Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([CH2:25][O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH:22]=[CH:21][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[O:10][C:11]=1[CH3:12].C[Sn]([N:41]=[N+:42]=[N-:43])(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([CH2:25][O:26][Si:27]([CH:28]([CH3:29])[CH3:30])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH:22]=[CH:21][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:14]=[C:15]([C:16]3[NH:43][N:42]=[N:41][N:17]=3)[CH:18]=[CH:19][CH:20]=2)[O:10][C:11]=1[CH3:12]
Reactant: COc1cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COc1cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1OCc1nc(-c2cccc(-c3nnn[nH]3)c2)oc1C
Yield: 63.8 %

Procedure:
A mixture of 3-{4-[(2-methoxy-4-{[(triisopropylsilyl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (0.52 g), trimethyl tin azide (0.62 g) and toluene (10 mL) was heated under reflux for 15 hrs. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography to give 5-(3-{4-[(2-methoxy-4-{[(triisopropylsilyl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)-1H-tetrazole as colorless crystals (0.36 g, yield 65%), from a fraction eluted with ethyl acetate-methanol (95:5, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 152-153° C.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([O:14][CH3:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Br:17])=[C:9]([O:14][CH3:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C(=O)NC(C)(C)C)ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C(=O)NC(C)(C)C)ccc1CBr
Temperature: 30 °C

Procedure:
A mixture of 3 g of N-tert-butyl-4-methyl-3-methoxybenzamide, 2.4 g of N-bromosuccinimide and 0.16 g of benzoyl peroxide in 40 ml of carbon tetrachloride is stirred at 30° C. while irradiating in the visible spectrum for 48 hours. The solvent is evaporated and then, successively, 25 ml of water are added, extraction is carried out with diethyl ether, drying is carried out over MgSO4, the solvent is evaporated and the residue is chromatographed on silica gel, elution being carried out with an 8/2 (v/v) cyclohexane/ethyl acetate mixture. The expected reactant is isolated after crystallization from isopropyl ether; M.p.=114° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.C(O[CH:10]1[C@H:15]([N:16]=[C:17]=[S:18])[C@@H:14]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]([O:23][C:24](=[O:26])[CH3:25])[C@@H:12]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:11]1)(=O)C.C(N(CC)CC)C>ClCCl>[C:24]([O:23][C@@H:13]1[C@@H:12]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:11][C@H:10]2[C@H:15]([N:16]=[C:17]([N:2]3[CH2:5][CH2:4][CH2:3]3)[S:18]2)[C@H:14]1[O:19][C:20](=[O:22])[CH3:21])(=[O:26])[CH3:25]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H]2SC(N3CCC3)=N[C@@H]2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of azetidine hydrochloride (12 g, 129 mmol) and (3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (48 g, 123 mmol) in dichloromethane (500 mL) was treated with triethylamine (18.7 g, 185 mmol) for 1 h at room temperature, and followed by addition oftrifluoroacetic acid (56.2 g, 493 mmol). The reaction mixture was stirred overnight at room temperature, and then quenched by aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous MgSO4, and condensed under vacuum to give a residue, which was purified by a silica gel column, eluted with 1% methanol in dichloromethane to provide compound 2 as a light yellow syrup (29 g, 61%). (ES, m/z) [M+H]+ 386.9; 1H NMR (300 MHz, CDCl3) 6.28-6.30 (d, J=6.6 Hz, 1H), 5.44-5.46 (m, 1H), 4.95-4.99 (m, 1H), 4.34-4.37 (t, J=5.4 Hz, 1H), 4.04-4.17 (m, 6H), 3.86-3.92 (m, 1H), 2.34-2.44 (m, 2H), 2.06-2.14 (m, 9H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([C@@H:14]1[O:16][CH2:15]1)Cl.C(=O)([O-])[O-].[Na+].[Na+].CC(C)([O-])C.[K+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(O)(C)C>[CH2:12]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6])[C@H:14]1[O:16][CH2:15]1
Reactant: ClC[C@H]1CO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: O=C1NC(=O)c2c(C[C@@H]3CO3)cccc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Into a reaction vessel were put phthalimide (2.00 g, 13.6 mol), (R)-epichlorohydrin (2.52 g, 27.2 mol), anhydrous sodium carbonate (144 mg, 1.36 mol), benzyltrimethylammonium chloride (252 mg, 1.36 mol) and isopropanol (13 ml) and the mixture was reacted at room temperature for 15 hours. After removal unreacted epichlorohydrin, to the residue was added isopropanol (13 ml) and the mixture is cooled to 20° C. Then thereto was gradually dropped a mixture of potassium tert-butoxide (1.83 g, 16.3 mol) and isopropanol (7 ml) and the mixture was stirred for 1 hour at the same temperature. The solvent was removed and to the residue was added ethyl acetate (13 ml). The mixture was washed with water (7 ml), and then ethyl acetate was removed to give crude (R)-glycidylphthalimide (2.16 g, yield 78%, optical purity 98% e.e.) as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:27][S:28]([O-:30])=[O:29].[Na+].N1CCC[C@H]1C(O)=O.[OH-].[Na+]>O1CCOCC1.[Cu]I>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:3][CH:4]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[C:20]([CH3:26])[CH:21]=1
Reactant: CS(=O)[O-]
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(C(=O)C[C@H](c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2C)ccn1

