Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]([NH2:10])[C@@H:2]1[OH:11].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[CH2:20][CH2:21][CH3:22]>C1COCC1>[OH:11][C@@H:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:10][C:19](=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(=O)Cl
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)N[C@H]1c2ccccc2C[C@H]1O
Temperature: 0 °C

Procedure:
(1S,2R)-cis-1-Amino-2-indanol (XIV, 1.5 g) was dissolved with triethylamine (1.5 mL) in dry THF (45 mL), and cooled to 0° C. Butyryl chloride (XIII, 1.05 mL) was added by syringe, and the resultant solution stirred 0° C. for 20 min, whereupon the reaction mixture was partitioned between half-saturated NH4Cl (45 mL) and EtOAc(2×45 mL). The combined organic layers were dried dried (MgSO4), filtered, and concentrated under reduced pressure to give a solid, which was taken to the next reaction without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]=3[O:29][C:30]3[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-]#N.[Na+].[CH3:41][OH:42]>C(Cl)Cl.CCOC(C)=O.O=[Mn]=O>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:24]([C:25]([F:27])([F:26])[F:28])=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]=3[O:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([O:42][CH3:41])=[O:35])=[CH:36][CH:37]=3)=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(Oc2c(-c3ccc(OCc4ccccc4)cc3)c(C(F)(F)F)cc3ccccc23)cc1
Reactant: CO
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Oc2c(-c3ccc(OCc4ccccc4)cc3)c(C(F)(F)F)cc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 4-{[2-{4-[(phenylmethyl)oxy]phenyl}-3-(trifluoromethyl)-1-naphthalenyl]oxy}benzaldehyde (187) (0.23 g, 0.45 mmol) in MeOH (4 mL) and CH2Cl2 (2 mL) was added NaCN (0.12 g, 2.26 mmol) followed by MnO2 (0.56 g, 5.42 mmol). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc (50 mL) and filtered through a pad of celite on top of a layer of silica gel. The filtrate was washed with water, brine, dried over Na2SO4, filtered, and concentrated to give the crude product as a light yellow solid, which upon trituration with 1% MeOH in hexanes, gave 0.21 g (86%) of the title compound (188) as a white solid. mp 131-132° C. 1H NMR (400 MHz, CDCl3): δ 3.85 (s, 3H), 5.01 (s, 2H), 6.58 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.6 Hz, 2H), 7.30-7.44 (m, 5H), 7.55-7.66 (m, 2H), 7.79 (d, J=8.8 Hz, 2H), 7.89 (d, J=8.2 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H), 8.24 (s, 1H). LCMS (ESI): m/z 551 (M+Na)+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH:14]([CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH:25]=[O:26])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1>C(O)C>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11]2[CH2:12][CH2:13][CH:14]([CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[CH2:15][CH2:16]2)=[CH:7][CH:8]=1
Reactant: O=CCCC1CCC(C2CCC(CCc3ccc(C(F)(F)F)cc3)CC2)CC1
Solvent: CCO
Product: OCCCC1CCC(C2CCC(CCc3ccc(C(F)(F)F)cc3)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Ethanol (10 ml) was added to the above 3-(4-(4-(2-(4-trifluoromethylphenyl)ethyl)cyclohexyl)cyclohexyl)propanal (1.21 g, 3.07 mmol), followed by cooling the mixture down to 0° C. in a nitrogen gas atmosphere, adding thereto, sodiumboronhydride (0.13 g, 3.43 mmol) so that the solution temperature could not exceed 10° C., stirring the mixture at 0° C. for 2 hours, extracting the resulting product with ethyl acetate, washing the organic layer successively with a saturated, aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, and distilling off the solvent, to obtain 3-(4-(4-(2-(4-trifluoromethylphenyl)ethyl)cyclohexyl)cyclohexyl)propanol (1.20 g, 3.03 mmol). The yield was 98.7%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)=[CH:6][C:5]=1[CH:22](C(OCC)=O)[C:23]([O:25][CH2:26]C)=[O:24])([O-:3])=[O:2].[ClH:33]>O1CCOCC1>[ClH:33].