Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][C@H:14]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].O.ON1C2C=CC=CC=2N=N1.[C:39]([NH:49][C@H:50]([C:55](O)=[O:56])[CH2:51][CH2:52][S:53][CH3:54])([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40].C(#N)C>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:42]([O:41][C:39]([NH:49][C@@H:50]([CH2:51][CH2:52][S:53][CH3:54])[C:55]([NH:12][C@H:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][C@H:14]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:56])=[O:40])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CCOC(=O)[C@@H]1CC2(CC[C@@H]1N)OCCO2
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)[C@@H]1CC2(CC[C@@H]1NC(=O)[C@H](CCSC)NC(=O)OCc1ccccc1)OCCO2

Procedure:
Ethyl (7R,8S)-8-amino-1,4-dioxa-spiro[4.5]decane-7-carboxylate 4-toluenesulfonate salt 1 (450.1 g; the product of reductive deprotection of a known compound—see R. J. Chemey, WO 2004/098516 and G. V. Delucca & S. S. Ko, WO 2004/110993), was combined with 1-ethyl-3-(3-dimethyl-amino-propyl)carbo-diimide hydrochloride (236.3 g), 1-hydroxy benzotriazole hydrate (171.9 g), N-carbobenzyloxy-L-methionine (333.4 g) and acetonitrile (3.1 L). To the stirred mixture was added triethylamine (249.5 g) below 30° C. Upon reaction completion (HPLC), the mixture was diluted with ethyl acetate (8.2 L) and washed with aqueous 25% potassium bicarbonate solution (2×4.5 L) followed by water (4.5 L). The organic phase was separated and concentrated under reduced pressure to obtain a solution of ethyl (7R,8S)-8-((S)-2-benzyloxycarbonylamino-4-methylsulfanyl-butyrylamino)-1,4-dioxa-spiro[4.5]decane-7-carboxylate 2 (1.4 L). Methyl iodide (2.39 kg) was added, the vessel was shielded from light and the mixture was held under slow agitation for approx. 24 h. To the thick yellow precipitate was added methyl tert-butyl ether (2.7 L) and the mixture was held for approx. 1 h. The product was isolated by filtration and the cake was washed with methyl tert-butyl ether (2×1.4 L), then dried under vacuum, yielding [(S)-3-benzyloxy-carbonylamino-3-(7R,8S)-7-ethoxycarbonyl-1,4-dioxa-spiro[4.5]dec-8-ylcarbamoyl)-propyl]-dimethylsulfonium iodide 3 (671.4 g, ˜94% yield) as an off-white solid (HPLC purity 99.9%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7](O)O[C:9](=[O:10])[C:4]2=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.CO.B.[K]>C(O)(=O)C.O>[O:10]=[C:9]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:7][N:12]1[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: O=C1OC(O)c2ccccc21
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: B
Agent: [K]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(N2Cc3ccccc3C2=O)cc1
Yield: 94.3 %

Procedure:
1.5 g of o-phthalaldehydic acid and 1.5 g of p-aminophenylacetic acid were added to 30 ml of methanol to form a mixture which was agitated at room temperature for one hour and incorporated with 0.54 g of potassium boron hydride in several portions. Then, the whole was reacted at room temperature of 5 hours and then freed from the solvent under a reduced pressure. The resulting residue was incorporated with 50 ml of water and then with a small amount of acetic acid to obtain an acidic solution, after which crystals precipitated from the thus obtained solution were filtered off, dried and recrystallized from ethanol to obtain 2.5 g of 1-oxo-2 -{p-(carboxymethyl)-phenyl}-isoindoline.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][O:8][C:9]1[C:14]([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25](=[O:27])[CH3:26])[CH2:20][CH:19]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH2:37][CH3:38])[CH:29]=2)=O)=[CH:13][CH:12]=[C:11]([O:39][CH3:40])[N:10]=1.C(N(CC)CC)C.O>ClCCl>[CH3:7][O:8][C:9]1[C:14]([C:15]2[C:33]3[C:28](=[CH:29][C:30]([O:36][CH2:37][CH3:38])=[C:31]([O:34][CH3:35])[CH:32]=3)[CH:19]3[CH:18]([CH2:23][CH2:22][CH:21]([O:24][C:25](=[O:27])[CH3:26])[CH2:20]3)[N:17]=2)=[CH:13][CH:12]=[C:11]([O:39][CH3:40])[N:10]=1
