Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[CH3:17][S:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1)(=[O:20])=[O:19].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:29](=[O:30])[CH2:28][C:25]2[CH:24]=[CH:23][C:22]([NH:21][S:18]([CH3:17])(=[O:19])=[O:20])=[CH:27][CH:26]=2)[CH2:7]1
Reactant: CS(=O)(=O)Nc1ccc(CC(=O)O)cc1
Reactant: NCC1CN(Cc2cccc(F)c2)CCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc(CC(=O)NCC2CN(Cc3cccc(F)c3)CCO2)cc1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A mixture of Intermediate 29 (0.0134 g), {4-[(methylsulfonyl)amino]phenyl}acetic acid (0.0137 g, known compound WO 9929655 A1), 1-hydroxybenzotriazole (0.0097 g) and N,N-diisopropylethylamine (0.01 ml) in N,N-dimethylformamide (0.5 ml) was treated with a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.00138 g) in N,N-dimethylformamide (0.5 ml). The mixture was stirred at 20° C. for 24 h. The mixture was partitioned between dichloromethane (4 ml) and saturated aqueous sodium hydrogen carbonate (4 ml). The phases were separated and the organic phase applied to an ion exchange cartridge (2 g Isolute SCX, prewashed with methanol). The SCX cartridge was eluted with methanol (10 ml) followed by 10% 0.880 ammonia in methanol (10 ml) and the appropriate fractions were concentrated in vacuo to give the title compoundas a colourless (0.0174 g).
Reaction SMILES: [Na].[C:2]([O:6][C:7]([N:9]1[CH2:13][CH2:12][C@H:11]([C:14]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=[O:15])[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]>CO>[C:2]([O:6][C:7]([N:9]1[CH2:13][CH2:12][C@H:11]([CH:14]([CH:16]2[CH2:17][CH2:18][CH2:19]2)[OH:15])[CH2:10]1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)C2CCC2)C1
Agent: [Na]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](C(O)C2CCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
Add sodium borohyride (1.19 g, 31.4 mmol) to a stirred solution of (S)-3-cyclobutanecarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5.30 g, 20.9 mmol) in MeOH (105 mL) kept under an atmosphere of nitrogen at 0° C. Stir the mixture for 2 hours while warming to room temperature. Concentrate the MeOH, dilute with dichloromethane and wash the organics with saturated aqueous NaHCO3, water and brine. Dry (MgSO4), filter and concentrate under reduced pressure to yield the title compound (4.4 g, 82%) as a mixture of diastereomers (S-mix).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[CH:8][C:9]=2[CH2:11][CH2:12][CH3:13])[S:4][C:3]=1[C:21]#[N:22].[N:23](OCCC(C)C)=O.[ClH:31]>CCO>[Cl:31][C:21]1[C:3]2[S:4][C:5]3[N:6]=[C:7]([N:14]4[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]4)[CH:8]=[C:9]([CH2:11][CH2:12][CH3:13])[C:10]=3[C:2]=2[N:1]=[N:23][N:22]=1
Reactant: CCCc1cc(N2CCC(O)CC2)nc2sc(C#N)c(N)c12
Reactant: CC(C)CCON=O
Reactant: Cl
Solvent: CCO
Product: CCCc1cc(N2CCC(O)CC2)nc2sc3c(Cl)nnnc3c12
Temperature: 25 °C
Yield: 35 %

Procedure:
3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carbonitrile (316 mg, 1.00 mmol) (see Example 2) was dissolved in 3 mL of HCl in EtOH (1.25 M). To this solution at 0° C. was added isoamyl nitrite (0.42 mL, 3.0 mmol). The reaction mixture was warmed up to room temperature in 2 h. The resulting precipitate was collected by filtration and washed with MeOH to give 1-(4-chloro-9-propyl-pyrido[3′,2′:4,5]thieno[3,2-d][1,2,3]triazin-7-yl)-piperidin-4-ol as a yellow solid (120 mg, 35%).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].F[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=1)=[N:9][CH:10]=[N:11]2>>[NH2:4][CH2:3][CH2:1][O:2][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=1)=[N:9][CH:10]=[N:11]2
Reactant: NCCO
Reactant: Cc1cc(Nc2ncnc3cccc(F)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(OCCN)c23)ccc1O
