Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](N)[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]1.N([O-])=[O:20].[Na+]>S(=O)(=O)(O)O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[F:1][C:2]1[CH:7]=[C:6]([OH:20])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]1
Reactant: O=N[O-]
Reactant: Cc1nn(-c2ccc(N)cc2F)c(=O)n1C(F)F
Agent: [Cu+2]
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1nn(-c2ccc(O)cc2F)c(=O)n1C(F)F
Yield: 60.7 %

Procedure:
A solution of 20.0 g (0.0774 mole) of 1-(2-fluoro-4-aminophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 100 mL of concentrated sulfuric acid was cooled to 15°-20° C. A solution of 5.3 g (0.0774 mole) of sodium nitrite in 20 mL of water was added slowly to the sulfuric acid solution while the temperature was maintained between 15° C. and 20° C. The dark orange solution was stirred for an hour at this temperature. The solution was then added rapidly to a solution of 250 g (1.00 mole) of copper (II) sulfate pentahydrate and 2.0 g (0.0072 mole) of iron (II) sulfate heptahydrate in 250 mL of water and 250 mL of mixed xylenes. This two-phase solution was heated at reflux for one hour, after which it was cooled and the phases separated. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure, leaving a brown oil. The aqueous layer was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and then filtered. The extract was combined with the brown oil from the organic phase, and the solvent was evaporated under reduced pressure, again leaving a brown oil. This brown oil was placed on a silica gel column and eluted with methylene chloride/ethyl acetate (90/10). The product-containing fractions were combined, and the solvent was evaporated under reduced pressure, leaving 12.17 g of 1-(2-fluoro-4-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, m.p. 112°-114° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][Si:8]([O:14][Si:15]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:9])=[CH:4][CH:3]=1.Br[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[C:36]#[N:37]>C1COCC1.CCOCC.[Cl-].[Cl-].[Zn+2].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>[C:36]([C:35]1[CH:34]=[C:33]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][Si:8]([O:14][Si:15]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:33]4[CH:40]=[CH:39][CH:38]=[C:35]([C:36]#[N:37])[CH:34]=4)=[CH:25][CH:24]=3)([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:9])=[CH:30][CH:31]=2)[CH:40]=[CH:39][CH:38]=1)#[N:37]
Reactant: N#Cc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(CCc1ccc(Br)cc1)O[Si](C)(CCc1ccc(Br)cc1)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(CCc1ccc(-c2cccc(C#N)c2)cc1)O[Si](C)(CCc1ccc(-c2cccc(C#N)c2)cc1)C(C)(C)C
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
To a cooled (−78° C.) solution of 4-bromo-benzyl-(t-butyldimethylsilyl)-ether (2.73 g, 9 mmol) (reference example 10) in THF (40 mL) was added, dropwise, n-buLi (4.4 mL, 2.5M in hexanes). On complete addition, the resulting solution was stirred for 10 min then ZnCl2 (10 mL, 0.5M in THF) was added. The cold bath was removed and stirring continued for 10 min. To this solution was added a solution comprised of 3-bromo-benzonitrile (1.82 g, 10 mmol) (Aldrich), (Ph3P)4Pd (410 mg, 0.35 mmol) in THF (5 mL). The resulting mixture was heated to 65° C. and stirred at this temperature for 20 min. The reaction mixture was allowed to cool to room temperature then diluted with ether, washed, sequentially, with sat. ammonium chloride solution and brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (eluting with 5% EtOAc in hexanes) to give 2.0 g of the title compound. 1H NMR (CDCl3) d 0.15 (s, 6H), 1.00 (s, 9H), 4.80 (s, 2H), 7.43 (d, J=8 Hz, 2H), 7.45-7.65 (m, 4H), 7.80 (m, 1H), 7.85 (bs, 1). MS (ion spray) m/z 324 (M+H)+.
Reaction SMILES: O[N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][N:5]([CH3:14])[C:4]1=[O:15].C(O)C.Cl.[OH-].[Na+]>[Pd].ClCCl>[NH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][N:5]([CH3:14])[C:4]1=[O:15]
Reactant: CN1CCc2ccccc2C(=NO)C1=O
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CN1CCc2ccccc2C(N)C1=O
Yield: 81.9 %

