Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[C:15]([C:31]([F:34])([F:33])[F:32])=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C@:24]3([CH3:30])[CH2:28][O:27]C(=O)[NH:25]3)[CH:18]=[CH:17]4)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].C(O)C.O>>[NH2:25][C@@:24]([C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([O:13][C@H:10]3[CH2:9][CH2:8][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:12][CH2:11]3)[C:15]=2[C:31]([F:33])([F:34])[F:32])[CH:20]=1)([CH3:30])[CH2:28][OH:27]
Reactant: C[C@@]1(c2ccc3c(C(F)(F)F)c(O[C@H]4CC[C@@H](c5ccccc5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@](N)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@@H](c4ccccc4)CC3)ccc2c1
Yield: 50.1 %

Procedure:
The mixture of (R)-4-(6-(cis-4-phenyl-cyclohexyloxy)-5-trifluoromethylnaphthalen-2-yl)-4-methyloxazolidin-2-one (46.7 mg, 0.0000995 mol) and lithium hydroxide (26 mg, 0.0011 mol) in ethanol (2 mL, 0.04 mol) and water (0.4 mL, 0.02 mol) was heated to reflux overnight. LCMS showed reaction complete. The solvent was removed under vacuum and the residue was partitioned between water and CH2Cl2. The aqueous layer was extensively extracted with CH2Cl2. The combined organic phase was dried over Na2SO4. The concentrated residue was taken up into DCM and subjected to chromatographic purification with CH2Cl2/MeOH (10:90 to 80:20) to give the product as a white solid (22.1 mg, 50% yield). LCMS 427.26 ([M−NH2]+, 100%). 1H NMR (400 MHz, CD3OD) δ ppm 1.52 (s, 3H), 1.67 (brd, J=11.8 Hz, 2H), 1.82 (dd, J=13.4, 13.1 Hz, 2H), 2.02 (ddd, J=13.1, 12.8, 3.0 Hz, 2H), 2.20 (d, J=14.8 Hz, 2H), 2.65 (ddd, J=12.2, 12.2, 3.8 Hz, 1H), 3.68 (d, J=10.9 Hz, 1H), 3.73 (d, J=10.9 Hz, 1H), 5.01 (brs, 1H), 7.14-7.30 (m, 5H), 7.50 (d, J=9.3 Hz, 1H), 7.71 (dd, J=9.3, 2.2 Hz, 1H), 7.95 (d, J=2.1 Hz, 1H), 8.08 (d, J=9.3 Hz, 1H), 8.16 (d, J=9.3 Hz, 1H).
Reaction SMILES: C[O:2][C:3]1[C:15]2[CH:14]=[CH:13][S:12][C:11]=2[C:10]([O:16]C)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.[C:18](Cl)(=[O:20])[CH3:19].[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClCCCl.CC(O)C.CC(O)=O>[C:18]([C:13]1[S:12][C:11]2[C:10](=[O:16])[C:9]3[C:4]([C:3](=[O:2])[C:15]=2[CH:14]=1)=[CH:5][CH:6]=[CH:7][CH:8]=3)(=[O:20])[CH3:19]
Reactant: COc1c2ccccc2c(OC)c2sccc12
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CC(C)O
Product: CC(=O)c1cc2c(s1)C(=O)c1ccccc1C2=O
Temperature: 5 °C
Reaction time: 4 h

