Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][C:21]=2[CH:31]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Li+].O>C1COCC1.CO>[C:6]1([CH2:5][C@@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][C:21]=3[CH:31]=2)=[O:14])[C:3]([OH:32])=[O:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccc2oc(-c3ccccc3)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccc2oc(-c3ccccc3)cc2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a solution of (R)-3-phenyl-2-(2-phenyl-benzofuran-5-ylmethoxy-carbonylamino)-propionic acid methyl ester 28(0.7 g, 1.63 mmol) in THF (15 ml) and methanol (15 ml) was added a solution of lithium hydroxide (1N) in water (2 ml, 2 mmol). The reaction mixture was heated at 50° C. for 6 hrs then left at room temperature overnight. The solvent was evaporated and water (20 ml) was added. The mixture was acidified with 1N HCl and ethyl acetate was added. The solid obtained after precipitation and evaporation of the solvent was purified by recrystallization to give about 0.35 g of (R)-3-phenyl-2-(2-phenyl-benzofuran-5-ylmethoxycarbonylamino)-propionic acid 29, mp. 172.8–173.5° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:28]>ClCCl.FC(F)(F)C(O)=O.C(OCC)C>[ClH:28].[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)=[CH:15][C:16]=1[C:23]([F:26])([F:24])[F:25])([O-:22])=[O:21].[ClH:28]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of piperidin-4-yl-carbamic acid tert-butyl ester (400 mg; 2.0 mmol), 5-fluoro-2-nitrobenzotrifluoride (418 g; 2.0 mmol) and potassium carbonate (1.11 g; 8.0 mmol) in dimethylsulfoxide (5 mL) is heated at 100° C. for 5 hours. The mixture is allowed to reach room temperature, is diluted with ethyl acetate (50 mL) and filtered. The filtrate is washed with aq. sat. sodium hydrogencarbonate (2×10 mL) and with water (10 mL). The organic layer is then dried over magnesium sulfate and evaporated under reduced pressure to afford the desired product (797 mg; 2.0 mmol). The [1-(4-Nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester obtained (797 mg; 2.0 mmol) is dissolved in a 2 to 1 mixture of dichloromethane and trifluoroacetic acid (5 mL) and the resulting solution is stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue obtained is co-evaporated with dichloromethane (2×10 mL), is then dissolved in diethylether (2 mL) and a molar solution of hydrochloric acid in diethylether (5 mL) is added. The precipitate formed is triturated in ethylacetate (5 mL), filtered and is dried under high vacuum to yield the desired product as hydrochloride (624 mg; 1.6 mmol).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[NH:25]1[CH2:30][CH:29]=[C:28]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)[CH2:27][CH2:26]1>CS(C)=O.C(OCC)(=O)C>[CH3:24][O:23][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[O:14][C@@H:13]([CH2:12][N:25]1[CH2:26][CH:27]=[C:28]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[CH2:29][CH2:30]1)[CH:22]=[CH:21]2
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)C=C2
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc2c1O[C@@H](CN1CC=C(c3c[nH]c4ccccc34)CC1)C=C2
Temperature: 80 °C
Yield: 58 %

Procedure:
To a solution of [(2R)-8-methoxy-2H-chromen-2-yl]methyl 4-methyl-benzenesulfonate (0.350 g, 1.01 mmol) in methyl sulfoxide (20 mL) was added 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.601 g, 3.03 mmol) and the reaction mixture was heated to 80° C. for 12 h. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.218 g (58%, >97% ee) of 3-(1-{[(2R)-8-methoxy-2H-chromen-2-yl]methyl}-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole as a yellow solid. [α]D25=+0.588 (c 10.21 in chloroform, >97% ee); Rf=0.43 (silica, methanol:ethyl acetate 1:9); mp 198-200° C. dec; Anal. Calcd. for C24H24N2O2.0.3 H2O: C, 76.29; H, 6.56; N, 7.41. Found: C, 76.02; H, 6.63; N, 7.43.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]([F:20])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23](I)[CH3:24].O>CN(C)C=O>[CH2:23]([N:9]([C:10]1[C:11]([F:20])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:24]
Reactant: CCI
Reactant: COC(=O)c1cccc(NC(=O)c2ccccc2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)c1ccccc1)c1cccc(C(=O)OC)c1F
Yield: 61.2 %

