Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[CH3:38][O:39][C:40]1[CH:49]=[CH:48][C:43]2B(O)[O:45][CH2:46][C:42]=2[CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[OH:45][CH2:46][C:42]1[CH:41]=[C:40]([O:39][CH3:38])[CH:49]=[CH:48][C:43]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1)=[O:29]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: COc1ccc2c(c1)COB2O
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: COCCOC
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)c(CO)c1
Yield: 99.9 %

Procedure:
Dissolve trifluoro-methanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (300 mg, 0.56 mmol), 5-methoxy-3H-benzo[c][1,2]oxaborol-1-ol(275 mg, 1.7 mmol) and 2M sodium carbonate (0.5 mL, 13 mmol) in dimethoxyethane (5.0 mL). Degas the solution with nitrogen for 15 min. Add tetrakis(triphenylphosphine)palladium (130 mg, 0.11 mmol) and heat at 60° C. for 2 hours. Cool reaction to room temperature and purify on a SCX column to yield 294 mg (100%) of the title compound as a pale yellow foam. 1H NMR (CDCl3) 7.84 (d, J=8.4 Hz, 1H), 7.67 (m, 2H), 7.48 (m, 1H), 7.39 (m, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.23 (d, J=2.5 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 7.03 (bs, 1H), 6.82 (m, 2H), 6.57 (m, 1H), 4.44 (m, 1H), 4.28 (bs, 1H), 4.15 (bs, 2H), 3.94 (s, 3H) 3.78 (s, 3H), 2.81 (bs, 2H), 2.52 (bs, 4H) 1.61 (m, 4H), 1.44 (bs, 2H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[C:13]([O:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:14][C:15]2[O:20][C:19](=[O:21])[C:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[C:17]([CH3:32])[C:16]=2[CH:33]=1.[C:40](Cl)(=[O:42])[CH3:41].O>C1COCC1>[Cl:11][C:12]1[C:13]([O:34][C:35](=[O:39])[N:36]([CH3:37])[CH3:38])=[CH:14][C:15]2[O:20][C:19](=[O:21])[C:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[C:17]([CH2:32][C:40](=[O:42])[CH3:41])[C:16]=2[CH:33]=1
Reactant: Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)c(Cl)cc12
Reactant: CC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)c(Cl)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
LiHMDS (11.5 mL, 1.0 M in THF) was added under nitrogen atmosphere at −78° C. to a suspension of dimethylcarbamic acid 6-chloro-4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester (compound 1g-1-3) (4.0 g, 9.60 mmol) in anhydrous THF (100 mL), and the mixture was stirred at −78° C. for 30 minutes and at 0° C. for 30 minutes. Acetyl chloride (1.36 mL, 19.2 mmol) was then added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. A crude solid was obtained by vacuum concentration, and purified by column chromatography (ethyl acetate:hexane=1:3) to yield the title compound (1.28 g, 29%) as a white powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][C@H:16]([CH3:20])[C:17](O)=[O:18])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:24])=O>CN(C)C=O.C(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][C@H:16]([CH3:20])[C:17]([Cl:24])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a mixture of 675 m9 (2.2 mmol) of (2R)-2-(2,4-di-t-butylphenyloxy)propanoic acid (18) and 4 drops of N,N-dimethylformamide in methylene chloride (20 mL) at 0° C. under a nitrogen atmophere was added 1.21 mL (2.4 mmol) of a 2M solution of oxalyl chloride in methylene chloride dropwise over a 10 min period. The reaction mixture was allowed to stir at room temperature overnight. The solvent and any excess oxalyl chloride was removed by rotary evaporation and dried (under vacuum) to afford 715 mg (99%) of (2R)-2-(2,4-di-t-butylphenyloxy)propanoyl chloride (16) as a crude yellow liquid: 1H NMR (CDCl3) δ1.29 (s, 9 H), 1.42 (s, 9 H), 1.76-1.79 (d, 3 H), 4.94-5.00 (q, 1 H), 6.50-6.(d, 1 H), 7.12-7.16 (d, 1 H), 7.36 (s, 1 H); 13C NMR (CDCl3) δ175.0, 152.8, 144.1, 137.4, 124.6, 123.4, 110.6, 78.6, 35.1, 34.3, 1.5, 30.0, 18.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1([CH2:11]C(O)=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N-:16]=[N+]=[N-].[N-]=C=O>>[NH2:16][CH2:11][C:5]1([CH2:4][C:3]([O:2][CH3:1])=[O:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)CC1(CC(=O)O)CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [N-]=C=O
Product: COC(=O)CC1(CN)CCCCC1

