Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][NH:7][C:6]1=[O:15].[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>ClCCl>[Cl:16][CH2:17][CH2:18][C:19]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[NH:5][C:6](=[O:15])[NH:7][CH2:8]2)=[O:20]
Reactant: O=C(Cl)CCCl
Reactant: O=C1NCc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1NCc2cc(C(=O)CCCl)ccc2N1
Temperature: 20 °C

Procedure:
20 g of aluminium chloride (0.15 mol) are taken up in 100 ml of dichloromethane. 7.43 g of 1,2,3,4-tetrahydroquinazolin-2-one (0.05 mol) are added in portions with stirring at a maximum of 20° C. The reaction mixture thus obtained is subsequently stirred for 30 minutes. A solution consisting of 6.98 g of 3-chloropropionyl chloride (0.055 mol) and 50 ml of dichloromethane is then added dropwise with stirring at a temperature of at most 25° C. and the mixture is subsequently stirred for a further hour. After completion of the reaction, the reaction mixture obtained is stirred into 300 g of ice, and the precipitate is filtered off with suction and washed with plenty of water and small amounts of methanol. The reaction forms a slightly more polar product than the starting material, which can be separated by thin-layer chromatography using an eluent consisting of chloroform and methanol in the mixture ratio 95:5. Yield: 11.37 g of 6-(3-chloro-1-oxopropyl)-1,2,3,4-tetrahydroquinazolin-2-one (95.3% of theory); m.p: >270° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([C:12]2[CH:13]=[N:14][C:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)=[O:11])=[CH:2]1.[BH4-].[Na+].O>CN(C)C=O.C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]([C:12]2[CH:13]=[N:14][C:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)[OH:11])=[CH:2]1
Reactant: O=C(c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1)c1c[nH]c2ncccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: OC(c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
Into a round bottom flask was added compound 13 (210.0 mg, 0.53 mmol) and sodium tetrahydroborate (80.0 mg, 2.11 mmol) and dissolved in N,N-dimethylformamide (5.0 mL) and ethanol (20.0 mL). The reaction was stirred at room temperature overnight, poured into water, and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage (methylene chloride/methanol 1:20) to give product 14 (63 mg, yield=30%) as a white solid (M+1=399)
Reaction SMILES: Cl[CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[CH3:23][NH2:24]>CC(O)C>[CH3:23][NH:24][CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CN
Reactant: CC(C)(C)C(=O)Nc1ccccc1CC(Cl)c1ccccc1
Solvent: CC(C)O
Product: CNC(Cc1ccccc1NC(=O)C(C)(C)C)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
N-[2-(2-chloro-2-phenylethyl)phenyl]-2,2-dimethylpropanamide (1.0 g, 3.17 mol) was reacted with monomethyl amine (7 g of 40% aqueous solution) in 2-propanol (3 g). The mixture was heated to 80° C. and stirred for 1 hour. Formation of product was indicated by TLC (silica gel/70 ethyl acetate/30 methanol).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[C:23]([F:24])=[CH:22][C:21]([NH:25][C:26]([C:28]5[C:29](=[O:41])[N:30]([C:34]6[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=6)[N:31]=[CH:32][CH:33]=5)=[O:27])=[C:20]([Cl:42])[CH:19]=4)=[C:11]3[C:10]([NH:43][CH:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[Cl:42][C:20]1[CH:19]=[C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:8][N:9]=[C:10]([NH:43][CH:44]4[CH2:45][CH2:46][N:47]([CH3:50])[CH2:48][CH2:49]4)[C:11]=23)[C:23]([F:24])=[CH:22][C:21]=1[NH:25][C:26]([C:28]1[C:29](=[O:41])[N:30]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[N:31]=[CH:32][CH:33]=1)=[O:27]
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4cc(Cl)c(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(Nc2n[nH]c3nccc(Oc4cc(Cl)c(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Temperature: 50 °C
Yield: 41.8 %

