Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][C@@H:13]2[CH2:17][C@H:16]([O:18][CH2:19][C:20]([O-:22])=[O:21])[C@@H:15]([OH:23])[C@H:14]2[OH:24])[C:3]=1[N+:25]([O-])=O.CO.[C:30](O)(=O)[CH3:31]>>[NH2:25][C:3]1[C:4]([NH:12][C@@H:13]2[CH2:17][C@H:16]([O:18][CH2:19][C:20]([O:22][CH2:30][CH3:31])=[O:21])[C@@H:15]([OH:23])[C@H:14]2[OH:24])=[N:5][C:6]([S:8][CH2:9][CH2:10][CH3:11])=[N:7][C:2]=1[Cl:1]
Reactant: CCCSc1nc(Cl)c([N+](=O)[O-])c(N[C@@H]2C[C@H](OCC(=O)[O-])[C@@H](O)[C@H]2O)n1
Reactant: CC(=O)O
Solvent: CO
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCC(=O)OCC)[C@@H](O)[C@H]2O)n1
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Compound 7a (5 g, 0.011 mol) was added to methanol (25 mL) at 25-30° C. Acetic acid (15 mL) was added slowly to the reaction mixture over 30 min. The reaction mixture was stirred at 25-30° C. for 2 h. After 2 hrs, the reaction was monitored by TLC and showed completion. The reaction mixture was passed through a diatomaceous earth (Celite) pad and the pad was washed with methanol (25 mL). The filtrate was concentrated under reduced pressure at 50° C. The thus obtained residue was mixed with water (50 mL) and basified with aqueous NaHCO3 to pH 9.0. The aqueous layer was extracted with ethyl acetate (3×25 mL). The combined extract was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide the crude product (89%), which was used for next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:18]=[C:17]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:16]=2)=[CH:9][C:8]=1[CH3:35])C.[OH-].[Na+].Cl>C(O)C>[CH2:31]([O:30][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:18]=1)[CH2:14][S:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:36])=[O:3])=[C:8]([CH3:35])[CH:9]=1)[CH:32]([CH3:34])[CH3:33]
Reactant: CCOC(=O)COc1ccc(SCc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(SCc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (140 mg; 0.27 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness, redissolved in dichloromethane and evaporated to dryness. Yield: 113 mg (86%). HPLC-MS: m/z: 484.9 (M+H)+; Rt: 1.70 min. δH(400 MHz; CDCl3) 1.03 (d, 6H), 2.04-2.12 (m, 1H), 2.24 (s, 3H), 2.90-3.30 (m, 2H), 3.40-3.70 (m, 2H), 3.71 (d, 2H), 3.74 (s, 2H), 3.95-4.05 (m, 4H), 4.17 (s, 2H), 4.69 (s, 2H), 6.14 (m, 1H), 6.53 (d, 1H), 6.77 (dd, 1H), 6.81 (m, 1H), 6.89 (m, 1H), 7.23 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[CH2:16][CH2:17][Cl:18].C([O-])(=O)C.[Na+]>[Pd].CO>[Cl:18][CH2:17][CH2:16][C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][CH:2]=1
Reactant: COC(=O)c1cc(CCCl)c(Cl)nc1C(=O)OC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(CCCl)cnc1C(=O)OC
Reaction time: 23 h
Yield: 56.1 %

