Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15]([C:17]1[C:29](=[O:30])[N:25]2[CH2:26][CH2:27][O:28][C:23]3[C:24]2=[C:19]([CH:20]=[C:21]([O:31][CH3:32])[CH:22]=3)[C:18]=1[OH:33])=[O:16])=[O:5])C.[OH-].[Na+].C(O)C>O1CCCC1>[C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15]([C:17]1[C:29](=[O:30])[N:25]2[CH2:26][CH2:27][O:28][C:23]3[C:24]2=[C:19]([CH:20]=[C:21]([O:31][CH3:32])[CH:22]=3)[C:18]=1[OH:33])=[O:16])([OH:5])=[O:3]
Reactant: CCOC(=O)C1Cc2ccccc2N1C(=O)c1c(O)c2cc(OC)cc3c2n(c1=O)CCO3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc2c3c(c1)c(O)c(C(=O)N1c4ccccc4CC1C(=O)O)c(=O)n3CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
A mixture of 2,3-dihydro-6-(2-ethoxycarbonyl-1-indolinylcarbonyl)-7-hydroxy-9-methoxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (2.8 g), 1N-sodium hydroxide (20 ml), ethanol (20 ml) and tetrahydrofuran (20 ml) was stirred for 2 hours at room temperature. The solvent was evaporated. The residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid to give precipitates, which were collected and washed with ethanol to afford crystals of 2,3-dihydro-6-(2-carboxy-1-indolinylcarbonyl)-7-hydroxy-9-methoxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (1.6 g).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][CH2:13][CH2:12][C:11]2=O>O.C(O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][CH2:13][CH2:12][C:11]2=[N:2][OH:3]
Reactant: COc1ccc2c(c1)C(=O)CCO2
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)C(=NO)CCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 140 g (2.02 mole) of hydroxylamine hydrochloride in 630 ml of water, contained in a 3-l Erlenmeyer flask, was treated with 560 ml of 10% NaOH, and a solution of 250 g (1.40 mole) of 6-methoxy-4-chromanone in 560 ml of ethanol, all with rapid stirring. The reaction mixture was heated to boiling over 15 min., and continued to boil for 5 min. The mixture was stirred rapidly at room temperature for 3 hrs., refrigerated overnight and filtered. A white crystalline solid was washed with 1-l of water and air dried for 3 days; m.p. 120°-121°, Yield: 266 g (99%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[C:13]([C:15]1[CH:23]=[CH:22][C:18]2[N:19]=[CH:20][S:21][C:17]=2[CH:16]=1)#[N:14].C([Li])CCC>>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]([C:20]1[S:21][C:17]2[CH:16]=[C:15]([C:13]#[N:14])[CH:23]=[CH:22][C:18]=2[N:19]=1)([OH:4])[CH2:2][Cl:1]
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: N#Cc1ccc2ncsc2c1
Agent: [Li]CCCC
Product: N#Cc1ccc2nc(C(O)(CCl)c3ccc(F)cc3F)sc2c1

Procedure:
2-Chloro-2',4'-difluoroacetophenone is added to 6-cyanobenzothiazole in the presence of n-butyllithium to form 1-(2,4-difluorophenyl)-1-(6-cyanobenzothiazol-2-yl)-2-chloroethanol.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH3:12])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.Br[C:14]([CH3:19])([CH3:18])[C:15](Br)=[O:16].Cl>C(Cl)Cl>[CH3:18][CH:14]1[CH2:19][C:9]2[C:10](=[C:5]([CH3:12])[CH:6]=[C:7]([CH3:11])[CH:8]=2)[C:15]1=[O:16]
Reactant: Cc1cccc(C)c1
Reactant: CC(C)(Br)C(=O)Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1)CC(C)C2=O
Yield: 93 %

