Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:4]1[C:13]2=[C:14]3[C:19](=[CH:20][CH:21]=[C:12]2[C:11]2[C:10]([OH:25])=[CH:9][CH:8]=[CH:7][C:6]=2[O:5]1)[NH:18][C:17]([CH3:23])([CH3:22])[CH:16]=[C:15]3[CH3:24])[CH:2]=[CH2:3].[C:26](O[K])(C)(C)C.IC.[NH4+].[Cl-]>C1COCC1.CC(OC)(C)C>[CH2:1]([C@H:4]1[C:13]2=[C:14]3[C:19](=[CH:20][CH:21]=[C:12]2[C:11]2[C:10]([O:25][CH3:26])=[CH:9][CH:8]=[CH:7][C:6]=2[O:5]1)[NH:18][C:17]([CH3:23])([CH3:22])[CH:16]=[C:15]3[CH3:24])[CH:2]=[CH2:3]
Reactant: CC(C)(C)O[K]
Reactant: C=CC[C@@H]1Oc2cccc(O)c2-c2ccc3c(c21)C(C)=CC(C)(C)N3
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C=CC[C@@H]1Oc2cccc(OC)c2-c2ccc3c(c21)C(C)=CC(C)(C)N3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 9 (157 mg) in THF (10 ml) was treated with a 1.0 M solution of tBuOK (1.0 ml) at 0° C. and then treated with iodomethane (0.1 ml). After stirring at room temperature for 2 hours, the mixture was poured into a solution of saturated NH4Cl (15 mL) and stirred briefly before MTBE (15 mL) was added. After stirring for 5 minutes, the organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by column chromatography to give the title compound (134 mg). Anal. calcd for C23H25NO2: C, 79.51; H, 7.25 and N, 4.03; Found: C, 79.26; H, 7.12 and N, 3.80; 1H NMR [(CD3)2SO] δ1.16 (3H, s) 1.17 (3H, s), 2.18 (3H, s), 2.22 (1H, m), 2.46 (1H, m), 3.85 (3H, s), 5.01 (2H, m), 5.44 (1H, br s), 5.77 (1H, dd), 5.82 (1H, M), 6.10 (1H, br s), 6.52 (1H, d), 6.60 (1H, d), 6.70 (1H, d), 7.06 (1H, t) and 7.96 (1H, d); 13CNMR [(CD3)2SO] δ23.8, 28.8, 28.9, 36.5, 49.7, 55.6, 73.4, 105.6, 110.5, 113.4, 113.4, 116.1, 116.4, 127.3, 117.3, 127.3, 127.7, 132.2,133.8, 134.5, 145.8, 151.1, 156.4; APCI-MS: m/z 348 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][NH:12][CH2:11][CH2:10]2.[CH:20]([O:23][C:24]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=1[C:26](O)=[O:27])([CH3:22])[CH3:21]>>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][N:12]([C:26]([C:25]1[CH:29]=[C:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=[CH:32][C:24]=1[O:23][CH:20]([CH3:22])[CH3:21])=[O:27])[CH2:11][CH2:10]2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Fc1cccc(COc2ccc3c(c2)CCNC3)c1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc(OCc3cccc(F)c3)ccc2C1

Procedure:
Prepared in analogy to example 1.1 from 6-(3-fluoro-benzyloxy)-1,2,3,4-tetrahydro-isoquinoline ((CA [620606-74-8]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 498.4 (M+H+).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([OH:5])=O.C([Li])CCC.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[C:26]([O:28][CH3:29])=[O:27])C(Cl)=O>O1CCCC1.CCCCCC.Cl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[C:26]([O:28][CH3:29])=[O:27])[C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1OC
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(C(=O)OC)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of ethyl hydrogen malonate (4.38 g, 33.2 mmol) in dry tetrahydrofuran (100 ml) cooled under an atmosphere of nitrogen to -60° C. with efficient stirring was added a solution of n-butyllithium in hexane (2.5M, 26.5 ml) rapidly dropwise, allowing the temperature to rise to -10° C. during the addition. After stirring the resulting suspension for 15 min at -10° C. it was recooled to -70° C. and a solution of 3-methoxy-4-methoxycarbonylbenzoyl chloride (4.46 g, 19.5 mmol) in dry tetrahydrofuran (30 ml) added dropwise. After addition, the reaction mixture was allowed to warm to room temperature and after 1 h diluted with cold aqueous hydrochloric acid (2M, 35 ml) and ice. The mixture was extracted with diethyl ether (200 ml) and the extract washed twice with a saturated solution of sodium bicarbonate, water and a saturated solution of sodium chloride. The organic layer was dried over magnesium sulphate, filtered and evaporated. The residue was purified on flash silica eluting with dichloromethane to give ethyl 3-methoxy-4-methoxycarbonylbenzoylacetate as an oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:5][CH:4](OS(C)(=O)=O)[CH2:3]1.[CH2:22]([O:24][C:25]([C:27]1[CH:28]=[N:29][NH:30][CH:31]=1)=[O:26])[CH3:23].[C:32](=O)([O-])[O-].[K+].[K+].CC(C)=O>CCOC(C)=O.CCCCCC>[CH2:22]([O:24][C:25]([C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH:4]2[CH2:3][C:2](=[O:1])[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=3)[CH2:5]2)[CH:31]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)OC1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1cnn(CC2CC(=O)N(c3cccc(C(F)(F)F)c3)C2)c1
Temperature: 80 °C
Yield: 75.3 %

