Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([CH:15]3[CH2:20][NH:19][CH2:18][CH2:17][N:16]3[CH3:21])[O:12][N:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.[OH-].[Na+]>ClCCl>[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:19]2[CH2:18][CH2:17][N:16]([CH3:21])[CH:15]([C:13]3[O:12][N:11]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=4)[N:14]=3)[CH2:20]2)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCNCC1c1nc(-c2ccc(F)cc2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(F)cc2)CC1c1nc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
To a suspension of 2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-methyl-piperazine dihydrochloride (0.285 g, 0.86 mmol) in anhydrous dichloromethane (6 mL), under nitrogen atmosphere, triethylamine (374 mL, 2.7 mmol) and 4-fluorobenzoyl chloride (102 mL, 0.86 mmol) were subsequently added at 0° C. The reaction mixture was allowed to warm at room temperature and stirred for 2 h. NaOH 1N (6 mL) was added and the phases were separated. The organic layer was washed sequentially with NaOH 1N (6 mL) and with water, then was dried over sodium sulphate and evaporated under reduced pressure. Purification of the crude by flash chromatography (silica gel, eluent: DCM/MeOH/NH4OH 99/1/0.1) afforded (4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methyl-piperazin-1-yl}-methanone (0.12 g).
Reaction SMILES: C[Si](CC(N)=O)(C)C.[NH2:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])=[CH:14][CH2:15][S:16][C@H:11]12.[CH:32]([NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:44][O:45][CH3:46])[C:41](Cl)=[O:42])[N:39]=1)=[O:33].O>C(Cl)Cl>[CH:32]([NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:44][O:45][CH3:46])[C:41]([NH:9][CH:10]2[C:30](=[O:31])[N:12]3[C:13]([C:17]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)=[O:18])=[CH:14][CH2:15][S:16][C@H:11]23)=[O:42])[N:39]=1)=[O:33]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: CON=C(C(=O)Cl)c1csc(NC=O)n1
Agent: C[Si](C)(C)CC(N)=O
Solvent: ClCCl
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Temperature: 40 °C
Yield: 93.9 %

Procedure:
N,N-Dimethylformamide (3 drops) was added to a suspension of 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 23 g.) in thionyl chloride (230 ml), and stirred at 60° C. for 5 minutes. After concentrating the solution in vacuo, benzene was added to the residue. The presipitates were collected by filtration, washed with benzene (30 ml.) three times and diethyl ether in turn to give 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetyl chloride (anti isomer, 18 g.). On the other hand, trimethylsilylacetamide (46 g.) was added to a suspension of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (16.8 g.) in methylene chloride (168 ml.), and stirred at 40° C. for an hour. To the suspension was gradually added 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetyl chloride (anti isomer, 13.6 g.) at -5° to 0° C., and stirred at the same temperature for an hour. Water (150 ml.) was added to the resultant solution and stirred for 15 minutes. The recipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyimino-acetamido]-3-cephem-4-carboxylate (anti isomer, 25.7 g.).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl:18]N1C(=O)CCC1=O.N(OC(C)(C)C)=O>ClCCl>[Cl:18][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1N
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2ccccn2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 5-amino-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate (200 mg, 0.861 mmol) and 1-chloropyrrolidine-2,5-dione (172 mg, 1.292 mmol) in dichloromethane (8 mL) was added tert-butyl nitrite (0.154 mL, 1.292 mmol). The reaction mixture was stirred at rt for 30 minutes, after which time it was concentrated to yield a crude product which was purified on a silica gel column eluting with hexanes/EtOAc to yield ethyl 5-chloro-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate. The material from Method 1 and Method 2 were combined (106 mg, 0.42 mmol). HPLC ret. time=2.50 min. HPLC: Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 mL/min; Solvent A=10% MeOH—90% Water—0.2% H3PO4; Solvent B=90% MeOH—10% water—0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=252.1. 1H NMR (400 MHz, MeOD) δ ppm 8.61 (1 H, dd, J=4.89, 1.13 Hz), 8.16 (1 H, s), 8.09 (1 H, td, J=7.78, 1.76 Hz), 7.74 (1 H, d, J=8.03 Hz), 7.57 (1 H, ddd, J=7.53, 4.77, 1.00 Hz), 4.36 (2 H, q, J=7.28 Hz), 1.38 (3 H, t, J=7.15 Hz).
Reaction SMILES: I[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH2:29]([OH:32])[C:30]#[CH:31]>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([C:31]#[C:30][CH2:29][OH:32])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: Ic1cccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCC#Cc1cccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of N-(4-(3-iodopyridin-2-yloxy)phenyl)pyridin-2-amine (0.300 g, 0.771 mmol), copper(I) iodide (3.91 μL, 0.116 mmol), trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.034 g, 0.048 mmol), triethylamine (0.800 mL, 5.74 mmol) and propargyl alcohol (0.150 mL, 2.54 mmol) in THF (5 mL) was stirred at rt under an atmosphere of argon for 3.5 h. The reaction was evaporated onto silica gel and purified by flash chromatography (Isco, (60 gram)) eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97). The material was stirred over MeOH, filtered and dried in vacuo to give a white crystalline solid. MS (ESI, pos. ion) m/z: 318.0. IC50 (uM)=0.2612.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([N+:13]([O-])=O)=[CH:4][CH:3]=1.ClC1C(C(OC)=O)=C(C)C=CC=1[N+]([O-])=O.O.O.Cl[Sn]Cl>CCO>[NH2:13][C:5]1[C:6]([CH3:12])=[C:7]([C:2]([Cl:1])=[CH:3][CH:4]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(Cl)ccc([N+](=O)[O-])c1C
Agent: COC(=O)c1c(C)ccc([N+](=O)[O-])c1Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COC(=O)c1c(Cl)ccc(N)c1C
Temperature: 25 °C