[NH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(CN2C(=O)c3ccccc3C2=O)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1cc(CN)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A solution of diethyl 2-nitro-5-phthalimidomethylphenylmalonate in a mixture of concentrated hydrochloric acid (150 mL) and 1,4-dioxane (150 mL) was heated at 120° C. for 24 h. The solvents was removed in vacuo and the residual solid was dissolved in methanol (100 mL). To the solution was added thionyl chloride (11.8 g) dropwise at 0° C. The mixture was stirred for 2 h at 40° C. and the solvent and the excess reagent was removed in vacuo. The residue was washed with diethyl ether and dried to give 6.5 g of the title compound (quant).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:59][C:60]1[S:61][CH:62]=[CH:63][N:64]=1>C(Cl)Cl.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[C:8]([NH:59][C:60]2[S:61][CH:62]=[CH:63][N:64]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C#Cc2ccccn2)cc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(C#Cc2ccccn2)cc1
Yield: 71 %

Procedure:
A solution of 3-cyclopentyl-2-(4-pyridin-2-ylethynyl-phenyl)-propionic acid (150 mg, 0.47 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.20 mL, 1.41 mmol) and 2-aminothiazole (75 mg, 0.75 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 18 h. At this time, the reaction was diluted with water (10 mL). The organic phase was separated and washed with a 1N aqueous sodium hydroxide solution, and a saturated aqueous sodium chloride solution. The aqueous layers were each back-extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-pyridin-2-ylethynyl-phenyl)-N-thiazol-2-yl-propionamide (134 mg, 71%) as a pale yellow solid: mp 185-187° C.; EI-HRMS m/e calcd for C24H23N3OS (M+) 401.1561, found 401.1555.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:14]1([C:20]2[O:24][N:23]=[CH:22][C:21]=2[CH2:25][CH2:26][C:27](O)=[O:28])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O.C(N(CC)CC)C>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][CH2:3][NH:2][C:27](=[O:28])[CH2:26][CH2:25][C:21]2[CH:22]=[N:23][O:24][C:20]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:6]1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1cnoc1-c1ccccc1)NCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A mixture of 3-(2-aminoethyl)indole hydrochloride (0.46 g), triethylamine (0.6 ml) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 1 hr. To the obtained mixture was added 3-(5-phenyl-4-isoxazolyl)propionic acid (0.42 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.37 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[2-(3-indolyl)ethyl]-3-(5-phenyl-4-isoxazolyl)propionamide (0.63 g, yield 91%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl3) δ: 2.32–2.44 (2H, m), 2.88–3.04 (4H, m), 3.54–3.66 (2H, m), 5.45 (1H, br s), 6.93 (1H, d, J=2.2 Hz), 7.04–7.28 (2H, m), 7.32–7.62 (5H, m), 7.64–7.74 (2H, m), 8.05 (1H, br s), 8.17 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.[C:21]([NH:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:24])[CH:22]=[CH2:23].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:5]3=[N:6][CH:7]=[C:2]([C:28]4[CH:27]=[C:26]([NH:25][C:21](=[O:24])[CH:22]=[CH2:23])[CH:31]=[CH:30][CH:29]=4)[CH:3]=[C:4]3[C:10]([CH3:11])=[N:9]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(Br)cnc32)cc1
Reactant: C=CC(=O)Nc1cccc(B(O)O)c1
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: [Cs+]
Solvent: COCCOC
Product: C=CC(=O)Nc1cccc(-c2cnc3c(c2)c(C)nn3Cc2ccc(OC)cc2)c1
Temperature: 100 °C

Procedure:
The starting material 5-bromo-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine (7) (134 mg, 0.402 mmol, 1 eq) and (3-acrylamidophenyl)boronic acid (153) (100 mg, 0.366 mmol, 1 eq) in DME (10 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (233 mg, 0.732 mmol, 2 eq) followed by addition of Pd(PPh3)4 (0.016 mg, 0.03 mmol) and degassing and purging under argon for additional 10 min. The reaction mixture was heated at 100° C. for 16 h in a sealed tube. After completion of the reaction, the solvents were removed and reaction mixtures were extracted into EtOAc, dried over Na2SO4 and the solvents distilled off. The crude material was submitted for flash column purification using 40% EtOAc in hexane to obtain off-white solid compound N-(3-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)acrylamide 154. MS m/z 397.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][C:14]=1[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH3:16])=[CH:13][C:12]([Br:19])=[C:11]([O:17][CH3:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(OC)cc1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1cc(Br)c(OC)cc1OCc1ccccc1

