Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:14]=1[O:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]=[CH:19][O:18]1>C(OCC)C.O=P(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:12][C:13]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:14]=1[O:15][CH2:16][C@@H:17]1[O:18][C@@H:19]([O:11][CH:3]([C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=2)[CH2:2][Br:1])[CH2:20][CH2:21][CH2:22]1
Reactant: OC(CBr)c1ccc(Cl)cc1
Reactant: Clc1ccc(OCC2CCC=CO2)c(Cl)c1
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Clc1ccc(C(CBr)O[C@H]2CCC[C@H](COc3ccc(Cl)cc3Cl)O2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.3 %

Procedure:
To a solution of 259 mg of α-bromomethyl-4-chlorobenzyl alcohol and 311 mg of 2-(2,4-dichlorophenoxymethyl)-3,4-dihydro-2H-pyran in 6 ml of diethyl ether was added one drop of phosphorus oxytrichloride, and the mixture was stirred at room temperature for 1 day. After 3 drops of triethylamine had been added, the solvent was evaporated off under reduced pressure and the residue was purified by column chromatography through silica gel eluted with a 5:50:11 by volume mixture of benzene, hexane and ethyl acetate, to give 147 mg of the isomer of lesser polarity of trans-6-(2,4-dichlorophenoxymethyl)-2-[2-bromo-1-(4-chlorophenyl)ethoxy]tetrahydropyran melting at 86°-87° C., 165 mg of the isomer of greater polarity melting at 97°-98° C., and 80 mg of a mixture thereof.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>O>[N:1]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(Br)cc1
Reactant: C1COCCN1
Solvent: O
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Yield: 59.6 %

Procedure:
A mixture of morpholine (3 g, 34 mmol) and 4-bromobenzonitrile (1.95 g, 10.7 mmol) is heated at 120° C. The conversion of the 4-bromobenzonitrile is complete after 24 hours. Water (10 ml) is then added into the reaction mixture. The precipitate is filtered off, washed with water and dried under vacuum (30° C.). Recrystallisation (50% aqueous ethanol) of the dried crude product gives 1.2 g of the title-compound. Yield: 65%, m.p. 82-83° C.; MS 188 (100, M+); H1 NMR (CDCl3): δ 7.46 (dd, 2H), 6.81 (dd, 2H), 3.79 (t, 4H), 3.22 (t, 4H); C13 NMR (CDCl3): δ 153.69, 133.71, 120.07, 114.26, 101.16, 66.65, 47.49.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[N:11]([CH2:19][CH3:20])[CH:10]=[C:9]([C:21](O)=[O:22])[C:8]2=[O:24])(=[O:3])[CH3:2].S(Cl)([Cl:27])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[N:11]([CH2:19][CH3:20])[CH:10]=[C:9]([C:21]([Cl:27])=[O:22])[C:8]2=[O:24])(=[O:3])[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(OC(C)=O)c(OC(C)=O)cc21
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)Cl)c(=O)c2cc(OC(C)=O)c(OC(C)=O)cc21

Procedure:
A mixture of 6,7-diacetoxy-1-ethyl-1,4-dihydro-4-oxoquinoline-3-caroxylic acid (60 mg), thionyl chloride (40 μL), and dimethylformamide (one drop) was heated under reflux for 3 hours in benzene (40 mL), and then the solvent was evaporated. To the residue was added benzene (20 mL). Benzene was evaporated and the residue was vacuum dried to give 6,7-diacetoxy-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carbonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.O>ClCCl>[CH2:19]([O:18][C:16]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]2[C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:22]2=[O:24])[CH2:15][CH2:14]1)=[O:17])[CH3:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)N1CCC(Nc2c(C)cccc2N)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3cccc(C)c32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
4-[(2-Amino-6-methylphenyl)amino]-1-ethoxycarbonylpiperidine (75.2 mg) was dissolved in dichloromethane (1.5 ml), added with triphosgene (80.5 mg) and triethylamine (76 μl) and stirred at room temperature for 2 hours. The reaction mixture was added with water (5 ml) and extracted twice with ethyl acetate (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=1:1) to obtain 59.1 mg of the title compound. Yield: 72%.
Reaction SMILES: [CH:1]1([C:4](=O)[CH:5]([CH3:13])[C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[NH:16][NH2:17]>C(O)C>[CH:1]1([C:4]2[N:16]([C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:17]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]=2[CH3:13])[CH2:3][CH2:2]1.[CH:1]1([C:4]2[C:5]([CH3:13])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:16]([C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:17]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)C(C)C(=O)C1CC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Product: CCOC(=O)c1c(C)c(C2CC2)nn1C(=O)OC(C)(C)C
Product: CCOC(=O)c1nn(C(=O)OC(C)(C)C)c(C2CC2)c1C
Yield: 190.3 %