Procedure:
To above stirred mixture of methyl 6-chloro-2-methyl-3-nitrobenzoate 62 and methyl 6-chloro-2-methyl-5-nitrobenzoate in EtOH (500 mL), SnCl2.2H2O (224 g, 992 mmol, 4 eq) was added and the resulting mixture was stirred at reflux for 3 h. The reaction mixture was allowed to cool to RT and concentrated in vacuo. The residue was poured into water (1 L) and extracted with ethyl acetate (5×500 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (2-10% ethyl acetate-hexanes) to afford the regio-isomer methyl 3-amino-6-chloro-2-methylbenzoate 63.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1)[CH3:2].C(O)C.Cl.[N:15]([O-])=[O:16].[Na+]>O>[CH2:1]([C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[C:8]=1[N:15]=[O:16])[CH3:2]
Reactant: CCc1cc(C)cc(O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1cc(O)cc(C)c1N=O
Temperature: 0 °C

Procedure:
102 g (749 mmol) of 3-ethyl-5-methylphenol are introduced into 600 ml of ethanol. While stirring vigorously, 600 ml of concentrated hydrochloric acid are added dropwise, keeping the reaction vessel at room temperature by cooling. The reaction mixture is then cooled to 0° C. At this temperature, 77.5 g (1123.5 mmol) of sodium nitrite in 78 ml of deionised water are added dropwise. The resulting mixture is then stirred at 5° C. for 2 hours and subsequently poured into 3 liters of ice-water, when the title compound crystallises out. It is filtered off, washed several times with ice-water and recrystallised from methanol. Yield 88.7 g (71.8% of theory); melting point 138° C. (with decomposition).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N-]>C(Cl)Cl>[CH:1]1([O:7][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)COC1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
To a mixture of cyclohexanol (2.40 g, 24.0 mmol) and Rh2(OAc)4 (50 mg, 0.11 mmol) in DCM (50 mL) was added ethyl 2-diazoacetate (2.73 g, 23.9 mmol) and the mixture was stirred at rt for 5 min. It was then filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=15:1) to give the title compound as colorless oil (3.8 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15]([CH3:18])(=O)=O)[N:3]=1.[CH2:19](S)[CH2:20][CH2:21]C.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([S:15][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CCCCS
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCCCSc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, butylmercaptan and DBU in DME. ES-MS m/e (%): 275 (M+H+, 100).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][N:9]=1.Br[C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[C:41]([NH2:46])[CH:40]=[CH:39]2.CCO>C(Cl)Cl.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>[NH2:46][C:41]1[CH:40]=[CH:39][C:38]2[C:43](=[CH:44][CH:45]=[C:36]([C:11]3[CH:12]=[C:13]([NH:14][S:15]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)(=[O:16])=[O:17])[C:8]([Cl:7])=[N:9][CH:10]=3)[CH:37]=2)[N:42]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2Cl)cc1
Reactant: Nc1ccc2cc(Br)ccc2n1
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: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4nc(N)ccc4c3)cnc2Cl)cc1
Temperature: 90 °C
Yield: 11.6 %