Reactant: CCOc1cc(C2CC(OC(C)=O)CCC2NC(=O)c2ccc(OC)nc2OC)ccc1OC
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=NC1CCC(OC(C)=O)CC21
Temperature: 25 °C
Yield: 60.6 %

Procedure:
1.67 g of phosphorus pentachloride are suspended in 5 ml of dichloromethane. 1.227 g of crude acetic acid (1RS,3RS,4RS)-4-{[1-(2,6-dimethoxy-pyridin-3-yl)methanoyl]amino}-3-(3-ethoxy-4-methoxyphenyl)cyclohexyl ester (compound A1) dissolved in 15 ml of dichloromethane are added and the reaction mixture stirred at room temperature over night. The reaction mixture is cooled with an ice bath and 20 ml of triethylamine are added, than cautiously 10 ml of water with vigorous strirring. The organic layer is separated, concentrated and the crude product purified by flash chromatography to give 715 mg of the title compound.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.F[C:17]1[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].C(O)(=O)C.Cl>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:17]2[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1
Reactant: COc1cnc(F)c(C(=O)O)c1
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cnc(Oc2ccc(Br)cc2)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To a slurry of NaH (60% dispersion) (21.74 g, 543 mmol) in DMF (351 mL, 175 mmol) at 0° C. was added 4-bromophenol (60.7 g, 351 mmol) over the course of 5 minutes. Stirred at 0° C. for two minutes then removed from the ice bath and stirred for an additional 5 minutes at RT. Added 2-fluoro-5-methoxynicotinic acid (30 g, 175 mmol) portionwise over 10 minutes and heated the resulting slurry at 140° C. After cooling to RT the mixture was then poured onto 1 kg of ice and was quenched with acetic acid (50.2 mL, 877 mmol) and then 75 mL of 6 N HCl. Stirred vigorously for 1 hr; leading to the formation of a red slurry containing a very fine white precipitate. The slurry was filtered to provide 2-(4-bromophenoxy)-5-methoxynicotinic acid.
Reaction SMILES: [CH:1]([C:4]1[CH:37]=[CH:36][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18](=[O:20])[CH3:19])[CH2:15][CH2:14][N:13]2[S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[C:26](I)[CH:25]=2)(=[O:23])=[O:22])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br-].C([O:41][C:42](=[O:47])[CH2:43][CH2:44][CH2:45][Zn+])C.O1CCCC1.Cl>O1CCCC1.C1([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:18]([N:16]1[CH2:15][CH2:14][N:13]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:33])([F:32])[F:34])=[C:26]([CH2:45][CH2:44][CH2:43][C:42]([OH:47])=[O:41])[CH:25]=2)(=[O:22])=[O:23])[C@@H:12]([C:10](=[O:11])[NH:9][CH2:8][C:7]2[CH:36]=[CH:37][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[CH2:17]1)(=[O:20])[CH3:19]
Reactant: CCOC(=O)CCC[Zn+]
Reactant: CC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)c(I)c2)[C@@H](C(=O)NCc2ccc(C(C)C)cc2)C1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)c(CCCC(=O)O)c2)[C@@H](C(=O)NCc2ccc(C(C)C)cc2)C1

Procedure:
Under an argon stream, to a suspension of the compound (46 mg) obtained in Example 10, 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (5 mg) and bis(dibenzylideneacetone)palladium(0) (4 mg) in tetrahydrofuran was added, with stirring under ice-cooling, 0.5M 4-ethoxy-4-oxobutylzinc bromide/tetrahydrofuran solution (422 μl). After stirring at room temperature for 24 hr, 1N aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtrated and concentrated under reduced pressure. Methanol (0.5 ml) was added to the residue, and 4N aqueous sodium hydroxide solution (35 μl) was added with stirring under ice-cooling. After stirring at room temperature for 3 hr, 2N aqueous hydrochloric acid solution (70 μl) was added, and the mixture was concentrated under reduced pressure. The residue was purified by thin layer chromatography (chloroform:methanol:acetic acid=90:10:1) and recrystallized from water-containing methanol to give the title compound (2.4 mg).
