Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH2:3][N:4]1[C:8]([CH3:9])=[CH:7][CH:6]=[N:5]1>C(O)=O>[CH3:9][C:8]1[N:4]([CH2:3][C:2]2([CH3:1])[CH2:10][CH2:11][CH2:12][C:13]([CH3:15])([CH3:14])[O:16]2)[N:5]=[CH:6][CH:7]=1
Reactant: CC(C)=CCCC(C)(O)Cn1nccc1C
Solvent: O=CO
Product: Cc1ccnn1CC1(C)CCCC(C)(C)O1

Procedure:
A mixture of EXAMPLE 186A (6.5 g) and formic acid (20 mL) was heated at 100° C. for 3 hours. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography, eluting with 1% ethyl acetate in petroleum ether, to give the title product.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:13]([O:15]C#C)[CH3:14].[CH2:18](N(CC)CC)[CH3:19].CCOC(C)=O>C1COCC1.CO>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([C:13](=[O:15])[CH:14]=[C:10]2[O:11][CH2:18][CH3:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C#COCC
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC1=CC(=O)C12CCN(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 120 h
Yield: 67.4 %

Procedure:
A solution of 1-acetyl piperidine-4-carbonyl chloride (5.0 g, 26.4 mmol) and ethoxyacetylene (4.0 g, 55.5 mmol) in THF (60 ml) was treated dropwise with triethylamine (7.6 ml, 55.0 mmol). The resulting slurry was stirred at room temperature for 5 d prior to filtration and concentration of the filtrate in vacuo. Chromatography (SiO2, 100% EtOAc to 95:5 EtOAc:MeOH) gave the title compound as a white powder (3.97 g, 17.8 mmol, 67%). 5H (CDCl3, 300K) 4.79 (1H, s), 4.17 (2H, q, J 7.1 Hz), 3.87-3.81 (1H, m), 3.56-3.42 (3H, m), 2.02 (3H, s), 1.85-1.67 (4H, m), 1.39 (3H, t, J 7.1 Hz); m/z (ES+, 70V) 223.9 (MH+).
Reaction SMILES: [C:1](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[NH2:17][C@H:18]([C:20]([O-:22])=[O:21])[CH3:19].Cl>C(O)C.C(OC([C@@H](N[C@H](C(O)=O)C)CC(=O)C1C=CC=CC=1)=O)C>[CH2:14]([O:13][C:11]([CH:10]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])[CH2:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12])[CH3:15]
Reactant: C[C@H](N)C(=O)[O-]
Reactant: CCOC(=O)/C=C/C(=O)c1ccccc1
Agent: CCOC(=O)[C@H](CC(=O)c1ccccc1)N[C@@H](C)C(=O)O
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CCOC(=O)C(CC(=O)c1ccccc1)N[C@@H](C)C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 68.2 %

Procedure:
To a solution of 25.9 g of ethyl trans-β-benzoylacrylate in 770 ml of ethanol was added a solution of 6.03 g of L-alanine lithium salt in 426 ml of ethanol over 30 minutes at room temperature. After completion of addition, the mixture was stirred for an additional 5 minutes, and then 5.29 ml of concentrated hydrochloric acid was added, followed by cooling with ice-water. As seed crystals, 679 mg of N-(1(S)-ethoxycarbonyl-3-oxo-3-phenylpropyl)-L-alanine was added, and the mixture was stirred for 4 hours. The crystals separating out were collected by filtration, washed with ethanol, and dried, whereby 12.7 g of N-(1-ethoxycarbonyl-3-oxo-3-phenylpropyl)-L-alanine (1S/1R ratio=95/5) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Fc1ccc(S)cc1
Product: COc1ccc2c(Sc3ccc(F)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 305 was used, starting from 4-fluoro-benzenethiol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenylsulfanyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 381 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.N1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.OC1C=CC=CC=1C=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:10]2[C:11](=[O:12])[O:13][C:14]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:15]=3)=[O:16])=[CH:7][CH:8]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Solvent: CCO
Solvent: O=Cc1ccccc1O
Product: COc1ccc(C(=O)c2cc3ccccc3oc2=O)cc1
Reaction time: 8 h
Yield: 87.6 %

