Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:37])[C:10]=1[CH2:11][S:12][C:13]1[N:14]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:15]([C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[CH:22]=2)([CH3:20])[CH3:19])=[CH:16][N:17]=1)[C:5](O)=[O:6].[NH2:38][C@@H:39]([CH2:47][CH2:48][CH2:49][NH:50][C:51]([NH2:53])=[NH:52])[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:37])[C:10]=1[CH2:11][S:12][C:13]1[N:14]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[C:15]([C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[CH:22]=2)([CH3:19])[CH3:20])=[CH:16][N:17]=1)[C:5]([NH:38][C@@H:39]([CH2:47][CH2:48][CH2:49][NH:50][C:51]([NH2:53])=[NH:52])[C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41])=[O:6]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCCNC(=N)N
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)N[C@@H](CCCNC(=N)N)C(=O)OC(C)(C)C)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzoic acid (0.96 g, 1.70 mmol) and (S)-tert-butyl 2-amino-5-guanidinopentanoate (0.54 g, 1.79 mmol) in DMF (4 mL) at 0° C. was added HATU (0.69 g, 1.79 mmol) and DIPEA (0.82 mL, 5.27 mmol). The reaction was stirred at room temperature for 1 h, quenched with satd NaHCO3 and diluted with EtOAc. The mixture was washed with water (10 mL), brine (10 mL) and dried with Na2SO4. The residue was purified by column chromatography (silica, MeOH/DCM) to afford (S)-tert-butyl 2-(3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzamido)-5-guanidinopentanoate (1.2 g) as a white solid. The solids were dissolved in 4N HCl in dioxane (8 mL) and stirred for 3 h. The reaction was concentrated and purified by chromatography (silica, MeOH/DCM) to yield the title compound (380 mg) as a white solid. 1H-NMR (DMSO-d6, 400 MHz) δ 8.84 (d, J=7.6 Hz, 1H), 7.81 (s, 1H), 7.64-7.61 (m, 1H), 7.46-7.43 (m, 1H), 7.21 (d, J=8.30 Hz, 1H), 7.18 (s, 1H), 7.01-6.93 (m, 2H), 6.61-6.57 (m, 1H), 6.54-6.49 (m, 3H), 4.37-4.31 (m, 1H), 4.07 (s, 2H), 3.68 (s, 3H), 3.15-3.11 (m, 2H), 1.88-1.70 (m, 2H), 1.61-1.54 (m, 2H), 1.47-1.46 (m, 6H), 1.42 (s, 9H); MS (EI) m/z 719 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][C@@H:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32][N:10]([CH2:9][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1)[CH:11]1[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: Cc1cnc(CN[C@H]2CCCc3cccnc32)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncc(C)cc1C)C1CCCc2cccnc21

Procedure:
Using General Procedure A: Reaction of (S)-(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine in CH3CN with 2-Bromomethyl-5-cyano-benzoic acid methyl ester, DIPEA and KI gave 5-cyano-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8yl)-amino]-methyl}-benzoic acid methyl ester as a red oil. 1H NMR (CDCl3) δ 1.76 (m, 1H), 2.06 (m, 2H), 2.16 (s, 3H), 2.27 (s, 3H), 2.28 (m, 1H), 2.75 (m, 2H), 3.86 (m, 2H), 3.90 (s, 3H), 4.15 (m, 1H), 4.29 (m, 2H), 6.99 (d, 2H, J=15.8 Hz), 7.35 (d, 1H, J=6.6 Hz), 7.46 (d, 1H, J=7.9 Hz), 7.88 (s, 1H), 8.01 (s, 2H), 8.51 (s, 1H).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:22])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]3[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:14]=3[S:13][C:12]=2[CH:21]=1)C>C(O)C>[Cl:20][C:16]1[C:15]2[C:11]3[CH:10]=[CH:9][C:8]([CH2:7][C:6]([OH:22])=[O:5])=[CH:21][C:12]=3[S:13][C:14]=2[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)sc1cccc(Cl)c12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc2c(c1)sc1cccc(Cl)c12