Reaction SMILES: O[Li].O.C[O:5][C:6]([C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)=[O:7].CO.O>C1COCC1>[C:13]1([N:11]2[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[N:9]=[CH:10]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1cn(-c2ccccc2)cn1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccccc2)cn1
Reaction time: 3 h
Yield: 87 %

Procedure:
A stirred solution of 1H-imidazole-4-carboxylic acid (0.5 g, 0.00446 mmol), concentrated sulfuric acid (0.5 mL) and MeOH (20 mL) was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with cold water, extracted with ethyl acetate and washed the organic layer with sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 325 mg (58% Yield) of 1H-imidazole-4-carboxylic acid methyl ester. A mixture of 1H-imidazole-4-carboxylic acid methyl ester (225 mg, 1.8 mmol), cuprous oxide (225 mg, 1.8 mmol), iodobenzene (736 mg, 3.6 mmol), 1,10-phenanthroline (320 mg, 1.8 mmol) and cesium carbonate (1.74 g, 5.3 mmol) in DMSO (2 mL) in a seal tube was subjected to reaction in a microwave reactor (time: 5 min, temp: 90° C., power: zero) The reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. The residue was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to afford the residue. Purification by column chromatography (using 60-120 silica gel and 50% ethyl acetate in hexane as eluent) to afford 200 mg (55% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid methyl ester. LiOH.H2O (143 mg, 3.4 mmol) was added to a stirred solution of 1-phenyl-1H-imidazole-4-carboxylic acid methyl ester (231 mg, 1.1 mmol) in a mixture of THF (3 mL), MeOH (1 mL), H2O (1 mL) and stirring was continued at ambient temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure. Cold water was then added and acidified it with 10% aqueous HCl, the solid was collected to afford 180 mg (83.7% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[C:4]([O:15][C:16]([F:19])([F:18])[F:17])[CH:3]=1.[C:20]([C:22]1[N:26]([CH3:27])[C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:20]([C:22]1[N:26]([CH3:27])[C:25]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]3[CH2:14][CH2:13]3)(=[O:10])=[O:9])=[C:4]([O:15][C:16]([F:19])([F:18])[F:17])[CH:3]=2)=[CH:24][CH:23]=1)#[N:21]
Reactant: O=S(=O)(NC1CC1)c1ccc(Br)cc1OC(F)(F)F
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NC2CC2)c(OC(F)(F)F)c1
Reaction time: 16 h
Yield: 28.6 %

Procedure:
According to general procedure B, 4-bromo-N-cyclopropyl-2-(trifluoromethoxy)benzenesulfonamide (216 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-(trifluoromethoxy)benzenesulfonamide (65 mg, 29%) was provided after purification. MS (ESI) m/z 385. HPLC purity 99.2% at 210-370 nm, 9.5 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][C:36]1([C:39](O)=[O:40])[CH2:38][CH2:37]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:39]([C:36]2([CH3:35])[CH2:38][CH2:37]2)=[O:40])[CH2:4][CH2:5]1)=[O:27]
Reactant: CC1(C(=O)O)CC1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C3(C)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 98 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by 1-methylcyclopropanecarboxylic acid (29 mg, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give 5-Fluoro-N-{cis-4-[(1-methyl-cyclopropanecarbonyl)-amino]-cyclohexyl}-2-(3-methylsulfanyl-phenoxy)-nicotinamide (109 mg) as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([NH2:18])=[CH:5][C:6]2[N:7]([N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.C(N(CC)CC)C.C[Al](C)C.[N:30]1([C:34]([C:36]2[CH:37]=[N:38][N:39]([CH3:46])[C:40]=2[C:41](OCC)=[O:42])=[O:35])[CH2:33][CH2:32][CH2:31]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[N:30]1([C:34]([C:36]2[CH:37]=[N:38][N:39]([CH3:46])[C:40]=2[C:41]([NH:18][C:4]2[C:3]([CH3:2])=[CH:8][N:7]3[N:9]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:11]=[C:6]3[CH:5]=2)=[O:42])=[O:35])[CH2:31][CH2:32][CH2:33]1