Yield: 23 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using ethanolamine and 4-[(5-fluoroquinazolin-4-yl)amino]-2-methylphenol (obtained as described in Example 3, preparation of starting materials) to give 4-{[5-(2-aminoethoxy)quinazolin-4-yl]amino}-2-methylphenol as a grey solid in 23% yield; NMR spectrum (DMSO-d6) 2.14 (s, 3H), 3.09 (d, 2H), 3.28 (s, 2H), 4.25 (t, 2H), 6.77 (d, 1H), 7.08 (d, 1H), 7.28 (d, 1H), 7.46 (dd, 1H), 7.55 (d, 1H), 7.66 (t, 1H), 8.40 (s, 1H), 10.31 (s, 1H); Mass spectrum MH+ 311.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:17][C:16]([C:18](O)=[O:19])=[C:15]([CH3:21])[CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[NH2:55][CH2:56][C:57]1[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:17][C:16]([C:18]([NH:55][CH2:56][C:57]4[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=4)=[O:19])=[C:15]([CH3:21])[CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: NCc1cccnc1
Reactant: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a stirred mixture of 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid (0.13 g, 0.38 mmol), 1-hydroxybenzotriazole (0.077 g, 0.57 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g, 0.57 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (0.20 mL, 1.14 mmol) and 3-(aminomethyl)pyridine (0.04 mL, 0.39 mmol). The resulting reaction mixture was stirred for 18 h at ambient temperature, then diluted with ethyl acetate (75 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (3×35 mL) and water (35 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with dichloromethane in hexanes to afford the title compound as a colorless solid in 87% yield (0.14 g): mp 180-182° C.: 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.52 (d, J=4.1 Hz, 1H), 7.72 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.39-7.33 (m, 2H), 7.30-7.24 (m, 1H), 7.06-6.98 (m, 2H), 6.87 (s, 1H), 6.43 (t, J=5.6 Hz, 1H), 4.95 (s, 2H), 4.59 (d, J=5.6 Hz, 2H), 2.50 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.64 (d, JC-F=247.1 Hz), 162.6, 150.4, 149.3, 149.1, 140.8, 135.7, 134.5, 133.7, 132.3, 131.2 (d, JC-F=3.2 Hz), 130.3 (d, JC-F=8.3 Hz), 125.3, 123.7, 120.2, 115.8 (d, JC-F=21.6 Hz), 49.0, 41.5, 16.0; MS (ES+) m/z 424.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[CH:8][CH:7]=[CH:6][N:5]2[C:21]=1[C:22](OCC)=[O:23].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:14][CH2:13]3)=[CH:8][CH:7]=[CH:6][N:5]2[C:21]=1[CH2:22][OH:23]
Reactant: CCOC(=O)c1c(C)nc2c(OCC3(c4ccccc4)CC3)cccn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2c(OCC3(c4ccccc4)CC3)cccn2c1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a cold (0°), stirred solution of ethyl 2-methyl-8-[(1-phenylcyclopropyl)methoxy]imidazo[1,2-α]pyridine-3-carboxylate (0.629 g, 1.83 mmol, see example 30) in anhydrous tetrahydrofuran (12 mL) under argon was added lithium aluminum hydride (0.104 g, 2.74 mmol). The reaction mixture was stirred for 1 h at 0° C., then quenched with water (25 mL) and extracted successively with ethyl acetate (75 mL) and dichloromethane (3×30 mL). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to yield 0.485 g (86% yield) of {2-methyl-8-[(1-phenylcyclopropyl)methoxy]imidazo[1,2-α]pyridin-3-yl}methanol free base as a pale yellow solid. A stirred solution of the free amine (0.479 g, 1.55 mmol) in anhydrous methanol (27 mL) was treated with ethereal hydrogen chloride to form the hydrochloride salt. After the solvent was removed in vacuo, the residue was triturated in anhydrous diethyl ether to yield a gummy solid. Recrystallization of this material from a mixture of diethyl ether and methanol yielded 0.509 g (95% yield) of the title compound as an off-white solid. 