Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:20]([OH:21])[CH:19]([CH3:22])[CH:18]=[C:17]([CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14](=[O:26])[O:13][CH:12]([CH:27]([CH:29]([OH:48])[CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44](O)=[O:45])/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH3:28])[CH:11]([O:49][CH3:50])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:51])[CH2:6][CH:5]([CH3:52])[CH:4]1[OH:53])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[CH3:64][N:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1.O>ClCCl>[OH:48][CH:29]([CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44]([N:68]1[CH2:69][CH2:70][N:65]([CH3:64])[CH2:66][CH2:67]1)=[O:45])/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH:27]([CH:12]1[O:13][C:14](=[O:26])[C:15]([O:24][CH3:25])=[CH:16][C:17]([CH3:23])=[CH:18][CH:19]([CH3:22])[CH:20]([OH:21])[CH:3]([CH2:1][CH3:2])[CH:4]([OH:53])[CH:5]([CH3:52])[CH2:6][C:7]([CH3:51])=[CH:8][CH:9]=[CH:10][CH:11]1[O:49][CH3:50])[CH3:28]
Reactant: CN1CCNCC1
Reactant: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)N1CCN(C)CC1)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)N1CCN(C)CC1)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Reaction time: 0.33 h

Procedure:
To a solution of compound of example 10 (10 mg) in dichloromethane (2 mL) dicyclohexylcarbodiimide (3 mg), and HOBt (2 mg) were added. After 20 min, N-methyl-piperazine (1.5 mg) was added. The reaction mixture was stirred for 18 h under nitrogen atmosphere. Cold water was added to the reaction mixture, the organic layer was separated. The reaction mixture was extracted with dichloromethane (3×5 mL). The combined organic layer was washed with water (2×5 mL). The organic layer was dried over sodium sulphate, and was concentrated. The crude product was purified by preparative HPLC [Eurospere-100, C18 column (250 mm×8 mm), mobile phase: acetonitrile-water (1:1 isocratic)] to obtain the title compound.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH2:6]([N:13]1[CH2:22][CH2:21][C:20]2[C:19](=O)[NH:18][CH:17]=[CH:16][C:15]=2[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>C1(OC)C=CC=CC=1.C(#N)C.ClCCl>[CH2:6]([N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[N:18][C:19]=2[Br:3])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1[nH]ccc2c1CCN(Cc1ccccc1)C2
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: CC#N
Solvent: ClCCl
Product: Brc1nccc2c1CCN(Cc1ccccc1)C2