Procedure:
1,1-Cyclohexanediacetic acid monomethyl ester is converted via the corresponding acid chloride into the azide. The azide is degraded by the Curtius method to the isocyanate. The isocyanate is then hydrolyzed to give methyl 1-aminomethyl-1-cyclohexaneacetate. Heating this substance in alkaline methanol under reflux for three days affords 8-azaspiro[5,4]decan-9-one or gabapentin lactam.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:34][C@H:35]([CH2:37][OH:38])[CH3:36]>C1COCC1>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:34][C@H:35]([CH2:37][OH:38])[CH3:36])=[O:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: C[C@H](N)CO
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
4.98 g (20 mmol) N-carbobenzoxy-L-proline, 2.73 g (20 mmol) isobutyl chloroformate, 2.02 g (20 mmol) N-methylmorpholine, and 1.50 g (20 mmol) L-alaninol were contacted and reacted in THF substantially according to the mixed anhydride procedure described in Example 1. Recrystallization of crude product from 50 ml ehtyl acetate provided 3.61 g (11.8 mmol, 59%) of colorless, crystalline N-carbobenzoxy-L-prolyl-L-alaninol; m.p. 126.5°-127.6°, α25D-48.9° (C=1.03 g/100 mL in acetone).
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][C:6]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2C)=[CH:5][N:4]=1.I[C:21]1C=CC(C)=CC=1>>[OH:9][C:8]1[C:3](=[O:2])[NH:4][CH:5]=[C:6]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:21])[CH:18]=2)[CH:7]=1
Reactant: COc1cc(C#Cc2ccccc2C)cnc1OC
Reactant: Cc1ccc(I)cc1
Product: Cc1cccc(CCc2c[nH]c(=O)c(O)c2)c1

Procedure:
Prepared as described for 2,3-dimethoxy-5-[(2-methylphenyl)ethynyl]pyridine (Intermediate 33) but using 1-iodo-4-methylbenzene instead of 1-iodo-2-methylbenzene.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[O:12]=[C:5]1[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=2[C:2](=[O:3])[O:4]1
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)oc(=O)c2ccccc21
Reaction time: 1 h

Procedure:
Isatoic anhydride (10 g, 1 equiv) in dimethylformamide (30 ml) was added dropwise to a suspension of sodium hydride (2.45 g, 60% in mineral oil, 1 equiv) in dimethylformamide (70 ml) at room temperature. The reaction was stirred for 1 hour prior to the addition of ethyl bromoacetate (6.8 ml, 1 equiv) and the resulting mixture stirred for 16 hours. Solvent evaporated, the residue suspended in water and the solid collected. The title compound was obtained by crystallisation from ethyl acetate (10.5 g). 1H-NMR (CDCl3) δ 1.29 (3H, t), 4.27 (2H, q), 4.82 (2H, s), 6.96 (1H, d), 7.33 (1H, t), 7.74 (1H, dt), 8.19 (1H, dd).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1COCC1.I[CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44]>CN(P(N(C)C)(N(C)C)=O)C.CN(C=O)C>[CH3:42][C:43]([CH3:46])([CH3:45])[CH2:44][CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[N:5][C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC(C)(C)CI
Reactant: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CC(C)(C)C)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 9.9 %