Procedure:
107 g (810 mmol) of AlCl3 are slowly added to a solution of 34.4 g (324 mmol) of m-xylene (99% pure) and 74 g (324 mmol) of 2-bromoisobutyryl bromide (98% pure) in 600 ml of analytical grade methylene chloride via a solids metering funnel at room temperature, while stirring vigorously, whereupon vigorous evolution of gas started. The mixture was stirred at room temperature for 15 hours, poured onto ice-water, which was acidified with 25 ml of concentrated HCl and extracted several times with ether. The combined organic phases were washed first with a saturated NaHCO3 solution and then with a saturated NaCl solution and dried with magnesium sulfate. The oil which remained after the solvent had been stripped off under reduced pressure was distilled over a short distillation bridge. 52.4 g of the indanone 1 passed over at 81-90° C./0.1-0.2 mbar in the form of a colorless oil which crystallized at room temperature. The yield was 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and p-anisidine and was obtained as a white solid as described in Example 1. 1H NMR (CDCl3): 8.85 (d, J=2.1, 1H), 8.19-8.15 (m, 1H), 7.65 (s, 1H), 7.54-7.46 (m, 3H), 6.96-6.91 (m, 2H), 3.83 (s, 3H).
Reaction SMILES: Cl[P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Mg].P(=O)(O)(O)O.C1(C)C=CC=CC=1>CN(C)C=O>[C:9]1([PH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: O=P(O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
1.04 g (4.71 mmol) of chlorodiphenylphosphine was added dropwise under a nitrogen gas atmosphere to a suspension of 229 mg (9.42 mmol) of magnesium (turning) in 10 cm3 of N,N-dimethylformamide and the mixture was stirred at 100° C. for one hour. To the reaction mixture was added dropwise 10 cm3 (10 mmol) of 1 mol·dm-3 phosphoric acid and then 10 cm3 of toluene. The mixture was stirred, the aqueous layer and the toluene layer were separated off, the toluene layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, giving 710 mg (3.81 mmol) of diphenylphosphine in 81% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)=[O:33])=[CH:4][N:3]=1.[CH3:41][N:42]([CH3:47])[C:43](=[O:46])[CH:44]=[CH2:45]>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][N:37]([CH2:45][CH2:44][C:43]([N:42]([CH3:47])[CH3:41])=[O:46])[CH2:36]2)=[O:33])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(C(=O)NC4CCCNC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: C=CC(=O)N(C)C
Product: COc1cc(-c2csc3c(C(=O)NC4CCCN(CCC(=O)N(C)C)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
A mixture of 4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)-N-piperidin-3-ylthieno[3,2-c]pyridine-7-carboxamide (150 mg, 0.270 mmol) and N,N-dimethylacrylamide (28 mg, 0.283 mmol, 3 portions at 2 hour intervals) were reacted according to General Procedure K. The residue was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (28-30% solution) (80:20:0.05) mixture as the mobile phase to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 1.39 (m, 1H), 1.51(m, 1H), 1.70 (m, 1H), 1.81 (m, 1H), 1.98 (m, 2H), 2.48 (m, 2H), 2.58 (m, 2H), 2.76 (m,1H), 2.81 (s, 3H), 2.91 (m, 1H), 2.99 (s, 3H), 3.91 (s, 3H), 3.99 (m 1H), 4.04 (m, 3H), 7.07 (d, 1H), 7.15 (t, 1H), 7.18 (s, 1H), 7.33 (t, 1H), 7.35 (s, 1H), 7.60 (m, 2H), 7.71 (d, 1H), 8.16 (d, 1H), 8.59 (s, 1H), 9.50 (s, 1H). LCMS (Conditions a): MH+=654.1, Rt=2.55 min.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([OH:16])(=O)=[O:14])[CH:8]=1>C1(C)C=CC=CC=1>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([Cl:2])(=[O:16])=[O:14])[CH:8]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
Phosphorus pentachloride (1.57 g, 7.5 mmol) was added to a stirred solution of pyridine-3-sulfonic acid (1.00 g, 6.3 mmol) in toluene (5 mL). The mixture was heated at reflux for 16 hours and then cooled to room temperature. The mixture was filtered through celite, and the celite was washed with benzene (2×10 mL). The combined filtrates were concentrated under reduced pressure to give crude pyridine-3-sulfonyl chloride (0.70 g, 100%), which was used directly in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)([O-])=O>CO.C(OCC)(=O)C.[Pd]>[F:13][C:12]([F:14])([F:15])[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
1-Nitro-4-(2,2,2-trifluoroethoxy)benzene (5.5 g) was dissolved in methanol (100 ml), 10% palladium/activated carbon (50% in water, 2.5 g) was added thereto, and the mixture was stirred at room temperature for 24 hr under a hydrogen atmosphere. The palladium/activated carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to give a dark orange oil residue. The obtained residue was dissolved in ethyl acetate (200 ml), and the solution was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained dark orange oil residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.5 g) as an orange oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH3:14].[CH2:24]=[O:25]>C1COCC1>[CH2:13]([C:15]([CH2:24][OH:25])([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH3:14]
Reactant: CCCCC(CC)C(=O)OC
Reactant: C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCC(CC)(CO)C(=O)OC
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
47 ml (0.334 mol) of diisopropylamine are added dropwise at 20° C. to a solution of 118 ml (0.319 mol) of n-butyllithium (2.7 M in heptane) in 118 ml of THF, and the mixture is stirred at 20° C. for 30 min. Within approx. 15 min, 48 g (0.304 mol) of methyl 2-ethylhexanoate are added dropwise at −20° C., and the mixture is stirred at −20° C. for 30 min and subsequently admixed with 27 g (0.90 mol) of paraformaldehyde. After 30 min at −20° C., the mixture is stirred at 0° C. for a further 2 h. After the solvent has been removed at 20° C. and 20 mbar (approx. 250 ml), 100 ml of MTBE and 200 ml of saturated aqueous solution of ammonium chloride are added to the oily residue and the mixture is stirred at RT for 2 h. The organic phase is removed, the aqueous phase is re-extracted 1× with 100 ml of MTBE and the combined organic phases are concentrated on a rotary evaporator. The crude product (97% conversion based on methyl 2-ethylhexanoate) can be purified by distillation to obtain methyl 2-ethyl-2-hydroxymethylhexanoate (b.p.: 100° C., 6 mbar) in 91% yield with a purity of >99%.
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:17][CH:14]1[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Product: FC(F)(F)c1cccc(CNC2CC2)c1Cl