Procedure:
Methyl 3-benzamido-2-fluorobenzoate (3.10 g, 11.0 mmol) was dissolved in N,N-dimethylformamide (30 ml), and the solution was cooled. 60% Sodium hydride (0.53 g, 13.2 mmol) was added thereto, and the reaction mixture was agitated without heating or cooling. 10 minutes later, ethyl iodide (2.05 g, 13.0 mmol) was added to the mixture, and the mixture was agitated overnight at room temperature. Water was added dropwise to the reaction mixture, and the reaction mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The sodium sulfate was filtered away, and then the filtrate was concentrated under reduced pressure. The concentration residue was purified by silica gel column chromatography (developer solvent: ethyl acetate/n-hexane=1/5), as a result of which 2.03 g (yield: 61%) of the indicated compound was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])=[C:5]([C:18]([F:21])([F:20])[F:19])[N:4]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])=[C:5]([C:18]([F:21])([F:20])[F:19])[N+:4]=1[O-:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(C(F)(F)F)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Nc1nc(N)[n+]([O-])c(C(F)(F)F)c1-c1cccc(Cl)c1Cl

Procedure:
This compound was made from the compound of Example 14 by reaction with MCPBA in CHCl3 at room temperature. Mp. 275°-278° C.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)C.CC(C)=O.S(=O)(=O)(O)O>O>[F:14][C:13]([F:15])([F:16])[C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[O:6][CH2:5][CH:4]=[O:3]
Reactant: CCOC(COc1cccc(C(F)(F)F)c1)OCC
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=CCOc1cccc(C(F)(F)F)c1

Procedure:
A mixture of 3-trifluoromethylphenoxyacetaldehyde diethyl acetal (146.3 g.; 0.527 mole), acetone (600 ml.), water (550 ml.), and concentrated sulfuric acid (3.5 ml.) is heated under reflux for 22 hours.
Reaction SMILES: COS([O-])(=O)=O.CN(C)[C:9]1[CH2:13][CH2:12][CH2:11][N+:10]=1[CH3:14].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)([O-:18])=[O:17].O>C(O)(C)(C)C.CN(C)C=O>[CH3:14][N:10]1[CH2:11][CH2:12][CH2:13][C:9]1=[CH:25][C:22]1[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C1=[N+](C)CCC1
Agent: COS(=O)(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: CN1CCCC1=Cc1ccc([N+](=O)[O-])cc1
Yield: 22.8 %

Procedure:
Add a solution of 2.35 g of potassium tert. butylate in 15 ml of tert. butanol and 10 ml of dimethylformamide dropwise at 130° to a mixture of 5.0 g of 2-dimethylamino-1-methyl-1-pyrrolinium methylsulfate and 2.2 g of 4-nitrotoluene in 15 ml of dimethylformamide. Stir the thus-prepared reaction mixture at this temperature for 2 hours. Allow the mixture to cool, add water to it and then extract it several times with chloroform. Combine and then concentrate the chloroform extracts. Distil off a slight excess of 4-nitrotoluene under a high vacuum and recrystallize the produced residue from 10 ml of ethanol to obtain 0.8 g of title compound.
Reaction SMILES: [C:1]([Si:5]([CH3:29])([CH3:28])[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][CH2:11][C:10]2([CH3:27])[CH3:26])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)[CH:61]=[O:62].[CH2:64]([OH:66])[CH3:65]>CCCCCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:64]([O:66][C:61]([C:13]1[C:14]2[C:9](=[CH:8][C:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:28])[CH3:29])=[C:16]([CH3:17])[CH:15]=2)[C:10]([CH3:27])([CH3:26])[CH2:11][CH:12]=1)=[O:62])[CH3:65]
Reactant: Cc1cc2c(cc1O[Si](C)(C)C(C)(C)C)C(C)(C)CC=C2OS(=O)(=O)C(F)(F)F
Reactant: CN(C)C=O
Reactant: CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=CCC(C)(C)c2cc(O[Si](C)(C)C(C)(C)C)c(C)cc21

