Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[N:7]([C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[CH:41][C:40]=1[NH2:51])[C:8]1[CH:13]=[C:12]([N:14]([CH3:38])[C:15]([N:17]([C:26]2[C:31]([Cl:32])=[C:30]([O:33][CH3:34])[CH:29]=[C:28]([O:35][CH3:36])[C:27]=2[Cl:37])[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:16])[N:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:53](Cl)(=[O:56])[CH:54]=[CH2:55].O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:52])[N:7]([C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:46][CH2:47][O:48][CH2:49][CH2:50]2)=[CH:41][C:40]=1[NH:51][C:53](=[O:56])[CH:54]=[CH2:55])[C:8]1[CH:13]=[C:12]([N:14]([CH3:38])[C:15]([N:17]([C:26]2[C:27]([Cl:37])=[C:28]([O:35][CH3:36])[CH:29]=[C:30]([O:33][CH3:34])[C:31]=2[Cl:32])[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:24])[CH3:25])=[O:16])[N:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(N(C(=O)OC(C)(C)C)c3ccc(N4CCOCC4)cc3N)ncn2)c1Cl
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(N2CCOCC2)ccc1N(C(=O)OC(C)(C)C)c1cc(N(C)C(=O)N(COCC[Si](C)(C)C)c2c(Cl)c(OC)cc(OC)c2Cl)ncn1

Procedure:
To a solution of (2-amino-4-morpholin-4-yl-phenyl)-{6-[3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-ureido]-pyrimidin-4-yl}-carbamic acid tert-butyl ester (80 g, 0.103 mmol) in DCM (5 mL) was added a solution of TEA (10 mg/mL, 1.2 mL, 0.12 mmol) and a solution of acryloyl chloride (10 mg/mL, 1 mL, 0.11 mmol) dropwise at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. Water (5 mL) was added to quench the reaction, and the reaction mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum to give crude product, which was used for the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:16][C:17]1[C:22]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][N:9]=1.Cl.N1C=CC([C:33]([NH2:35])=[NH:34])=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:14][C:13]1[C:8]([CH2:7][N:6]([CH2:16][C:17]2[C:22]([C:23]([OH:26])([CH3:24])[CH3:25])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:33]([NH2:35])=[NH:34])=[N:9][CH:10]=[C:11]([CH3:15])[CH:12]=1
Reactant: N=C(N)c1cc[nH]n1
Reactant: Cc1cnc(CN(CCCCN)Cc2ncccc2C(C)(C)O)c(C)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(CN(CCCCNC(=N)N)Cc2ncccc2C(C)(C)O)c(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 122.5 %