Procedure:
Phosphorous oxybromide (7.5 g, 26 mmol) is added portion wise to a suspension of 6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one (1.6 g, 6.7 mmol) in anisole (20 mL) and acetonitrile (10 mL). The reaction mixture is stirred under reflux for 4 hours. The cooled mixture is poured onto ice and diluted with dichloromethane. The mixture is slowly neutralized using saturated sodium bicarbonate solution. The aqueous phase is extracted with dichloromethane three times. The organic phase are combined and washed with brine, dried over Na2SO4 and taken to dryness by rotary evaporation. The crude product as purified by column chromatography on silica gel to afford 2-benzyl-5-bromo-1,2,3,4-tetrahydro-2,6-naphthyridine as a white solid. MS m/z 303.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].C(O)=O.C(N[C@H](C(O)=O)CS)(=O)C.Cl>O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[OH:12]
Reactant: O=C1CCc2c(Br)ccc(F)c21
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=CO
Product: O[C@H]1CCc2c(Br)ccc(F)c21
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
20.0 g (87.3 mmol) 4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one, 142 ml toluene and 13.9 g (138 mmol) TEA are added into a vessel. The mixture is degassed and heated to 40° C. Then, 272 mg (0.44 mmol) chloro{[(1S,2S)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}-(mesitylene)ruthenium(II) is added before a mixture of 7.03 g (153 mmol) formic acid (98%) and 3.00 mL toluene is added over a time period of 60 min. The funnel is rinsed with 7.00 ml toluene. Stirring is continued at 40° C. for approx. 90 min until full conversion (HPLC). 1.43 g (8.73 mmol) N-acetyl-L-cystein is added and stirring is continued for 30 min. A mixture of 15.8 g (160 mmol) conc. HCl in 24 ml water is added and the aqueous phase is separated. The organic phase is washed with 35.0 ml water and 140 ml solvent is distilled off. 90 ml IPA is added and 70 ml solvent is distilled off. To the residue 50 ml water is added and the mixture is cooled to 35° C. Then, seeds are added followed by 50 ml water. The suspension is cooled to 22° C. and stirred for 2 h. The product is filtered off, washed with water (2×30 ml) and dried. Yield: 18.6 g; LC (method 1): tR=0.91 min; Mass spectrum (ESI+): m/z=213 [M+H—H2O]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:11][OH:12])[CH:7]=[C:8]([F:10])[CH:9]=1.[CH3:13]I>CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([CH2:11][O:12][CH3:13])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: OCc1cc(F)cc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COCc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
NaH (60% dispersion in mineral oil, 245 mg, 6.12 mmol) was added to a solution of (3-bromo-5-fluorophenyl)methanol (1.195 g, 5.83 mmol) in 2-Me THF (20 mL). After gas evolution had ceased, MeI (0.455 mL, 7.29 mmol) was added and the resulting mixture was stirred at r.t. for 16 h. Another portion of NaH (50 mg, 2.1 mmol) and MeI (0.10 mL, 1.6 mmol) were added and the mixture was heated to 60° C. for 2 h. The cooled mixture was diluted with EtOAc, washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (gradient of 0-15% EtOAc in heptane) to give 0.810 g (63% yield) of the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.30 (s, 3 H), 4.38-4.46 (m, 2 H), 7.18 (m, 1 H), 7.37 (s, 1 H), 7.44-7.50 (m, 1 H); MS (EI) m/z 218 M+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].CCN(C(C)C)C(C)C.[SH:24][CH2:25][CH2:26][CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][CH2:25][S:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: OCCCS
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc2ccc(I)cc2c1SCCCO

Procedure:
Similar procedure as described in example 39a was used, starting from 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c), DIEA and 3-mercapto-1-propanol to give 4-(3-hydroxy-propylsulfanyl)-6-iodo-quinoline-3-carbonitrile. LC-MS m/e 371 (MH+).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][C:7]=1[N+:21]([O-])=O)[CH2:2][CH2:3][CH3:4].[H][H]>[C].[Pd].O1CCCC1>[CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][C:7]=1[NH2:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCNc1ccc(-c2nc3ccccc3o2)cc1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.9 %

Procedure:
To a tetrahydrofuran solution (5 mL) of 2-(4-n-butylamino-3-nitrophenyl)benzoxazole (see Working Example 74-1) (353 mg, 1.13 mmol) was added 10% palladium-carbon (50 mg), a hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 15 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (305 mg, 96% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][C:22]1[CH:23]=[N:24][N:25]([CH:28]([CH3:30])[CH3:29])[C:26]=1[NH2:27].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])=[CH:7][C:2]([NH:27][C:26]2[N:25]([CH:28]([CH3:30])[CH3:29])[N:24]=[CH:23][C:22]=2[CH3:21])=[N:3][CH:4]=1
Reactant: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Reactant: Cc1cnn(C(C)C)c1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CONC(=O)c1ccccc1Nc1cc(Nc2c(C)cnn2C(C)C)ncc1Cl
Reaction time: 0.67 h

