Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[CH2:11]1>CCOCC>[CH2:1]([NH:8][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([OH:19])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(Br)c2ccccc21
Reactant: NCc1ccccc1
Solvent: CCOCC
Product: OC1CC(NCc2ccccc2)c2ccccc21

Procedure:
Cool a solution of benzylamine (3.22 g.) in dry ether (25 ml.) to below 0° C. With stirring under nitrogen add a cooled (below 0° C.) solution of 3-bromo-1-indanone (3.17 g.) in ether (25 ml.) dropwise over 1.5 hours. Store the reaction under nitrogen at -10° C. for one day. Quickly filter the cold solution and add it cold to a stirring solution of one molar borane in tetrahydrofuran (60 ml.) below 0° C. and under nitrogen. Stir the solution for 18 hours at room temperature. Carefully add a solution of water (3.24 ml.) in tetrahydrofuran (20 ml.) dropwise, followed by 8.0 ml. of 5M isopropanolic --HCl, and continue stirring overnight. Store the reaction at -10° C. overnight, then filter the precipitate through filter-aid. Extract the dry solid mixture with methanol-methylene chloride, filter and evaporate the solvents in vacuo. Triturate the resulting solid with cold ethyl acetate, filter and dry to obtain 2.36 g. of the title product as the hydrochloride salt, m.p. 233-235°. λmaxKBr 3.0 μ (OH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:25]=[CH:24][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH:26](/B(O)O)=[CH:27]\[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1>[CH:26](/[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:25]=[CH:24][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]=3[CH:9]=2)=[CH:6][CH:7]=1)=[CH:27]\[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Brc1ccc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc1
Reactant: OB(O)/C=C/c1ccccc1
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: [K+]
Solvent: Cc1ccccc1
Product: C(=C/c1ccc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc1)\c1ccccc1
Temperature: 60 °C
Yield: 75 %

Procedure:
The product B (400 mg, 1.04 mmol) or B1, (E)-styrylboronic acid (185 mg, 1.25 mmol), potassium carbonate solution (2.0 M, 4.0 mL) and dried toluene (12 mL) were charged in a two-necked bottle. The bottle was deoxygenated and purged with nitrogen, and the mixture in the bottle was stirred at 60° C. until it was totally dissolved. The nitrogen pressure of the bottle was increased, and Pd(PPh3)4 (120 mg, 0.1 mmol) was rapidly added into the bottle. The reaction was heated to 110° C., and stirred for 48 hours. The resulting was cooled to room temperature to precipitate a solid, and the solid was collected by filtering. The solid was washed by water and methanol, and then sublimated at a temperature of 230° C. to obtain TSP (317 mg, yield=75%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@@H:7]([CH3:12])[C:8]([O:10]C)=[O:9])=[CH:4][C:3]=1[CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](=[O:38])[NH:26][C@H:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[CH:30]=3)[CH3:28])=[CH:22][CH:23]=2)[C:18]([CH3:39])=[C:17]1[CH3:40].O.[OH-].[Na+]>CO.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@@H:7]([CH3:12])[C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](=[O:38])[NH:26][C@H:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:36])[CH3:37])[CH:30]=3)[CH3:28])=[CH:22][CH:23]=2)[C:18]([CH3:39])=[C:17]1[CH3:40]
Reactant: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: Cc1c(C)n(Cc2cc(O[C@@H](C)C(=O)O)ccc2Cl)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12

Procedure:
The (S)-methyl 2-(4-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate was dissolved in methanol (1.5 mL) and DMSO (˜1 mL), water (0.1 mL) and NaOH (2 N, 0.1 mL) were added dropwise. The reaction was monitored by LC/MS. It was stirred until all the starting material was consumed (˜3 h). It was acidified with trifluoroacetic acid, filtered and purified by preparative HPLC to yield the title compound. ESI-MS (m/z): 547.1 [M+H]+.
Reaction SMILES: C([O:4][C:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[N:18]([CH3:21])[C:17]3[CH:22]=[C:23]([O:26][CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:25][C:16]=3[S:15]2(=[O:31])=[O:30])=[CH:10][CH:9]=1)=[O:6])(C)C.O.Cl>O1CCOCC1>[C:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[N:18]([CH3:21])[C:17]3[CH:22]=[C:23]([O:26][CH:27]([CH3:28])[CH3:29])[CH:24]=[CH:25][C:16]=3[S:15]2(=[O:31])=[O:30])=[CH:10][CH:9]=1)([OH:6])=[O:4]
Reactant: CC(C)OC(=O)Cc1ccc(N2C(=O)N(C)c3cc(OC(C)C)ccc3S2(=O)=O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Oc1ccc2c(c1)N(C)C(=O)N(c1ccc(CC(=O)O)cc1)S2(=O)=O
Yield: 70.9 %

