Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.O>CN(C=O)C>[CH3:8][C:3]1[C:2]([O:1][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
3-Hydroxy-2-methylpyridine (40 g, 0.37 mole) in dry DMF (1.3 L) under argon was cooled to 0° C. Sodium hydride (11.1 g of an 80% dispersion in oil, 0.37 mole) was added portionwise and the mixture stirred at 0° C. for 15 minutes and then room temperature for 3 hours. 2-Chloro-5-nitropyridine (58.6 g, 0.37 mole) was added and the mixture stirred for 18 hours at r.t. Water (50 ml) was added dropwise and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2, washed with 10% aqueous sodium hydroxide, and water, dried (Na2SO4) and evaporated in vacuo to afford the title compound (81.1 g, 95%) as a yellow solid.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH3:5][Li].[F:7][C:8]1[CH:37]=[CH:36][C:11]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][N:17]([C:20]3[CH:21]=[CH:22][C:23]4[N:27]=[C:26]([CH:28]5[CH2:31][C:30](=[O:32])[CH2:29]5)[N:25]([CH3:33])[C:24]=4[CH:34]=3)[C:16](=[O:35])[CH:15]=2)=[CH:10][CH:9]=1>C1COCC1>[F:7][C:8]1[CH:37]=[CH:36][C:11]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][N:17]([C:20]3[CH:21]=[CH:22][C:23]4[N:27]=[C:26]([CH:28]5[CH2:31][C:30]([OH:32])([CH3:5])[CH2:29]5)[N:25]([CH3:33])[C:24]=4[CH:34]=3)[C:16](=[O:35])[CH:15]=2)=[CH:10][CH:9]=1
Reactant: [Li]C
Reactant: Cn1c(C2CC(=O)C2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cn1c(C2CC(C)(O)C2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of cerium chloride (532 mg) in THF (30 ml) was added methyllithium (3 M in diethoxymethane, 719 μl) at −78° C. A cold solution of 4-((4-fluorobenzyl)oxy)-1-(1-methyl-2-(3-oxocyclobutyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one (150 mg) in dry THF (3 ml) was slowly added to the reaction mixture at −78° C. and stirred for 1 h at the same temperature. The reaction mixture was quenched with saturated NH4Cl at −78° C. and then warmed up to room temperature. The mixture was extracted with DCM, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) followed by purification by preparative HPLC to give the title compound (33 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:26][CH3:27])[C:24]=1[OH:25])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[CH3:27][O:26][C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:24]=1[O:25][S:36]([CH3:35])(=[O:38])=[O:37])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:9]1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(OC)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OS(C)(=O)=O
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,5-dimethoxy-4-hydroxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.95 g, 2.6 mmol) and triethylamine (1.0 mL, 7.7 mmol) in dichloromethane (15 mL). Cool the reaction mixture to −5° C. with an salt-ice bath. Slowly, add methanesulfonyl chloride (0.45 mL, 5.8 mmol). Warm to ambient temperature. After 18 hours, quench the reaction by the addition of ice. Separate the organic layer and extract with aqueous 1M hydrochloric acid solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:21]=[C:22]([CH2:23][OH:24])[C:4]=2[N:3]=1.[H-].[Na+].[CH3:33]I.O>CN(C)C=O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:21]=[C:22]([CH2:23][O:24][CH3:33])[C:4]=2[N:3]=1
Reactant: CI
Reactant: Cc1c(Cn2c(C)nc3c(CO)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the mixture of [2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazol-4-yl]methanol, prepared as described in Example 43 (160 mg, 0.381 mmol) in N,N-Dimethylformamide (DMF) (15 mL), sodium hydride (30.5 mg, 0.763 mmol) was added in and followed by the addition of methyl iodide (0.048 mL, 0.763 mmol). The reaction was stirred at rt for 3 hours. More sodium hydride (30.5 mg, 0.763 mmol) and methyl iodide (0.048 mL, 0.763 mmol) was added in. The reaction was stirred at rt for another 2 hours then Water (70 mL) was added in. The mixture was extracted with EtOAc (100 mL). The organic phase was washed with Brine (100 mL), dried (MgSO4) and concentrated. The crude was subjected to ISCO purification (0-2% MeOH/DCM) to give the product. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3H) 2.54 (s, 3H) 3.00-3.07 (m, 4H) 3.37 (s, 3H) 3.68-3.75 (m, 4H) 4.76 (s, 2H) 5.52 (s, 2H) 6.32 (d, J=7.83 Hz, 1H) 6.88 (m, 2H) 7.25 (s, 1H) 7.60 (d, 1H). MS(ES+) m/e 434.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[C:36]=2[CH3:42])[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[C:36]=2[CH3:42])[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c1C
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: Cc1nccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)c1C