Procedure:
1-Hydroxyimino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (625 g, 3.06 mol) and 3A ethanol (15.6 L), was added to an autoclave along with palladium on carbon (10%, 120 g) as a as a dilute HCl (concentrated aqueous hydrochloric acid (312 g in 320 mL water) slurry. The resulting mixture was hydrogenated at 50° C. and 250 psi (1723 kPa) with vigorous agitation until the reaction was completed (about 4 hours). The reaction mixture was filtered over a pad of celite using ethanol as solvent and the filtrate concentrated give a solid. The solid was treated with dichloromethane (6 L) and 1N aqueous sodium hydroxide solution was added until the pH to of the aqueous layer was between 11-11.5. The mixture was agitated, the layers were separated, and the aqueous layer was extracted with dichloromethane (2 L). The organic layers were dried over magnesium sulfate, filtered, and evaporated in a rotary evaporator to give the title compound 477 g (81.9%).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[NH2:11][C:12]1[C:31]([Cl:32])=[CH:30][C:15]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][C@H:20]2[O:28][CH3:29])=[O:17])=[C:14]([O:33][CH3:34])[CH:13]=1.[I-].[K+].[OH-].[NH4+]>CN(C)C(=O)C.O.ClCCl>[NH2:11][C:12]1[C:31]([Cl:32])=[CH:30][C:15]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:2]3[NH:6][C:5]4[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=4[N:3]=3)[CH2:21][C@H:20]2[O:28][CH3:29])=[O:17])=[C:14]([O:33][CH3:34])[CH:13]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCN)C[C@H]1OC
Reactant: Clc1nc2ccccc2[nH]1
Agent: [I-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNc2nc3ccccc3[nH]2)C[C@H]1OC
Temperature: 120 °C
Reaction time: 4 h
Yield: 18.6 %

Procedure:
A dry mixture of 1.8 parts of 2-chloro-1H-benzimidazole, 4.28 parts of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide and 0.1 parts of potassium iodide was pulverized. A few drops of N,N-dimethylacetamide were added and the whole was stirred for 4 hours at 120° C. The reaction mixture was taken up in a mixture of water and dichloromethane. The whole was treated with ammonium hydroxide. The organic layer was separated, washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.06 parts (18.6%) of cis-4-amino-N-[1-[2-(1H-benzimidazol-2-ylamino)ethyl]-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide; mp. 205.8° C. (compound 28).
Reaction SMILES: [CH2:1]([C:3]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])=[CH:4][C:5](=[N:8][OH:9])[CH:6]=[O:7])[CH3:2].[BH4-].[Na+].Cl>C(O)C>[CH2:1]([C:3]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])=[CH:4][C:5](=[N:8][OH:9])[CH2:6][OH:7])[CH3:2]
Reactant: CCC(=CC(C=O)=NO)C(C)[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC(=CC(CO)=NO)C(C)[N+](=O)[O-]
Yield: 79.2 %

Procedure:
To a solution of 4-ethyl-2-hydroxyimino-5-nitro-3-hexenal (100 mg) in dry ethanol (10 ml) was added sodium borohydride (15 mg) at 0° C. with stirring. The resulting mixture was stirred at the same temperature for 10 minutes and 1N hydrochloric acid was added thereto. The reaction mixture was extracted with ethyl acetate and the extract was washed with successively with water, an aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and then evaporated to dryness in vacuo to give an oil. The oil was purified by a preparative thin layer chromatography [solvent:methanol-chloroform (10:90)] to give 4-ethyl-2-hydroxyimino-5-nitro-3-hexen-1-ol (80 mg).
Reaction SMILES: Br.[NH2:2][CH2:3][C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:5].CN1CCOCC1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]=[C:42]=[O:43].CCOC(C)=O>CN(C=O)C>[NH2:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:7]2[NH:6][C:4](=[O:5])[CH2:3][NH:2][C:42]([NH:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[C:34]([F:33])([F:44])[F:45])=[O:43])=[O:25])=[CH:20][CH:19]=1)(=[O:23])=[O:22]
Reactant: NCC(=O)N[C@H]1CCCC[C@H]1NC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Agent: Br
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(C(=O)N[C@@H]2CCCC[C@@H]2NC(=O)CNC(=O)Nc2ccccc2C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
N-(cis)-{2-[(aminoacetyl)amino]cyclohexyl}-4-(aminosulfonyl)benzamide hydrogen bromide, (61b), (100 mg) was dissolved in DMF (3 mL) prior to the addition of 4-methylmorpholine (0.13 mL) and 2-trifluoromethylphenyl isocyanate (0.05 mL). After stirring overnight, EtOAc was added and the solution was washed with 1N HCl. The EtOAc was dried, filtered, and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title benzamide (50 mg). MS found: (M+Na)+=564.3.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:15]([O:17][C:18]1[CH:27]=[CH:26][C:21]2[N:22]=[C:23]([SH:25])[S:24][C:20]=2[CH:19]=1)[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[CH2:15]([O:17][C:18]1[CH:27]=[CH:26][C:21]2[N:22]=[C:23]([S:25][CH:2]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]3)[S:24][C:20]=2[CH:19]=1)[CH3:16]
Reactant: CCOc1ccc2nc(S)sc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc2nc(SC3CCN(C(=O)OC(C)(C)C)CC3)sc2c1
Reaction time: 20 h
Yield: 65 %