Procedure:
Synthesized according to typical procedure J from 2-chloro-3-trifluoromethylbenzaldehyde and cyclopropylamine.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].CN(C)C=O.[OH:19][CH:20]1[CH2:24][CH2:23][O:22][C:21]1=[O:25]>C(OCC)(=O)C>[Si:6]([O:19][CH:20]1[CH2:24][CH2:23][O:22][C:21]1=[O:25])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1OCCC1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CCOC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.0 g of imidazole and 15.9 g of t-butyldimethylsilyl chloride were added in order to a dimethylformamide (180 ml) solution of 9.0 g of 3-hydroxydihydrofuran-2-(3H)-one, and the reaction liquid was stirred for 1 hour at room temperature. The reaction liquid was diluted with ethyl acetate, washed with water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=5/1) to obtain the entitled compound as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[ClH:11].[H][H]>O.C(O)C>[ClH:11].[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1c(F)cccc1F
Reactant: [H][H]
Agent: Cl
Solvent: O
Solvent: CCO
Product: NCc1c(F)cccc1F

Procedure:
A mixture of 5.00 g. of 2,6-difluorobenzonitrile and 1.0 g. of 50% water-wet 5% palladium on carbon catalyst in 100 ml. of concentrated HCl and 100 ml. of absolute ethanol is shaken at room temperature under 20 lbs. pressure of hydrogen for 48 hours. The mixture is filtered and the filtrate is diluted with 500 ml. of diethyl ether and allowed to stand. Filtration gives the desired product as colorless crystals, m.p. 197°-200° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[BrH:9].[NH+]1C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1
Reactant: Cc1ccnc(N)c1
Reactant: Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: Cc1cc(N)ncc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.5 %