1H-NMR (300 MHz, CDCl3) δ 14.92 (s, 1H, +NH), 8.41 (s, 1H, Ar), 7.57 (m, 2H, Ar), 7.21 (m, 2H, Ar), 7.10 (m, 1H, Ar), 6.96 (m, 1H, Ar), 6.70 (m, 1H, Ar), 4.86 (s, 2H, HOCH2), 4.21 (s, 2H, CH2O), 2.59 (s, 3H, CH3), 1.06 (m, 4H, CH2CH2); 13C-NMR (75 MHz, CDCl3, APT) δ 144.21 (+), 142.21 (+), 132.30(+), 131.66(+), 129.87(−), 128.32(−), 126.81 (−), 123.23 (+), 119.12(−), 116.61 (−), 109.86 (−), 77.85 (+), 51.30 (+), 25.34 (+), 11.59 (+), 9.90 (−); LRMS-FAB m/z: MH+ 309 (100%); Anal. calcd for C19H20N2O2.HCl: C, 66.18; H, 6.14; N, 8.12%. found: C, 64.67; H, 6.36; N, 7.64%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:22]([Cl:41])(C1C=CC=CC=1)(C1C=CC=CC=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.OCC1C=CC(CCl)=CC=1.C1(C)C=CC=CC=1>Cl.CCCCCCC>[C:16]1([C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:2][CH2:1][C:26]2[CH:27]=[CH:28][C:23]([CH2:22][Cl:41])=[CH:24][CH:25]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: OCc1ccc(CCl)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: ClCc1ccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A 100 mL round bottom flask was charged with triphenylmethyl methyl ether (2.74 g, 10 mmol), trityl chloride (2.79 g, 10 mmol), p-hydroxymethylbenzyl chloride (3.13 g, 20 mmol), toluene (12 mL), heptane (12 mL) and 32% HCl (2 drops). The solution was heated to reflux and 12 mL solvent was distilled over 2 hours. The solution was cooled to room temperature and the resulting slurry diluted with 12 mL heptane. After cooling in an ice bath, the product was isolated by vacuum filtration and dried in vacuo at 40° C. to give 6.27 g (79% yield) of crude product. Recrystallization from 20 mL acetonitrile gave 5.46 g (88% recovery) of the desired product. The product had a melting point of 126°-128° C. 1H NMR spectral data were as follows: (CDCl3, 300 MHz): δ7.6-7.2 (complex, 19H), 4.6 (s, 2H), 4.2 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19]Br>CN(C)C=O>[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CN1C(=O)NC(C)(C)C1=O)OC
Temperature: 25 °C

Procedure:
85.46 g (0.667 mol) of 5,5-dimethylhydantoin, 110.6 g (0.80 mol) of anhydrous potassium carbonate and 124.0 g (0.7336 mol) of 2-bromoacetaldehyde dimethyl acetal in 600 ml of dimethylformamide are reacted for about 6 hours analogously to Example 1 in a glass apparatus. The reaction mixture is subsequently cooled to room temperature and filtered with suction, the filtrate is evaporated in a rotary evaporator, and the residue is dried at 110° C./0.1 mbar. The crude yield is 143.2 g (99.3% of theory) of 3-(2,2-dimethoxyethyl)-5,5-dimethylimidazolidine-2,4-dione. 21 g of the crude product are dissolved in 50 ml of 0.1N sodium hydroxide solution at room temperature, and the solution is extracted 3 times by shaking with 30 ml of tert-butyl methyl ether in each case in a separating funnel. The organic phases are combined, the solution is dried using anhydrous sodium sulfate and subsequently filtered, the clear filtrate is evaporated in a rotary evaporator, and the residue is dried for 1 hour at 60° C./0.1 mbar, giving 12.3 g of pure, highly viscous 3-(2,2-dimethoxyethyl)-5,5-dimethylimidazolidine-2,4-dione having the following analytical data:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.O[NH:61][C:62](=[NH:64])[CH3:63]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([N:10]2[CH2:17][CH2:16][CH2:15][CH:11]2[C:12]2[O:14][N:64]=[C:62]([CH3:63])[N:61]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(=N)NO
Reactant: Cc1c(N2CCC[C@H]2C(=O)O)ccc(C#N)c1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C2CCCN2c2ccc(C#N)c(Cl)c2C)n1
