Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][C:3]=1[CH:16]([CH3:18])[CH3:17].C([Li])(C)(C)C.CN([CH:27]=[O:28])C>CCCCC.O>[C:10]([Si:7]([CH3:9])([CH3:8])[O:6][C:5]1[CH:14]=[CH:15][C:2]([CH:27]=[O:28])=[C:3]([CH:16]([CH3:18])[CH3:17])[CH:4]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCCCC
Product: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)ccc1C=O
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A solution of (4-bromo-3-isopropyl-phenoxy)-tert-butyl-dimethyl-silane (Intermediate 145, 1.03 g, 3.13 mmols) in 25 mL E2O was cooled to −78° C. and treated with tert-butyllithium (401.0 mg, 6.26 mmols; 3.7 mL of a 1.7M solution in pentane). After 30 minutes the reaction was quenched with DMF (913.0 mg, 12.5 mmols) and warmed to room temperature. The solution was diluted with H2O, extracted with Et2O and the combined organic layers washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. Column chromatography (2% EtOAc-hexanes) afforded 480.0 mg (55%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=O)=[CH:17][C:18]=4[N:9]3[CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C1N=C[N:24](C(N2C=NC=C2)=O)C=1.CNC(N)=O.C(O)(C(F)(F)F)=O>>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:24])=[O:21])=[CH:17][C:18]=4[N:9]3[CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2cc3n(c2c1)C=CCc1ccccc1-3
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC(N)=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc2cc3n(c2c1)C=CCc1ccccc1-3

Procedure:
(5H-indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6,7-dihydro-3-methoxy-6-[methyl[(tetrahydro-2H-pyran-4-yl)carbonyl]amino]-) was prepared from (5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6,7-dihydro-3-methoxy-6-[methyl[(tetrahydro-2H-pyran-4-yl)carbonyl]amino]-) using CDI as a coupling reagent in a similar manner as described before; Analytical HPLC method: Solvent A=10% MeO{tilde over (H)}90% H2Õ0.1% TFA, Solvent B=90% MeO{tilde over (H)}10% H2O0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=637.27, HPLC Rt=1.958 min.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[C:24]([NH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(C)c(-c2c3ccccc3nc3ccc(N)cc23)c1
Solvent: ClCCl
Product: Cc1ccc(C)c(-c2c3ccccc3nc3ccc(NC(=O)c4ccccc4)cc23)c1
Reaction time: 8 h

Procedure:
2.98 pbw of 2-amino-9-(2,5-dimethylphenyl)acridine (compound 1d) were dissolved in 75 pbv of methylene chloride at 23° C. and 2.1 pbw of benzoyl chloride were gradually added while stirring. The temperature rose to 27°-28° C. during this process. The solution was stirred for 4 hours and, after standing overnight, extracted by shaking with sodium hydroxide solution, and the organic phase was distilled off after drying over anhydrous sodium sulfate. Yield: 3.96 pbw (98% of theory), yellowish green crystals. Mp.: 253°-255° C.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH2:11][Cl:12])=[O:9].[CH2:13]([OH:19])[CH2:14][O:15][CH2:16][CH2:17][OH:18]>ClCCl>[Cl:12][CH2:11][O:10][C:8]([O:19][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][C:8]([O:10][CH2:11][Cl:12])=[O:9])=[O:9]
Reactant: OCCOCCO
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCCl)OCCOCCOC(=O)OCCl
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of chloromethyl chloroformate (1.32 ml, 14.83 mmol) and diethylene glycol (0.47 ml, 5.00 mmol) in dichloromethane (10 ml) at 7° C. with good stirring under a dry N2 atmosphere. After 10 min. at 7° C. and 6 hours at 20° C. the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is washed with hydrochloric acid (1.00 M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (10 ml). The organic phase is dried (MgSO4) and the solvent evaporated under reduced pressure (10 mm Hg) to give 1.26 g (86%) title product. 1H NMR (300 MHz, CDCl3): δ 3.72 (m, 2×CH2 --O), 4.34 (m, 2×CH2 --O--C=O), 5.71 (s, 2×Cl--CH2 --O). 13C NMR (75 MHz, CDCl3): δ 67.6 (2×CH2 --O), 68.5 (2×CH2 --O--C=O), 72.1 (2×Cl--CH2 --O), 153.2 (2×C=O).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][C@@H:10](O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C[I:50]>C1COCC1>[CH3:16][O:15][C:13]([C@@H:12]1[CH2:11][C@H:10]([I:50])[CH2:9][N:8]1[C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])=[O:14]