Procedure:
A microwave tube was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]-N-(methyloxy)benzamide (100 mg, 0.32 mmol), 4-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (93.6 mg, 0.67 mmol), cesium carbonate (312.8 mg, 0.96 mmol) and DMF (5 mL). The reaction mixture was degassed under nitrogen for 10 min and palladium (II) acetate (3.6 mg, 0.016 mmol) and BINAP (19.9 mg, 0.032 mmol) were added. The reaction mixture was heated in an oil bath for 6 hours and then in a microwave at 150° C. for 40 min. The solvent was evaporated and the residue dissolved in MeOH. It was filtered thru celite and thru an Acrodisc to be purified on preparative Agilent HPLC (5 to 95% water:acetonitrile with 0.1% formic acid). Fractions were combined and evaporated. The brown oil residue was diluted in DMF and water was added. A precipitate crashed out. It was filtered and dried under vacuum at 40° C. for 6 hrs. LC-MS [M+H]+=415.1. 1H NMR (400 MHz, DMSO-d6) ppm 11.93 (s, 1 H) 9.48 (br. s., 1 H) 8.23 (s, 1 H) 7.93 (s, 1 H) 7.58 (d, J=7.83 Hz, 1 H) 7.50 (d, J=3.79 Hz, 2 H) 7.24 (s, 1 H) 7.12 (dt, J=7.83, 4.17 Hz, 1 H) 6.40 (br. s., 1 H) 4.33 (dt, J=13.14, 6.57 Hz, 1 H) 3.71 (s, 3 H) 1.78 (s, 3 H) 1.26 (d, J=6.57 Hz, 6 H).
Reaction SMILES: [F:1][CH:2]([CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]1=[O:18])[CH:3]=O.[NH2:19][CH:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=3[CH:35]=2)[C:22](=[O:36])[CH2:21]1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[F:1][CH:2]([CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]1=[O:18])[CH2:3][NH:19][CH:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=3[CH:35]=2)[C:22](=[O:36])[CH2:21]1
Reactant: COc1ccc2ncc(=O)n(CC(F)C=O)c2c1
Reactant: NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CC(F)CNC3CC(=O)N(c4ccc5c(c4)NC(=O)CO5)C3)c2c1
Reaction time: 14 h
Yield: 17.5 %

Procedure:
A crude product of 2-Fluoro-3-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propanal (196 mg) and 6-(4-amino-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-one (Reference Example 6; 147 mg, 0.595 mmol) were dissolved in a mixed solution of dichloromethane (20 ml) and N,N-dimethylformamide (2 ml). Acetic acid (0.068 ml, 1.190 mmol) and anhydrous sodium sulfate (300 mg) were added to the solution at room temperature and the mixture was stirred for 14 hours. Sodium triacetoxyborohydride (252 mg, 1.190 mmol) was added to the reaction solution, the mixture was stirred for 4 hours and then the solvent was removed under reduced pressure. A lower layer solvent of chloroform/methanol/water (7:3:1) was added to the residue and the resultant was alkalized by adding saturated sodium bicarbonate water under cooling on ice. The mixture was extracted with a lower layer solvent of chloroform/methanol/water (7:3:1), the extract was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) and preparative thin layer chromatography (silica gel, chloroform/methanol=20:1) to yield 50 mg (18%) of the title compound in the form of a white solid.
Reaction SMILES: N1C=CC=CC=1C(=C)C(N)=O.Cl[C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>>[C:15]([OH:17])(=[O:16])[C:14]1[CH:18]=[CH:19][CH:20]=[N:21][CH:13]=1
Reactant: O=C(O)c1cccnc1Cl
Agent: C=C(C(N)=O)c1ccccn1
Product: O=C(O)c1cccnc1

Procedure:
The Scheme 14 shows a proposed process for synthesizing pyridinyl acrylamide (64). 2-Chloro-nicotinic acid compound (23) is reacted with various amines to yield nicotinic acid compound (60) with 2-alkylamino, 2-dialkylamino, 2-arylamino, or 2-N-alkyl-N-aryl-amino group, which undergoes similar reactions to scheme 5 to give pyridinyl acrylic acid (63). Pyridinyl acrylamide (64) is then obtained by the reaction of pyridinyl acrylic acid (63) with the amine compound (1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([C:24]1[CH:29]=[C:28]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:27]([OH:36])=[C:26]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:25]=1)=[O:23].Cl>C(OCC)(=O)C>[CH:30]1([C:28]2[CH:29]=[C:24]([C:22](=[O:23])[CH2:21][O:1][C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=3[O:10][CH3:11])[CH:25]=[C:26]([CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)[C:27]=2[OH:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: O=C(CBr)c1cc(C2CCCCC2)c(O)c(C2CCCCC2)c1
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Product: COc1cc(C=O)ccc1OCC(=O)c1cc(C2CCCCC2)c(O)c(C2CCCCC2)c1
Reaction time: 0.5 h
Yield: 30 %