Procedure:
A reaction tube was charged with sodium carbonate (353 μl, 706 μmol), Pd(Ph3P)4 (16 mg, 14 μmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (100 mg, 235 μmol), 6-bromoquinolin-2-amine (53 mg, 235 μmol) and 1.2 mL EtOH. The tube was sealed and the mixture was heated at 90° C. for 2 h. The mixture was diluted with CH2Cl2 and washed with water. The organic portion was dried with MgSO4, filtered and concentrated. The crude material was dissolved in MeOH/DMSO and purified by reverse phase chromatography, 10-90% ACN/0.1% TFA in water over 15 min. The aqueous portion was brought to ˜pH 7 and extracted. The organic portion was dried, filtered and concentrated to provide N-(5-(2-aminoquinolin-6-yl)-2-chloropyridin-3-yl)-4-methoxybenzenesulfonamide (12 mg, 12% yield) as a light yellow solid. MS (ESI pos. ion) m/z calc'd for C21H17ClN4O3S: 440.9/442.9; found 441.0/443.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3 H), 6.88 (br s, 2 H), 6.89 (d, 1 H, J=8), 7.15-7.18 (m, 2 H), 7.61 (d, 1 H, J=8), 7.75-7.80 (m, 3 H), 7.97-8.00 (m, 2 H), 8.03-8.06 (m, 1 H), 8.62-8.63 (m, 1 H), 10.46 (br, s, 1 H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH:12][C:13](=[O:16])[CH2:14]Cl)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:17][NH2:18]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH:12][C:13](=[O:16])[CH2:14][NH:18][CH3:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(CCl)NCCc1ccc2c(c1)OCO2
Reactant: CN
Solvent: CCO
Product: CNCC(=O)NCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
N-(2-Benzo[1,3]dioxol-5-yl-ethyl)-2-chloro-acetamide (32 mg, 0.13 mmol) was dissolved in methylamine in anhydrous ethanol (33% by wt., 5 mL). The solution was allowed to stir at room temperature for 16 hours. After this time, the solution was concentrated down under N2 gas. The crude material was purified by prep-LCMS to afford 21 mg (68%) of N-(2-benzo[1,3]dioxol-5-yl-ethyl)-2-methylamino-acetamide. 1H-NMR (400 MHz, CD3OD) δ 6.73-6.65 (m, 3H), 5.89 (s, 2H), 3.46-3.39 (t, 2H), 3.31-3.29 (m, 2H), 2.74-2.70 (t, 2H), 2.35 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]=2[N:4]=[CH:3]1.Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:18][O:17][N:16]([CH3:15])[C:11]([C:10]1[C:5]2[N:4]=[CH:3][NH:2][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:13]
Reactant: O=C(O)c1cccc2[nH]cnc12
Reactant: CNOC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
To a stirred solution of 1H-benzoimidazole-4-carboxylic acid hydrochloride (2.0 g, 10.1 mmol), N,O-dimethylhydroxylamine hydrochloride (1.47 g, 15.1 mmol) and ethyldiisopropylamine (7.02 mL, 40.3 mmol) in DMF (10 mL) at room temperature was added O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (3.90 g, 10.3 mmol) in a single portion. The mixture was stirred at room temperature overnight then concentrated in vacuo. Purification by SiO2 chromatography followed by trituration with EtOAc provided 1H-benzoimidazole-4-carboxylic acid methoxy-methyl-amide (945 mg).
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]1[CH:12]([O:13][Si](C(C)(C)C)(C)C)[CH2:11][CH2:10][N:9]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[C:31](=[O:32])[CH2:30][CH2:29][N:28]([C:33](=[O:44])/[CH:34]=[CH:35]/[C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=3)[CH2:27][CH2:26]2)[CH2:8]1)(C)(C)C.Cl>CO.O1CCOCC1>[ClH:42].[Cl:43][C:38]1[CH:37]=[C:36](/[CH:35]=[CH:34]/[C:33]([N:28]2[CH2:29][CH2:30][C:31](=[O:32])[N:25]([CH2:24][CH2:23][CH2:22][CH2:21][N:9]3[CH2:10][CH2:11][CH:12]([OH:13])[CH:7]([OH:6])[CH2:8]3)[CH2:26][CH2:27]2)=[O:44])[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(CCCCN2CCN(C(=O)/C=C/c3ccc(Cl)c(Cl)c3)CCC2=O)CC1O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCN2CCC(O)C(O)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 145.4 %