Procedure:
To a solution of 2-(2-{[(4-Amino-butyl)-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-propan-2-ol (0.1423 g, 0.28 mmol) in DMF (3 mL) was adde 1H-pyrazole-carboxamidine hydrochloride (0.0440 g, 0.28 mmol) and DIPEA (0.29 mL, 1.68 mmol) and stirred at room temperature for 20 hours. The reaction mixture was concentrated, and purification of the crude material by column chromatography on silica gel (5:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica gel (10:2:1 CH2Cl2-MeOH—NH4OH) provided 0.1367 g (41%) of COMPOUND 197 as a white solid. 1H NMR (CDCl3) δ 1.43-1.48 (m, 8H), 1.68-1.70 (m, 2H), 2.21 (s, 3H), 2.25 (s, 3H), 2.71-2.73 (m, 4H), 3.15-3.17 (m, 3H), 3.47 (s, 2H), 3.91 (s, 2H), 4.32 (s, 2H), 7.18-7.21 (m, 1H), 7.59-7.63 (m, 1H), 7.92-7.93 (m, 1H), 8.17 (s, 1H), 8.37-8.39 (m, 1H). 13C NMR (CDCl3) δ 18.31, 18.65, 22.77, 26.67, 31.59, 41.57, 54.09, 56.32, 61.95, 72.43, 123.57, 132.52, 132.92, 135.02, 139.67, 144.31, 146.94, 147.10, 150.68, 153.40, 158.00. ES-MS m/z 400 (M+H). Anal. Calcd. for C22H34N6O.1.9CH2Cl2O.1.5H2O: C, 48.91; H, 7.01; N, 14.32. Found: C, 48.68; H, 6.83; N, 14.68.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].C([Li])(C)(C)C.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.[OH-].[Na+]>O1CCCC1.O>[F:10][C:9]([F:12])([F:11])[O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:18]([OH:23])[OH:19]
Reactant: FC(F)(F)Oc1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1ccccc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 2 g (9.5 mmol) of 1-bromo-2-trifluoromethoxy benzene in 28 mL of tetrahydrofuran (THF) at −78° C., was carefully added 5.9 mL of a 1.7 M solution of t-butyl lithium in hexanes (9.5 mmol). This reaction mixture was stirred at −78° C. for 45 min. To this reaction mixture at −78° C. was added 2.58 mL (11.1 mmol) of tri-isopropyl borate, followed by slow warming of the mixture to room temperature (RT) over a period of 16 h. The reaction mixture was diluted with water and made basic with 2N NaOH solution. The mixture was then washed with EtOAc. The aqueous fraction was acidified with 2N HCl solution and stirred for 1 h at RT. The reaction mixture was extracted with EtOAc and the organic fractions were washed with water and saturated NaCl solution (brine), dried over Na2SO4 and filtered. The filtrate was concentrated to give the title compound as a white solid. 1H NMR (CDCl3) (δ, ppm): 7.96 (dd, J=7.2, 1.6 Hz, 1 H), 7.53 (ddd, J=9.1, 7.3, 1.8 Hz, 1 H), 7.38 (td, J=7.3, 0.7 Hz, 1 H), 7.28 (d, J=8.2 Hz, 1 H), 5.25 (br s, 2H). MS (M+H): 206.9.
Reaction SMILES: COC([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=O.N.ClCCl>C(O)C>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: CCCCCCCCOC(=O)c1ccc(-c2ccc(OC(=O)OC)cc2)cc1
Agent: N
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCCOC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
A solution of compound 5 (5.25 g, 0.014 mol) and aqueous ammonia (35% w/v, 100 ml) in ethanol (200 ml) was stirred for 1 h at room temperature. TLC analysis (dichloromethane) revealed a complete reaction. The solvent was removed in vacuo and the white solid was recrystallised from ethanol to give colourless crystals.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:24][C:25]([F:35])([F:34])[CH:26]([C:30]([F:33])([F:32])[F:31])[CH2:27][CH2:28]Br.O>CN(C=O)C>[CH3:12][C:10]1[N:11]=[C:3]2[C:2]([O:1][CH2:28][CH2:27][CH:26]([C:25]([F:24])([F:34])[F:35])[C:30]([F:31])([F:33])[F:32])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]2[C:9]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Reactant: FC(F)(F)C(CCBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(OCCC(C(F)(F)F)C(F)(F)F)cc(C)cn12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.89 g (8.07 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Example 87A were initially charged in 60 ml of DMF, 7.89 g (24.2 mmol) of caesium carbonate and 2.30 g (8.88 mmol) of 4,4,4-trifluoro-3-(trifluoromethyl)butyl bromide were added and the reaction mixture was stirred at RT for 90 min. 60 ml of water were then added, the precipitated solid was filtered off and the filter residue was washed with 100 ml of water and twice with 20 ml of tert-butyl methyl ether. The precipitate obtained from the filtrate was filtered off and washed with mother liquor. Both filter residues were taken up in 50 ml of ethyl acetate. The solution was concentrated on a rotary evaporator and the residue was dried under reduced pressure overnight. This gave 2.25 g of the target compound (95% pure, 64% of theory).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3]1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH3:20])[CH:19]=[C:8]([N:5]1[CH:4]=[CH:3][C:2](=[O:1])[CH:7]=[CH:6]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cn1ccc(=O)cc1
Product: CCOC(=O)C(=CN(C)C)n1ccc(=O)cc1

