Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:6]=[N:7][C:8]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)(=O)=O.[OH-:24].[K+].Cl>O.C1COCC1>[C:11]1([C:9]2[C:8]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[N:7][NH:6][C:5](=[O:24])[N:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [OH-]
Reactant: Cc1ccc(-c2nnc(S(C)(=O)=O)nc2-c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2n[nH]c(=O)nc2-c2ccccc2)cc1
Yield: 92.1 %

Procedure:
To a solution of 3-(methylsulfonyl)-5-phenyl-6-p-tolyl-1,2,4-triazine (98.9 mg, 0.304 mmol) in a 1:1 mixture of H2O/THF (6.0 mL) was added potassium hydroxide (109.1 mg, 1.945 mmol). The mixture was heated at reflux for 1 h. The reaction mixture was cooled to room temperature and neutralized with 1 M HCl, then extracted with CH2Cl2. The combined organic phases were washed with H2O and brine, dried over MgSO4, and concentrated to give the title compound as a yellow solid (73.7 mg). LCMS m/z=264.1 [M+H]+.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[CH2:9]([O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:15])[CH:10]=[CH2:11].C>O1CCOCC1>[N-:15]=[C:4]=[O:3].[CH2:9]([O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[NH2:15])[CH:10]=[CH2:11]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: C=CCOC(=O)[C@@H](N)CC(C)C
Solvent: C1COCCO1
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of leucine allyl ester, prepared as described by H. Waldmann and H. Kunz in Liebigs Ann. Chem., 1983, 1712-1725, and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give leucine allyl ester isocyanate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8](Cl)[N:7]=1.C(=O)([O-])[O-:15].[K+].[K+]>O1CCOCC1.O>[Cl:12][C:10]1[CH:11]=[C:6]2[NH:5][CH2:4][CH2:3][CH2:2][N:7]2[C:8](=[O:15])[N:9]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1cc(NCCCBr)nc(Cl)n1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1nc(Cl)cc2n1CCCN2
Temperature: 60 °C
Reaction time: 2 h
Yield: 232.5 %

Procedure:
To a solution of N-(3-bromopropyl)-2,6-dichloropyrimidin-4-amine (2.0 g, 7.02 mmol) in 1,4-dioxane (15 mL) and water (15 mL) was added potassium carbonate (2.0 g, 14.47 mmol), stirred for 2 h at 60° C. and then concentrated. The residue was neutralized to pH˜6 by hydrochloride solution (6M), extracted by ethyl acetate to remove byproduct, and then neutralized by sodium hyroxide (2M) to pH˜7. The water was removed in vacuum to afford the title compound (3.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:28]1(CS(Cl)(=O)=O)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH2:26][CH:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)(=[O:24])=[O:25])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)CC1CCCC1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Product: O=S(=O)(CC1CCCC1)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 58 %