Procedure:
In an oven dried two-necked round-bottomed flask, the methanesulfonic acid 5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-yl ester (3.2 g, 9.4 mmol), 1H-pyrazole-4-carboxylic acid ethyl ester (1.46 g, 10.0 mmol), and potassium carbonate (3.93 g, 28.0 mmol) were mixed under an argon atmosphere followed by the addition of the dry acetone (60 mL) at room temperature. The reaction mixture was refluxed at 80° C. for 24 h. The reaction mixture was filtered, evaporated and extracted with DCM (100×3 mL), dried over Na2SO4 and concentrated on a rotary evaporator to afford the crude product mixture. The product was isolated by flash column chromatography (eluting with hexane:EtOAc, 2:3) as a viscous oil (2.7 g, 75%).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1)([O-:3])=[O:2].C(O)(=O)C.[B-].[Na+].O>CS(C)=O>[N+:1]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])/C=C/c1ccc(Oc2ccccc2)nc1
Agent: [B-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-((E)-2-nitro-vinyl)-2-phenoxy-pyridine described in Manufacturing Example 232-1-3 (5.97 g, 24.6 mmol) and acetic acid (3.2 mL) in dimethyl sulfoxide (52 mL) was added sodium borohydrate (1.4 g, 36.9 mmol), at room temperature while cooling appropriately. This mixture was stirred for 30 minutes at room temperature. This mixture was cooled appropriately, then, water was added, which was stirred for 30 minutes at room temperature. This mixture was liquid-separated, and the organic layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (5.72 g) as a crude product.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[S:6][CH:7]=1)=O.[Br-].[C:13]([C:16]1[CH:41]=[CH:40][C:19]([CH2:20][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:18]([F:42])[C:17]=1[F:43])([OH:15])=[O:14]>>[C:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH:1]=[CH:20][C:19]2[CH:40]=[CH:41][C:16]([C:13]([OH:15])=[O:14])=[C:17]([F:43])[C:18]=2[F:42])[N:4]=1)(=[O:11])[CH3:10]
Reactant: O=C(O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c1F
Reactant: CC(=O)Nc1nc(C=O)cs1
Agent: [Br-]
Product: CC(=O)Nc1nc(C=Cc2ccc(C(=O)O)c(F)c2F)cs1
Yield: 76 %

Procedure:
N-(4-Formyl-1,3-thiazol-2-yl)acetamide (1.071 g, 6.292 mmol) and (4-carboxy-2,3-difluorobenzyl)(triphenyl)phosphoniumbromide (3.227 g, 6.287 mmol) were condensed by a method similar to that of Production Example 4, step 3, to give 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]vinyl}-2,3-difluorobenzoic acid (1.550 g, 4.778 mmol, yield 76.0%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ncccc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccnc2C)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (288 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine as a colorless oil (yield 220 mg, 97%). A solution of the obtained 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine in ethyl acetate (3 mL) was added dropwise to a solution of fumaric acid (67 mg) in ethanol (3 mL) and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as a white solid (yield 253 mg, 88%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])N=2)=[CH:4][CH:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].[C:29](Cl)(=[O:31])[CH3:30]>CCC(C)=O>[C:29]([NH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][C:13]2[CH:23]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[N:18]=2)=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1nc(N)ccc1Oc1nc(OC)cc(OC)n1
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1nc(NC(C)=O)ccc1Oc1cc(OC)cc(OC)n1
Temperature: 75 °C
Yield: 81 %