Reactant: CI
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](I)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 91 %

Procedure:
To a round-bottom flask equipped with a magnetic stir bar and an addition funnel under N2 was added N-Boc-L-trans-4-hydroxy-proline methyl ester (60 mmol, 1 equiv), P(Ph)3 (72 mmol, 1.2 equiv) and anhydrous THF (275 ml). The solution was cooled to 0 centigrade, DEAD (1.2 equiv) in dry THF was added dropwise; followed by the addition of MeI (1.2 equiv). Upon addition of MeI, the solution turned from dark brown to bright yellow. The reaction mixture was allowed to warm to ambient temperature and stirred for 10 hours. The solvent was removed under reduced pressure and the crude oil was purified by chromatography on silica gel to afford title product (19.44 g) as colorless oil in 91% yield. MS m/e=356.4 [M+H]+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH2:15]([NH:17][C:18]([NH:20][C:21]1[N:39]=[C:24]2[CH:25]=[C:26]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[CH:27]=[C:28]([C:29]([NH:31][NH2:32])=[O:30])[N:23]2[N:22]=1)=[O:19])[CH3:16]>O1CCOCC1>[C:1]([NH:32][NH:31][C:29]([C:28]1[N:23]2[N:22]=[C:21]([NH:20][C:18]([NH:17][CH2:15][CH3:16])=[O:19])[N:39]=[C:24]2[CH:25]=[C:26]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:27]=1)=[O:30])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)NN)n2n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)NNC(C)=O)n2n1

Procedure:
Acetic anhydride (0.95 mL, 10 mmol), triethylamine (1.2 mL, 8.6 mmol) and the product of Step 1 (0.996 g, 2.93 mmol) in dioxane (100 mL) was refluxed for 6 h. The solution was cooled and the product was filtered, washed with water and then dried to give 1-[5-(N′-acetyl-hydrazinocarbonyl)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-ethyl-urea as a solid ACPI-MS Found: [M+H]+=383.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[CH2:14]([O:17][NH2:18])[CH:15]=[CH2:16]>>[CH2:14]([O:17][N:18]=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[C:9]([OH:11])=[O:10])[CH:15]=[CH2:16]
Reactant: C=CCON
Reactant: O=C(O)C(=O)c1cccc(O)c1
Agent: Cl
Product: C=CCON=C(C(=O)O)c1cccc(O)c1
Yield: 101.4 %

Procedure:
2-(3-Hydroxyphenyl)glyoxylic acid (2.0 g.) and O-allylhydroxylamine hydrochloride (1.7 g.) were reacted according to a similar manner to that of Preparation (5-2) (a) to give oil of 2-allyloxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (2.7 g.).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21](=[O:38])[C@H:22]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[NH:23][C:24](OC1C=CC=CC=1)=[O:25].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:19][O:20][C:21](=[O:38])[C@H:22]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[NH:23][C:24]([N:14]([CH2:13][C:10]1[S:9][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:12][CH:11]=1)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:25]
Reactant: CC(C)CNCc1ccc(C(=O)OC(C)(C)C)s1
Reactant: COC(=O)C[C@H](NC(=O)Oc1ccccc1)C(=O)OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C[C@H](NC(=O)N(Cc1ccc(C(=O)OC(C)(C)C)s1)CC(C)C)C(=O)OC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The compound (1.1 g, 4.1 mmol) obtained in step 1 and the compound (1.2 g, 4.1 mmol) obtained in step 2 were dissolved in acetonitrile (40 ml), N,N-diisopropylethylamine (0.71 mL, 4.1 mmol) was added, and the mixture was stirred at 60° C. for 2 hours. The solvent was evaporated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:15][C:3]1[C:4]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: Cc1cccc(Nc2ccccc2)c1N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cccc(Nc2ccccc2)c1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