Procedure:
In analogy to example 358, step 1, from (R)-3-(4-bromo-phenyl)-3-(4-chloro-2-methyl-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one (example 282, step 1) in the presence of sodium methanesulfinate, L-proline, sodium hydroxide and copper(I) iodide in 1,4-dioxane was prepared the title compound as an yellow oil, MS (ESI+): m/z=428.1 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[C:10]([N:18]=C3C=CC(=O)C=C3)[C:9]=2[F:26])=[CH:4][CH:3]=1.OS(O)(=O)=O.CC#N.O.C(Cl)Cl>CCOC(C)=O.CCCCCC>[NH2:18][C:10]1[C:9]([F:26])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=1
Reactant: COC(=O)c1cc(N=C2C=CC(=O)C=C2)c(F)c(-c2ccc(Cl)cc2)n1
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)c1cc(N)c(F)c(-c2ccc(Cl)cc2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A mixture of methyl 6-(4-chlorophenyl)-5-fluoro-4-((4-oxocyclohexa-2,5-dien-1-ylidene)amino)picolinate (0.074 g, 0.20 mmol) and 0.1 M H2SO4 (0.2 mL) in a 1:1 mixture of CH3CN/H2O (2 mL) was heated to 80° C. for 1 h. After stirring at room temperature for 2 h, the reaction mixture was added to CH2Cl2 (10 mL). The organic layer was washed with a saturated solution of NaCl and dried (MgSO4), and the solvent was removed. Preparative TLC on silica gel eluting with 20% EtOAc/hexane gave methyl 4-amino-6-(4-chlorophenyl)-5-fluoropicolinate (0.050 g, 0.169 mmol, 85% yield) as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.83 (m, 2H), 7.45 (d, J=6.2 Hz, 1H), 7.37 (m, 2H), 4.40 (br s, 2H), 3.90 (s, 3H). ESIMS m/z 279.77 ([M−H]−); 19F NMR (376 MHz, CDCl3) δ −145.11.
Reaction SMILES: B.[CH2:2]([C:6]1[C:15]2[C:10](=[C:11]([O:16][CH3:17])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[C:18](O)=[O:19])[CH2:3][CH2:4][CH3:5]>O1CCCC1>[CH2:2]([C:6]1[C:15]2[C:10](=[C:11]([O:16][CH3:17])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH2:18][OH:19])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1c(C(=O)O)ccc2c(OC)cccc12
Agent: B
Solvent: C1CCOC1
Product: CCCCc1c(CO)ccc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of borane in tetrahydrofuran (1M; 10 mL) was added to a solution of 1-butyl-5-methoxy-2-naphthalenecarboxylic acid in tetrahydrofuran (15 mL) at 0°-5° C. and the mixture was stirred at room temperature for 3 hours. After the solvent was evaporated off, the reaction was diluted with 1N sodium hydroxide and extracted with dichloromethane. The organic layer was washed with brine then was dried (MgSO4), evaporated and crystallized from hexane to give 1.58 g of 1-butyl-5-methoxy-2-naphthalenemethanol, mp 100°-102° C. Recrystallization of a portion from diethyl ether-hexane afforded the pure alcohol, 101°-102° C. Anal. Calcd for C16H20O2 : C, 78.65; H, 8.25 Found: C, 78.36; H, 8.33
Reaction SMILES: [C:1](=[O:3])=[O:2].[OH-:4].[CH3:5][N+:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C1(C)C=CC=CC=1>[C:1](=[O:4])([OH:3])[O-:2].[CH3:5][N+:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: [OH-]
Reactant: O=C=O
Agent: C[N+]1(C)CCCCC1
Solvent: Cc1ccccc1
Product: O=C([O-])O

