Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:20])[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1)=[O:2].C(O)C.[BH4-].[Na+]>C1COCC1>[OH:20][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][OH:2])=[CH:4][CH:5]=1)[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16]
Reactant: CN(CC(O)c1ccc(C=O)cc1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(CC(O)c1ccc(CO)cc1)C(=O)OC(C)(C)C
Yield: 99.8 %

Procedure:
tert-Butyl 2-(4-formylphenyl)-2-hydroxyethyl(methyl)carbamate (1.808 g, 6.48 mmol) was dissolved in dry THF (50 ml) and absolute ethanol (10 ml) then cooled in an ice bath. Sodium borohydride (0.25 g, 6.61 mmol) was added then after 1 hr the solvent was evaporated. The residue was treated with satd. ammonium chloride solution (15 ml), water (35 ml) and chloroform (50 ml). The aqueous layer was extracted with additional chloroform (2×50 ml). The combined organics were washed with brine (30 ml), dried (magnesium sulfate), filtered and evaporated to afford the product as a white gum (1.82 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Br:9])[N:3]=1.[NH4+:10].[Cl-]>C1(C)C=CC=CC=1>[Br:9][C:4]1[N:3]=[C:2]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:10]=2)[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: [NH4+]
Reactant: Cc1cc(Br)nc(Br)c1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2cc(C)cc(Br)n2)c1
Reaction time: 0.5 h
Yield: 25 %

Procedure:
Dibromocompound 2,6-dibromo-4-methylpyridine (1 mmol), 2-tributylstannyl-picolines (1 mol) and (Ph3Ph)4Pd (0.01 equiv) were heated under N2 in toluene (50 mL) for 16 h. Upon cooling to room temperature aqueous saturated NH4Cl solution (20 mL) was added. The mixture was stirred for further 30 min and then filtered over Celite. The precipitate was washed with CH2Cl2 (50 mL) and the organic phase was separated. The aqueous phase was extracted with toluene. The combined organic phases were dried (MgSO4) and the solvent was removed. Concentrated HCl (30 mL) was added to the residue followed by extracting with CH2Cl2. The aqueous phase was cautiously neutralized by solid NaOH. The product was then extracted with CH2Cl2 and dried. The solvent was removed and the product purified by chromatography on silica gel with CH2Cl2/hexane (1:2) as eluent. Yield: 25%. Anal. C12H11BrN2: Calcd: C, 54.77; H, 4.21; N, 10.65. Found: C, 54.54; H, 4.30; N, 10.45. MS (ESIMS): m/z: 262.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]=2[CH:15]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]=2[CH:15]=1
Reactant: COC(=O)C1Cc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Product: COC(=O)C1Cc2ccc(N)cc21

Procedure:
9.74 g of methyl 5-nitro-1-benzocyclobutanecarboxylate are hydrogenated for 6 hours 30 minutes, at ambient temperature and atmospheric pressure, in the presence of 10% Pd/C. After filtration and concentration under reduced pressure, the expected product is isolated.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1F>CC(C)=O.CCOC(C)=O>[Cl:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[O:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: Cc1ccc(O)cn1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2Cl)cn1
Temperature: 25 °C

Procedure:
6-methyl-pyridin-3-ol Compound 80b (3.10 g, 28.4 mmol) and potassium carbonate (7.80 g, 56.8 mmol) were added to a solution of 2-chloro-1-fluoro-4-nitro-benzene Compound 80a (5.0 g, 28.4 mmol) in acetone (50 mL). The suspension was refluxed for 20 hrs and then cooled to 25° C. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic solution was dried over Na2SO4, then filtered and concentrated to yield 5-(2-chloro-4-nitro-phenoxy)-2-methyl-pyridine Compound 80c (5.6 g, 80%). MS 350 (M−).
Reaction SMILES: [NH2:1][C@@:2]1([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:7][O:6][C@@H:5]([CH:8]2[CH2:10][CH2:9]2)[CH2:4][C@H:3]1[C@@H:11]([OH:14])[CH2:12][F:13].C1([C@@H]2OC[C@@](N[C:41]([NH:43][C:44](=[O:51])[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[S:42])(C3C=CC(F)=CC=3F)[C@H]([C@@H](O)C)C2)CC1>>[CH:8]1([C@@H:5]2[O:6][CH2:7][C@@:2]([NH:1][C:41]([NH:43][C:44](=[O:51])[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[S:42])([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[C@H:3]([C@@H:11]([OH:14])[CH2:12][F:13])[CH2:4]2)[CH2:10][CH2:9]1
Reactant: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](C2CC2)C[C@H]1[C@@H](O)CF
Reactant: C[C@H](O)[C@@H]1C[C@H](C2CC2)OC[C@@]1(NC(=S)NC(=O)c1ccccc1)c1ccc(F)cc1F
Product: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](C2CC2)C[C@H]1[C@@H](O)CF)c1ccccc1

