Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:34]=3[N:33]=[C:32]2[CH:42]([F:44])[F:43])[N:20]=1>C1COCC1.C(O)(=O)C.O>[F:44][CH:42]([F:43])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:24]=[C:19]([NH:1][C:2]3[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:34]=2[N:33]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: COc1ccc(N)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)cn1
Reaction time: 0.33 h
Yield: 3.4 %

Procedure:
To a solution of 0.310 g (2.50 mmol) of 5-amino-2-methoxypyridine in THF (3 mL) at 0° C. was added 1.35 mL of lithium diisopropylamide (2 M solution in benzene/heptanes/THF), and the mixture was stirred for 20 min. A solution of 0.240 g (0.61 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole in THF (5 mL) was added, and the resulting mixture was stirred for 1 hr at RT. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried, and concentrated. Chromatography on alumina, eluting first with hexanes/EtOAc (1:1) and then with CH2Cl2/EtOAc (1:3) gave a reddish powder. Recrystallization from ethanol/CH2Cl2 gave 0.010 g (4% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-(6-methoxy-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 201-202° C.; 1H NMR (CDCl3) δ8.33 (br s, 1H), 7.93 (br s, 1H), 7.79 (dd, J=8.8, 2.7 Hz, 1H), 7.32-7.31 (m, 2H), 6.88-6.79 (m, 3H), 4.04 (s, 3H), 3.97 (s, 3H), 3.90 (s, 4H), 3.79 (s, 4H); Anal. Calcd. for C22H22F2N8O3: C, 54.5; H, 4.6; N, 23.1. Found: C, 54.6; H, 4.5; N, 22.9%.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=1.[C-:20]#[N:21].[K+].O>CS(C)=O>[C:14]1([C:5]2[N:4]=[C:3]([CH2:2][C:20]#[N:21])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[N:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [C-]#N
Reactant: ClCc1nc(-c2ccccc2)nn1-c1ccccn1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1nc(-c2ccccc2)nn1-c1ccccn1
Temperature: 50 °C
Yield: 87.7 %

Procedure:
A mixture of 2-(5-(chloromethyl)-3-phenyl-1H-1,2,4-triazol-1-yl)pyridine (130 mg, 480 μmol) and potassium cyanide (43.8 mg, 672 μmol) in DMSO (3.5 mL) was heated to 50° C. for 1.5 h. The cooled reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic phase was washed with water (2×25 mL), dried over MgSO4 and concentrated in vacuo to give 110 mg crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as white solid (30 mg, 114 μmol, 23.7%).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:9]([OH:11])=O)[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-].[Na+]>C(O)C(O)C>[ClH:1].[NH2:2][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1=[O:11]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(O)CO
Product: NC1CCCCNC1=O
Yield: 73.9 %

Procedure:
A stirred mixture of L-lysine hydrochloride 1 (55 g, 300 mmol) and NaOH (12 g, 300 mmol) in 1,2-propanediol (1.2 L) is heated to reflux. A Dean-Stark trap is used to withdraw the first 120 mL of condensed solvent. The reaction solution is refluxed for an additional 2 hours until all starting material is consumed (which maybe determined by 1H NMR). The solution is cooled and is concentrated under vacuum. Ethanol is used to completely dissolve the α-amino-ε-caprolactam 2. Byproduct NaCl is removed by filtration. The filtrate is concentrated and the resulting crude α-amino-ε-caprolactam 2 is dissolved in water. After acidification to pH 6 with addition of concentrated HCl and subsequent partial concentration, crystals maybe formed at room temperature to afford α-amino-ε-caprolactam hydrochloride (36.5 g) in 74% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][C:26](=[O:31])C(Cl)(Cl)Cl)[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.C1(C)C=CC=CC=1>CN(C)C=O>[CH:16]([CH:15]1[C:19]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:25][C:26](=[O:31])[N:14]1[CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)([CH3:17])[CH3:18]
Reactant: CC(C)C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)C1c2ccccc2NC(=O)N1C1CCN(Cc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 73.5 %

