Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:28]([C:39]([CH3:41])=[CH2:40])=[CH:27][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C.CCOC(C)=O.O>[CH2:44]([N:13]([C:14]1[CH:15]=[CH:16][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:18][CH:19]=1)[C:11](=[O:12])[C:10]1[CH:27]=[C:28]([C:39]([CH3:41])=[CH2:40])[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:30][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: C=C(C)c1cc(C(=O)Nc2ccc(CN3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)c1cc(C(=O)N(Cc2ccccc2)c2ccc(CN3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
2,4-Bis-benzyloxy-5-isopropenyl-N-(4-morpholin-4-ylmethyl-phenyl)-benzamide (0.245 g, 0.45 mmol) [prepared using Method A2 from (2,4-bis-benzyloxy-5-isopropenyl)-benzoic acid (Preparation B5) and 4-morpholin-4-yl-methyl-phenylamine] dissolved in DMF (3 ml), was treated with 60% NaH in mineral oil (27 mg, 1.5 eq) and stirred for 15 minutes followed by the addition of benzyl bromide (0.052 ml, 0.45 mmol), then stirred for a further 2 hours at room temperature. The reaction was diluted with EtOAc and water. The EtOAc layer was separated, washed with brine, dried (MgSO4) and evaporated to afford 0.2 g of the title compound as a yellow oil. MS: [M+H]+ 639
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10]C)=[O:9])[CH:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1>[OH-].[Na+]>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1
Reactant: COC(=O)C1CCC(C)=CC1NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC1=CC(NC(=O)OC(C)(C)C)C(C(=O)O)CC1
Temperature: 50 °C
Yield: 73.7 %

Procedure:
5 g (18.6 mmol) of tert-butyl (3-methyl-6-carbomethoxy-2-cyclohexen-1-yl)-carbamate are introduced into 40 ml of 1 N sodium hydroxide solution, and the mixture is stirred at 50° C. until a clear solution has formed. The solution is extracted once using diethyl ether, and a pH of 1 is then established at 0° C. using concentrated hydrochloric acid. After the mixture has been extracted using diethyl ether and evaporated, 3.5 g (74% of theory) of tert-butyl 3-methyl-6-carboxy-2-cyclohexen-1-yl-carbamate of melting point 132°-136° C. are obtained. ##STR76##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[C:19](Cl)=[N:20][C:21]([CH3:24])=[N:22][CH:23]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=1[NH2:29]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[C:19]([NH:29][C:28]3[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:27]=3[CH3:26])=[N:20][C:21]([CH3:24])=[N:22][CH:23]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ncc(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(Cl)n1
Reactant: COc1ccc(N)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2nc(C)ncc2S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(C)c1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a solution of 5-(4-benzyloxy-benzenesulfonyl)-4-chloro-2-methyl-pyrimidine (38 mg, 0.106 mmol) and 2-methyl-4-methoxy aniline (31 mg, 0.23 mmol) in toluene (1 mL) was added p-toluenesulfonic acid monohydrate (1.6 mg, 0.0081 mmol). The resulting mixture was heated at reflux under N2 for 1 h and then cooled to room temperature. The mixture was quenched by addition of water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified using preparative TLC on silica (1:1 hexanes/EtOAc) to provide the desired product (46 mg, 95%) as a pale yellow solid: mp 110–114° C.; 1H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 8.61 (s, 1H), 7.86 (d, J=9.1 Hz, 2H), 7.49 (d, J=8.6 Hz, 1H), 7.38–7.33 (m, 4H), 7.07–7.04 (m, 2H), 6.79–6.75 (m, 2H), 5.12 (s, 2H), 3.81 (s, 3H), 2.46 (s, 3H), 2.17 (s, 3H); ESI MS m/z 476 [(M+H)+, calcd for C26H26N3O4S, 476.2].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(Br)cn2)CC1

Procedure:
Prepared from 2,5-dibromopyridine and 4-methylpiperazine in a similar manner to Example 9(d).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Cl.O>CN(C)C=O>[CH:3]1([CH2:9][O:10][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: ClCCCCCBr
Reactant: OCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCCCOCC1CCCCC1
Yield: 419.4 %

