Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[NH:14][C:10]=3[CH:9]=2)[C:5]2[CH:18]=[C:19]([C:22]([OH:24])=O)[CH:20]=[CH:21][C:4]=2[O:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH3:53][N:54]([CH3:58])[CH2:55][CH2:56][NH2:57]>CN(C=O)C.O>[CH3:53][N:54]([CH3:58])[CH2:55][CH2:56][NH:57][C:22]([C:19]1[CH:20]=[CH:21][C:4]2[O:3][C:2](=[O:1])[N:6]([CH2:7][C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[NH:14][C:10]=4[CH:9]=3)[C:5]=2[CH:18]=1)=[O:24]
Reactant: O=C(O)c1ccc2oc(=O)n(Cc3ccc4[nH]c(=O)[nH]c4c3)c2c1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCNC(=O)c1ccc2oc(=O)n(Cc3ccc4[nH]c(=O)[nH]c4c3)c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
330 mg (0.76 mmol) of 2-oxo-3-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl-methyl)-2,3-dihydrobenzoxazole-5-carboxylic acid are dissolved in 3 ml of DMF, and 294 mg (1.52 mmol) of EDCI, 106 mg (0.76 mmol) of HOBt and 157 μl (1.52 mmol) of N-methylmorpholine are added. 81 mg (0.91 mmol) of 2-dimethylaminoethylamine are subsequently added, and the reaction solution is stirred at room temperature for 3 days. The reaction mixture is subsequently added to water and extracted with dichloromethane. The organic phase is dried over sodium sulfate, evaporated to dryness and purified by column chromatography on silica gel. The product is purified again by preparative HPLC; 100 mg of “A35” trifluoromethylacetate; ESI 397 (M+H), HPLC: Rt=3.89 min (method A).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5](=[O:16])[C:4]([S:17]([CH3:19])=[O:18])=[CH:3]1.CO.C(OCC)(=[O:24])C>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=2)[C:5](=[O:16])[C:4]([S:17]([CH3:19])(=[O:24])=[O:18])=[CH:3]1
Reactant: CCOC(C)=O
Reactant: Cn1cc(S(C)=O)c(=O)c2ccc(C(F)(F)F)cc21
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(C(F)(F)F)cc21

Procedure:
1-methyl-3-methylsulphinyl-7-trifluoromethyl-4-quinolone was oxidised in dichloromethane at 0° to give 1-methyl-3-methylsulphonyl-7-trifluoromethyl-4-quinolone, m.p. 300°-301° (from methanol:ethyl acetate)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[CH:7]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: COc1ccc(Nc2cncc(Br)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(Nc2cncc(-c3cccc(N)c3)c2)cc1

Procedure:
A stirred solution of 3-bromo-5-(p-methoxyphenylamino)pyridine (0.5 g, 1.8 mmol), 3-aminophenyl boronic acid (0.28 g, 1.8 mmol) and Na2CO3 (0.56 g, 5.3 mmol) in dimethoxyethane (10 ml) and water (3.5 ml) is deoxygenated using argon before adding Pd(PPh3)4 (0.06 g) and heating the mixture at reflux for 16 hours. The mixture is diluted with ethyl acetate, washed with brine, dried over Na2SO4 and concentrated. The residue is chromatographed on silicagel to afford the product; 1H NMR (400 MHz, d6-DMSO): δ 8.16 (m, 2H), 8.10 (s, 1H), 7.34 (m, 1H), 7.10 (m, 3H), 6.91 (d, J=8.84 Hz, 2H), 6.75 (s, 1H), 6.71 (m, 1H), 6.57 (m, 1H), 5.21 (br s, 2H), 3.73 (s, 3H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].C(=O)(O[CH2:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)OC.O>C1COCC1.C(Cl)(Cl)Cl>[C:19]1([CH:18]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[CH:17]=[CH2:16])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CC(=O)OC
Reactant: COC(=O)OCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: C=CC(c1ccccc1)C(C(=O)OC)C(=O)OC
Temperature: 60 °C