Temperature: 21 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(3-chloro-4-cyano-2-methylphenyl)proline (0.200 g, 0.756 mmol), TBTU (0.364 g, 1.136 mmol), diisopropylethylamine (0.458 g, 3.78 mmol) and N-hydroxybenzotriazole (0.023 g, 0.150 mmol) in DMF add N-hydroxyacetamidine (0.084 g, 1.136 mmol). Stir the solution at 21° C. for 18 h. then heat the reaction at 100° C. in a microwave for 1 h. Partition the reaction between ethyl acetate and 2N aqueous hydrochloric acid. Extract the organic phase with 2N aqueous sodium hydroxide and brine, dry over magnesium sulphate, filter and remove the solvent under reduced pressure. Purify the resulting residue by reverse phase HPLC (Princeton SPHER C-18 column, gradient of 80:20 to 5:95 [water:acetonitrile], with 0.1% acetic acid modifier)) to yield the title compound. (0.81 g, 35%) mass spectrum (m/e): 303.1 (M+Na)); 1H NMR (400 MHz, CDCl3): δ 7.35 (d, 1H), 6.99 (d, 1H), 5.11 (t, 1H), 3.88 (m, 1H), 3.16 (m, 1H), 2.56 (m, 1H), 2.39 (s, 3H), 2.31 (s, 3H), 2.30-2.15 (m. 3H), 2.06 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:14]=[C:15]4[C:20](=[N:21][CH:22]=3)[N:19]([CH3:23])[C:18](=[O:24])[CH:17]=[C:16]4[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=3)OCC[O:9]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:13]2[CH:14]=[C:15]3[C:20](=[N:21][CH:22]=2)[N:19]([CH3:23])[C:18](=[O:24])[CH:17]=[C:16]3[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: COc1cccc(-c2cc(=O)n(C)c3ncc(C4(c5ccc(Cl)cc5)OCCO4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(-c2cc(=O)n(C)c3ncc(C(=O)c4ccc(Cl)cc4)cc23)c1
Temperature: 70 °C
Yield: 92.2 %

Procedure:
To a solution compound H (0.3 g, 0.67 mmol) in dioxane (5 mL) was added 6 N HCl (0.5 mL) at 0° C. The mixture was heated at 70° C. for 1.5 h and cooled to RT. Dioxane was removed under reduced pressure; the reaction mixture was neutralized with saturated NaHCO3 solution and extracted with EtOAc (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 0.25 g (92%) of compound I as off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH3:14])[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15].Cl[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][N:21]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CC(O)C>[Br:1][C:2]1[C:7]2[N:8]([CH3:14])[C:9]([C@@H:11]([NH:13][C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][NH:21]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15]
Reactant: C[C@H](N)c1nc2ccc(F)c(Br)c2n1C
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(Br)c2n1C
Temperature: 85 °C
Reaction time: 21 h
Yield: 62.7 %

Procedure:
A mixture of (S)-1-(7-Bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamine, (0.50 g, 1.84 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.61 g, 2.57 mmol) and DIPEA (0.60 mL, 3.31 mmol) in IPA (7 mL) was stirred at 85° C. in a sealed tube for 21 h. After cooling, the was mixture partitioned between DCM (3×) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4), concentrated in vacuo and the residue purified by chromatography (SiO2, 0-5% (2M ammonia in methanol) in DCM). The product was dissolved in methanol (15 mL), treated with HCl/dioxane (4M, 2.0 mL, 8.0 mmol) then stirred for 10 minutes. The reaction mixture was concentrated in vacuo and the residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo to give 430 as a white solid (0.45 g, 63%). LCMS (Method K): RT 3.12 min [M+H]+ 390.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.99 (1H, s), 8.27-7.97 (3H, m), 7.62 (1H, dd, J=8.72, 4.66 Hz), 7.23-7.16 (1H, m), 5.76 (1H, m), 4.09 (3H, s), 1.67 (3H, d, J=6.76 Hz). Signals split due to presence of tautomers
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[NH:23]1[CH:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[N:24]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][N:23]2[CH:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[N:24]2)=[CH:4][CH:5]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.8 %

Procedure:
A mixture of 4-(4-chloromethylphenoxy)methyl-5-methyl-2-phenyloxazole (3.55 g), ethyl 1H-pyrazol-4-carboxylate (1.50 g), potassium carbonate (2.76 g), and N,N-dimethylformamide (25 ml) was stirred at room temperature for 24 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration, and ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-carboxylate (3.79 g, yield: 91%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 108–109° C.
