Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].Cl.[C:17]([O:21][C:22](=[O:37])[CH:23]([NH2:36])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-]>CN(C)C(=O)C>[C:17]([O:21][C:22](=[O:37])[CH:23]([NH:36][CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:29][CH:30]=1)([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccc(OC(C)(C)C)cc1
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(Cc1ccc(OC(C)(C)C)cc1)NCc1cnc2nc(N)nc(N)c2n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 37.8 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (53.7 mg, 0.1598 mmol) in anhydrous N,N dimethylacetamide was added 2-amino-3-(4-tert-butoxy-phenyl)-propionic acid tert-butyl ester hydrochloride (51.58 mg, 0.1758 m mol). Under positive pressure of Argon, iPr2EtN (33.69 ul) was added. The reaction mixture was stirred at 50° C. for 4 hrs and then at room temperature overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 27.6 mg product was obtained. Yield: 41%; 1H NMR (500 MHz, DMSO-d6): δ 1.22491(s, 9H), 1.26835 (s, 9H), 2.921–2.971 (m, 2H), 4.130 (b, 1H), 4.427(s, 2H), 6.91485–6.93165(d, J=8.4 Hz, 2H), 7.16037–7.17723(d, J=8.43 Hz, 2H), 8.89353 (s, 1H); 9.13119 (s, 2H), 9.30829 (s, 2H); ESI-MS: m/z 468 (M++1)
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH2:18][CH:19]([NH:46][C:47]([O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:48])[C:20](=[O:45])[NH:21][CH:22]([C:31](=[O:44])[N:32]([CH2:36][CH:37]([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40])[CH:33]([CH3:35])[CH3:34])[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>>[CH2:50]([O:49][C:47](=[O:48])[NH:46][CH:19]([C:20](=[O:45])[NH:21][CH:22]([C:31](=[O:44])[N:32]([CH2:36][CH:37]([O:38][CH2:39][CH3:40])[O:41][CH2:42][CH3:43])[CH:33]([CH3:35])[CH3:34])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[CH2:18][NH2:17])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)OCc1ccccc1)C(C)C)OCC
Solvent: CCNCC
Product: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CN)NC(=O)OCc1ccccc1)C(C)C)OCC

Procedure:
The Fmoc protective group was eliminated from 9H-fluoren-9-ylmethyl(2-benzyloxycarbonylamino-2-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate using diethylamine and employing the method as described under b). The desired product is obtained with MW=576.27 (calculated, monoisotopic); measured value (M+H)+=577.22
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:22][S:23]([CH2:26][CH2:27][CH2:28]Cl)(=[O:25])=[O:24])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:28][CH2:27][CH2:26][S:23]3(=[O:25])=[O:24])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1
Reactant: O=S(=O)(CCCCl)NC1CCN(Cc2ccc([C@H]3COc4ccccc4O3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S1(=O)CCCN1C1CCN(Cc2ccc([C@H]3COc4ccccc4O3)cc2)CC1
Temperature: 80 °C

Procedure:
To a solution of 3-chloro-propane-1-sulfonic acid {1-[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-piperidin-4-yl}-amide (410 mg, 0.88 mmol) in DMF (5 mL) is added NaH (60% dispersion in mineral oil, 71 mg, 1.8 mmol). The reaction is heated to 80° C. for 1 h, diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue is purified by reversed phase HPLC eluting with a gradient of 0-80% MeCN in water (+0.1% TFA). The desired fractions are lyophilized, partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated to provide the title compound (LC/MS method 1: ES+ m/z 429.4 [M+H]+, Rt=0.63 min).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]([F:21])([F:20])[F:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:6]2)#[N:2].Cl[CH2:23][C:24]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31](C(F)(F)F)[CH:30]=2)[O:26][N:25]=1>>[C:1]([C:3]1[C:4]([C:18]([F:21])([F:20])[F:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:23][C:24]1[N:28]=[C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=3[C:18]([F:21])([F:20])[F:19])[O:26][N:25]=1)[C:7]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:6]2)#[N:2]
Reactant: COC(=O)CCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Product: COC(=O)CCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2ccccc2C(F)(F)F)n1