Procedure:
Cycloheptyl ligand IV (10.2 mg, 0.030 mmol) and Mo(CO)3(EtCN)3 (6.9 mg, 0.020 mmol) were dissolved in 1.0 ml of THF at rt. The reaction mixture was heated at 60° C. for 1 h. After cooling to rt, 1.0 ml of THF solution of sodium dimethylmalonate enolate, prepared from dimethyl malonate (58.0 mg, 0.44 mmol) and sodium hydride (10.2 mg, 0.40 mmol) in tetrahydrofuran, and methyl 3-phenyl-2-propenyl carbonate were added successively. The reaction mixture was heated at 65° C. for 8 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, and the solvent was removed under reduced pressure. The ratio of 1,1-dimethoxycarbonyl-2-phenyl-3-butene and linear compound was determined by 1H NMR (400 MHz) to be 34.2/1. The residue was chromatographed on silica (1/8 ethyl acetate/petroleum ether, Rf=0.3) to yield the mixture of branched and linear compound (36.7 mg, 74%). [α]D−29.7° (c 1.27, CHCl3); 99% ee.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]([CH3:14])[CH3:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:15]1([C:20]2[CH:39]=[CH:38][C:23]([CH2:24][NH:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]([CH3:14])[CH3:13])=[C:6]([CH:10]=1)[C:7]([N:25]([CH2:24][C:23]1[CH:22]=[CH:21][C:20]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:39][CH:38]=1)[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=1)=[O:9]
Reactant: FC(F)(F)c1cccc(CCNCc2ccc(C3CCCC3)cc2)c1
Reactant: CC(C)Nc1ccc(Cl)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)Nc1ccc(Cl)cc1C(=O)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(C2CCCC2)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of 50 mg of 5-chloro-2-isopropylamino-benzoic acid (0.23 mmol) and 81 mg (0.23 mmol) of (4-cyclopentyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine in 4 ml of DMF were added 75 mg of TBTU (0.23 mmol) and 0.2 ml (1.17 mmol) of N,N-di-isopropylethyl amine. After stirring the reaction mixture over night at RT it was diluted with 50 ml water and extracted with ethyl acetate. The combined organic phases were washed with 10%-aqueous KHCO3 solution, 0.1M HCl solution and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The remaining oil was purified by column chromatography (silica gel; heptane 100% to heptane/EtOAc 4:1) to give 90 mg (71%) of a colorless oil. MS (ISP) 543.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]#[N:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:27]=1.[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O.O.[Zn+2].[Br-].[Br-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12]([N:11]=3)=[CH:13][CH:14]=[C:15]([C:25]3[NH:30][N:29]=[N:28][N:26]=3)[CH:16]=4)=[CH:7][C:6]=2[CH:27]=1
Reactant: CC(C)N(C)c1nc2cc(C#N)ccc2nc1-c1cc2cc(F)ccc2o1
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)N(C)c1nc2cc(-c3nnn[nH]3)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 130 °C
Reaction time: 48 h
Yield: 36.9 %

Procedure:
To a solution of 2-(5-fluorobenzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carbonitrile (150 mg, 0.42 mmol) in DMSO (30 ml) and water (2 ml) was added ZnBr2 (46.9 mg, 0.21 mmol) and NaN3 (81.3 mg, 1.25 mmol), and the resulting mixture was stirred for 48 h at 130° C. The reaction mixture was quenched with water (100 ml) and adjusted to pH 3 with HCl (2N), extracted with ethyl acetate (4×60 ml), and the organic layers combined and concentrated in vacuo to give the residue, which was purified by silica gel column chromatography (12% methanol in dichloromethane) to afford 3-(5-fluorobenzofuran-2-yl)-N-methyl-N-(propan-2-yl)-7-(1H-tetrazol-5-yl)quinoxalin-2-amine as a yellow solid (62.6 mg, 37%).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]=[CH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].Cl.C(O)C>O>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7](/[CH:10]=[CH:11]/[C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C=Cc2ccc(C#N)cc2)CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCC[C@H]1CC[C@H](/C=C/c2ccc(C#N)cc2)CC1