Procedure:
To a cooled (−15° C.) solution of methyl 2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)acetate (0.200 g; 0.589 mmol) in a mixture of dry DMF (1.2 mL) and HMPA (0.3 mL) was wadded a 1N solution of KHMDS in THF (0.825 mL; 0.825 mmol) dropwise and the mixture was stirred at (−15° C.) for 15 min, followed by the dropwise addition of 1-iodo-2,2-dimethylpropane (0.313 mL; 2.357 mmol). After stirring for 1 h at (−15° C.) the mixture was allowed to warm up to room temperature and stirring was carried on 4 h. The reaction was quenched by adding a saturated solution of ammonium chloride and the mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.024 g (9%) of the title compound.
Reaction SMILES: O[N:2]=[C:3]1[CH2:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[C:4]1([CH3:12])[CH3:11].[OH-].[NH4+].[H][H]>CO.[Ni]>[NH2:2][CH:3]1[CH2:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[C:4]1([CH3:12])[CH3:11]
Reactant: COC(=O)C1CC(=NO)C1(C)C
Reactant: [H][H]
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1CC(N)C1(C)C
Yield: 82.3 %

Procedure:
To a solution of methyl 3-(hydroxyimino)-2,2-dimethylcyclobutanecarboxylate (1.0 equiv.) in MeOH (0.4 M) was added ammonium hydroxide (0.2 M) and Raney nickel (20 wt percent). The mixture was stirred at 50° C. under 50 psi hydrogen atmospheres for about 6 h. After completion of the reaction, the mixture was filtered through celite. The filtrate was concentrated in vacuo to give the crude title compound methyl 3-amino-2,2-dimethylcyclobutanecarboxylate (82.3% yield) as green liquid. The product was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.56 (s, 3H), 2.50 (s, 0.4H), 2.14 (s, 0.24H), 1.94 (s, 0.35H), 1.71 (s, 0.73H), 1.05 (s, 2.0H), 0.76 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:32][C:25]=3[S:24]4)=[CH:17][CH:16]=2)=[O:13])[CH:7]=1)([CH3:5])[CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:5][C:3]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:37][CH2:38][O:39][CH2:40][CH2:41]5)=[CH:32][C:25]=3[S:24]4)=[CH:19][CH:20]=2)=[O:13])[CH:7]=1)([CH3:4])[CH:2]=[O:1]
Reactant: CC(C)(CO)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C=O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Temperature: 25 °C

Procedure:
A mixture of 1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-1) (1 equivalent) and Dess-Martin periodinane (1-1.5 equivalents) in anhydrous dichloromethane is stirred at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is filtered through Celite and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford 1-[5-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-4a).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C[Mg+].[Br-].[C:29]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][C:32]=1[F:39])#[N:30]>C(Cl)Cl.CCOCC.C1COCC1>[C:29]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:6]=2)[OH:36])=[CH:33][C:32]=1[F:39])#[N:30]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(C=O)cc1F
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: N#Cc1ccc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-iodo-1-(triphenylmethyl)imidazole (2.93 g, 6.71 mmol) in dry CH2Cl2 (30 mL), under argon, was added MeMgBr (2.35 mL of a 3.0M solution in Et2O, 7.05 mmol), dropwise. The resulting solution was stirred at ambient temperature for 1 hour, then transferred dropwise into a stirred solution of 4-cyano-3-fluorobenzaldehyde, as described in Example 11, Step B, (1.00 g, 6.71 mmol) in dry THF (30 mL), under argon, at −78° C. After 30 min, the reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with EtOAc to yield the desired alcohol as a white solid.
Reaction SMILES: [NH2:1][OH:2].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]=O)=[CH:6][CH:5]=1.BrC1C2C(=CC=CC=2)C(Br)=CC=1>C(O)C>[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]=[N:1][OH:2])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(Br)c2ccccc12
Reactant: NO
Agent: Brc1ccc(Br)c2ccccc12
Solvent: CCO
Product: ON=Cc1ccc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An aqueous solution of hydroxylamine (1.25 mL, 50% in water) was added to a stirred solution of 4-bromo-1-naphthalenecarboxaldehyde (3.7 g, 15.7 mmol, prepared from commercially available 1,4-dibromonaphthalene by the method described in European Journal of Organic Chemistry 2006, 10, 2329-2335) in ethanol (30 mL). After stirring at room temperature for 3 h, the reaction mixture was concentrated under reduced pressure to provide the title compound as a pale yellow solid (3.8 g). 1H NMR (Me2S(O)-d6): δ 11.60 (s, 1H), 8.81 (s, 1H), 8.71 (d, 1H), 8.24 (d, 1H), 7.95 (d, 1H), 7.74 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[C@H:13]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[O:11][C@@H:13]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](O)c3ccccc3)CC2)c1
Reactant: COc1ccc(O)cc1OC
Product: COc1ccc(O[C@H](CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1OC