Reaction SMILES: CC[O-].[Na+].[C:5]([CH2:7][C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:9])#[N:6].[NH2:22][C:23]1[C:28]([CH:29]=O)=[CH:27][CH:26]=[CH:25][N:24]=1>CCO>[NH2:6][C:5]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=2)=[O:9])=[CH:29][C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: Nc1ncccc1C=O
Reactant: N#CCC(=O)NCc1cccc(C(F)(F)F)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc2ncccc2cc1C(=O)NCc1cccc(C(F)(F)F)c1
Yield: 57.4 %

Procedure:
To a solution of NaOEt prepared by dissolving Na (50 mg, 1.47 mmol) in EtOH (2.5 ml), was added 2-cyano-N-(3-(trifluoromethyl)benzyl)acetamide (297.5 mg, 1.23 mmol) and 2-amino-3-pyridine-carboxaldehyde (150.0 mg, 1.23 mmol). The mixture was refluxed for 30 minutes. The solvent was removed under reduced pressure and the residue chromatographed CH2Cl2/MeOH 95:5→92:8, yielding 244.5 mg (57%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12(C(OCC)=O)CC(C=C1)[CH:20]1[CH:16]2[CH:17]=[C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19]1>O1CCOCC1>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]2[CH:10]([C:18]3([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH:20]2[CH:16]=[CH:17]3)[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=CC2C(C1)C1C=CC2(C(=O)OCC)C1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)C12C=CC(C1)C1C(=O)N(Cc3ccccc3)C(=O)C12

Procedure:
32.8 g (0.17 mol) of N-benzylmaleimide are heated under reflux with 24.2 g (0.17 mol) of diethyl tricyclo[5.2.1.02,6 ]deca-3,8-diene-1,4-dicarboxylate in 200 ml of 1,4-dioxane overnight. The mixture is concentrated, the residue is taken up in 80 ml of isopropanol and the product is allowed to crystallize out.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:51]([N:58]1[CH2:62][CH:61]([C:63]2[CH:68]=[CH:67][C:66]([Cl:69])=[C:65]([Cl:70])[CH:64]=2)[CH:60]([CH:71](O)[CH3:72])[CH2:59]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C1COCC1>[CH2:51]([N:58]1[CH2:62][CH:61]([C:63]2[CH:68]=[CH:67][C:66]([Cl:69])=[C:65]([Cl:70])[CH:64]=2)[CH:60]([CH:71]([O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=2)[CH3:72])[CH2:59]1)[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1ccc(O)nc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccc(C#N)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (1.97 g) in THF (300 mL) at 0° C. were added 6-hydroxy-nicotinonitrile (0.61 g, 5.1 mmol) and then DBAD (1.10 g). After 5 minutes was added (RS)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (1.20 g, 3.4 mmol, described herein above). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:4) yielded 1.02 g (66%) of the title compound as a colorless oil. ES-MS m/e: 452.0 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:18][CH:17]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[N:25]=1.[NH2:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]=1[O:36][CH3:37]>C(O)C.O.Cl>[F:14][C:9]1([F:15])[CH2:8][N:7]([C@@H:16]2[CH2:18][C@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[N:25]=[C:2]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]=3[O:36][CH3:37])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: CN1C(=O)C(F)(F)CN(C2CC2c2ccccc2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N([C@@H]1C[C@H]1c1ccccc1)CC(F)(F)C(=O)N2C
Yield: 69.9 %

Procedure:
A mixture of 1.0 g (0.0028 mole) of 2-chloro-7,7-difluoro-5-methyl-9-(2-phenyl-cyclopropyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-287) and 0.55 g (0.0034 mole) of 4-amino-3-methoxy-benzoic acid in 6.4 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then cooled and partially concentrated under reduced pressure. The resulting solid was collected by filtration, washed with water and dried to give 0.97 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(trans-2-phenyl-cyclopropyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-287).