Procedure:
To 4 (1.5 g) in 1,2-dichloroethane (120 mL) were added acetyl chloride (4.3 mL, 55 mmol) and AlCl3 (7.3 g, 55 mmol). The resulting mixture was stirred at 5±2° C. for 4 h and then poured into ice water and acidified with conc. HCl. The organic layer was washed with water, dried over anhydrous MgSO4 and evaporated. CrO3 (0.5 g, 50 mmol) and HOAc (12 mL) were added to the residue. The mixture was stirred at room temperature for 8 h, and then i-PrOH (30 mL) was added, and the resulting solution extracted with CHCl3. The organic layer was washed with saturated NaHCO3, dried over anhydrous MgSO4 and evaporated. Column chromatography (silica gel, CHCl3) gave compounds 5, 6, and 7 in 20, 11, and 9% yields, respectively.
Reaction SMILES: [NH:1]1[C:5](B(O)O)=[CH:4][CH:3]=[N:2]1.Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([N:21]([CH3:32])[CH:22]3[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]3)=[N:18][N:17]=2)=[C:12]([O:33][CH3:34])[CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:34][O:33][C:12]1[CH:11]=[C:10]([C:5]2[NH:1][N:2]=[CH:3][CH:4]=2)[CH:15]=[CH:14][C:13]=1[C:16]1[S:20][C:19]([N:21]([CH3:32])[CH:22]2[CH2:27][C:26]([CH3:28])([CH3:29])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)=[N:18][N:17]=1
Reactant: COc1cc(Cl)ccc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Reactant: OB(O)c1ccn[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2ccn[nH]2)ccc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Temperature: 120 °C
Yield: 23.1 %

Procedure:
To a stirred suspension of (1H-pyrazol-5-yl)boronic acid (14 mg, 0.139 mmol) and 5-(4-chloro-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (50 mg, 0.127 mmol) in dioxane (1 mL) was added Pd(PPh3)4 (7 mg, 0.006 mmol) followed by a solution of Na2CO3 (40 mg, 0.380 mmol) in water (0.25 mL). The reaction mixture was purged with nitrogen, sealed, and heated at 120° C. under microwave irradiation for 30 minutes, then again at 145° C. Additional catalyst and boronate were added and the mixture was heated for an additional 30 minutes under microwave irradiation at an increased temperature of 160° C. The reaction mixture was diluted with DCM (20 mL), washed with saturated NaHCO3(aq) (10 mL) and the organic phase was separated and concentrated in vacuo to afford the crude product as an oily residue. The crude material was purified by mass directed preparative HPLC under basic conditions (NH4OH midified) to afford the title compound as a white solid (12.5 mg, 23% yield). LC-MS: Rt 0.81 min; MS m/z 427.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.99 (br. s., 1H), 8.12 (d, J=8.08 Hz, 1H), 7.82 (br. s., 1H), 7.60 (s, 1H), 7.54 (d, J=6.06 Hz, 1H), 6.84 (d, J=2.02 Hz, 1H), 4.31-4.41 (m, 1H), 4.01 (s, 3H), 2.99 (s, 3H), 1.61 (dd, J=12.13, 3.54 Hz, 2H), 1.42 (t, J=12.13 Hz, 2H), 1.27 (br. s., 1H), 1.22 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: N(Cl)Cl.[Cl:4][C:5]1[CH:20]=[CH:19][C:8]2[S:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=O)[NH:13][C:7]=2[CH:6]=1.ClC1C=CC2OC3C=CC=CC=3C(=O)NC=2C=1.[C:38]([O:42][C@@H:43]1[CH2:51][N:50]2[C@H:45]([CH2:46][NH:47][CH2:48][CH2:49]2)[CH2:44]1)([CH3:41])([CH3:40])[CH3:39]>C(#N)C>[Cl:4][C:5]1[CH:20]=[CH:19][C:8]2[S:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12]([N:47]3[CH2:46][C@H:45]4[N:50]([CH2:51][C@@H:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:44]4)[CH2:49][CH2:48]3)=[N:13][C:7]=2[CH:6]=1
Reactant: O=C1Nc2cc(Cl)ccc2Sc2ccccc21
Reactant: CC(C)(C)O[C@H]1C[C@H]2CNCCN2C1
Agent: ClNCl
Agent: O=C1Nc2cc(Cl)ccc2Oc2ccccc21
Solvent: CC#N
Product: CC(C)(C)O[C@H]1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Sc4ccccc43)CCN2C1
Temperature: 25 °C
Yield: 37.2 %