Procedure:
To the mixture of tert-butyl 4-hydroxy-1-piperidinecarboxylate (2 g, 10 mmol), 6-ethoxy-1,3-benzothiazol-2-thiol (2.54 g, 12 mmol), triphenylphosphine (3.9 g, 15 mmol) and THF (60 ml) was dropwise added a solution of 40% diethyl azodicarboxylate in toluene (5.23 g, 15 mmol) under ice cooling over a period of 10minutes. The mixture was stirred at room tmperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was dissolved in ethyl acetate (50 ml). The organic layer was washed with aqueous solution of 0.5N-sodium hydroxide (30 ml),and saturated aqueous solution of sodium chloride (30 ml), successively, dried-over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was subjected to flash column chromatography (silica gel 50 g, ethyl acetate/hexane=1/20 to 1/5), and the desired fraction was concentrated under reduced pressure. To the concentrate was added hexane (10 ml) and the precipitates were collected by filtration to give the titled compound (2.6 g, 6.5 mmol) as white powdery crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:33][N:34]([CH3:38])[C:35]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:9]([CH2:8][O:7][C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:32])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:28])([CH3:29])[CH:12]=[C:11]3[CH3:30])=[C:20]([O:26][CH3:27])[CH:21]=1)=[O:36]
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc(OC(=O)N(C)C)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 100 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 5-1, 25 mg, 0.058 mmol) was dissolved in pyridine (1 mL), N,N-dimethylcarbamoyl chloride (6.9 μL, 0.075 mmol) was added thereto, and then the mixture was stirred at 100° C. for 3 hours. N,N-Dimethylcarbamoyl chloride (3.0 μL, 0.033 mmol) was added to the reaction mixture and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL). The mixture was washed with 0.2 N aqueous HCl solution (75 mL), water (50 mL), and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (1st time: hexane-ethyl acetate, 2nd time: toluene-ethyl acetate) to give the titled compound (8.5 mg) as a colorless amorphous product. (Yield 29%)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:12]([C:13]3[CH:32]=[CH:31][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:15]([F:33])[C:14]=3[F:34])[N:11]=[N:10][N:9]=2)=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1.C([O-])(O)=O.[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:7]([C:8]2[N:12]([C:13]3[CH:32]=[CH:31][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:15]([F:33])[C:14]=3[F:34])[N:11]=[N:10][N:9]=2)=[CH:6][C:5]([C:40]2[CH:39]=[N:38][N:37]([CH3:36])[CH:41]=2)=[CH:4][N:3]=1
Reactant: CN(CCCCOc1ccc(-n2nnnc2-c2cc(Br)cnc2N)c(F)c1F)C(=O)OC(C)(C)C
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CN(CCCCOc1ccc(-n2nnnc2-c2cc(-c3cnn(C)c3)cnc2N)c(F)c1F)C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 50 %

Procedure:
As shown in step 4-v of Scheme 4, tert-butyl 4-(4-(5-(2-amino-5-bromopyridin-3-yl)-1H-tetrazol-1-yl)-2,3-difluorophenoxy)butylmethylcarbamate (Compound 1019, 554 mg, 1.00 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (250 mg, 1.20 mmol) were dissolved in 8.0 mL of DMF and 4.0 mL of saturated NaHCO3 (aq) were added. The mixture was flushed with argon gas for 1 hour and PdCl2(dppf) (43.2 mg, 53.0 mmol) was added. The reaction mixture was flushed with argon for an additional 30 minutes followed by heating to 100° C. for 1 hour. After cooling, the mixture was diluted with EtOAc (80 mL), washed with water (3×40 mL), washed with brine (40 mL), and dried over sodium sulfate. After filtration, the organics were concentrated under reduced pressure and the residue purified by silica gel chromatography (40% EtOAc/hexanes) to provide tert-butyl 4-(4-(5-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-tetrazol-1-yl)-2,3-difluorophenoxy)butylmethylcarbamate (278 mg, 50% yield), which was used as is in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[C:14]([OH:15])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:14]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][S:23][C:20]2[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=2)=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: CC1(C)OC(=O)Nc2cc(Cl)c(O)cc21
Reactant: ClCCCCSc1ccc(Cl)cc1
Product: CC1(C)OC(=O)Nc2cc(Cl)c(OCCCCSc3ccc(Cl)cc3)cc21