Procedure:
To a 100 ml. flask, fitted with a condenser and containing a solution of 0.28 g. of potassium hydroxide in 50 ml. of ethanol was added 1.1 g. of 9-chlorodibenzothiophene-3-acetic acid ethyl ester. After the solution was refluxed for four hours, the solvent was removed in vacuo on the steam bath, the residue was dissolved in 50 ml. of water, and the aqueous solution was acidified with dilute hydrochloric acid. The product was filtered, washed with 20 ml. of water, and dried at 60° in a vacuum over for 12 hours. The yield of 9-chlorodibenzothiophene-3-acetic acid, after crystallization from methanol, was 0.8 g. (m.p. 203°-206°).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[N:13]1([C:18]2[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=2)[NH2:21])[CH:17]=[CH:16][CH:15]=[CH:14]1>C(O)C>[N:13]1([C:18]2[CH:19]=[C:20]([N:21]3[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]3=[O:11])[CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:15][CH:16]=[CH:17]1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1cccc(-n2cccc2)c1
Solvent: CCO
Product: O=C(O)C1CCN(c2cccc(-n3cccc3)c2)C1=O
Yield: 78.8 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and 3-(1H-pyrrol-1-yl)aniline (0.697 g; 4.41 mmol) in ethanol (3 mL). 1-(3-(1H-pyrrol-1-yl)phenyl)-2-oxopyrrolidine-3-carboxylic acid 0.313 g (80%) was obtained as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[C:9]([N+]([O-])=O)[CH3:10])[CH:5]=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].Cl.C1C[O:22]CC1>O.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](=[O:22])[CH3:10])[CH:5]=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CC(=Cc1ccc(S(C)(=O)=O)c(F)c1)[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [Fe]
Agent: Cl
Solvent: O
Product: CC(=O)Cc1ccc(S(C)(=O)=O)c(F)c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Iron powder (25 g, 0.45 mol) is added to a stirred mixture of freshly prepared 2-fluoro-1-methanesulfonyl4-(2-nitro-propenyl)-benzene (Example AA2) (29 g, 0.112 mol) in THF (50 ml). Water (110 ml) is added and the mixture is heated to 60° C. Concentrated hydrochloric acid (50 ml) is added slowly over 1 h at 60-90° C. The reaction is then stirred at 100° C. for 20 hours then diluted with cold water (500 ml) and filtered through Celite™ filter material washing with chloroform (500 ml). he organic extract is washed with water (200 ml) followed by brine (200 ml). After drying (MgSO4) the mixture is absorbed on silica and purified by chromatography, eluting with hexane-ethyl acetate (1:1) to give the titled compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[CH:12]=[CH:13][C:14]([OH:16])=[O:15])[CH3:2].CCN(C(C)C)C(C)C>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:2]
Reactant: CCc1cc(C=O)cc(C)c1C=CC(=O)O
Agent: [Pd]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CO)cc(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 3-(2-ethyl-4-formyl-6-methyl-phenyl)-acrylic acid (2.75 g, 12.6 mmol) and DIPEA (1.8 g, 13.8 mmol) in ethanol (80 mL), Pd/C (275 mg, 10% Pd, moistened with 50% water) is added. The mixture is stirred for 16 h at rt under 1 atm of H2. The catalyst is filtered off and the filtrate is concentrated. The residue is dissolved in EA, washed with 2 N aq. HCl, followed by 1 N aq. HCl and brine. The organic extract is dried over Na2SO4, filtered and evaporated to give 3-(2-ethyl-4-hydroxymethyl-6-methyl-phenyl)-propionic acid (2.8 g) as a white solid; LC-MS: tR=0.76 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[N:13][C:12]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[N:20][C:11]2=3)[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH3-])(=O)C.[Na+].CO>ClCCl>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:15](=[O:16])[CH:14]=[N:13][C:12]5[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[N:20][C:11]4=5)[CH2:6][CH2:7]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2n1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2n1
Yield: 64.4 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (Intermediate 202, 75 mg) was reacted with 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (48 mg) and sodium acetoxyborohydride (0.11) as described for Example 107. Chromatography on silica gel with 0-2% methanol in dichloromethane to give 72 mg of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:26]=[C:15]3[C:16]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[S:27]([O-])(=[O:30])(=[O:29])[CH3:28].CS(Cl)(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:26]=[C:15]3[C:16]([N:20]4[CH2:25][CH2:24][N:23]([S:27]([CH3:28])(=[O:30])=[O:29])[CH2:22][CH2:21]4)=[N:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CS(=O)(=O)[O-]
Reactant: COc1cc(Nc2nc3c(N4CCNCC4)nccn3n2)cc(OC)c1
Agent: CS(=O)(=O)Cl
Product: COc1cc(Nc2nc3c(N4CCN(S(C)(=O)=O)CC4)nccn3n2)cc(OC)c1