Procedure:
The title compound was prepared in a manner similar to Example Preparation 10 using ethyl 2-(4-oxopyridin-1(4 H)-yl)acetate and 1,1-diethoxy-N,N-dimethylmethanamine to give the title compound. MS m/z 237 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.1 Hz, 3 H) 2.86 (br. s, 6 H) 4.06 (q, J=7.1 Hz, 2 H) 6.01-6.11 (m, 2 H) 7.43-7.47 (m, 2 H) 7.48 (s, 1 H).
Reaction SMILES: C([C:3]1[C:7]2[CH:8]=[C:9]([O:12]C)[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:14]([OH:16])=[O:15])C.B(Br)(Br)Br>ClCCl>[OH:12][C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([C:14]([OH:16])=[O:15])=[CH:3][C:7]=2[CH:8]=1
Reactant: CCc1c(C(=O)O)oc2ccc(OC)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1cc2cc(O)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a stirred solution of ethyl 5-methoxybenzofuran-2-carboxylic acid (5.0 g, 26 mmol) in dichloromethane (CH2Cl2) (100 mL) at 0 ° C. was added boron tribromide (8.6 mL, 91 mmol) and the resulting dark solution was allowed to stir at room temperature for 2 hours. The reaction solution was poured over ice, stirred for 30 minutes and extracted with ethyl acetate, (EtOAc). The organic phase was washed with water, saturated aqueous brine, dried over sodium sulfate, (Na2SO4), and concentrated in vacuo to afford 5-hydroxybenzofuran-2-carboxylic acid (4.0 g; m.p. 223-228° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[C-:10]#[N:11].[Na+]>CS(C)=O>[C:10]([CH2:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1)#[N:11]
Reactant: [C-]#N
Reactant: ClCCCC1OCCO1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCC1OCCO1
Temperature: 80 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
In a flame dried flask fitted with a nitrogen inlet, magnetic stirrer, and oil bath was dissolved the 2-(3-chloropropyl)-1,3-dioxolane (25.4 g, 169 mmol) in 70 ml of dimethylsulfoxide. Sodium cyanide (9.1 g, 186 mmol) in 100 ml of dimethylsulfoxide was added and the mixture was heated to 80° C. for 18 hours. The reaction was cooled to room temperature then poured onto ice water and stirred for 1 hour. The mixture was extracted thoroughly with diethyl ether, testing the aqueous after each extraction by TLC for the presence of product. The ether was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a colorless oil. The oil was purified by silica gel chromatography (50/50 ethyl acetate/hexane) to give 19.2 g of product. (80.7%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH3:15][CH:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH:16]([CH3:15])[C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=1
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Reactant: CC#CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CC(C)Oc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 449 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 272 mg of 3-pentyn-2-ol, to which 130 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 510 mg of 4-(2-fluorophenyl)-6-(1-methyl-2-butynyloxy)pyrimidine (the present compound (151)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24].[OH-].[Na+].C(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH:16][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([Cl:19])[CH:21]=3)[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)c3cccc(Cl)c3)ncc2C1
Reaction time: 2 h
Yield: 53.1 %

Procedure:
2-Amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 1202 mg (4.8 mmol) was added at 0° C. to a solution of 3-chlorobenzoic acid chloride 615 μl (4.8 mmol) in pyridine (25 ml) and stirring was performed for 2 h at 0° C. and then overnight at RT under nitrogen as inert gas. After the addition of aqueous 1 M NaOH (40 ml) and stirring for 20 minutes, CH2Cl2 (50 ml) was added and the aqueous phase extracted with CH2Cl2 (3×20 ml). The combined organic phases were dried over Na2SO4. After filtration and removal of the solvent, purification was performed by means of column chromatography and the product 2-(3-chloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 790 mg (2.55 mmol, 53% of theoretical) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]3[NH:27][CH:28]=[CH:29][C:22]=23)[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[NH:27]1[C:23]2=[N:24][CH:25]=[CH:26][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([NH2:14])[CH2:16][CH2:17]3)=[C:22]2[CH:29]=[CH:28]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccnc3[nH]ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(c2ccnc3[nH]ccc23)CC1
Reaction time: 2.5 h
Yield: 96.7 %