Procedure:
49.2 g of ethyl 4-cyclopropyl-3-methyl-2,4-dioxobutanoate 1-13-1 (248 mmol, 1.0 eq.) and 32.81 g of tert-butyl carbazate were refluxed for 4 hours in 200 mL of ethanol. The mixture was concentrated in vacuo. The residue was purified by flash chromatography to provided 2.17 g (7.37 mmol, 3.0%) of analytically pure target compound and 69.6 g (236 mmol, 95%) of a mixture of regioisomers which was used for the following step without further purification.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:15]([OH:18])[CH2:16]Cl)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C.ClCCl>[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:15]1[O:18][CH2:16]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
A solution of potassium hydroxide (6.52 g. 0.116 mol, 1.2 equiv.) in 970 mL of absolute ethanol was treated with N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol (32.3 g, 0.097 mol). This solution was stirred at room temperature for 15 minutes and then concentrated in vacuo to give a white solid. The solid was dissolved in dichloromethane and washed with water, dried over anhyd MgSO4, filtered and concentrated in vacuo to give a white solid. The solid was crystallized from hexanes and ethyl acetate to give 22.3 g, 77% of 3(S)-[N-(benzyloxycarbonyl) amino]-1,2(S)-epoxy-4-phenylbutane, mp 102-103° C., FAB MS: MH+ =298.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]([NH:12][C:13]1[N:18]=[N:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=1)=[O:11].[Li+].[OH-]>CO.C1COCC1.O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]([NH:12][C:13]1[N:18]=[N:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)=[O:11]
Reactant: COC(=O)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-(isoindoline-2-carboxamido)pyridazine-3-carboxylate (3.7 g, 12.4 mmol) in MeOH (40 mL) and THF (40 mL), a solution of LiOH (0.7 g, 29.2 mmol) in water (10 mL) was added at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water (100 mL), extracted with EtOAc (2×50 mL) and the aqueous layer was acidified by addition of 2 NHCl to pH 3 to give a precipitate. The precipitate was washed with water and dried in high vacuum to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([OH:24])[C:21]([F:25])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].[CH3:26]OC(OC)N(C)C.CO.Cl>C1C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[C:11](=[CH:20][C:21]([F:25])=[C:22]([OH:24])[N:23]=2)[C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:26]1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Agent: Cl
Solvent: CO
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(O)c(F)cc2c1=O
Yield: 38.9 %

Procedure:
In 2 ml of benzene was suspended 200 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinoyl]acetate, and 87 mg of N,N-dimethylformamide dimethylacetal was added thereto, after which the resulting mixture was subjected to reaction under reflux for 10 hours. Thereafter the crystals thus deposited were collected by filtration. To the crystals thus obtained were added 0.5 ml of methanol and 1 ml of water, and the pH thereof was adjusted to 1.0 with 2N hydrochloric acid, after which the crystals thus deposited were collected by filtration to obtain 80 mg (yield 38.9%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 243°-248° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[CH3:32][N:33]([CH2:35][C:36]#[CH:37])[CH3:34]>O1CCCC1.C(N(CC)CC)C.[Cu]I.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>[CH3:32][N:33]([CH3:34])[CH2:35][C:36]#[C:37][C:28]1[CH:29]=[CH:30][C:25](/[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(I)cc2)cc1C
Reactant: C#CCN(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(C#CCN(C)C)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (Z)-[4-[3-(4-Fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.75 mmol; example 10 was dissolved in a mixture of anhydrous tetrahydrofuran (10 mL) and anhydrous triethylamine (20 mL). The solution was degassed and a solution of N,N-dimethylpropargylamine (125 mg, 1.50 mmol) in anhydrous tetrahydrofuran (2 mL) was added under inert atmosphere. The resulting solution was degassed once more, copper(I) iodide (23 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) were added and the mixture was degassed again. The reaction mixture was stirred at ambient temperature overnight and the resulting suspension was filtered through a paddle of silica gel. Silica gel was washed thoroughly with ethyl acetate; the filtrate was evaporated in vacuo and the residue was dissolved in dichloromethane (50 mL). The solution was washed with water (2×30 mL) and brine (2×30 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, dichloromethane/methanol 99:1) yielding methyl (E)-[4-[3-[4-[3-(dimethylamino)propynyl)-phenyl]-3-(4-fluorophenyl)allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: O[C:2]1[CH:7]=CN=C[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:41][O:42][CH:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]CCC)[CH2:44][OH:45]>C1COCC1.N1C=CC=CC=1>[CH3:41][O:42][CH:43]([CH:46]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:3][CH2:2][CH3:7])[CH2:44][OH:45]
Reactant: CCCCCCCCCCCCCCCCC(CO)OC
Reactant: Oc1ccncc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCC(CCC)C(CO)OC
Reaction time: 8 h
Yield: 199.7 %

