Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C:12]1[C:13](=[O:38])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:35]([CH3:37])[CH3:36])[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[NH2:11][C:12]1[C:13](=[O:38])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:35]([CH3:36])[CH3:37])[C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(=O)C(F)(F)F
Temperature: 25 °C
Yield: 65 %

Procedure:
To a solution of 2-(3-benzyloxycarbonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (10 g) and anisole (6.6 g) in dichloromethane (100 mL) at 0° C. was added trifluoromethanesulphonic acid (9 mL, 15.3 g) while maintaining the temperature below 2° C. The reaction mixture was allowed to warm to room temperature in 30 min and kept at room temperature for a further 45 min before saturated aqueous sodium bicarbonate was added slowly to pH 7. Ethyl acetate was added, the phases separated and the aqueous phase extracted further with ethyl acetate. The combined organic extract was washed (brine), dried (MgSO4) and evaporated. The crude product was purified by trituration with hexane followed by trituration with diethyl ether to give the title product (which can be recrystallized from dichloromethane/hexane) as a white solid (4.85 g); TLC: Rf =0.40, ethyl acetate; 300 MHz NMR: 0.78-0.91 (m,6), 2.07-2.30 (m,1), 4.39 (d,1), 4.49 (d,1), 4.61 (t,1), 5.17 (s,1), 5.98 (d,1), 6.51 (d,1), 7.28-7.41 (m,5), 8.68 (d,1); MS: m/z=396(M+1).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:34])[CH:7]([CH:13]([C:20]1[CH:21]=[N:22][C:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:34])[CH:7]([CH:13]([C:20]1[CH:21]=[N:22][C:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)O)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A solution of KOH (0.266 g, 4.11 mmol) in ethanol (14 mL) was added to a solution of 2-[(6-tert-butoxycarbonylamino-pyridin-3-yl)-phenyl-methyl]-malonic acid diethyl ester (1.82 g, 4.11 mmol) in ethanol (12 mL) and methylene chloride (13 mL) at 0° C. The mixture was stirred overnight at room temperature. More KOH (80 mg dissolved in 3 mL ethanol) was added at 0° C. The reaction mixture was stirred for additional 18 h. The mixture was concentrated under reduced pressure and ethyl acetate, and 0.5 M HCl were added to the residue. The organic layer was washed with brine and dried. After filtration and evaporation in vacuo, the residue was suspended in hexane. Filtration of the crystals gave 2-[(6-tert-butoxycarbonylamino-pyridin-3-yl)-phenyl-methyl]-malonic acid monoethyl ester (1.7 g, 98%).
Reaction SMILES: [C:1]([NH:8][C@:9]1([C:14]([OH:16])=[O:15])[CH2:11][C@H:10]1[CH:12]=[CH2:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+](=C)=[N-].[C:20](OCC)(=O)[CH3:21].[CH3:26]CCCCC>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:20]([O:15][C:14]([C@@:9]1([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:11][C@H:10]1[CH:12]1[CH2:26][CH2:13]1)=[O:16])[CH3:21]
Reactant: CCCCCC
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: C=[N+]=[N-]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)[C@@]1(NC(=O)OC(C)(C)C)C[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
A solution of N-Boc-(1R,2S)-1-amino-2-vinylcyclopropane carboxylic acid (255 mg, 1.0 mmol) in diethyl ether (10 mL) was treated with palladium acetate (5 mg, 0.022 mmol). The orange/red solution was placed under a nitrogen atmosphere. An excess of diazomethane in diethyl ether was added dropwise over the course of 1 hour. The resulting solution was stirred at room temperature for 18 hours. The excess diazomethane was removed using a stream of nitrogen and the resulting solution was concentrated by rotary evaporation to give the crude product. Flash chromatography (10% ethyl acetate/hexane) provided 210 mg (78%) of (1R,2S)—N-Boc-1-amino-2-cyclopropylcyclopropane carboxylic acid ethyl ester as a colorless oil. MS m/z 270 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:23][CH3:24])[CH:17]=1.[CH2:25]([N:27]1[C:32](=[O:33])[N:31]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:30](=[O:41])[C:29]([C:42](O)=[O:43])=[N:28]1)[CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:42]([C:29]2[C:30](=[O:41])[N:31]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:32](=[O:33])[N:27]([CH2:25][CH3:26])[N:28]=2)=[O:43])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Reactant: CCn1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1nc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2OC)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methoxy-phenylamine and 2-ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid using the procedure for example 1. mp=264-6° C.; LCMS m/z=588 (M+1); ); 1H NMR (DMSO): 11.00 (s, 1H), 8.47-8.52 (m, 2H), 7.51 (s, 1H), 7.38-7.46 (m, 5H), 7.10 (m, 1H), 6.88 (m, 1H), 6.53 (d, 1H, J=5Hz), 4.10 (q, 2H, J=7 Hz), 3.94 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 1.35 (t, 3H, J=7Hz).
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[C:16]([C:29](O)=[O:30])=[CH:15]2.[NH2:32][C:33]1[CH:34]=[N:35][C:36]([N:39]([CH3:41])[CH3:40])=[CH:37][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:40][N:39]([CH3:41])[C:36]1[N:35]=[CH:34][C:33]([NH:32][C:29]([C:16]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)=[O:30])=[CH:38][CH:37]=1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: CN(C)c1ccc(N)cn1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Reaction time: 0.17 h