Procedure:
A solution of N-(4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2-chloro-5-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (100 mg, 0.138 mmol) was dissolved in TFA (2 mL) and the solution was heated to 50° C. for 1 hour. Excess TFA was evaporated and the crude material was dissolved in EtOAc. The organic layer washed with saturated aqueous NaHCO3, brine, dried with Na2SO4, filtered and concentrated to afford a yellow solid. The solid washed with diethyl ether to afford the product (35 mg, 41.9% yield) as a yellow solid. LRMS (APCI pos) m/e 607.0 (M+H). 1H NMR (DMSO-d6, 400 MHz) δ 12.32 (s, 1H), 12.22 (s, 1H), 8.70 (d, 1H), 8.42 (dd, 12H), 8.17 (d, 1H), 7.91 (d, 1H), 7.74-7.67 (m, 2H), 7.49-7.41 (m, 2H), 6.17-6.13 (m, 1H), 5.23-5.18 (m, 1H), 3.60-3.42 (m, 1H), 2.85-2.73 (m, 2H), 2.20 (s, 3H), 2.10-1.96 (m, 4H), 1.65-1.53 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]5[CH:29]=[N:30][N:31](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[CH:32]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[ClH:52]>>[ClH:52].[ClH:52].[F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]5[CH:32]=[N:31][NH:30][CH:29]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1
Reactant: CS(=O)(=O)c1cc(F)cc(N2CCN(c3ncnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc34)CC2)c1
Agent: Cl
Product: CS(=O)(=O)c1cc(F)cc(N2CCN(c3ncnc4ccc(-c5cn[nH]c5)cc34)CC2)c1

Procedure:
130 mg 4-[4-(3-fluoro-5-methylsulfonylphenyl)piperazin-1-yl]-6-(1-trityl-1H-4-pyrazolyl)quinazoline obtained in Example 731 was subjected to deprotection of the trityl group and converted into the corresponding hydrochloride by the same method as in Example 163, to give 62 mg of the title compound as pale yellow crystals. 1H-NMR data are those of the salt in a free form.
Reaction SMILES: Cl.[CH3:2][S:3][CH2:4][O:5][N:6]=[C:7]([C:30]1[N:31]=[C:32]([NH:36]C=O)[S:33][C:34]=1[Cl:35])[C:8]([NH:10][CH:11]1[C:28](=[O:29])[N:13]2[C:14]([C:25]([O-:27])=[O:26])=[C:15]([CH2:18][N+:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][S:17][C@H:12]12)=[O:9]>CO>[CH3:2][S:3][CH2:4][O:5][N:6]=[C:7]([C:30]1[N:31]=[C:32]([NH2:36])[S:33][C:34]=1[Cl:35])[C:8]([NH:10][CH:11]1[C:28](=[O:29])[N:13]2[C:14]([C:25]([O-:27])=[O:26])=[C:15]([CH2:18][N+:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:16][S:17][C@H:12]12)=[O:9]
Reactant: CSCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nc(NC=O)sc1Cl
Agent: Cl
Solvent: CO
Product: CSCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nc(N)sc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.8 %

Procedure:
Conc. hydrochloric acid (1.5 g) was added to the mixture of 7-[2-methylthiomethoxyimino-2-(2-formamido-5-chlorothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (2.8 g) and methanol (30 ml), and stirred at ambient temperature for 5 hours. After removal of solvent, and the residue was dissolved in water and the solution was adjusted to pH 4.0 with 10% aqueous sodium hydroxide under ice-cooling. The solution was subjected to column chromatography on macroporus non-ionic adsorption resin "Diaion HP-20" and eluted with 20% aqueous solution of isopropyl alcohol. The fractions containing the object compound were collected and concentrated and lyophilized to give 7-[2-methylthiomethoxyimino-2-(2-amino-5-chlorothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.7 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH:29]1[CH:28]=[C:27]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:31]=[N:30]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 125 °C