Procedure:
The iminochloride of 8-chloro-10,11-dihydrodibenz[b,f]-1,4-thiazepine-11-one (0.580 g, 2.07 mmol), prepared in a like manner to the iminochloride of 8-chloro-10,11-dihydrodibenz[b,f]-1,4-oxazepine-11-one described in example 2(a), was dissolved in anhydrous acetonitrile (20 mL) under argon and (6S,8S)-8-t-butoxy-1,4-diazabicyclo[4.3.0]nonane (0.970 g, 4.89 mmol) was added as a solution in anhydrous acetonitrile (5 mL) via syringe and the resulting solution was heated to reflux for 5 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure and the residue partitioned between water and methylene chloride. The organic layer was washed with brine, dried (MgSO4) and evaporated to dryness. The product was purified on silica gel using 10% acetone in hexanes as the eluent to give 0.34 g (37%) of 8-chloro-11-[(6S,8S)-8-t-butoxy-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenz[b,f]-1,4-thiazepine as an off-white solid; mp 132°-134° C.; Rf (10% acetone/hexanes): 0.10; HRMS (FAB): MH+ of C24H28 N3OSCl, calculated 442.1720, found 442.1728.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2C(=O)C3=CC=CC=C3C2=O)[CH:6]=[CH:5][C:4]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH2:10])[CH:6]=[CH:5][C:4]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(CN2C(=O)c3ccccc3C2=O)ccc1-c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc(CN)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 31 h
Yield: 100.7 %

Procedure:
To a solution of N-(2-methoxybiphenyl-4-ylmethyl)-phthalimide (0.414 g) in chloroform (5.0 mL) was added dropwise a mixture of hydrazinemonohydrate (0.241 g) and ethanol (1.0 mL), and the resulting mixture was stirred at room temperature for 31 hours. The insoluble material was filtered out, and the filtrate was partitioned between dichloromethane (40 mL) and water (15 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.259 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:24]([OH:26])=[O:25].FC1C=C(C=CC=1OCCCCCCC)C(O)=O>>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:21]([F:20])=[C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCOc1ccc(C(=O)O)cc1F
Reactant: CCCCCCCC(C)C(=O)c1ccc(O)cc1F
Agent: CCCCCCCOc1ccc(C(=O)O)cc1F
Product: CCCCCCCCCOc1ccc(C(=O)O)c(-c2ccc(C(=O)C(C)CCCCCCC)c(F)c2)c1F

Procedure:
The same procedure as in Example 20 was repeated, except that (+)-3-fluoro-4-(2-methylnonanoyl) phenol was used instead of (+)-3-fluoro-4-(2-methyloctanoyl) phenol in Example 20 and 3-fluoro-4-nonyloxy benzoic acid was instead of 3-fluoro-4-heptyloxy benzoic acid in Example 20, to obtain an objective compound having the aforementioned physical and chemical properties.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][N:5]=[CH:4][C:3]=1[CH:9]=[O:10].[Br:11]C1C=NC=CC=1Cl>CN(C=O)C>[Br:11][C:7]1[C:2]([Cl:1])=[C:3]([CH:9]=[O:10])[CH:4]=[N:5][CH:6]=1
Reactant: Clc1ccncc1Br
Reactant: O=Cc1cncc(Cl)c1Cl
Solvent: CN(C)C=O
Product: O=Cc1cncc(Br)c1Cl
Yield: 73 %

Procedure:
Following the procedure described for 4,5-dichloropyridine-3-carbaldehyde, 3-bromo-4-chloropyridine and DMF were reacted to afford the title compound as a white solid (3.74 g, 73% yield). 1H NMR (300 MHz, CDCl3): δ 10.48 (d, J=0.4 Hz, 1H), 8.95-8.92 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].Cl.[CH:31]([NH:34][C@H:35]([CH3:49])[CH2:36][O:37][C:38](=[O:48])[C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)([CH3:33])[CH3:32]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:34]([CH:31]([CH3:33])[CH3:32])[C@H:35]([CH3:49])[CH2:36][O:37][C:38](=[O:48])[C:39]4[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=4)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)Cl)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: CC(C)N[C@H](C)COC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@H](C)COC(=O)c3ccc([N+](=O)[O-])cc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridin-6-yl)benzoyl chloride and 4-nitro-benzoic acid (R)-2-isopropylamino-propyl ester hydrochloride as described for example 9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:25])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2ccc(CC)cc2)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(CC)cc2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(4-ethylphenyl)thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 12, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=1)=[CH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:18][N:17]([C:19](=[O:23])[CH:20](C)[CH3:21])[CH2:16]1)[O:11][CH2:10]2)=O.[NH2:35][NH2:36]>C(O)C.C(OCC)(=O)C>[Cl:32][C:26]1[CH:25]=[C:24]([C:3]2([C:2]([F:34])([F:33])[F:1])[NH:36][N:35]=[C:5]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[C:12]3([CH2:18][N:17]([C:19](=[O:23])[CH2:20][CH3:21])[CH2:16]3)[O:11][CH2:10]4)[CH2:4]2)[CH:29]=[C:28]([Cl:30])[C:27]=1[Cl:31]
Reactant: CC(C)C(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc12
Reactant: NN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(=O)N1CC2(C1)OCc1cc(C3=NNC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)ccc12