Procedure:
Prepared by Procedure B and Scheme B1 using 3,4-dimethoxyphenol and N-(3-{1-[(2R)-2-hydroxy-2-phenylethyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 503.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[N:8]=[C:7](SC)[CH:6]=[N:5]1)[CH:2]=[CH2:3].Cl.C([OH:16])C>>[CH2:1]([N:4]1[C:9](=[O:10])[NH:8][C:7](=[O:16])[CH:6]=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1ncc(SC)nc1=O
Reactant: CCO
Agent: Cl
Product: C=CCn1ncc(=O)[nH]c1=O
Temperature: 25 °C
Yield: 84.8 %

Procedure:
A mixture of 1.49 g 2-allyl-3-oxo-5-methylthio-2,3-dihydro-1,2,4-triazine, 6 ml conc. hydrochloric acid and 12 ml ethyl alcohol was heated under reflux for 1.5 hours. After cooling to room temperature, the solvent was removed under reduced pressure to obtain a yellow solid. This solid was recrystallized from ethyl alcohol to obtain 1.06 g of a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][NH:11][CH:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].F[C:25]1[C:30]([F:31])=[C:29]([I:32])[CH:28]=[CH:27][N:26]=1.CS(C)=O>C(OCC)(=O)C>[F:31][C:30]1[C:25]([N:11]2[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=3)=[CH:10]2)=[N:26][CH:27]=[CH:28][C:29]=1[I:32]
Reactant: COc1ccc(COc2c[nH]ccc2=O)cc1
Reactant: Fc1nccc(I)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(COc2cn(-c3nccc(I)c3F)ccc2=O)cc1
Temperature: 85 °C

Procedure:
To a 20 mL microwave vial (Biotage) was added 0.70 g (3.03 mmol) 3-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one, 1.26 g (9.08 mmol) potassium carbonate, 1.10 g (4.54 mmol) 2,3-difluoro-4-iodopyridine and 15 mL DMSO. A yellow suspension formed and the vial was sealed and heated at 85° C. for 48 h on a heat block. The suspension was cooled, diluted with ethyl acetate, and washed twice with 10 mL brine. The organic layer was dried over sodium sulfate, filtered, and evaporated onto silica gel. Purification by flash chromatography (silica gel 0-100% hexanes/EtOAc gradient, followed by 10% MeOH in EtOAc) afforded 3′-fluoro-4′-iodo-3-[(4-methoxybenzyl)oxy]-4H-1,2′-bipyridin-4-one as a yellow solid. LCMS (M+H)+ 453.3.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(Cl)Cl>CN(C=O)C>[CH2:30]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([O:8][CH3:7])=[O:17])=[CH:11][CH:12]=1)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
To a thoroughly degassed suspension of K2CO3 (127 g, 921 mmol) in DMF (600 mL) was added methyl-4-hydroxybenzoate (70 g, 461 mmol) and the mixture heated to 70° C. after which was added bromododecane (126 g, 507 mmol) and the reaction allowed to stir at 70° C. under argon for 3 hours, after which TLC (CH2Cl2) showed completion. Reaction was cooled to room temperature and precipitated into cold water. The precipitate was collected by suction filtration and purified by re-crystallization from acetone to give the title compound (140 g, 95%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH2:16][CH3:17])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:18](/[CH3:30])=[CH:19]\[CH:20]=[CH:21]\[C:22](\[CH3:29])=[CH:23]\[C:24]([O:26]CC)=[O:25])[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH2:16][CH3:17])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:18](/[CH3:30])=[CH:19]\[CH:20]=[CH:21]\[C:22](\[CH3:29])=[CH:23]\[C:24]([OH:26])=[O:25])[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/C)c1cc2c(cc1OCC)OC(C)(C)C=C2CC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc2c(cc1/C(C)=C\C=C\C(C)=C\C(=O)O)C(CC)=CC(C)(C)O2