Procedure:
A solution of 2-(4-isopropoxycarbonylmethylphenyl)-6-isopropoxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (95 mg) in a mixture of 1,4-dioxane (6 ml), water (2 ml) and conc. hydrochloric acid (1 ml) was refluxed for two hours. After the mixture was concentrated in vacuo, the residue was extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4. After the solvent was evaporated under reduced pressure, the crystalline residue was recrystallized from ethanol to yield 2-(4-carboxymethylphenyl)-6-isopropoxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (61 mg) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22]([OH:24])=O)[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]=2[N:3]=1.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2C=CC=[CH:38][C:33]=2N=N1.C(N(CC)CC)C.C(N)CC>CN(C)C=O.O>[CH2:34]([NH:30][C:22]([C:9]1[C:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:14][C:15]=2[C:4]2[N:3]=[C:2]([CH3:1])[N:6]([CH3:7])[C:5]=2[CH:8]=1)=[O:24])[CH2:33][CH3:38]
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CCCN
Solvent: CN(C)C=O
Product: CCCNC(=O)c1cc2c(nc(C)n2C)c2c1CCC(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
To a solution of 0.3 g (0.93 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid and 0.3 g (0.93 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) in dimethylformamide (5 ml) were added 240 μl (1.9 mmol) triethylamine and 76 μl (0.93 mmol) propylamine and the suspension was stirred overnight at room temperature. The reaction was poured into water, the precipitate filtered off and purified by column chromatography on silica gel (dichloromethane/methanol=50:1) to afford 154 mg (46%) of the toe compound as a white powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH:7]1[CH2:16][CH2:15][CH2:14][CH:8]12.[Li][N:25]=[N+:26]=[N-:27]>CN(C=O)C>[N:25]([CH2:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH:7]1[CH2:16][CH2:15][CH2:14][CH:8]12)=[N+:26]=[N-:27]
Reactant: Oc1ccc(C2Cc3c(CBr)cc(O)cc3C3CCCC23)cc1
Reactant: [Li]N=[N+]=[N-]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(O)cc2c1CC(c1ccc(O)cc1)C1CCCC21

Procedure:
Combine 6-Bromomethyl-4-(4-hydroxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-8-ol (0.037 g, 0.1 mmol), LiN3 (0.0213 g, 0.43 mmol), and DMF (1.5 ml) and heat at 90° C. for 3 hours. Cool, add ice and extract with ethyl acetate. Wash organic layer with 3× with water. Dry over anhydrous sodium sulfate and concentrate to a residue which yields after separation on silica gel with 20% EtOAC/hexanes, the titled compound (0.01 g, 34%). 1H NMR (CDCl3) 7.2 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.73 (s, 1H), 6.68 (s, 1H), 4.35 (s, 2H), 3.45 (m, 1H), 3.15 (m, 1H), 2.95 (m, 1H), 2.85 (m, 1H) 2.55 (m, 1H), 2.25 (m, 1H), 1.7-1.2 (m, 5H). MS m/z 334 (M−1).
Reaction SMILES: CS(O)(=O)=O.[C:6]([C:10]1[C:15]2[CH:16]=[C:17]([CH3:19])[O:18][C:14]=2[CH:13]=[CH:12][C:11]=1[OH:20])([CH3:9])([CH3:8])[CH3:7].[C:21](O)([CH3:24])([CH3:23])[CH3:22].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:6]([C:10]1[C:15]2[CH:16]=[C:17]([CH3:19])[O:18][C:14]=2[CH:13]=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:11]=1[OH:20])([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1cc2c(C(C)(C)C)c(O)ccc2o1
Reactant: CC(C)(C)O
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(C(C)(C)C)c(O)c(C(C)(C)C)cc2o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 11.2 %