Procedure:
Prepared analogously to Example 4 from 7-chloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-chloro-phenylmercapto)-butylchloride.
Reaction SMILES: [CH:1]1[C:9]([Br:10])=[CH:8][N:7]2[C:3](=[N:4][CH:5]=[CH:6]2)[CH:2]=1.C[O:12][C:13]1[C:18]2C=CNC=2N=C(N)[N:14]=1.N1C=CC=CC=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:10][C:9]1[CH:1]=[CH:2][C:3]2[N:7]([CH:6]=[C:5]([NH:14][C:13](=[O:12])[CH3:18])[N:4]=2)[CH:8]=1
Reactant: Brc1ccc2nccn2c1
Reactant: COc1nc(N)nc2[nH]ccc12
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cn2cc(Br)ccc2n1
Temperature: 35 °C
Reaction time: 3 h
Yield: 49.4 %

Procedure:
To a 100 mL round-bottomed flask was added 6-bromoH-imidazo[1,2-a]pyridin-2-amine (0.771 g, 3.6 mmol), DCM (30 mL), pyridine (0.44 mL, 5.5 mmol), acetic anhyride (0.41 mL, 4.4 mmol) and DMAP (0.0022 g, 0.018 mmol). The mixture was stirred at 35° C. for 3 h. After cooling to rt, the mixture was concentrated and then taken up in water (100 mL) and extracted with 25% iPrOH/CHCl3 (3×75 mL). The combined extracts were washed with brine (75 mL), dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in MeOH (2 M in NH3)/CH2Cl2 and concentrated onto silica. Purification by silica gel chromatography MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as an orange solid (0.452 g, 49%). MS (ESI, positive ion) m/z: 254 (M(79Br)+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])[CH3:28].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:27]([C:30]1[CH:35]=[CH:34][C:33]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])=[CH:32][CH:31]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCCc1nc(C)n(-c2ccc(C(C)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (3.0 g), (4-acetylphenyl)boronic acid (3.0 g), triethylamine (6.0 mL), pyridine (3.0 mL) and molecular sieves 4 A (6.0 g) in methylene chloride (30 mL) was added copper(II) acetate (3.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (2.34 g, 58%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([OH:16])=[CH:13][CH:14]=2)[C@@H:9]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[C:21]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:20][N:19]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2].[H-].[Na+].[CH2:49](I)[CH3:50].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH2:49][CH3:50])=[CH:13][CH:14]=2)[C@@H:9]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:26]=3)[C:21]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[CH:20][N:19]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)N1c2ccc(O)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OCC)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-hydroxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (207 mg) is dissolved in N,N-dimethylformamide (3 ml), then thereto is added sodium hydride (62.7%, 15 mg) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. After addition of ethyl iodide (50 μl) under ice-cooling, the mixture is stirred at room temperature for 2 hours. Water and ethyl acetate are added to the mixture, the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=9:1→7:3) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-ethoxy-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (141 mg). MS (m/z): 683 [M+H]+
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[S:8][C:7]([C@H:9]([N:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:13]([C:16]2[CH:24]=[CH:23][C:19]3[N:20]=[CH:21][S:22][C:18]=3[CH:17]=2)(=[O:15])=[O:14])[CH2:10][OH:11])=[CH:6][CH:5]=1.[CH3:29][O:30][C:31]([NH:33][C@H:34]([C:48](O)=[O:49])[CH:35]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:32].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[S:22]1[C:18]2[CH:17]=[C:16]([S:13]([N:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[C@@H:9]([C:7]3[S:8][C:4]([CH2:3][NH:2][C:48](=[O:49])[C@H:34]([CH:35]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[NH:33][C:31]([O:30][CH3:29])=[O:32])=[CH:5][CH:6]=3)[CH2:10][OH:11])(=[O:15])=[O:14])[CH:24]=[CH:23][C:19]=2[N:20]=[CH:21]1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)CN([C@H](CO)c1ccc(CN)s1)S(=O)(=O)c1ccc2ncsc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)NCc1ccc([C@@H](CO)N(CC(C)C)S(=O)(=O)c2ccc3ncsc3c2)s1)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of N-{(1R)-1-[5-(aminomethyl)thiophen-2-yl]-2-hydroxyethyl}-N-(2-methylpropyl)-1,3-benzothiazole-6-sulfonamide hydrochloride (30 mg, 0.065 mmol), N-(methoxycarbonyl)-β-phenyl-L-phenylalanine (21 mg, 0.071 mmol) and DIPEA (45 μL, 0.26 mmol) in DMF (300 μL) at 0° C. was added BOP (32 mg, 0.071 mmol). The reaction mixture was stirred at 0° C. for 4 hours before being quenched with a saturated solution of sodium bicarbonate (3 mL). The quenched mixture was extracted with ether/ethyl acetate (1/1 3×3 mL). The organic layers were combined and washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified on silica gel eluting with hexanes and ethyl acetate. MS: m/z=729.1 (MNa+).