Procedure:
Conversion of rel-(1R)-1-[(2R,4R,5S)-5-amino-2-cyclopropyl-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]-2-fluoroethanol (C45) to the product was carried out according to the method described for synthesis of N-({(3S,4R,6R)-6-cyclopropyl-3-(2,4-difluorophenyl)-4-[(1S)-1-hydroxyethyl]tetrahydro-2H-pyran-3-yl}carbamothioyl)benzamide (C30) in Example 3. The product was obtained as a solid. Yield: 155 mg, 0.324 mmol, 60%. LCMS m/z 479.2 [M+H+].
Reaction SMILES: [C:1]([N:3]=[S:4]([C:7]1[CH:24]=[CH:23][C:10]([CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:9][CH:8]=1)([CH3:6])=[O:5])#[N:2].[C:25](N=S(C1C=CC(CN2C(=O)C3C(=CC=CC=3)C2=O)=CC=1)CC)#N>>[C:1]([N:3]=[S:4]([C:7]1[CH:24]=[CH:23][C:10]([CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:9][CH:8]=1)([CH2:6][CH3:25])=[O:5])#[N:2]
Reactant: CCS(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: CS(=O)(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Product: CCS(=O)(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1

Procedure:
The title compound is prepared in analogy to preparation 6c, substituting 2-(4-(N-cyano-S-methylsulfinimidoyl)benzyl)isoindoline-1,3-dione with 2-(4-(N-cyano-S-ethylsulfinimidoyl)benzyl)isoindoline-1,3-dione (preparation 13a). ESI mass spectrum: [M+H]+=354; r.t. HPLC: 3.33 min (LCMS-FA-8).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:4]2[N:3]=1.C(N(CC)CC)C.[F:28][C:29]([F:38])([F:37])[C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>C(O)CCC>[CH2:15]([N:14]1[C:10]2[N:9]=[CH:8][C:7]3[C:2]([NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[C:30]([C:29]([F:28])([F:37])[F:38])[CH:31]=4)=[N:3][C:4]4[N:5]([N:17]=[C:18]([CH3:20])[CH:19]=4)[C:6]=3[C:11]=2[CH:12]=[N:13]1)[CH3:16]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCn1ncc2c1ncc1c(Cl)nc3cc(C)nn3c12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCn1ncc2c1ncc1c(Nc3cccc(C(F)(F)F)c3)nc3cc(C)nn3c12
Yield: 72.9 %