Procedure:
Into a solution of 6.58 g (13.6 mmol) of 1-benzyl-4-[2-methyl-1-(2-trichloroacetylaminophenyl)propylamino]piperidine in 136 ml of dimethylformamide, 9.42 g (68 mmol) of potassium carbonate were added and stirred at 90° C. for 5 hours. The reaction mixture was cooled to room temperature, and then 0.5% aqueous potassium carbonate solution and ethyl acetate-toluene (1:1) were added thereto and stirred. The separated oil layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (chloroform/methanol 100/2) to give 3.65 g (10.0 mmol) of the above-titled compound.
Reaction SMILES: Cl.CN.[CH2:4]([C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([OH:23])=O)[CH2:18][N:19]=1)=[CH:11]2)[CH3:5].O[N:36]1[C:40]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O.C(N(CC)CC)C>[CH2:4]([C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([NH:36][CH3:40])=[O:23])[CH2:18][N:19]=1)=[CH:11]2)[CH3:5]
Reactant: On1nnc2ccccc21
Reactant: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC)S3)[nH]c12
Reaction time: 48 h
Yield: 95.3 %

Procedure:
To a mixed solution of methylamine hydrochloride (147 mg), triethylamine (0.31 mL), and N,N-dimethylformamide (25 mL) were added [2-(7-ethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (500 mg), 1-hydroxybenzotriazole (300 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (420 mg) under ice-cooling, and the mixture was stirred under ice-cooling and then at room temperature for 2 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 90:10, volume ratio), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (490 mg, yield 95%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[N:6][CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)[CH3:2].Br[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH2:39])=[O:38])=[C:32]([F:40])[CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH2:39])=[O:38])=[C:32]([F:40])[CH:31]=2)[CH:7]=[N:6][C:5]=1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH3:2]
Reactant: NC(=O)Cc1ccc(Br)cc1F
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OCc1ccc(OC)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc(-c2ccc(CC(N)=O)c(F)c2)cnc1OCc1ccc(OC)cc1
Yield: 63.5 %

