Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1>C(N(CC)CC)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][C:14]1[CH:13]=[N:12][CH:11]=[C:10]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1cncc(C#Cc2ccccc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
Add phenylacetylene (0.460 mL, 4.2 mmol), copper (I) iodide (0.072 g, 0.38 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.133 g, 0.19 mmol) to a solution of 3-bromo-5-methylpyridine, (prepared essentially as described in PREPARATION 1), (0.654 g, 3.8 mmol) in degassed triethylamine (20 mL) and stir under nitrogen at 80° C. for 16 h. Cool the reaction mixture to room temperature, filter through diatomaceous earth, wash with ethyl acetate, and concentrate. Purify the residue by silica gel chromatography, eluting with 80:20 hexanes:ethyl acetate, to give the title compound as a brown oil (0.398 g, 54%).
Reaction SMILES: S(O)(=O)(=O)C.[CH2:6]([C:8]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:9]=1[CH2:10][NH:11][C:12]1[C:13]2[N:14]([C:21]([CH3:25])=[C:22]([CH3:24])[N:23]=2)[CH:15]=[C:16]([C:18](N)=[O:19])[CH:17]=1)[CH3:7].[OH-:31].[Na+]>C(O)C>[CH2:6]([C:8]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:9]=1[CH2:10][NH:11][C:12]1[C:13]2[N:14]([C:21]([CH3:25])=[C:22]([CH3:24])[N:23]=2)[CH:15]=[C:16]([C:18]([OH:19])=[O:31])[CH:17]=1)[CH3:7]
Reactant: CCc1cccc(C)c1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Reactant: [OH-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CCO
Product: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Yield: 90.1 %

Procedure:
8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesylate (11.0 g, 0.025 mol) and sodium hydroxide (7.0 g, 0.17 mol) were solved in ethanol(95%) (120 ml) and was refluxed for 20 h. The solvent was evaporated under reduced pressure and to the residue was added water (150 ml). The pH was adjusted to 5 by addition of conc HCl and acetic acid and the solid that precipitated was isolated by filtration, washed with water and acetone, and dried to give 7.6 g (88%) of the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[Sn](Cl)Cl>Cl.CC(C)=O>[CH:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2ccccc2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(C)=O
Product: Nc1ccc(/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In an embodiment of the invention, a method for preparing the aforesaid alignment film in a laboratory level is illustrated as an example. 10 g of 4-nitrobenzyl bromide is mixed with 12 g of triphenylphosphine and dissolved in 150 ml of a dry tetrahydrofuran solution, heated to 75° C. and agitated under reflux for 48 hours, to obtain 8.2 g of a dry white p-nitrobenzyl triphenylphosphine. The p-nitrobenzyl triphenylphosphine is mixed with 2.6 g of p-nitrobenzaldehyde in a 150 ml tetrahydrofuran solution, and agitated under room temperature for about 24 hours to obtain 4.2 g of p-nitrostilbene. The resultant p-nitrostilbene is mixed with 14.7 g of tin dichloride, dissolved in a mixed solution of 30 ml/40% hydrochloride acid and 100 ml acetone, agitated under the room temperature for about 2 hours and refluxed for 8 hours to obtain p-aminostilbene. The p-aminostilbene is mixed with 9,9′-bianthracyl tetracarboxylic dianhydride in a dry NMP (N-methyl-pyrrolidone) solution under agitation for 24 hours, under protection of nitrogen gas, to obtain the precursor of the polyimide alignment film involved in the embodiment. The precursor is heated to 230° C. to obtain the final alignment film, which is a light sensitive alignment film.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[C:10]([Cl:25])[CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:28]I.[Cl-].[NH4+]>CN(C)C=O>[CH3:1][S:2][C:3]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[C:10]([Cl:25])[CH:9]=1)([CH3:28])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(SC)c1ccc(N2C(=O)c3ccccc3C2=O)c(Cl)c1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(SC)c1ccc(N2C(=O)c3ccccc3C2=O)c(Cl)c1
Yield: 68 %

Procedure:
Methyl α-methylthio(3-chloro-4-phthalimidophenyl)acetate was dissolved in 4.0 ml of dimethylformamide, and with ice cooling and stirring, 82 mg (65% content) of sodium hydride was added. The mixture was stirred for 10 minutes. With ice cooling, 0.2 ml of methyl iodide was added, but the deep red color did not vanish. Hence, 0.2 ml of methyl iodide was further added, and the mixture was stirred for about 1.5 hours at room temperature. The color of the solution became lighter, and turned orange. To the reaction solution was added 20 ml of an aqueous solution of ammonium chloride, and the mixture was extracted twice with 10 ml of methylene chloride. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual orange oil was chromatographed on a column of Florisil using methylene chloride as an eluent to afford 0.453 g (68%) of methyl α-methylthio-α-(3-chloro-4-phthalimidophenyl)propionate as colorless crystals.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:15]1([C:18]2[C:19]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:20][C:21]3[O:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[C:23]([C:33]([NH:35][CH3:36])=[O:34])[C:22]=3[CH:37]=2)[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.CCOC(C)=O>[CH:15]1([C:18]2[C:19]([N:38]([C:2]3[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=3)[C:7]([O:9][CH3:10])=[O:8])[S:39]([CH3:42])(=[O:41])=[O:40])=[CH:20][C:21]3[O:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[C:23]([C:33](=[O:34])[NH:35][CH3:36])[C:22]=3[CH:37]=2)[CH2:17][CH2:16]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 60 °C
Reaction time: 72 h
Yield: 55.4 %

Procedure:
A mixture of methyl 5-fluoro-2-nitrobenzoate (2.138 g, 10.73 mmol), 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (4.0 g, 9.94 mmol) and K2CO3 (4.12 g, 29.8 mmol) in hexamethylphosphoramide (25 mL) in a seal tube was stirred at 60° C. for 3 days. Cooled down to room temperature, the mixture was diluted with EtOAc and then filtered through a pad of Celite. The filtrate was washed with water and brine and dried over Na2SO4. Concentrated under reduced pressure, the residue was purified by flashing chromatography on silica gel eluted with 0-50% EtOAc in hexane to give the product (3.2 g, 55%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 (d, J=9.17 Hz, 1H) 7.89 (dd, J=8.78, 5.27 Hz, 2H) 7.55 (d, J=9.37 Hz, 2H) 7.50 (dd, J=9.07, 2.63 Hz, 1H) 7.44 (d, J=2.73 Hz, 1H) 7.23 (t, J=8.68 Hz, 2H) 5.81 (d, J=4.49 Hz, 1H) 3.91 (s, 3H) 3.35 (s, 3H) 3.02 (d, J=4.88 Hz, 3H) 1.86-1.96 (m, 1H) 0.97-1.05 (m, 1H) 0.89 (br. s., 2H) 0.59 (br. s., 1H). LCMS (m/z, ES+)=582 (M+H+).
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1>CN(C)P(N(C)C)(N(C)C)=O>[CH:1]1([CH2:7][NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCC1CCCCC1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCC2CCCCC2)cc1

Procedure:
A solution of 6 g. of cyclohexylmethyl bromide and 11.19 g. of ethyl p-aminobenzoate in 30 ml. of hexamethylphosphoramide is heated in an oil bath for 20 hours. The solution is poured into ice-cold water and extracted several times with diethyl ether. The combined ether extracts are washed with water, dried with anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to furnish ethyl p-cyclohexylmethylaminobenzoate as an oil.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][C:8]#[CH:9].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:10][CH2:6][CH2:7][C:8]#[C:9][C:23]([C:22]1[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=1)=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#CCCOCc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(C#CCCOCc1ccccc1)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
At −70° C., 2.56 ml of a 1.6 M butyllithium solution are added dropwise to a solution of 505 mg (3.15 mmol) of benzyl but-3-yn-1-yl ether in 10 ml of THF, and the mixture is stirred for 30 min. 500 mg (5.15 mmol) of 4-fluorobenzoyl chloride are added dropwise to this solution, and the temperature is allowed to rise to 0° C. After 1 h, 10 ml of a saturated ammonium chloride solution are added, and the reaction mixture is extracted with 3×50 ml of ethyl acetate. The combined organic phases are washed with water, dried over MgSO4 and freed from the solvent under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 430 mg (45%) of the desired product; log P(HCOOH): 3.89; 1H-NMR (DMSO-d6): 8.15 (dd, 2H), 7.34 (m, 7H), 4.57 (s, 2H), 3.70 (t, 2H), 2.90 (t, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([O:14]C)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH-].[Na+].Cl.O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COC(=O)[C@H](Nc1ccc(C#N)c(Br)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(N[C@@H](C(=O)O)c2ccccc2)cc1Br
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a solution of (R)-methyl 2-(3-bromo-4-cyanophenylamino)-2-phenylacetate (98 mg, 0.28 mmol) in THF (2 mL), 1N aq. NaOH (1.00 mL, 1.00 mmol) was added. After being stirred for 18 h, the solution was acidified with 1N HCl to pH 1-2. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(3-bromo-4-cyanophenylamino)-2-phenylacetic acid (90 mg).