Procedure:
Synthesized as described in Example 4 using methyl 3-[5-cyano-4-(trifluoromethyl)-1H-indol-2-yl]propanoate (Example 355A) and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.24 (d, J=7.8 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.67 (m, 2H), 7.57 (d, J=8.5 Hz, 1H), 6.63 (s, 1H), 5.54 (s, 2H), 3.73 (s, 3H), 3.33 (d, J=7.7 Hz, 2H), 2.94 (d, J=7.7 Hz, 2H): MS (ES) m/z 523 (M+1).
Reaction SMILES: N[C:2]1[C:3]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1.ClCCl.N([O:19][C:20]([CH3:23])(C)C)=O.CCCCC.C[O:30]CCOC>>[C:20]([O:19][C:2]1[C:3]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:30])[CH3:23]
Reactant: CC(C)(C)ON=O
Reactant: COCCOC
Reactant: COC(=O)COc1ncccc1N
Solvent: ClCCl
Solvent: CCCCC
Product: COC(=O)COc1ncccc1OC(C)=O
Reaction time: 0.17 h

Procedure:
First, 1.6 g of a boron trifluoride diethyl ether complex was added dropwise to a mixture of 1.0 g of 3-amino-2-(methoxycarbonyl)methoxypyridine, 3 ml of 1,2-dimethoxyethane, and 1 ml of dichloromethane at −10° C. After stirring at the same temperature for 10 minutes, a solution of 0.68 g of t-butyl nitrite in 1 ml of 1,2-dimethoxyethane was added dropwise to the reaction mixture at −5° C. or lower. After stirring at the same temperature for 30 minutes, n-pentane was poured into the mixture. The lower one of the two layers separated was dissolved in 5 ml of acetic anhydride, and the solution was stirred at 80° C. for 1 hour. After the solvent was distilled out, the residue was subjected to silica gel chromatography to give 0.45 g of 3-acetoxy-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[O:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1>>[O:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][NH:28][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH2:22][CH2:21]1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCCC1CCOCC1
Product: CCc1cc(-c2cncc(C(=O)NCCC3CCOCC3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(tetrahydropyran-4-yl)-ethyl-amine to afford the title compound. MS: m/e=370 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[CH2:3][CH2:2]1.[Cl:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]2[C:20]=1[CH2:21][CH2:22][C:23](=[O:31])[NH:24]2>>[ClH:15].[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:19]([O:18][CH2:17][CH2:16][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([O:9][CH2:10][CH:11]3[CH2:12][CH2:13]3)=[O:14])[CH2:5][CH2:6]2)=[C:20]2[C:25]=1[NH:24][C:23](=[O:31])[CH2:22][CH2:21]2
Reactant: O=C(NC1CCNCC1)OCC1CC1
Reactant: COc1ccc(OCCCl)c2c1NC(=O)CC2
Product: COc1ccc(OCCN2CCC(NC(=O)OCC3CC3)CC2)c2c1NC(=O)CC2
Product: Cl

Procedure:
Proceeding as in part A above, but replacing isobutyl 4-piperidylcarbamate with cyclopropylmethyl 4-piperidylcarbamate, and replacing 5-(3-chloropropoxy)-3,4-dihydrocarbostyril with 5-(2-chloroethoxy)-3,4-dihydro-8-methoxycarbostyril there was obtained 8-methoxy-3,4-dihydro-5-[2-(4-((cyclopropylmethoxy)carbonylamino)-1-piperidyl)ethoxy]carbostyril hydrochloride, m.p. 218°-220° C.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([C:7]([NH:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[O:8])[N:6]=1.FC(F)(F)C(O)=O.C(Cl)[Cl:34]>>[ClH:34].[ClH:34].[NH2:1][C:2]1[O:3][C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([C:7]([NH:9][CH2:10][CH2:11][NH2:12])=[O:8])[N:6]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1nc(N)oc1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCNC(=O)c1nc(N)oc1-c1ccccc1
Reaction time: 2.5 h
Yield: 94 %