Procedure:
In a nitrogen atmosphere, 1.08 g of 2-amino-4-methylpyridine was dissolved in 75 mL of tetrahydrofuran, and tetrahydrofuran (75 mL) solution of 3.20 g of pyridinium hydrobromide perbromide was dropwise added thereto at room temperature, over 1.5 hours. After the addition, this was stirred at room temperature for 40 minutes, and 100 mL of aqueous saturated sodium sulfite solution was added to the reaction mixture. This was extracted with ethyl acetate, and the ethyl acetate layer was dried with magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=4/1 to ethyl acetate) to obtain 1.00 g of the entitled compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[Cl:12]([O-])(=O)=O.[Na+]>O>[OH:1][C:2]1[C:7]([Cl:12])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)nc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(Cl)c1
Temperature: 50 °C

Procedure:
2-Hydroxy-5-nitro pyridine (1 g, 7.14 mmol) was added portion wise to 4.5 mL of concentrated HCl under constant stirring and then heated to 50° C. To this was slowly added a solution of sodium chlorate (266 mg, 2.5 mmol) in water (4 mL). The reaction was maintained at the same temperature for an additional hour, and then cooled to 0° C. The precipitate obtained was filtered, washed thoroughly with water and dried to obtain 2-hydroxy-3-chloro-5-nitro pyridine.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:12](=O)[NH:11][C:10]([CH:14]2[CH2:16][CH2:15]2)=[N:9][C:8]=1[C:17]([OH:19])=[O:18].N>C(#N)C>[Cl:6][C:7]1[C:8]([C:17]([OH:19])=[O:18])=[N:9][C:10]([CH:14]2[CH2:16][CH2:15]2)=[N:11][C:12]=1[Cl:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1nc(C2CC2)[nH]c(=O)c1Cl
Agent: N
Solvent: CC#N
Product: O=C(O)c1nc(C2CC2)nc(Cl)c1Cl
Temperature: 85 °C

Procedure:
Phosphorus oxychloride (14 mL, 23 g, 0.15 mol) and 5-chloro-2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (i.e. the product of Step B1 or B2) (75 g, 300 mmol) were combined and heated at 85° C. for 3 h. The reaction mixture was cooled to 30° C. and added over 30 minutes to a mixture of acetonitrile (50 mL) and ice water (80 mL), with the temperature maintained at 5-10° C. and the pH maintained in the range 1-3 by co-feeding aqueous ammonia (28%). The pH was adjusted to about 2, the mixture was concentrated at 25° C. with a rotary evaporator to remove acetonitrile, and the precipitated product was isolated by filtration and washed with water (2×25 mL). The solid was dried in a vacuum oven to afford the title compound (ca. 7.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([C:10]#[N:11])[CH2:6][CH2:7][CH:8]=[CH2:9])[CH3:2].CN(C=O)C.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]=1[N+:35]([O-:37])=[O:36]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]([C:10]#[N:11])([CH2:21][C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]=1[N+:35]([O-:37])=[O:36])[CH2:6][CH2:7][CH:8]=[CH2:9])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1CCl
Reactant: C=CCCC(C#N)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCC(C#N)(Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(=O)OCC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a round bottom flask equipped with a nitrogen inlet 2-cyano-hex-5-enoic acid ethyl ester (2.0 g, 11.96 mmol) and DMF (40 mL) were added. The reaction mixture was cooled to 0° C. followed by addition of NaH (0.48 g, 12.0 mmol, 60% dispersion in mineral oil). The reaction mixture was allowed to stir at 0° C. for another 5 min, followed by addition of 2-chloromethyl-1-nitro-4-phenoxy-benzene (2.6 g, 9.86 mmol). The reaction turned a dark purple color. After 3 h the reaction was quenched with 1N HCl, and the solvent was evaporated to yield crude mixture. The crude mixture was dissolved in ethyl acetate and washed 3 times with 1N HCl followed by a wash with saturated brine solution. The phases were separated, and the organic phase was dried with sodium sulfate and filtered, and the solvent was removed under reduced pressure to yield a residue. The residue was purified by flash chromatography using heptanes/ethyl acetate as the mobile phase 9:1 to yield a residue.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:15])=[CH:11][CH:12]=2)[NH:7][CH2:6]1)[CH3:3].[C:16]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[ClH:49]>C1COCC1>[ClH:49].[C:16]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:17]=[CH:18][C:19]([CH2:22][O:15][C:10]2[CH:9]=[C:8]3[C:13]([CH2:14][CH:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][NH:7]3)=[CH:12][CH:11]=2)=[CH:20][CH:21]=1
Reactant: OCc1ccc(-c2ccccc2)cc1
Reactant: CN(C)CC1CNc2cc(O)ccc2C1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CC1CNc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethylazodicarboxylic acid (348 mg) was added dropwise to a THF solution (20 ml) of 3-(dimethylamino)methyl-1,2,3,4-tetrahydro-7-quinolinol (344 mg), 4-biphenylylmethanol (368 mg), and triphenylphosphine (525 mg). The reaction mixture was stirred at room temperature for one hour, which was poured into 1N hydrochloric acid and washed with ethyl acetate. The aqueous layer was neutralized with 1N aqueous sodium hydroxide solution, to which was added a saturated aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/4), converted into its hydrochloride, and then recrystallized from ethanol-IPE to give the entitled compound (214 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].C([O-])([O-])=O.[Na+].[Na+].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=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>[C:17]1([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=2)[C:5]([OH:7])=[O:6])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)c1ccnc(Br)c1
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: CN(C)C=O
Product: O=C(O)c1ccnc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.2 %