To a solution of 3-methyl-N1-phenylbenzene-1,2-diamine (381 mg, 1.92 mmol) in anhydrous DCM (10 mL) were added (S)-2-tertbutoxycarbonylaminopropionic acid (399 mg, 2.11 mmol), HOBt (285 mg, 2.11 mmol), 4-methylmorpholine (464 μL, 4.22 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (405 mg, 2.11 mmol). The mixture was stirred at RT for 2 h then additional amounts of (S)-2-tertbutoxycarbonylaminopropionic acid (145 mg, 0.77 mmol) and of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (148 mg, 0.77 mmol) were added. Stirring was continued for 18 h and then additional amounts of (S)-2-tertbutoxycarbonylaminopropionic acid (545 mg, 2.88 mmol), HOBt (285 mg, 2.11 mmol), 4-methylmorpholine (464 μL, 4.22 mmol) and of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (553 mg, 2.88 mmol) were added. Stirring was continued for 24 h and then the crude mixture was purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane) affording [(S)-1-(2-methyl-6-phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester as an orange oil (395 mg, 56%). LCMS: RT 3.69 min [M+H]+ 370.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[C:5]([F:21])[CH:4]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1.[NH2:39][O:40][CH2:41][CH2:42][OH:43]>C1COCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([NH:39][O:40][CH2:41][CH2:42][OH:43])=[O:14])=[C:5]([F:21])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reactant: NOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Product: CCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
The title compound was prepared from the reaction of the product of Step D, 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid (93 mg, 0.32 mmol) dissolved in dry THF (5 mL), and carbonyldiimidazole (CDI) (102 mg, 0.63 mmol). Within 10 minutes, a bright yellow solution was obtained and conversion to the imidazolide was confirmed by TLC (50% EtOAc/hexanes). A solution of 2-(aminooxy)ethanol (97 mg, 1.26 mmol) in THF (5 mL) was then added and the mixture stirred for 15 hours at room temperature. The reaction solvent was removed under reduced pressure and the residue partitioned between 1 M HCl (50 mL) and EtOAc (50 mL). The EtOAc layer was then washed with water (50 mL) and saturated NaCl solution (50 mL), dried (Na2SO4), and the solvent removed under reduced pressure to afford an oil which was purified by flash column chromatography on silica gel (50% EtOAc/hexanes) to give 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a cream solid (65%); m.p. (EtOAc/hexanes) 134–138° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.84 (br s, 1 H), 8.76 (br s, 1 H), 7.43–7.37 (m, 1 H), 7.14–7.02 (m, 2 H), 6.90 (dd, J=8.3, 1.5 Hz, 1 H), 6.83. (td, J=8.6, 4.4 Hz, 1 H), 4.70 (br s, 1 H), 3.86 (t, J=4.9 Hz, 2 H), 3.57 (t, J=4.9 Hz, 2 H), 2.54 (q, J=7.6 Hz, 2 H), 1.15 (t, J=7.6 Hz, 3 H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([N:14]1[C:23]2[C:18](=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[CH3:31])[CH:20]=[CH:21][CH:22]=2)[C:17](=[O:32])[C:16]([CH:33]=O)=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:7]([N:14]1[C:23]2[C:18](=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[CH3:31])[CH:20]=[CH:21][CH:22]=2)[C:17](=[O:32])[C:16]([CH:33]=[CH2:1])=[N:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(-c2cccc3c2c(=O)c(C=O)nn3Cc2ccccc2)c(C)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: C=Cc1nn(Cc2ccccc2)c2cccc(-c3ccc(C)cc3C)c2c1=O
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
To a slurry of 0.081 g (0.72 mmol) of potassium tert-butoxide in 10 mL of ether was added 0.22 g (0.60 mmol) of methyl triphenylphosphonium bromide. The resulting ylide solution was stirred for 30 min then 0.11 g (0.30 mmol) of 1-benzyl-5-(2,4-dimethylphenyl)-4-oxo-1,4-dihydrocinnoline-3-carbaldehyde was added. The reaction mixture was stirred for 3 h, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography eluting with a 9% ethyl acetate/hexanes mixture to give 0.035 g (32%) of the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Cl[C:38]1[CH:39]=[CH:40][C:41](=[O:44])[NH:42][N:43]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:16]=[CH:17][C:18]([C:38]3[CH:39]=[CH:40][C:41](=[O:44])[NH:42][N:43]=3)=[CH:19][CH:20]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Reactant: O=c1ccc(Cl)n[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]n2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Yield: 13.4 %