Procedure:
Carbon dioxide was passed for 1 hour into 553 g of a 15.56% strength aqueous N,N-dimethylpiperidinium hydroxide solution. The solution heated up from 20° C. to 38° C. within °minutes, and then cooled down again. 300 ml of toluene was added to 100 ml of the solution. The resultant mixture was refluxed and the water was distilled off azeotropically over a period of 11 hours.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[CH2:10][N:9]([C:11](=[O:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1.[CH2:20]([NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[C:28]([F:41])[CH:27]=1)=[O:24])[CH3:21]>>[C:11]([N:9]1[CH2:10][C:5]2[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:3][C:2]([C:29]3[CH:30]=[CH:31][C:26]([NH:25][C:23]([NH:22][CH2:20][CH3:21])=[O:24])=[CH:27][C:28]=3[F:41])=[N:7][C:6]=2[CH2:8]1)(=[O:13])[CH3:12]
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: CC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(C)=O)C3)c(F)c1
Yield: 8 %

Procedure:
Method as described for example 147 using 1-(2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)ethanone (intermediate 23) and 1-ethyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) (intermediate 28) as starting materials. The crude reaction mixture was purified by SCX-2 cartridge (loaded in MeOH eluted with 2M methanolic ammonia). Ammonia eluent was concentrated in vacuo. Residue was then purified by prep. HPLC at high pH to afford an off white solid (17.4 mg, 0.04 mmol, 8%).
Reaction SMILES: [CH2:1]([C:8]1([CH2:11]O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:20][CH2:11][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:9]1
Reactant: BrC(Br)(Br)Br
Reactant: OCC1(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: BrCC1(Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
To a solution of the title C compound, (1-benzyl-cyclopropyl)-methanol (0.8 g, 4.93 mmol), pyridine (994 uL, 12.3 mmol) and CBr4 (1.8 g, 5.42 mmol) in methylene chloride (25 mL) is added triphenylphosphine (1.8 g, 6.9 mmol), with stirring at 0° C. After completion of the reaction, the mixture is poured into a saturated aqueous solution of NaHCO3. The aqueous layer is extracted twice with methylene chloride and the combined organic extracts are dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is taken up into ether and the triphenylphosphine oxide precipitate is filtered off. The filtrate is concentrated under reduced pressure and purified by flash column chromatography on silica gel (hexane/EtOAc 9/1) to afford the title compound: TLC, Rf (hexane/AcOEt 99/1)=0.54. Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 6.41 min.
Reaction SMILES: C(=O)(O)[O-].[Na+].Br.Br[C:8]1[S:12][C:11]([NH2:13])=[N:10][CH:9]=1.[N:14]1([CH2:19][CH2:20][SH:21])[CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)(C)C>[N:14]1([CH2:19][CH2:20][S:21][C:8]2[S:12][C:11]([NH2:13])=[N:10][CH:9]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: SCCN1CCCC1
Reactant: Nc1ncc(Br)s1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Nc1ncc(SCCN2CCCC2)s1
Temperature: 60 °C
Reaction time: 96 h
Yield: 30.5 %

