Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(C(C)C)C(C)C)C>CS(C)=O>[CH:7]([C:5]1[S:6][C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[CH:3][CH:4]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(Br)s1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)s2)CC1
Temperature: 130 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
A mixture of 5-bromothiophene-2-carboxaldehyde (3.82 g, 20.0 mmol), tert-butyl piperazine-1-carboxylate (4.1 g, 22.0 mmol), N-ethyl-N,N-diisopropylamine (7.0 ml, 40.0 mmol) and dimethylsulphoxide (5.0 ml) were stirred at 130° C. under an atmosphere of nitrogen for 18 h. The cooled mixture was partitioned between ethyl acetate and water. The organics were washed with water, brine, dried over magnesium sulphate and evaporated. The resultant dark red solid was purified by silica column chromatography, eluting with dichloromethane followed by ethyl acetate/dichloromethane (15%) to give tert-butyl 4-(5-formylthien-2-yl)piperazine-1-carboxylate (4.3 g, 73%).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:23]([O:25]CC)=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].S(=O)(=O)(O)O.C(O)(=O)C>O>[F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)c(F)c2c1=O
Yield: 92.5 %

Procedure:
40.1 g of ethyl 5,6,7,8-tetrafluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate are added to a mixture of 28.5 ml of concentrated sulphuric acid, 250 ml of glacial acetic acid and 200 ml of water and the mixture is heated under reflux for 2 hours. The hot solution is poured onto ice and the precipitate is filtered off with suction, washed with water and dried. 34.5 g of the title compound of melting point 250°-252° C. are obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[C:12][CH:13]([OH:17])[CH2:14][CH:15]=[CH2:16]>C1(C)C=CC=CC=1.[Pt](Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]12[CH2:16][CH:15]1[CH2:14][C:13](=[O:17])[CH2:12]2
Reactant: C=CCC(O)C#Cc1ccc2ccccc2c1
Agent: Cl[Pt]Cl
Solvent: Cc1ccccc1
Product: O=C1CC2CC2(c2ccc3ccccc3c2)C1
Temperature: 80 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To a stirred solution of 1-naphthalen-2-yl-hex-5-en-1-yn-3-ol (1.00 g, 4.50 mmol) under an atmosphere of nitrogen in toluene (100 mL) was added platinum chloride (0.06 g, 0.22 mmol, 5 mol %); the resulting black mixture was stirred at 80° C. for 24 hr. TLC indicated that the reaction was complete. The organics were concentrated in vacuo to afford a black residue. The crude material was purified by flash chromatography (SiO2, ethyl acetate:petroleum ether 40-60; 10%:90%) to afford the desired compound as a yellow oil (0.64 g, 64%). 1H NMR (400 MHz, CDCl3) δ ppm 0.70 (1H, t, J 4.0 Hz, CH), 0.83-0.86 (1H, m, CH), 1.41-1.44 (1H, m, CH), 2.44 (1H, d, J 18.0 Hz, CH), 2.75 (1H, d, J 18 Hz, CH2), 2.86-2.91 (1H, m, CH), 3.05 (1H, d, J 18.0 Hz, CH), 7.24-7.26 (1H, m, ArH), 7.44-7.49 (2H, m, ArH), 7.63 (1H, s, ArH), 7.80 (1H, d, J 8.0 Hz, ArH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH2:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])CO)[CH2:9][CH2:10][CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCC(CO)CCCC
Reactant: COc1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCC(CCCC)COc1ccsc1
Reaction time: 15 h
Yield: 83 %

Procedure:
Under a nitrogen atmosphere, 3-methoxythiophene (5.0 g, 44.8 mmol), 2-butyloctanol (16.7 g, 89.6 mmol), and p-toluenesulfonic acid (850 mg, 4.48 mmol) were dissolved in toluene (40 ml), and refluxing was performed for 15 hours. Then, water was added to the reaction solution. The reaction solution was then extracted with methylene chloride, and an organic layer was washed with a saturated saline solution and water. The organic layer was dried with anhydrous magnesium sulfate, and, after filtration, the solution was distilled off under reduced pressure. By separating and purifying the obtained reaction solution by silica gel column chromatography in which hexane was used as a mobile phase, a target substance was obtained as clear oil (83% yield). 1H-NMR (400 MHZ, CDCl3, TMS) δ 7.17 (dd, J=5.2 Hz, 1.6 Hz, 1 H), 6.76 (d, J=5.2 Hz, 1 H), 6.21 (d, J=1.6 Hz, 1 H), 3.81 (d, J=5.8 Hz, 2 H), 1.25 (m, 17 H), 0.88 (m, 6 H)
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si](C(C)(C)C)(C)C)=[CH:11][CH:10]=1)[C:3]([NH2:5])=O.B>C1COCC1.CO>[NH2:1][C@@H:2]([CH2:3][NH2:5])[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCC[C@@H](N)C(N)=O)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: NC[C@H](N)CCCc1ccc(O)cc1
Temperature: 5 °C

Procedure:
A solution of (R)-2-Amino-5-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-pentanoic acid amide (7.74 g, 24 mmol) in THF is stirred at 5° C. and borane (96 ml of a 1 M solution in THF, 96 mmol) is added. The mixture is stirred at 5° C. until a homogeneous mixture is obtained and then stirred at room temperature for 30 minutes and 35° C. for 3 hours. After this time, further borane (24 ml of a 1 M solution in THF, 24 mmol) is added and the reaction is heated at 35° C. for 18 hours. After this time, a further portion of borane (24 ml of a 1 M solution in THF, 24 mmol) is added and the reaction heated at 35° C. for a further 24 hours. After this time, the reaction is cooled to 10° C., and quenched by adding dropwise to MeOH (50 ml) at −5° C. After allowing to warm to room temperature the solvent is removed in vacuo to afford a yellow oil. The oil is dissolved in MeOH (250 ml) and SCX-2 silica (180 g, 0.63 mmol/g, 120 mmol) is added. The silica suspension is shaken for 18 hours, the silica is removed by filtration, washed with MeOH (3×100 ml), then suspended in 7M NH3 in MeOH and shaken for 18 hours. The silica is removed by filtration and the 7M NH3 in MeOH is removed in vacuo to afford the title compound as a yellow oil; [M+H]+ 195
Reaction SMILES: [CH2:1]([C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)([CH2:7][CH2:8][OH:9])[CH2:4][CH2:5][OH:6])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1(C)C=CC=CC=1>[CH3:26][S:27]([O:6][CH2:5][CH2:4][C:3]([CH2:1][CH3:2])([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:7][CH2:8][O:9][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CCO)(CCO)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(CCOS(C)(=O)=O)(CCOS(C)(=O)=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-ethyl-3-(3-nitrophenyl)-1,5-pentanediol (Preparation 61, 661 mg, 2.27 mmol) in toluene (24 ml) was added triethylamine (0.76 ml, 5.43 mmol) followed by methanesulfonyl chloride (0.42 ml, 5.4 mmol). The reaction mixture was stirred at room temperature under nitrogen for 18 h. The reaction mixture was poured onto water (10 ml), the phases were separated and the aqueous layer was extracted with dichloromethane (10 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an oil which was used without further purification (850 mg, 81% crude yield).
Reaction SMILES: [N:1]1([C:6]2[C:11]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.C1([O:22][C:23](=O)[NH:24][C:25]2[N:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[N:26]=2)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl>O1CCOCC1.O>[CH3:32][O:31][C:29]1[CH:28]=[C:27]([O:33][CH3:34])[N:26]=[C:25]([NH:24][C:23]([NH:15][S:12]([C:11]2[C:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[N:7][CH:8]=[CH:9][CH:10]=2)(=[O:13])=[O:14])=[O:22])[N:30]=1
Reactant: NS(=O)(=O)c1cccnc1-n1cncn1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccnc2-n2cncn2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a suspension containing 0.5 g of the sulfonamide prepared in Example 4 in 10 ml of p-dioxane was added 0.6 g of phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate followed by 0.33 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The suspension was stirred at room temperature for about two hours then diluted with about 75 ml of water to form a solution. After acidifying the solution with conc. hydrochloric acid (red to litmus) and stirring 0.5 hour, a precipitate formed. The mixture was filtered and the isolated solid was washed with 10 ml water and suction-dried for 24 hours to yield 0.7 g of the subject compound; m.p. 226°-230°.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.O>C1COCC1>[N:9]1[N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[N:3][C:2]=3[O:18][C:19]3([CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]3)[C:12]2=[CH:11][CH:10]=1
Reactant: Clc1ncccc1-n1cccn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1nccc12
Temperature: 70 °C
Yield: 5.4 %

Procedure:
To a solution of 2-chloro-3-pyrazol-1-yl-pyridine (338 mg, 1.88 mmol) in THF (3.4 mL) at −78° C. was added butyllithium (979 μL of 2.5 M, 2.45 mmol) dropwise over 5 minutes. The reaction mixture was then stirred at the temperature for 15 minutes before the addition of tert-butyl 4-oxopiperidine-1-carboxylate (562.5 mg, 2.82 mmol). The reaction was allowed to come to 25° C., then heated at 70° C. for 4 hours. The reaction mixture was poured into water, and extracted with EtOAc (3×). The organics were combined, washed with brine, dried (Na2SO4) and evaporated to dryness to yield a crude mixture that was purified by column chromatography (5 to 30% EtOAC in hexanes) to give the title product (35 mg, 5%) that was used in the next step without further purification. ESI-MS m/z calc. 342.2. found 343.3 (M+1)+. Retention time: 1.46 minutes (3 min run).
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].[N+]([C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:10]=1[C:11]#[N:12])([O-])=O>>[N+:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:9]([S:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:10]=1[C:11]#[N:12])([O-:19])=[O:18]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCCCS
Product: CCCCSc1cccc([N+](=O)[O-])c1C#N
Yield: 90 %

Procedure:
Prepared as in Example 215c from butane-1-thiol and 2,6-dinitrobenzonitrile in 90% yield. 1H NMR (400 MHz, CDCl3) δ 0.97 (t, J=7.2 Hz, 3H), 1.42-1.55 (m, 2H), 1.70-1.77 (m, 2H), 3.09 (t, J=7.2 Hz, 2H), 7.63-7.69 (m, 2H), 7.99-8.01 (m, 1H).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])[CH:22]=1>>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:35](=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(=C(c1ccccc1)c1ccccc1)C1CCNCC1
Reactant: O=C(O)CCCCCCCCc1cccnc1
Product: O=C(CCCCCCCCc1cccnc1)N1CCC(C=C(c2ccccc2)c2ccccc2)CC1
Yield: 86 %

Procedure:
The title compound was prepared in a manner similar to that employed for the compound of Example 10 starting with 7.9 g of 4-(2,2-diphenylethenyl)piperidine and the acid chloride prepared from 8.24 g of 3-pyridinenonanoic acid. The toluene extracts were evaporated and the residue was crystallized from ether to give 12.4 g (73.7%) of 4-(2,2-diphenylethenyl)-1-[1-oxo-9-(3-pyridinyl)nonyl]piperidine, mp 82°-83° C. Analysis Calculated for C33H40N2O: C, 82.46; H, 8.39; N, 5.83. Found: C. 82.76; H. 8.33; N, 5.83.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([N+:24]([O-])=O)=[CH:16][C:15]=2[N+:27]([O-])=O)[C:9](=[O:13])[O:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>CO.[Cl-].[Ti+3].[Cl-].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:14]2[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][C:17]([NH2:24])=[CH:16][C:15]=2[NH2:27])[C:9](=[O:13])[O:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)N(c1ccc(Cl)cc1)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Ti+3]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CO
Product: CCOC(=O)N(c1ccc(Cl)cc1)c1c(N)cc(N)cc1C(F)(F)F
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Ethyl 4-chlorophenyl[2,4-dinitro-6-(trifluoromethyl)phenyl]carbamate (1.7323 g) was dissolved in methanol (100 ml), and to the solution was added titanium(III) chloride solution (36.967 g) under ice-cooling. The reaction mixture was stirred for 2 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate solution (800 ml), and the mixture was extracted 2 times 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 silica gel column (70 g, CHCl3:methanol=10:1) to give the title compound (1.2292 g, 82%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:36]([O:21][C:19]1[CH:18]=[CH:17][C:15]2[C:16]3[N:10]([CH2:11][CH2:12][O:13][C:14]=2[CH:20]=1)[C:9]1[CH:22]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[CH:24]=[CH:25][C:8]=1[C:7]=3[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(O)ccc1-3
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OCc2ccccc2)ccc1-3
Temperature: 60 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a solution of methyl 12-cyclohexyl-3-hydroxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (150 mg, 0.38 mmol) in N,N-dimethylformamide (2.0 ml) were added potassium carbonate (132 mg, 0.96 mmol) and benzyl bromide (0.07 ml, 0.61 mmol) and the mixture was stirred at 60° C. for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give methyl 3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (173 mg, yield 94%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[NH2:7][C:8]1[C:13]([N:14]([CH3:16])[CH3:15])=[N:12][C:11]([Br:17])=[CH:10][N:9]=1>>[Br:17][C:11]1[N:12]=[C:13]([N:14]([CH3:16])[CH3:15])[C:8]2[N:9]([CH:5]=[C:3]([CH2:2][Cl:1])[N:7]=2)[CH:10]=1
Reactant: CN(C)c1nc(Br)cnc1N
Reactant: O=C(CCl)CCl
Product: CN(C)c1nc(Br)cn2cc(CCl)nc12

Procedure:
1.17 g (9.2 mmol) of 1,3-dichloroacetone is added dropwise to a solution of 2 g (9.2 mmol) of 2-amino-5-bromo-3-dimethylaminopyrazine. After 3 hours under reflux, the alcohol is evaporated off under reduced pressure and the residue taken up with water, alkalinized and extracted with dichloromethane. After purification by chromatography, 6-bromo-2-chloromethyl-8-dimethylaminoimidazo[1,2-a]pyrazine is obtained.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[C:12]([F:19])[CH:11]=1)#[N:9].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[OH:44][CH2:45][CH:46]1[NH:51][CH2:50][CH2:49][N:48]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:47]1>C1COCC1.O.C(OCC)(=O)C>[C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:51]2[CH2:50][CH2:49][N:48]([C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])[CH2:47][CH:46]2[CH2:45][OH:44])=[O:16])=[C:12]([F:19])[CH:11]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCNC(CO)C1
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C#N)cc2F)C(CO)C1
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
Triethylamine (892 μL, 6.40 mmol) was added to a mixture of 4-cyano-2-fluorobenzoic acid (275 mg, 1.66 mmol, Alfa Aesar) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (580 mg, 1.52 mmol) in THF (13 mL). After stirring for 15 min, tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (0.30 g, 1.4 mmol, racemic, AstaTech) was added. The reaction was stirred overnight. Ethyl acetate and water were added, the mixture shaken, and layers separated. The organic layer was washed with water, 0.1N NaOH, and brine; dried over sodium sulfate, decanted and concentrated. Flash chromatography on a 40 g silica gel cartridge, eluting with a gradient from 0-100% EtOAc in hexanes afforded the racemic product as a white solid (400 mg, 71%). 1H NMR (300 MHz, CDCl3): δ 7.61-7.38 (m, 3H), 4.90-2.51 (m, 9H), 1.47 (s, 9H); LCMS (M-tBu+2H)+: 308.1.
Reaction SMILES: C(NC(=O)C(C)=CC1C=C(OC)C(OC)=CC=1N)CC1C=CC=CC=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]=[C:34]([CH3:40])[C:35]([O:37]CC)=[O:36].[OH-].[Na+].Cl>O1CCCC1>[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]=[C:34]([CH3:40])[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C(C)=Cc1ccccc1N
Agent: COc1cc(N)c(C=C(C)C(=O)NCCc2ccccc2)cc1OC
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=Cc1ccccc1N)C(=O)O

Procedure:
Into 10 ml of tetrahydrofuran (THF), 1.50 g (7.31 mmol) of (E) ethyl 3-(2-aminophenyl)-2-methyl-2-propenate were dissolved; and, with 10 ml of a 1-N aqueous sodium hydroxide solution being added thereto, the mixture was reacted at 40° C. for 4 hours. After the completion of the reaction was verified by TLC, the mixture was cooled with 10 ml of 1-N hydrochloric acid being added thereto. The precipitated crystal was filtered out, whereby 1.30 g of the aimed compound were obtained (yield: quantitative).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]([B:8](CC)[CH2:9][CH3:10])[CH3:7].CC>>[C:1]([NH:5][B:8]([CH2:9][CH3:10])[CH2:6][CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CCB(CC)CC
Agent: CC
Product: CCB(CC)NC(C)(C)C
Reaction time: 2.5 h

Procedure:
A mixture of 14.6 g. (0.2 moles) of t-butylamine and about 30 g. (0.3 moles) of triethyl borane after addition of about 1 g. of diethyl boryl pivalate is heated to 60° to 80° C. with stirring. Within 2.5 hours, 6.2 normal liters (92%) of ethane are evolved. Distillation under vacuum gives 24 g. (85%) of pure t-butylamino-diethyl borane boiling at 45° C./18 mm. Hg after having collected unconsumed triethyl borane. The residue weighs about 1 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[S:38](Cl)(=[O:40])=[O:39])[CH:31]=[CH:30][CH:29]=1.N1C=CC=CC=1>O1CCCC1>[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[S:38]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]3[NH:13][C:12](=[O:14])[C:11]4=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:10]4[N:9]=3)[CH:7]=2)(=[O:40])=[O:39])[CH:31]=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCOc1ccc(NS(=O)(=O)c2cccc3cccnc23)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
150 mg (0.408 mmol) of the compound from example 44A are reacted with 221 mg (0.96 mmol) of quinoline-8-sulfonyl chloride and 0.33 ml (4.08 mmol) of pyridine in 8 ml of tetrahydrofuran overnight.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cccc2cc(C=O)c(-c3ccccc3F)nc12

Procedure:
Prepared according to Procedure A using 2-chloro-8-methylquinoline 3-carbaldehyde (1.0 g, 4.86 mmol), 2-fluorophenyl boronic acid (0.749 g, 5.35 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (0.281 g, 0.24 mmol, 0.05 eq), and sodium carbonate (2.58 g, 24 mmol, 5 eq) in acetonitrile (36 mL) and water (12 mL). After purification, 2-(2-fluorophenyl)-8-methylquinoline-3-carbaldehyde was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.03 (1 H, d, J=3.5 Hz), 8.99 (1 H, s), 8.12 (1 H, d, J=7.8 Hz), 7.85 (1 H, d, J=7.0 Hz), 7.76 (1 H, td, J=7.5, 1.8 Hz), 7.58-7.70 (2 H, m), 7.45 (2 H, td, J=7.5, 1.0 Hz), 7.38 (2 H, td, J=9.4, 1.2 Hz), 2.75 (3 H, s) Mass Spectrum (ESI) m/e=266.0 (M+1)
Reaction SMILES: [CH3:1][C:2]([C:4]1[C@@:8]2([CH3:23])[CH2:9][CH2:10][C@@H:11]3[C@@:16]4([CH3:22])[CH2:17][CH2:18][C@H:19]([OH:21])[CH2:20][C:15]4=[CH:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH:5]=1)=[O:3].[Br:24]C1(Br)C(=O)NC(=O)NC1=O.Br>O1CCCC1.C(Cl)Cl>[Br:24][CH2:1][C:2](=[O:3])[C:4]1[C@:8]2([CH3:23])[C@H:7]([C@H:12]3[C@H:11]([CH2:10][CH2:9]2)[C@:16]2([CH3:22])[C:15]([CH2:20][C@@H:19]([OH:21])[CH2:18][CH2:17]2)=[CH:14][CH2:13]3)[CH2:6][CH:5]=1
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(C(=O)CBr)=CC[C@@H]12
Yield: 104.4 %

Procedure:
Dissolve 16-dehydropregnenolone (5.00 g, 15.90 mmol) and 5,5-dibromobarbituric acid (4.55 g, 15.90 mmol) in tetrahydrofuran (60 mL). Add concentrated aqueous hydrogen bromide (100 μL of a 48% solution) to the stirring solution and heat the reaction at reflux for 1 hour. Cool slightly and then concentrate under vacuum to produce a brown oily foam. Dissolve the residue in methylene chloride (350 mL), rinse with 50% saturated sodium bicarbonate (2×200 mL), brine (125 mL), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum to provide 21-bromo-3β-hydroxypregna-5,16-dien-20-one (6.53 g) as an orange-brown solid, slightly contaminated with starting material.