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K18) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow oil (310 mg, 78%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](Cl)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:34])[CH3:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]>>[C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:41]5[CH:40]=[C:39]([F:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:34])[CH3:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1

Procedure:
Following general procedure II, tert-butyl(1-{5-[(3-acetyl-6-chloro-1,5-naphthyridin-4-yl)amino]pyridin-2-yl}piperidin-3-yl)carbamate (100 mg, 0.20 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.24 mmol) to afford crude product which was carried forward without any purification: ESI MS m/z 607 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[C:4]([C:11]([NH2:13])=[O:12])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.C(N(CC)CC)C.[C:28]([N:32]=[C:33]=[O:34])([CH3:31])([CH3:30])[CH3:29].[OH-].[Na+]>>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:33]([NH:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:10][C:5]2=[C:4]([C:11]([NH2:13])=[O:12])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1
Reactant: NC(=O)c1c(-c2cccc(F)c2)c(Br)n2c1CNCC2
Reactant: CC(C)(C)N=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)N1CCn2c(Br)c(-c3cccc(F)c3)c(C(N)=O)c2C1
Yield: 51.5 %

Procedure:
To a suspension of 0.24 g (0.71 mmol) of 6-bromo-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide is added 0.30 ml (2.13 mmol) of triethylamine and then, at 0° C., 0.10 ml (0.85 mmol) of tert-butyl isocyanate. After reaction for 1 hour at room temperature, the mixture is treated with aqueous 1N sodium hydroxide solution and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column of 40 g of silica gel, eluting with a mixture of 4% methanol in dichloromethane, to give 0.16 g of 6-bromo-7-(3-fluorophenyl)-N2-(tert-butyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a powder after recrystallization from 10 ml of acetonitrile, filtering and drying under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:19][CH3:20])=[C:10]([CH:12]3[C:16](=[O:17])[CH:15]=[CH:14][C:13]3=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.C[Si]([CH2:27][S:28]([CH2:30][Si](C)(C)C)=O)(C)C>CN1CCCN(C)C1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:19][CH3:20])=[C:10]([CH:12]3[C:16](=[O:17])[CH:15]4[CH2:27][S:28][CH2:30][CH:14]4[C:13]3=[O:18])[CH:11]=2)=[CH:21][CH:22]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C=CC1=O
Reactant: C[Si](C)(C)CS(=O)C[Si](C)(C)C
Solvent: CN1CCCN(C)C1=O
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C2CSCC2C1=O
Temperature: 100 °C

Procedure:
A suspension of 2-(4′-chloro-4-ethylbiphen-3-yl)cyclopent-4-ene-1,3-dione (0.200 g, 0.65 mmol) and crude bis(trimethylsilylmethyl)sulphoxide (0.406 g, 0.97 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3 ml) is heated at 100° C. for 20 minutes under microwave irradiation. The reaction mixture is then partitioned between diethylether and distilled water, and the organic phase is washed with water (×2) then brine. After drying over magnesium sulfate the crude mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is purified by preparative reverse phase HPLC to afford 5-(4′-chloro-4-ethylbiphenyl-3-yl)-tetrahydrocyclopenta[c]thiophene-4,6-dione.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:6]=[C:5]1[NH2:25])[CH:2]=[CH2:3].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:12]=2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:6]=[C:5]1[NH2:25])[CH:2]=[CH2:3]
Reactant: C=CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C=CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)n(-c3ccccc3)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.2 %

Procedure:
In a flask were placed 3-allyl-2-amino-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone (20 mg, 0.06 mmol), copper acetate (3 mg, 0.01 mmol), phenylboronic acid (15 mg, 0.12 mmol), pyridine (11 μL, 0.12 mmol) and N,N-dimethylformamide (1 mL), followed by stirring at room temperature for 24 hours. After filtering off the insoluble matters by filtration, the filtrate was purified by HPLC, to give the title compound (8 mg).
Reaction SMILES: N1CC[CH2:4][CH2:3][CH2:2]1.[C:7]([NH:24][CH2:25][C:26]([OH:28])=[O:27])([O:9][CH2:10][CH:11]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][C:54]1[CH:59]=[C:58]([CH3:60])[N:57]=[C:56](C)[CH:55]=1>CN(C=O)C>[NH:24]([C:7]([O:9][CH2:10][CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:8])[CH2:25][C:26]([OH:28])=[O:27].[CH2:56]1[C:55]2[C:54](=[CH:53][CH:2]=[CH:3][CH:4]=2)[CH2:59][CH:58]([CH2:60][C:7]([OH:9])=[O:8])[NH:57]1
Reactant: Cc1cc(C)nc(C)c1
Reactant: C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Product: O=C(O)CC1Cc2ccccc2CN1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.072 mmol of A is washed with DMF (1×2 ml). The compound is subsequently deprotected twice using 20% of piperidine in DMF (2×2 ml), firstly for 5 minutes and then for 15 minutes, and washed with DMF (6×2 ml). An approximately 0.1M solution of 2.5 equivalents (based on the resin loading, 0.18 mmol) of Fmoc-glycine, 2.4 equivalents (0.17 mmol) of HATU and 30 equivalents (2.16 mmol) of sym-collidine in dry DMF is added to the resin-bound free amine, and the mixture is shaken at room temperature for 90 minutes. The reaction is terminated by washing in DMF (6×2 ml).
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Br:12]Br>N1C=CC=CC=1.[Cl-].[Na+].O>[Br:12][C:9]1[C:8]([OH:11])=[CH:7][CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[N:10]=1
Reactant: BrBr
Reactant: CC(C)(C)c1ccc(O)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1ccc(O)c(Br)n1
Reaction time: 1 h