Procedure:
A mixture of 18 g of 6-chloro-5-(2-chloroethyl)pyridine-2,3-dicarboxylic acid, dimethyl ester, 1 g of 10% palladium on carbon, and 7 g of sodium acetate in 100 mL methanol is shaken in a hydrogenation apparatus under 15 psi for 23 hours. The reaction is then filtered through celite, and the catalyst is washed with a little methanol. The combined filtrates are concentrated in vacuo, and the residue is partitioned between methylene chloride and water. The organic phase is washed with saturated bicarbonate, dried, and concentrated in vacuo. The residue is chromatographed on silica gel using hexane-ethyl acetate mixtures to afford 8.9 g of the desired product as an oil.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].BrCCC1C=CC2[O:42][CH2:41][CH2:40]C=2C=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[O:42]1[C:21]2[CH:20]=[C:19]([CH2:18][CH2:17][N:16]([C@H:25]3[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]3)[C:14](=[O:15])[NH:13][C:11]3[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=3)[CH:24]=[CH:23][C:22]=2[CH2:40][CH2:41]1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: BrCCc1ccc2c(c1)CCO2
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2ccc3c(c2)OCC3)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 5-(2-bromo-ethyl)-2,3-dihydro-benzofuran and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [CH2:1]([C:5](=[CH2:9])[C:6]([OH:8])=O)[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.C(Cl)(=O)C(C)(C)C.[CH2:26]([C@H:33]1[CH2:37][O:36][C:35](=[O:38])[NH:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([Li])CCC>C1COCC1>[CH2:26]([CH:33]1[CH2:37][O:36][C:35](=[O:38])[N:34]1[C:6](=[O:8])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH2:9])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C=C(CCCC)C(=O)O
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=C(CCCC)C(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-n-butyl acrylic acid (9.90 g, 77.2 mmol, and 1 equiv.) is dissolved in dry THF (260 mL) and cooled to −78° C. under nitrogen. Hunig's base (17.5 mL, 100.4 mmol, 1.3 equiv.) and pivaloyl chloride (9.5 mL, 77.2 mmol, 1 equiv.) are added at such a rate that the temperature remains below −60° C. The mixture is stirred at −78° C. for 30 minutes, warmed to rt for 2 hours, and finally cooled back to −78° C. In a separate flask, (S)-(−)-4-benzyl-2-oxazolidinone (13.49 g, 77.24 mmol) is dissolved in dry THF (150 mL) and cooled to −78° C. under nitrogen. n-butyllithium (2.5 M solution in hexanes, 30.9 mL, 77.2 mmol, 1 equiv.) is added slowly at −78° C., and the mixture is stirred for 30 minutes at rt. The resulting anion is slowly transferred via a cannula into the original reaction vessel. The mixture is allowed to warm to rt and is stirred overnight at rt. The reaction is quenched with 1 M KHCO3, and the solvents are removed under reduced pressure. The residue is partitioned between EtOAc and water. The organic layer is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil which is purified by FC (hexane:EtOAc=4:1) to yield the title compound A-3 as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([C:18]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)=[CH:19][CH:20]1[CH:22]([C:23]([OH:25])=[O:24])[C:21]1([CH3:27])[CH3:26])#[N:17].C(N(CC)CC)C.O>CN(C)C=O>[C:16]([C:18]([C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)=[CH:19][C@H:20]1[C@H:22]([C:23]([O:25][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)=[O:24])[C:21]1([CH3:27])[CH3:26])#[N:17]
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: Cc1ccc(C(C#N)=CC2C(C(=O)O)C2(C)C)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(C#N)=C[C@H]2[C@H](C(=O)OCc3cccc(Oc4ccccc4)c3)C2(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
m-Phenoxybenzylbromide (3.68 g; 0.014 mole) is added to a solution of 3-(β-cyano-p-methylstyryl)-2,2-dimethylcyclopropanecarboxylic acid (3.19 g; 0.0125 mole) and triethylamine (1.27 g; 0.0125 mole) in dry dimethylformamide and the reaction mixture stirred for 18 hours at room temperature. The reaction mixture, containing some precipitated salts, is poured into water and extracted with ether (2×75 ml). The combined ether extracts are washed several times with water, then with sodium bicarbonate solution and saturated sodium chloride solution. Evaporation of the ether solution yields 3.42 g (62.5%) of a yellow oil. Purification of this yellow oil by dry column chromatography (silica gel; eluent: 1:1 methylene chloride:hexane) affords 0.96 g of the trans isomer and 0.6 g of the cis isomer.
Reaction SMILES: [N:1]1([CH:10]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:11](OS(C)(=O)=O)[CH2:12]OC(=O)C2C=CC([N+]([O-])=O)=CC=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-:36].[Na+]>O1CCOCC1.O>[O:36]1[CH2:12][CH:11]1[CH:10]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: [OH-]
Reactant: CS(=O)(=O)OC(COC(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)n1ccc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(C(C2CO2)n2ccc3ccccc32)cc1

Procedure:
A solution of (2RS,3RS)-4-nitro-benzoic acid-3-indol-1-yl-2-methanesulfonyloxy-3-phenyl-propyl ester in dioxane (30 mL) and a 2N aqueous solution of sodium hydroxide (15 mL) were stirred at room temperature for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with 5% aqueous sodium carbonate and water, dried over anhydrous sodium sulfate, filtered, and concentrated to give (1RS,2SR)-1-(oxiranyl-phenyl-methyl)-1H-indole as an oil. MS (ESI) m/z 250 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]3[CH2:16][CH:15]3[CH3:17])[C:7]=12.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:24][C:2]2[N:3]=[N:4][CH:5]=[C:6]3[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]4[CH2:16][CH:15]4[CH3:17])[C:7]=23)=[CH:21][CH:20]=1
Reactant: OCc1ccc(F)cc1
Reactant: Cc1c(C)n(CC2CC2C)c2c(Cl)nncc12
Product: Cc1c(C)n(CC2CC2C)c2c(OCc3ccc(F)cc3)nncc12
Yield: 91.6 %