Procedure:
Methanesulfonic acid (1.2 ml) was added dropwise to a chloroform solution of 4-tert-butyl-5-hydroxy-2-methylbenzofuran (250 mg, 1.2 mmol) and tert-butyl alcohol (500 mg, 6.0 mmol) under cooling with ice. After stirring at 0° C. for 15 min, the mixture was poured into ice water. The mixture was then neutralized with 1N aqueous sodium hydroxide and subjected to extraction with ethyl acetate. The extracted layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (n-hexane) to afford 4,6-di-tert-butyl-5-hydroxy-2-methylbenzofuran (35 mg) as a pale yellow oil. Mass 260(M+), 245, 57
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([CH:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3].Cl.[CH:21](=[NH:30])OCC1C=CC=CC=1.[OH-].[Na+].Cl>>[CH:21]([N:17]1[CH2:18][CH2:19][CH:15]([C:7]2[CH2:6][C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([OH:14])=[O:13])[CH2:16]1)=[NH:30]
Reactant: N=COCc1ccccc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(C3CCNC3)C[C@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(C3CCN(C=N)C3)C[C@H]12
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a solution of (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-(pyrrolidin-3-yl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (250 mg) was added benzyl formimidate hydrochloride (0.48 g) at 0° C. while adjusting pH to 8.5 with 30% aqueous sodium hydroxide solution. After 30 minutes at the same temperature, the solution was adjusted to pH 6.5 with 1N hydrochloric acid, washed with ethyl acetate and concentrated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) eluting with 3% aqueous isopropyl alcohol. The fractions containing the desired compound were collected and lyophilized to give (5R,6S)-3-(1-formimidoylpyrrolidin-3-yl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (120 mg).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[Br:7][C:8]1[NH:9][C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14].C(I)C=C>>[CH2:3]([N:9]1[C:10]([Br:16])=[C:11]([Br:15])[C:12]([C:13]#[N:14])=[C:8]1[Br:7])[CH:2]=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Agent: C=CCI
Agent: [K+]
Product: C=CCn1c(Br)c(Br)c(C#N)c1Br
Yield: 93.3 %

Procedure:
Potassium t-butoxide (0.75 g, 6.7 mmol) is added portionwise at room temperature to a solution of 2,4,5-tribromopyrrole-3-carbonitrile (2.0 g, 6.1 mmol) in anhydrous tetrafuran (20 mL). After 30 minutes allyl iodide (1.12 g, 6.7 mmol) is added dropwise and then refluxed for 2 hours. Work-up as described in Example 15 gives the product as a pale pink liquid (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:9]=[C:10](CC#N)[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.O.S(=O)(=O)(O)O.[C:25]([OH:28])(=[O:27])[CH3:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[C:12]([CH2:26][C:25]([OH:28])=[O:27])[CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:17][CH:18]=1
Reactant: CC(=O)O
Reactant: N#CCc1cccc(C(=O)c2ccc(Cl)cc2)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1cccc(C(=O)c2ccc(Cl)cc2)c1
Reaction time: 2 h

Procedure:
A mixture of 9.61 g of 3-p-chlorobenzoyl phenyl acetonitrile, 75 cc of water, 75 cc of acetic acid and 75 cc of sulfuric acid was refluxed with stirring for 21/2 hours and then cooled and iced for 1 hour. The mixture was vacuum filtered and the precipitate was empasted with water and taken up in 50 cc of a 10% aqueous sodium carbonate solution. The solution was filtered and the filter was washed with water. The pH of the filtrate was adjusted to 5-6 by addition of acetic acid and after being iced for 30 minutes, the mixture was vacuum filtered. The recovered precipitate was washed with water and dried under reduced pressure. The residue was dissolved in 50 cc of refluxing toluene and the solution was treated with activated carbon and filtered. The filter was washed with boiling toluene. The filtrate was cooled and iced for 1 hour and then vacuum filtered. The recovered precipitate was empasted with iced toluene and dried under reduced pressure to obtain 8.37 g of 3-p-chlorobenzoyl phenyl-acetic acid melting at 148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7](CC3C=CC(OC)=CC=3)[C:8](=[O:15])[C:9]3[CH:10]=[CH:11][CH:12]=[N:13][C:14]=3[C:5]=2[CH:4]=1.C1(OC)C=CC=CC=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[NH:7][C:8](=[O:15])[C:9]3[CH:10]=[CH:11][CH:12]=[N:13][C:14]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc(Cn2c(=O)c3cccnc3c3cc(OC)ccc32)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2[nH]c(=O)c3cccnc3c2c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 78.9 %