Procedure:
Following General Procedure G, ethyl 7-(7-ethoxy-4-ethyl-2,2-dimethyl-2H-chromen-6-yl)-3-methyl-octa-2E,4E,6Z-trienoate (Compound 35,23 mg, 0.058 mmol) was hydrolyzed with 1M NaOH. Purification by column chromatography (silica gel, 30% ethyl acetate in hexanes) followed by recrystallization from acetonitrile gave rise to the title compound as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[C:23](=[O:24])[CH2:22][N:21]([CH3:25])[C:20]4=[O:26])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:27]#[N:28])[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:30].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[NH4+].[Cl-]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[C:23](=[O:24])[CH2:22][N:21]([CH3:25])[C:20]4=[O:26])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:27]([NH2:28])=[O:30])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CN1CC(=O)N(Cc2ccc3c(-c4ccc(F)cc4)cc(C#N)nc3c2)C1=O
Agent: OO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O
Product: CN1CC(=O)N(Cc2ccc3c(-c4ccc(F)cc4)cc(C(N)=O)nc3c2)C1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
4-(4-Fluorophenyl)-7-[(3-methyl-2,5-dioxoimidazolidin-1-yl)methyl]quinoline-2-carbonitrile (2-2, 44.9 mg, 0.120 mmol, 1.0 equiv.) was dissolved in acetone (1.5 mL)/water (0.75 mL) and sodium percarbonate (188.0 mg, 0.600 mmol, 5.0 equiv) was added. The resulting mixture was stirred at 50° C. for two hours. The mixture was cooled and poured over aqueous NH4Cl (1.0 mL), extracted with ethyl acetate (3×5.0 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 4-(4-fluorophenyl)-7-[(3-methyl-2,5-dioxoimidazolidin-1-yl)methyl]quinoline-2-carboxamide (2-3, 35.3 mg, 75.0%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 8.498 (br s, 1H); 8.221 (d, J=1.29 Hz, 1H); 8.180 (s, 1H); 7.947 (d, J=8.60 Hz, 1H); 7.672 (dd, J1=8.79 Hz, JZ=1.83 Hz, 1H); 7.532 (br s, 1H); 7.462-7.512 (m, 2H); 7.219-7.276 (m, 2H); 4.918 (s, 2H); 3.985 (s, 2H); 3.040 (s, 3H). LRMS m/z (M+H)+ 393.1 found, 393.1 required.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]=[N+]=[N-])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4]>C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH2:10])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4]
Reactant: COC(=O)C1CC(N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(N)CN1C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
4-Azido-pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (303.10 mg, 1.12 mmol) was taken up in ethyl acetate in a Paar vessel. The solution was flushed with argon and Pd/C (400.00 mg) was added to the vessel. The argon atmosphere was replaced by hydrogen at 50 psi. The vessel was shaken for 12 h. The hydrogen atmosphere was replaced by argon and the solution was filtered through a celite pad. The pad was washed twice with ethyl acetate. The solvent was removed under reduced pressure. The product was used without further purification. Yield 262.66 mg. C11H20N2O4 MS m/e=244.2 (M+).