Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:11][O:10]2)[N:6]=[CH:5][C:4]=1[C:12]#[N:13].[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CCO>[C:12]([C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH:9]([OH:10])[CH2:11][N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)=[N:6][CH:5]=1)#[N:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(C2CO2)ncc1C#N
Solvent: CCO
Product: COc1cc(C(O)CN2CCN(C(=O)OC(C)(C)C)CC2)ncc1C#N
Temperature: 25 °C

Procedure:
A 20 mL Pyrex vessel was charged with magnetic stirring bar, (1.68 g, 9.54 mmol) of 4-methoxy-6-(oxiran-2-yl)pyridine-3-carbonitrile, (2.66 g, 14.3 mmol) of tert-butyl piperazine-1-carboxylate, and 10 mL of EtOH. Then it was introduced in the microwave reactor and irradiated at 150° C. for 1 h. The mixture was cooled to room temperature and the solvent was evaporated and the resulting residue was purified by column chromatography (silica gel, 1-10% MeOH/dichloromethane) which afforded the product as an isomeric mixtures. LC/MS: (IE, m/z) 307.09 [(M+1)−t-Bu]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16]CC)=[O:15])[C:9]2=[O:19])=[CH:4][CH:3]=1.[OH-].[Li+]>C(O)C.O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=[O:15])[C:9]2=[O:19])=[CH:25][CH:24]=1
Reactant: CCOC(=O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Temperature: 80 °C

Procedure:
The product from Example 58C (0.90 g, 2.50 mmol) was dissolved in ethanol (20 mL). A solution of lithium hydroxide (0.57 g, 23.97 mmol) in water (5 mL) was added, and the reaction was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated, neutralized with 2 N HCl, and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to supply the title compound. MS (APCI+) m/z 332.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1cncnc1)N1CCOCC1
Product: O=C(NCC(c1cncnc1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-morpholin-4-yl-2-pyrimidin-5-yl-ethylamine.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:28])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:6][CH:5]=1.[CH2:29](I)[CH3:30].C([O-])([O-])=O.[K+].[K+]>C(O)C>[ClH:1].[CH3:2][N:3]([CH3:28])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH2:14][N:13]([CH2:29][CH3:30])[CH2:12][C@H:11]2[CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)=[CH:6][CH:5]=1
Reactant: CN(C)c1ccc([C@@H]2CCNC[C@H]2COc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2ccc(C(F)(F)F)cc2)C1
Temperature: 60 °C
Yield: 38 %

Procedure:
Was prepared from (41) (0.35 g) and ethyl iodide (0.4 g) in abs. ethanol (30 ml). heating to 60° C. for 8 h, and subsequently at room temperature for 48 h in the presence of K2CO3 (0.4 g). Purification as described for compound (7) gave a yield of 38% of (42). M.p. 225.8°-228.1° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH:10]([CH3:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH3:19])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]=2)[N:7]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CC#N
Product: Cc1c(-c2ccccc2)nc2ccc(Cl)nn12
Yield: 80.9 %

Procedure:
A stirred solution of 6-chloropyridazin-3-amine (1.00 g, 7.71 mmol) and 2-bromo-1-phenylpropan-1-one (Sigma-Aldrich, 1.54 g, 7.71 mmol) in acetonitrile (50 mL) is heated at 80° C. for 16 hours. The mixture is concentrated to dryness and purified via chromatography (hexanes to EtOAc) to afford the title compound (1.52 g, 81%) as a tan solid: Rf 0.52 (1:1 EtOAc:hexanes); LCMS (m/z)=244.2, 246.3 [M+H]+, tR=2.61 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH2:14][CH:5]3[C:4]=2[CH:3]=1.[CH2:27](I)[CH3:28].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:27]([N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[CH:5]2[CH2:14][N:13]([CH2:15][CH2:16][CH2:17][C:18](=[O:26])[C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:12][CH2:11][CH:6]12)[CH3:28]
Reactant: Cc1ccc2c(c1)C1CN(CCCC(=O)c3ccc(F)cc3)CCC1N2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCN1c2ccc(C)cc2C2CN(CCCC(=O)c3ccc(F)cc3)CCC21
Reaction time: 20 h