Procedure:
To a stirred solution of 6-(1,1-dimethylethyl)-3-pyridinol, (3.8 g) in pyridine (150 ml) was added bromine (1.29 ml), diluted in pyridine, dropwise at 20 C. The reaction mixture was allowed to stir at 25-30 C. for 1 h. The reaction had gone to completion by tlc. It was poured into brine and extracted with ethyl acetate. The organics were dried over sodium sulphate and concentrated under reduced pressure. The crude material was subjected to flash chromatography using a 0-5% gradient of ethyl acetate in hexane to give the title compound, 2.9 g
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:64]([N:71]1[CH2:76][CH2:75][N:74]([CH:77]2[CH2:82][CH2:81][CH:80]([NH2:83])[CH2:79][CH2:78]2)[CH2:73][CH2:72]1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C>[CH2:64]([N:71]1[CH2:72][CH2:73][N:74]([C@H:77]2[CH2:82][CH2:81][C@H:80]([NH:83][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([NH:21][C:19]4[N:18]=[CH:17][C:8]5[N:9]([CH3:16])[C:10](=[O:15])[C:11]6([CH2:14][CH2:13]6)[CH2:12][N:6]([CH:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)[C:7]=5[N:20]=4)=[C:23]([O:31][CH3:32])[CH:24]=3)[CH2:79][CH2:78]2)[CH2:75][CH2:76]1)[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reactant: NC1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(Cc4ccccc4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (66 mg, 0.15 mmol, 1 eq), DIPEA (52 μl, 0.3 mmol, 2 eq) and TBTU (54 mg, 0.17 mmol, 1.1 eq) were added to 1 mL DMF and the resulting solution was stirred at rt for min before the addition of 4-(4-benzylpiperazin-1-yl)cyclohexanamine (Intermediate 18) (35 mg, 0.18 mmol, 1.2 eq) dissolved in DMF (0.5 mL). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide N-((trans)-4-(4-benzylpiperazin-1-yl)cyclohexyl)-4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzamide (white solid, 13 mg, 13%).
Reaction SMILES: C(OC(=O)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.Br[CH:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])=[CH:31][CH:30]=1)[CH3:28].[C:43]([O:46]CC)(=[O:45])[CH3:44].[OH-].[K+]>CO>[F:42][C:36]1[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=1[C:32]1[CH:33]=[CH:34][C:29]([CH:27]([CH3:28])[CH2:44][C:43]([OH:46])=[O:45])=[CH:30][CH:31]=1
Reactant: CCOC(C)=O
Reactant: CC(Br)c1ccc(-c2ccc(F)cc2F)cc1
Agent: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
69.7 g. of triphenylphosphoranylideneacetic acid ethyl ester and 29.7 g. of 4-(1-bromoethyl)-2',4'-difluorobiphenyl in 300 ml. of absolute ethyl acetate are heated under reflux for 54 hours. The precipitate is filtered off and the filtrate is evaporated. Crude [1-(2',4'-difluoro-4-biphenylyl)ethyl]-triphenylphosphoranylideneacetic acid ethyl ester thus obtained is dissolved in 500 ml. of methanol to which 150 ml. of 20% potassium hydroxide solution are added and the mixture is heated under reflux for one hour. The methanol is distilled off, water is added and the reaction mixture is washed with ether and acidified with hydrochloric acid to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[C:11](=O)([O-])[O-:12].[Na+].[Na+].Cl>O.CC(C)=O>[OH:6][CH:5]([C@H:3]1[O:4][C:11](=[O:12])[NH:1][CH2:2]1)[CH:7]([OH:8])[CH2:9][OH:10]
Reactant: NC[C@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1NC[C@@H](C(O)C(O)CO)O1
Reaction time: 8 h
Yield: 28.2 %