Procedure:
A mixture of 1.52 g (10 mmol) of 4-hydroxy-3-methoxy-benzaldehyde, 0.3 g (2.0 mmol) of sodium iodide and 3.05 g (22 mmol) of potassium carbonate in 80 ml of ethyl acetate is stirred for 30 minutes. Then 3.8 g (10 mmol) of 2-bromo-1-(4-hydroxy-3,5-di-cyclohexylphenyl)-ethanone is added and stirring at room temperature is continued for 16 hours. Then the mixture is acidified with 2N HCl and extracted with ethyl acetate. The combined extracts are washed with water, dried and evaporated. Crystallization of the crude product from dichloro-methane/di-isopropylether yields 1.35 g of compound 103, m.p. 163-164° C.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C-:10]#[N:11].[K+].CS(C)=O>O>[C:10](#[N:11])[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [C-]#N
Reactant: CCCCCC#CCBr
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCC#CCC#N

Procedure:
A mixture of 5 g. of 1-bromo-2-octyne, 7 g. of potassium cyanide and 35 ml. of dimethylsulfoxide is stirred and heated under nitrogen for about 2.5 hrs. at reflux temperature. The mixture is then poured into water and extracted with ether. The ether extract is washed with water, than with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated under reduced pressure leaving a residue comprising 3-nonynenitrile. The thus obtained residue is mixed with 45 ml. of 25% hydrogen chloride in methanol containing 0.5 ml. of water while cooling in an ice bath. The ice is allowed to melt and the mixture is stirred for about 18 hrs., then is poured into water and extracted with ether. The ether extract is washed with water, aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over sulfate, and evaporated under reduced pressure leaving a residue comprising methyl 3-nonynoate. A mixture of the thus obtained methyl 3-nonynoate, 500 mg. of 5% palladium-barium sulfate catalyst and 40 ml. of pyridine is shaken under hydrogen for about 2 hrs., until the uptake of hydrogen practically ceases. The mixture is then filtered, diluted with water, and extracted with ether. The ether extract is washed with water, dilute hydrochloric acid, and aqueous sodium bicarbonate, then is dried over sodium sulfate and evaporated to leave a residue comprising methyl 3-nonenoate.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:16][C:17](=[O:31])[CH:18]([NH2:30])[C:19]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:32][C@H:33]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:34](O)=[O:35].CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>ClCCl>[CH2:22]([NH:21][C:19](=[O:20])[CH:18]([NH:30][C:34](=[O:35])[C@H:33]([Br:32])[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:17]([NH:16][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)[C@H](Br)Cc1ccccc1
Reactant: NC(C(=O)NCCc1ccccc1)C(=O)NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCc1ccccc1)C(NC(=O)[C@H](Br)Cc1ccccc1)C(=O)NCCc1ccccc1
Yield: 60 %