Procedure:
Preparation of pyridine terminated 4-hexadecylethylene glycol monomethylether (Ligand 2). 4-hydroxypyridine (2.0 g, 22 mmol), triphenylphosphine (6.3 g, 24 mmol), and diisopropyl azodicarboxylate (4.8 g, 24 mmol) in THF (250 mL) were stirred at room temperature under nitrogen for 30 min.; hexadecylethylene glycol monomethylether (14.3 g, 20 mmol) was added, and the mixture was stirred overnight. THF was removed under vacuum, and the residue was purified by column chromatography eluting with chloroform:acetone:methanol mixtures to yield 2 (12.0 g, 78%). 1H NMR (300 MHz, CDCl3) δ 8.42 (d, aromatic), 6.82 (d, aromatic), 4.15 (t, pyr-O—CH2—CH2), 3.86 (t, pyr-O—CH2—CH2), 3.66 (br, CH2, 3.37 (s, CH3) ppm; 13C NMR (75 MHz, CDCl3) δ 164.7, 150.9, 110.2, 72.6, 71.8, 70.8, 70.4, 70.1, 67.1, 69.2, 58.9 ppm; HRMS calcd. 769.4441; Found M−H 768.4385.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:35]1([CH2:41][CH2:42][C:43](Cl)=[O:44])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:43](=[O:44])[CH2:42][CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)CCc1ccccc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with 3-phenyl-propionyl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H41N2O2Cl2 [(M+H)+] 627.2540, observed 627.2541.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)[C:11]([O:13]CC)=[O:12])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2].[OH-].[Na+].C(Cl)Cl.CO.[NH4+].[OH-]>CO>[C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)[C:11]([OH:13])=[O:12])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCc1cc(C(=O)OC)ccc1OC(C(=O)OCC)c1ccc2c(c1)OCO2
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc(C(=O)OC)ccc1OC(C(=O)O)c1ccc2c(c1)OCO2
Yield: 96.4 %

Procedure:
To a nitrogen flushed 5 L 3 neck round bottom flask equipped with a mechanical stirrer, a dropping funnel, and a nitrogen inlet was charged with 697.3 g (1.68 mol) of the crude product of Step A and 2 L of methanol. 500 mL of 5.0N (1.5 eq) aqueous sodium hydroxide was added over a 20 minute period via an addition funnel. The reaction mixture was stirred at room temperature for an additional 1 hr at which point TLC analysis (CH2Cl2 --MeOH--NH4OH 90:10:1) indicated that the starting material had been consumed. The reaction mixture neutralized with 420 mL of 6N HCl, and the bulk of the organic solvent was removed in vacuo. The residue was dissolved in ether and extracted with a combination of aqueous NaOH and NaHCO3. The aqueous layer was extracted with ether and the combined organic layer was washed with aqueous NaHCO3. The aqueous layer was acidified with HCl and extracted with ether. The ether solution was dried with magnesium sulfate, filtered, and concentrated to afford 708.9 g (theoretical 625 g) of the title compound as a viscous orange oil. NMR indicated that it was ca 85% product by weight (15% ether) thus providing a corrected yield of 602.6 g (96.4% yield)
Reaction SMILES: [C:1]([N:8]1[C@H:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([N:8]1[C@H:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:13][CH:14]=2)[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CCOC(=O)[C@@H]1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2CN1C(=O)OC(C)(C)C
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)[C@@H]1Cc2ccc(-c3ccccc3)cc2CN1C(=O)OC(C)(C)C

Procedure:
The triflate from Step 2 was coupled with phenyl boronic acid following the procedure of Example 11 to give the title compound as an oil.
Reaction SMILES: [H-].[Na+].CI.[Br:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[CH:11]2.[C:15]([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH3:15][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[Br:5])[CH:11]=[CH:12]1
Reactant: O=C([O-])O
Reactant: Brc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1ccc2cccc(Br)c21
Reaction time: 1 h