Procedure:
To a mixture of 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (1.4 g, 0.0049 mol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g, 0.0074 mol) in DMF (40 mL, 0.5 mol) was added potassium carbonate (2.0 g, 0.015 mol) in 15 mL of water. The mixture was purged with a steady stream of nitrogen for 15 minutes. Tetrakis(triphenylphosphine)-palladium(0) (0.41 g, 0.00036 mol) was added and the reaction was heated to 125° C. for 30 min. The mixture was allowed to cool then diluted with ethyl acetate. The diluted reaction mixture was washed with water, brine, dried over Na2SO4 and concentrated to give a solution in a small volume of DMF (about 2-3 mL). Water was added, causing the material to form a gum on the walls of the flask. Then water was decanted, and the solids were dissolved in ethyl acetate. The solution was dried over Na2SO4, and concentrated in vacuo to afford a yellow solid. The product was triturated with ethyl ether to yield 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine as a white powder which was dried under vacuum (1 g, 60%). 1H NMR (300 MHz, CDCl3): δ 10.80 (br s, 1H), 8.93 (s, 1H), 8.46 (s, 2H), 7.46 (d, 1H), 6.88 (d, 1H), 5.73 (s, 2H), 3.61 (dd, 2H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES):316(M+1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:27])[C@@H:6]([CH3:26])[NH:7][S:8]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([Cl:25])=[CH:16][N:17]=[C:18]2[NH:21][C:22]([NH2:24])=[NH:23])=[CH:13][CH:12]=1)(=[O:10])=[O:9].Cl>CO>[ClH:25].[Cl:25][C:15]1[C:14]2[C:19](=[CH:20][C:11]([S:8]([NH:7][C@@H:6]([C:5]([OH:27])=[O:4])[CH3:26])(=[O:9])=[O:10])=[CH:12][CH:13]=2)[C:18]([NH:21][C:22]([NH2:24])=[NH:23])=[N:17][CH:16]=1
Reactant: COC(=O)[C@@H](C)NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)O
Temperature: 60 °C
Yield: 95.5 %

Procedure:
A solution of NaOH (1 mL, 2 M, 2 mmol) was added to a solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-alanine methyl ester (17 mg, 0.044 mmol) in MeOH (3 mL) and the mixture was heated at 60° C. for 18 h. The cooled mixture was neutrilised with dilute HCl (2 M), the MeOH was evaporated in vacuo, and the residue triturated with water (10 mL). The solid was collected by filtration, with water washing, and dried under high vacuum to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-alanine hydrochloride (9 mg, 0.021 mmol) as an off-white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9](=[O:12])[NH:10][N:11]=2)[CH:5]=[N:6][C:7]=1[Cl:8].Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:4]([C:9](=[O:12])[N:10]([CH2:14][C:15]3[CH:20]=[N:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)[N:11]=2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: Nc1c(Cl)ncn2c(=O)[nH]nc12
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(Cl)ncn2c(=O)n(Cc3ccc(C(F)(F)F)nc3)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.6 %