Procedure:
The title compound (trans) was prepared as a white powder in 91.60% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine and 4-fluorobenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5](=[N:7][OH:8])[NH2:6].[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:13]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=[O:17])[O:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: NC(=NO)c1ccc(Cl)c(Cl)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Product: O=C(O)c1ccccc1-c1nc(-c2ccc(Cl)c(Cl)c2)no1
Temperature: 90 °C
Yield: 15.1 %

Procedure:
A mixture of 14.17 g (0.0691 mol) of 3,4-dichlorobenzamide oxime and 10.24 g (0.0691 mol) of phthalic anhydride was heated gently with stirring to about 90° C., at which time a very vigorous exotherm carried the temperature to above 170° C.; the mixture was cooled in water to 130° C. and held at 130° C. for a few minutes, and then was cooled to 25° C. The mixture was extracted with 1 liter of ethanol and was filtered to give 3.5 g of insoluble solid, mp 200°-215° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20])[CH3:2].[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=2)=[CH:27][NH:26][N:25]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:13]([F:16])([F:15])[F:14])[N:25]3[N:26]=[CH:27][C:28]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=4)=[C:24]3[N:23]=2)=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20])[CH3:2]
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Reactant: CCOc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C(F)(F)F
Product: CCOc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccnc(C)c4)c3n2)cc1C(F)(F)F
Yield: 62.2 %

Procedure:
Reaction of 1-(4-ethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (164 mg, 0.5 mmol), prepared from 4-ethoxy-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (145 mg, 62%). MS (ISP) 467.2 [(M+H)+]; mp 250° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4]
Reactant: C1CCNC1
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)cc2c1NC(c1cccc(N3CCCC3)c1)CC2(C)C
Temperature: 120 °C
Yield: 65.4 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (500 mg, 1.28 mmol), pyrrolidine (140 mg, 1.92 mmol), palladium (II) acetate (14.4 mg, 0.064 mmol), xantphos (44.4 mg, 0.077 mmol) and cesium carbonate (830 mg, 2.56 mmol) in toluene (10 mL) was heated for 3 h at 120° C. After colling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (50% ethyl acetate/hexanes) to afford 6-fluoro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.32 g, 65%) as a white solid: MS (ESI) M+1=383.3.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11](OC)=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: COC(=O)c1ccc2c(Cl)n[nH]c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2c(Cl)n[nH]c2c1
Reaction time: 2 h
Yield: 44.9 %

Procedure:
A solution of methyl 3-chloro-1H-indazole-6-carboxylate (891 mg, 4.2 mmol) in tetrahydrofuran (10 mL) was cooled to −78° C., and then thereto was added dropwise diisobutylaluminum hydride (tetrahydrofuran solution, 1 mol/L, 12.7 mL, 12.6 mmol) at the same temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography hexane→hexane:ethyl acetate=2:1) to give (3-chloro-1H-indazol-6-yl)methanol (344 mg, 45%) as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)[CH2:3][CH2:2]1.C1(COC2N=C(C(O)=O)C=CC=2C2CCCO2)CC1.[NH2:39][C@@H:40]([CH2:44][CH:45]1[CH2:47][CH2:46]1)[C:41]([NH2:43])=[O:42]>>[C:41]([C@@H:40]([NH:39][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:44][CH:45]1[CH2:47][CH2:46]1)(=[O:42])[NH2:43]
Reactant: NC(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1ccc(C2CCOC2)c(OCC2CC2)n1
Agent: O=C(O)c1ccc(C2CCCO2)c(OCC2CC2)n1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(C2CCOC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using the mixture of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (mixture from Example 114 d), and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=374.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:14])=[C:9]([CH:12]=[O:13])[C:10]=1[CH3:11])=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23]1[CH:27]=[C:26]([C:28]2[S:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[O:25][N:24]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]2[CH:27]=[C:26]([C:28]3[S:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[O:25][N:24]=2)[C:8]([CH3:14])=[C:9]([CH:12]=[O:13])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: CCOC(=O)c1[nH]c(C)c(C=O)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)c(C=O)c(C)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To 4-formyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.60 g) in DMF (26 mL) was added Cs2CO3 (6.51 g). The mixture was stirred for 30 min at RT, then 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole (3.71 g) was added. Stirring was continued for 2 h at RT. Water was added and the phases were separated. The aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried (MgSO4) and was concentrated under reduced pressure to give crude 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-4-formyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (4.20 g), which was directly used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[O:15])[CH2:7]1>Cl.O1CCOCC1>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:15])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCC1CCNCC1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 268 %