Procedure:
A 60% dispersion of sodium hydride in mineral oil (1.40 g, 97 mmol) was washed with hexanes (3×10 mL, 1×5 mL), suspended in THF (50 mL) and CH3I added (1.64 mL, 26.3 mmol) followed by a solution of 7-bromoindole (4.06 g, 20.7 mmol) in THF (15 mL), with vigorous gas evolution. After 1 h at rt, the mixture was treated with additional CH3I (0.28 mL, 4.5 mmol) and stirred overnight. Saturated aq NaHCO3 was added and the mixture poured into EtOAc, which was separated, washed with saturated aq NaHCO3, dried (MgSO4) and concentrated to afford 1-methyl-7-bromoindole as an off-white semisolid which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Na+].[Na+].[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>O1CCOCC1.CCOCC.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:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)c1cc(C(=O)OC)cc(-c2cccc(Cl)c2)c1
Temperature: 90 °C

Procedure:
To dimethyl 5-bromoisophthalate (880 mg, 3.22 mmol) (commercial source: Matrix scientific) in 1,4-dioxane (15 ml), 3-chlorophenyl boronic acid) (756 mg, 4.83 mmol), sodium carbonate (2M aqueous solution) (1.38 gms in 6.5 ml water) and Pd(PPh3)4 (370 mg, 0.32 mmol) was added and heated at 90° C. for 5 h. Then reaction mixture was diluted with ether, washed with water, brine and dried. Volatiles were removed under vacuum and the crude residue was column chromatographed (10% ethylacetate/90% hexanes) to yield 700 mg of dimethyl 3′-chlorobiphenyl-3,5-dicarboxylate.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=C[C:11]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)O)([O:12]N=C(C)C)[C:6]2=[CH:5][NH:4]1)[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:11]([OH:12])=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCN1NC=C2C1=NC=CC2(ON=C(C)C)C(O)c1ccccn1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCn1ncc2c(O)c(-c3ccccn3)cnc21
Reaction time: 1 h
Yield: 95.2 %

Procedure:
(1-Ethyl-4-isopropylideneaminooxy-1H-pyrazolo[3,4-b]-pyridine-4-yl)(2-pyridyl)carbinol (8.3 g) was dissolved in 150 ml of dichloromethane and to this was added 6.5 g of pyridinium chlorochromate The reaction mixture was stirred 1 hour and then 300 ml of ether was added, after which the mixture was filtered through a pad of magnesium silicate. The pad was washed with a total of 2 liters of ether and then with 1 liter of 5% methanol/dichloromethane. Concentration of the combined filtrate under a reduced pressure gave 5.8 g of the 1-ethyl-4-hydroxy-5-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine, whose identity was confirmed by its mass spectrum.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2.Cl>ClCCl>[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([F:12])[CH:14]=2)[NH:18][CH:17]=1)=[O:10]
Reactant: O=C(Cl)CCCCl
Reactant: Fc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCCCl)c1c[nH]c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To a magnetically stirred mixture of AlCl3 (25 g, 0.19 mol) in dichloromethane, 4-chloro-butyryl chloride (21 ml, 0.19 mol) was slowly added at 0° C. The resulting mixture was stirred for 30 minutes and 5-fluoro-1H-indole (25 g, 0.19 mol) was slowly added. After stirring for another 30 minutes the formed orange mixture was poured onto concentrated hydrochloric acid (140 ml) and ice (200 ml) to give a pink precipitate. The precipitate was collected by filtration to give pink 4-chloro-1-(5-fluoro-1H-indol-3-yl)-butan-1-one (29 gram, 65% yield). 1H-NMR (400 MHz, DMSO-d6) δ 2.09 (quintet, J=7, 2H), 3.02 (t, J=7, 2H), 3.70 (t, J=7, 2H), 7.07 (dt, J˜9 and 2, 1H), 7.49 (dd, J˜9 and 4, 1H), 7.85 (dd, J˜9 and 2, 1H), 8.41 (d, J˜3, 1H), 12.21 (br s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[Na].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[OH:23]>CN(C=O)C>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCOC(=O)CCCCCBr
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCOc1ccc2ccccc2c1

Procedure:
Ethyl 6-bromohexanoate and the sodium salt of 2-naphthol are reacted in DMF at 70° to provide ethyl 6-(2-naphthyloxy)hexanoate, which after the usual workup is reduced with lithium aluminum hydride in THF to provide 6-(2-naphthyloxy)hexanol.