Procedure:
0.27 ml (1.67 mmol) of diethyl cyanophosphonate is added dropwise at 20° C. under argon to a solution of 0.4 g (1.39 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (obtained in Example 1.1) and 0.229 g (1.67 mmol) of 3-amino-6-(dimethylamino)pyridine in 3.5 ml of dry dimethylformamide. The mixture is stirred for 10 minutes and then 0.43 ml (3.06 mmol) of triethylamine is added dropwise. The mixture is stirred at ambient temperature for 18 hours and concentrated under reduced pressure, and then the residue is taken up in 50 ml of ethyl acetate. This solution is then successively washed with three times 20 ml of a saturated sodium hydrogencarbonate solution, 50 ml of water and 20 ml of a saturated sodium chloride solution and then dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid obtained is triturated from hot isopropyl ether. 0.423 g of a solid is collected by filtration, which solid is dried under reduced pressure and used as in the following stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:17]([N:23]=[C:24]=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:17]([NH:23][C:24]([N:13]1[CH:14]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10](=[O:16])[NH:11][C:12]1=[O:15])=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCN=C=O
Reactant: COc1ccc(-c2c[nH]c(=O)[nH]c2=O)cc1
Product: CCCCCCNC(=O)n1cc(-c2ccc(OC)cc2)c(=O)[nH]c1=O
Temperature: 100 °C
Yield: 17 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 6, starting from 5-(4-methoxyphenyl)-1H-pyrimidine-2,4-dione (0.06 g, 0.27 mmol); 5.4 equivalents of hexyl isocyanate were used herein, splitted into three aliquots (1.8 equiv each) and the reaction mixture was heated under microwave irradiation to 100° C. for 1 hr (3 cycles of 20 min each). The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 80:20) to afford the title compound (0.02 g, 17% over two steps) as white powder. 1H NMR (400 MHz, CDCl3) δ 0.90 (d, J=6.8 Hz, 3H), 1.29-1.43 (m, 6H), 1.58-1.67 (m, 2H), 3.41 (td, J=7.1, 5.5 Hz, 2H), 3.83 (s, 3H), 6.89-7.00 (m, 2H), 7.41-7.57 (m, 2H), 8.46 (s, 1H), 8.51 (s, 1H), 9.11 (t, J=5.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 14.63, 22.47, 26.85, 29.26, 31.63, 41.34, 55.37, 11414, 116.32, 123.66, 129.39, 134.34, 149.83, 150.71, 159.87, 161.58.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5](O)[CH:6]=1.[OH-:8].[K+].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[CH:23][O:24][CH3:25])[C:19]([O:21][CH3:22])=[O:20]>C(O)C.CN(C)C=O>[Cl:1][C:2]1[C:3]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[CH:23][O:24][CH3:25])[C:19]([O:21][CH3:22])=[O:20])=[N:4][NH:5][CH:6]=1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: On1cc(Cl)cn1
Reactant: [OH-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COC=C(C(=O)OC)c1ccccc1COc1n[nH]cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