Procedure:
A mixture of 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile (150 mg, 0.31 mmol), 6-chloropyridazin-3-(2H)-one (62 mg, 0.47 mmol), Pd(Ph3P)2Cl2 (15 mg), and aq. Cs2CO3 solution (2 mL, 2M) in 1,4-dioxane (10 mL) was stirred at reflux for 2 h. When the reaction was finished, the mixture was diluted with water, and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative TLC to give 2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (18.9 mg, 15%). LC-MS Method 2 tR=1.053 min, m/z=457.3; 1H NMR (CDCl3): δ1.16 (s, 3H), 1.25 (s, 3H), 1.38 (d, 3H), 2.21 (s, 2H), 2.24 (m, 1H), 2.40 (m, 2H), 2.86 (m, 1H), 5.61 (m, 1H), 6.86 (m, 2H), 6.95 (m, 1H), 7.29 (m, 5H), 7.32 (m, 2H), 7.56 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([C:10]([CH3:16])([CH2:12][CH2:13][CH:14]=O)[CH3:11])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[N+](=[C:19](P(=O)(OC)OC)C(=O)C)=[N-].C([O-])([O-])=O.[K+].[K+]>CO.O>[CH3:1][N:2]([C:10]([CH3:16])([CH2:12][CH2:13][C:14]#[CH:19])[CH3:11])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CN(C(=O)OC(C)(C)C)C(C)(C)CCC=O
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#CCCC(C)(C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To 150 mg of 12e in 3 ml of methanol was added 250 mg of dimethyl 1-diazo-2-oxopropylphosphonate and 250 mg of K2CO3. The mixture was stirred at RT overnight. Then reaction was diluted with water and the product was extracted with ether. The extract was washed once with sat. NaCl, dried, concentrated and filtered over a short silica column, using a pentane-ether gradient as eluent, to give 130 mg of 12f as colorless oil; Rf 0.55 (heptane/ether 3/1). NMR (CDCl3) δ 1.33 (s, 3, 2×CH3), 1.48 (s, 9, tertC4H9), 1.92 (t, 1, acetylene-H), 2.10 (m, 4, CH2CH2), 2.88 (s, 3, NCH3).
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:19][CH2:18]1)[CH2:4][O:5][C:6]1[C:14]2[NH:13][CH:12]=[N:11][C:10]=2[C:9]([CH3:15])=[CH:8][CH:7]=1.[C:31](O)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C=CC=CC=1>CN(C)C=O>[ClH:1].[C:31]([O:2][CH:3]([CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:19][CH2:18]1)[CH2:4][O:5][C:6]1[C:14]2[NH:13][CH:12]=[N:11][C:10]=2[C:9]([CH3:15])=[CH:8][CH:7]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1ccc(OCC(O)CN2CCC(COc3ccccn3)CC2)c2[nH]cnc12
Reactant: O=C(O)c1ccccc1
Agent: Cl
Agent: O=C(OC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cc1ccc(OCC(CN2CCC(COc3ccccn3)CC2)OC(=O)c2ccccc2)c2[nH]cnc12

Procedure:
4.87 g. 4-{2-Hydroxy-3-[4-(2-pyridyloxymethyl)-piperidino]-propoxy}-7-methylbenzimidazole (preparation see Example 13), 19.5 g. benzoic acid and 2.12 g. benzoic anhydride are heated under reflux for 2 hours in 100 ml. benzene and 25 ml. dimethylformamide. After removing the solvent, the residue is taken up in 100 ml. water, rendered alkaline with concentrated aqueous ammonia solution and extracted with chloroform. The chloroform phase is washed with water, dried over anhydrous sodium sulphate and evaporated. The residue is taken up in ethanol and mixed with ethereal hydrochloric acid. After adding isopropanol and diethyl ether, there crystallize out 2.1 g. (41% of theory) 4-{2-benzoyloxy-3-[4-(2-pyridyloxymethyl)-piperidino]-propoxy}-7-methylbenzimidazole hydrochloride; m.p. 178°-181° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:26])[C:17]([CH2:19][C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3.C(=O)([O-])[O-].[K+].[K+].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]Cl)[CH:34]=1>CS(C)=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:26])[C:17]([CH2:19][C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:39][C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)[CH:10]=3