Procedure:
Following General Procedure E and using trifluoro-methanesulfonic acid 6-(tert-butyl-dimethyl-silanyloxy)-4,4,7-trimethyl-3,4-dihydro-naphthalen-1-yl ester (Intermediate 189, 3.4 g, 7.55 mmol), palladium acetate (0.36 g, 1.62 mmol), 1,3-bis(diphenylphosphino)propane (0.36 g, 0.86 mmol), N,N-dimethylformamide (7 mL), ethanol (7 mL) and triethyl amine (7 mL) followed by flash column chromatography over silica gel (230–400 mesh) using 7% ethyl acetate in hexane as the eluent the title compound was obtained (1.35 g, 48%).
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=3)[NH2:27])[CH2:18][CH2:17]2)[N:7]=1.[C:31]1([C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]O1)=[O:32].C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O>ClCCl>[CH3:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][C:24]3[CH:25]=[C:26]([N:27]4[CH2:34][C:35]5[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:31]4=[O:32])[CH:28]=[CH:29][CH:30]=3)[CH2:20][CH2:21]2)[N:7]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C1OCc2ccccc21
Agent: CS(=O)(=O)Cl
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5Cc6ccccc6C5=O)c4)CC3)cccc2n1
Reaction time: 0.25 h
Yield: 45 %

Procedure:
A solution of trimethylaluminium (2.0 M in hexane, 1 eq) was added slowly to a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6, 1 eq) in dichloromethane (0.1 M) at 0° C. The reaction mixture was stirred for 15 min then a solution of phthalide (1 eq) in dichloromethane was added dropwise. The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was dried over sodium sulfate and the solution was concentrated under reduced pressure. The crude 2-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in dichloromethane then N,N-diisopropylethylamine (1 eq.) and methanesulfonyl chloride (1 eq.) were added successively. The reaction mixture was stirred for 2 hours at room temperature then partitioned between saturated aqueous ammonium chloride solution and dichloromethane. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (SPE cartridge, Silica) eluting with a gradient from dichloromethane-methanol (100:2) to (98:2) affording the title compound (yield 45%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[C:10]([NH:12][C:13](=[O:15])[CH3:14])=[CH2:11])C1C=CC=CC=1.Br[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([CH:25]([CH3:27])[CH3:26])[CH:19]=1.BrC1C=CC(N)=C(CC)C=1>>[C:13]([NH:12]/[C:10](=[CH:11]\[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([CH:25]([CH3:27])[CH3:26])[CH:19]=1)/[C:9]([O:8][CH3:1])=[O:16])(=[O:15])[CH3:14]
Reactant: C=C(NC(C)=O)C(=O)OCc1ccccc1
Reactant: CC(C)c1cc(Br)ccc1N
Agent: CCc1cc(Br)ccc1N
Product: COC(=O)/C(=C/c1ccc(N)c(C(C)C)c1)NC(C)=O

Procedure:
The titled compound was prepared according to the method described in Example 1B substituting 2-acetylamino-acrylic acid methyl ester for 2-acetylamino-acrylic acid benzyl ester and 4-bromo-2-isopropylaniline for 4-bromo-2-ethylaniline.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([O:16][CH3:17])=[N:11][C:10]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:11][C:12]([O:16][CH3:17])=[N:13][C:14]=1[O:15][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nc(C(=O)OC(C)(C)C)c(OCc2ccccc2)c(=O)[nH]1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1nc(OC)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.9 %

Procedure:
tert-Butyl 5-(benzyloxy)-2-methoxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (300 mg, 0.903 mmol) and sodium hydride (36.1 mg, 0.903 mmol) were stirred in anhydrous DMF (903 μl) at 0° C. under argon for 30 min. Methyl 2-bromoacetate (83 μl 0.90 mmol) was added and the mixture was stirred at rt for 3 h. The reaction was carefully quenched with water at 0° C. The reaction mixture was extracted with EtOAc (3×). The combined organic layers were washed with water, brine, dried over Na2SO4, concentrated and purified by flash chromatography (hexanes/EtOAc, eluted at ca. 30% EtOAc) to give tert-butyl 5-(benzyloxy)-2-methoxy-6-(2-methoxy-2-oxoethoxy)pyrimidine-4-carboxylate (109 mg, 0.270 mmol, 29.9% yield) as a colorless oil and Example 267A (117 mg, 0.289 mmol, 32.1% yield) as a colorless oil. 1H NMR (500 MHz, chloroform-d) δ 7.49-7.44 (m, 2H), 7.37-7.32 (m, 2H), 7.32-7.27 (m, 1H), 5.12 (s, 2H), 4.74 (s, 2H), 4.00 (s, 3H), 3.75 (s, 3H), 1.51 (s, 9H). LC-MS (ESI) 349.0 (M+H-t-Bu), retention time=2.07 min (Method B).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:13])[N:9]=[C:10]([CH3:12])[CH2:11][C:3]=12.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH3:13][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:3]2[CH2:11][C:10]([CH3:12])=[N:9]1
Reactant: OB(O)c1ccccc1
Reactant: CC1=NN(C)c2ncnc(Cl)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=NN(C)c2ncnc(-c3ccccc3)c2C1
Temperature: 100 °C
Yield: 37.5 %