Procedure:
Trifluoroacetic acid (1 ml) was added dropwise to a solution of [1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (19 mg, 0.06 mmol) in dichloromethane (1 ml), with stirring and cooling on ice. After 2.5 hours, the solvents were concentrated in vacuo and the crude product was purified on a basic resin NH2 cartridge (2 g, 15 ml) eluting with methanol to afford the required compound (12.5 mg, 0.058 mmol, 96%). LC-MS (LCT) Rt 0.95 [M+H]+ 217
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C([Li])CCC.[B:26](OC)([O:29]C)[O:27]C.Cl>CCCCCC.O1CCCC1>[C:4]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][C:17]([B:26]([OH:29])[OH:27])=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: -80 °C
Yield: 59.9 %

Procedure:
10 g (30 mmol) of 4-bromotriphenylamine was put into a 500 mL three-neck flask. The air in the flask was replaced with nitrogen. To the mixture were added 20 mL of tetrahydrofuran (THF), and then the mixture was stirred at −80° C. Into this solution, 20 mL (32 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) was dropped by a syringe. After the dropping, this solution was stirred at the same temperature for 1 hour. After the stirring, 40 mL (60 mmol) of trimethyl borate was added to the solution, and the solution was stirred for 1 hour while the temperature of the solution was being increased to room temperature. To the solution was added 200 mL (1.0 mol/L) of hydrochloric acid, and then the solution was stirred for about 15 hours. The organic layer was washed with a saturated sodium hydrogen carbonate solution and then a saturated saline solution. Then, the organic layer was dried with magnesium sulfate. This mixture was subjected to gravity filtration. The obtained filtrate was condensed to give a white solid. The obtained solid was recrystallized with chloroform/hexane to give 5.2 g of a white powdered solid, which was the object of the synthesis, at a yield of 58%. A synthesis scheme of Step 2 is shown in (c-2) given below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[F:9].[CH2:10]([N:12]([CH2:34][CH3:35])[CH:13]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[C:24]([CH3:25])=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[CH:33])[CH:27]=3)[NH:22][N:21]=2)=[O:19])[CH2:14]1)[CH3:11]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:33]#[C:32][C:28]2[CH:27]=[C:26]([C:23]3[NH:22][N:21]=[C:20]([C:18]([N:15]4[CH2:16][CH2:17][CH:13]([N:12]([CH2:34][CH3:35])[CH2:10][CH3:11])[CH2:14]4)=[O:19])[C:24]=3[CH3:25])[CH:31]=[CH:30][CH:29]=2)[CH:5]=[CH:4][C:3]=1[F:9]
Reactant: C#Cc1cccc(-c2[nH]nc(C(=O)N3CCC(N(CC)CC)C3)c2C)c1
Reactant: Fc1ccc(I)cc1Cl
Product: CCN(CC)C1CCN(C(=O)c2n[nH]c(-c3cccc(C#Cc4ccc(F)c(Cl)c4)c3)c2C)C1
Yield: 68 %

Procedure:
In analogy to the procedure described in Example 31F], 2-chloro-1-fluoro-4-iodobenzene and (3-diethylamino-pyrrolidin-1-yl)-[5-(3-ethynyl-phenyl)-4-methyl-1H-pyrazol-3-yl]-methanone (Example 31E]) gave the title compound in 68% yield light yellow foam. MS: 479.2 (MH+, 1 Cl).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1.C1C=CC=CC=1>O>[C:20]1([CH3:30])[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[C:20]1([CH3:30])[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[CH2:11]([O:9][C:8](=[O:10])[C@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][NH2:7])[NH2:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: NCCCC[C@H](N)C(=O)OCc1ccccc1
Yield: 84 %