Procedure:
60% Sodium hydride (1.16 g) was suspended in dimethylformamide (40 ml), and a solution of cyclohexanemethanol (0.3 g) in dimethylformamide (10 ml) was dropwise added under ice-cooling with stirring, which was followed by stirring at room temperature for 1 hr. The mixture was again ice-cooled, and a solution of 1-bromo-5-chloropentane (4.88 g) in dimethylformamide (10 ml) was dropwise added, which was followed by stirring at room temperature for 2.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 2.9 g of 5-(cyclohexylmethoxy)pentyl bromide.
Reaction SMILES: [N:1]([CH2:4][CH3:5])=[C:2]=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][C:16]3[N:17]([C:19]([CH2:22][C:23]4[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=4)[NH2:26])=[CH:20][N:21]=3)[N:18]=2)=[CH:9][C:8]=1[F:30].C(N(CC)CC)C>C(#N)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][C:16]3[N:17]([C:19]([CH2:22][C:23]4[CH:24]=[C:25]([NH:26][C:2]([NH:1][CH2:4][CH3:5])=[O:3])[CH:27]=[CH:28][CH:29]=4)=[CH:20][N:21]=3)[N:18]=2)=[CH:9][C:8]=1[F:30]
Reactant: CCN=C=O
Reactant: Nc1cccc(Cc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1cccc(Cc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
Isocyanatoethane (1.3 μL, 0.019 mmol) were added to a mixture of 3-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylaniline (5 mg, 0.01 mmol) and triethylamine (7.0 μL, 0.050 mmol) in acetonitrile (0.5 mL). After the reaction mixture was stirred at RT for 30 min, it was purified by RP-HPLC (pH 10) to afford the desired product (2 mg, 30%). LCMS: (M+H)=469.0/470.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:17]=[C:16]([CH:18]([NH2:20])[CH3:19])[O:15][N:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:17]=[C:16]([CH:18]([NH:20][C:30](=[O:32])[CH3:31])[CH3:19])[O:15][N:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(Oc2ncc(-c3cc(C(C)N)on3)s2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2ncc(-c3cc(C(C)NC(C)=O)on3)s2)cc1
Reaction time: 0.33 h
Yield: 95.1 %

Procedure:
To a solution of Example 53A (740 mg, 2.33 mmol) and triethylamine (975 μL, 7 mmol) in dichloromethane (15 mL) was added acetic anhydride (282 μL, 2.8 mmol) at ambient temperature. The reaction was stirred for 20 minutes, concentrated, and purified by flash chromatography on silica gel eluting with a solvent gradient from 30% to 80% ethyl acetate in hexanes to provide 796 mg (95%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.42 (d, J=6.99 Hz, 3H) 1.87 (s, 3H) 3.80 (s, 3H) 5.09 (m, 1H) 6.89 (s, 1H) 6.99-7.12 (m, 2H) 7.27-7.46 (m, 2H) 7.95 (s, 1H) 8.51 (d, J=8.09 Hz, 1H); MS (ESI) m/z 360.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:14][C:15]2[CH:16]=[C:17]([CH2:18][OH:19])[CH:20]=[CH:21][CH:22]=2)[N:4]=1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccco2)nc1COc1cccc(CO)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (22.3 g), 3-hydroxybenzyl alcohol (10.0 g), potassium carbonate (11.14 g) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 4 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:1, v/v) to give (3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}phenyl)methanol as colorless crystals (12.75 g, yield 55%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 100-101° C.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][O:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[N:32]=[C:15]3[CH:16]=[CH:17][C:18]([NH:20][C:21]([C:23]4[N:27]([CH3:28])[N:26]=[CH:25][C:24]=4[C:29](O)=[O:30])=[O:22])=[CH:19][N:14]3[N:13]=2)[CH2:8]1>>[CH3:5][O:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[N:32]=[C:15]3[CH:16]=[CH:17][C:18]([NH:20][C:21]([C:23]4[N:27]([CH3:28])[N:26]=[CH:25][C:24]=4[C:29]([N:1]4[CH2:4][CH2:3][CH2:2]4)=[O:30])=[O:22])=[CH:19][N:14]3[N:13]=2)[CH2:8]1
Reactant: COC1CCN(c2nc3ccc(NC(=O)c4c(C(=O)O)cnn4C)cn3n2)C1
Reactant: C1CNC1
Product: COC1CCN(c2nc3ccc(NC(=O)c4c(C(=O)N5CCC5)cnn4C)cn3n2)C1