Procedure:
To methyl ethyl ketone (60 ml) are added 8-methyl-2-[γ-(p-fluorobenzoyl)propyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido-[4,3-b]indole (6.6 g), ethyl iodide (3.8 g) and potassium carbonate (5.3 g) and the mixture is refluxed with stirring for 20 hours. After cooling, the insoluble materials are filtered off and the filtrate is concentrated. To the resulting residue is added water and the mixture is extracted with benzene. The benzene layer is dried over anhydrous sodium sulfate and distilled to remove benzene. The resulting residue is treated with ethanolic hydrogen chloride in the same manner as described in Example 1 (1) to give the dihydrochloride of the titled compound (5.2 g), m.p. 150° - 153°C (recrystallized from ethanol).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([NH:13][C@H:14]([C:23]([O:25][CH3:26])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:33][O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>O.C(Cl)(Cl)Cl>[CH3:33][O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([NH:2][C@H:3]([C:11]([NH:13][C@H:14]([C:23]([O:25][CH3:26])=[O:24])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[O:12])[CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:40])=[CH:37][CH:36]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(OC)cc1
Yield: 81.8 %

Procedure:
In a mixture of 10 ml of water and 50 ml of chloroform were suspended 3.79 g of methyl phenylalanyltyrosinate hydrochloride and 0.53 g of sodium carbonate. To the mixture was added dropwise 175 g of 4-methoxybenzoylchloride in parallel with 10 ml of sodium carbonate solution (0.75 g), while stirring and cooling with ice. The mixture was stirred for 2 hours and the chloroform layer was collected. The layer was washed with 5% hydrochloric acid and water, dried and concentrated to dryness. The residue was crystallized from ethylacetate to give 3.9 g of methyl N-(4-methoxybenzoyl)-phenylalanyltyrosinate with a mp. 195°-197° C in a yield of 82%. Analysis, calculated for C27H28O6N2C 68.05, H 5.92, N 5.88, found C 68.42, H 6.08, N 5.74.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[CH2:14]([C:11]1[CH:10]=[CH:9][C:8]([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([N:7]([C:8]4[CH:9]=[CH:10][C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:12][CH:13]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)Cc1ccc(Nc2ccccc2)cc1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Cc1ccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4ccc(CC(C)C)cc4)cc3)cc2)cc1
Yield: 45.6 %

Procedure:
17.6 g (0.078 mol) of N-phenyl-p-isobutylaniline, 12.6 g (0.031 mol) of 4,4'-diiodobiphenyl, 12.9 g (0.093 mol) of anhydrous potassium carbonate, and 0.89 g (0.014 mol) of copper powder were mixed. The mixture was then allowed to undergo reaction at a temperature of 190° to 220° C. for 12 hours. The reaction product was then extracted with 70 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated to obtain an oily material. The crude product thus obtained was then purified by column chromatography (carrier: silica gel; elute: 1/6 mixture of toluene and n-hexane) to obtain 8.5 g (yield: 45.7%) of N,N'-bis(p-isobutylphenyl)-N,N'-diphenylbenzidine. The melting point of the product was from 133.8° C. to 135.3° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(S(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of N-methylpiperazine (3.0 g, 29.9 mmol), triethylamine (3.6 g, 35.9 mmol) and methanesulfonyl chloride (Compound 19, 4.11 g, 35.9 mmol) in tetrahydrofuran (20 ml) was stirred at 0° C. for 2 hours. The mixture was filtered and the filtrate was evaporated to dryness to give a solid. The solid was redissolved in ethyl acetate and washed with water. Evaporation of the dried (magnesium sulfate) organic phase gave the title sulfonamide. 1HNMR(CDCl3): 2.35 (s, 3H), 2.53 (t, 4H, J=5.0 Hz), 2.79 (s, 3H) and 3.27 (t, 4H, J=5.0 Hz).
Reaction SMILES: C(OC([N:8]1[C@@H:13]([C@@H:14]([OH:29])[C@@H:15]([NH:25][C:26](=[O:28])[CH3:27])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:30][CH2:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:9]1)=O)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][C@H:15]([NH:25][C:26](=[O:28])[CH3:27])[C@@H:14]([C@H:13]1[CH2:12][O:11][C@@H:10]([O:30][CH2:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:9][NH:8]1)[OH:29]
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCCC(C)(C)C)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCCC(C)(C)C)CN1
Reaction time: 0.17 h
Yield: 98.8 %

