2 mL) were stirred at 110° C. in a microwave oven for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phases were washed with saturated NaCl solution, dried and concentrated. The residue thus obtained was purified using silica gel chromatography, eluting with dichloromethane:methanol 95:5 to give a white solid (330 mg, 35%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[OH:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>CN(C)C=O>[OH:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2](=[O:3])[O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[CH:13][CH:12]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(O)cc1)OCC(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
4.3 g (0.02 mol) of 2,2,2-trichloroethyl chloroformate are dissolved in 20 ml of DMF (dimethyl formamide) and added dropwise to a solution of 10.9 g (0.1 mol) of 4-hydroxyaniline in 100 ml of DMF. After the mixture has been stirred for a further hour at room temperature, it is poured into ice water, acidified and filtered with suction, and the material filtered off is washed with water. The product is recrystallized from toluene using activated charcoal. 2.3 g of a substance of melting point 134° C. are obtained; 1H NMR: --NH-- 9.17 ppm (s, 1H), --CH2 4.9 ppm (s, 2H), --OH (+H2O) 3.31 ppm (s), aromatics 6.67 ppm (d, 2H) 7.27 ppm (d, 2H).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.B([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]2)=[CH:29][CH:28]=1)(O)O>>[O:41]=[S:37]1(=[O:40])[CH2:38][CH2:39][N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:2]3[N:10]4[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]5[CH:17]=[CH:16][C:15]([N:18]6[CH2:19][CH2:20][O:21][CH2:22][CH2:23]6)=[CH:14][CH:13]=5)=[N:9]4)=[CH:4][CH:3]=3)=[CH:28][CH:29]=2)[CH2:35][CH2:36]1
Reactant: O=S1(=O)CCN(Cc2ccc(B(O)O)cc2)CC1
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Product: O=S1(=O)CCN(Cc2ccc(-c3ccc4cnc(Nc5ccc(N6CCOCC6)cc5)nn34)cc2)CC1

Procedure:
{7-[4-(1,1-Dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl}-(4-morpholin-4-yl-phenyl)-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine and 4-[(4-boronophenyl)methyl]-thiomorpholine 1,1-dioxide in an analogous manner to Example 1031b. Product isolated as a yellow solid (36 mg, 24%). m.p.=251-255° C.; LCMS (m/e) 519 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.69 (s, 1H), 8.13 (d, 2H, J=7.8 Hz), 7.55 (d, 2H, J=7.4 Hz), 7.42 (d, 2H, J=7.8 Hz), 7.02-6.97 (m, 1H), 6.92 (d, 2H, J=7.0 Hz), 6.85-6.80 (m, 1H), 6.73-6.64 (m, 1H), 3.93-3.85 (m, 4H), 3.73 (s, 2H), 3.17-3.00 (m, 12H).