Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:24]=[C:23]([CH3:25])[C:16]([O:17][CH2:18][CH:19]([OH:22])[CH2:20]O)=[C:15]([CH3:26])[CH:14]=3)[N:9]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1.CC[N:30](C(C)C)C(C)C.CS(Cl)(=O)=O.N>C1COCC1.CO>[NH2:30][CH2:20][CH:19]([OH:22])[CH2:18][O:17][C:16]1[C:15]([CH3:26])=[CH:14][C:13]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([CH3:27])[N:3]=[C:2]([Cl:1])[CH:7]=3)[O:12][N:11]=2)=[CH:24][C:23]=1[CH3:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)cc(Cl)n1
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CN)c(C)c3)no2)cc(Cl)n1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of (RS)-3-{4-[5-(2-chloro-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol (134 mg, 0.345 mmol) in THF (5 mL), DIPEA (89 mg, 0.69 mmol) followed by methanesulfonylchloride (43 mg, 0.379 mmol) is added at 0° C. The mixture is stirred at it for 2 h before 7 M NH3 in MeOH (1.2 mL) is added. The mixture is stirred at 65° C. for 16 h before the solvent is removed in vacuo to give crude (RS)-1-amino-3-{4-[5-(2-chloro-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol as beige resin; LC-MS: tR=0.80 min, [M+1]+=388.96.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:9](Cl)=[O:10].[NH2:19][C@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21]1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:9]([NH:19][C@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH2:21]1)=[O:10]
Reactant: Cc1ccccc1C(C(=O)Cl)c1ccccc1C
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: Cc1ccccc1C(C(=O)N[C@H]1CCN(CCc2ccc(F)cc2)C1)c1ccccc1C
Yield: 15 %

Procedure:
2,2-Bis(2-methylphenyl)acetyl chloride (0.74 g) and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine (0.42 g) were reacted under the same conditions as in Example 53 to give (S)-2,2-bis(2-methylphenyl)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)acetamide (0.13 g), melting point 108-110° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9]([Cl:12])(Cl)[Cl:10]>>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:9]1([Cl:12])[CH2:1][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClC(Cl)Cl
Solvent: C=Cc1ccccc1
Product: ClC1(Cl)CC1c1ccccc1

Procedure:
312 g of styrene are reacted with chloroform as described in (I). After a post-reaction time of 5 hours, fractional distillation gives 45 g of styrene and 444 g of 2,2-dichloro-1-phenyl-cyclopropane of boiling point 103°-104° C./11 mm. This corresponds to 79.2% of theory or 93% based on styrene converted.
Reaction SMILES: [C:1]([NH:5][C:6]([CH3:13])([CH3:12])[CH2:7][S:8]([OH:11])(=[O:10])=[O:9])(=[O:4])[CH:2]=[CH2:3].[CH3:14]O>OS(O)(=O)=O.O=S(=O)=O>[C:1]([NH:5][C:6]([CH3:13])([CH3:12])[CH2:7][S:8]([O:11][CH3:14])(=[O:9])=[O:10])(=[O:4])[CH:2]=[CH2:3]
Reactant: CO
Reactant: C=CC(=O)NC(C)(C)CS(=O)(=O)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: C=CC(=O)NC(C)(C)CS(=O)(=O)OC
Reaction time: 0.17 h