Procedure:
According to the procedure for compound 398 using cyclopentylmethyl sulfonyl chloride (30 mg, 0.16 mmol) afforded 26.7 mg (58% yield) of 479, as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.[C:23]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24]1.O>C(COC)OC>[C:19]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:11]=1[OH:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)c1cc(-c2ccc(NC(=O)CCCC(=O)O)cc2)cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
To a hot (70° C.) solution of 10.0 g (0.0336 mole) of the known compound 4'-amino-3,5-di-tertiary-butyl-4-hydroxybiphenyl in 100 ml of glyme was added 5.0 g (0.044 mole) of glutaric anhydride. After stirring for one hour, the mixture was cooled and poured into water. The precipitate was separated by filtration and recrystallized from a chloroform-hexane mixture to provide tan needles of N-(3',5'-di-tertiary-butyl-4'-hydroxy-4-biphenylyl)glutaramic acid, m.p. 217.5°-219° C. Analysis: Calculated for C25H33NO4 : % C, 73.0; % H, 8.1; % N, 3.4; Found: % C, 72.6; % H, 8.1; % N, 3.1.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]([C:16](=[O:37])[CH2:17][CH:18]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])[CH2:7][C:6]1=[O:38].[OH-].[Li+].Cl>C1COCC1.O>[C:33]([O:32][C:30]([NH:29][CH:18]([CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[F:28])[CH2:17][C:16]([N:8]1[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:5]([CH2:4][C:3]([OH:39])=[O:2])[C:6](=[O:38])[CH2:7]1)=[O:37])=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)CN1C(=O)CN(C(=O)CC(Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)Cc2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CC(=O)N1CC(=O)N(CC(=O)O)c2ccccc2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a stirred solution of {4-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-2-oxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-acetic acid methyl ester (90 mg, 0.16 mmol) in THF (2 mL) and water (2 mL), was added lithium hydroxide (40 mg, 0.95 mmol). The reaction mixture was stirred at r.t. overnight. After the completion of the reaction as confirmed by TLC, the reaction mixture was cooled to 0° C. and neutralized with 10% HCl solution and the pH was adjusted to 1. The crude compound was extracted with ethylacetate (10 mL). The organic layer was washed with water, dried over Na2SO4. The solvents were removed in vacuo to afford {4-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-2-oxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-acetic acid (70 mg, 82%) as a viscous oil.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[CH:21](O)[CH2:22][CH2:23][C:24]1([C:41]([O:43][CH3:44])=[O:42])[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][O:32][C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])[CH2:26][CH2:25]1)=[CH:18][C:17]([O:46][CH3:47])=[CH:16][CH:15]=2.C(=O)([O-])O.[Na+]>ClCCl>[Cl:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[CH:21]([F:7])[CH2:22][CH2:23][C:24]1([C:41]([O:43][CH3:44])=[O:42])[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][O:32][C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])[CH2:28][CH2:29]1)=[CH:18][C:17]([O:46][CH3:47])=[CH:16][CH:15]=2
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)C1(CCC(O)c2c(Cl)cnc3ccc(OC)cc23)CCN(CCOc2cc(F)ccc2F)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1(CCC(F)c2c(Cl)cnc3ccc(OC)cc23)CCN(CCOc2cc(F)ccc2F)CC1
Temperature: 3 °C

Procedure:
0.2 cm3 of diethylaminosulfur trifluoride was added to a solution of 0.5 g of methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]-1-[2-(2,5-difluorophenoxy)ethyl]piperidine-4-carboxylate in 20 cm3 of dichloromethane, with stirring and under an inert atmosphere, at a temperature in the region of 3° C. After stirring for 7 hours at a temperature in the region of 20° C., saturated sodium hydrogencarbonate solution was added to the reaction mixture. The aqueous phase was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200μ; diameter 1.5 cm; mass: 15 g), eluting with a mixture of ethyl acetate/petroleum ether (40-60° C.) (8/2 by volume). Fractions 9 to 11 were combined and then concentrated to dryness under the above conditions. 0.21 g of methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(2,5-difluorophenoxy)ethyl]piperidine-4-carboxylate was obtained in the form of a thick yellow oil.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([OH:16])=[C:9]([C:14]#[N:15])[CH:10]=[N:11]2)=[CH:6][CH:5]=1.[CH3:17][O:18][CH2:19][CH2:20][OH:21]>>[CH3:17][O:18][CH2:19][CH2:20][O:21][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:16])[C:9]([C:14]#[N:15])=[CH:10][NH:11]2)=[CH:6][CH:5]=1
Reactant: COCCO
Reactant: N#Cc1cnc2cc(F)ccc2c1O
Agent: [H-]
Agent: [Na+]
Product: COCCOc1ccc2c(=O)c(C#N)c[nH]c2c1
Temperature: 25 °C