Procedure:
N-(3,5-dimethoxyphenyl)-8-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyrazin-2-amine (synthesized as described earlier) was converted into the mesylate by treatment with Methanesulfonylchloride under standard conditions.
Reaction SMILES: [CH:1]1[C:6]([C@@H:7]([OH:10])[CH2:8][NH2:9])=[CH:5][CH:4]=[C:3]([OH:11])[CH:2]=1.[C:12]([C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21](=O)[CH3:22])=[CH:17][CH:16]=1)(=[O:14])[NH2:13]>[Pt]=O.C(O)C>[OH2:10].[C:12]([C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH:21]([NH:9][CH2:8][CH:7]([C:6]2[CH:5]=[CH:4][C:3]([OH:11])=[CH:2][CH:1]=2)[OH:10])[CH3:22])=[CH:17][CH:16]=1)(=[O:14])[NH2:13].[C:12]([C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH:21]([NH:9][CH2:8][CH:7]([C:6]2[CH:5]=[CH:4][C:3]([OH:11])=[CH:2][CH:1]=2)[OH:10])[CH3:22])=[CH:17][CH:16]=1)(=[O:14])[NH2:13]
Reactant: NC[C@H](O)c1ccc(O)cc1
Reactant: CC(=O)COc1ccc(C(N)=O)cc1
Agent: O=[Pt]
Solvent: CCO
Product: CC(COc1ccc(C(N)=O)cc1)NCC(O)c1ccc(O)cc1
Product: O
Yield: 29.4 %

Procedure:
A mixture of DL-octopamine (4.6 g.), 4-carbamoylphenoxy acetone (5.8 g.) and ethanol (150 ml.) was boiled under reflux for 8 hours in the presence of molecular sieves, then hydrogenated over platinum oxide at 50 p.s.i. and 50°C. Filtration and evaporation in vacuo of the filtrate gave a viscous oil which was triturated with ether to provide a semi-solid material. This material was then triturated with ethanol and the residual white solid crystallized from aqueous dimethylformamide to afford DL-2-[2-(4-carbamoyl-phenoxy)-1-methylethylamino]-1-(4-hydroxyphenyl)ethanol hemihydrate (2.0 g.), m.p. 195-198°C.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[CH2:11]([C:27](O)=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.ClCCCl>[OH:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][C:27]([O:9][CH2:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([OH:10])=[CH:2][CH:1]=3)=[O:28])=[CH:14][CH:15]=2)=[CH:25][CH:24]=1
Reactant: OCCc1ccc(O)cc1
Reactant: O=C(O)CCc1ccc(Oc2ccc(O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: O=C(CCc1ccc(Oc2ccc(O)cc2)cc1)OCCc1ccc(O)cc1
Temperature: 25 °C