Procedure:
5.8 g of 5-chloro-8-ethyl-2-methyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine (0.02 mol), 3 g of triethylamine and 3.3 g of 3-trifluoromethylaniline are refluxed in butyl alcohol for 24 hours with stirring. The solvent is removed in vacuo and the residue treated with 20 ml of water and filtered off. Recrystallization from alcohol yields 6 g of 8-ethyl-2-methyl-N-[3-(trifluoromethyl)phenyl]-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5-amine; yield (73%) m.p. 205°-206°.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[B:20](OC)([O:23]C)[O:21]C.Cl>C1COCC1>[CH3:9][C:8]([CH3:11])([CH3:10])[C:7]([NH:6][C:5]1[CH:13]=[CH:14][C:2]([B:20]([OH:23])[OH:21])=[CH:3][CH:4]=1)=[O:12]
Reactant: COB(OC)OC
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cc1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-N-pivaloylaniline (1.56 g, 6 mmol) in dry THF (50 ml) at −78° C. was added t-BuLi (1.5 M in pentane, 13.3 ml, 20 mmol) and the yellow mixture was stirred for 1 h at −78° C. under N2. The reaction was quenched with B(OCH3)3 (1.7 ml, 15 mmol) and stirred for another 1 h at −78° C. The reaction mixture was then warmed to room temperature and hydrolysed with 0.5 M hydrochloric acid (50 ml) and extracted with EtOAc (3×80 ml), dried (Na2SO4) and concentrated to ca. 40 ml. n-Hexane (120 ml) was added slowly and the colorless crystalline product was filtered off and dried, yielding 1.26 g (95%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:55])=[N:14][C:15]2[N:16]([N:50]=[C:51]([CH2:53][OH:54])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:55])=[N:14][C:15]2[N:16]([N:50]=[C:51]([CH:53]=[O:54])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(CO)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
To a solution of (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (2 g, 2.59 mmol) in CH2Cl2 (30 mL) was added Dess-Martin periodinane (1.317 g, 3.10 mmol) and the resulting mixture was stirred at room temp for 3 h. Sat. NaHCO3 solution was then added and the mixture was extracted with dichloromethane (50 mL), dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-30% EtOAc/hexane) to afford (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-formyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (1.9 g, 2.464 mmol, 95% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 10.15 (d, J=5.4 Hz, 1H), 7.74-7.66 (m, 4H), 7.47-7.34 (m, 6H), 7.02 (s, 1H), 5.88 (br. s., 1H), 4.30-4.18 (m, 2H), 3.94-3.81 (m, 1H), 3.40-3.28 (m, 3H), 2.64 (s, 3H), 2.02-1.85 (m, 3H), 1.68 (br. s., 1H), 1.57-1.52 (m, 2H), 1.50-1.39 (m, 3H), 1.31 (s, 3H), 1.28-1.25 (m, 3H), 1.25 (s, 9H), 1.09 (d, J=6.1 Hz, 3H), 1.07 (s, 9H). 4 missing piperidine hydrogens. LCMS (M+H)=772.3.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1>C(OCC)(=O)C>[N:5]([C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[C:1]=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)c1cc(N)no1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(N=C=O)no1
Reaction time: 8 h

Procedure:
99 g of phosgene was dissolved in 500 ml of ethyl acetate, then a solution of 71.6 g of 1A in 400 ml of ethyl acetate was added drop-by-drop to the stirred mixture. The mixture was stirred at reflux temperature for five hours, left standing overnight at room temperature, and filtered. The solid was dried at room temperature for two days to give dimeric 3-isocyanato-5-(1,1-dimethylethyl)-isoxazole (3A) m.p.: 165°-167° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH2:10][C:8](=[O:9])[CH2:7][C:6]([CH3:12])([CH3:11])[CH:5]=1.CC1[CH2:15][CH:16]([OH:22])CC(C)(C)C=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>CO>[C:16]([O:9][CH:8]1[CH2:7][C:6]([CH3:12])([CH3:11])[CH:5]=[C:4]([CH3:3])[CH2:10]1)(=[O:22])[CH3:15]
Reactant: CC1=CC(C)(C)CC(O)C1
Reactant: CC1=CC(C)(C)CC(=O)C1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC1CC(C)=CC(C)(C)C1

Procedure:
Prepared by reduction by means of sodium borohydride in methanol of β-isophorone [obtained according to J. Am. Chem. Soc., 63, 2308 (1941)] and subsequent acetylation of the obtained 3,5,5-trimethyl-cyclohex-3-en-1-ol by means of acetic anhydride in the presence of sodium acetate at 50°C during 20 hours.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH2:12][O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)(=O)=O)=CC=1.[F-:35].C([N+](CCCC)(CCCC)CCCC)CCC>O>[F:35][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1)[CH2:12][O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1
Reactant: Cc1ccc(S(=O)(=O)OC(COc2ncnc3ccccc23)c2ccc(C(C)(C)C)cc2)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: CC(C)(C)c1ccc(C(F)COc2ncnc3ccccc23)cc1