Procedure:
This nitrile in an amount of 11.7 g (0.05 ml) was added to a mixture of 13.9 g (0.07 ml) of dihydrated sodium benzenesufinate, 12 ml of 6N-HCl, and 70 ml of ethanol, and reacted under reflux for 4 hours. After finishing of the reaction, 50 ml of water was added to the reaction product and then extracted with 150 ml of toluene. The organic layer thus obtained was washed with saturated aqueous sodium carbonate solution thrice and with water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: toluene) to obtain 12.0 g of a crude (E)-4-(2-(trans-4-propylcyclohexyl)vinyl)benzonitrile.
Reaction SMILES: C1([C@H](OC(=O)[NH:11][C@@H:12]2[C@@H:21]([O:22][CH3:23])[CH2:20][C:19]3[C:14](=[CH:15][C:16]([OH:24])=[CH:17][CH:18]=3)[C:13]2([CH2:27][CH3:28])[CH2:25][CH3:26])C)C=CC=CC=1.Cl.O1CCOCC1>>[NH2:11][C@H:12]1[C:13]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:14]2[CH:15]=[C:16]([OH:24])[CH:17]=[CH:18][C:19]=2[CH2:20][C@@H:21]1[O:22][CH3:23]
Reactant: CCC1(CC)c2cc(O)ccc2C[C@H](OC)[C@H]1NC(=O)O[C@H](C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCC1(CC)c2cc(O)ccc2C[C@H](OC)[C@H]1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 115.8 %

Procedure:
((2S,3S)-1,1-Diethyl-7-hydroxy-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid (R)-1-phenyl-ethyl ester (635 mg, 1.60 mmol) was treated with 4.0 N HCl in dioxane (6.0 mL, 24 mmol) and stirred at RT. After 3 days, the solvent was removed at reduced pressure and the residual solid was triturated with 50% dichloromethane in heptane (4 mL). The solid was collected on a Buchner funnel and dried under vacuum to give the hydrochloride salt of the title compound (462 mg). (m/z): [M+H]+ calcd for C15H23NO2 250.36; found 250.2. 1H NMR (d6-DMSO, 400 mHz) δ (ppm) 9.23 (s, 1H), 8.02 (br s, 3H), 6.92 (d, J=8.2 Hz, 1H), 6.61 (m, 2H), 3.77 (m, 1H), 3.41 (s, 3H), 3.30 (m, 1H), 3.17 (m, 1H), 2.44 (dd, J=15.9 Hz, 9.8 Hz, 1H), 1.85 (m, 2H), 1.62-1.52 (m, 2H), 0.66 (t, J=7.2 Hz, 3H), 0.55 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.[OH-].[NH4+]>C(O)(=O)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[C:6]1[CH2:5][CH2:4][NH:3][CH2:8][CH:7]=1
Reactant: O=C1CCNCC1
Reactant: COc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
44 g of the hydrochloride of 4-piperidone monohydrate were added at 100° C. to a solution of 12.6 g of 5-methoxy-1H-indole in 240 ml of acetic acid and the mixture was held at 100° C. for 30 minutes and was then cooled. The mixture was poured into ice water containing 400 ml of concentrated ammonium hydroxide and was extracted with ethyl acetate. The organic phase was washed with aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness to obtain 20 g of raw product. The latter was chromatographed over silica gel and was eluted with a 7-2-1 chloroform-methanol-triethylamine mixture to obtain 5.26 g of 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole in the form of a resin.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)([OH:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:16]2[CH:17]=[CH:18][C:13]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)=[C:3]([CH3:9])[CH:4]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(N)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(N)ccc1-c1ccc(C(=O)O)cc1
Yield: 105.6 %