Procedure:
1.46 g (4.2 mmol) of t-butyl [2-(2-amino-5-phenyl-4-oxazolecarboxamido)ethyl]carbamate were dissolved in 50 ml of methylene chloride and treated with 5 ml of trifluoroacetic acid. The reaction mixture was heated to reflux while stirring for 2.5 hours and thereafter evaporated under reduced pressure. The residue was dissolved in methanol, treated with 5 ml of 2 M methanolic hydrochloric acid and evaporated. Recrystallization of the residue from methanol/diethyl ether yielded 1.3 g (94%) of 2-amino-N-(2-aminoethyl)-5-phenyl-4-oxazolecarboxamide dihydrochloride as white crystals, melting point 260°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH2:10]([O:12][C:13](=[O:20])[CH:14]=[C:15]([NH2:19])[O:16][CH2:17][CH3:18])[CH3:11]>C(O)(C)C>[CH2:10]([O:12][C:13]([C:14]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[CH:14]([C:13]([O:12][CH2:10][CH3:11])=[O:20])[C:15]([O:16][CH2:17][CH3:18])=[N:19][C:15]=1[NH2:19])=[O:20])[CH3:11]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CCOC(=O)C=C(N)OCC
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1cccc(Cl)c1

Procedure:
Upon boiling a solution of 7.1 g of 3-chlorobenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 40 ml of isopropanol for 8 hours, 2-amino-4-(3-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 121°C is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C(N(CC)CC)C.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18]>C(#N)C.CO>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([NH:6][C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[O:18]
Reactant: Nc1cc[nH]n1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC#N
Product: O=C(Nc1cc[nH]n1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To a solution of 1H-pyrazol-3-amine (160 mg, 1.93 mmol, Fluka) in acetonitrile (10 ml) was added triethylamine (0.537 ml, 3.85 mmol, Aldrich) and the stirred solution cooled in an ice-water bath. A solution of 2,6-dichlorobenzoyl chloride (0.276 ml, 1.926 mmol, Aldrich) in acetonitrile (5 ml) was added dropwise. The mixture was stirred under nitrogen and allowed to warm slowly to ambient temperature overnight. The mixture was concentrated in vacuo. The residue was partitioned between DCM (20 ml) and water (20 ml). Insoluble material precipitated. The layers were separated and the aqueous phase then extracted with ethyl acetate (approximately 50 ml). The combined organic layers were filtered through a hydrophobic frit and concentrated in vacuo to give the crude material as an off-white foam. The residue was dissolved in methanol and adsorbed onto fluorosil. The sample was purified on silica 50 g using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give the title compound as a colourless solid (0.303 g).
Reaction SMILES: [CH2:1]([CH:4]([CH2:17][CH2:18][CH3:19])[CH2:5][O:6][C:7]1[N:12]=[C:11]([C:13]([O:15]C)=O)[CH:10]=[CH:9][CH:8]=1)[CH2:2][CH3:3].[CH3:20][C:21]#[N:22]>>[O:15]=[C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([O:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:17][CH2:18][CH3:19])[N:12]=1)[CH2:20][C:21]#[N:22]
Reactant: CCCC(CCC)COc1cccc(C(=O)OC)n1
Reactant: CC#N
Product: CCCC(CCC)COc1cccc(C(=O)CC#N)n1

