Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19][N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2nccs2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
N-Boc-piperazine (1.42 g, 7.6 mmol, 1.1 eq) was dissolved in 1,2-DCE (20 mL). To this solution, 2-thiazolecarboxaldehyde (0.780 g, 6.91 mmol, 1 eq) in 1,2-DCE (4 mL) was added followed by the portionwise addition of sodium triacetoxyborohydride (2.05 g, 9.68 mmol, 1.4 eq). The mixture was stirred at room temperature for 3 h and then washed with an aqueous saturated solution of NaHCO3. The organic layer was dried (MgSO4), the solvent removed in vacuo and the crude product was purified by column chromatography on a Biotage SP1 system (hexanes/EtOAc; v/v 6:4) to give the title compound (1.95 g, 100%); 1H-NMR (500 MHz, CDCl3): δ 1.47 (s, 9H, C(CH3)3), 2.54 (t, 4H, J=4.7 Hz, piperazine N(CH2)2), 3.48 (t, 4H, J=5.0 Hz, piperazine N(CH2)2), 3.89 (s, 2H, NCH2), 7.30 (d, J=3.5 Hz, 1H, thiazole 5-H), 7.72 (d, J=3.5 Hz, 1H, thiazole 4-H); LC (Method B)-MS (ESI, m/z): Rt=2.84 min—306 [(M+Na)+, 100%].
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:21]Br>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:21][CH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reaction time: 0.5 h
Yield: 995.8 %

Procedure:
13.2 Grams (0.006 mole) of tert-butyl 4-methylbenzoate, 0.3 g (0.0012 mole) of benzoyl peroxide and 6 g (0.006 mole) of sodium carbonate were suspended in 100 ml of carbon tetrachloride, and 9.6 g (0.06 mole) of bromine was added dropwise at 50° C. over 30 minutes with stirring. After completion of the addition, reaction was continued for further 30 minutes. The reaction solution was then cooled and filtered to remove carbon tetrachloride-insoluble matters. Carbon tetrachloride was then removed by evaporation under reduced pressure to obtain 16.2 g of tert-butyl 4-bromomethylbenzoate as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1.[Br:19][C:20]1[C:25]([F:26])=[CH:24][C:23]([S:27](Cl)(=[O:29])=[O:28])=[C:22]([F:31])[CH:21]=1>>[Br:19][C:20]1[C:25]([F:26])=[CH:24][C:23]([S:27]([NH:18][C:15]2[S:16][CH:17]=[C:13]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=3[Cl:12])[N:14]=2)(=[O:28])=[O:29])=[C:22]([F:31])[CH:21]=1
Reactant: Nc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cs1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Product: O=S(=O)(Nc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cs1)c1cc(F)c(Br)cc1F

Procedure:
The title compound was prepared 4-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (85 mg) and 4-bromo-2,5-difluorobenzenesulfonyl chloride (79 mg) as described in the synthetic METHOD B to give a white solid (38.2 mg) with purity >90%: MS (pos) m/z 567.2, 569.2, 571.2; MS (neg) m/z 565.5, 567.5, 569.5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[OH:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[CH3:32].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][S:28]([C:25]2[CH:26]=[CH:27][C:22]([OH:21])=[C:23]([CH3:32])[CH:24]=2)(=[O:30])=[O:29])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1O
Reactant: COc1ncc(Br)cc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncc(Br)cc1NS(=O)(=O)c1ccc(O)c(C)c1
Reaction time: 1 h
Yield: 11.6 %

Procedure:
5-Bromo-2-methoxypyridin-3-amine (1.08 g, 5.32 mmol) was dissolved in THF (2.5 ml) and cooled with an ice bath. A solution of sodium bis(trimethylsilyl)amide (1 M in THF, 8 ml, 8 mmol) was added dropwise. Ten minutes later, 4-hydroxy-3-methylbenzene-1-sulfonyl chloride (1.65 g, 5.91 mmol, prepared according to JP 47015818 B4 19720511) in THF (3 ml) was added and the reaction mixture was allowed to reach room temperature. After stirring for 1 h, a saturated solution of sodium bicarbonate was added dropwise and the reaction mixture was extracted with dichloromethane (×3). The organic phase was dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The resulting residue was purified by reverse phase chromatography using SP1® Purification System (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give 230 mg (12% yield) of the title compound. Purity 100%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1(/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([O:33][CH2:34][CH2:35][CH2:36][C:37]#[CH:38])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C>C1COCC1.[Cu]I.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>[C:1]([O:5][C:6]([NH:8][C:9]1(/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([C:38]#[C:37][CH2:36][CH2:35][CH2:34][O:33][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(/C=C/c2ccc(Br)cc2)COC(C)(C)OC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(/C=C/c2ccc(C#CCCCOCc3ccccc3)cc2)COC(C)(C)OC1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
To a solution of 17 (0.21 g, 0.51 mmol) and 5-benzyloxy-1-pentyne (133 mg, 0.77 mmol) in N,N-diisopropylethylamine (1 mL, 5.7 mmol) and dry THF (5 mL) were added CuI (9.7 mg, 51 μmol) and tetrakis(triphenylphosphine)palladium(0) (29.5 mg, 25.5 μmol) under nitrogen. The mixture was heated at reflux under nitrogen for one day, and then was cooled to room temperature and filtered through a short pad of silica gel to remove insoluble and very polar components in the mixture. The filtrate was concentrated and dissolved in CH2Cl2 (50 mL). The solution was washed with water (2×20 mL) and brine (2×20 mL), and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified by column chromatography (hexanes/EtOAc 20:1 to 6:1) to give 18 (0.14 g, 53%). 1H NMR δ 7.43-7.19 (m, 4H), 6.49 (d, 1H, J=16.4 Hz), 6.21 (d, 1H, J=16.4 Hz), 5.43 (s, 1H), 4.50 (s, 2H), 3.98 (d, 2H, J=11.2 Hz), 3.87 (d, 2H, J=11.2 Hz), 3.59 (t, 2H, J=6.0 Hz), 2.53 (t, 2H, J=6.8 Hz), 1.89 (m, 2H), 1.45 (s, 15H); 13C NMR δ 154.4, 138.1, 135.5, 131.3, 129.3, 127.9, 127.2, 127.1, 125.9, 122.8, 97.8, 90.1, 80.6, 79.0, 72.5, 68.3, 65.6, 52.7, 28.5, 28.0, 27.1, 19.3, 15.9. HRMS m/z: calcd for C31H39NNaO5 (MNa+), 528.2720; found, 528.2727.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([CH3:34])=[C:27]([CH:33]=4)[C:28]([O:30]CC)=[O:29])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>CC(C)(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([CH3:34])=[C:27]([CH:33]=4)[C:28]([OH:30])=[O:29])[CH2:16]3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(CO[C@H]2CCC[C@@H](OCc3coc(-c4ccc(F)cc4)n3)C2)ccc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1ccc(CO[C@H]2CCC[C@@H](OCc3coc(-c4ccc(F)cc4)n3)C2)cc1C(=O)O
Temperature: 85 °C