Reactant: ClCc1cccnc1
Reactant: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(OCc4cccnc4)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
9-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (200 mg) produced in Example 102 was suspended in dimethyl sulfoxide (8 ml). After adding potassium carbonate (204 mg), the mixture was stirred at room temperature for 30 minutes, and 3-picolylchloride (0.09 ml) was added. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water (20 ml) and the crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with water, ethanol and ether in succession and recovered by filtration to obtain the title compound (177 mg, 72%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10]1([C:16]2[O:21][C:20](=[O:22])[CH2:19][CH2:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1>[CH2:3]([N:2]([CH3:1])[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCC=C(c2ccccc2)O1
Reactant: CNCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(Cc1ccccc1)C(=O)CCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 5-oxo-5-phenylpentanoic acid benzyl-methyl amide was prepared by refluxing N-methylbenzylamine (10.5 mmol) and 6-phenyl-3,4-dihydro-pyran-2-one (10.5 mmol) in toluene for one hour. The reaction was allowed to stir overnight at room temperature. It was poured into 100 mL of ethyl acetate and 100 mL of 1N HCl. The organic extracts were washed with 100 mL of 1N NaOH, 100 mL of water and dried over MgSO4. The crude product was flash chromatographed (CH2Cl2 /MeOH 98/2) to afford a liquid. 1H NMR (CDCl3) δ 2.0-2.2 (m, 2 H), 2.5 (t, 2 H), 2.93/2.96 (s/s, 3 H), 3.0-3.2 (m, 2 H), 4.5/4.6 (s/s, 2 H), 7.1-7.6 (m, 8 H), 7.8-8.0 (m, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](F)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])#[N:2].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.O>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[O:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][CH:16]=1)#[N:2]
Reactant: OB(O)c1ccc(O)cc1
Reactant: N#Cc1cc(F)ccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(Oc2ccc(B(O)O)cc2)ccc1C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 3-cyano-4-trifluoromethyl-1-fluorobenzene (70, g, 0.37, mol, Oakwood), 4-hydroxyphenylboronic acid (50, g, 0.36, mol, Boron Molecular), K2CO3, (70, g) and DMF/water (400, mL/40, mL) was heated to 100° C. for 3, h. After cooling to RT, the mixture was diluted with water (1, L) and extracted with EtOAc (1.5, L). The organic layer was washed with water (0.5, L) and brine, concentrated and purified by chromatographed over silica gel with 4% MeOH in chloroform to give (4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid as pink solid (50, g, 45%). 1H NMR (400, MHz, CD3OD) 7.70-7.70, (3H, m), 7.35, (1H, d, J=2.4, Hz), 7.24, (1H, dd, J=2.2, & 8.8, Hz), 7.00, (2H, d, J=7.7, Hz). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17, mg, 0.022 mmol, Aldrich) was added to a mixture of 2-(6-bromopyridin-2-yl)-2-hydroxyacetamide (50, mg, 0.22, mmol), (4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid (100, mg, 0.32, mmol) and cesium carbonate (140, mg, 0.43 mmol) in EtOH/DME/water (2, mL/2, mL/1, mL) at room temperature. The reaction mixture was flushed with argon, then, shaken at 90° C. for 3, h. After cooling to RT, the reaction was quenched with water (2, mL), and extracted with EtOAc (10 mL). The organic layer was separated, concentrated and purified by reverse-phase prep HPLC (C18, 0-100% 0.1% TFA in water/0.1% TFA in ACN) to give 2-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2-hydroxyacetamide (Cpd. No. 6) as off-white solid (45, mg, 50%). LC/MS: m/z=414.1, [M+H]+, ; 1H NMR (400, MHz, DMSO-d6) 8.15, (2H, d, J=8.4, Hz), 7.93 (1H, d, J=9.2, Hz), 7.82-7.86, (3H, m), 7.37-7.45, (3H, m), 7.26, (2H, d, J=9.2, Hz), 4.95, (1H, s).