Procedure:
318.9 g (1.04 mol) of methyl 6-amino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate and 157.6 g (1.14 mol) of potassium carbonate were dissolved in MEK, and 89.8 g (1.14 mol) of acetyl chloride was added thereto at room temperature. The mixture was refluxed under heating (75° C.) for two hours. MEK was concentrated to a half amount and then cooled. The reaction solution was poured into ice water and crystallized. Crystals thereby obtained was collected by filtration and washed with water. The crystals were dissolved in dichloromethane and subjected to liquid separation. The dichloromethane layer was dried over anhydrous magnesium sulfate and then concentrated. A small amount of diisopropyl ether were added thereto, and the mixture was cooled for crystallization. The crystals thereby obtained were recrystallized from 100 ml of ethanol. The crystals thereby obtained were washed with diisopropyl ether and then dried at 50° C. for 24 hours to obtain the desired product as a white powder.
Reaction SMILES: C(OC(=O)COC1C=CC(SCC2C=C(C3C=CC(C(F)(F)F)=CC=3)OC=2)=CC=1C)C.[CH2:32]([O:34][C:35](=[O:46])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([SH:44])=[CH:40][C:39]=1[CH3:45])[CH3:33].[CH3:47][C:48]1[CH:52]=[C:51]([C:53]2[CH:58]=[CH:57][C:56]([O:59][C:60]([F:63])([F:62])[F:61])=[CH:55][CH:54]=2)[S:50][C:49]=1[CH2:64]O>>[CH2:32]([O:34][C:35](=[O:46])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([S:44][CH2:64][C:49]2[S:50][C:51]([C:53]3[CH:54]=[CH:55][C:56]([O:59][C:60]([F:62])([F:63])[F:61])=[CH:57][CH:58]=3)=[CH:52][C:48]=2[CH3:47])=[CH:40][C:39]=1[CH3:45])[CH3:33]
Reactant: CCOC(=O)COc1ccc(S)cc1C
Reactant: Cc1cc(-c2ccc(OC(F)(F)F)cc2)sc1CO
Agent: CCOC(=O)COc1ccc(SCc2coc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(SCc2sc(-c3ccc(OC(F)(F)F)cc3)cc2C)cc1C

Procedure:
The title compound was prepared by a method analogous to that used for the preparation of ethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate (example 1) using ethyl(4-mercapto-2-methylphenoxy)acetate (intermediate 4) and {3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methanol (intermediate 118).
Reaction SMILES: [OH-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl>C(O)CCC>[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH2:13][O:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: Oc1ccc(I)cc1
Reactant: ClCCOCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CCOCCOc1ccc(I)cc1

Procedure:
A mixture prepared by adding 3.08 g of sodium hydroxide and 40 ml of n-butanol to 15.4 g of 4-iodophenol was refluxed. 2 ml of n-butanol solution of 5.01 g of 1,5-dichloro-3-oxapentane was added dropwise to the above prepared mixture over a period of 5 minutes.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[N:9][CH:8]=1)(=O)[CH3:2]>O1CCCC1.C(OCC)(=O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[O:14][C:1]([CH3:2])=[N:4][N:5]=2)=[CH:8][N:9]=1
Reactant: CC(=O)NNC(=O)c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccc(Cl)nc2)o1
Temperature: 120 °C

Procedure:
N′-Acetyl-6-chloronicotinohydrazide (95 mg, 0.45 mml) and 3,3,3-triethyl-1-(methoxycarbonyl)diazathian-3-ium-1-ide 2,2-dioxide (159 mg, 0.67 mmol) were taken up in tetrahydrofuran (4.5 mL) and heated in a microwave at 120° C. for 30 minutes. The reaction was then diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, water, and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound.
Reaction SMILES: C[C:2](P(OC)(O)=O)([C:4]([O-:6])=[O:5])[CH3:3].[H-].[Na+].[C:14]1(=O)[CH2:19][CH2:18]C[CH2:16][CH2:15]1.[CH2:21](Cl)Cl>>[C:3]1(=[CH:2][C:4]([O:6][CH3:21])=[O:5])[CH2:18][CH2:19][CH2:14][CH2:15][CH2:16]1
Reactant: O=C1CCCCC1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C=C1CCCCC1