Procedure:
In a bromination reaction, the 3-benzyloxy-4-ethyl-1-methoxybenzene (3) is combined with N-bromosuccinimide (NBS) and silica gel 60 (EM Science, 480 Democrat Road, Gibbstown, N.J. 08027, an affiliate of Merck KGaA, Darmstadt, Germany) in a nonpolar solvent such as carbon tetrachloride at a temperature from about 0° C. to about room temperature. Preferably, the reaction is conducted at about room temperature. This reaction is allowed to stir, in the absence of light, to yield 5-benzyloxy-2-bromo-4-ethyl-1-methoxybenzene (4).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19]O)[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19][Cl:3])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1cc(OCc2ccccc2)ccn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1cc(OCc2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.76 ml (24.16 mmol) of thionyl chloride are added to 2 g (9.29 mmol) of [4-(benzyloxy)pyridin-2-yl]methanol [described in J. Org. Chem., (1996), 61(8), 2624] in 46 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 18 hours and then concentrated under reduced pressure. The residue obtained is taken up in a saturated aqueous sodium carbonate solution and then extracted with dichloromethane. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. 2.1 g of a brown oil are collected. Mass spectrometry (ES+Mode): MH+=234
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH:43]1([C:46]2[O:50][N:49]=[CH:48][C:47]=2[C:51](O)=[O:52])[CH2:45][CH2:44]1>CN(C=O)C>[CH:43]1([C:46]2[O:50][N:49]=[CH:48][C:47]=2[C:51]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[CH2:2]2)=[O:52])[CH2:45][CH2:44]1
Reactant: O=C(O)c1cnoc1C1CC1
Reactant: c1cncc(C2CCNC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cnoc1C1CC1)N1CCC(c2cccnc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
A solution of 3-pyrrolidin-3-yl-pyridine (15 mg, 0.1 mmol), TBTU (48 mg, 0.15 mmol, 1.5 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.1 mmol) in DMF (0.6 mL) was added to 5-cyclopropylisoxazole-4-carboxylic acid (15 mg, 0.1 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (12 mg). MS (ESI, pos. ion) m/z calcd for C16H17N3O2: 283.1321, found 283.1316.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C@@H:10]([NH:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:19]3[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:21]=[CH:20]3)[CH:8]=2)[NH:3]1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[C:29]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([N:19]3[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:21]=[CH:20]3)=[CH:6][CH:5]=2)[C@H:10]([NH:12][C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])[CH2:11][C@@H:2]1[CH3:1])(=[O:31])[CH3:30]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3)cn1
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
Acetic anhydride (20 mL) was added to ethyl 1-[(cis)-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazole-4-carboxylate (for a preparation see intermediate 83) (3.5 g, 9.06 mmol). The resulting mixture was stirred at room temperature for 24 h then most of the solvent was removed in vacuo. The residue was dissolved in AcOEt (30 mL) and washed repeatedly with a saturated NaHCO3 aqueous solution until the later was basic. The organic phase was then washed with water and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 5% MeOH in DCM) gave ethyl 1-[(cis)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazole-4-carboxylate (3.8 g, 8.87 mmol, 98%) as a colourless foam. LCMS (method G): Retention time 0.83 min, [M+H]+=429.11
Reaction SMILES: [C:1]([C:8]1[C:9]([NH2:19])=[C:10]([C:14](=O)[C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:21][OH:22]>>[C:1]([C:8]1[C:9]([NH2:19])=[C:10]([C:14](=[N:21][OH:22])[C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)c1cccc(C(=O)C(=O)O)c1N
Agent: Cl
Product: CC(C)(C)OC(=O)c1cccc(C(=NO)C(=O)O)c1N

Procedure:
11.7 g of 2-(3-BOC-aminophenyl)-glyoxylic acid are reacted with 5 g of hydroxylamine hydrochloride in the manner described in Example 4. 2-(3-BOC-Aminophenyl)-2-hydroxyiminoacetic acid is obtained.