Procedure:
To the stirred solution of 4,4,4-trifluoro-1-(1-isobutyryl-3′H-spiro[azetidine-3,1′-isobenzofuran]-5′-yl)-3-(3,4,5-trichlorophenyl)but-2-en-1-one (Preparation 27, 0.5 g, 0.938 mmol, 1 eq) in ethanol (5 mL) was added hydrazine (1.0M solution in THF, 1.40 mL, 1.41 mmol, 1.5 eq). Resulting reaction mixture was refluxed for 2 hours under nitrogen atmosphere. After consumption of starting material, Reaction mixture was concentrated to get crude compound. Crude compound was dissolved in minimum quantity of ethyl acetate and adsorbed on silica gel (100-200 mesh). Crude compound purified by Combiflash chromatography using 40 g Redisep column. Desired compound was eluted in 55% ethyl acetate in hexane to afford title compound as off white solid (0.16 g, 31%). 1H NMR (400 MHz, DMSO-d6) δ: 1.00-1.06 (m, 6H), 2.53-2.56 (m, 1H), 3.75-3.88 (m, 2H), 4.10 (s, 2H), 4.40-4.45 (m, 2H), 5.08 (s, 2H), 7.57-7.58 (m, 2H), 7.66 (d, J=8.44 Hz, 1H), 7.88 (s, 2H), 8.91 (s, 1H). LC-MS (m/z): 546.0 (M+H). HPLC Purity: 96.43%.
Reaction SMILES: C1(C([N:20]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][C:34]([CH2:37][N:38]4[C:42]([CH2:43][OH:44])=[C:41]([Cl:45])[N:40]=[C:39]4[CH2:46][CH2:47][CH2:48][CH3:49])=[CH:33][CH:32]=3)=[N:23][N:22]=[N:21]2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[OH-].[Na+].O>CO.C(OCC)(=O)C>[CH2:46]([C:39]1[N:38]([CH2:37][C:34]2[CH:35]=[CH:36][C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24]3[NH:23][N:22]=[N:21][N:20]=3)=[CH:32][CH:33]=2)[C:42]([CH2:43][OH:44])=[C:41]([Cl:45])[N:40]=1)[CH2:47][CH2:48][CH3:49]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
1-[(2'-(Triphenylmethyltetrazol-5-yl)-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole (920 g), and methanol (2.10 L) were charged to a 12-liter round-bottomed flask, equipped with mechanical stirrer, condenser with N2 inlet and thermometer. The slurry was cooled to ~10° C. and 3.4 N hydrochloric acid (700 ml) was added over 10 minutes. After stirring two hours at 10°-20°C., the thick slurry was diluted with methanol (500 ml) and warmed to 30° C. After one hour at 30° C., the reaction was neutralized to pH 13 with 10 N sodium hydroxide (420 ml). Solvent (largely methanol, 2.3 L) was distilled while 2.3 L D.I. water was added. Heating was discontinued and D.I. water (700 ml) and toluene (1.40 L) was added. After cooling to ~30° C., the organic phase was removed. The aqueous phase was reextracted with toluene (700 ml). Ethyl acetate (1.20 L) was added to the pot containing the aqueous phase. After stirring 10 minutes, acetic acid (130 ml) was added. The mixture was stirred one hour, then let stand overnight. Agitation was restarted and the slurry cooled to ~5° C. The product was isolated by vacuum filtration, reslurried with 1.50 L D.I. water and sucked semi-dry. The wet cake was charged to a 12 L round bottomed flask and reslurried 1/2 hour at ambient temperature with ethyl acetate (4.0 L). The product was isolated by vacuum filtration, washed with 200 ml ethyl acetate and dried in vacuo overnight at 50° C. Yield: 518 g, 88.5%. M.P.: 184°185° C. Purity by HPLC: 98.8%.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=2)[CH:9]=[C:10]([C:12]([OH:14])=O)[CH:11]=1.C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.[NH2:56][CH2:57][C@@H:58]([OH:60])[CH3:59]>O.CN(C)C=O>[CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=2)[CH:9]=[C:10]([C:12]([NH:56][CH2:57][C@@H:58]([OH:60])[CH3:59])=[O:14])[CH:11]=1
Reactant: Cc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Reactant: C[C@H](O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1CNc1cc(C(=O)NC[C@H](C)O)cn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid (30 g, 0.0928 mol) and 30 g diisopropylethylamine (30 g, 0.233 mol) were added to dimethylformamide (DM) (250 ml). o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (36 g, 0.112 mol) was added. The mixture was stirred for 15 min at room temperature. (S)-1-amino-2-propanol (8.4 g, 0.112 mol) was added and the stirring was continued for 1 h at room temperature. Water (100 ml) was added and the reaction mixture was heated to 70° C. The product was precipitated by slowly adding more water (200 ml). The mixture was then stirred for 5 h at 65-70° C. After cooling to room temperature the product was filtered off and washed with 40% methanol solution. 33.7 g of the compound of the invention was obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([NH2:8])[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][C:23](Cl)=[O:24])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][C:23]([NH:8][C@H:6]2[CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]2[CH:9]([CH3:11])[CH3:10])=[O:24])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][C:23]([NH:8][C@@H:6]2[CH2:7][C@@H:2]([CH3:1])[CH2:3][CH2:4][C@@H:5]2[CH:9]([CH3:11])[CH3:10])=[O:24])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: CC1CCC(C(C)C)C(N)C1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Product: COc1ccc(CC(=O)N[C@@H]2C[C@@H](C)CC[C@@H]2C(C)C)cc1OC
Product: COc1ccc(CC(=O)N[C@H]2C[C@H](C)CC[C@H]2C(C)C)cc1OC