Procedure:
2.184 g trimethylphosphonoacetate was dissolved in DCM, stirred on ice-water bath, and 384 mg NaH was added. After 6 hours 980 mg cyclohexanone was added into the reaction flask, and stirred at ambient temperature overnight. The next day, the reaction mixture was washed with water twice, saturated aqueous NaCl solution once, dried over anhydrous MgSO4 for 2 hours, filtrated, and the filtrate was dried under vacuum to give 1.227 g of the title crude product.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.Cl.[CH2:12]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH3-]C#N.[Na+]>CO>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:24][CH:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1]2)=[CH:25][CH:26]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C1Cc2ccccc2C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(COc2ccc(NC3Cc4ccccc4C3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
A solution of 2.00 g (15.1 mmol, Aldrich) of 2-indanone and 3.57 g (15.1 mmol, Aldrich) of 4-benzyloxyaniline hydrochloride in 30 ml of methanol was stirred over 3Å molecular sieves at 25° C. and 476 mg (7.57 mmol, Aldrich) of NaBH3CN was added in four portions. The resulting yellow solution was stirred at 25° C. for approximately two hours, filtered and the filtrate added to saturated NaHCO3. This was extracted with EtOAc twice, the organic layers were combined, dried (MgSO4) and concentrated in vacuo. Purification via flash chromatography (silica gel, 1:7 EtOAc/petroleum ether) afforded 3.02 g (64%) of title compound as an off-white solid: m.p. 74°-76° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][O:5][CH2:6][CH:7]1[O:9][CH2:8]1)[CH3:2].[NH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17].C(OCC1OC1)C1OC1>>[OH:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][OH:20])[CH2:8][CH:7]([OH:9])[CH2:6][O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(CC)COCC1CO1
Reactant: OCCNCCO
Agent: C(OCC1CO1)C1CO1
Product: CCCCC(CC)COCC(O)CN(CCO)CCO
Temperature: 77.5 °C

Procedure:
A three-necked, septum capped, 250 mL, round-bottom flask equipped with an addition funnel and containing a magnetic stirring bar is flushed with argon and charged with 2-ethylhexylglycidyl ether (66.53 g, 0.35 mol). Diethanolamine (40.89 g, 0.38 mol) is added during 10 min to the glycidyl ether, with stirring. The flask is placed in an oil bath and heated at a bath temperature of 75-80° C. overnight. The reaction is cooled and checked by 1H NMR to ensure the complete consumption of the glycidyl ether. A colorless viscous liquid is obtained.
Reaction SMILES: C(OCC)(=O)C.[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][OH:16])[CH:8]=1.CS(C)=O>C(N(CC)CC)C>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH:15]=[O:16])[CH:8]=1
Reactant: OCCCc1cccnc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=CCCc1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To an ethyl acetate (30 mL) solution of 3-(3-pyridyl)propanol (1.5 g), dimethyl sulfoxide (15 mL) and triethylamine (9 mL) were added. Additionally, a pyridine sulfur trioxide complex (5.2 g) was added with stirring at 0° C. for 2 hours as it was. The reaction mixture was concentrated under reduced pressure, and purified by silica gel column chromatography (hexane:ethyl acetate=30:70→0:100) to obtain a titled compound (1:1 g) having the following physical property values.
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(OCC)(=O)C.O>[CH2:26]([O:25][C:23](=[O:24])[NH:13][C:12]1[CH:14]=[CH:15][C:9]([CH2:1][C:2]2[CH:3]=[CH:4][C:5]([NH2:6])=[CH:7][CH:8]=2)=[CH:10][CH:11]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(Cc2ccc(NC(=O)OCc3ccccc3)cc2)cc1

Procedure:
A mixture of 4,4′-methylenedianiline (19.8 g), potassium carbonate (20 g) in ethyl acetate (300 mL) and water (200 mL) was stirred in an ice bath. Benzyl chloroformate (15 mL) was slowly added to the mixture. The resulting mixture was stirred for 1 hour, then the organic layer was separated, and the aqueous layer extracted with additional ethyl acetate. The combined organic extracts were washed with water and brine, dried (Na2SO4), and the solvent removed in vacuo. The crude mixture was isolated by column chromatography on silica gel, eluting with 30% ethyl acetate/hexanes, to give 4-(4-aminobenzyl)phenyl-carbamic acid benzyl ester as solid.
Reaction SMILES: ClC1C=CC(C2C3C(C)=NN(C4CN(C(OC(C)(C)C)=O)C4)C=3C(=O)N2C2C=C(C)C3N(C(C)=NN=3)C=2)=CC=1.CCCCCCC.CCO.[Cl:50][C:51]1[CH:56]=[CH:55][C:54]([CH:57]2[C:64]3[C:63]([CH:65]4[CH2:67][CH2:66]4)=[N:62][N:61]([CH3:68])[C:60]=3[C:59](=[O:69])[N:58]2[C:70]2[CH:71]=[C:72]([CH3:80])[C:73]3[N:74]([C:76]([CH3:79])=[N:77][N:78]=3)[CH:75]=2)=[CH:53][CH:52]=1>C(OCC)C>[Cl:50][C:51]1[CH:52]=[CH:53][C:54]([C@@H:57]2[C:64]3[C:63]([CH:65]4[CH2:67][CH2:66]4)=[N:62][N:61]([CH3:68])[C:60]=3[C:59](=[O:69])[N:58]2[C:70]2[CH:71]=[C:72]([CH3:80])[C:73]3[N:74]([C:76]([CH3:79])=[N:77][N:78]=3)[CH:75]=2)=[CH:55][CH:56]=1
Reactant: Cc1cc(N2C(=O)c3c(c(C4CC4)nn3C)C2c2ccc(Cl)cc2)cn2c(C)nnc12
Agent: Cc1nn(C2CN(C(=O)OC(C)(C)C)C2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Solvent: CCO
Solvent: CCOCC
Solvent: CCCCCCC
Product: Cc1cc(N2C(=O)c3c(c(C4CC4)nn3C)[C@H]2c2ccc(Cl)cc2)cn2c(C)nnc12