Procedure:
Sodium bicarbonate ((1.232 kg, 14.7 mol) is added slowly in portions to a mixture of 5-bromo-thiazol-2-ylamine hydrobromide (1.53 Kg, 5.87 mol) in 7.5 L of isopropanol. 2-Pyrrolidin-1-yl-ethanethiol (1.060 Kg, 8.07 mol) is then added over 15 min, and the resulting mixture is stirred at 60° C. for 96 h. The temperature is increased to 70° C. for 1 h, and then the mixture is cooled to room temperature. Most of the isopropanol is removed under vacuum, and the residue is taken up in 4 L of an isopropanol/chloroform solution (1:9). Saturated aqueous sodium bicarbonate (4 L) is added, and the resulting mixture is stirred for 30 minutes. The layers are separated and the aqueous phase is extracted with three 4 L portions of an isopropanol/chloroform solution (1:9). The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue is triturated with 3 L of diethylether, and filtered off to give a first portion of the title compound as a pale-yellow solid (410 g). The filtrate is concentrated to an orange solid, which is triturated with 2 L of diethylether, and isolated as a beige solid by filtration. This solid is then dissolved in 2 L of methanol, and the solution is heated at 45° C. for 30 min. Upon cooling to room temperature, a solid is formed. This material is isolated by filtration, triturated with diethyl ether as above, and dried under vacuum to afford an additional 310 g of the title compound. MS (m/e): 230 [M+H]
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#[N:2].Cl.[NH2:13][OH:14].C([O-])([O-])=O.[Na+].[Na+]>O.CCO>[OH:14][NH:13][C:1]([C:3]1[C:4]2[CH:5]=[CH:6][NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1)=[NH:2]
Reactant: NO
Reactant: N#Cc1cccc2[nH]ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1cccc2[nH]ccc12
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
A mixture of 4-cyanoindole (0.64 g; 4.5 mmol), HCl×H2NOH (1.1 g; 15.8 mmol), and Na2CO3 (0.79 g; 7.43 mmol) in H2O (8 ml) and EtOH (2 ml) was gently stirred for 15 min, then refluxed for 6 h under N2. After cooling most of the EtOH was removed under reduced pressure and the product was extracted with EtOAc (3×10 ml). The organic phase was separated, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.74 g; 94%), as a creamy foam. 1H-NMR (DMSO-d6+CDCl3+CD3OD) 1.71 (broad s, H2O); 3.68 (HDO); 6.74 (d, 1H, J=3.1 Hz); 7.01 (tr, 1H, J=7.8 Hz); 7.12-7.2 (m, 2H); 7.3-7.4 (m, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[NH:21][CH2:22][CH2:23][NH2:24]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:24][CH2:23][CH2:22][NH:21][C:15]2[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:14]=2[CH3:13])=[CH:7][CH:8]=1
Reactant: Fc1ccc(OCC2CO2)cc1
Reactant: Cc1cccc(C)c1NCCN
Product: Cc1cccc(C)c1NCCNCC(O)COc1ccc(F)cc1
Reaction time: 48 h

Procedure:
3.36 g. 4-Fluorophenyl glycidyl ether are left to stand for 2 days at ambient temperature with 6.6 g. N-(2,6-dimethylphenyl)-ethylenediamine. The reaction mixture is separated by chromatography on silica gel with the elution agent ethyl acetate-methanol-triethylamine (100:10:1 v/v/v) to give, after evaporation of the pure fractions, 5.0 g. of the desired product in the form of a viscous oil. After dissolving in diethyl ether and adding 2.5 g. benzoic acid, the corresponding benzoate precipitates out and is recrystallized from isopropyl alcohol. The desired product is obtained in a yield of 5.2 g. (57% of theory) in the form of colorless crystals; m.p. 105°-106° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[S:6][CH:7]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>O1CCCC1>[CH2:25]([N:28]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[S:6][CH:7]=1)[CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]
Reactant: CCCNCCC
Reactant: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccc(F)cc2C1=O
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)n1
Reaction time: 12 h
Yield: 28.9 %