Reactant: Cc1cn2nc(-c3ccccc3)nc2cc1N
Reactant: CCOC(=O)c1c(C(=O)N2CCC2)cnn1C
Agent: C[Al](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cn2nc(-c3ccccc3)nc2cc1NC(=O)c1c(C(=O)N2CCC2)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
To an argon purged solution of 6-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride (147 mg, 564 μmol) and triethylamine (78.6 μl, 564 μmol) in dioxane (8 ml) is added trimethylaluminum (2M solution in toluene, 705 μl, 1.41 mmol). The resulting mixture is stirred for 1 hour at 25° C., then ethyl 4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylate (134 mg, 564 μmol) is added; the mixture is heated to 100° C. and stirred for 18 hours. As no conversion is detected N-ethyl diisopropylamine (246 μl, 1.41 mmol) and another portion of trimethylaluminum (2M solution in toluene, 705 μl, 1.41 mmol) are added, the mixture is stirred for 1 hours at 25° C. and then for further 20 hours at 100° C. The crude material is loaded on silica and purified by flash chromatography on a 20 g silica column using heptane/ethyl acetate 10-100% as eluent affording 4-(azetidine-1-carbonyl)-1-methyl-N-(6-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (57 mg, 24.3%) as a light yellow solid. mp.: 226-8° C. MS: m/z=416.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=[O:19])[N:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:11][CH2:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([C:29]2[CH:39]=[C:38]([CH3:40])[C:32]3[N:33]([CH3:37])[C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)=[O:28])[CH:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[CH3:37][N:33]1[C:32]2[C:38]([CH3:40])=[CH:39][C:29]([C:27]([C:23]3[N:24]=[CH:25][N:26]=[C:21]([N:16]4[CH2:15][CH2:14][CH:13]([N:10]5[CH2:11][CH2:12][C:6]6[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:7]=6[NH:8][C:9]5=[O:19])[CH2:18][CH2:17]4)[CH:22]=3)=[O:28])=[CH:30][C:31]=2[O:35][C:34]1=[O:36]
Reactant: O=C1Nc2c(F)cccc2CCN1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(C(=O)c2cc(N3CCC(N4CCc5cccc(F)c5NC4=O)CC3)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
61 mg (0.23 mmol) 9-fluoro-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 70 mg (0.23 mmol) 6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.080 mL (0.46 mmol) DIPEA were combined in 2 mL DMF and stirred for 2 h at RT. Then the reaction mixture was diluted with MeOH, the precipitate formed was suction filtered, washed with MeOH and diethyl ether and dried.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][OH:11])[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
To a stirred solution of (S)-2-(tert-butoxycarbonylamino)-4-methoxy-4-oxobutanoic acid (9.0 g, 35.7 mmol) in THF (180 mL) at −10° C. was added N-methylmorpholine (3.9 mL, 35.7 mmol) followed by ethyl chloroformate (3.91 g, 35.7 mmol). After 10 min, the mixture was transferred slowly to a mixture of NaBH4 (2.7 g, 71.4 mmol) and ice water (900 mL). The resulting solution was stirred for 1 h, NaHCO3 (˜20 g) was added, and the organic layer was separated. The aqueous layer was extracted with EtOAc (4×200 mL). The combined organic layers were washed with 1 N aq HCl (20 mL) and brine (15 mL), dried over Na2SO4, and concentrated to give (S)-methyl 3-(tert-butoxycarbonylamino)-4-hydroxybutanoate (7.06 g, 85%) as an oil. MS m/z 234 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([B:13]3[O:17]C(C)(C)C(C)(C)[O:14]3)=[CH:9][CH:8]=2)[N:3]=1.I([O-])(=O)(=O)=O.[Na+].C([O-])(=O)C.[NH4+]>CC(C)=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([B:13]([OH:17])[OH:14])=[CH:11][CH:12]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)no1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1nc(-c2ccc(B(O)O)cc2)no1