Procedure:
CH3CN addition to methyl 6-((2-propylpentyl)oxy)picolinate following the method used in Example 6 gave 3-oxo-3-(6-((2-propylpentyl)oxy)pyridin-2-yl)propanenitrile in quantitative yield as a solid which was directly used in next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([NH:15][C:16]2[C:17](Cl)=[CH:18][C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])=[N:20][CH:21]=2)=[O:14])=[CH:11][C:10]=1[F:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.[Cu]I>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]2[O:14][C:17]3[CH:18]=[C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[N:20]=[CH:21][C:16]=3[N:15]=2)=[CH:11][C:10]=1[F:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2ccc(OCc3ccccc3)c(F)c2)cn1)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](COc1cc2oc(-c3ccc(OCc4ccccc4)c(F)c3)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
A suspension of tert-butyl ((2S)-1-((5-((4-(benzyloxy)-3-fluorobenzoyl)amino)-4-chloropyridin-2-yl)oxy)propan-2-yl)carbamate (6.02 g), potassium carbonate (3.14 g) and copper(I) iodide (216 mg) in DMF (30 mL) was stirred at 160° C. for 2 hr. The reaction mixture was subjected to silica gel chromatography (NH, ethyl acetate), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained solid was washed with ethyl acetate/hexane to give the title compound (1.35 g).
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3]Cl.[C:9]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:25]C(OC(C)(C)C)=O)[CH2:17][C@:18]([CH2:23][OH:24])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1.CCN(CC)CC>CC(C)=O>[CH2:6]([O:5][C:1]([O:2][CH2:3][O:21][C:19](=[O:20])[C@@:18]([CH2:23][OH:24])([CH3:22])[CH2:17][C@H:16]([NH2:25])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:10][CH:11]=1)=[O:8])[CH3:7]
Reactant: CCOC(=O)OCCl
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
Chloromethyl ethyl carbonate (54 mg, 387 nmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid ethoxycarbonyloxymethyl ester.
Reaction SMILES: [CH2:1]([NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:2]=[CH2:3].C(Cl)(Cl)=O>CN(C)C=O.O1CCCC1.C1C=CC=CC=1>[CH2:13]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[NH:4][CH:1]=[CH:2][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CCNC(=O)c1ccccc1OCc1ccccc1
Agent: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(COc2ccccc2-c2ccc[nH]2)cc1

Procedure:
2.7 (10 millimoles) of o-benzyloxybenzoic acid allylamide in 20 ml of a 20 per cent strength by weight solution of phosgene in tuluene are stirred, in the presence of 2 drops of dimethylformamide, at room temperature overnight. The residue which remains after distilling off the toluene under reduced pressure at 40° C. bath temperature is taken up in 30 ml of tetrahydrofuran, and the solution is filtered through a pad of glass wool and introduced, in the course of 45 minutes, into an ice-cooled solution of 4.0 g (30 millimoles) of potassium tert.-butylate in 60 ml of a 1:1 (by volume) tetrahydrofuran/benzene mixture, under argon as protective gas. 10 minutes after completion of the addition, the solvent is distilled off under reduced pressure, the residue is partitioned between methylene chloride and water, and the water is extracted twice with methylene chloride.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[S:15](=[O:18])(=[O:17])[NH2:16].[C:19]1([O:25][CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:26][O:25][C:19]1[CH:24]=[CH:23][C:22]([C:10]([C:9]2[CH:13]=[CH:14][C:6]([CH3:5])=[C:7]([S:15]([NH2:16])(=[O:18])=[O:17])[CH:8]=2)=[O:11])=[CH:21][CH:20]=1
Reactant: COc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1S(N)(=O)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc(C(=O)c2ccc(C)c(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
To a suspension of aluminium chloride (906 mg, 6.8 mmol) in methylene chloride (20 mL) is added 4-methyl-3-sulfamoyl-benzoyl chloride (1.1 g, 4.7 mmol) and anisole (1.1 g, 10.2 mmol). After the mixture is stirred at room temperature for 16 h, the reaction is quenched with 6 N HCl, and extracted with methylene chloride three times. The combined organic layers are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. On standing, crystals form and trituration with diethyl ether and ethyl acetate provides 0.84 g (58% yield) of the title compound as a white solid. MS (m/z): 306 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].N1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[CH2:29]([O:28][C:26]([N:11]1[CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:15]([F:18])([F:16])[F:17])[CH:4]=2)([OH:14])[CH2:13][CH2:12]1)=[O:27])[CH3:30]
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1CCC(O)(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
4-[4-Chloro-3-(trifluoromethyl)phenyl]-4-hydroxypiperidine (ACROS Co., 2.0 g) was dissolved in methylene chloride (10 ml), and pyridine (0.6 ml) and ethyl chloroformate (0.8 ml) were added thereto. The mixture was stirred at room temperature for 5 hr. After completion of the reaction, the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (1:2)) to give 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinecarboxylic acid ethyl ester (2.03 g, yield 81%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:7]([CH:9]=1)[NH2:8])#[N:2].[C:16](Cl)(Cl)=[S:17]>O1CCOCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:7]([N:8]=[C:16]=[S:17])[CH:9]=1)#[N:2]
Reactant: N#Cc1ccc(N2CCOCC2)c(N)c1
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(N2CCOCC2)c(N=C=S)c1

