Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([Cl:37])[CH:31]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C([O-])([O-])=O.[K+].[K+].[Br:44][CH2:45][CH2:46]Br.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Br:44][CH2:45][CH2:46][O:36][C:33]1[CH:34]=[CH:35][C:30]([C:6]2[CH:7]=[C:8]3[C:16](=[C:4]([C:1](=[O:3])[NH2:2])[CH:5]=2)[NH:15][C:14]2[CH:13]=[C:12]([N:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)[CH:11]=[CH:10][C:9]3=2)=[CH:31][C:32]=1[Cl:37]
Reactant: BrCCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4ccc(O)c(Cl)c4)cc23)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4ccc(OCCBr)c(Cl)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 155.6 %

Procedure:
A 100 ml round bottom flask was loaded with tert-butyl 4-(8-carbamoyl-6-(3-chloro-4-hydroxyphenyl)-9H-carbazol-2-yl)piperazine-1-carboxylate (estimated purity ˜50%, 365 mg, ˜0.35 mmol, Example 409B), K2CO3 (1.12 g, 8.10 mmol), DMF (20 ml) and 1,2-dibromoethane (0.64 ml, 7.4 mmol) and stirred at room temperature for 17 hours. The reaction mixture was poured into a separating funnel that was loaded with 500 ml water+citric acid (0.5 M solution in water) (60 ml, 30 mmol) and extracted with ethyl acetate. The organic layer was washed with dilute (1+5) aq. NaHCO3 solution, then brine, dried over MgSO4, filtered and evaporated to dryness to give 342 mg tert-butyl 4-(6-(4-(2-bromoethoxy)-3-chlorophenyl)-8-carbamoyl-9H-carbazol-2-yl)piperazine-1-carboxylate, which was used without further purification. Estimated purity (from LCMS) ˜55%. MS (ESI) m/e+=627/629/631, m/e−=625/627/629 consistent with isotope pattern for 1 Br and 1 Cl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)/[C:21](=[C:22](\[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)/[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: Clc1cccc(I)c1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3cccc(Cl)c3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-3-iodo-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.01 (s, 1H), 7.93 (d, 1H), 7.50 (d, 1H), 7.26-7.46 (m, 10H), 7.08 (t, 1H), 6.70 (t, 1H), 6.65 (d, 1H), 6.44 (d, 1H), 4.96 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:14]=[C:13]([CH3:15])[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.O>CN(C=O)C.CCOC(C)=O>[Cl:16][C:17]1[N:18]=[CH:19][N:20]=[C:21]([O:3][C:4]2[CH:14]=[C:13]([CH3:15])[C:7]3[N:8]([CH3:12])[C:9](=[O:11])[O:10][C:6]=3[CH:5]=2)[CH:22]=1
Reactant: Cc1cc(O)cc2oc(=O)n(C)c12
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
30 mg (0.70 mmol) sodium hydride (55%, suspension in mineral oil) were added to 0.12 g (0.70 mmol) 6-hydroxy-3,4-dimethyl-3H-benzoxazol-2-one in 5.0 ml DMF and the mixture was stirred for 10 min at RT. Then 0.10 g (0.70 mmol) 4,6-dichloropyrimidine was added and the mixture was stirred for 1 h at RT. Then water and EtOAc were added, the organic phase was separated off, dried on sodium sulphate, filtered and evaporated down.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:25])[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:5][CH:4]=1)#[N:2].[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27].C(Cl)Cl>>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:25])[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccc(C#N)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C(=O)CCC2CCNCC2)cc1

Procedure:
A solution of 4-(3-(4-cyanophenyl)-3-oxo-propyl)-1-tert-butoxycarbonyl-piperidine (75 mg) in 30% TFA/CH2Cl2 was stirred for 30 min then concentrated and dried under vacuum to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>C1COCC1.O>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCC(=O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 99.7 %