Procedure:
Using azetidine and 5-[2-(3-Methoxy-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Off white solid (57 mg, 43%). MS: m/z=425 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:12])=[N:9][C:10]=1[CH3:11])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][C:15]=1[C:24]([F:27])([F:26])[F:25]>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:12][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][O:3][CH2:1][CH3:2])=[C:10]([CH3:11])[N:9]=2)(=[O:21])=[O:22])=[CH:16][C:15]=1[C:24]([F:27])([F:25])[F:26]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOCc1ccc(N)nc1C
Product: CCOCc1ccc(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)nc1C

Procedure:
This material was prepared in analogy to example 1 from 5-ethoxymethyl-6-methyl-pyridin-2-ylamine (0.07 g) and 4-chloro-3-(trifluoromethyl)- benzenesulfonyl chloride (0.129 g) as a yellow gum (0.068 g). MS (ESI−): 407.2 ([M−H]−)
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1C(OCC1C=CC=CC=1)=O>C(O)C.[Pd]>[CH2:12]([O:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]2)=[C:2]([NH2:1])[N:10]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Agent: [Pd]
Solvent: CCO
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Yield: 77.9 %

Procedure:
Phenylmethyl 2-{3-[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]propyl}-1-piperidinecarboxylate (for example, as prepared for Intermediate 11) (1.16 g, 2.336 mmol) in ethanol (130 mL) was hydrogenated over 10% palladium on carbon (0.497 g, 0.467 mmol) at ambient temperature overnight. The mixture was filtered through a Celite cartridge under nitrogen, washed with ethanol and evaporated in vacuo to give the title compound as a cream solid (0.66 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([CH3:16])[CH:10]=2)=[O:6].[C:17](Cl)(=[O:19])[CH3:18].O>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[N:8]([C:17](=[O:19])[CH3:18])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([CH3:16])[CH:10]=2)=[O:6]
Reactant: COC(=O)c1cc2ccc(C)cc2[nH]1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(C)cc2n1C(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.5 %

Procedure:
Sodium hydride (4.70 g. of 50% dispersion in mineral oil) was added portionwise with stirring to a stirred solution of 6-methylindole-2-carboxylic acid methyl ester (18.0 g.) in dry N,N-dimethylformamide (100 ml.) and the mixture was stirred at room temperature for 1.5 hours. Acetyl chloride (8.0 g.) was then added dropwise with stirring and cooling and the resulting mixture was stirred at room temperature for 5 hours and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform first gave mineral oil followed by pure product. Evaporation of the product-containing fractions gave a solid which are crystallized from methanol to give 1-acetyl-6-methylindole-2-carboxylic acid methyl ester (14.4 g.), m.p. 51°-53° C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[N:9]=[CH:8][N:7]2[N:10]=[CH:11][N:12]=[C:6]2[C:5]=1[CH2:13][CH2:14][CH3:15]>CC(O)=O>[Br:1][CH2:3][C:4]1[N:9]=[CH:8][N:7]2[N:10]=[CH:11][N:12]=[C:6]2[C:5]=1[CH2:13][CH2:14][CH3:15]
Reactant: CCCc1c(C)ncn2ncnc12
Reactant: BrBr
Solvent: CC(=O)O
Product: CCCc1c(CBr)ncn2ncnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Br2 (0.153 ml, 3 mmol) is added dropwise to a solution of 7-methyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine (3 mmol) heated at 100° C. in HOAc (10 ml). After the addition, the mixture is stirred at 100° C. overnight. The solvent is removed in vacuo and the residue dissolved in EtOAc (15 ml), washed with Na2S2O3 solution (sat. 5 ml), followed by NaHCO3 (10 ml), and brine (10 ml). The organic phase is dried (Na2SO4) and evaporated. The resulting yellow oil is purified by PTLC, which provides the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH:20](=[O:22])[CH3:21]>C1COCC1>[OH:22][CH:20]([C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1)[CH3:21]
Reactant: CC(C)(C)C(=O)Nc1cccc(Br)n1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1cccc(NC(=O)C(C)(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of N-(6-bromopyridin-2-yl)-2,2-dimethylpropanamide (2 g, 7.77 mmol, 1 eq.) in 25 ml of THF was cooled to −78° C. and n-BuLi (1.6 M, 9.72 ml, 15.55 mmol) was added dropwise. After 1 h, acetaldehyde (0.376 g, 8.55 mmol, 1.1 eq.) was added and the mixture was warmed to 0° C. within 1 h. The reaction was quenched with H2O, and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc. The organics were combined, dried over MgSO4 and concentrated. The crude material was purified by chromatography on silica gel to give N-[6-(1-hydroxyethyl)pyridin-2-yl]-2,2-dimethylpropanamide (1.45 g, 83% yield) as a white solid.
Reaction SMILES: C([N:4]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([Cl:46])[CH:44]=2)[C@@:6]2([C@@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=3[F:18])[C@H:9]([C:19]([NH:21][CH:22]3[CH2:27][CH2:26][CH:25]([O:28]C(=O)C)[CH2:24][CH2:23]3)=[O:20])[N:8]([C:32](=[O:34])[CH3:33])[C@H:7]2[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:5]1=[O:47])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:28][C@H:25]1[CH2:24][CH2:23][C@H:22]([NH:21][C:19]([C@@H:9]2[N:8]([C:32](=[O:34])[CH3:33])[C@@H:7]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@:6]3([C:40]4[C:45](=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=4)[NH:4][C:5]3=[O:47])[C@H:10]2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[F:18])=[O:20])[CH2:27][CH2:26]1
Reactant: CC(=O)OC1CCC(NC(=O)[C@H]2[C@H](c3cccc(Cl)c3F)[C@]3(C(=O)N(C(C)=O)c4cc(Cl)ccc43)[C@H](CC(C)(C)C)N2C(C)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)N1[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@@H](c2cccc(Cl)c2F)[C@@H]1C(=O)N[C@H]1CC[C@H](O)CC1