Procedure:
A solution of 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (133 mg, 0.345 mmol), 2-(4-bromo-2-fluorophenyl)acetamide (80 mg, 0.345 mmol), Cs2CO3 (225 mg, 0.690 mmol) and PdCl2(dppf) (25.2 mg, 0.034 mmol) in 1,4-dioxane (9 mL) and H2O (3 mL) was stirred at 110° C. for 15 min. After LCMS analysis showed the starting material had disappeared, the mixture was dissolved in H2O (20 mL) and extracted by EA (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=3/1) to yield a yellow solid of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (90 mg, 0.219 mmol, 63.6% yield): 1H NMR (400 MHz, CD3OD) 7.93 (d, J=2.0 Hz, 1H), 7.43-7.34 (m, 6H), 6.91-6.89 (m, 2H), 5.35 (s, 2H), 4.16-4.11 (m, 2H), 3.78 (s, 3H), 1.41 (t, J=7.0 Hz, 3H); ES-LCMS m/z 291.1 (M−120).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>C(OCC)C.O>[F:15][C:16]1[CH:17]=[C:18]([C:2]2([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccc([Mg]Br)cc1F
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
A stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (4.5 g, 22.6 mmol) in diethyl ether (100 mL) at 0° C. was treated with a solution of (3-fluoro-4-methoxyphenyl)magnesium bromide (49.7 mL, 24.8 mmol, 0.5 M in tetrahydrofuran). The reaction mixture was allowed to warm to rt and was stirred at for 12 h. It was then diluted with 100 mL water and the layers were separated. The aqueous layer was extracted three times with 150 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography (120 g column) eluting with 30% ethyl acetate in petroleum ether to obtain 6.5 g of tert-butyl 4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate as a clear liquid; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.47 (m, 11H) 1.52-1.61 (m, 2H) 1.69-1.84 (m, 2H) 3.03-3.22 (m, 2H) 3.77-3.89 (m, 6H) 5.09 (s, 1H) 7.10 (s, 1H) 7.17-7.26 (m, 1H) 7.25-7.33 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:3]=1.[Li+].CC([N-]C(C)C)C.[Br:32][C:33]1[C:42]2[CH2:41][CH2:40][CH2:39][C:38](=[O:43])[C:37]=2[CH:36]=[CH:35][C:34]=1[C:44]([O:46][CH3:47])=[O:45]>C1COCC1>[Br:32][C:33]1[C:42]2[CH2:41][CH2:40][CH2:39][C:38]([OH:43])([C:11]3[S:12][C:8]([C:6]4[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([NH:13][C:14]5[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=5)[N:5]=4)=[CH:9][N:10]=3)[C:37]=2[CH:36]=[CH:35][C:34]=1[C:44]([O:46][CH3:47])=[O:45]
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cncs2)c1
Reactant: COC(=O)c1ccc2c(c1Br)CCCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1Br)CCCC2(O)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To an oven-dried flask was added 4-methyl-6-(thiazol-5-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (300 mg, 0.892 mmol) and THF (7.1 mL) and the solution was cooled to −78° C. LDA (1.34 mL, 2.68 mmol) was slowly added, and the resulting mixture was stirred for 30 minutes at −78° C. In a separate oven-dried flask, methyl 1-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (316 mg, 1.12 mmol) was then dissolved in THF (5 mL), and this solution was added to the reaction mixture, which was then allowed to warm to rt. over a period of 3 hours. The reaction was then quenched with MeOH (5 mL) and concentrated. Purification by chromatography on silica gel furnished methyl 1-bromo-5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate 17A (210 mg, 38%) as a light yellow solid. MS ESI calcd for C27H22BrF3N4O3S [M+H]+ 619, found 619.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]([F:28])([F:27])[C:5]([F:26])([F:25])[O:6][C:7]([F:24])([F:23])[C:8]([F:22])([F:21])[O:9][C:10]([F:20])([F:19])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.BrCCCCCBr.FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)CO.[CH2:62]([C:70]1[CH:71]=[N:72][C:73]([C:76]2[CH:81]=[CH:80][C:79]([OH:82])=[CH:78][CH:77]=2)=[N:74][CH:75]=1)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69]>>[CH2:62]([C:70]1[CH:75]=[N:74][C:73]([C:76]2[CH:81]=[CH:80][C:79]([O:82][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:10]([O:9][C:8]([F:21])([F:22])[C:7]([F:23])([F:24])[O:6][C:5]([F:25])([F:26])[C:4]([F:27])([F:28])[O:3][C:2]([F:29])([F:30])[F:1])([F:20])[F:19])=[CH:78][CH:77]=2)=[N:72][CH:71]=1)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COCCCCCBr
Agent: BrCCCCCBr
Agent: OCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)1-bromopentane (18.3 g, 38.5 mmol; prepared from 1,5-dibromopentane (107 g, 0.7 mol) and 2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol (125 g, 0.31 mol) essentially as in Example 2 ) with 5-octyl-2-(4-hydroxyphenyl)pyrimidine (10 g, 35 mmol) to provide product boiling at 200°-210° C. at 0.4 torr (yield of 20.8 g).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([N+:18]([O-:20])=[O:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([N+:18]([O-:20])=[O:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1nn(Cc2ccccc2)cc1CO
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
A solution of C2 (1.35 g, 4.90 mmol) in tetrahydrofuran (40 mL) was cooled to −40° C. and treated with lithium aluminum hydride (99%, 1 M, 10.3 mL, 10.3 mmol). The reaction was allowed to stir for 20 minutes at −40° C., then was quenched with saturated aqueous ammonium chloride solution. After addition of EtOAc and water, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to provide C3 as a solid. Yield: 1.29 g, 5.53 mmol, quantitative. 1H NMR (500 MHz, CDCl3) δ 2.63 (br t, J=6 Hz, 1H), 4.79 (br d, J=5.4 Hz, 2H), 5.33 (s, 2H), 7.29-7.32 (m, 2H), 7.36-7.41 (m, 3H), 7.42 (s, 1H).
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.Br[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]>>[NH2:2][O:1][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: N#Cc1cccc(CBr)c1
Product: N#Cc1cccc(CON)c1