Procedure:
The 5-chloro-1,3-dimethyl-1,4-dihydropyridazino[3,4-d]pyrimidine (1.1 g), phenyl boronic acid (682 mg) and potassium carbonate (771 mg) were dissolved in toluene (15 mL) and water (1.5 mL). After the reaction mixture was degassed with nitrogen for 30 minute, Pd(PPh3)4 (323 mg) was added. The reaction mixture was again degassed with nitrogen for 20 minutes and then heated to 100° C. for 3 hours in a sealed tube. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (2×20 mL). The combined filtrate was washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography using MeOH/CHCl3 (0.8:9.2) as eluent to afford 1,3-dimethyl-5-phenyl-1,4-dihydropyridazino[3,4-d]pyrimidine (500 mg) as colorless viscous liquid. 1H NMR (DMSO-d6): δ 1.89 (s, 3H), 3.37 (s, 3H), 3.52 (s, 2H), 7.47-7.57 (m, 5H), 8.60 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[O:5])[CH3:3].[Br:6][C:7]1C(O)=NC=[C:11]([I:13])[CH:12]=1.IC.C([O-])([O-])=O.[K+].[K+]>O>[Br:6][C:7]1[C:4](=[O:5])[N:2]([CH3:3])[CH:1]=[C:11]([I:13])[CH:12]=1
Reactant: Oc1ncc(I)cc1Br
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: Cn1cc(I)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with DMF (50 mL), 214a (6.0 g, 20.0 mmol), iodomethane (4.26 g, 30.0 mmol), and K2CO3 (5.52 g, 40.0 mmol). The mixture was stirred at room temperature for 2 h and diluted with water (200 mL). The resulting white solid was collected by filtration to afford 214b (5.97 g, 95%) as a white solid. MS-ESI: [M+H]+ 314
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:18]I.O>CN(C=O)C>[F:3][C:4]1[C:12]2[N:11]([CH3:18])[C:10]3[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1NCCc2[nH]c3c(F)cccc3c21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c3cccc(F)c31)C(=O)NCC2
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in oil; 196 mg) was added to a stirred suspension of 6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (500 mg) in dry DMF (10 ml) under nitrogen. After 30 min the solution was cooled (0°), and methyl iodide (0.153 ml) was added. After stirring for 15 min the suspension was poured into water 950 ml) and extracted with dichloromethane (3×25 ml). The combined, dried organic extracts were evaporated to give a solid (ca. 530 mg) which was purified by FCC eluting with System A (250:10:1) to give the title compound (130 mg), m.p. 242°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].O[CH2:23][C:24]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:26][N:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:23][C:24]2[CH:29]=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:26][N:25]=2)=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C)c1
Reactant: CCOC(=O)CCc1ccnc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccnc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Reaction time: 1 h
Yield: 31.7 %

Procedure:
Under an argon atmosphere, to a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-ol (164 mg), ethyl 3-(2-(hydroxymethyl)pyridin-4-yl)propanoate (99 mg) and triphenylphosphine (248 mg) in THF (1.5 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (430 μL), and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (72 mg) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][CH2:11][C:12]#[N:13])[CH2:7][C:6]=2[CH:14]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])O.[Na+]>>[C:12]([CH2:11][CH2:10][CH:8]1[CH2:7][C:6]2[CH:14]=[C:2]([NH:1][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=[CH:4][C:5]=2[O:9]1)#[N:13]
Reactant: N#CCCC1Cc2cc(N)ccc2O1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)Nc1ccc2c(c1)CC(CCC#N)O2
Yield: 87.8 %