Procedure:
To a solution of 117 mg (0.17 mmol) of acetic acid 4-{[(2′S,3′R,4′S,5′R)-1,1′-diacetyl-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-cyclohexyl ester in 10.0 mL of methanol under argon, was added 10 mL (81 mmol) of a saturated potassium carbonate solution. The resulting mixture was stirred at room temperature for 1 hour, upon which the methanol was evaporated under reduced pressure. The remaining aqueous phase was extracted 3 times with 20 mL of dichloromethane. The combined organic extracts were washed with 20 mL of brine, dried with magnesium sulfate and then concentrated to dryness under reduced pressure. 92 mg of (2′S,3′R,4′S,5′R)-1′-acetyl-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (trans-4-hydroxy-cyclohexyl)-amide were obtained as a white powder. mp: 220° C. (Kofler); LC-MS: tR (min)=0.97; [M+H]+: m/z 604; [M−H]−: m/z 602 (method A); 1H NMR (60° C., CHLOROFORM-d, 400 MHz): 0.68 (s, 9H); 0.75 to 2.62 (m partially hidden, 14H); 3.51 (m, 1H); 3.65 (m, 1H); 4.28 (m broad, 1H); 4.48 (dd, J=3.4 and 5.9 Hz, 1H); 4.98 (d, J=10.3 Hz, 1H); 6.65 (d, J=1.5 Hz, 1H); 6.99 (t, J=7.8 Hz, 1H); 7.05 to 7.48 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:22]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([NH2:35])=[C:31]([NH2:34])[CH:32]=2)[C:27]([CH3:37])([CH3:36])[CH2:26]1)(=[O:24])[CH3:23]>>[C:22]([N:25]1[C:33]2=[CH:32][C:31]3[NH:34][C:3]([C:2]([F:7])([F:6])[F:1])=[N:35][C:30]=3[CH:29]=[C:28]2[C:27]([CH3:37])([CH3:36])[CH2:26]1)(=[O:24])[CH3:23]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)N1CC(C)(C)c2cc(N)c(N)cc21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC(=O)N1CC(C)(C)c2cc3nc(C(F)(F)F)[nH]c3cc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
A mixture of 60 g. polyphosphoric acid, 1.6 ml. trifluoroacetic acid, 18 g. phosphorus pentoxide and 4.0 g. (18 mmole) 1-acetyl-5,6-diamino-3,3-dimethylindoline (Example 2b) is stirred for 7 hours at 150°-160° C. The reaction mixture is allowed to cool to 90° C., poured on to ice, left to stand overnight and filtered to give 1.7 g. (31%) of the title compound; m.p. 290°-291° C.
Reaction SMILES: C([NH:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10]O)=[S:7])(C)(C)C.[ClH:19]>C(OCC)C>[ClH:19].[C:13]1([CH2:12][C@@H:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)NC(=S)N[C@@H](CO)Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: NC1=N[C@H](Cc2ccccc2)CS1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The process is performed as in Example 2, starting with 2 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(phenylmethyl)ethyl]thiourea and 20 cm3 of aqueous 6N hydrochloric acid. The reaction lasts 1 h 30 min. After cooling the reaction mass to a temperature in the region of 0° C., the solution is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. Crystallization of the oil obtained is initiated by addition of diethyl ether. The resulting precipitate is spin-filtered, washed with twice 10 cm3 of diethyl ether and then dried under reduced pressure (10 Pa) at a temperature in the region of 60° C. The product is purified by taking it up in 100 cm3 of dichloromethane with stirring for 30 minutes. After filtration of the suspension, the filter cake is washed with twice 10 cm3 of dichloromethane and is then dried under the same conditions as above. 