Procedure:
A mixture of sodium hydride (500 mg, 12.5 mmol) and 7-fluoro-4-hydroxyquinoline-3-carbonitrile (1.30 g, 6.9 mmol) in 2-methoxyethanol (30 mL) is heated at reflux overnight. Additional sodium hydride (250 mg, 6.25 mmol) is added and the reaction mixture is heated at reflux overnight. Additional sodium hydride (250 mg, 6.25 mmol) is added and the reaction mixture is heated at reflux for 8 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The basic layer is acidified with aqueous HCl and the resultant solid is collected by filtration to provide 1.05 g of 7-(2-methoxyethoxy)-4-oxo-1,4-dihydroquinoline-3-carbonitrile as a white solid, mp>250° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19]CN(C3C=NC(OC)=CC=3)C[CH2:15]2)[CH2:11][C@H:10]1[NH:28][C:29](=[O:44])[CH2:30][NH:31][C:32](=[O:43])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1)[C:2]1C=CC=C[CH:3]=1.O[C@@H]1CN(C2C[CH2:55][O:54][CH2:53]C2)C[C@H]1NC(=O)CNC(=O)C1C=CC=C(C(F)(F)F)C=1.C(OC(NC1C(O)CN(C(OCC2C=CC=CC=2)=O)C1)=O)(C)(C)C.C(Br)C=C.C(Br)C1C=CC=CC=1>>[CH2:1]([O:8][C@@H:9]1[CH2:13][N:12]([CH:14]2[CH2:15][CH2:55][O:54][CH2:53][CH2:19]2)[CH2:11][C@H:10]1[NH:28][C:29](=[O:44])[CH2:30][NH:31][C:32](=[O:43])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:41])([F:40])[F:42])[CH:34]=1)[CH:2]=[CH2:3]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CN(C2CCOCC2)C[C@H]1O
Reactant: COc1ccc(N2CCC(N3C[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)[C@H](OCc4ccccc4)C3)CC2)cn1
Agent: BrCc1ccccc1
Agent: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CC1O
Solvent: C=CCBr
Product: C=CCO[C@@H]1CN(C2CCOCC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was synthesized in similar fashion to rel-N-[2-({(3R,4R)-4-(benzyloxy)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, rel-N-(2-{[(3R,4R)-4-hydroxy-[1-tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide was substituted for benzyl rac-(3R,4R)-3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylate and allyl bromide was substituted for benzyl bromide. The title compound was isolated as a white solid. 1H-NMR (CDCl3) δ: 1.56 (m, 2H), 1.76 (m, 2H), 2.34-2.48 (m, 2H), 2.80 (m, 2H), 3.30-3.42 (m, 3H), 3.84 (m, 1H), 3.93-4.03 (m, 3H), 4.13 (m, 2H), 4.18 (m, 1H), 4.34 (m, 1H), 5.14 (m, 1H), 5.26 (m, 1H), 5.87 (m, 1H), 6.66 (b, 1H), 7.13 (b, 1H), 7.57 (t, J=7.4 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 8.05 (d, J=7.7 Hz, 1H), 8.09 (s, 1H). MS m/z: 456 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH:15]1([CH2:18][O:19][C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[C:22]([C:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=2)=[CH:23][NH:24]3)[CH2:17][CH2:16]1.[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37]>C(OCC)(=O)C>[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:32]3[CH2:33][CH:34]=[C:29]([C:22]4[C:21]5[C:25](=[CH:26][CH:27]=[CH:28][C:20]=5[O:19][CH2:18][CH:15]5[CH2:16][CH2:17]5)[NH:24][CH:23]=4)[CH2:30][CH2:31]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: C1=C(c2c[nH]c3cccc(OCC4CC4)c23)CCNC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: C1=C(c2c[nH]c3cccc(OCC4CC4)c23)CCN(CCCOc2cccc3[nH]ccc23)C1