Procedure:
A solution of 0.100 g (0.14 mmol) of 4-{4-[(3RS,4SR)-3,4-bis-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-butyl}-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one in 2 mL of MeOH was cooled (0° C.), treated with 0.35 ml (1.40 mmol) of 4M HCl in dioxane and stirred at RT for 2 h. The solution was evaporated, dissolved in toluene and evaporated (2×) to yield 0.053 g (73%) of the title compound as light brown foam. MS: 484.2 (MH+, 2Cl).
Reaction SMILES: BrC1CCC(=O)CC1.[Na].[C:10]1([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:23][OH:24]>CN(C)C=O>[C:17]1([S:16][CH:10]2[CH2:11][CH2:12][C:13](=[N:23][OH:24])[CH2:14][CH2:15]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(Sc2ccccc2)cc1
Reactant: NO
Agent: O=C1CCC(Br)CC1
Agent: [Na]
Solvent: CN(C)C=O
Product: ON=C1CCC(Sc2ccccc2)CC1

Procedure:
The title compound is prepared by reacting 4-bromocyclohexanone with the sodium salt of phenyl sulfide in dimethylformamide followed by reacting with hydroxylamine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][NH2:13]>O1CCCC1.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CNc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.1 %

Procedure:
A solution of 5.82 g (30 mmol) of 2,4-dichloro-5-nitropyrimidine (N. Whittaker, J. Chem. Soc., 1951;1565–1570) in 100 mL of tetrahydrofuran (THF) is cooled to −78° C. and a solution of 4.66 g (60 mmol) of 40% aqueous methylamine in 20 mL of 2-propanol is added dropwise over 5 minutes. After a further 10 minutes at −78° C., the mixture is allowed to warm to room temperature, and the solvent is removed under vacuum. The residue is then extracted into ethyl acetate (EtOAc), washed with water, and dried with sodium sulfate (Na2SO4). Removal of the solvent and chromatography on silica, eluting with hexane/EtOAc (92:8), gives 4.87 g (86%) of the title compound: mp (hexane) 86–87° C. (lit. mp: 90–91° C.; G. B. Barlin, J. Chem. Soc. (B), 1967:954–958).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]1([CH:15]2[CH2:20][CH2:19][CH:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.BrCCCl.C1C[O:31][CH2:30][CH2:29]1>CN1C(=O)N(C)CCC1>[C:21]([CH:18]1[CH2:19][CH2:20][CH:15]([C:9]2[CH:14]=[CH:13][C:12]([C:30](=[O:31])[CH3:29])=[CH:11][CH:10]=2)[CH2:16][CH2:17]1)(=[O:23])[CH3:22]
Reactant: C1CCOC1
Reactant: CC(=O)C1CCC(c2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCBr
Solvent: CN1CCCN(C)C1=O
Product: CC(=O)c1ccc(C2CCC(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of freshly prepared LDA (132 mL of n-butyl lithium, 2.5 M in hexane, 51 mL of diisopropylamine) in THF (anhydrous, 420 mL), DMPU (200 mL) at −78° C. was added a solution of A1 (60 g, 300 mmol) in THF (60 mL) at −78° C. After stirring for 40 min, 1-bromo-2-chloroethane (24.9 mL, 300 mmol) was added. After stirring for another 20 min at −78° C., the dry ice-acetone bath was removed and the reaction was slowly warmed up to rt. After stirring for an additional hour, the reaction mixture was cooled back to −78° C. and a solution of DMPU (200 mL) in THF (420 mL) was added. Another portion of freshly prepared LDA (120 mL of n-butyl lithium, 2.5 M in hexane, 47 mL of di-isopropylamine in THF (anhydrous, 420 ml)) was added into the reaction mixture by cannula at −78° C. After stirring for 1.5 h at −78° C., the dry ice-acetone bath was removed and the reaction was slowly warmed up to rt. After 5-6 h, the reaction was quenched with saturated aqueous ammonium chloride (300 mL) and concentrated. The residue was diluted with H2O (480 mL) and extracted with ethyl acetate/hexane (1:5 (v/v), 3×360 mL). The combined organic layers were washed with brine (500 mL) and then dried, filtered, and concentrated. The resulting crude product was purified by silica gel flash column chromatography (Hexanes/EtOAc=10/1 (v/v)) to provide A2 (35 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])[O:6]C(C)C.C(Cl)(Cl)Cl.C[Si](Br)(C)C>C(O)(C)C.C1OC1C>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:6])[OH:10]
Reactant: CC(C)OP(=O)(CCCN)Cc1ccccc1
Agent: CC1CO1
Agent: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: NCCCP(=O)(O)Cc1ccccc1
Reaction time: 4 h