2.4 g (0.02 mol) of 4-chloro-1-hydroxypyrazole in 30 ml of ethanol are added dropwise to a solution of 1.2 g (0.02 mol) of potassium hydroxide in 50 ml of ethanol. The reaction mixture is stirred at room temperature for two hours and then concentrated. The residue is taken up in 60 ml of dimethylformamide, and 5.7 g (0.02 mol) of methyl α-(2-bromomethylphenyl)-β-methoxyacrylate in 30 ml of dimethylformamide are added. The mixture is stirred at 100° C. for two hours, a solvent is removed under reduced pressure and the residue is taken up in methyl tertbutyl ether. The organic phase is washed with water, dried and concentrated. 5.0 g (77%) of the title compound are obtained as an oil (compound no. 9).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[N:19]=[C:18](O)[CH:17]=[N:16][C:15]=3[C:14]([C:22]#[N:23])=[CH:13][CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:18]1[CH:17]=[N:16][C:15]2[C:14]([C:22]#[N:23])=[CH:13][CH:12]=[C:11]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[C:20]=2[N:19]=1
Reactant: COc1cc(OC)cc(-c2ccc(C#N)c3ncc(O)nc23)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(OC)cc(-c2ccc(C#N)c3ncc(Cl)nc23)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 8-(3,5-dimethoxy-phenyl)-2-hydroxy-quinoxaline-5-carbonitrile (Step 85.5) (100 mg, 0.33 mmol) and POCl3 (1 mL) was stirred at 120° C. for 3 h, allowed to cool to rt and concentrated. The residue was diluted with DCM/NaHCO3 saturated aqueous solution and extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (Hex/EtOAc, 7:3) to afford 90 mg of the title compound as a yellow solid: ES-MS: 326.1 [M+H]+; tR=5.02 min (System 1); Rf=0.34 (Hex/EtOAc, 7:3).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[C:11](#[N:16])[CH2:12][CH2:13][CH2:14][CH3:15].Cl.[NH4+].[OH-]>O1CCOCC1>[CH2:12]([C:11]1[NH:16][C:7](=[O:9])[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[N:1]=1)[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)c1sccc1N
Reactant: CCCCC#N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCc1nc2ccsc2c(=O)[nH]1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 3.14 g (0.02 mol) of methyl 3-amino-thiophene-2-carboxylate in 30 ml of dioxane was added 1.83 g (0.022 mol) of valeronitrile. Dry HCl was added over a period of 5 hours and the reaction mixture was then heated to 70° C. for 3 hours. The mixture was allowed to stand overnight at room temperature. The reaction mixture was diluted with 200 ml of ice water, made basic by addition of NH4OH and after standing for 30 minutes was filtered, and the filtrate concentrated in vacuo. The residue was purified by flash chromatography eluting with 50% EtOAc/hexanes after applying a suspension of the product in CH2Cl2 to the column.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([NH:6][CH:7]=[C:8]([C:14]([O:16]CC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:2]1>O(C1C=CC=CC=1)C1C=CC=CC=1>[OH:16][C:14]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:6]=[C:3]2[CH:4]=[CH:5][S:1][C:2]=12
Reactant: CCOC(=O)C(=CNc1ccsc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccsc2c1O
Temperature: 25 °C
Yield: 50.8 %