Procedure:
The title compound was prepared in similar fashion from 1-chloro-3-(1H-indole-4-oxy)propane and 4-(4-cyclopropylmethoxy-1H-indol-3-yl)-1,2,3,6-tetrahydropyridine (which was prepared by condensing 4-cyclopropylmethoxyindole with 4-piperidone monohydrate hydrochloride in refluxing methanol with potassium hydroxide). The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 20% overall yield as a white foam. FDMS m/e=441 (M+ of free base).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:6]1[C:7]2[C:12](=[C:11]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]=[CH:9][CH:8]=2)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5]1)[CH3:29]
Reactant: CC(C)(C)OC(=O)Cc1cccc2[nH]cc([N+](=O)[O-])c12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc([N+](=O)[O-])c2c(CC(=O)OC(C)(C)C)cccc21
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl [3-nitro-1H-indol-4-yl]acetate from Step D (385 mg, 1.39 mmol) in DMF (5 mL) at ambient temperature was added sodium hydride (60 mg of a 60% dispersion in mineral oil, 1.50 mmol). The reaction mixture was stirred for 5 min, then ethyl bromoacetate (256 mg, 1.53 mmol) was added and stirring was continued for 10 min. The reaction was quenched with saturated aqueous NaHCO3 (5 mL) and extracted with CHCl3 (2×25 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 40:60, to give the title compound. MS: m/z=307 (M−C4H7).
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:8]([CH3:10])([CH3:9])[CH:7]1[C:11]#[N:12])=[O:5])C.[OH-].[K+].Cl>O.C(O)C>[C:11]([CH:7]1[C:8]([CH3:10])([CH3:9])[CH:6]1[C:4]([OH:5])=[O:3])#[N:12]
Reactant: CCOC(=O)C1C(C#N)C1(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)C(C#N)C1C(=O)O
Reaction time: 15 h
Yield: 76.2 %

Procedure:
A suspension of 33.4 g (0.2 mol) of 2-cyano-3,3-dimethyl-cyclopropane-carboxylic acid ethyl ester and 16.8 g (0.3 mol) of potassium hydroxide in 200 ml of water and 100 ml of ethanol was stirred at 20°-25° C. for 15 hours. The alcohol was then stripped off and the aqueous solution was acidified with dilute hydrochloric acid and extracted twice with 100 ml of ether (or methylene chloride) each time. The combined organic extracts were dried over Na2SO4 and concentrated and the residue was distilled. 21.2 g (76% of theory) of 2-cyano-3,3-dimethyl-cyclopropane-carboxylic acid were obtained in the form of an oil of boiling point 110°-120° C., which crystallized on cooling (melting point: 101°-106° C.). ##STR45##
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].[Cl:18][C:19]1[C:20](Cl)=[N:21][CH:22]=[C:23]([CH:29]=1)[C:24]([NH:26][CH2:27][CH3:28])=[O:25]>COCCOC.O.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>[Cl:18][C:19]1[C:20]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)=[N:21][CH:22]=[C:23]([CH:29]=1)[C:24]([NH:26][CH2:27][CH3:28])=[O:25]
Reactant: CCNC(=O)c1cnc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(B(O)O)cc1
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
Solvent: O
Product: CCNC(=O)c1cnc(-c2ccc(C=O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
2.44 g of Na2CO3 (23.0 mmol), 1.15 g of 4-formylphenylboronic acid (7.67 mmol), and 0.21 g of Pd(PPh3)4 were added to 1.68 g of 5,6-dichloro-N-ethyl-nicotinamide (5) (7.67 mmol) prepared in Example 2 dissolved in 30 mL of 1,2-dimethoxyethane and 30 mL of distilled water, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, concentrated about 50% under reduced pressure to extract the aqueous layer with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 5-chloro-N-ethyl-6-(4-formyl-phenyl)-nicotinamide 1.78 g (yield 80%).
Reaction SMILES: C([Li])CCC.[I:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16]>O1CCCC1.CCCCCC>[CH2:19]([O:18][C:15](=[O:17])[CH:16]=[CH:11][C:10]1[CH:13]=[CH:14][C:7]([I:6])=[CH:8][CH:9]=1)[CH3:20]
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C=Cc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred, cooled (−78° C.) solution of triethylphosphonoacetate (11.1 mL, 56 mmol) in anhydrous tetrahydrofuran (100 mL) was treated with a 1.6M solution of n-butyl lithium in hexanes (27 mL, 43.75 mmol). After 10 min, the reaction mixture was cannulated into a cooled (−78° C.) solution of 4-iodo-benzaldehyde (6.5 g, 28 mmol) in tetrahydrofuran (20 mL). The reaction mixture was allowed to warm to 0° C. over 1 h. It was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford an oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 6-8% ethyl acetate in hexane as the eluent to afford the title compound (2.7 g pure, 3.2 g ˜95% pure, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH:25]([O:28][CH3:29])[O:26][CH3:27])[CH:17]=1.O>CC(N(C)C)=O>[CH3:29][O:28][CH:25]([O:26][CH3:27])[C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[N+:22]([O-:24])=[O:23])[O:8][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
3-Amino-phenol (0.050 mol) was dissolved in DMA (100 ml). K2CO3 (0.050 mol) was added. 4-Chloro-2-dimethoxymethyl-1-nitro-benzene (0.050 mol) was added and the reaction mixture was stirred overnight at 100° C., then for 2 hours at 120° C. The reaction mixture was poured out into water and this mixture was extracted with diisopropyl ether. The separated organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2:CH3OH 100:0 (to remove starting material) up to 70:30). The desired fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([CH3:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[C:29](O)(=[O:32])[CH:30]=[O:31].O>ClCCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]([CH3:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]2[O:11][C:30](=[O:31])[CH:29]([OH:32])[C:9]=2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CC(=O)O
Reactant: CCCCCCCCCCCCCCC(C)c1cc(C(C)(C)C)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCCl
Product: CCCCCCCCCCCCCCC(C)c1cc(C(C)(C)C)cc2c1OC(=O)C2O
Yield: 99.6 %