Procedure:
Dissolve (2R,5R)-5-[(1S,2S)-2-acetylamino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-(3,3-dimethylbutoxy)-morpholine-4-carboxylic acid tert-butyl ester (0.14 g, 0.27 mmol) in trifluoroacetic acid (2 mL) and stir 10 minutes. Concentrate to give the title compound. (0.14 g, 98.8% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH:30]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[NH:29][C:28]([C:38]3[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][C:39]=3[O:48][CH2:49][CH3:50])=[N:27]2)=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[CH:30]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)[N:29]([C:7]([C:6]3[CH:10]=[CH:11][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=3)=[O:8])[C:28]([C:38]3[CH:43]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:41]=[CH:40][C:39]=3[O:48][CH2:49][CH3:50])=[N:27]2)=[CH:24][CH:25]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: CCOc1ccc(C(F)(F)F)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(C(F)(F)F)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
4-Chloromethylbenzoyl chloride (140 mg, 0.74 mmol) was added to a cooled solution of triethylamine (0.20 mL, 1.44 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-1H-imidazole (300 mg, 0.61 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was diluted with methylene chloride and washed with water and brine, and dried over anhydrous sodium sulfate. The solvents were removed under reduced pressure and flash chromatography of the residue over silica gel using 10-25% ethyl acetate in hexanes gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-chloromethyl-phenyl)-methanone (330 mg, 84%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[CH3:32][O:33][CH2:34][CH2:35][NH2:36].Cl>O>[C:26]([C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([F:20])[C:17]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([NH:36][CH2:35][CH2:34][O:33][CH3:32])=[N:3][C:4]([C:28]([F:31])([F:30])[F:29])=[CH:5][CH:6]=1)#[CH:27]
Reactant: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc(F)c1NS(C)(=O)=O
Reactant: COCCN
Agent: Cl
Solvent: O
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2NCCOC)cc(F)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 12 %