Procedure:
Into a 500 mL round bottomed flask fitted with an overhead stirrer, and a modified Dean-stark trap for solvents heavier than water are added 10 g (72 mmol) of tyrosol, 30 g (78 mmol) of desaminothyronine, 0.65 g (3.4 mmol) of 4-toluenesulfonic acid monohydrate and 200 mL of 1,2-dichloroethane (DCE). A water-cooled reflux condenser is placed on top of the modified Dean-stark trap and the contents of the flask are heated to reflux while being stirred. The reaction is continued until approximately 1.4 mL of water collected in the modified Dean-stark trap above the DCE and the water collection essentially stops (about 4 hours of reflux). The reaction mixture is cooled to room temperature and the crude product is dissolved in 100 mL of ethyl acetate and washed twice with 100 mL portions of 5% sodium bicarbonate solution. After drying over magnesium sulfate the organic layer is concentrated and precipitated with hexane. The resulting white crystalline solid is collected by filtration and dried in a vacuum oven at 25° C. The product is characterized by elemental analysis, hplc, and 1H NMR.
Reaction SMILES: [C:1]([O:4][CH:5]1[NH:8][C:7](=[O:9])[CH:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:47](Cl)(=[O:49])[CH3:48]>C1COCC1>[C:1]([O:4][CH:5]1[N:8]([C:47](=[O:49])[CH3:48])[C:7](=[O:9])[CH:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)OC1NC(=O)C1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC1C(CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(C)=O
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
To a -78° C. THF (20 mL) solution of compound 13 (trans:cis ratio, 2:1; 580 mg; 1.16 mmol) was added IN THF solution of sodium bis(trimethylsilyl)amide (1.36 mL, 1.36 mmol), followed by 10 min stirring of the resultant solution. Acetyl chloride (96 mL, 1.36 mmol) was added, and the temperature of the resultant solution was raised to room temperature, stirred for 30 min, and concentrated. The residue was partitioned between ether and water. The organic phase was dried (Na ) and concentrated. The residue was purified by silica gel chromatography (4:1/ether:hexane) to afford 420 mg (57%) of the product as a mixture of trans and cis (2:1) isomers.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[Cl:11][C:12]1[N:17]=[C:16]([CH:18]=[O:19])[C:15]2[C:20]([O:42][CH3:43])=[N:21][N:22]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:13]=1.CC(=CC)C>O.CC(O)(C)C.C1COCC1>[Cl:11][C:12]1[N:17]=[C:16]([C:18]([OH:6])=[O:19])[C:15]2[C:20]([O:42][CH3:43])=[N:21][N:22]([C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:14]=2[CH:13]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=O)c12
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium chlorite (120 mg, 1.322 mmol) and sodium dihydrogen phosphate (159 mg, 1.322 mmol) were dissolved in water (1.5 ml). A suspension of 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (Intermediate 11B, 100 mg, 0.220 mmol) in tBuOH (1.5 ml) and THF (1.5 ml) and 2-methyl-2-butene (233 μl, 2.203 mmol) was then added to the aqueous mixture. The resulting solution was stirred at rt overnight. The reaction contents were concentrated in vacuo, resuspended in water, the solid was filtered, and washed with water. The solids were triturated in MeOH to give 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid. MS: [M+H]+ m/z 470.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([NH2:9])=[O:8].[CH3:10][O:11][C:12]([NH:14][C@@H:15]([CH:19]([CH3:21])[CH3:20])[C:16](O)=[O:17])=[O:13].O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>ClCCl>[C:7]([C@@H:3]1[CH2:4][CH2:5][CH2:6][N:2]1[C:16](=[O:17])[C@@H:15]([NH:14][C:12](=[O:13])[O:11][CH3:10])[CH:19]([CH3:21])[CH3:20])(=[O:8])[NH2:9]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To the product of Example 116A (21.6 g, 144 mmol), the product of Example 116B (29.1 g, 166 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (27.6 g, 180 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (34.6 g, 180 mmol) and 4-methylmorpholine (63.5 mL, 578 mmol) was dissolved in dichloromethane (960 mL) and stirred at room temperature for 18 hrs. The resultant solution was then concentrated to a residue, water was then added and the solution extracted with a 25% isopropanol in chloroform solution (2×2000 mL) the organic layer washed with brine then the organic extract dried over MgSO4, then concentrated to a yellow oil which was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane to provide 25 g (64%) of the title compound as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 7.28 (m, 2H), 6.81 (s, 1H), 4.24 (dd, J=8.1, 4.4 Hz, 1H), 4.00 (t, J=8.4 Hz, 1H), 3.75 (m, 1H), 3.55 (m, 1H), 3.50 (s, 3H), 2.02 (m, 1H), 1.97 (m, 2H), 1.80 (m, 2H), 0.92 (d, J=6.7 Hz, 3H), 0.86 (d, J=8.6 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[I:25]N1C(C)(C)C(=O)N(I)C1=O.O>C(Cl)(Cl)Cl>[I:25][C:14]1[C:15]2[C:20]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Reactant: CC1(C)C(=O)N(I)C(=O)N1I
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: Ic1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: 70 °C
Reaction time: 3 h
Yield: 117.3 %

Procedure:
In a 500 mL Erlenmeyer flask was added 4.5 g (18 mmol) of 9-phenylanthracene. To the flask was added 200 mL of acetic acid, followed by heating at 70° C. to dissolve 9-phenylanthracene therein. To the resulting solution was added 5.2 g (13 mmol) of 1,3-diiodo-5,5-dimethylimidazolidine-2,4-dione (DIH), and the solution was stirred under air at 70° C. for 3 hours. After the reaction, ca. 100 mL of water and ca. 200 mL, of chloroform were added to this solution. The resulting mixture was washed with water twice, and the organic layer was separated from the aqueous layer. The aqueous layer was extracted with chloroform. The extract was combined with the organic layer and washed with brine, and then the combined organic layer was dried with magnesium sulfate. This mixture was gravity filtered, and the filtrate obtained was concentrated to give a brown solid. This solid was washed with hexane to give 5.8 g of a yellow solid in a yield of 86%, which was the desired substance. The synthetic scheme is shown in the following (A-2).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH3:24][O:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:28](=[O:29])[CH2:27][CH2:26][O:25][CH3:24])[CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: COCCC(=O)Cl
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)CCOC)C2)cc1