Procedure:
To a solution of 5.7 g (0.0224 mol) of isopropyl 3-aminopropyl(benzyl)phosphinate in 50 ml of chloroform 9.91 ml (0.0922 mol) of trimethylsilylbromide are added raising the temperature to 44°. The reaction mixture is stirred at 50° for 4 hours and then at room temperature overnight. Removal of the chloroform and excess trimethylsilylbromide under reduced pressure yields an oil which is taken up in isopropanol and 20 ml of propylene oxide. After stirring for 10 minutes, a white solid precipitates. The solid is filtered off and dried over phosphorous pentoxide yielding 3-aminopropyl(benzyl)phosphinic acid, m.p. 278-280°.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[F:44])[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.[F:83]C1C=C(B(O)O)C=CC=1F>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:41]=[CH:42][C:43]([F:44])=[C:2]([F:83])[CH:3]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2ccc(F)c(F)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 25 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 3,4-difluorophenylboronic acid (42 mg, 0.2625 mmol) to produce the title compound (26 mg, 25% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][NH:9][C:8]2[N:7]=[CH:6][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[O:19])=[CH:14][CH:13]=3)=[CH:4][C:3]1=2.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30](O)[CH:29]=1>CO.C(Cl)Cl>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([O:1][CH:2]2[C:3]3[C:8](=[N:7][CH:6]=[C:5]([C:12]4[CH:13]=[CH:14][C:15]([C:18]([N:20]5[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]5)=[O:19])=[CH:16][CH:17]=4)[CH:4]=3)[NH:9][CH2:10][CH2:11]2)[CH:29]=1
Reactant: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(O)CCN4)cc2)CC1
Reactant: CC(=O)c1ccc(F)cc1O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1ccc(F)cc1OC1CCNc2ncc(-c3ccc(C(=O)N4CCN(C)CC4)cc3)cc21
Yield: 53 %

Procedure:
[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-(4-methylpiperazin-1-yl)methanone (30 mg) was reacted with 1-(4-fluoro-2-hydroxyphenyl)ethanone (39.4 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-15% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (53% yield). LCMS: m/z=489.14 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.11-2.25 (m, 2H), 2.32 (s, 3H), 2.32-2.58 (m, 4H), 2.45 (s, 3H), 3.40-3.68 (m, 4H), 3.70-3.90 (m, 2H), 5.31 (bs, 1H), 5.51 (t, J=3.3 Hz, 1H), 6.75-6.82 (m, 1H), 6.89 (dd, J=2.1 and 10.7 Hz, 1H), 7.41-7.51 (m, 4H), 7.57-7.61 (m, 1H), 7.80 (dd, J=7.1 and 8.6 Hz, 1H, 8.33 (bs, 1H).
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CCCCCCCCCC.C1([CH2:24][CH2:25][CH2:26][C:27]([O-])=[O:28])C=CC=CC=1>>[C:1]1([O:17][C:27](=[O:28])[CH2:26][CH2:25][CH3:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])CCCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCO
Product: CCCC(=O)Oc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
65 g of white petrolatum (Riedel-de Haen), 15 g of cetyl alcohol (Riedel-de Haen), 260 g of soft paraffin (Merck), 155 g of liquid paraffin (Merck), and 5 g of 4-phenylbutyrate (Merck) were mixed in a beaker and heated at 70° C. to form a paste. The paste was stirred at 400 rpm for 1 hour, and then cooled at room temperature.