Procedure:
A mixture of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanone (2.80 g, 9.11 mmol) in THF (61 mL) at 0° C. (ice/water bath) was treated drop-wise with a mixture of sodium borohydride (689 mg, 18.21 mmol) in water (11 mL) over 5-10 minutes. The resulting mixture was stirred at this temperature for 2.5 hours and was then partitioned between EtOAc (200 mL) and water (200 mL) and the layers separated. The aqueous was re-extracted with EtOAc (200 mL) and the combined organic layer washed with brine (250 mL), dried (MgSO4), filtered and reduced. Purification by Biotage™ chromatography (silica) eluting with cyclohexane:EtOAc (gradient 20:1 to 5:1) afforded the title compound as a colourless oil (2.81 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH2:13][Si](C)(C)C)[C:9]=2[CH2:18][OH:19])=[CH:4][CH:3]=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:18][OH:19])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cn1nnc(-c2ccc(F)cc2)c1CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnc(-c2ccc(F)cc2)c1CO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
To a solution of [5-(4-fluoro-phenyl)-3-trimethylsilanylmethyl-3H-[1,2,3]triazol-4-yl]-methanol (616 mg, 2.20 mmol) in THF (37 mL) was added water (79 μL, 4.41 mmol) and then tetrabutylammonium fluoride (1 M in THF, 2.65 mL, 2.65 mmol) added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 15 min. The resulting mixture was poured into water and then the THF was evaporated. The aqueous layer was then extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (410 mg, 90%) as an off white solid. MS: m/e=208.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15](OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.O>C1COCC1.[NH4+].[OH-]>[CH2:1]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CN1C[C@@H]2C[C@H]1CN2Cc1ccccc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of (1S,4S)-2-benzyl-5-ethoxycarbonyl-2,5-diazabicyclo(2.2.1)heptane (3.3 g, 0.013 mol) in THF at -10° C., was added dropwise 1M LiAlH4 in ether (26.3 mL, 0.026 mol). The reaction mixture was slowly warmed to room temperature and mixed overnight. Upon cooling to 0° C., 4 mL of 95% THF:H2O was slowly added followed by 4 mL of H2O. The mixture was diluted with NH4OH (40 mL), filtered through a celite pad and concentrated in vacuo. The remaining NH4OH solution was further diluted with NH4OH (15 mL) and extracted with CH2Cl2. The combined organic phases were dried (K2CO3) and concentrated in vacuo to yield (1S,4S)-2-benzyl-5-methyl-2,5-diazabicyclo(2.2.1)heptane (2.2 g, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[O:16]C(OCC)=O)=[O:5])[CH3:2].Cl>CN(C)C=O.O>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[CH:8]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7]1=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)Oc1cc2cc(Cl)ccc2n1C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(=O)N(C(=O)OCC)c2ccc(Cl)cc21
Yield: 70 %

Procedure:
To a solution of ethyl-5-chloro-2-[(ethoxycarbonyl)oxy]-1H-indole-1-carboxylate, intermediate 49, (36.87 g, 118.28 mmol) in N,N-dimethylformamide (100 ml) 4-dimethylaminopyridine (14.45 g, 118.28 mmol) was added portionwise at 0-5° C. such that the internal temperature did not exceed 5° C. A thick suspension was obtained, which was repeatedly diluted with N,N-dimethylformamide (total volume: 350 ml) to ease up stirring. After two hours at 0-5° C. a solution of hydrogen chloride (fuming, 37%; 9.8 ml) in water (480 ml) was added at such a rate that the internal temperature could be kept below 15° C. The precipitate was filtered, washed with water at 0-5° C. (2×100 ml) and dried to yield the title compound (27.45 g, 70%) as off-white powder (HPLC purity: 94%). MS (ESI+): 312.2; MS (ESI−): 310.2
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CI
Product: Cn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of 6-bromo-1H-indole (1.530 mmol) in dimethyl sulfoxide (10 mL) was treated with potassium carbonate (4.59 mmol) and was stirred at room temperature for 30 min. The solution was then treated with methyl iodide (1.683 mmol) and was stirred at room temperature overnight. The solution was diluted with water (100 mL) and was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (hexanes) to provide the title compound as a yellow oil (62%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.70 (s, 1H) 7.50 (d, J=8.34 Hz, 1H) 7.35 (d, J=3.03 Hz, 1H) 7.14 (dd, J=8.34, 1.77 Hz, 1H) 6.44 (d, J=3.03 Hz, 1H) 3.78 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:17]=[CH:16][C:9]([C:10](N(C)OC)=[O:11])=[CH:8][CH:7]=1.[CH:22]([Mg]Br)=[CH2:23]>C1COCC1>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10](=[O:11])[CH:22]=[CH2:23])=[CH:16][CH:17]=1
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(OCc2ccccc2F)cc1
Solvent: C1CCOC1
Product: C=CC(=O)c1ccc(OCc2ccccc2F)cc1
Temperature: -78 °C
Yield: 91 %