Procedure:
To a stirred solution of 8-amino-7-chloro-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1.41 g, 7.6 mmol) in DMF (10 mL) at room temperature under argon was added 5-(chloromethyl)-2-(trifluoromethyl)pyridine (1.78 g, 9.1 mmol), followed by K2CO3 (2.1 g, 15.2 mmol). The resulting mixture was stirred at room temperature for 5 h. Analysis by HPLC/MS indicated that the reaction was complete. Water (50 mL) was added to the reaction mixture. The solid precipitate was collected by filtration and was washed with water (10 mL×3). After the resulting solid was dried under vacuum, the title compound (2.4 g) was obtained as an off-white solid. HPLC/MS: retention time 2.43 min, [M+H]30 =345. 1H NMR (CDCl3): δ 8.81 (s, 1H), 8.12 (s, 1H), 7.92 (d, J=7.0 Hz, 1H), 7.69 (d, J=7.0 Hz, 1H), 5.21 (s, 2H), 4.42 (s, 2H). N-alkylation, rather than O-alkylation, was demonstrated by the presence of a 13C NMR resonance at 46.9 ppm.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1)=[O:3].CN1CCOCC1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>O1CCCC1>[C:25](=[O:26])([O:27][C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=1)[O:16][C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][CH:14]=1)[NH:9][CH:8]=[C:7]2[CH2:6][CH2:5][NH:4][C:2](=[O:3])[CH3:1]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)NCCc1c[nH]c2ccc(O)cc12
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(=O)NCCc1c[nH]c2ccc(OC(=O)Oc3ccc([N+](=O)[O-])cc3)cc12
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To N-acetylserotonin (0.9 g; 4 mmol) was added N-methylmorpholine (0.92 ml, 8 mmol), and 4-nitrophenyl chloroformate (1.61 g; 8 mmol) dissolved in tetrahydrofuran. Reaction was carried out for 0.5 h under an argon atmosphere. The solvent was evaporated. The residue was purified by column chromatography (SiO2, methanol/methylene chloride) to give 0.92 g (yield 60%) of crystalline yellow product with a melting point 153-156° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[CH3:29][O:30][C:31]1[C:36]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[C:3]([C:34]2[CH:35]=[C:36]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[C:31]([O:30][CH3:29])=[N:32][CH:33]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(C)(=O)=O
Yield: 8.9 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.10 mol) was treated with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (51 mg, 0.16 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14 mg, 0.02 mol) and sodium carbonate (2M, 231 μl, 0.46 mol) according to the method described in Example 3 to give 8 mg (14% yield) of the title compound as a white solid. Purity 97%.
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]4[CH2:20][CH2:19]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C@:29]([OH:33])([C:31]#[CH:32])[CH3:30])[CH:25]=1>>[CH:18]1([C:12]2[N:8]3[CH2:9][CH2:10][O:11][C:5]4[CH:4]=[C:3]([F:22])[C:2]([C:32]#[C:31][C@@:29]([OH:33])([C:26]5[CH:25]=[C:24]([CH3:23])[O:28][N:27]=5)[CH3:30])=[CH:21][C:6]=4[C:7]3=[N:14][C:13]=2[C:15]([NH2:17])=[O:16])[CH2:20][CH2:19]1
Reactant: NC(=O)c1nc2n(c1C1CC1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2cc3c(cc2F)OCCn2c-3nc(C(N)=O)c2C2CC2)no1