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][CH2:12][C:11]2([CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])[CH2:10]1)(=O)C1C=CC=CC=1.Cl>CO>[NH:9]1[CH2:14][CH2:13][CH2:12][C:11]2([CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])[CH2:10]1
Reactant: O=C(c1ccccc1)N1CCCC2(Cc3ccccc3C2=O)C1
Agent: Cl
Solvent: CO
Product: O=C1c2ccccc2CC12CCCNC2
Yield: 28.2 %

Procedure:
1′-benzoylspiro[indene-2,3′-piperidin]-1(3H)-one (2.476 g, 8.11 mmol) was dissolved in methanol (40 mL). 1 N aq HCl (80 mL) was added dropwise and the mixture was refluxed overnight. The methanol was removed in vacuo. The pH of the solution was adjusted to 8 using saturated Na2CO3, and the solution was extracted with CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4 and then concentrated to afford a residue, which was purified by silica gel column chromatography to afford spiro[indene-2,3′-piperidin]-1(3H)-one (460 mg, 28%). 1H NMR (CD3OD, 400 MHz): δ=1.63 (m, 2H), 1.82 (m, 1H), 1.87-2.00 (m, 1H), 2.70 (d, 1H), 2.82 (m, 1H), 3.00 (m, 3H), 3.20 (d, 1H), 7.32 (m, 1H), 7.45 (m, 1H), 7.57 (m, 1H), 7.79 (m, 1H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[N:13]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.[H-].[Na+]>>[CH2:1]([C:5]1([CH2:5][CH2:1][CH2:2][CH3:3])[N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:18][CH:17]=2)[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnccc2[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCC1(CCCC)Nc2ccncc2N1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
2-butyl-3-[(2'-tert-butoxycarbonylbiphen-4-yl)methyl]-2-butyl-3H-imidazo[4,5-c]pyridine was prepared according to the procedure described in Example 1, Part A from 2-butylimidazo[4,5-c]pyridine (220 mg, 1.25 mmol), tert-butyl 4'-bromomethylbiphenyl-2-carboxylate (414 mg, 1.19 mmol), and NaH (1.88 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([O:4][C:5](=[O:20])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:19])[C:16]([OH:18])=O)=[CH:10][CH:9]=1)[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:37]([N:40]1[C:47]([NH2:48])=[C:46]([NH2:49])[C:44](=[O:45])[N:43]([CH2:50][CH2:51][CH3:52])[C:41]1=[O:42])[CH2:38][CH3:39]>O1CCCC1.CN(C)C=O.C(OCC)C>[NH2:48][C:47]1[N:40]([CH2:37][CH2:38][CH3:39])[C:41](=[O:42])[N:43]([CH2:50][CH2:51][CH3:52])[C:44](=[O:45])[C:46]=1[NH:49][C:16](=[O:18])[CH:15]([CH3:19])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][CH2:6][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:21])=[O:20])=[CH:13][CH:12]=1
Reactant: CC(Cc1ccc(NCC(=O)OC(C)(C)C)cc1)C(=O)O
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: CCCn1c(N)c(NC(=O)C(C)Cc2ccc(NCC(=O)OC(C)(C)C)cc2)c(=O)n(CCC)c1=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Dissolve 4-[[2-(1,1-dimethylethoxy)-2-oxoethyl]amino]-alpha-methyl-benzenepropanoic acid (1.07 g, 3.64 mmol) in tetrahydrofuran (15 mL) and treat with N-methylmorpholine (0.4 mL, 3.64 mmol). Cool to -20° C. and treat with isobutyl chloroformate (0.47 mL, 3.64 mmol). Stir for 30 minutes and add a solution of 1,3-dipropyl-5,6-diaminouracil (0.82 g, 3.64 mmol) in dimethylformamide (5 mL). Stir for 3 hours at -20° C., warm to room temperature and