Procedure:
A mixture of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (30 mg, 0.28 mmol) and 2-methoxyethylamine (100 μl) was stirred at ambient temperature for 48 hrs. The reaction mixture was diluted with water and then acidified with 2N HCl solution. The aqueous phase was extracted with EtOAc and the combined organic phase was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc=2/3) to give the title compound (4.0 mg, 12%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)[C:14]([NH:16][CH2:17]CC)=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.CN.Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1.Cl.ClC1C=CC(C(C2C=CC(Cl)=CC=2)N2CC(C(C3C=C(F)C=C(F)C=3)C(O)=O)C2)=CC=1>O1CCCC1.ClCCl.C(N(CC)CC)C>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH:11]([CH:13]([C:20]3[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=3)[C:14]([NH:16][CH3:17])=[O:15])[CH2:12]2)=[CH:33][CH:32]=1
Reactant: CCCNC(=O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
(RS)-2-{1-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-propylacetamide may be prepared in the following manner: 0.050 cm3 of a 2 M solution of methylamine in tetrahydrofuran, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20° C. The solution obtained is stirred at a temperature in the region of 20° C. for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm) conditioned and eluted with dichloromethane with the aid of a Duramat pump. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 19 mg of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-methylacetamide are thus obtained in the form of a white solid [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.66 (mt: 1H); 2.76 (d, J=5 Hz: 3H); 2.93 (mt: 1H); 3.10 (mt: 2H); 3.44 (broad t, J=7.5 Hz: 1H); 3.59 (d, J=10.5 Hz: 1H); 4.28 (s: 1H); 5.41 (unresolved complex: 1H); 6.71 (tt, J=9 and 2.5 Hz: 1H); 6.83 (mt: 2H); from 7.20 to 7.35 (mt: 8H)].
Reaction SMILES: O.[OH-].[Li+:3].[Cl:4][C:5]1[C:13]2[O:12][CH:11]([C:14]([O:16]CC)=[O:15])[O:10][C:9]=2[CH:8]=[C:7]([CH:19]=[O:20])[C:6]=1[Cl:21].C(OC(C)C)(C)C>CO>[Cl:4][C:5]1[C:13]2[O:12][CH:11]([C:14]([O-:16])=[O:15])[O:10][C:9]=2[CH:8]=[C:7]([CH:19]=[O:20])[C:6]=1[Cl:21].[Li+:3]
Reactant: CCOC(=O)C1Oc2cc(C=O)c(Cl)c(Cl)c2O1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CO
Solvent: O
Product: O=Cc1cc2c(c(Cl)c1Cl)OC(C(=O)[O-])O2
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
1.03 g of lithium hydroxide monohydrate are added to a solution of 7.0 g of ethyl 4,5-dichloro-6-formyl-1,3-benzodioxole-2-carboxylate in methanol under ice-cooling and the mixture is stirred at room temperature for 4 hours. Isopropyl ether is added to the reaction mixture and the resultant powdery materials are collected by filtration to give 6.48 g of lithium 4,5-dichloro-6-formyl-1,3-benzodioxole-2-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[C@@:21]12(O)[N:28](C)[C@@H:25]([CH2:26][CH2:27]1)[CH2:24][CH:23]=[CH:22]2.[Na]>>[F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([O:9][C@@:10]23[N:28]([CH3:21])[C@@H:25]([CH2:26][CH2:27]2)[CH2:24][CH:23]=[CH:22]3)=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Agent: [Na]
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1)CC2

Procedure:
11.13 g (0.04 mol) of methyl 4,4′-difluorobenzilate 3d and 5.57 g (0.04 mol) of tropenol are reacted with 0.09 g sodium analogously to Example 3, step 3.2. The product is recrystallised from acetonitrile.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[CH:11][C:6]2[CH2:7][O:8][B:9]([OH:10])[C:5]=2[CH:4]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].Cl>ClCCl>[Cl:20][C:21]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:22]=1[C:23]([NH:2][C:3]1[CH:12]=[CH:11][C:6]2[CH2:7][O:8][B:9]([OH:10])[C:5]=2[CH:4]=1)=[O:24]
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(c1)B(O)OC2)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A 250 ml round bottom flask was charged with a mixture of 6-amino-1-hydroxy-2,1-benzoxaborolane hydrochloride (1 g, 5.4 mmol, 1 eq), triethylamine (2.3 ml, 16.2 mmol, 3 eq) and dichloromethane (100 ml). 2-Chloro-4-fluorobenzoyl chloride (1.14 g, 5.9 mmol, 1.1 eq) was added, and the reaction mixture was allowed to stir at room temperature overnight. Aqueous hydrochloric acid (1 M, 50 ml) was added to the mixture and the suspension was vigorously mixed. The resulting white precipitate was then collected by vacuum filtration and dried under vacuum. LCMS (m/e) 306 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.96 (s, 2H) 7.29-7.45 (m, 2H) 7.59 (dd, J=9.0, 2.3 Hz, 1H) 7.63-7.78 (m, 2H) 8.15 (d, J=1.8 Hz, 1H) 9.25 (s, 1H) 10.53 (s, 1H). Amount Obtained: 1.1 g, 67% yield.
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH2:18][C@@H:19]([NH2:21])[CH2:20][C@H:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:27]Br.[OH-].[Na+]>C(O)(=O)C.C(OCC)C.O>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([Br:27])=[C:13]3[CH2:18][C@@H:19]([NH2:21])[CH2:20][C@H:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1Cc2cccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: N[C@@H]1Cc2c(Br)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Yield: 88.7 %