Procedure:
9-Methoxy-6-(4-methoxybenzyl)benzo[h][1,6]naphthyridine-5(6H)-one (50 mg, 0.14 mmol) prepared in step 3 of Example 3 was dissolved in trifluoroacetic acid (5 ml), sequentially added with anisol (157 μl, 1.44 mmol) and 12N sulfuric acid (240 μl, 2.89 mmol. The mixture was stirred for one day at 90° C. The reaction mixture was cooled to room temperature and poured into a cold saturated sodium bicarbonate aqueous solution. After extraction with chloroform, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was washed with ethyl acetate, filtered, and dried in vacuo to obtain the title compound (25 mg, yield: 77%, white solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]Cl)=[CH:7][CH:6]=[CH:5][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].[C-:19]#[N:20].[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:5][CH:6]=[CH:7][C:8]=1[CH2:9][C:19]#[N:20]
Reactant: [C-]#N
Reactant: COc1c(CCl)cccc1Oc1ccccc1Cl
Agent: [K+]
Solvent: CS(C)=O
Product: COc1c(CC#N)cccc1Oc1ccccc1Cl
Yield: 98.5 %

Procedure:
A solution of 2-chlorophenyl 2-methoxy-3-chloromethylphenyl ether (6.3 g) in dimethyl sulfoxide (40 ml) and powdered potassium cyanide (1.55 g) were treated in a similar manner to that of Example 3-(7) to give oily 2-[2-methoxy-3-(2-chlorophenoxy)phenyl]acetonitrile (6.0 g).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=C[CH:2]=1.[NH2:12][C:13]1[N:17]([C:18]([NH2:20])=[O:19])[N:16]=[C:15]([CH3:21])[C:14]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[CH3:30].C(OC)(OC)(OC)C.O>C(#N)C>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:14]2[C:15]([CH3:21])=[N:16][N:17]3[C:18]([OH:19])=[N:20][C:1]([CH3:2])=[N:12][C:13]=23)=[C:23]([CH3:30])[CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(-c2c(C)nn(C(N)=O)c2N)c(C)c1
Agent: COC(C)(OC)OC
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2c(C)nn3c(O)nc(C)nc23)c(C)c1
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
p-Toluenesulfonic acid (29.2 g, 154 mmol) in acetonitrile (100 mL) was added to the reaction mixture described in Example 3 containing 5-amino-4-(4-methoxy-2-methylphenyl)-3-methylpyrazole-1-carboxylic acid amide. The resulting mixture was heated to 85–90° C. and trimethyl orthoacetate (160 mL, 1.26 mol) was added over 5 minutes during the heating. The reaction was held for about 45 minutes in the desired range with a total of 1.5 hours of heating time from the initiation of the heating cycle. Reaction progress was monitored by HPLC. Water (1.50 L) was added over 5 minutes with a temperature drop to about 60° C. The resulting mixture was cooled to about 20° C. over 1 hour and the product isolated by filtration. The yield was 136 g (78.0% with a purity of 99.5 A %).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[O:8]([CH2:15][CH2:16][CH2:17]Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:17][CH2:16][CH2:15][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][CH2:6][OH:7]
Reactant: BrCCCOc1ccccc1
Reactant: OCCNCCO
Product: OCCN(CCO)CCCOc1ccccc1

Procedure:
2-[(2 Hydroxy-ethyl)-(3-phenoxy-propyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (15.8 g, 151 mmol). and 3-Phenoxypropyl bromide (21.5 g, 100 mmol). Yield 21.31 g, (95%); yellow oil; MS: 238.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>C(OCC)(=O)C>[ClH:32].[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCCC(C(=O)NCCC(=O)O)C2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)CCNC(=O)C1CCCN(C(=O)CCC2CCNCC2)C1
Temperature: 0 °C