Procedure:
4-(2-fluorobenzyloxy)-N-methyl-N-methoxybenzamide (P3, 6.0 g, 20.7 mmol) was dissolved in THF (100 mL) and cooled to −78° C. A 1.0 M solution of vinyl magnesium bromide in THF (31 mL, 31 mmol) was added and the cold bath was removed. Upon warming to 20-25° C., the mixture was poured into a vigorously stirred solution of 1 M HCl. The resulting mixture was extracted twice with CH2Cl2. The combined organic layers were then washed with 1 M HCl, then with a saturated NaHCO3 solution, dried over Na2SO4, and concentrated to a thick residue. The product was purified by flash column chromatography eluting with 0→40% acetone hexanes (gradient). Concentration of the fractions containing 4 gave an oil that crystallized upon standing (4.83 g, 91% yield).
Reaction SMILES: C([O:4][C:5]1[C:13]2[S:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.ClCCl>[OH:4][C:5]1[C:13]2[S:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2sc(C)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(O)c2sc(C)cc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
Ethyl 7-(acetyloxy)-2-methyl-1-benzothiophene-5-carboxylate was dissolved in absolute ethanol (500 mL). Potassium carbonate (18 g, 0.13 mol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 200 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The residue was crystallized from ether/hexane mixture (1:5) to give the desired product 10 g (42 mmol, 84%) as a cream solid. 1H NMR (DMSO-d6): δ ppm 1.30 (t, 3H), 2.50 (s, 3H), 4.30 (qt, 2H), 7.20 (s, 1H), 7.95 (s, 1H), 7.85 (s, 1H); MS (APCI, pos): 237.1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:36])[CH2:14][N:15]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][CH:25]([C:28]([O:30]C)=O)[CH2:24][CH2:23]5)=[C:18]([C:32]([F:35])([F:34])[F:33])[CH:17]=4)[C:5]=3[C:4]=2[CH:3]=1.O.[OH-].[Li+].Cl.[CH3:41][N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C1COCC1.O.O.CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:36])[CH2:14][N:15]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:23][CH2:24][CH:25]([C:28]([NH:48][CH:45]6[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]6)=[O:30])[CH2:26][CH2:27]5)=[C:18]([C:32]([F:33])([F:34])[F:35])[CH:17]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCC(N)CC1
Reactant: COC(=O)C1CCN(c2ccc(N3CC(=O)Nc4cnc5ccc(Br)cc5c43)cc2C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(NC(=O)C2CCN(c3ccc(N4CC(=O)Nc5cnc6ccc(Br)cc6c54)cc3C(F)(F)F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a solution of compound 8.4 methyl 1-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (55 mg, 0.10 mmol, 1 equiv.) in THF/H2O (1.0 mL/1.5 mL) was added lithium hydroxide monohydrate (13 mg, 0.30 mmol, 1 equiv.). The resulting mixture was stirred overnight at room temperature. Upon completion, the reaction was diluted with CH2Cl, (5 mL) and water (5 mL). The aqueous layer was adjusted with 1 N HCl to about pH3 and extracted with CH2Cl2 (5 mL×3). The combined organic layer was washed with brine (20 mL) and dried over Na2SO4. After removal of solvent under vacuum, the resulting residue was used for the next step without further purification. To a solution of the above acid in DMF (2 mL) was added 1-methylpiperidin-4-amine (25 μL, 0.20 mmol, 2 equiv.), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (95 mg, 0.25 mmol, 2.5 equiv.) and DIEA (52 μL, 0.30 mmol, 3 equiv.). The reaction mixture was stirred at room temperature for overnight. After removal of the solvent, the residue was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL). The organic phase was dried over Na2SO4. Removal of solvent under vacuum afforded crude product 8.5 1-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)-N-(1-methylpiperidin-4-yl)piperidine-4-carboxamide 46 mg. It was used for next step without further purification. LC-MS (M+H): 645.22
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][C:7]2[N:8]3[CH2:13][CH:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[S:11][C:9]3=[N:10][C:6]=2[CH:5]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:27]>>[CH2:1]([O:3][C:4]1[CH:21]=[CH:20][C:7]2[N:8]3[CH2:13][CH:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[S:11](=[O:27])[C:9]3=[N:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(c1)nc1n2CC(c2ccccn2)S1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCOc1ccc2c(c1)nc1n2CC(c2ccccn2)S1=O

Procedure:
In a manner analogous to Example 4 7-ethoxy-2,3-dihydro-2-(2-pyridyl)thiazolo[3,2-a]-benzimidazole (1.65 g) was reacted with m-chloroperoxy benzoic acid (1.25) to give the title compound (0.56 g, mp 145°-147° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C([O-])([O-])=O.[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: COc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C#N)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To 4-hydroxy-3-methoxybenzonitrile (20.0 g, 134 mmol) in acetone (200 ml) were added K2CO3 (55.6 g, 402 mmol) and benzyl chloride (23.2 ml, 201 mmol). The resulting reaction mixture was refluxed overnight. After cooling to room temperature, acetone was removed by evaporation under reduced pressure and the residue was recrystallized to obtain 4-benzyloxy-3-methoxy-benzonitrile(28.5 g, 88%). Then, according to the similar procedure of Example 1, 7-(4-Benzyloxy-3-methoxy-phenyl)-5-ethylsulfanyl-imidazo[1,2-c]pyrimidine was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:27])[CH:3]=1.Br[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:35][O:34][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:25][CH:24]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)cc1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)CCCOc1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2C)cc1