Procedure:
1-Amino-1-deoxy-D-ribitol (2.1 g, 0.014 mole prepared from D-ribose as described by Wolfron et. al. J. Org. Chemi. 23, 571 [1958]) was dissolved in water (30 ml), and sodium carbonate (2.9 g, 28 mole) and a solution of p-nitrophenyl-chloroformate (3.2 g, 0.016 mole) in acetone (10 ml) were added at 0° C. The solution was stirred and allowed to stand at room temperature overnight. The solution was acidified with 5N hydrochloric acid and extracted several times with ethyl acetate. The aqueous phase was evaporated and the residue extracted with ethanol. Chromatography on silica eluting with a gradient of chloroform and ethanol gave 5-(S)-(1',2',3'-trihydroxypropyl)-1,3-oxazolidin-2-one (0.7 g) an an oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12]P(=O)(OCC)OCC)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>C1COCC1.O1CCOCCOCCOCCOCC1>[CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH:12]=[C:36]2[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1cccc(Oc2cccc(C)n2)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)n1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
Diethyl 3-(6-methylpyridin-2-yloxy)benzylphosphonate (4.7 g, 14 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.05 mL, 0.28 mmol) were combined in THF (150 mL). Sodium hydride (617 mg, 60% dispersion in mineral oil, 15.4 mmol) was added. The reaction was stirred for 30 min and then a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.07 g, 15.4 mmol) in THF (15 mL) was added. After 16 h, water was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-30%, EtOAc:heptane) to afford the title compound (4.4 g, 83% yield) as a thick oil.
Reaction SMILES: C[N:2](C)/[CH:3]=[N:4]\[C:5]([C:7]1[N:16]=[C:15]2[N:9]([CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:14]=32)[CH:8]=1)=O.Cl.[CH:24]([NH:27]N)([CH3:26])[CH3:25]>C(O)(=O)C>[Br:21][C:19]1[CH:18]=[CH:17][C:14]2[C:15]3[N:9]([CH:8]=[C:7]([C:5]4[N:27]([CH:24]([CH3:26])[CH3:25])[N:2]=[CH:3][N:4]=4)[N:16]=3)[CH2:10][CH2:11][O:12][C:13]=2[CH:20]=1
Reactant: CN(C)/C=N\C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)NN
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 100 °C
Yield: 89.6 %

Procedure:
Alternatively, to a suspension of 8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid 1-dimethylamino-meth-(Z)-ylideneamide (8.52 g, 23.5 mmol) in acetic acid (50 mL) was added isopropylhydrazine hydrochloride (3.37 g, 30.5 mmol) and the reaction mixture heated at 100° C. for 1 h. The reaction mixture was allowed to cool to RT and was poured onto water (500 mL) causing the product to precipitate as an off-white solid. The product was collected by filtration, washed with water (˜200 mL) and dried in vacuo at 45° C. for 16 h to yield 194 as an off-white solid (7.88 g, 86%). 1H NMR (400 MHz, d6-DMSO) 8.43 (1H, d, J=8.6 Hz), 7.97 (1H, s), 7.92 (1H, d, J=0.6 Hz), 7.36 (1H, dd, J=8.6, 2.0 Hz), 7.30 (1H, d, J=2.0 Hz), 5.86 (1H, sept, J=6.6 Hz), 4.56-4.52 (4H, m), 1.48 (6H, d, J=6.6 Hz). LCMS: RT=4.69 min, M+H+=374/376. 1H NMR showed product to contain ˜5% 8-iodo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:42])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:16][N:15]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39](=[O:41])[CH3:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.BrC1(Br)C(=O)NC(=O)NC1=O.[CH2:54]([NH:56][CH2:57][CH3:58])[CH3:55]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:42])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:16][N:15]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39](=[O:41])[CH2:40][N:56]([CH2:57][CH3:58])[CH2:54][CH3:55])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(C)=O)cn3)CC2)C[C@H]1c1ccc(F)cc1
Reactant: CCNCC
Agent: O=C1NC(=O)C(Br)(Br)C(=O)N1
Solvent: C1COCCO1
Product: CCN(CC)CC(=O)c1ccc(N2CCC(C(=O)N3C[C@@H](N(CC)C(=O)Oc4ccc(F)cc4)[C@H](c4ccc(F)cc4)C3)CC2)nc1
Temperature: 85 °C
Yield: 26.5 %

Procedure:
A mixture of 0.17 g (0.285 mmol) [(3S,4R)-1-(5′-Acetyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester (example 38) and 84.3 mg (0.295 mmol) 5,5-dibromobarbituric acid in 10 mL dioxane was heated to 85° C. for 40 h. At room temperature 0.216 g (2.95 mmol) diethylamine was added and heated to 45° C. for 2 h and evaporated. the residue was taken up in methanol and subjected to preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 49 mg (26%) of the title compound as light brown solid. MS m/e: 648.3 [M+H]+.