Procedure:
62 mg (0.18 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 33 mg (0.27 mmol, 1.5 eq.) of methoxypropionyl chloride were reacted according to General Method 2. Yield: 65 mg (91% of theory)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]([O:10]C)=[O:9].O.[OH-].[Li+].Cl>O1CCCC1.O.CO>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@@H:12]1[C:4]1[CH:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[C:2]([F:1])[CH:3]=1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1ccc([C@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a solution of EXAMPLE 92A (2.65 g, 8.2 mmol) in tetrahydrofuran (20 mL) was added lithium hydroxide monohydrate (688 mg, 16.4 mmol) in 20 mL of water and methanol added until a transparent solution formed. This mixture was stirred at ambient temperature for 2 hours and acidified with 2N hydrochloric acid to pH 2. The mixture was concentrated to about 10 mL, diluted with water and let stand at ambient temperature overnight. The white solid was collected by filtration, washed with water and dried to give the title compound (2.21 g). Recrystallization from methanol and water gave 1.61 g of title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[C:11]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[CH3:21]I.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[C:11]([C:13]([CH3:21])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9][N:8]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)C(C)c1ccnc(Oc2ccc(Cl)cc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1ccnc(Oc2ccc(Cl)cc2)c1
Reaction time: 0.5 h

Procedure:
Methyl 2-(2-p-chlorophenoxy-4-pyridyl)propionate (3.13 g) is treated with methyl iodide in the presence of 50 % sodium hydride in anhydrous tetrahydrofuran in a nitrogen atmosphere at room temperature for 1 hour and then at 40° C for 30 minutes, whereby methyl 2-(2-p-chlorophenoxy-4-pyridyl)isobutyrate (2.59 g) is obtained as crystals melting at 92° to 92.5° C. Then, this substance is treated with a mixture of 20 % aqueous potassium hydroxide and 95 % ethanol with refluxing for 10 minutes, whereby 2-(2-p-chlorophenoxy-4-pyridyl)isobutyric acid (2.35 g) is obtained as crystals melting at 135° to 136° C.
Reaction SMILES: C[C:2]1([CH3:22])[CH2:6][C:5]2[C:7]([CH3:21])=[C:8]([CH3:20])[C:9]([CH3:19])=[C:10]([CH:11]3[CH2:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[CH2:12]3)[C:4]=2[O:3]1.[C:23]([OH:28])(=O)[CH2:24][CH2:25][CH3:26].[CH3:29]N(C1C=CC=CN=1)C>C1(C)C=CC=CC=1>[C:23]([C:14]1[C:13](=[O:18])[CH2:12][CH:11]([C:10]2[C:4]3[O:3][CH:2]([CH3:22])[CH:6]([CH3:29])[C:5]=3[C:7]([CH3:21])=[C:8]([CH3:20])[C:9]=2[CH3:19])[CH2:16][C:15]=1[OH:17])(=[O:28])[CH2:24][CH2:25][CH3:26]
Reactant: Cc1c(C)c2c(c(C3CC(=O)CC(=O)C3)c1C)OC(C)(C)C2
Reactant: CN(C)c1ccccn1
Reactant: CCCC(=O)O
Solvent: Cc1ccccc1
Product: CCCC(=O)C1=C(O)CC(c2c(C)c(C)c(C)c3c2OC(C)C3C)CC1=O
Temperature: 25 °C

Procedure:
To a solution of 8.3 g of the 5-(2,3-dihydro-2,2,4,5,6-pentamethylbenzofuran-7-yl)cyclohexane-1,3-dione in 80 ml of absolute toluene was added 18 ml of anhydrous butyric acid and refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure to afford a residue. To the solution of the residue in 100 ml of toluene was added 1.6 g of dimethylaminopyridine. After refluxing for 15 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford a crude product. Final purification was carried by silica-gel column chromatography to afford 6.1 g of 2-butyryl-5-(2,3-dihydro-2,3,4,5,6-penta-methylbenzofuran-7-yl)-3-hydroxycyclohex-2-en-1-one as a yellow solid.