Procedure:
The diethyl 2-((thiophen-3-ylamino)methylene)malonate 2 (1.0 g, 3.7 mmol, 1 eq) was heated to 240° C. in Ph2O (10 mL) for 6 h. After the starting material was consumed, the reaction mixture was allowed to cool to room temperature and solid was filtered. The solid was washed with water and dichloromethane to obtain the desired compound as a light brown powder (0.42 g 50% yield). LC/MS (10-99% CH3CN/0.05% TFA gradient over 5 min): m/z 224.0, retention time 0.40 minutes. 1H NMR (DMSO-d6) δ: 12.80 (s, 1.0H), 8.50 (s, 1.0H), 8.05 (d, 1.0H, J=5.4 Hz), 7.30 (d, 1.0H, J=5.4 Hz), 4.20 (q, 2H, J=7.0 Hz), 4.10 (q, 2H, J=7.0 Hz), 1.30 (t, 3H, J=7.0 Hz).
Reaction SMILES: Cl[C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Product: CN1CCN(c2cccc(N)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 59 %

Procedure:
A mixture of 3-chloro-2-nitro-phenylamine (172.6 mg, 1 mmol) and 1-methyl-piperazine (1.5 mL) was heated at 200° C. in a Biotage Initiator Sixty microwave reactor for 15 min, cooled to the room temperature, and concentrated under reduced pressure. The residue was purified by chromatography (500:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (139 mg, 59%). 1H NMR (MeOH-d4) δ 2.32 (s, 3H), 2.55 (m, 4H), 2.99 (m, 4H), 6.45 (d, J=9 Hz, 1H), 6.57 (d, J=9 Hz, 1H), 7.15 (dd, J=9 Hz and 9 Hz, 1H). ESI-MS m/z 237.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[N+:13]([O-])([OH:15])=[O:14]>O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6]
Reactant: COc1cccc(C=O)c1OC
Reactant: O=[N+]([O-])O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(C=O)c1OC
Reaction time: 0.08 h

Procedure:
50.0 g (301 mmol) 2,3-Dimethoxy-benzaldehyd (Aldrich) were slowly added to nitric acid at 0° C. The reaction mixture was stirred for 5 minutes, diluted with water until no further precipitate was obtained. After filtration the residue was washed with methanol.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH2:8]([CH2:10][NH2:11])[OH:9].C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1>[NH3:11].[O:4]1[CH2:5][CH2:6][O:7][CH:3]1[CH2:2][NH:11][CH2:10][CH2:8][OH:9]
Reactant: BrCC1OCCO1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: N
Product: OCCNCC1OCCO1
Yield: 38.9 %

Procedure:
2-(bromomethyl)-1,3-dioxolane (4.4 ml, 42.5 mmol) in dioxane (60 ml) was reacted with ethanolamine (4 ml, 66.3 mmol) in the presence of potassium carbonate (6.9 g, 50 mmol) at 75° C. for 7 hours. The mixture was concentrated and purified by chromatography on silica gel, eluting with dichloromethane:methanol (97:3) then dichloromethane:methanolic ammonia (94:6), to yield 2-((1,3-dioxolan-2-ylmethyl)amino)ethanol (1.90 g, 24% yield):
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:33].[OH:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][C:39]=1[I:45]>ClCCCl>[ClH:33].[I:45][C:39]1[CH:40]=[C:41]([NH:42][C:9]2[C:4]3[CH:3]=[C:2]([CH3:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:43]=[CH:44][C:38]=1[OH:37]
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1cc2c(=O)[nH]cnc2cn1
Reactant: Nc1ccc(O)c(I)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: Cc1cc2c(Nc3ccc(O)c(I)c3)ncnc2cn1
Product: Cl
Temperature: 60 °C

Procedure:
6-Methyl-pyrido[3,4-d]pyrimid-4-one (161 mg, 1.00 mmol) was added to polymer-supported triphenylphosphine (1.66 g of about 3 mmol P/g polymer; 5.0 mmol) along with CCl4 (1.54 g, 10.0 mmol) in 1,2-dichloroethane (6 mL). The reaction mixture was heated to 60° C. for 2 hours and then the resin was filtered and washed with 1,2-dichloroethane. The filtrate was collected in a flask containing 4-hydroxy-3-iodo-aniline (0.235 g, 1.00 mmol) and concentrated to 5 mL by evaporation. After 12 hours reflux under nitrogen followed by cooling to 20° C., the title product was collected by filtration (347 mg; 83%; M.P. 261-265° C.; LC-MS: 379 (MH+); anal. RP-HPLC: 3.20 min.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](OC1C=CC=CC=1CO)[CH2:12][CH:13]=[CH2:14]>>[CH2:14]([O:10][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=1[CH2:7][OH:8])[CH2:13][CH:12]=[CH2:11]
Reactant: C=CCCOc1ccccc1CO
Reactant: O=Cc1cc(F)ccc1O
Product: C=CCCOc1ccc(F)cc1CO
Yield: 39 %