Procedure:
The aforementioned product is obtained as a colorless solid containing in total 94.2% of the desired neomenthylamine derivatives from racemic neomenthylamine, as in the GP, by reaction with (3,4-dimethoxyphenyl)acetyl chloride. Furthermore, two further isomeric menthylamine derivatives are present at 2.7% and 2.5%, corresponding to a purity over all stereoisomers of 99.4%.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:15][CH:16]([CH3:18])[CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[O:25][C:26]=1[CH3:27]>>[CH:16]([O:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[O:25][C:26]=1[CH3:27])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:19])([CH3:18])[CH3:17]
Reactant: COc1ccccc1-c1nc(CCl)c(C)o1
Reactant: COC(=O)C(Cc1ccc2[nH]ccc2c1)OC(C)C
Product: COc1ccccc1-c1nc(Cn2ccc3cc(CC(OC(C)C)C(=O)O)ccc32)c(C)o1

Procedure:
In analogy to the procedure described in example 44, rac-3-(1H-indol-5-yl)-2-isopropoxy-propionic acid methyl ester (preparation 8) was reacted with 4-chloromethyl-2-(2-methoxy-phenyl)-5-methyl-oxazole to give rac-2-isopropoxy-3-{1-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-propionic acid as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: ClCc1ccncc1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Agent: Cl
Product: CCOC(=O)N1CCC(c2cn(Cc3ccncc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 11 g (40 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 8 g (48 mmol) of 4-chloromethyl-pyridine hydrochloride, stirring at room temperature for 18 hours. After standard work-up, 11.8 g (81% of the yield) of 4-(1-pyridin-4-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.