Procedure:
A 15 ml round bottom flask is charged with 4-(2-p-toluenesulfonyloxy-2-(4-tert-butylphenyl)ethoxy)quinazoline (0.3 g, 0.84 mmol). Tetrabutylammonium fluoride solution (1M in THF, 4.2 ml, 4.2 mmol) is then added to it and the solution is heated at reflux for 60 minutes. The mixture is then cooled and water is added to it. It is then extracted with dichloromethane, washed with water and dried. The crude obtained after concentration is purified by silica gel flash chromatography (ethyl acetate/hexanes) to obtain the desired compound.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[C:7]([NH:9][N:10]([CH3:21])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[S:12])=[O:8])(OC)=[O:2].[BH4-].[Na+].O.Cl>C(O)C>[OH:2][CH2:1][C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[C:7]([NH:9][N:10]([CH3:21])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[S:12])=[O:8]
Reactant: COC(=O)c1ccccc1C(=O)NN(C)C(=S)Nc1cccc(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(NC(=O)c1ccccc1CO)C(=S)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
1-(2-Carbomethoxybenzoyl)-2-methyl-4-(3-fluorophenyl)-3-thiosemicarbazide (7.2 g) was dissolved in ethanol (100 ml). The solution was cooled to below 10° and sodium borohydride (1.1 g) added. The mixture was then stirred at room temperature for 60 hours. Water was then added with production of an amorphous precipitate. Dilute hydrochloric acid was then added to the filtrate to bring it to pH 7 and further precipitate removed by filtration. The filtrate was thereupon acidified to yield the title product as a solid, m.p.136°-137°, yield 3.4 g.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][CH:10]([CH:13]2[CH2:18][CH:17]3[CH2:19][CH:14]2[CH:15]=[CH:16]3)[N:9]1[C:20](=[O:37])[CH2:21][NH:22][C:23](=[O:36])[NH:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([O:34]C)=[O:33])[CH:28]=[CH:29][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][CH:10]([CH:13]2[CH2:18][CH:17]3[CH2:19][CH:14]2[CH:15]=[CH:16]3)[N:9]1[C:20](=[O:37])[CH2:21][NH:22][C:23](=[O:36])[NH:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([OH:34])=[O:33])[CH:28]=[CH:29][CH:30]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C3CC4C=CC3C4)SC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)[C@@H]1CSC(C2CC3C=CC2C3)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 5.1 %

Procedure:
The procedure is as in Example 4, but starting with 0.6 g of methyl (4R)-3-[3-{2-[4-tert-butoxycarbonyl-2-[(2RS)-5-norbornen-2-yl]-3-thiazolidinyl]-2-oxoethyl}ureido]phenylacetate (mixture of isomers C and D) and 0.074 g of potassium hydroxide. 0.03 g of (4R) -3- [3-{2-[4-tert-butoxycarbonyl-2-[(2RS) -5-norbornen-2-yl]-3-thiazolidinyl]-2-oxoethyl}ureido]-phenylacetic acid (mixture of isomers C and D) is thereby obtained in the form of an amorphous white product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:9]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].C([O:23][C:24](=O)[CH2:25][C:26](=[O:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:28]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:9]=1[NH:17][C:24](=[O:23])[CH2:25][C:26](=[O:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=2)[CH:28]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1ccc(N)c(NC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: CCOc1ccc(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)c(NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-phenyl)-carbamic acid tert-butyl ester (Example J14) (193 mg, 0.76 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (221 mg, 0.74 mmol) according to the general procedure M. Obtained as an off-white foam (227 mg, 65%).
Reaction SMILES: C(OC([CH2:8][NH:9][C:10]1[N:15]=[C:14]([CH:16]([OH:18])[CH3:17])[CH:13]=[CH:12][CH:11]=1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:8][NH:9][C:10]1[N:15]=[C:14]([CH:16]([OH:18])[CH3:17])[CH:13]=[CH:12][CH:11]=1
Reactant: CC(O)c1cccc(NCC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1cccc(C(C)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To 6-[(tert-butoxycarbonyl)methylamino]-2-pyridylethanol (17.9 g, 71 mmole) was added a solution of 4N HCl in dioxane (200 mL). The reaction was stirred at room temperature for 1 h (gentle gas evolution was observed) then was concentrated to dryness. The product as the hydrochloride salt solidified under vacuum. The solid was dissolved in NaCl-saturated 1.0 N NaOH solution (75 mL), and the solution was extracted with Et2O (2×200 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to afford the title compound (9.12 g, 85%) as a waxy solid: 1H NMR (400 MHz, CDCl3) δ 7.37 (t, 1 H). 6.42 (d, J=7.3 Hz, 1 H), 6.27 (d, J=8.3 Hz, 1 H), 4.62 (br s, 1H), 3.96 (t, 2H). 2.90 (d, J=5.2 Hz, 3H), 2.84 (t, 2H); MS (ES) m/e 153 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:29][CH2:30]CS([O-])(=O)=O)[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=4)[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[C:37]1([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:29][CH2:30][N:46]4[CH2:45][CH2:44][C:43]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]4)[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]4[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=4)[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc4c(c3)OCO4)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc4c(c3)OCO4)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(benzo[1,3]dioxol-5-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:11]([O:23][CH3:24])=[C:10]([O:25][CH3:26])[CH:9]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:26][O:25][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[C:12]([O:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[C:11]=1[O:23][CH3:24]
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc(OCCN2CCOCC2)c1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N)cc(OCCN2CCOCC2)c1OC
Reaction time: 1 h