Procedure:
4-Bromo-3-methylaniline (7.40 g, 40 mmol) and 4-carboxybenzeneboronic acid (7.90 g, 48 mmol) were stirred in 1,2-dimethoxyethane (DME) (150 ml). Anhydrous sodium carbonate (19.0 g, 179 mmol) was dissolved in water (150 ml) and added to the above. The mixture was then purged with a stream of Ar for 15 min. Tetrakis (triphenylphosphine)palladium (O) (0.25 g, 0.2 mmol) was added, and the mixture was stirred at reflux for 20 h under Ar. DME was removed by evaporation under reduced pressure, and the clear residue was acidified (5M HCl) to yield a thick grey suspension. The solid was filtered off, washed with water and dried in vacuo at 60° C., to give the title compound (9.60 g, quantitative).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].[C:13]([C:17]1[CH:18]=[C:19](C=C[CH:23]=1)N)([CH3:16])([CH3:15])[CH3:14].NC1C=[CH:41][C:28]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH2:37][CH2:38][CH2:39][OH:40])[N:31]=2)=[CH:27][CH:26]=1>ClCCl>[C:13]([C:17]1[CH:23]=[C:12]([NH:8][C:1]([NH:3][C:7]2[CH:6]=[CH:41][C:28]([O:29][C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH2:37][CH2:38][CH2:39][OH:40])[N:31]=3)=[CH:27][CH:26]=2)=[O:2])[CH:11]=[CH:19][CH:18]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)c1cccc(N)c1
Solvent: ClCCl
Product: CC(C)(C)c1cccc(NC(=O)Nc2ccc(Oc3ccnc(NCCCO)n3)cc2)c1
Reaction time: 12 h

Procedure:
172 mg (1.06 mmol) 1,1′-Carbonyl-diimidazol (CDI) were given to a solution of 144 mg (0.964 mmol) 3-t-butylaniline in 4.0 ml dichloromethane and stirred for 12 h. A solution of 263 mg (0.964 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 6.0 ml dichloromethane was added within 30 min. and the mixture stirred for 12 h at r.t. The reaction mixture was filtered, the filtrate evaporated and the residue purified by chromatography on silica gel (dichloromethane/methanol 95:5). The obtained material was washed with ether and the precipitate was isolated by filtration and dried. Yield: 170 mg (41%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:28]([Cu])#[N:29].C(Cl)Cl>CN(C=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccc(C)cc3)ccc2c1O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc(C)cc3)ccc2c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Bromo-4-hydroxy-7-p-tolyloxy-isoquinoline-3-carboxylic acid butyl ester (130 mg, 0.30 mmol) and CuCN (54 mg, 0.61 mmol) were suspended in DMF (1.2 mL). The resulting mixture was heated to reflux for 40 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-30% EtOAc/hexanes) to give the title compound in 65 mg. MS: (−) m/z 375.29 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:8]([OH:10])=O)[NH:6][CH:7]=1)#[N:2].ClC(N(C)C)=C(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([C:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=3)[CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CC#N>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:8]([C:5]3[NH:6][CH:7]=[C:3]([C:1]#[N:2])[CH:4]=3)=[O:10])=[C:34]([C:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=3)[CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: N#Cc1c[nH]c(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCCCC3)c2)CC1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3cc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 12.3 %

Procedure:
A suspension of 101 mg (0.741 mmol) 4-cyano-1H-pyrrole-2-carboxylic acid (Canadian J. Chem. 59: 2673 (1981)) in 20 mL CH3CN was treated with 116 μL (0.741 mmol) (1-chloro-2-methyl-propenyl)-dimethylamine at RT for 20 min. The mixture was added to a solution of 220 mg (0.617 mmol) of 4-(4-amino-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step) in 10 mL CH3CN, stirred at RT for 20 h and the solvents evaporated in vacuo. Silica gel chromatography of the residue on a Varian MegaBond Elut 25-gm column with 10-25% EtOAc-hexane afforded 36.0 mg (12%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C24H27N4O3, 419.2 (M−C4H9+2H), found 419.1.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].C(N(C(C)C)CC)(C)C.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>C(Cl)Cl>[CH2:2]([NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:17]=1[O:16][CH3:15])[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCBr
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCNCc1ccc(OC)cc1OC
Yield: 40 %

Procedure:
0.5 ml of 1-Bromo-3-butene (4.93 mmol) and 0.94 ml of diisopropyl ethylamine (5.40 mmol) were added to the reaction solution containing 0.74 ml of 2,4-dimethoxybenzylamine (a) (4.93 mmol) dissolved in methylene chloride with stirring and the mixture was stirred at room temperature for overnight. The reaction mixture was washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with EtOAc solvent as an eluant to give 436 mg of the pure title compound (b) (yield: 40%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:22])=[C:16]([S:19][CH2:20][CH3:21])[N:17]=2)[C:12](=[O:23])[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:10]1.ClC1C=CC=C(C(OO)=[O:37])C=1.[OH2:40].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:22])=[C:16]([S:19]([CH2:20][CH3:21])(=[O:37])=[O:40])[N:17]=2)[C:12](=[O:23])[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:10]1
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(SCC)c(F)cc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(S(=O)(=O)CC)c(F)cc2c1=O
Reaction time: 4 h
Yield: 87.2 %