Procedure:
A solution of N-[1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-β-alanine (1.58 g) in ethyl acetate (16 ml) was added 4N HCl in ethyl acetate (13.5 ml) under stirring at 0° C. After stirring at ambient temperature for 2 hours, resulting precipitate was collected by filtration to give N-[1-{3-(4-piperidyl)-propionyl}-3-piperidylcarbonyl]-β-alanine hydrochloride (1.27 g).
Reaction SMILES: C(OC1C(F)=CC=C2C=1C(CCN(C)C)=CN2)C1C=CC=CC=1.[CH2:24]([N:26]1[C:34]2[C:29](=[C:30]([O:41][CH3:42])[CH:31]=[C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:33]=2)[C:28]([C:43](=[O:49])[C:44]([N:46]([CH3:48])[CH3:47])=O)=[CH:27]1)[CH3:25]>>[CH3:48][N:46]([CH3:47])[CH2:44][CH:43]([C:28]1[C:29]2[C:34](=[CH:33][C:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:31][C:30]=2[O:41][CH3:42])[N:26]([CH2:24][CH3:25])[CH:27]=1)[OH:49]
Reactant: CCn1cc(C(=O)C(=O)N(C)C)c2c(OC)cc(-c3ccccc3)cc21
Agent: CN(C)CCc1c[nH]c2ccc(F)c(OCc3ccccc3)c12
Product: CCn1cc(C(O)CN(C)C)c2c(OC)cc(-c3ccccc3)cc21
Yield: 68 %

Procedure:
Following the procedure (step 6, scheme 1) used to prepare compound 1-7a, compound 36-4 gave compound 36-5 (68%), which was taken on to the final step without further purification. LCMS: calc 338.2 and found: 313.1 [MH−water]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[C:16]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[N:21]=[CH:20]3)=[CH:15][C:14]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:13](OS(C(F)(F)F)(=O)=O)[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].O.C(OCC)(=O)C.[CH3:54][N:55](C)C(=O)C>[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[K+].[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[C:16]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[N:21]=[CH:20]3)=[CH:15][C:14]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:13]([C:54]#[N:55])[CH:12]=1
Reactant: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c(OC2Cc3ccccc3C2)cc1OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c(OC2Cc3ccccc3C2)cc1C#N

Procedure:
A solution of Intermediate 6 (30 mg) in N,N-dimethylacetamide (1 ml) was added with K4[Fe(CN)6].3H2O (6.6 mg, Ald), sodium carbonate (5.5 mg), and palladium acetate (1.1 mg, WAKO), and stirred at 120° C. for 5 hours. The reaction mixture was added with water (3 ml), and ethyl acetate (3 ml×2) for extraction, and then successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine, the organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Yamazen, n-hexane:ethyl acetate=3:1), and the solvent was evaporated under reduced pressure by using a rotary evaporator to obtain the title compound (yield: 10 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:36]([CH3:37])=[CH:35][C:12]([C:13]([NH:15][CH2:16][C:17](OCC)([O:29]CC)[C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH:19]=2)=[O:14])=[CH:11][C:10]=1[CH2:38][CH3:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(C)=O.Cl>[CH2:1]([O:8][C:9]1[C:36]([CH3:37])=[CH:35][C:12]([C:13]([NH:15][CH2:16][C:17]([C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH:19]=2)=[O:29])=[O:14])=[CH:11][C:10]=1[CH2:38][CH3:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CNC(=O)c1cc(C)c(OCc2ccccc2)c(CC)c1)(OCC)c1cc(C)nc(CC(C)C)c1
Agent: Cl
Solvent: CC(C)=O
Product: CCc1cc(C(=O)NCC(=O)c2cc(C)nc(CC(C)C)c2)cc(C)c1OCc1ccccc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 36.3 %

Procedure:
To a solution of the above 4-benzyloxy-N-[2,2-diethoxy-2-(2-isobutyl-6-methyl-pyridin-4-yl)-ethyl]-3-ethyl-5-methyl-benzamide (112 mg, 0.210 mmol) in acetone (5 mL), 1 N aq. HCl (5.5 mL) is added and the mixture is stirred at 70° C. for 5 h. The acetone is evaporated and the remaining mixture is cooled to 0° C. before it is neutralized with aq. NaOH solution and extracted twice with EA (2×20 mL). The combined org. extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by prep. TLC using heptane:EA 1:2 to give 4-benzyloxy-3-ethyl-N-[2-(2-isobutyl-6-methyl-pyridin-4-yl)-2-oxo-ethyl]-5-methyl-benzamide (35 mg) as a yellow wax; LC-MS: tR=1.03*, [M+1]+=458.91.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2].[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([F:20])[CH:26]=3)[N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: N#CCc1cccc(NC(=O)c2cccc(Br)n2)c1
Product: N#CCc1cccc(NC(=O)c2cccc(-c3cccc(F)c3)n2)c1

Procedure:
The pyridyl bromide (91) (150 mg, 0.47 mmol) was coupled to 3-fluoro-phenylboronic acid (73 mg, 0.52 mmol) using Method E. The crude residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.