Procedure:
A 25-gram portion of 65% oleum (containing 0.203 mole of sulfur trioxide) is poured over 20 grams (0.097 equivalent) of 2-acrylamido-2-methylpropanesulfonic acid. The mixture warms as the acid dissolves in the oleum. The viscous mixture is stirred for 10 minutes and is then poured into 300 ml. (7.42 equivalents) of methanol, while the vessel containing the latter is cooled with ice. After the mixture becomes homogeneous it is stripped to about 100 ml. and extracted with chloroform. The chloroform extracts are combined and dried over sodium sulfate, and the desired methyl 2-acrylamido-2-methylpropanesulfonate is obtained upon stripping the chloroform.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:32]([CH2:40][C:41](=O)[CH3:42])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([C:18]2[O:19][C:20]([CH3:21])=[C:16]([CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:2]([NH:1]/[C:41](/[CH3:42])=[CH:40]\[C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=3)[N:17]=2)=[CH:27][CH:26]=1)([CH3:31])[CH3:30]
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: C/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 75 mg (0.18 mmol) of Intermediate 51 and 32 mg (0.194 mmol) of benzoylacetone to yield 55 mg of Example 44: TLC (DCM/MeOH (4:1): Rf=0.50; 1H NMR (DMSO-d6, 400 MHz) δ11.5 (d, 1H, J=9.0), 7.85 (m, 4H), 7.45 (m, 3H), 7.18 (d, 2H, J=8.4); 7.06 (d, 2H, J=8.8), 6.87 (d, 2H, J=8.5), 5.82 (s, 1H), 4.74 (m, 1H), 4.19 (t, 2H, J=6.6), 4.1 (m, 1H), 3.19 (m, 1H), 2.92 (t, 2H, J=6.6), 2.81 (dd, 1H, J=13.9. 9.1), 2.36 (s, 3H), 1.74 (s, 3H), 1.34 (d, 6H, J=6.0); low resolution MS (ES−)m/e 567.2 (M-)
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:26]1SC2CCCCC=2C=1C(OCC)=O.CC1C=CC=CC=1S(Cl)(=O)=O>>[CH3:26][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[S:7]([NH:10][C:11]1[S:15][C:14]2[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=2[C:12]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8]
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Agent: Cc1ccccc1S(=O)(=O)Cl
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2C)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate and 2-methylbenzene-sulphonyl chloride.
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH2:14].[Br:15][C:16]1[C:21]([CH2:22][CH3:23])=[C:20](Br)[N:19]=[CH:18][N:17]=1>CC(N(C)C)=O.C(N(C(C)C)CC)(C)C>[Br:15][C:16]1[N:17]=[CH:18][N:19]=[C:20]([NH:14][CH2:13][CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][NH:9][C:10]=3[N:1]=2)[C:21]=1[CH2:22][CH3:23]
Reactant: NCCCc1ccc2c(n1)NCCC2
Reactant: CCc1c(Br)ncnc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCc1c(Br)ncnc1NCCCc1ccc2c(n1)NCCC2
Reaction time: 6 h

Procedure:
A mixture of 0.20 g (1 mmole) of 3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-ylpropylamine [prepared according to J. Org. Chem. 2004, 69, (1959-1966)] and 0.30 g (1.1 mmoles) of 4,6-dibromo-5-ethyl-pyrimidine in 20 ml of dimethylacetamide and 1 ml of diisopropylethylamine is taken to 120° C. for 6 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silica gel eluting with a gradient of 100% heptane to 100% ethyl acetate. 0.21 g of expected product is obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[NH:7][C:8]([CH:10]3[O:15][CH2:14][CH2:13][NH:12][CH2:11]3)=[N:9][C:5]=2[CH:4]=1.CCN(C(C)C)C(C)C.[Cl:27][C:28]1[CH:33]=[C:32](Cl)[N:31]=[C:30]([NH2:35])[N:29]=1>C(O)C>[Cl:27][C:28]1[CH:33]=[C:32]([N:12]2[CH2:13][CH2:14][O:15][CH:10]([C:8]3[NH:7][C:6]4[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[N:9]=3)[CH2:11]2)[N:31]=[C:30]([NH2:35])[N:29]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc2[nH]c(C3CNCCO3)nc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2[nH]c(C3CN(c4cc(Cl)nc(N)n4)CCO3)nc2c1
Temperature: 25 °C
Yield: 38.8 %