Procedure:
Prepared by a similar procedure as described for preparation 15, starting from N-hydroxyphthalimide and 3-bromomethyl-benzonitrile. 13C-NMR (CDCl3) δ 139.5, 132.5, 131.7, 131.5, 129.2, 118.7, 112.6, 76.5.
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]([NH:10][C:11](=[O:33])[CH2:12][CH2:13][C@H:14](O)[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[CH:8]=[CH2:9].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.Cl>C1COCC1.O>[CH2:7]([N:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:13][CH2:12][C:11]1=[O:33])[CH:8]=[CH2:9]
Reactant: C=CCNC(=O)CC[C@H](O)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C=CCN1C(=O)CC[C@@H]1c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under argon, KOtBu (0.64 g, 5.7 mmol) is suspended, in a Schlenk tube which had been dried by heating, in THF (5 ml, anhydrous). At 0° C., a solution of (4S)-N-allyl-4-hydroxy-4-[4′-(trifluoromethoxy)-1,1′-biphenyl-4-yl]butanamide (XVI-1) (0.99 g, 2.6 mmol) in THF (8 ml, anhydrous) is added dropwise. The reaction mixture is stirred at 0° C. for 1 h and a solution of tosyl chloride (0.52 g, 2.7 mmol) in THF (5 ml, anhydrous) is then added dropwise over a period of 20 min. The mixture is stirred at 0° C. for 2 h and at room temperature for 16 h. For work-up, the mixture is admixed with water, adjusted to pH 5 using HCl and extracted with ethyl acetate. The combined organic phases are dried (Na2SO4) and concentrated. The residue (0.85 g, content: 81%, HPLC, 100% method) is further purified by flash chromatography (mobile phase: ethyl acetate/petroleum ether (40/60), 1:1).
Reaction SMILES: II.[CH2:3]([C@@H:10]1[C:25](=[O:26])[NH:24][C@H:23]([CH2:27][S:28]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:22](=[O:48])[NH:21][C@H:20]([CH:49]([CH3:51])[CH3:50])[C@@H:19]([OH:52])[CH2:18][C:17](=[O:53])[O:16][O:15][C@H:14](/[CH:54]=[CH:55]/[CH2:56][CH2:57][S:58]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[NH:13][C:12](=[O:78])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.CO>[CH2:3]([C@@H:10]1[C:25](=[O:26])[NH:24][C@@H:23]2[CH2:27][S:28][S:58][CH2:57][CH2:56][CH:55]=[CH:54][C@@H:14]([O:15][O:16][C:17](=[O:53])[CH2:18][C@H:19]([OH:52])[C@@H:20]([CH:49]([CH3:51])[CH3:50])[NH:21][C:22]2=[O:48])[NH:13][C:12](=[O:78])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)[C@H]1NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](Cc2ccccc2)CC(=O)N[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OOC(=O)C[C@@H]1O
Agent: CC(C)[C@H]1NC(=O)[C@H]2CSSCC/C=C/[C@H](NC(=O)C[C@H](Cc3ccccc3)C(=O)N2)OOC(=O)C[C@@H]1O
Agent: II
Agent: O=S([O-])([O-])=S
Solvent: CO
Solvent: ClCCl
Product: CC(C)[C@H]1NC(=O)[C@H]2CSSCCC=C[C@H](NC(=O)C[C@H](Cc3ccccc3)C(=O)N2)OOC(=O)C[C@@H]1O

Procedure:
To a solution of iodine (198.4 mg, 0.78 mmol) in CH2Cl2/MeOH (9:1, 272 mL) was added dropwise a solution of 6A (79.4 mg, 0.08 mmol) in CH2Cl2/MeOH (9:1) (134 mL) over 30 min, the reaction mixture was then allowed to stir for a further 30 min after which time sodium thiosulfate (88 mL, 0.05 M) was added. The layers were separated and the product was extracted with CH2Cl2 (3×45 ml) dried (MgSO4) and the solvent was removed in vacuo. Purification was then carried out by column chromatography on silica gel (eluent 3:97 MeOH/CH2Cl2) which gave 7A (30 mg, mmol, 68%) as a white solid: Rf 0.19 CH2Cl2/MeOH (97:3); [α]26D=−83.7 (c 0.38, MeOH).
Reaction SMILES: [C:1]1(B(O)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:10]([NH:14][S:15]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22](Br)[CH:21]=1)(=[O:17])=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([NH:14][S:15]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH:21]=1)(=[O:17])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: OB(O)C1=CCCCC1
Reactant: CC(C)(C)NS(=O)(=O)CCc1ccc(N)c(Br)c1
Product: CC(C)(C)NS(=O)(=O)CCc1ccc(N)c(C2=CCCCC2)c1