Procedure:
3.64 g (16.38 mmol) of ethyl 3-(4-methoxyphenyl)-3-oxopropanoate and 1.39 g of piperidine (16.38 mmol) are added to a solution of 2 g (16.38 mmol) of 2-hydroxybenzaldehyde in 15 ml of ethanol. The reaction mixture is stirred for 8 hours at reflux. The solution is cooled, and then the white solid formed is filtered and rinsed with a minimum of ethanol to yield 4.02 g (88%) of 3-(4-methoxybenzoyl)-2H-chromen-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[CH3:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=1[F:26])=[O:18].Cl[CH2:28][C:29]([NH:31][CH3:32])=[O:30].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[CH3:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([CH:22]=[CH:21][C:20]=1[F:26])[O:25][CH2:28][C:29]([NH:31][CH3:32])=[O:30])=[O:18]
Reactant: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc(O)ccc2F)c(Cl)c1
Reactant: CNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)COc1ccc(F)c(C(=O)c2ccc(Nc3ccc(Cl)cc3C)cc2Cl)c1
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
Compound 513 (36 mg, 0.09 mmol) was dissolved in acetonitrile (2 mL) in a reaction vial. 2-Chloro-N-methyl-acetamide (30 mg, 0.28 mmol), K2CO3 (38 mg, 0.28 mmol) were added. The reaction vial was flushed with argon, closed and then stirred at 130° C. for 45 min. in a microwave oven. The reaction mixture was poured into a mixture of EtOAc:H2O (1:1, 10 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×5 mL). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and purified by continuously gradient flash chromatography using EtOAc/petroleum ether (40-60)(v:v=1:3 to 100:0) as the eluent, affording the title compound as a yellow oil. 13C NMR (CDCl3) δ 190.1, 168.2, 155.7 (d), 153.2 (d), 149.2, 136.6, 135.0, 134.5, 133.4, 131.2, 130.5, 128.7 (d), 128.1, 127.1, 125.3, 119.6 (d), 117.4 (d), 116.1 (d), 115.6, 112.4, 68.0, 25.8, 17.9
Reaction SMILES: C([O:3][C:4](=[O:44])[C:5]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:36][CH:35]=1)([CH3:33])[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:32])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=1)([CH3:21])[C:16]([O:18]CC)=[O:17])C.O.[OH-].[K+]>C(O)C>[CH2:28]([C:25]1[CH:24]=[CH:23][C:22]([C:15]([CH3:21])([CH2:14][CH2:13][CH2:12][CH2:11][C:10](=[O:32])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([C:34]2[CH:35]=[CH:36][C:37]([CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:38][CH:39]=2)([CH3:33])[C:4]([OH:44])=[O:3])[C:16]([OH:18])=[O:17])=[CH:27][CH:26]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: CCOC(=O)C(C)(CCCCC(=O)CCCCC(C)(C(=O)OCC)c1ccc(CC(C)C)cc1)c1ccc(CC(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(CC(C)C)cc2)C(=O)O)cc1
Yield: 86.2 %

Procedure:
2,12-Bis-(4-isobutyl-phenyl)-2,12-dimethyl-7-oxo-tridecanedioic acid diethyl ester (3.0 g, 4.95 mmol) was dissolved in ethanol (40 mL) and water (10 mL) with potassium hydroxide (4.4 g 85%). The solution was heated to reflux for six hours, cooled and concentrated. After the ethanol was removed, water (200 mL) was added and the solution was extracted with diethyl ether (100 mL). The aqueous fraction was acidified with concentrated hydrochloric acid (10 mL, to pH=1). The product was then extracted with diethyl ether (2×100 mL). The ether fractions were combined and dried with sodium sulfate (5 g). After filtration, concentration and drying under high vacuum, the reaction yielded 2,12-bis-(4-isobutyl-phenyl)-2,12-dimethyl-7-oxo-tridecanedioic acid (2.35 g, 82% yield) as a light yellow foam. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 10.02 (bs, 2H), 7.24 (d, 4H, J=8.0 Hz), 7.09 (d, 4H, J=8.0 Hz), 2.43 (d, 4H, J=7.0 Hz), 2.33 (t, 4H, J=7.3 Hz), 2.05-1.88 (m, 2H), 1.96-1.77 (m, 4H), 1.55-1.42 (m, 10H), 1.22-1.08 (m, 4H), 0.88 (d, 12H, J=6.6). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 211.48, 182.94, 140.43, 140.24, 129.27, 125.94, 49.71, 45.06, 42.58, 42.58, 38.91, 30.25, 24.45, 24.24, 22.58, 22.40. HRMS (LSIMS, nba): Calcd. for C35H50O5Na (MNa+): 573.3555, found: 573.3459.
Reaction SMILES: [NH2:1][C@H:2]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][S:21]([OH:24])(=[O:23])=[O:22].O>C1(C)C=CC=CC=1.C(OC)(C)(C)C>[CH3:20][S:21]([OH:24])(=[O:23])=[O:22].[NH2:1][C@H:2]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3]([O:5][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: N[C@@H](C(=O)O)C1CCCCC1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: COC(C)(C)C
Product: N[C@@H](C(=O)OCc1ccccc1)C1CCCCC1
Reaction time: 6 h
Yield: 92 %