Procedure:
In analogy to example 221, step 6, 5-[3-(4-chloro-2-methyl-phenyl)-3-(4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 346, step 1) was reacted with methyl 4-bromobutyrate in N,N-dimethylacetamide in the presence of cesium carbonate to give the title compound as a colourless foam, MS (ESI+): m/z=482.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14]C)=[O:13].O>[OH-].[Na+].CC(O)C>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)CCc1cc(F)cc(F)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)CCc1cc(F)cc(F)c1Br

Procedure:
Methyl 3-(2-bromo-3,5-difluorophenyl)propanoate (prepared as described in Step 1, 4.3 g) in aqueous NaOH (4 M, 13.5 mL) and 2-propanol (30 mL) is heated at 50° C. for 2 hours. Water is added, the mixture washed with diethyl ether, acidified to ca. pH 5 by adding concentrated aqueous HCl, and extracted twice with diethyl ether. The combined extracts of the acidified mixture are washed with brine and volatiles evaporated under reduced pressure. The resulting material (Yield 3.6 g) is used in the next step without further purification. LC (METHOD 7): tR=0.99 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:25](=[O:26])[C:24]3[N:27]4[C:17](=[CH:18][N:19]=[C:20]4[CH:21]=[CH:22][CH:23]=3)[C:16]2=[O:28])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>C(O)C>[ClH:29].[ClH:29].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:25](=[O:26])[C:24]3[N:27]4[C:17](=[CH:18][N:19]=[C:20]4[CH:21]=[CH:22][CH:23]=3)[C:16]2=[O:28])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2c(=O)c3cccc4ncc(c2=O)n43)CC1
Agent: Cl
Solvent: CCO
Product: O=c1c2cccc3ncc(c(=O)n1CC1CCNCC1)n32
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 7.99 g (20.8 mmol) of 4,5-dihydro-4-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione in 50 ml of ethanol was added dropwise 25 ml of conc.HCl. The mixture was stirred for two hours at room temperature. The resulting crystalline precipitates were collected by filtration, washed with ethanol and then with ether to afford 7.07 g (87.4%, a colorless solid substance) of the desired compound
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[S:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.[C-]#N.[K+].N12CCN(CC1)CC2>C1C=CC=CC=1>[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:14]2[C:15](=[S:16])[C:6]3([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]3)[NH:7][C:8]32[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:25])=[CH:19][CH:18]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: S=C1NC2(CCCCC2)NC12CCCCC2
Agent: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [K+]
Solvent: c1ccccc1
Product: Cc1ccc(NC(=O)N2C(=S)C3(CCCCC3)NC23CCCCC3)cc1
Reaction time: 24 h

Procedure:
4.8 Parts of 7,14-diazadispiro[5.1.5.2]pentadecane-15-thione, 2.92 parts of p-tolyl isocyanate, 0.2 parts of potassium cyanide and a trace of 1,4-diazabicyclo[2.2.2]octane in 100 parts of dry benzene were heated at reflux for 24 hours. The solvent was then evaporated off in vacuo and the residue treated with excess water and allowed to stand for 24 hours. The solution was extracted with chloroform and the axtracts dried and evaporated in vacuo. The residue was crystallised from ethanol to yield 5.4 parts of 14-p-tolylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecane-15-thione as a colourless solid of melting point 127° to 129°C. This material gave the following elemental analysis by weight:
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:2]([C:7]([N:9]2[CH2:14][C:13](=O)[CH2:12][CH2:11][CH:10]2[CH2:16][NH:17][C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[O:19])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:36][NH2:37]>>[C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:2]([C:7]([N:9]2[CH2:14][CH:13]([NH:37][CH3:36])[CH2:12][CH2:11][CH:10]2[CH2:16][NH:17][C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[O:19])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(CNC(=O)c2cccc3cccnc23)N(C(=O)c2ccccc2-c2ccccc2)C1
Reactant: CN
Product: CNC1CCC(CNC(=O)c2cccc3cccnc23)N(C(=O)c2ccccc2-c2ccccc2)C1

Procedure:
N-((1-(Biphenylcarbonyl)-5-(methylamino)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N-((1-(biphenylcarbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide and methyl amine. (ESI) 479 (M+H).
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH:3]12[CH2:9][CH:5]3[CH:6]([CH2:7][CH2:8]1)[C:5]([CH2:8][CH2:3][CH2:4]3)=[CH:4]2
Reactant: Cc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Product: C1=C2CCCC3CC1CCC23
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 8.22 g (36 millimoles) of 3-bromo-4-homoisotwistane in 20 ml of dry toluene was added 1.4 g (36 millimoles) of sodium amide, and the mixture was stirred for 2 hours under reflux of toluene. After completion of the reaction, the reaction mixture was filtered and the filtrate was fractionally distilled to give 2.75 g (52% yield) of colorless tricyclo[5.3.1.03,8 ]undec-2-ene (boiling point of 90° to 92° C/19 mm Hg). Elementary Analysis Values: