Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH:9]=2)[O:4][CH:3]=1.[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:16][C:13]1[O:12][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([C:22]4[CH:23]=[CH:24][C:19]([S:18][CH3:17])=[CH:20][CH:21]=4)=[CH:3][O:4][C:5]3=[CH:6][N:7]=2)=[N:15][N:14]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: Cc1nnc(-c2cc3c(Br)coc3cn2)o1
Product: CSc1ccc(-c2coc3cnc(-c4nnc(C)o4)cc23)cc1
Yield: 52 %

Procedure:
In the same manner as in Example 132 and using 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine instead of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole and using [4-(methylthio)phenyl]boronic acid instead of (4-fluorophenyl)boronic acid, the title compound (yield 52%) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>ClCCl.C(OCC)(=O)C>[C:23]([NH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:26])[CH2:24][CH3:25]
Reactant: Nc1cccc2c1-c1ccccc1C2=O
Reactant: CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cccc2c1-c1ccccc1C2=O
Yield: 65.3 %

Procedure:
To a stirred solution of 4-amino-9-fluorenone (0.20 g, 1.0 mmol) in dichloromethane (40 ml) was added triethylamine (0.5 ml, 3.5 mmol), followed by propionyl chloride (0.5 ml, 5.8 mmol). After 20 min the mixture was diluted with ethyl acetate (150 ml) and washed with 2N HCl (100 ml) followed by saturated sodium carbonate (100 ml). The organic phase was separated, dried (MgSO4) and the solvent removed in vacuao. The residue was purified by flash chromatography (silica, heptane:ethyl acetate 7:3) to give 164 mg (63%) of the desired material as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([CH2:39][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3([CH2:31][O:30][C:29]4[CH:32]=[C:33]5[C:37](=[CH:38][C:28]3=4)[CH2:36][CH2:35][O:34]5)[C:19]2=[O:18])=[CH:41][CH:42]=1)[CH3:2]
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: CCc1ccccc1N
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: CCc1ccccc1NC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-ethylaniline to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-ethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (49%) as a colorless solid: mp 203-204° C.; 1H NMR (300 MHz, CDCl3) δ7.96-7.83 (m, 3H), 7.69 (s, 1H), 7.52-7.44 (m, 2H), 7.31-7.13 (m, 5H), 7.10-7.02 (m, 1H), 6.82-6.74 (m, 1H), 6.49 (s, 1H), 6.44 (s, 1H), 5.03 (ABq, 2H), 4.86 (ABq, 2H), 4.60-4.51 (m, 2H), 3.11-2.92 (m, 2H), 2.67 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 178.0, 165.2, 161.9, 161.3, 141.8, 139.8, 135.1, 134.9, 134.6, 132.7, 128.8, 128.6, 127.8, 127.7, 126.8, 125.8, 124.1, 123.7, 120.0, 119.9, 118.8, 109.1, 93.3, 80.6, 72.4, 57.7, 43.8, 29.0, 24.4, 14.0; MS (ES+) m/z 517.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[N:16]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:21][CH2:20][CH2:19][CH:18]([OH:22])[CH2:17]1.[Na+].[Cl-]>C(#N)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:26]2[CH2:25][CH2:24][CH:23]([N:16]3[CH2:21][CH2:20][CH2:19][CH:18]([OH:22])[CH2:17]3)[CH2:28][CH2:27]2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: OC1CCCN(C2CCNCC2)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OC1CCCN(C2CCN(c3ncnc(Cl)n3)CC2)C1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
200 mg (1.27 mmol) of 2,4-dichloro-1,3,5-triazine are dissolved in 2 ml of acetonitrile, cooled to 0° C., 176 μl of triethylamine and 223 mg (1.27 mmol) of 1,4′-bipiperidinyl-3-ol are added. The reaction mixture is stirred at 0° C. for 2 h and subsequently at room temperature for 48 h. Sat. NaCl solution is subsequently added, and the mixture is extracted three times with ethyl acetate. The combined organic phases are washed with 1N NaOH and water, dried over Na2SO4 and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]=[C:17]([O:20][CH2:21][CH3:22])[CH2:18]Br)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[NH3:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]=[C:17]([O:20][CH2:21][CH3:22])[CH2:18][N:23]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=1
Reactant: N
Reactant: CCOC(CBr)=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: ClCCl
Product: CCOC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of a solution of 0.38 part of 5-chloro-2-(2-bromo-1-ethoxyethylideneamino)benzophenone in 8 parts by volume of methylenechloride and 2 parts by volume of liquid ammonia is stirred in a sealed vessel at room temperature for 1 hour, followed by evaporation at room temperature to remove the ammonia. The resultant is shaken well with a mixture of 10 parts by volume of methylenechloride and 5 parts by volume of water. The methylene chloride layer is washed with water and dried over sodium sulfate, followed by evaporation of the solvent gives 7-chloro-2-ethoxy-5-phenyl-3H-1,4-benzodiazepine as an oily substance.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1B(O)O>>[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1
Reactant: Cc1ccncc1B(O)O
Reactant: BrCc1ccc(-c2ccccc2)nc1
Product: Cc1ccncc1Cc1ccc(-c2ccccc2)nc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 61a (100 mg, 0.40 mmol) and 4-methylpyridine-3-boronic acid (83 mg, 0.61 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using ethyl acetate as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. Light yellow solid. Yield: 54 mg, 52%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=2.22-2.29 (m, 3H), 4.02 (s, 2H), 7.11 (d, J=5.0 Hz, 1H), 7.37-7.51 (m, 4H), 7.64 (dd, J=8.2, 0.6 Hz, 1H), 7.95-8.01 (m, 2H), 8.38-8.46 (m, 2H), 8.52-8.57 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=19.3, 33.8, 120.5, 125.7, 126.9, 129.0, 129.1, 133.2, 133.8, 136.8, 139.2, 146.1, 148.7, 149.9, 150.7, 155.9; (ESI): m/z=260.85 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8]([Cl:11])(=O)C>CO>[ClH:11].[CH3:8][O:6][C:5](=[O:7])[C@@H:2]([CH2:3][OH:4])[NH2:1]
Reactant: N[C@H](CO)C(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)[C@H](N)CO
Product: Cl
Reaction time: 0.5 h
Yield: 91 %

Procedure:
D-serine (100 g, 0.9515 mole) was suspended in 600 ml methanol at room temperature. Acetyl chloride (224.0 g, 2.8545 mole) was added drop wise at −5° C. to 0° C. and stirred for 30 minutes. The reaction mixture was refluxed for 15 hours. Evaporation of the reaction mixture under reduced pressure followed by crystallization of the resulting residue from methanol and methyl tert-butyl ether, resulted in colorless solid of D-serine methyl ester hydrochloride (134.7 g, Yield: 91%, HPLC: 99.6%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14](Cl)=[O:15])=[CH:4][CH:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1.C(N(CC)CC)C>ClCCl>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:15]
Reactant: c1ccc2oc(CC3CCCCN3)cc2c1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3ccccc3o2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
5-(4-Fluorophenyl)-2-methyl-thiazole-4-carbonyl chloride (136 mg, 0.53 mmol) in dichloromethane (1 ml) was added to a solution of (RS)-2-(2-benzofuranylmethyl)piperidine (104 mg, 0.48 mmol) and triethylamine (0.20 ml, 1.45 mmol) in dichloromethane (4 ml) and the mixture shaken at ambient temperature for 30 min. The resultant was washed with saturated aqueous sodium hydrogen carbonate (8 ml). The organic layer was applied directly onto a pre-packed silica gel column and chromatographed eluting with ethyl acetate hexane mixtures to give the title compound (50 mg, 24%) as an off-white solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[C:5]([F:17])=[C:4]([F:18])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:18][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[C:5]=1[F:17]
Reactant: O=C1NCCCn2c1cc1c(F)c(F)cc(Br)c12
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(F)c(F)c3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, grey solid (82 mg, 96%), MS (ISP) m/z=343.2 [(M+H)+], mp 207.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9,10-difluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 5) (78.8 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1OC)[CH:5]=[O:6].[CH2:12]([Mg]Br)[CH3:13]>>[CH3:12][CH2:13][CH:5]([OH:6])[C:4]1[CH:7]=[CH:8][CH:9]=[CH:2][CH:3]=1
Reactant: COc1ccc(C=O)cc1C
Reactant: CC[Mg]Br
Product: CCC(O)c1ccccc1

Procedure:
The synthesis of the title compound (26F) was accomplished in a four-step, three-pot reaction sequence. Commercially available 3-methyl-p-anisaldehyde was reacted with ethylmagnesium bromide to provide its phenylpropanol derivative. This alcohol was then oxidized to the corresponding ketone in the usual manner with PCC. This ketone was subsequently reacted with (R)-naphthyl-1-ethylamine in the presence of Ti(i-PrO)4 to provide the imine. This imine was reduced in high diastereoselective yield by catalytic hydrogenation in the presence of Raney-nickel.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][N:6]=1.[CH3:9][NH2:10]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:10][CH3:9])=[CH:5][N:6]=1
Reactant: CN
Reactant: ClCc1cnc(Cl)s1
Solvent: CCO
Product: CNCc1cnc(Cl)s1
Temperature: 20 °C

Procedure:
2-Chloro-5-thiazolylmethylchloride (5.0 g, 0.03 mol) and methylamine (4.6 g, 0.15 mol) were dissolved in ethanol (50 ml). The resulting solution was heated under reflux for 2 hours. The resulting mixture was allowed to cool to ambient temperature (20° C.) and the solvent was removed by evaporation under reduced pressure. The residue was added to a mixture of dichloromethane (150 ml) and aqueous sodium hydroxide (2N, 50 ml) and the mixture agitated. The two phases were allowed to separate and the aqueous phase was removed. Further aqueous sodium hydroxide (2N, 50 ml) was added to the organic phase and the step repeated. The aqueous phases were combined and washed with dichloromethane (50 ml). The dichloromethane product so obtained was combined with the original organic phase, washed with saturated brine (100 ml) and dried using magnesium sulphate. The solvent was evaporated to give N-(2-chloro-5-thiazolylmethyl)-N-methylamine as a yellow oil in a yield of 3.55 g (73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>ClCCl.ClCCl.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17]([CH3:18])=[O:27])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCCCCC
Product: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reaction time: 0.03 h
Yield: 73.4 %

Procedure:
To a solution of 2-methylsulfanylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (2.00 g, 7.60 mmol) in dichloromethane (76 mL) was added m-CPBA (67%, 2.02 g, 7.84 mmol) in one portion. Solid precipitate appeared within 2 min, and after 10 min the solution was diluted with 2/1 dichloromethane/hexane (60 mL). The solids were collected by filtration and washed with 50% dichloromethane/hexane to afford, after drying, 1.558 g (73% yield) of the titled sulfoxide. A second crop was obtained by concentrating the filtrate and triturating the solids first with hot 2/1 dichloromethane/hexane, and then after filtration by a second trituration with acetone. An additional 0.22 g (10%) of titled product was obtained, and was shown by 1H NMR to be contaminated with 10% sulfone.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[CH2:27]([NH2:31])[CH:28]([CH3:30])[CH3:29].Cl>CN(C)C=O>[CH2:27]([NH:31][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CNc1c([N+](=O)[O-])cnc2ccccc12
Yield: 111.2 %

Procedure:
To 50.0 g (0.269 mole) of 4-hydroxy-3-nitroquinoline in 300 ml of N,N-dimethylformamide in a 500 ml erlenmeyer flask was added, gradually, 44.3 g (0.2892 mole) of phosphorus oxychloride. The resulting mixture was heated on a steam bath for about 15 minutes, and was then poured onto ice with stirring. After neutralization with saturated sodium bicarbonate solution, the resulting light-colored solid was separated by filtration and washed sequentially with a saturated sodium bicarbonate solution and water. The solid was dissolved in methylene chloride and the solution obtained was dried over sodium chloride, filtered and transferred to a 2 l erlenmeyer flask. Triethylamine (159.6 g, 1.577 moles) was added at one time, followed by the slow addition of 21.2 g (0.2892 mole) of isobutylamine. After the isobutylamine had been added, the mixture was heated on a steam bath for about 30 minutes. The methylene chloride was removed by rotary evaporation. Water was added to the residue obtained, and concentrated hydrochloric acid was subsequently added to dissolve the residue. The solution was filtered, and the filtrate was brought to pH 8-9 with concentrated ammonium hydroxide. The resulting yellow solid was filtered, washed with water, and dried to provide 73.4 g of crude 4-isobutylamino-3-nitroquinoline, m.p. 114°-118° C. The product was further purified by recrystallization from ethanol.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:27])[F:26])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][O:30]C(OC)OC.[C:36]1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])[O-].C[O-].[Na+]>CO>[CH3:36][O:8][C:7]([O:30][CH3:29])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:25]([F:28])([F:26])[F:27]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(OC)OC
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]C([O-])[O-]
Solvent: CO
Product: COC(OC)(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reaction time: 5 h
Yield: 813.4 %

Procedure:
phenyl[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone (0.210 g, 0.56 mmol) in MeOH (5 mL) is refluxed with trimethylorthoformate (0.12 mL, 1.12 mmol) and para-toluenesulfonic acid (0.005 g). After 5 h, additional orthoformate (0.20 mL) is added. After 3 h more, more orthoformate (0.20 mL) is added. After refluxing overnight, the reaction is cooled and treated with NaOMe in methanol (0.5 mL). After 10 min of stirring, the reaction is concentrated and the residue chromatographed eluting with 5:95 ethyl acetate:hexanes to afford the title compound as a white solid (0.100 g). MS (ESI) m/z 424; HRMS: calcd for C25H20F3NO2+H, 424.15244; found (ESI, [M+H]+), 424.1519.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([I:16])=[C:10]3I)[C:6]=2[CH:17]=1.CC[Mg+].[Br-]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([I:16])=[CH:10]3)[C:6]=2[CH:17]=1
Reactant: Brc1ccc2c(c1)-c1nc(I)c(I)n1CCO2
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Temperature: -30 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
Into a 20 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 9-Bromo-2,3-diiodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (900 g, 1.74 mol, 1.00 equiv) in tetrahydrofuran (9 L), followed by the addition of EtMgBr (755 mL, 1.30 equiv) dropwise with stirring at −30° C. over 60 min. The resulting solution was stirred at −30-15° C. for 10 min, quenched by the addition of 1500 mL of saturated aqueous NH4Cl and extracted with 3×3000 mL of tetrahydrofuran. The combined organic layers were washed with 2×2000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 450 g (66%) of 9-Bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as a yellow solid.
Reaction SMILES: [C:1]([CH2:4]CN(CC)CCNC([C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O)(O)=O.C[O:53][C:54](=[O:103])[CH2:55][CH2:56][NH:57][CH2:58][CH2:59][CH2:60][NH:61][C:62]([C@:64]12[CH2:99][CH2:98][C@@H:97]([C:100]([CH3:102])=[CH2:101])[C@@H:65]1[C@@H:66]1[C@@:79]([CH3:82])([CH2:80][CH2:81]2)[C@@:78]2([CH3:83])[C@@H:69]([C@:70]3([CH3:96])[C@@H:75]([CH2:76][CH2:77]2)[C:74]([CH3:85])([CH3:84])[C:73]([C:86]2[CH:95]=[CH:94][C:89]([C:90]([O:92]C)=[O:91])=[CH:88][CH:87]=2)=[CH:72][CH2:71]3)[CH2:68][CH2:67]1)=[O:63].ICC>>[C:54]([CH2:55][CH2:56][N:57]([CH2:1][CH3:4])[CH2:58][CH2:59][CH2:60][NH:61][C:62]([C@:64]12[CH2:99][CH2:98][C@@H:97]([C:100]([CH3:102])=[CH2:101])[C@@H:65]1[C@@H:66]1[C@@:79]([CH3:82])([CH2:80][CH2:81]2)[C@@:78]2([CH3:83])[C@@H:69]([C@:70]3([CH3:96])[C@@H:75]([CH2:76][CH2:77]2)[C:74]([CH3:85])([CH3:84])[C:73]([C:86]2[CH:87]=[CH:88][C:89]([C:90]([OH:92])=[O:91])=[CH:94][CH:95]=2)=[CH:72][CH2:71]3)[CH2:68][CH2:67]1)=[O:63])([OH:53])=[O:103]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCCNCCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC)CCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCI
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCCN(CC)CCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-((2-carboxyethyl)(ethyl)amino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (example 89) using methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(3-methoxy-3-oxopropylamino)propylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as amine and iodoethane as alkylating reagent. The product was isolated as a white solid (3 mg, 30%). LCMS: m/e 715.49 (M+H)+, 2.11 min (method 1). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 8.03 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=5.19 Hz, 1H), 4.78 (s, 1H), 4.65 (s, 1H), 3.50 (t, J=7.17 Hz, 2H), 3.46-3.40 (m, 2H), 3.39-3.31 (m, 2H), 3.27 (t, J=7.63 Hz, 2H), 3.21-3.08 (m, 1H), 2.97 (t, J=7.02 Hz, 2H), 2.67-2.54 (m, 1H), 2.25-2.17 (m, 2H), 1.74 (s, 3H), 1.39 (t, J=7.17 Hz, 3H), 2.05-1.10 (m, 21H), 1.08 (s, 3H), 1.06 (s, 6H), 1.01 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [CH2:1]([Cl:4])[C:2]#[CH:3].[CH2:5]([O:7][SiH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[CH3:6]>C([Si](C)(C)O[Si](C=C)(C)C)=C.[Pt]>[Cl:4][CH2:1][CH:2]=[CH:3][Si:8]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:7][CH2:5][CH3:6]
Reactant: CCO[SiH](OCC)OCC
Reactant: C#CCCl
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Product: CCO[Si](C=CCCl)(OCC)OCC
Reaction time: 1 h

Procedure:
A 250 ml 3-neck round-bottom flask was equipped with a reflux condenser, addition funnel and stir bar. Propargyl chloride (50 g, 0.671 mol) and 0.15 g of Platinum (0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (3% Weight in xylenes) were added to the flask. Triethoxysilane (115.6 g, 0.705 mol) was added dropwise from the addition funnel to the reaction mixture. The flask quickly became warm. After the completion of addition, the flask was kept at 100° C. for one hour. The final product 103 g was purified by distillation (108° C./49 mmHg) as a mixture of isomers. NMR showed a ratio of 1:0.13 of the two isomers.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[Si]([C:17]#[N:18])(C)(C)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[CH3:31][C:32]([CH3:34])=O>C(Cl)Cl>[C:17]([C:32]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1)([CH3:34])[CH3:31])#[N:18]
Reactant: C[Si](C)(C)C#N
Reactant: CNC(=O)c1ccc(N)cc1F
Reactant: CC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1ccc(NC(C)(C)C#N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 4-amino-2-fluoro-N-methylbenzamide (2 g, 11.9 mmol), TMSCN (2.2 mL, 17.9 mmol), TMSOTf (0.1 mL, 0.6 mmol), and acetone (10 mL, 140 mmol) in DCM (20 mL) was stirred at room temperature overnight. The white solid was filtered, washed with a small amount of DCM, and dried to afford 1.12 g of 4-((2-cyanopropan-2-yl)amino)-2-fluoro-N-methylbenzamide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.79 (t, 1H), 7.56 (t, 1H), 6.88 (s, 1H), 6.67 (dd, 1H), 6.54 (dd, 1H), 2.75 (d, 3H), 1.67 (s, 6H).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH3:9].C(N(CC)CC)C.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C1COCC1.[Cu](I)I>[CH3:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17]
Reactant: Cc1cnccc1Br
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cnccc1C#C[Si](C)(C)C
Temperature: 50 °C
Yield: 86.9 %

Procedure:
To a solution of 4-bromo-3-methyl pyridine hydrochloride (5.0 g, 24.0 mmol) in THF (degassed, 80 mL) was added copper iodide (450 mg, 2.40 mmol) and triethylamine (20.0 mL, 143.9 mmol). After degassing for 15 min, palladium tetrakis triphenylphosphine (830 mg, 0.72 mmol) and trimethylsilylacetylene (6.10 mL, 43.16 mmol) were added. The mixture was heated at 50° C. for 16 h then cooled to rt and filtered. The crude residue was purified via silica gel chromatography (EtOAc-Hexanes, 10%) to afford the title compound (3.95 g, 87%) as clear but dark oil.