Procedure:
To a suspension of (2R)-2-amino-2-cyclohexylethanoic acid (200 g, 1.27 mol) and benzyl alcohol (276 g, 2.54 mol) in toluene (1600 mL) was added methanesulphonic acid at a rate which did not allow the temperature to reach 100° C. The reaction was stirred for an additional six hours at between 110 and 115° C. The water that was produced was distilled off using a Dean-Stark trap. An additional portion of benzyl alcohol (276 g, 2.54 mol) was added and the mixture was refluxed for a further twelve hours with water distillation. The reaction mixture was then cooled and methyl tert-butyl ether was added to initiate crystallisation. The product was filtered and dried to yield 404 g (92%) of the sub-title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([C:41]#[N:42])([C:38]([OH:40])=O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([C@H:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([C@H:50]([NH:52][C:38]([C:35]2([C:41]#[N:42])[CH2:34][CH2:33][N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[CH2:37][CH2:36]2)=[O:40])[CH3:51])=[CH:46][CH:45]=1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@@H](NC(=O)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.255 g, 3.30 mmol) was added in one portion to 1-(tert-butoxycarbonyl)-4-cyanopiperidine-4-carboxylic acid (Intermediate 43) (0.763 g, 3 mmol), (R)-1-(4-chlorophenyl)ethanamine (0.462 mL, 3.00 mmol) and DIPEA (1.572 mL, 9.00 mmol) in DMA (20 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (150 mL), and washed sequentially with 1M aqueous citric acid (50 mL), water (50 mL), and saturated sodium hydrogen carbonate (100 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product thus obtained was concentrated, then purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to afford (R)-tert-butyl 4-(1-(4-chlorophenyl)ethylcarbamoyl)-4-cyanopiperidine-1-carboxylate (1.100 g, 94%) as a colourless gum which solidified on drying under high vacuum. This material was then redissolved in DCM (20.00 mL), and trifluoroacetic acid (2.311 mL, 30.00 mmol) was added. The solution was stirred at room temperature for 3 hours, after which the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness to afford (R)—N-(1-(4-chlorophenyl)ethyl)-4-cyanopiperidine-4-carboxamide (0.720 g, 82%) as a colourless gum. This material was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:38][C:39]([F:52])([F:51])[C:40]1[CH:41]=[C:42]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[NH2:43]>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[CH:24]=2)[CH:12]=[C:13]([NH:43][C:42]2[CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=[C:40]([C:39]([F:38])([F:51])[F:52])[CH:41]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 47 %

Procedure:
The title compound was prepared in 47% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester and 3,5-bis-trifluoromethyl-aniline under the conditions described in Example 37, step (b).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=O)[CH2:5][CH2:4][S:3]1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:31]=1)[NH:28][CH:27]=[CH:26]2.C([SiH](CC)CC)C>C(Cl)Cl>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:6]1[CH2:5][CH2:4][S:3][C:2]([CH3:9])([CH3:1])[CH2:7]1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: CC1(C)CC(=O)CCS1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CCSC(C)(C)C3)c[nH]c12
Temperature: 0 °C
Yield: 114 %