Procedure:
Prepared from 5-fluoro-2-hydroxybenzaldehyde in 39% yield following the same procedure as (2-(but-3-en-1-yloxy)phenyl)methanol. 1H NMR (400 MHz, CDCl3) δ 7.03 (dd, J=8.7, 3.1 Hz, 1H), 6.94 (td, J=8.5, 3.0 Hz, 1H), 6.80 (dd, J=9.0, 4.3 Hz, 1H), 5.90 (ddt, J=17.1, 10.3, 6.8 Hz, 1H), 5.26-5.09 (m, 2H), 4.65 (d, J=6.8 Hz, 2H), 4.06 (t, J=6.3 Hz, 2H), 2.66-2.53 (m, 2H), 2.40 (t, J=6.8 Hz, 1H).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=O)OC(C)(C)C)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.[F:35][C:36]([F:46])([F:45])[C:37]1[CH:44]=[CH:43][C:40](C=O)=[CH:39][CH:38]=1.[B-]C#N.[Na+].C(O)(=O)C>C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][CH2:21][C:40]3[CH:43]=[CH:44][C:37]([C:36]([F:46])([F:45])[F:35])=[CH:38][CH:39]=3)[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [B-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(CN2CCC(NCc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
Tert-butyl (S)-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]carbamate prepared in Example 283 (0.300 g, 0.787 mmol) was dissolved in methylene chloride (4 ml). To the solution, trifluoroacetic acid (2 ml) was added followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and added methylene chloride (4 ml) and triethylamine (4 ml). The mixture was stirred at room temperature for 20 minutes and then concentrated under reduced pressure. The residue was dissolved in methanol (5 ml). To the solution, 4-trifluoromethylbenzaldehyde (0.164 g, 0.945 mmol), sodium cyanotrihydroborate (0.099 g, 1.57 mmol) and acetic acid (0.09 ml, 1.57 mmol) were added followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. To the residue, water was added, and the solution was extracted with methylene chloride. The organic phases were combined, washed with a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) and recrystallized from isopropyl alcohol to afford (S)-N-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]-4-trifluoromethylbenzylamine (0.078 g, yield 22%) as a light yellow powder.
Reaction SMILES: Br[C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[C:4]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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.O.CCOCC>[F:33][C:34]1[CH:39]=[C:38]([C:2]2[C:3]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[C:4]3[CH:10]=[N:9][N:8]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[C:5]3=[N:6][CH:7]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Br)cnc32)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4cccc(F)c4)cnc32)cc1
Yield: 80.9 %

Procedure:
A solution of tert-butyl 4-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.30 g, 0.597 mmol, see Example 1), 3-fluorophenylboronic acid (0.125 g, 0.896 mmol), Pd(PPh3)4 (0.0690 g, 0.0597 mmol) and Cs2CO3 (0.778 g, 2.39 mmol) in dioxane:H2O (8 mL, 3:1) was heated at 80° C. for 6 hours. Ether (50 mL) and H2O (20 mL) were then added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of solvent, the resulting residue was purified by column chromatography (DCM:ethyl acetate, 5:1) to give tert-butyl 4-(5-(3-fluorophenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.25 g, 81%) as a solid. MS ESI (+) m/z 518.4 detected. 1H NMR (400 Hz, DMSO-d6) δ 8.31 (s, 1H), 8.16 (s, 1H), 7.51 (m, 1H), 7.39 (m, 2H), 7.23 (d, J=8.8 Hz, 2H), 7.18 (m,l H), 6.86 (d, J=8.8 Hz, 2H), 5.53 (s, 2H), 3.70 (s, 3H), 3.29 (m, 4H), 3.25 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][CH:13]([C:18](=O)[CH3:19])[C:14]([O:16][CH3:17])=[O:15])[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:6]=2[CH:28]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:18]([CH3:19])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:6]=2[CH:28]=1
Reactant: COC(=O)C(NC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc2n(c1C)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
1.40 g of methyl 2-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamino]-3-oxo-butyrate were taken up in 10 ml of dimethylformamide, 100 mg of p-toluenesulphonic acid monohydrate were added and the mixture was stirred at 80° C. for 2 h. For the working up the mixture was treated with 30 ml of water and extracted 5 times with 50 ml of diethyl ether each time. The combined organic phases were dried over magnesium sulphate, concentrated in a vacuum and purified by chromatography on 70 g of silica gel with dichloromethane containing 2% methanol. There were obtained 550 mg (41%) of methyl 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylate of m.p. 137-138° C. which was used without further purification for the step described below.