Procedure:
A suspension of the product obtained in Step D above (6.5 g, 22.7 mmol) in 230 ml of acetone is stirred for 24 hours in the presence of 18.4 g (86.0 mmol) of sodium meta-periodate and 70 ml of aqueous 1M ammonium acetate solution. The acetone is evaporated off using a rotary evaporator and, after adding water, the reaction mixture is extracted with ethyl acetate. The organic phases are combined, washed (NaCl) and dried (MgSO4) to yield, after evaporation, the expected product.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:18][C:19](Cl)=[O:20].CN(C)C=O.[H-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([N:8]1[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:18][C:19]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Oc1ccccc1CNCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1COc2ccccc2CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A mixture of 19.0 g of 2-(benzylamino-methyl)-phenol and 75 mL of toluene was cooled to 0° C., and a solution of chloroacetyl chloride (7.8 mL) in 75 mL of toluene was slowly added while stirring. Stirring was continued for 16 h. Dry N,N-dimethylformamide (60 mL,) was added and the solution was cooled to 0° C. In a nitrogen atmosphere 3.4 g of sodium hydride (95%; dispersion in mineral oil) were added in small portions and the mixture was allowed to stir at room temperature for 2 h. Water was added and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and the solvent was removed in vacuo yielding 12.4 g of 4-benzyl-4,5-dihydro-benzo[f][1,4]oxazepin-3-one. M.p. 95-97° C. EI-MS: 253 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[CH3:19])=[CH:4][CH:3]=1.CC1C(O)=C(C=O)C(COP(O)(O)=O)=CN=1.O>[Ni].C(Cl)Cl.CCO>[NH2:16][C:14]1[CH:13]=[CH:12][C:11]([CH3:19])=[C:10]([CH:15]=1)[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1ccc(Br)cc1
Agent: [Ni]
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(N)cc1C(=O)Nc1ccc(Br)cc1

Procedure:
Prepared analogously to example 2e with N-(4-bromo-phenyl)-2-methyl-5-nitro-benzamide (0.18 g; 0.54 mmol) and Ra-Ni (20 mg), 3 bar H2. Yield: 0.14 g (85%) MS: [m+H]+=305; HPLC Rt=1.2 min (Method MC-1); TLC (silica gel; DCM/EtOH 95/5) Rf=0.3
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH2:37][CH:38]=O)[C:32](=[O:40])[CH:31]=[CH:30]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:38][CH2:37][N:33]4[C:34]5[C:29](=[CH:28][C:27]([Cl:26])=[CH:36][CH:35]=5)[CH:30]=[CH:31][C:32]4=[O:40])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=CCn1c(=O)ccc2cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
To 4 mL of a chloroform solution containing 0.68 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.44 g of (6-chloro-2-oxoquinolin-1(2H)-yl)acetaldehyde and 40 μL of acetic acid were added, then, to the reaction mixture, 0.62 g of sodium triacetoxyborohydride was added and stirred at room temperature for 2 nights. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate], to give 0.65 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-chloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.