Procedure:
Starting from 2.6 g (14 mmol) of 5-amino-2-cyanoethyl-2,3-dihydrobenzofuran, 1.45 ml (15.2 mmol) of ethyl chloroformate and 1.7 g (21 mmol) of sodium hydrogencarbonate treated under the conditions described in step 6 of Example 1, 3.2 g of product were obtained.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[N+:14]([CH3:17])([O-])=O.[OH-].[Na+].C[C:21]([OH:23])=O>CCO>[I:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:3]=1[CH:4]1[O:5][C:21](=[O:23])[NH:14][CH2:17]1
Reactant: O=Cc1cc(C(F)(F)F)ccc1I
Reactant: CC(=O)O
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1NCC(c2cc(C(F)(F)F)ccc2I)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 0° C. solution of 0.2 g of 2-iodo-5-(trifluoromethyl)benzaldehyde in 3 mL of EtOH was added 0.13 mL of nitromethane, then 0.28 mL of a 2.5 N solution of NaOH. The mixture was stirred at 0° C. for 3 h, and then neutralized by addition of 2.1 mL of a 0.33 N aqueous solution of AcOH. The mixture was partitioned between 10 mL of water and 10 mL of EtOAc. The aqueous phase was extracted with 2×5 mL of EtOAc. The combined organics were washed with 10 mL of brine, dried over Na2SO4, and concentrated. The residue was dissolved in 4 mL of MeOH and 0.5 mL of 88% aqueous formic acid was added. Approximately 200 mg of a Raney nickel slurry was added and the mixture was flushed with H2, and stirred under an H2 balloon for 4 h. The mixture was filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated. The residue was partitioned between 10 mL of 10% aqueous NH4OH and 20 mL of EtOAc. The aqueous phase was extracted with 2×10 mL of EtOAc. The combined organics were washed with 10 mL of brine, dried over Na2SO4, and concentrated. The residue was dissolved in 2 mL of CH2Cl2. To the solution was added 0.114 mL of diisopropylethylamine, then 0.065 g of triphosgene. The mixture was stirred at 0° C. for 30 min, then diluted with 10 mL of EtOAc and 10 mL of saturated NaHCO3. The aqueous phase was extracted with 2×10 mL, of EtOAc. The combined organics were washed with 10 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 4% EtOAc in hexanes, followed by a linear gradient of EtOAc in hexanes from 4 to 100% over 10 CV to provide the title compound. Mass spectrum (ESI) 350.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.00 (d, J=8 Hz, 1H), 7.74 (br s, 1H), 7.33 (br d, J=8 Hz, 1H), 5.80 (dd, J=7 Hz, 9 Hz 1H), 5.05-5.50 (br, 1H), 4.28 (t, J=9 Hz, 1.5H), 3.36 (dd, J=7 Hz, 9 Hz, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[O:13][CH3:14].[C:15]1([CH2:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(=S)=S>[Cl:12][C:11]1[C:6]([Cl:5])=[C:7]([O:13][CH3:14])[CH:8]=[CH:9][C:10]=1[C:22](=[O:23])[CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)Cc2ccccc2)c(Cl)c1Cl
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Aluminum chloride (395 g.) is added portionwise to a stirred solution of 2,3-dichloroanisole (500 g.) and phenylacetyl chloride (392 ml.) in carbon disulfide (1200 ml.) with cooling to 5°C. in an ice-water bath. After the addition, the reaction mixture is allowed to warm to room temperature, whereupon it forms a solid mass. After standing at 20°-25°C. overnight, the reaction vessel is flushed with nitrogen for 15 minutes, and crushed ice (about 2 kg.) and 12N HCl (400 ml.) are slowly added alternately with cooling in an ice bath. The pale yellow gummy solid that precipitates is collected by suction filtration on a sintered glass funnel to remove water as well as carbon disulfide. The solid product is washed well with water and sucked dry. To remove any persistent carbon disulfide, the product is triturated with hexane and again collected by filtration. Yield after drying in a steam oven at 70°C. for 18 hours is 803.5 g. (98%), mp 125°-127°C. A sample recrystallized from benzene-cyclohexane (2:1) melts at 128°-129°C.