Procedure:
(2aR,4S)-1-Benzoyl-4-amino-1,2,2a,3,4,5-hexahydrobenz[cd]indole (29.4 g, 0.106 mole) was placed into a 500 ml three neck round bottom flask equipped with a mechanical stirrer, a nitrogen inlet and a constant addition funnel. The substrate was dissolved in glacial acetic acid (250 ml), and sodium acetate (34.7 g, 0.423 mole, 4 mol equiv) was then added. A solution of bromine (21.8 ml, 0.424 mole) in acetic acid was then added dropwise over a period of one hour with vigorous stirring and then stirred at room temperature overnight. The resulting thick slurry was diluted with ethyl ether, filtered and washed with ethyl ether. The material thus obtained was slurried in H2O and the pH adjusted to 11-12 with 5N NaOH. The solid was filtered, washed well with H2O and dried in vacuo to provide 33.6 g (88.8%) of the title compound. An analytical sample was prepared by recrystallization from isopropyl alcohol.
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][O:5][C:3]1=[O:4].C([O-])(=O)C.[Na+].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)Cl.CC1(C)N([O])C(C)(C)CCC1>[CH3:8][C:7]1([CH3:9])[C:2](=[O:1])[C:3](=[O:4])[O:5][CH2:6]1
Reactant: CC1(C)COC(=O)C1O
Agent: CC(=O)[O-]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: CC1(C)COC(=O)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
5 g (38.4 mmol) of 2-hydroxy-3,3-dimethyl-γ-butyrolactone (pantolactone) were dissolved in 118 ml of methylene chloride in a 200 ml sulphonation flask. 3.3 g (40.2 mmol) of sodium acetate and 3.6 g (15.5 mmol) of trichloroisocyanuric acid were added thereto. The mixture was cooled to 0° C. while stirring. A solution of 60 mg (0.28 mmol) of TEMPO derative B in 2 ml of methylene chloride was dosed in within 10 minutes. The temperature was held at 0°-3° C. by constant cooling. The reaction had finished after 3 hours. The white precipitate was filtered off and the filtrate was treated with sodium bisulphite solution in order to reduce the excess trichloroisocyanuric acid. Working up of the reaction mixture and subsequent recrystallization of the crude product gave 3.5 g (71%) of ketopantolactone, GC content: 99.6% (area percent).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[OH:4].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:15][CH2:16][NH2:17].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:15][CH2:16][NH:17][CH2:2][CH:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[OH:4]
Reactant: COc1ccc(CCN)cc1OC
Reactant: OC(CBr)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(CCNCC(O)c2cccs2)cc1OC
Temperature: 25 °C

Procedure:
A solution of the halohydrin, α-(bromomethyl)-2-thiophenemethanol (11.4 g, 0.055 mole), described in Example 4, and the primary amine, 3,4-dimethoxyphenethylamine (15 g, 0.083 mole), in 200 ml toluene is heated at reflux for 12 hr. The mixture is cooled to 25° C, shaken with 10% NaOH and the layers separated. The aqueous layer is extracted with chloroform and the combined organic phases washed with water and brine, dried (K2CO3) and concentrated. The resulting dark brown oil is purified by chromatography on silica gel to give the title compound as an oil; nmr (CDCI3) 2.9 (m, 6H), 3.45 (2H), 3.85 (s, 6H), 5.05 (m, 1H), 6.7 - 7.3 (m, 6H).