Procedure:
A suspension of 1.0 g (0.00275 mol) of 3-(4-chloromethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 50 ml of tetrahydrofuran was treated with 4.5 ml (0.033 mol) of dipropylamine. After stirring at 50° for 12 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with dichloromethane/methanol 19:1 as the eluent and recrystallized from hot isopropyl ether. There was obtained 0.34 g (29%) of 3-(4-dipropylaminomethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 134-136°.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]=O)=[CH:16][CH:15]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(CCC=O)cc1
Reactant: Cc1cc2ccccc2[nH]1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CCCc2c(C)[nH]c3ccccc23)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-Methyl-1H-indole (0.86 g, 5.2 mmol) and 4-(3-Oxo-propyl)-benzoic acid methyl ester (1.0 g, 5.2 mmol) in methylene chloride (50 mL), was added TFA (1.78 g, 15.6 mmol), followed by triethylsilane (1.81 g, 15.6 mmol). The reaction mixture was stirred overnight, quenched with sat. NaHCO3 solution (50 mL), and the organic layer was washed with sat. NaHCO3 solution, water, brine, and dried (Na2SO4). Solvent was removed under reduced pressure, and the residue was purified by flash column chromatography with 10-20% EtOAc/hexanes to yield the desired 4-[3-(2-Methyl-1H-indol-3-yl)-propyl]-benzoic acid methyl ester in 88% (1.67 g) yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(OC([CH:70]([NH2:77])[CH2:71][C@@H:72]1[CH2:76][CH2:75][CH2:74][NH:73]1)=O)(C)(C)C.FC(F)(F)C(O)=O>CS(C)=O>[NH2:77][CH2:70][CH2:71][C@@H:72]1[CH2:76][CH2:75][CH2:74][N:73]1[C:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5]([NH:15][CH:16]([C:18]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=4[N:19]=3)[CH3:17])=[N:6][CH:7]=[N:8]2)=[CH:3][C:2]=1[Cl:1])=[O:13]
Reactant: CC(C)(C)OC(=O)C(N)C[C@@H]1CCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@H]3CCN)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2S)-2-(2-tert.-butyloxycarbonyl-aminoethyl)-pyrrolidine in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH:26]=[CH:25][N:24]=[N:23]1.C(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:23]2[N:24]=[CH:25][CH:26]=[N:22]2)[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]nn1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1Cc1cccc(I)c1
Agent: CC(C)C
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1Cc1cccc(-n2nccn2)c1

Procedure:
(S)-2-(3-[1,2,3]Triazol-2-yl-benzyl)-piperidine-1-carboxylic acid tert-butyl ester was prepared from (S)-2-(3-iodo-benzyl)-piperidine-1-carboxylic acid tert-butyl ester and 1H-1,2,3-triazole in analogy to the procedure described for A-13. LC-MS C: tR=1.05 min; [M+H-tBu]+=287.08.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C[O-].[Na+].[I-].[K+].Br[CH:24]([C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)=[CH:31][CH:30]=1)[C:25]([O:27][CH3:28])=[O:26]>CO.C1C=CC=CC=1>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH:24]([C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]5[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=5)=[CH:31][CH:30]=4)[C:25]([O:27][CH3:28])=[O:26])=[CH:15][CH:16]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 5.7 g of p-(1-adamantyl)phenol, 1.19 g of sodium methoxide and 50 mg of potassium iodide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. After 20 minutes, a white solid separates. The mixture is refluxed overnight, cooled and filtered to remove the white solid. The solid is heated in 50 ml of hot chloroform and filtered to remove a small amount of insoluble residue. The filtrate is diluted with 50 ml of hexane and filtered to give the product as white crystals, mp 148.4°-150.5° C.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:34])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[K+]>O.CO>[CH3:8][C:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:34])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3ccccc3OC)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccccc1C(=O)NCCc1ccc(-c2ccc(OC(C)(C)C(=O)O)cc2)cc1

Procedure:
4gm (8.6 millimols) of ethyl 2-methyl-2-{4-[2-(2-methoxy-benzamido)-ethyl]-biphenyl-4'-oxy}-propionate were hydrolized at room temperature over a period of 12 hours with a solution of 1gm (17.2 millimols) of potassium hydroxide in 5 ml of water and 95 ml of methanol. After distilling off the methanol, 100 ml of water were added, and the mixture was extracted with ether. The pH of the aqueous phase was adjusted to between 1 and 2 with 2 N hydrochloric acid, and the acid mixture was extracted with chloroform. The combined chloroform extracts were dried over sodium sulfate and evaporated to dryness, and the residue was recrystallized from ether. Yield: 3.2 gm (86% of theory); m.p. 133° C.