Procedure:
2-Bromoisonicotinic acid (2.02 g, 10 mmol) was dissolved in DMF (80 mL) under argon. Pd(PPh3)4 (0.6 g, 0.52 mmol) was added, and the reaction mixture was stirred at room temperature for 15 min. Na2CO3 (aq. 2N, 40 mL) was then added, followed by the addition of phenylboronic acid (1.67 g, 13.7 mmol). The reaction mixture was heated at 95° C. (18 h), cooled to room temperature and filtered through a celite pad. Water (80 mL) was added, and the mixture was acidified with HCl (2 N) to pH=4. The precipitate was collected via filtration and rinsed with water (2×7 mL). The crude product was recrystallized from 2-methoxylethanol to give 2-phenylisonicotinic acid as a grey solid (1.2 g). 1HNMR (DMSO-d6, 400 MHz): δ 7.51 (m, 3H), 7.78 (d, J=4.8 Hz, 1H), 8.13 (t, J=1.6 Hz, 2H), 8.29 (s, 1H), 8.85 (d, J=4.8 Hz, 1H), 13.73 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[N:12]O)[CH2:9][CH2:8]2.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH2:12])[CH2:9][CH2:8]2
Reactant: [H][H]
Reactant: COc1cccc2c1C(=NO)CC2
Agent: [Pd]
Solvent: CO
Product: COc1cccc2c1C(N)CC2

Procedure:
7-Methoxy-indan-1-one oxime (5 g, 28 mmol) was suspended in 250 mL methanol. Palladium on charcoal (10%, 0.3 g) was added and the reaction was hydrogenated with a hydrogen ballon for 5 days. Palladium on charcoal was filtered off and the filtrate was evaporated. The title compound was obtained as a yellow liquid (1.89, 41%) and used without any further purification for the next step.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24](=[O:29])[C@H:25]([CH2:27][OH:28])[NH2:26].C(N(CC)CC)C>C1COCC1>[CH3:22][O:23][C:24](=[O:29])[C@H:25]([CH2:27][OH:28])[NH:26][C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 57.4 %

Procedure:
A solution of 10.75 g (38.56 mmol) of trityl chloride is added, at 0° C., to a solution of 6 g (38.56 mmol) of L-serine methyl ester hydrochloride and 7.8 g (77.12 mmol) of triethylamine in absolute THF and this solution is left to stir at 0° C. for 4 h and then at room temperature for 2 days. The solvent is removed in vacuo and the residue is partitioned between dichloromethane and a 10% aqueous solution of citric acid. The phases are separated and the organic phase is washed with water and dried over sodium sulfate. Following filtration, the solvent is removed in vacuo and the residue is chromatographed through silica gel using heptane/ethyl acetate=6/4. 8 g (58%) of (34.3) are obtained after concentrating the product fractions.