Procedure:
30 g of L-lysine (20.5·10-2 mole) and 70 ml of distilled benzyl alcohol (67.6·10-2 mole) are introduced into an extractor of the Dean-Stark type; 88.5 g of paratoluene sulfonic acid monohydrate (46.5·10-2 mole) and 300 ml of benzene are added. The mixture is heated at reflux until all of the water formed in the reaction has been removed. The solution is transferred to a beaker to which 100 ml of methanol are added. The salt is precipitated by the addition of 500 ml of ethyl ether at room temperature. The precipitate is taken up by warming in 300 ml of methanol and reprecipitated by ethyl ether. 100 g of the N,N'-ditosylate of L-lysine benzyl ester are recovered; yield=84%, M.P.=163° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][CH:48]([F:58])[C:49]1[N:53]2[CH2:54][CH2:55][NH:56][CH2:57][C:52]2=[N:51][N:50]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:58][CH:48]([F:47])[C:49]1[N:53]2[CH2:54][CH2:55][N:56]([C:4]([C:3]3[CH:7]=[C:8]([CH2:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[O:22])[NH:14][N:13]=4)[CH:9]=[CH:10][C:2]=3[F:1])=[O:6])[CH2:57][C:52]2=[N:51][N:50]=1
Reactant: FC(F)c1nnc2n1CCNC2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(nnc2C(F)F)C1
Reaction time: 12 h
Yield: 19.1 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (685 mg, 2.30 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.10 g, 3.45 mmol), crude 3-(difluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 23d (400 mg, 2.30 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.90 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-[3-(difluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 23 (200 mg, yield 20.0%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](=[CH:13]N(C)C)[C:3]1=[O:17].[OH2:18]>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([CH:13]=[O:18])[C:3]1=[O:17]
Reactant: O
Reactant: CN(C)C=C1C(=O)c2ccccc2N(C)C1=O
Product: Cn1c(=O)c(C=O)c(O)c2ccccc21

Procedure:
The product from Step (1) was dissolved in distilled water (50 ml) by gentle warming and then the resulting solution was filtered. The clear filtrate was cooled in an ice bath and acidified to pH3 with mineral acid. The resulting crystalline precipitate was washed with water and dried to give 1 -methyl-3-formyl-4-hydroxy-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data. MS: m/e 203 (M+); NMR (CDCl3): δ3.6 (s, 3H, NCH3), 10.28 (s, 1H, CHO) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][N:3]=1.[C:16](Cl)(=[O:26])[C:17]1[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:19](Cl)=[O:20]>N1C=CC=CC=1.CCOC(C)=O>[C:12]([O:11][C:9]([NH:8][C:5]1[CH:6]=[N:7][C:2]([N:1]2[C:19](=[O:20])[C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16]2=[O:26])=[N:3][CH:4]=1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cnc(N)nc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cnc(N2C(=O)c3ccccc3C2=O)nc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of N-(2-aminopyrimidin-5-yl)(tert-butoxy)carboxamide (0.237 g, 1.0 mmol) in pyridine (1 mL) was added phthaloyl dichloride (0.144 mL, 1.0 mmol). The resulting suspension was stirred at 45° C. for 2 hr, diluted with EtOAc, washed with water and brine, dried and concentrated in vacuo to give crude (tert-butoxy)-N-[2-(1,3-dioxobenzo[c]azolidin-2-yl)pyrimidin-5-yl]carboxamide (0.31 g). ES-MS (M+H)+=341; (M+H−tBu)+=285.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH:10]([CH2:18][OH:19])[CH2:9][N:8]3[CH:7]=1)=O.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH2:32][C:33]([NH2:35])=[O:34])=[CH:28][NH:29]2)=[CH:25][CH:24]=1>>[OH:19][CH2:18][CH:10]1[CH2:11][C:12]2[C:17]3=[C:16]([C:6]([CH:4]4[CH:32]([C:27]5[C:26]6[C:30](=[CH:31][C:23]([C:22]([F:36])([F:21])[F:37])=[CH:24][CH:25]=6)[NH:29][CH:28]=5)[C:33](=[O:34])[NH:35][C:3]4=[O:2])=[CH:7][N:8]3[CH2:9]1)[CH:15]=[CH:14][CH:13]=2
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CC(CO)C2
Reactant: NC(=O)Cc1c[nH]c2cc(C(F)(F)F)ccc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CC(CO)C3)C1c1c[nH]c2cc(C(F)(F)F)ccc12

Procedure:
Beginning with (5-(hydroxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl]oxo-acetic acid methyl ester and (6-(trifluoromethyl)-1H-indol-3-yl)acetamide, the title compound was prepared essentially as described in Example 1.