Procedure:
2,2-Dimethyltetrahydro-4H-thiopyran-4-one (0.675 g, 4.68 mmol) was placed in a dried flask fitted up with an addition funnel, a septum and an argon inlet, and dissolved in dry DCM (15 mL), cooled to 0° C., stirred, and then trimethylsilyl trifluoromethanesulfonate (1.692 mL, 9.36 mmol) was added dropwise through the addition funnel over 10 minutes. DCM (5 mL) was used to wash the addition funnel walls. To this mixture was added dropwise ethyl 5-bromo-1H-indole-7-carboxylate (1.341 g, 5 mmol) in DCM (15 mL) over 2 hours. Then triethylsilane (2.98 mL, 18.73 mmol) was added in one portion. The mixture was stirred 2 h at 0° C., and left stirring at 23° C. overnight. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate, and the resulting biphasic mixture extracted with DCM to give 2.115 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[NH2:21][CH2:22][C:23]1[NH:24][C:25](=[O:32])[C:26]2[CH2:31][CH2:30][CH2:29][C:27]=2[N:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:21][CH2:22][C:23]3[NH:24][C:25](=[O:32])[C:26]4[CH2:31][CH2:30][CH2:29][C:27]=4[N:28]=3)=[O:18])[CH2:13][CH2:14]2)=[O:8])=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Reactant: NCc1nc2c(c(=O)[nH]1)CCC2
Product: COc1ccc(C(=O)C2CCN(CC(=O)NCc3nc4c(c(=O)[nH]3)CCC4)CC2)cc1
Yield: 21.1 %

Procedure:
The title compound (70 mg) was prepared following the general procedure of Example 1 from 2-(4-(4-methoxybenzoyl)piperidin-1-yl)acetic acid (307 mg, 0.78 mmol, 70% purity) and 2-(aminomethyl)-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one (128 mg, 0.78 mmol). 1H NMR (400 MHz, CDC3) δ 10.58 (br. s., 1H), 8.06 (br. s., 1H), 7.95 (d, J=9.1 Hz, 2H), 6.98 (d, J=9.1 Hz, 2H), 4.41 (d, J=6.1 Hz, 2H), 3.90 (s, 3H), 3.28 (br. s., 3H), 3.02 (br. s., 2H), 2.70-2.95 (m, 4H), 2.43 (br. s., 2H), 2.09 (dq, J=7.8, 7.7 Hz, 2H), 1.91 (br. s., 4H). HRMS calculated for C23H28N4O4 425.2189. found (ESI, [M+H]+), 425.2180. Retention time=4.65 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]([O:12][CH:13]1[CH2:19][CH:18]2[N:20]([CH3:21])[CH:15]([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:28][CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>CN(C=O)C.C(#N)C>[Br-:28].[C:1]([O:5][C:6]([NH:8][CH:9]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10]([O:12][CH:13]1[CH2:14][CH:15]2[N+:20]([CH3:21])([CH2:29][C:30](=[O:31])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:18]([CH2:17][CH2:16]2)[CH2:19]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C2CCC1CC(OC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1)C2
Reactant: O=C(CBr)c1ccccc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(C(=O)OC1CC2CCC(C1)[N+]2(C)CC(=O)c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 56 %

Procedure:
To a solution of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate (C58) (230 mg, 0.61 mmol) in DMF (15 ml) and acetonitrile (5 ml), was added 2-bromo-1-phenylethanone (134 mg, 0.68 mmol). The reaction was stirred at RT for 15 hours, and then the solvent was evaporated. The crude was first triturated with i-Pr2O and then purified by flash chromatography (DCM/MeOH=94/6) to obtain 3-(2-(tert-butoxycarbonylamino)-2-phenylacetoxy)-8-methyl-8-(2-oxo-2-phenylethyl)-8-azoniabicyclo[3.2.1]octane bromide (196 mg; 56% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]3)=[C:26]([O:36][CH3:37])[CH:25]=2)[CH:20]=[C:19]([C:38]([F:41])([F:40])[F:39])[CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[CH:18]=[C:19]([C:38]([F:39])([F:40])[F:41])[CH:20]=[C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]4)=[C:26]([O:36][CH3:37])[CH:25]=3)[N:22]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: COc1cc(Nc2cc(C(F)(F)F)cc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cc(C(F)(F)F)cc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and (6-chloro-4-trifluoromethyl-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a yellowish solid (Yield=18%). MS ISP (m/e): 550.4 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.63 (d, 2H), 7.24 (d, 2H), 7.15 (d, 2H), 6.88 (s, 2H), 6.66 (s, 2H), 6.50 (s, 2H), 3.73 (s, 6H), 2.30 (, 6H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:8]([O:33]C)=[C:9]2[C:22](=[CH:23][CH:24]=1)[C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:15]1[C:14]([O:25]C)=[C:13]([O:27]C)[C:12]([O:29]C)=[C:11]([O:31]C)[C:10]2=1.O>ClCCl>[OH:6][C:7]1[C:8]([OH:33])=[C:9]2[C:22](=[CH:23][CH:24]=1)[C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:15]1[C:14]([OH:25])=[C:13]([OH:27])[C:12]([OH:29])=[C:11]([OH:31])[C:10]2=1
Reactant: COc1ccc2c3ccccc3c3c(OC)c(OC)c(OC)c(OC)c3c2c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc2c3ccccc3c3c(O)c(O)c(O)c(O)c3c2c1O
Temperature: 25 °C