Procedure:
18.7 g of 4-tert-butyl-2-(1-methyl-pentadecyl)-phenol (J.Amer.Chem.Soc., 74, 1952, 3599), 5.06 g of glyoxylic acid monohydrate and 0.05 g of p-toluenesulfonic acid are heated in 40 ml of 1 ,2-dichloroethane for 7 hours using a water separator. The reaction solution is then cooled, washed three times with 80 ml of water each time and freed of solvent using a rotary evaporator. 21.4 g of 5-tert-butyl-3-hydroxy-7-(1-methyl-pentadecyl)-3H-benzo-furan-2-one are obtained in the form of a yellowish oil. That yellowish oil is placed in 25 ml of toluene with 8 ml of thionyl chloride and 3 drops of DMF and the reaction mixture is then slowly heated to 373 K at such a rate that the evolution of HCl and SO2 remains vigorous yet controllable. The reaction mixture is then stirred at that temperature for a further hour. Approximately 25 ml of liquid are then distilled off in order to remove the excess thionyl chloride. The residue is diluted with 80 ml of toluene and, at room temperature, 7 ml of triethylamine are added dropwise thereto. The thick, red reaction mixture is then heated under reflux for 30 min. After cooling to room temperature, the triethylamine hydrochloride which has precipitated is filtered off and the filtrate is concentrated to an oily consistency using a rotary evaporator. The isoxindigo is isolated from the residue, in the form of a waxy red mass, by chromatography on silica gel (hexane/ethyl acetate 99:1). 4.1 g (20% of the theoretical yield, based on 4-tert-butyl-2-(1-methyl-pentadecyl)-phenol) of 5,5′-di-tert-butyl-7,7′-bis(1-methyl-pentadecyl)-[3,3′]bibenzofuranylidene-2,2′-dione of formula (LIIIa) are obtained.
Reaction SMILES: CC(C)=O.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.[C:35]([OH:40])(=[O:39])[C@H:36]([CH3:38])[OH:37]>O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.[C:35]([O-:40])(=[O:39])[CH:36]([CH3:38])[OH:37]
Reactant: C[C@H](O)C(=O)O
Agent: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Solvent: O
Solvent: CC(C)=O
Product: CC(O)C(=O)[O-]

Procedure:
A suitable reactor is charged with acetone (50 mL). The acetone solution is sequentially charged with carvedilol (15.0 grams) and water (7 mL). Upon addition of the water, the slurry dissolves completely with heating. To the solution is added 1N aqueous D, L-Lactic acid (1 equiv., 36.9 mL). The reaction mixture is stirred at between 17° C. and 35° C. and seeded in one portion. The solid precipitate is formed over 10 hours to 24 hours. Later, the mixture is filtered and the cake is washed with a mixture of acetone and water (10 to 1) at 2 volume or 30 mL. The cake is dried under vacuum to a constant weight. The final weight is 9.16 grams.