Procedure:
[3,4-Dimethoxy-5-(2-morpholin-4-yl-ethoxy)-phenyl]-carbamic acid tert-butyl ester, (97 mg, 0.24 mmol, was stirred in 1 mL DCM and 1 mL TFA. After ˜1 h, the TFA and DCM were evaporated and 2 mL sat. sodium bicarbonate solution was added. The aqueous layer was extracted with DCM which was evaporated affording 60 mg 3,4-Dimethoxy-5-(2-morpholin-4-yl-ethoxy)-phenylamine. MS ES+ 283.1
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[N+:18]([O-])=O)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[NH4+]>CO.[Zn]>[CH3:1][O:2][C:3](=[O:27])[CH:4]([CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[NH2:18])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C(=O)OC)C(Cc1ccc(F)cc1[N+](=O)[O-])c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COC(=O)C(C(=O)OC)C(Cc1ccc(F)cc1N)c1ccccc1
Yield: 89.1 %

Procedure:
To a solution of dimethyl[2-(4-fluoro-2-nitrophenyl)-1-phenylethyl]malonate (8a) (5.0 g) in methanol (20 mL) was added ammonium chloride (1.5 g) and zinc dust (11.0 g). The reaction mixture was then heated to reflux for 1 h. The reaction mixture was filtered through a diatomaceous earth pad, and the organic solvents were removed in vacuo. The resulting yellow oil was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous potassium carbonate solution (2×), the organic layer was dried, filtered, and concentrated in vacuo to afford the title compound as a tan gum (4.1 g, 90%). MS APCI, m/z=346 (M+1). LC/MS: 2.51 min.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25](=[O:28])[C:26]#[CH:27])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.ClCCl.CO.N>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25](=[O:28])[C:26]#[C:27][C:2]3[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=3)=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: OCc1ccc(I)cc1
Reactant: C#CC(=O)NCc1ccc(-c2ccc(Cl)cc2)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(CO)cc1)NCc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 1.2.a. from 4-iodobenzyl alcohol and propynoic acid-(4′-chlorobiphenyl-4-yl)methylamide. Yield: 0.52 g (90% of theory); C23H18ClNO2 (M=375.85); calc.: molecular ion peak (M+H)+: 376/378; found: molecular ion peak (M+H)+: 376/378; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (10:1:0.1)).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C@@H:6]1[CH2:10][CH2:9][C@@H:8]([CH3:11])[N:7]1[CH2:12][C:13]1[CH:18]=[C:17]([CH2:19]O)[CH:16]=[CH:15][C:14]=1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[F:29]>C(Cl)Cl>[Cl:3][CH2:19][C:17]1[CH:16]=[CH:15][C:14]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=2[F:29])=[C:13]([CH2:12][N:7]2[C@H:8]([CH3:11])[CH2:9][CH2:10][C@H:6]2[CH3:5])[CH:18]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2CN2[C@H](C)CC[C@H]2C)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2CN2[C@H](C)CC[C@H]2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
Thionyl chloride (0.25 g, 2.1 mmol) was added to a solution of 66.71B (0.029 g, 0.084 mmol) in DCM (0.7 mL) and the mixture was stirred at room temperature for 1 hour. After removing solvent, 66.71C (28 mg) was obtained.