Procedure:
The title compound (26 mg, 34% yield) was obtained enantiomerically pure (>99% ee) after chiral preparative chromatography (system: VWR prep HPLC; column: Chiralpak AD-H 20 μm, 76.5×393 mm; mobile phase: heptane/EtOH 60:40; flow: 80 mL/min; detection UV: 240 nm) of the racemic mixture of 4-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 129) followed by trituration in diethyl ether.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15]C)=[C:10]([CH3:14])[C:11]=2[CH3:13])[CH2:6][C:5]2([CH2:19][CH2:18][CH2:17]2)[CH2:4]1)[CH3:2].B(Br)(Br)Br.CCOC(C)=O.CCCCCC>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:15])=[C:10]([CH3:14])[C:11]=2[CH3:13])[CH2:6][C:5]2([CH2:17][CH2:18][CH2:19]2)[CH2:4]1)[CH3:2]
Reactant: CCN1CC2(CCC2)Cc2cc(OC)c(C)c(C)c21
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCN1CC2(CCC2)Cc2cc(O)c(C)c(C)c21
Reaction time: 4 h
Yield: 38 %

Procedure:
To a solution of 1′-ethyl-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (100 mg) in 2 mL chloroform cooled in ice bath (10° C.) was added BBr3 (2 mL, 1 M). After 4 hours, ice was added to quench the reaction. After separation of the two layers, dichloromethane was used to extract the aqueous phase. The combined organic phases were then washed with brine, dried and evaporated to give a crude oil which was then passed through a column (EtOAc: Hexane; 2-16%) to give 1′-ethyl-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinolin]-6′-ol (35.9 mg). 1H-NMR (300 MHz, CDCl3): δ=6.37 (s, 1H), 3.04 (s, 2H), 2.95-2.65 (q, 2H), 2.74 (s, 2H), 2.12 (s, 3H), 2.1 (s, 3H), 2.05-1.85 (m, 4H), 1.84-1.64 (m, 2H), 1.3-1.1 (t, 3H) ppm. 13C-NMR (75 MHz, CDCl3) δ=152.88, 143.52, 133.97, 130.4, 126.13, 116.74, 62.54, 55.07, 44.81, 42.13, 36.29, 19.77, 19.31, 16.6, and 15.79 ppm. MS: (m/z): 246.2 (M+H+)
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:19]1[O:23][C:22](=[O:24])[CH2:21][CH2:20]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1.CN1C(=O)N(C)CCC1>[C:1]([NH:8][C@H:9]([C@H:19]1[O:23][C:22](=[O:24])[C@H:21]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:20]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CCC(=O)O2)cc1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](Cc3ccccc3)C(=O)O2)cc1

Procedure:
In analogy with Example 5d), 4.17 g (12.44 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-methoxyphenyl)ethyl]dihydrofuran-2-(3H)-one, dissolved in 22.4 ml of THF and 2.5 ml of DMPU, are deprotonated, at -70° C., with 24 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and alkylated (-75° C., 1 h) with 1.5 ml (12.44 mmol) of benzyl bromide. Protonation, at -75° C., with 4.6 ml of propionic acid and 4.6 ml of water, extraction and column chromatography (SiO2, methylene chloride/ether 25:1) yields the title compound: TLC Rf (C)=0,74; tRet (II)=16.6 min; FAB-MS (M+H)+ =426.