Procedure:
Intermediate 17 (0.390 g) was stirred in 4.0M hydrogen chloride in dioxane (4 ml) for 2 h, at 23° C. under nitrogen. The solvent was removed in vacuo, azeotroped with dichloromethane (20 ml), and dried under vacuum to give the title compound as a pale yellow solid, (0.33 g).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[CH:12]([OH:14])[CH3:13].[H-].[Na+].[CH2:17](Br)[CH3:18].CO>C1C=CC=CC=1.O>[CH3:17][CH2:18][O:14][CH:12](/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])[CH3:13]
Reactant: CCBr
Reactant: CC1=C(/C=C/C(C)O)C(C)(C)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CO
Product: CCOC(C)/C=C/C1=C(C)CCCC1(C)C
Temperature: 20 °C
Yield: 81.4 %

Procedure:
A solution of 350 g (1.8 mol) of β-ionol in 600 ml of benzene was allowed to flow in over a period of 15 minutes to a suspension of 97.5 g (2.34 mol) of sodium hydride (ca 55%-60%) in 3 liters of benzene and the mixture was subsequently stirred at reflux for 8 hours. The mixture was cooled to ca 50° C. and treated over a period of 10 minutes with 232 g (2.13 mol) of ethyl bromide. The mixture was stirred at reflux for 20 hours, cooled to 20° C., cautiously treated with 50 ml of methanol and, after 20 minutes, with 1.2 liters of water. The phases were separated, the organic phase was washed with water until neutral, dried and concentrated. Crude distillation of the crude product gave 326 g of crude ether 2 of boiling point 120°-128° C./10 mmHg. Fine distillation finally gave 274 g (68.3%) of pure and olfactorily good β-ionyl ethyl ether 2 of boiling point 121° C./10 mmHg; nD20 =1.4752.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([O:9]CC)=O)=[CH:5][N:6]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH3:1][C:2]1[S:3][C:4]([C:7]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:9])=[CH:5][N:6]=1
Reactant: CCOC(=O)c1cnc(C)s1
Reactant: C1CCNC1
Product: Cc1ncc(C(=O)N2CCCC2)s1
Temperature: 120 °C
Reaction time: 36 h
Yield: 73 %

Procedure:
A mixture of 15.42 g (0.0901 mole) of ethyl 2-methyl-5-thiazolecarboxylate and 12 g pyrrolidine was stirred at 120° C. under a nitrogen atmosphere for 36 hours to give 12.91 g of the title compound, m.p. 71-2°C. (78.6% yield with respect to the ester).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1O.[OH:12]C1CC2C(=CC=CC=2)C1=NO.Cl>CO.[Pd]>[NH2:1][C:2]1([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: ON=C1c2ccccc2CC1O
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC1(O)CCc2ccccc21

Procedure:
U.S. Pat. No. 6,057,479 (Mitamura et al.) discloses the preparation of cis-1-amino-2-indanol by the catalytic hydrogenation of 2-hydroxy-1-indanone oxime in methanol. Example 21 of US '479 discloses the hydrogenation in the presence of Pd black and HCl to give an aminoindanol product having a cis/trans selectivity of 95.5:4.5. Examples 22-23 report similar results for analogous hydrogenations using Pd/C and Pd/alumina. Example 24 discloses an analogous hydrogenation using Pd black and aqueous HBr to provide 1-amino-2-indanol product with a cis/trans ratio of 95.6:4.4. Results substantially the same as in Example 24 are also reported in Kajiro et al., SYNLETT 1998, p. 51.
Reaction SMILES: [CH2:1](OS(OCC)(=O)=O)[CH3:2].[C:10]([C:18]1[C:19]([N:30]([CH2:41][CH3:42])S(C2C=CC(C)=CC=2)(=O)=O)=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:21][C:22]=1[CH3:23])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:10]([C:18]1[C:19]([NH:30][CH2:41][CH3:42])=[C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:21]([CH2:1][CH3:2])[C:22]=1[CH3:23])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: CCN(c1c(-c2ccccc2)[nH]c(C)c1C(=O)c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Product: CCNc1c(C(=O)c2ccccc2)c(C)n(CC)c1-c1ccccc1

Procedure:
Compound B) is transformed into the corresponding p-toluene sulfonamido derivative (M.p. 230°-33° C) by reaction with p-toluenesulfonychloride. This compound is subsequently reacted in strong alkaline solution with diethylsulfate, thus obtaining 4-benzoyl-3-(N-ethyl-p-toluenesulfonamido)-5-methyl-2-phenyl-pyrrole (M.p. 152°-53° C), which is in turn converted into the title compound (B.p. 220° C/0.015 mmHg) by acid hydrolysis.