Procedure:
Boron tribromide (8.6 g, 0.034 mol) in dry dichloromethane (80 ml) was added to hexamethoxytriphenylene (2 g, 0.0049 mol) in dry dichloromethane (100 ml) under a dry nitrogen atmosphere at -80° C. The mixture was allowed to warm to room temperature overnight. Water was added and the dichloromethane was removed under reduced pressure. The crude product was filtered off. The hexahydroxytriphenylene was purified by recrystallisation from water.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[Br:14][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:13])[C:9]([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)Cc1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Br)c1ccccc1
Yield: 99.5 %

Procedure:
17.6 g (0.1 mol) of 1-phenyl-3,3-dimethyl-butan-2-one were dissolved in 100 ml of carbon tetrachloride, 5 ml (0.1 mole) of bromine were added dropwise thereto while stirring and under reflux, and the mixture was heated to the boil for one hour. After cooling, the distilling off the solvent, 25.4 g of 1-bromo-1-phenyl-3,3-dimethyl-butan-2-one of melting point 38°-42° C. were obtained in quantitative yield.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[OH:12].C(Cl)Cl.[CH2:16]([Mg]Br)[C:17]([CH3:20])([CH3:19])[CH3:18]>C1COCC1.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]>[CH2:16]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[OH:12])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C[Mg]Br
Reactant: OC1CCOc2ccc(I)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)Cc1ccc2c(c1)C(O)CCO2
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a solution of 6-iodochroman-4-ol (1.0 g, 3.6 mmol) in 18 ml of THF, at 0° C., was added the Pd(dppf)Cl2.CH2Cl2 (0.15 g, 0.18 mmol), followed by neopentylmagnesium bromide (10.8 ml, 10.8 mmol, 1.0 M in Et2O). The cold bath was maintained for 10 min., then removed and stirring continued overnight. The mixture was quenched with NH4Cl (30 ml) and extracted with EtOAc (3×50 ml). The combined organic layers were dried over MgSO4 and concentrated in vacuo to yield a brown oil. The crude oil was absorbed onto silica gel followed by flash chromatography (biotage 40S) 10% EtOAc/heptanes to yield 0.36 g (46%) of 6-neopentylchroman-4-ol as a white solid. Rf=0.11. HRMS (ESI+) calcd for C14H20O2 m/z 220.1463 (M+H)+; found 220.1460.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][C@@H:6]([C:18]([O:20]CC2C=CC=CC=2)=[O:19])[CH2:5]1)=[N+:2]=[N-:3].[OH-].[Li+]>O1CCCC1.O>[N:1]([C@H:4]1[C@@H:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:8][CH2:7][C@@H:6]([C:18]([OH:20])=[O:19])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)C[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 125.7 %

Procedure:
Benzyl (1R,3R,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate (3.5 g) was dissolved in tetrahydrofuran (130 ml) and water (16 ml), and lithium hydroxide (291 mg) was added under ice cooling. After 10 minutes, the mixture was heated to room temperature to continue stirring. After 20 hours, the reaction was stopped, the solvent was distilled off under reduced pressure, and the resultant residue was subjected to column chromatography on silica gel (methanol:dichloromethane=1:20) to obtain (1R,3R,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylic acid (3.34 g) as a pale yellow oil. This product was dissolved in methanol (18 ml) and toluene (64 ml), trimethylsilyldiazomethane (2 M solution, 6.1 ml) was added under ice cooling, and the mixture was heated to room temperature and stirred. After 2 hours, the reaction was stopped, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the title compound (3.35 g) as a colorless oil.