Procedure:
To a suspension of 5-(methyloxy)-2-(2-morpholinyl)-1H-benzimidazole (500 mg, 2.143 mmol) and DIPEA (693 mg, 5.36 mmol) in ethanol (10 mL) stirred at room temperature was added solid 4,6-dichloro-2-pyrimidinamine (352 mg, 2.143 mmol). The reaction mixture was stirred at 85° C. overnight. The reaction mixture was cooled to room temperature and partitioned between EtOAc (25 mL) and water (25 mL). The solvent was evaporated in vacuo to give the crude product. The crude product was added to a silica gel column and was eluted with CH2Cl2/CH3OH to afford the title compound (300 mg). LC-MS (ES) m/z=361 [M+H]+.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Cl:9][C:10]1[C:15](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[N:11]=1>CS(C)=O>[Cl:9][C:10]1[C:15]([C@@H:16]2[CH2:2][C@H:17]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)[N:11]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1ccc(-c2cccc(C(F)(F)F)c2)nc1Cl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)nc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Trimethyl sulfoxonium iodide (4.6 g, 21.25 mmol) was added slowly in small portions over a period of 20 min, to a suspension of sodium hydride (850 mg, 21.25 mmol) in dry DMSO (120 mL) at RT stirred for 1 h, till the formation of clear solution. A solution of (E)-ethyl 3-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)acrylate (6.3 g, 17.71 mmol) in dry DMSO (100 mL) was added slowly dropwise and stirred at RT for 30 mins. After completion, the reaction mixture was poured into ice water (100 mL), extracted with EtOAc (2×100 mL). The combined extracts were washed with ice water (2×100 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated to afford trans-ethyl 2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanecarboxylate (crude) (5.5 g) as reddish brown liquid. The crude was carried to next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[F:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:48])=[C:43]([CH:47]=1)[C:44](Cl)=[O:45]>ClCCl>[CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][N:5]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:10][N:11]=1)[C:44](=[O:45])[C:43]1[CH:47]=[C:39]([F:38])[CH:40]=[CH:41][C:42]=1[CH3:48]
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: CN(C)CCNc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C(=O)N(CCN(C)C)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
To a solution of 0.75 g of 10-[[6-[2-(dimethylamino)ethylamino]-3-pyridinyl]carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 5 ml of diisopropylethylamine in 75 ml of dichloromethane is added (slowly) 0.35 g of 5-fluoro-2-methylbenzoyl chloride in 10 ml of dichloromethane. The mixture is stirred at room temperature for 16 hours and the solution washed well with water. The organic layer is dried (MgSO4) and the solvent removed under vacuum. The residue is purified by column chromatography on silica gel with 30% methanol in chloroform as eluent to give 0.80 g of yellow solid; mass spectrum (CI), 511 (M+1).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]([OH:9])=[O:8])[CH2:4][CH2:5][SH:6].[C:10](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>CN(C)C=O>[C:10]([S:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[NH2:2])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@@H](CCS)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@@H](CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of anhydrous homocysteine hydrochloride (0.1 mole) in 60 ml of dimethylformamide is added 42 g (0.15 mole) of tritylchloride. The reaction mixture is stirred at room temperature for 2 days. Upon addition of 10% sodium acetate solution (500 ml) S-trityl-homocysteine precipitates together with triphenylcarbinol. Recrystallization in acetone affords pure S-tritylhomocysteine.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:21]1[N:22]=[C:23]([NH2:39])[C:24]2[N:25]=[CH:26][N:27]([C:37]=2[N:38]=1)[C@@H:28]1[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[C@H:29]1[OH:30]>>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]([N:7]2[CH2:6][CH2:5][CH:4]([CH2:1][C:2]#[C:3][C:21]3[N:22]=[C:23]([NH2:39])[C:24]4[N:25]=[CH:26][N:27]([C:37]=4[N:38]=3)[C@@H:28]3[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[C@H:29]3[OH:30])[CH2:9][CH2:8]2)=[O:11])=[CH:14][CH:15]=1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCC1CCN(C(=O)Oc2ccc(C)cc2)CC1
Product: Cc1ccc(OC(=O)N2CCC(CC#Cc3nc(N)c4ncn([C@@H]5O[C@H](CO)[C@@H](O)[C@H]5O)c4n3)CC2)cc1