Procedure:
10-Bromo-3-cyclopropyl-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (62 mg) was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure E to afford 39.2 mg of 3-cyclopropyl-9-fluoro-10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 437 (M)+. 1H NMR (400 MHz, DMSO) δ 8.53 (d, J=18.5 Hz, 1H), 7.44 (s, 1H), 6.99 (d, J=10.5 Hz, 1H), 6.92 (s, 1H), 6.51 (s, 1H), 6.34 (s, 1H), 4.64-4.37 (m, 4H), 2.40 (s, 3H), 1.81 (s, 2H), 1.79-1.71 (m, 1H), 1.03-0.93 (m, 2H), 0.86-0.77 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[N:6]2[CH:25]=1.[N-:26]=[N+:27]=[N-:28].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[NH:26]1[C:23]([C:20]2[N:21]=[CH:22][C:17]([C:7]3[N:6]4[CH:25]=[C:3]([CH2:2][OH:1])[N:4]=[C:5]4[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[N:9][CH:8]=3)=[CH:18][CH:19]=2)=[N:24][N:28]=[N:27]1
Reactant: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CO)cn23)cn1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCc1cn2c(-c3ccc(-c4nnn[nH]4)nc3)cnc(N3CCOCC3)c2n1
Temperature: 105 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a solution of compound 1g (220 mg, 0.650 mmol) in DMF (15 mL) was added NaN3 (440 mg, 6.77 mmol) and triethylamine hydrochloride (440 mg, 3.21 mmol). The reaction mixture was stirred at 105° C. for 1 h. The resulting mixture was concentrated, and diluted with H2O (30 mL). The solids were collected by filtration and washed with Et2O to obtain compound 1h as a yellow solid (189 mg, 76% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C17H17N9O2: 380.2 (M+H). Found 380.2.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[OH:30][C:6]1[C:5]([C:3]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:10](=[O:23])[N:11]2[C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2[C@H](C)c2ccccc2)c1O
Reactant: NCCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: C[C@H](c1ccccc1)n1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCCC(=O)O)ncc21
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A mixture of (R)-5-hydroxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.1 mmol), 4-aminobutyric acid (670 mg, 6.5 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (10-80% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 18 mg of the title compound. MS: (+) m/z 472.34 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[CH2:13]([O:15][P:16]([CH2:21][PH:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN1CCOCC1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([P:22]([CH2:21][P:16]([O:15][CH2:13][CH3:14])([O:17][CH2:18][CH3:19])=[O:20])([O:24][CH2:25][CH3:26])=[O:23])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCO[PH](=O)CP(=O)(OCC)OCC
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc(P(=O)(CP(=O)(OCC)OCC)OCC)cc1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
A sealed pressure flask, flushed with N2, containing a mixture of 4-bromo-benzoic acid ethyl ester (3a) (5 g, 0.0218 mol), ethoxyphosphinoylmethyl-phosphonic acid diethyl ester (3b), (5.86 g, 0.024 mol), NMM (2.88 mL, 0.0262 mmol) and Pd(PPh3)4 (2.017 g, 0.00175 mol) in acetonitrile (20 mL) was stirred at ambient temperature for 5–10 min, then heated at 90° C. for 18 hours. The reaction mixture was filtered through celite, and the celite was washed with EtOAc (3—30 mL) until the filtrate showed little or no evidence of product by HPLC. The combined organics were dried over Na2SO4 and concentrated on rotary evaporator. The desired product (ix) was purified by silica gel flash chromatography to give a pale yellow oil (5.01 g). 1H NMR (300 MHz, CDCl3) δ (ppm)): 0.96 (t, J=7.07 Hz, 3H), 1.13 (m, 9H), 2.41 (t, J=18.2 Hz, 2H), 3.84 (m, 6H), 4.17 (q, J=7.11 Hz, 2H), 7.71 (m, 2H), 7.92 (m, 2H)., 31P NMR (121 MHz, CDCl3) δ 32.8 and 19.7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:21][CH2:20][NH:19][CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1.C(N(CC)CC)C.C(O)(=O)C.[Si:35]([O:42][CH2:43][CH:44]=O)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].C([BH3-])#N>ClCCl.CO>[Si:35]([O:42][CH2:43][CH2:44][N:19]1[CH2:20][CH2:21][CH:17]([C:15]2[NH:14][C:10]3=[N:11][CH:12]=[CH:13][C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:22][CH3:23])=[C:9]3[CH:16]=2)[CH2:18]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCNC3)cc12
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCN(CCO[Si](C)(C)C(C)(C)C)C3)cc12
Reaction time: 0.08 h

Procedure:
To a solution of Example 59F (50 mg, 0.130 mmol) in dichloromethane (1 mL)/methanol (1 mL) was added triethylamine (0.036 mL, 0.260 mmol) followed by acetic acid (0.037 mL, 0.651 mmol) and (t-butyldimethylsilyloxy)acetaldehyde (0.050 mL, 0.260 mmol). After stirring for 5 minutes, MP-cyanoborohydride (2.49 mmol/g, 209 mg, 0.52 mmol) was added and the mixture was shaken for 16 hours at room temperature. The resin was filtered off, and washed with methanol/dichloromethane (2×3 mL). The crude mixture was concentrated and used in the next step without further purification. LCMS: 470.3 (M+H)+.