1.1 g of (+)-(4R)-4-phenylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride are obtained in the form of a white solid melting at 168° C. (αD20=+8.7±0.3 at a concentration of 1% in methanol).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:18][CH:17]=1)[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH2:29]([O:31][C:32](=[O:38])/[CH:33]=[CH:34]/[C:35](O)=[O:36])[CH3:30].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C@H:3]([NH:2][C:35](=[O:36])/[CH:34]=[CH:33]/[C:32]([O:31][CH2:29][CH3:30])=[O:38])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C=C/C(=O)O
Reactant: N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/C(=O)N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (R)-benzyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate (87.6 mg, 0.183 mmol) is added a solution of HCl in 1,4-dioxane (0.456 mL, 1.825 mmol) at room temperature. After stirring for 3 hours, the reaction mixture is concentrated under reduced pressure to give (R)-benzyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride. A mixture of (R)-benzyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride, fumaric acid monoethyl ester (33.4 mg, 0.220 mmol), EDCl (63.3 mg, 0.330 mmol), DIPEA (0.058 ml, 0.330 mmol) and HOAt (44.9 mg, 0.330 mmol) in DMF (1.8 ml) is allowed to stir at room temperature for 3 hour. The reaction mixture is diluted with water, and then the products are extracted with EtOAc. The organic layer is washed with NH4OH, 1M HClaq and brine, dried over Na2SO4, filtered, and concentrated to give crude. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100) to give (R,E)-ethyl 4-(4-(benzyloxy)-1-(3′-chlorobiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobut-2-enoate (72.9 mg); HPLC retention time=1.40 minutes (condition B); MS (m+1)=506.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (t, J=7.1 Hz, 3H) 2.58 (A of ABX, Jab=16.4 Hz, Jax=5.3 Hz, 1H) 2.6 (B of ABX, Jab=16.4 Hz, Jbx=5.1 Hz, 1H) 2.88 (A of ABX, Jab=13.6 Hz, Jax=8.1 Hz, 1H) 3.03 (B of ABX, Jab=13.6 Hz, Jbx=6.3 Hz, 1H) 4.24 (q, J=7.1 Hz, 2H) 4.56-4.64 (m, 1H) 5.12 (A of AB, J=12.1 Hz, 1H) 5.18 (B of AB, J=12.1 Hz, 1H) 6.57 (br d, J=9.1 Hz, 1H) 6.77 (A of AB, J=15.4 Hz, 1H) 6.81 (B of AB, J=15.4 Hz, 1H) 7.19 (br d, J=8.1 Hz, 2H) 7.29-7.47 (m, 10H) 7.53-7.54 (m, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.Cl.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[CH2:30]>>[C:8]([C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:30][CH2:29][C:28]([O:32][CH2:33][CH3:34])=[O:31])#[N:9]
Reactant: C=CC(=O)OCC
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCC(C#N)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To an ethanolic solution (100 ml) of diphenylacetonitrile (28 g) were added DBU (6 ml) and ethyl acrylate (30 ml) and the mixture was heated and stirred at 80° C. for 16 hours. After cooling, 200 ml of 2N-hydrochloric acid was added to the reaction mixture, which was then extracted with isopropyl ether. The organic layer was washed with water, dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The resulting crude crystals were recrystallized from hexane/isopropyl ether to provide ethyl 4-cyano-4,4-diphenylbutyrate (34 g).