Procedure:
Batch: AB-10-019. 4-methylphenyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-105 (0.548 g, 2.130 mmol) was added to a solution of 2-iodoadenosine (0.629 g, 1.600 mmol) according to general procedure 2. Yield: 0.236 g, 28%. 1H NMR (CD3OD) δ 8.29 (s, 1H), 7.14-6.92 (2×m, 4H), 5.95 (d, 1H), 4.75 (m, 2H), 4.34-4.16 (2×m, 3H), 3.91-3.71 (2×d, 2H), 3.10-2.90 (2×bt, 4H), 2.28 (s, 3H), 2.43 (d, 5H), 1.92-1.41 (2×m, 5H). m/z MH+=523.16. HPLC rt=6.8 min.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1C=C(C2(O)CCC(CC)CC2CCN2CCN(C)CC2)C=CC=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]([C:43]2([OH:51])[CH2:48][CH2:47][CH:46]([CH2:49][CH3:50])[CH2:45][CH2:44]2)[CH2:36][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:32]=[CH:33][CH:34]=1>>[ClH:3].[ClH:28].[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]([C:43]2([OH:51])[CH2:48][CH2:47][CH:46]([CH2:49][CH3:50])[CH2:45][CH2:44]2)[CH2:36][N:37]2[CH2:42][CH2:41][N:40]([CH3:4])[CH2:39][CH2:38]2)[CH:32]=[CH:33][CH:34]=1
Reactant: CCC1CCC(O)(C(CN2CCNCC2)c2cccc(Cl)c2)CC1
Reactant: CCC1CCC(O)(c2cccc(Cl)c2)C(CCN2CCN(C)CC2)C1
Agent: Cl
Product: CCC1CCC(O)(C(CN2CCN(C)CC2)c2cccc(Cl)c2)CC1

Procedure:
In an analogous manner to Example 24 1-[1-(3-chlorophenyl)-2-(4-methylpiperazin-1-ylethyl]-4-ethylcyclohexanol dihydrochloride was prepared from 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]-4-ethylcyclohexanol. MS (ES) m/z 365.4; HRMS: calcd for C21H33ClN2O+H, 365.23597; found (ESI, [M+H]+), 365.236.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[C@H:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].C([O-])(=O)C(C(C([O-])=O)O)O.[C:39]1([S:45]([OH:48])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(O)(C)C.O>[CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[CH:42]1[CH:41]=[CH:40][C:39]([S:45]([OH:48])(=[O:47])=[O:46])=[CH:44][CH:43]=1
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@H]1c1ccccc1Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=S(=O)(O)c1ccccc1
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reaction time: 2 h
Yield: 69.4 %

Procedure:
68.8 gm (0.122 mole, 95.2% de) R (+) Amlodipine hemi L (+) tartarate mono DMSO solvate prepared as per example 1 was suspended in aqueous isopropanol (90 ml IPA: 250 ml distilled water) and a solution of benzene sulfonic acid (19.35 gm of 90% technical grade, 0.110 mole) in 150 ml water was added. The reaction mixture was stirred for 2 hrs and the slurry was filtered, washed with distilled water, hexane, the solid was dried under vac. at 40° C. till constant weight to give R(+) amlodipine besylate (51.6 gm, 69.4% yield) 99.3 ee by chiral HPLC.
Reaction SMILES: [CH3:1][S:2]([N:5]([C:10]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=[O:13])S(C)(=O)=O)(=[O:4])=[O:3].O.[OH-].[Li+].Cl>CO>[CH3:1][S:2]([NH:5][C:10]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cc1N(S(C)(=O)=O)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1cc(S(C)(=O)=O)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of methyl 2-[N,N-bis(methylsulphonyl)amino]-4-methylsulphonylbenzoate (22.9 g) and lithium hydroxide monohydrate (7.5 g) in aqueous methanol (50%) was stirred at room temperature for 18 hours. The resulting solution was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulphate), filtered and evaporated to yield 2-methylsulphonylamino-4-methylsulphonylbenzoic acid as a beige solid, NMR (acetone d6); 3.1(2s,6H), 7.57(dd,1H), 8.15(d,1H), 8.23(d,1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.C([Li])CCC.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26](Cl)[O:27][CH3:28])(=[O:24])=[O:23]>O1CCCC1.CCCCCC>[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26]([O:27][CH3:28])[NH:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1)(=[O:24])=[O:23]
Reactant: COC(Cl)=NS(=O)(=O)c1ccccc1C
Reactant: Cc1cc(C)nc(N)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=NS(=O)(=O)c1ccccc1C)Nc1nc(C)cc(C)n1
Reaction time: 0.25 h