Procedure:
In 15 ml of methylene chloride was dissolved 1.00 g of ethyl 1-(2,4-difluorophenyl)-7-ethylthio-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, and 1.06 g of m-chloroperbenzoic acid (purity: 80%) was added thereto, after which the resulting mixture was subjected to reaction with ice-cooling for 30 minutes, and then at room temperature for 4 hours. The precipitates were removed by filtration, and to the filtrate thus obtained was added 10 ml of water, after which the pH thereof was adjusted to 7.5 with saturated aqueous sodium hydrogencarbonate solution. The organic layer was thereafter separated, washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained was added 10 ml of diethyl ether, after which the crystals thus deposited were collected by filtration to obtain 940 mg (yield 87.2%) of ethyl 1-(2,4difluorophenyl)-7-ethylsulfonyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 215°-217° C. The physical properties of this compound were identical with those of the compound obtained in Example 44.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([I:11])=[CH:4][N:3]=1.Cl.[NH2:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C>C(O)C>[CH3:18][O:17][C:15](=[O:16])[C:14]([NH:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([I:11])=[CH:4][N:3]=1)([CH3:20])[CH3:19]
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)C(C)(C)Nc1ncc(I)cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 78 %

Procedure:
2-Chloro-5-iodo-3-nitro-pyridine (1.61 g) was dissolved in ethanol. Methyl α-aminoisobutyrate HCl was added (2.4 eq) followed by triethylamine (2.4 eq). The reaction mixture was heated to 150° C. in a microwave oven for 30 minutes. The reaction mixture was concentrated to dryness and triturated with H2O, Silica gel chromatography of the resulting brown solid afforded the title compound as a bright yellow crystalline solid (78% yield based on recovered starting material). M.p. 121-122° C., 1H-NMR (CDCl3, 400 MHz) δ 1.56 (s, 3H), 1.66 (s, 3H), 3.67 (s, 3H), 8.53 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.68 (d, J=2.3 Hz, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:16](=[O:29])[C:15]=1[Br:30].C(N(CC)CC)C.C[Si]([N:47]=[C:48]=[O:49])(C)C>C1COCC1>[Br:30][C:15]1[C:16](=[O:29])[N:17]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:18]([CH3:20])=[CH:19][C:14]=1[O:13][CH2:12][C:11]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:10]=1[CH2:9][NH:8][C:48]([NH2:47])=[O:49]
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1cc(OCc2ccc(F)cc2CN)c(Br)c(=O)n1-c1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2CNC(N)=O)c(Br)c(=O)n1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one trifluoroacetate (0.13 g, 0.00023 mol) in THF (3.0 mL), was added triethyl amine (0.07 mL, 0.0005 mol) followed by the addition of trimethylsilylisocyanate (0.066 mL). The reaction mixture was stirred at room temperature for 1 h, and the desired product was isolated by reverse-phase HPLC purification using 10-90% CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions (m/z=496 M+H) were combined and freeze-dried, and the residue was partitioned between 5% sod. bicarbonate (20 mL) and dichloromethane (20 mL). The organic phase was washed with water, dried (Na2SO4) and concentrated to dryness under reduced pressure, to afford the title compound as a white amorphous powder (0.065 g): 1H NMR (DMSO-d6/400 MHz) δ 7.62 (m, 1H), 7.52 (m, 1H), 7.35 (m, 2H), 7.09 (m, 2H), 6.77 (s, 1H), 6.51 (t, 1H), 5.61 (s, 2H), 5.38 (s. 2H), 4.28 (d, 2H, J=6.0 Hz), and 2.02 (s, 3H); 19F NMR (DMSO-d6/400 MHz) δ−114.044 (m), and −120.31 (m); ES-HRMS m/z 496.0460 (M+H C21H18N3O3F3Br requires 496.0478).