Reaction SMILES: B.C1COCC1.[N+:7](/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-])=[O:8].[BH4-].[Na+].Cl>O.C1COCC1>[C:12]1([CH2:11][CH2:10][NH:7][OH:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Agent: B
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Product: ONCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a THF solution (1.1 mL, 1.0 M) of BH3-THF (1.1 mmol) was added dropwise a THF solution (2.2 mL) of trans-β-nitrostyrene (160.0 mg, 1.1 mmol) at 0° C. under nitrogen atmosphere. NaBH4 (3.3 mg, 0.087 mmol) was added, and the mixture was stirred for 20 minutes at room temperature. Water (5 mL) was added at 0° C., and then the solution was made acidic by adding 2M HCl aqueous solution, and the solution was stirred for 4 hr at 65° C. The reaction mixture was extracted with ethyl acetate, and the aqueous layer was further extracted with ethyl acetate after the addition of 15% NaOH aqueous solution and NaCl. The organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flush column chromatography (chloroform:methanol=1:0→10:1) to obtain the objective substance (62.7 mg, 43%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]([CH3:34])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:5][C:6]1[S:7][C:8]([C:11](=[O:26])[CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:9][CH:10]=1.CO.[BH4-].[Na+].CCOC(C)=O>C1COCC1.CCCCCC>[CH3:1][O:2][C:3](=[O:35])[C:4]([CH3:34])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:5][C:6]1[S:7][C:8]([CH:11]([OH:26])[CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:17][C:18]=2[CH3:19])=[CH:9][CH:10]=1
Reactant: COC(=O)C(C)(Cc1ccc(C(=O)CCc2nc(-c3ccccc3)oc2C)s1)Oc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(C)(Cc1ccc(C(O)CCc2nc(-c3ccccc3)oc2C)s1)Oc1ccccc1
Reaction time: 0.75 h
Yield: 64.8 %

Procedure:
A sample of 2-methyl-3-{5-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propionyl]-thiophen-2-yl}-2-phenoxy-propionic acid methyl ester (1.00 g, 2.04 mmol) was dissolved in THF (40 mL) and MeOH (20 mL) and cooled to 0° C. Sodium borohydride (115 mg, 3.06 mmol) was added and allowed to stir at. 0° C. for 45 min. The reaction was monitored by HPLC. Upon the completion of the reaction, the bulk of the solvent was removed in vacuo and water (40 mL) was added. The mixture was acidified with 6 N HCl (20 mL) and stirred for 30 min. This aqueous mixture was then extracted with CH2Cl2 (2×50 mL). The organic fractions were combined, dried over NaCl, and solvent removed in vacuo to give a crude oil. Flash chromatography (gradient 20% to 40% EtOAc in hexane) provided 650 mg (65%) of desired product: 1H NMR (400 MHz, CDCl3) δ 8.02 (d, 2H), 7.47 (m, 3H), 7.19 (m, 2H), 6.96 (t, 1H), 6.79 (m, 3H), 6.68 (d, 2H), 4.96 (m, 1H), 3.72 (s, 3H), 3.43 (d, 1H), 3.29 (d, 1H), 2.71 (m, 2H), 2.30 (s, 3H), 2.17 (m, 2H), 1.42 (s, 3H); MS (EI) 492.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:5]=1[C:6]([O:12][CH:13]([CH3:15])[CH3:14])=[N:7]2.[OH-].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C.[O:53]1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:20][C:18]1[CH:17]=[CH:16][C:5]2[C:6]([O:12][CH:13]([CH3:15])[CH3:14])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:2](=[O:53])[C:3]=3[C:4]=2[CH:19]=1
Reactant: CC(C)Oc1nc2ccnc(Cl)c2c2cc(F)ccc12
Reactant: C1COCCO1
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(C)Oc1nc2cc[nH]c(=O)c2c2cc(F)ccc12
Temperature: 100 °C
Reaction time: 16 h

Procedure:
1-chloro-9-fluoro-6-isopropoxybenzo[c]-1,6-naphthyridine (107 mg, 0.368 mmol), potassium hydroxide (83.0 mg, 1.47 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (31.3 mg, 0.0740 mmol), and Pd2(dba)3 (33.7 mg, 0.0370 mmol) were combined in a vial. 1,4-Dioxane (2.2 mL) and water (1.5 mL), were added, and the resulting suspension was degassed with argon for 10 min. The reaction mixture was heated to 100° C. and stirred for 16 h. After cooling to room temperature, the reaction mixture was added to saturated aqueous ammonium chloride (40 mL). The aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to a crude residue. The crude material was purified by preparative reverse phase HPLC eluting with an acetonitrile/water (with 0.05% TFA as a modifier) gradient, to afford 9-fluoro-6-isopropoxybenzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (500 MHz, DMSO-D6) δ 11.74 (s, 1H), 9.55 (d, 1H), 8.33 (dd, 1H), 7.53 (overlapping m, 2H), 6.56 (d, 1H), 5.64 (septet, 1H), 1.43 (d, 6H). LRMS (ESI) calc'd for (C15H13FN2O2) [M+H]+, 273.1; found 273.0.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[N:17]12.[CH3:27][C:28]1[N:32]([C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[N:30][C:29]=1[CH:52]=[O:53].C(O)(=O)C(O)=O>O1CCCC1.CCCCCC.O>[OH:53][CH:52]([C:29]1[N:30]=[CH:31][N:32]([C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:28]=1[CH3:27])[CH:23]1[C:22](=[O:26])[N:17]2[C:18]3[C:14]([CH:15]=[C:16]2[CH2:25][CH2:24]1)=[CH:13][CH:21]=[CH:20][CH:19]=3
Reactant: O=C1CCCc2cc3ccccc3n21
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(O)C2CCc3cc4ccccc4n3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 63.3 %

Procedure:
To a solution of diisopropylamine (658 mg) in tetrahydrofuran (8 ml) at -70° C. under nitrogen atmosphere was added 1.64M butyllithium in hexane (3.96 ml). After being stirred at the same temperature for 20 minutes, the mixture was treated with a solution of 8,9-dihydropyrido[1,2-a]indol-6(7H)-one (1.21 g) in tetrahydrofuran (12 ml) over 15 minutes. The mixture was stirred at -70° C. for 30 minutes, and a solution of 5-methyl-1-trityl-1H-imidazole-4-carbaldehyde (2.29 g) in tetrahydrofuran (20 ml) was added dropwise over 20 minutes. After the mixture was stirred at -70° C. for further 60 minutes and at ambient temperature for 2 hours, it was diluted with water and neutralized with an aqueous solution of oxalic acid. Separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give 8,9-dihydro-7-[(hydroxy)-(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]-indol-6(7H)-one (2.21 g) as an amorphous powder. The product was a mixture of two diastereoisomers.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[NH2:51][CH2:52][C:53]1[C:62](=[O:63])[C:61]2[C:56](=[CH:57][C:58]([Cl:64])=[CH:59][CH:60]=2)[N:55]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:54]=1[C:71]1[O:72][CH:73]=[CH:74][N:75]=1>CN(C=O)C>[Cl:64][C:58]1[CH:57]=[C:56]2[C:61]([C:62](=[O:63])[C:53]([CH2:52][NH:51][C:14]([C:11]3[CH:12]=[CH:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:9](=[O:17])[CH:10]=3)=[O:16])=[C:54]([C:71]3[O:72][CH:73]=[CH:74][N:75]=3)[N:55]2[C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)=[CH:60][CH:59]=1
Reactant: O=C(O)c1ccn(Cc2ccccc2)c(=O)c1
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccn(Cc2ccccc2)c(=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a 10 mL round-bottomed flask, 1-benzyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (32.6 mg, 0.142 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (66.3 mg, 0.142 mmol) and N,N-diisopropylethylamine (73.5 mg, 0.099 mL, 0.569 mmol) were combined with DMF (2 mL). The reaction mixture was stirred at room temperature for 10 min. After this time, 3-aminomethyl-7-chloro-2-oxazol-2-yl-1-phenyl-1H-quinolin-4-one (intermediate A) was added (0.050 g, 0.142 mmol). The reaction mixture was stirred at room temperature for 3 hr. The product was purified using flash chromatography (40% ethyl acetate/hexane ramped to 100% ethyl acetate/hexanes). MS calcd. for C32H24ClN4O4 [(M+H)+] 563.1, obsd. 563.3.