Procedure:
To 1.2 g of 2-amino-4,6-dimethylpyrimidine in 50 ml of tetrahydrofuran is added 6.85 ml of 1.6 molar n-butyl lithium in hexane at 0°. The mixture is stirred for 15 minutes. To this solution is added dropwise, a solution of 2.1 g of methyl N-(2-methylphenylsulfonyl)carbonimidochloridate in 5 ml of tetrahydrofuran at 0°-10°. This reaction mixture is stirred for 30 minutes at 0°-10° and 30 minutes at ambient temperature. The reaction mixture is filtered and the solvent is stripped from the filtrate under reduced pressure to yield a crude product. The crude product is further purified via dry column chromatography on silica gel with ethyl acetate as the eluent. Pure N'-(2-methylphenylsulfonyl)-N-(4,6-dimethylpyrimidin-2-yl)carbamimidic acid, methyl ester is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=1.C(N(CC)CC)C.[CH3:15][C:16]1([CH3:23])[C:20]([CH3:22])([CH3:21])[O:19][BH:18][O:17]1>C1COCC1.CC(P[Pd]PC(C)(C)C)(C)C>[CH3:15][C:16]1([CH3:23])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:2]2[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=2)[O:17]1
Reactant: Cc1cc(Br)cs1
Reactant: CC1(C)OBOC1(C)C
Agent: CC(C)(C)P[Pd]PC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)cs1

Procedure:
To 4-bromo-2-methylthiophene (1.5 g, 8.5 mmol) in THF (17 ml) was added bis[(1,1-dimethylethyl)phosphanyl]palladium (218 mg, 0.43 mmol), then N,N-diethylethanamine (2.5 g, 25.4 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.63 g, 12.7 mmol) and the resulting mixture heated at 40° C. under argon for 2 hours. The reaction was cooled and then filtered, washing with tert-butyl methyl ether. The washings were reduced in vacuo and the residue purified by chromatography on silica gel (gradient of hexane to 3% ethyl acetate:hexane) to afford the title compound (D38). MS (ES+) m/e 225 [M+H]+.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1.[Cl-].[Na+].O>[C:8]1([CH:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: C1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(c1ccccc1)N1CCCCC1
Reaction time: 3 h
Yield: 34.1 %

Procedure:
To a solution of ethyl 2-bromo-2-phenylacetate 21 (1.50 g, 6.17 mmol) in THF (10 mL) at room temperature was added piperidine (0.641 mL, 6.48 mmol) and TEA (1.72 mL, 12.34 mmol) and the reaction mixture was stirred for 3 h then diluted with brine and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography with gradient of ethyl acetate (0-50%) in hexane to afford 22 as a colorless viscous oil (520 mg, 34%). LRMS (ESI): (calc) 247.3 (found) 248.3 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[S:7])=[O:4].[C:8]1([NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14]>C1C=CC=CC=1>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:14][C:9]1[C:8]([NH2:15])=[CH:13][CH:12]=[CH:11][CH:10]=1)=[S:7])=[O:4]
Reactant: COC(=O)N=C=S
Reactant: Nc1ccccc1N
Solvent: c1ccccc1
Product: COC(=O)NC(=S)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-(o-aminophenyl)-3thioallophanate is prepared by dissolving 11.7 parts of methoxycarbonyl isothiocyanate in 50 parts of benzene and adding this to 10.8 parts of o-phenylenediamine in 200 parts of benzene at 10°-15° C. After stirring for 1 hour at room temperature, 13.7 parts of methyl 4-(o-aminophenyl)-3-thioallophanate is recovered by filtration, m.p. 187° C.(D).
Reaction SMILES: N[C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[C:23]([Cu])#[N:24].N(OC(C)(C)C)=O.O>CS(C)=O>[Cl:16][C:12]1[CH:11]=[C:10]([N:6]2[C:5]3[C:17]([C:19]([F:21])([F:22])[F:20])=[CH:18][C:2]([C:23]#[N:24])=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])[CH:15]=[CH:14][CH:13]=1
Reactant: N#C[Cu]
Reactant: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1cccc(Cl)c1
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1cccc(Cl)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
5-Amino-1-(3-chlorophenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one (125.1 mg) was dissolved in dimethyl sulfoxide (5 ml), and to the solution was added CuCN (102.6 mg). The mixture was heated at 55° C. At the same temperature, t-butyl nitrite (0.134 ml) was added dropwise during 30 minutes. After the addition was completed, the mixture was stirred at 60° C. for 1 hour. After allowing to cool, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by preparative TLC (2 mm, 20×20 cm, CHCl3:methanol=10:1) and then preparative TLC (2 mm, 20×20 cm, hexane:ethyl acetate=2:1) to give the title compound (31.4 mg, 24%).