dilute with ethyl ether (200 mL). Separate the organic phase, wash with water (200 mL) and dry (MgSO4). Evaporate the solvent in vacuo and purify by flash chromatography to yield the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO.Cl>O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][C:23]([OH:25])=[O:24])[CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1cc(CNC(=O)OCc2ccccc2)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CNC(=O)OCc2ccccc2)cc1OCC(=O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture comprising 23.56 of N-benzyloxycarbonyl-3-ethoxycarbonylmethyloxy-4-methoxybenzylamine, 7.29 g of sodium hydroxide, 300 ml of methanol and 30 ml of water, was stirred at 60° C. for one hour. The reaction solution was neutralized by an addition of hydrochloric acid, and the solvent was distilled off under reduced pressure. Dilute hydrochloric acid was added to the obtained residue, and the mixture was extracted with chloroform. The extract layer was washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off. The obtained residue was crystallized from diethyl ether/n-hexane to obtain 21.55 g of the above-identified compound as white crystals.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Br:15]Br.O>C(O)(=O)C>[Br:15][C:5]1[CH:4]=[C:3]([C:12]([OH:14])=[O:13])[C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(Br)c2cccnc2c1O
Yield: 100.9 %

Procedure:
8-Hydroxyquinoline-7-carboxylic acid (1.00 g) is suspended in 25 mL acetic acid. To this is added bromine (0.845 g) dropwise. The mixture is heated to reflux for 1 h, then poured into cold water. The resulting solid is collected, washed with water and dried to yield 1.43 g of the title product as a yellow solid.
Reaction SMILES: Cl.Cl.N[C:4]1[C:5]([NH2:18])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[CH3:10].[CH3:19][C:20]([CH:22]=[CH2:23])=O>C(O)C.[Cl-].[Zn+2].[Cl-]>[CH3:19][C:20]1[C:4]2[C:5](=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]4[C:12]=3[N:18]=[CH:5][CH:4]=[C:9]4[CH3:8])[CH:7]=[CH:8][C:9]=2[CH3:10])[N:18]=[CH:23][CH:22]=1
Reactant: Cc1ccc(-c2ccc(C)c(N)c2N)cc1
Reactant: C=CC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: Cc1ccnc2c(-c3ccc(C)c4c(C)ccnc34)ccc(C)c12
Yield: 48.1 %

Procedure:
To a solution of 110 g (0.386 mol) of diaminodimethylbiphenyl dihydrochloride, 418 g (1.55 mol) of ferric chloride hexahydrate, and 10.2 g (0.075 mol) zinc chloride in 500 ml of 95% ethanol heated to 50° C. was added 55.6 g (0.78 mol) of methylvinyl ketone over a 90 minute period. The solution was refluxed for 2 hours then allowed to stand over night. Most of the ethanol was removed at reduced pressure and the residue made basic with 25% sodium hydroxide. The basic solution was evaporated to dryness and the dark residue was extracted four times with 400 ml portions of benzene. The extracts were evaporated to dryness to give a dark brown residue. Extraction of the residue with 150 ml of ethanol resulted in a light brown solid which was sublimed (250° C, 0.1 torr) to give 29 g (24%) of 4,4',5,5'-tetramethyl-8,8'-biquinoline, mp 290°-295° C. Crystallization from benzene/hexane afforded an analytical sample, mp 292°-295° C.