Procedure:
Reaction of 5-cyano-2-morpholinoaniline (2 g) with thiophosgene (1.15 ml) in dioxan (2 ml) and water (25 ml) at 0° C. for 30 minutes and then at room temperature for 2 hours yielded a residue which was extracted with dichloromethane to give 5-cyano-2-morpholinophenyl isothiocyanate as an oil.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.C[Si](Cl)(C)C.[CH2:15]([O:17][C:18](=[O:48])[CH2:19][CH2:20][N:21]([C:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:16].Cl>ClCCl>[CH2:15]([O:17][C:18](=[O:48])[CH2:19][CH2:20][N:21]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:39]1([C:45](=[O:46])[NH:2][OH:3])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[CH3:16]
Reactant: NO
Reactant: CCOC(=O)CCN(C1(C(=O)Cl)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCN(C1(C(=O)NO)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 mL (114 mmol, 7.5 equivalents) of dry pyridine at 0 ° C. is treated with 5.8 mL (45 mmol, 3.0 equivalents) of trimethylsilyl chloride, causing white solids to precipitate. The mixture is allowed to warm to ambient temperature overnight This mixture is then cooled to 0° C. aind treated with a solution of (15.1 mmol) of the product from Step F in 73 mL of dichloromethane causing an exotherm to about 8° C. This mixture is stirred at 0° C. for 30 minutes and at ambient temperature for about one hour. The reaction is then treated with 50 mL of 2N aqueous hydrochloric acid and was stirred at ambient temperature for one hour. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with 2N aqueous hydrochloric acid (2×50 mL) and water (50 mL). This solution of the title compound in dichloromethane is used in the next step.
Reaction SMILES: [CH2:1](NC)[CH2:2][CH2:3]C.[CH3:7][O:8][C:9]([O:14][CH3:15])([N:11]([CH3:13])[CH3:12])[CH3:10]>>[CH3:7][O:8][C:9]([O:14][CH3:15])([N:11]([CH2:13][CH2:1][CH2:2][CH3:3])[CH3:12])[CH3:10]
Reactant: COC(C)(OC)N(C)C
Reactant: CCCCNC
Product: CCCCN(C)C(C)(OC)OC
Temperature: 130 °C

Procedure:
6.1 g (0.07 mol) of n-butylmethylamine are stirred with 9.3 g (0.07 mol) of N,N-dimethylacetamide dimethyl acetal for 24 hours under reflux at a bath temperature of 130° C. Subsequent vacuum distillation gives N-butyl-N-methylacetamide dimethyl acetal, bp 72°-75° C./31 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].S([O-])([O-])=O.[Na+].[Na+].[C:22](=O)([O-])O.[Na+].IC>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12]([CH3:22])(=[O:14])=[O:13]
Reactant: O=C([O-])O
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Cc1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 75 °C

Procedure:
A stirred solution of 2-Chloro-5-(2-oxo-propyl)-benzenesulphonyl chloride (prepared as described in Example 174a) (20.0 g, 74.9 mmol) in dioxane (300 ml) at room temperature is treated with a solution of sodium sulphite (18.9 g, 150 mmol) and sodium hydrogen carbonate (12.6 g, 150 mmol) in water (200 ml). The reaction mixture is heated to 75° C. for 10 minutes and then allowed to cool to room temperature. The solvent is removed in vacuo and the residue dissolved in DMF (200 ml). The solution is stirred at room temperature and treated with iodomethane (21.2 g, 150 mmol). After stirring for 20 minutes, the reaction mixture is diluted with water (1000 ml) and extracted with ethyl acetate (3×250 ml). The combined organic layers are washed with water (2×200 ml), brine (100 ml), dried over MgSO4 and concentrated in vacuo to yield the titled compound.