Procedure:
Prepare by the method of Example 1.3 using N,N′-diphenethyl-2-aminomalonamide trifluoroacetic acid salt (0.61 g, 0.600 mmol), (R)-2-bromo-3-phenylpropionic acid (0.137 g, 0.600 mmol), N-methylmorpholine (0.20 mL, 1.8 mmol), 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloric acid salt (0.14 g, 0.72 mmol), and 1-hydroxybenztriazole hydrate (0.097 g, 0.72 mmol) in dichloromethane (10 mL). Purify by chromatography on silica gel eluting with 1/1 ethyl acetate/hexane to give the title compound (60%).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH:4]=[CH2:5].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[O:30]1[CH2:5][CH:4]1[CH2:3][CH2:2][CH2:1][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCOc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2ccc(OCCCC3CO3)cc2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To 250 ml of methylene chloride is added 28.3 g of 4-(4-penteneoxy)-4'-nitrobiphenyl. The solution is cooled to 0° C., and 18 g of meta-chloroperbenzoic acid is added slowly. The mixture is stirred at 0° C. for 24 hours, and allowed to warm to room temperature.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[NH:8][C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)#[N:2].C(Cl)Cl.C(N(CC)CC)C.Cl.[NH2:31][OH:32]>C(O)C.C(=O)(O)[O-].[Na+]>[OH:32][N:31]=[C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[NH:8][C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[NH2:2]
Reactant: COc1ccc(CC(=O)Nc2sccc2C#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(CC(=O)Nc2sccc2C(N)=NO)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-(3-cyanothiophen-2-yl)-2-(4-methoxyphenyl)acetamide (234 mg, 0.859 mmol) in a mixture of ethanol (5 mL), methylene chloride (0.5 mL) and triethylamine (202 μL, 1.46 mmol) was added hydroxylamine hydrochloride (90 mg, 1.29 mmol). The resulting solution was stirred at room temperature for 18 h and was subsequently diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases were combined, dried (Na2SO4), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/ethyl acetate, 7/3 to 2/8) to give N-(3-(N′-hydroxycarbamimidoyl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide. Retention time (min)=1.161, method [1], MS(ESI) 306.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[C:17]([O:25][CH3:26])[CH:16]=2)[O:4][CH2:3]1.[H-].[Na+].[CH3:31]I>CN(C)C=O>[CH3:1][C:2]1([CH3:28])[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]([CH3:31])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[C:17]([O:25][CH3:26])[CH:16]=2)[O:4][CH2:3]1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccccc2C2=NC(C)(C)CO2)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)N(C)c2ccccc2C2=NC(C)(C)CO2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[2-[4,4-dimethyl(2,5-oxazolinyl)]-phenyl]-3-methoxy-4-methoxycarbonylbenzamide (1.45 g) in N,N-dimethylformamide (18 ml) was added portionwise sodium hydride (167 mg) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. Methyl iodide (0.283 ml) was added to the mixture and the solution was stirred at 0° C. for 1 hour. The reaction was quenched with water and then the aqueous solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to give N-[2-[4,4-dimethyl-(2,5-oxazolinyl)]phenyl]-N-methyl-3-methoxy-4-methoxycarbonylbenzamide (1.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12].[CH3:15][C:16]1[NH:20][CH2:19][CH2:18][N:17]=1.CS(O)(=O)=O>C(O)C>[CH3:15][C:16]1[N:20]([CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH2:19][CH2:18][N:17]=1
Reactant: C=C(C)C(=O)Nc1c(C)cccc1C
Reactant: CC1=NCCN1
Agent: CS(=O)(=O)O
Solvent: CCO
Product: CC1=NCCN1CC(C)C(=O)Nc1c(C)cccc1C

Procedure:
Combine 30.0 gm. (0.16 M) N-(2,6-dimethylphenyl)-2-methylpropenamide [methacroyl-2',6'-xylidide], 13.3 gm. (0.16 M) lysidine, 3 gm. (0.03 M) methanesulphonic acid and 150 ml. of ethanol in a pressure bottle and heat at about 150° C. for about 48 hours. Remove the solvent in vacuo, add 200 ml. of water and adjust the pH to 7.8 with conc. HCl. Extract the aqueous phase with 4×100 ml. of methylene chloride and set these aside. Treat the aqueous phase with 20% NaOH to obtain a pH of about 13. Extract the aqueous phase with 4×100 ml. of methylene chloride. Wash the combined methylene chloride extracts with 3×10 ml. water and dry organic layer over sodium sulfate. Evaporate off the solvents to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10]CC)=O.[NH2:13][C:14]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:15]=1B(O)O.C([O-])(=O)C.[Na+]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN(C)C=O>[O:10]=[C:8]1[C:7]2[C:2](=[CH:3][N:4]=[CH:5][CH:6]=2)[C:15]2[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:14]=2[NH:13]1
Reactant: CCOC(=O)c1ccncc1Br
Reactant: COC(=O)c1ccc(B(O)O)c(N)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ccncc12
Temperature: 125 °C
Reaction time: 12 h
Yield: 55.7 %

Procedure:
Ethyl 3-bromo-4-pyridine carboxylate 1.15 g, 5.0 mmol), 2-amino-4-methoxycarbonyl-phenylboronic acid (1.04 g, 4.5 mmol), sodium acetate (1.64 g, 20 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride (complexed with dichloromethane) (182 mg, 0.25 mmol) and dimethylformamide (7.5 mL) were combined in a flask. The flask was evacuated and filled with nitrogen twice and heated to 125° C. with stirring for 12 hours or until LCMS indicated the absence of any starting material. The mixture was cooled to room temperature and water (100 mL) was added to form a brown precipitate. The precipitate was filtered to yield 637 mg of methyl 5-oxo-5,6-dihydrobenzo[c][2,6]naphthyridine-8-carboxylate. LCMS (ESI) 255.4 (M+1)+.