Procedure:
The title compound was prepared according to the Suzuki coupling procedure of Example 44, step (b) using cyclohex-1-enyl boronic acid (117 mg, 0.931 mmol) and 2-(4-amino-3-bromo-phenyl)-ethanesulfonic acid tert-butylamide (as prepared in the previous step, 250 mg, 0.745 mmol) and purified on silica (20% EtOAc/hexanes) (228 mg, 91%). 1H-NMR (CDCl3; 400 MHz): δ 6.87 (dd, 1H, J=8.0, 2.1 Hz), 6.82 (d, 1H, J=2.1 Hz), 6.64 (d, 1H, J=8.0 Hz), 5.72 (br s, 1H), 4.12 (s, 1H), 3.82 (br s, 2H), 3.28 (m, 2H), 2.96 (m, 2H), 2.19-2.23 (m, 4H), 1.62-1.82 (m, 4H), 1.31 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2
Reactant: COc1ccc2cccc(F)c2c1
Agent: BrB(Br)Br
Product: Oc1ccc2cccc(F)c2c1

Procedure:
The title compound was prepared by reacting 1-fluoro-7-methoxynaphthalene (7.99 g, 45.34 mmol) with boron tribromide (68 mL of 1N solution, 68 mmol) according to method D to yield 3.99 g (54%) of a red solid. An analytical sample was prepared by preparative reverse phase HPLC to yield a white solid: mp 89–92° C.; 1H NMR (DMSO-d6): δ 7.16 (1H, dd, J=2.42 Hz, J=8.90 Hz), 7.21–7.25 (3H, m), 7.62–7.65 (1H, m), 7.85 (1H, dd, J=1.72 Hz, J=8.87 Hz), 10.08 (1H, s); MS (ESI) m/z 161 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.C[N:22]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23]1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:25]3[CH:26]=[N:22][NH:23][CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: Cn1cc(B(O)O)cn1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3cn[nH]c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and N-methyl-pyrazole-4-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-[1-(1H-pyrazol-4-yl)-6-methoxy-isoquinolin-3-yl]-amine. LC-MS m/e 335(MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:18])=[C:8]([C:13]([O:15]CC)=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+]>C(O)(=O)C>[CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:18])=[C:8]([C:13]([OH:15])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(CC)ccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1ccc2c(O)c(C(=O)O)cnc2c1
Reaction time: 0.5 h

Procedure:
A stirred mixture of ethyl 7-ethyl-4-hydroxyquinoline-3-carboxylate and 5 M aqueous sodium hydroxide solution was heated to reflux. When all the solids had dissolved the solution was boiled for a further 30 minutes, cooled, and acidified to pH 4.0 with glacial acetic acid (30 ml.). The solid was collected, washed with water until the washings were neutral, and dried to give the novel compound 7-ethyl-4-hydroxyquinoline-3-carboxylic acid, m.p. 175°-178°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][C@:6]1([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[O:14][CH2:13][C:12]2[CH:11]=[C:10]([C:15]#[N:16])[CH:9]=[CH:8][C:7]1=2.[C:24]([OH:33])(=[O:32])[C@@H:25]([C@H:27]([C:29]([OH:31])=[O:30])[OH:28])[OH:26]>CO.O>[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][C@:6]1([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[O:14][CH2:13][C:12]2[CH:11]=[C:10]([C:15]#[N:16])[CH:9]=[CH:8][C:7]1=2.[C:29]([C@@H:27]([C@H:25]([C:24]([O-:33])=[O:32])[OH:26])[OH:28])([O-:31])=[O:30]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CNCCC[C@]1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Solvent: CO
Solvent: O
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a desmethylcitalopram (1.2 g) solution in Methanol (15 ML) was added a solution of L-tartaric acid (0.58 g) in water (2 mL). The reaction mixture was stirred at room temperature for 1 h.