Reaction SMILES: CC([Si]([O:8][CH2:9][C@H:10]([CH3:28])[C@@H:11]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C@@H:12]([CH3:17])/[CH:13]=[CH:14]\[CH:15]=[CH2:16])(C)C)(C)C.Cl>C1COCC1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:18][C@@H:11]([C@@H:12]([CH3:17])/[CH:13]=[CH:14]\[CH:15]=[CH2:16])[C@@H:10]([CH3:28])[CH2:9][OH:8])=[CH:25][CH:24]=1
Reactant: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of (1,1-dimethylethyl)[[(2S,3S,4S,5Z)-3-[(4-methoxyphenyl)methoxy]-2,4-dimethyl-5,7-octadienyl]oxy]dimethylsilane (6.74 g, 16.68 mmol) and THF (70 mL) is cooled to 0° C. 4 N aqueous HCl (70 mL) is added to the solution dropwise to maintain the reaction temperature at less than 5° C. The mixture is stirred at 0° C. for 1 h. The mixture is quenched by the addition of saturated aqueous NaCO3. The organic phase is separated. The aqueous phase is extracted with ethyl acetate (5×100 mL). The combined organic phase is washed with brine, dried over NaSO4 and concentrated. Flash chromatography gives the desired compound (4.17 g, 86%) as a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8](F)=[C:7]([F:13])[C:6]=1[F:14])[CH3:2].[C:16]([O:20][C:21](=[O:28])[NH:22][C@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:25]2[CH2:26][CH2:27][C@H:23]([NH:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:28])[CH2:24]2)=[C:7]([F:13])[C:6]=1[F:14])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CCOC(=O)c1cc(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1F
Yield: 74.5 %

Procedure:
A solution of 2,3,4,5-tetrafluorobenzoic acid ethyl ester (Example 1a, 4.03 g, 18.1 mmol), (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (4.02 g, 21.6 mmol) (Sanchez J. P., Domagala J. M., Heifetz C. L., Priebe S. R., Sesnie J. A., Trehan A. K., J. Med. Chem., 1992; 35(10):1764-1773), and triethylamine (18.0 mL, 129 mmol) in acetonitrile (50 mL) is heated at 50° C. under a nitrogen atmosphere for 4.5 hours. The yellow solution is concentrated in vacuo and poured into a saturated NaHCO3 solution. The mixture is then extracted with chloroform, and the combined organic extracts are washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The resulting residue is then purified by flash column chromatography (1:7 ethyl acetate/hexanes) to afford the title compound (5.24 g). 1H NMR (CDCl3): δ 7.35 (ddd, 1H), 4.70-4.65 (bs, 1H), 4.42-4.20 (m, 3H), 3.90-3.62 (m, 3H), 3.58-3.42 (m, 1H), 2.28-2.03 (m, 1H), 1.99-1.80 (m, 1H), 1.46 (s, 9H), 1.37 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23].O[CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:31]([O:30][C:29]([NH:28][CH2:27][CH2:26][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23])=[O:35])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)C(Cc1ccc(O)c([N+](=O)[O-])c1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)c([N+](=O)[O-])c1)Oc1ccccc1
Yield: 90.3 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using ethyl 3-(4-hydroxy-3-nitrophenyl)-2-phenoxypropionate (270 mg), which is the product of Reference example 53(a), t-butyl 2-hydroxyethylcarbamate (322 mg), triphenylphosphine (535 mg) and a solution of diethylazodicarboxylate in toluene (40%, 0.93 ml) and the reaction mixture was treated to afford the desired compound (349 mg) as a colorless oil.