Procedure:
A suspension of 47 mg of ethyl rac-cis-5-{3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]cyclohexyloxymethyl}-2-methylbenzoate 24, 2 ml of 1,1-dimethylethanol and 50% (w/w) potassium hydroxide was heated at 85° C. (oil bath) for 2 hours. The pH was adjusted to 3 using dilute hydrochloric acid and the mixture was extracted twice with MTBE. The extracts were dried over magnesium sulfate, filtered and concentrated on a rotary evaporator, and the product was then purified by chromatography. This gave the product 20 of molecular weight 439.49 (C25H26FNO5); MS (ESI): 440 (M+H+).
Reaction SMILES: [OH-].[Na+].[CH3:3][C@@H:4]1[CH2:9][O:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:15]=[C:14]([C:16]2([S:19]([CH3:22])(=[NH:21])=[O:20])[CH2:18][CH2:17]2)[N:13]=[C:12]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[N:29](S(C4C=CC(C)=CC=4)(=O)=O)[CH:30]=[CH:31][C:24]=23)[N:11]=1.O.Cl>COCCOC>[CH3:3][C@@H:4]1[CH2:9][O:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:15]=[C:14]([C:16]2([S:19]([CH3:22])(=[NH:21])=[O:20])[CH2:18][CH2:17]2)[N:13]=[C:12]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[NH:29][CH:30]=[CH:31][C:24]=23)[N:11]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4nc(N5CCOC[C@H]5C)cc(C5(S(C)(=N)=O)CC5)n4)ccnc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: C[C@@H]1COCCN1c1cc(C2(S(C)(=N)=O)CC2)nc(-c2ccnc3[nH]ccc23)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
Sodium hydroxide, 2M aqueous solution (9.95 ml, 19.90 mmol) was added to (3R)-3-methyl-4-(6-(1-(S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine (6.44 g, 11.37 mmol) in DME (100 ml)/water (25.00 ml). The resulting solution was stirred at 50° C. for 18 hours. Further NaOH, 2M aqueous solution (18 ml, 36.00 mmol) was added and the mixture was stirred at 50° C. for a further 3 days. The reaction mixture was acidified with 2M HCl (˜22 ml) to pH5. The reaction mixture was evaporated and the residue was dissolved in DCM (250 ml) and washed with water (200 ml). The organic layer was dried over MgSO4, filtered and then evaporated to approximately 50 ml in volume. The solution was purified by flash chromatography on silica, eluting with a gradient of 0 to 7% MeOH in DCM. Pure fractions were evaporated to afford 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (2.440 g, 52%); 1H NMR (400 MHz, DMSO-d6) 1.27 (3H, d), 1.42 (1H, dd), 1.47-1.58 (2H, m), 1.68-1.80 (1H, m), 3.10 (3H, s), 3.24-3.31 (1H, m), 3.51 (1H, t), 3.66 (1H, dd), 3.80 (1H, d), 3.83-3.88 (1H, m), 4.00 (1H, dd), 4.20 (1H, s), 4.57 (1H, s), 6.99 (1H, d), 7.22 (1H, dd), 7.53-7.63 (1H, m), 7.94 (1H, d), 8.34 (1H, t), 11.80 (1H, s); m/z: (ES+) MH+, 413.47.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:15](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:15][O:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(NC(=O)C(C)C)ccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.1 %

Procedure:
N-(3-hydroxy-4-methyl-phenyl)-isobutyramide (6.48 g, 33.5 mmol) was dissolved in 40 mL of acetone, potassium carbonate (13.9 g, 100.5 mmol) was added followed by methyl iodide (14.3 g, 100.5 mmol). The mixture was stirred at room temperature for about 3 days. The solution was filtered and evaporated under reduced pressure to give 6.6 g of N-(3-methoxy-4-methyl-phenyl)-isobutyramide (95%). 1H NMR (300 MHz, CDCl3, ppm): δ: 1.26 (d, J=7.03 Hz, 6 H), 2.17 (s, 3 H), 2.49 (m, 1 H), 3.83 (s, 3 H), 6.71 (dd, J=2.05 Hz, 8.21 Hz, 1 H), 7.02 (d, J=7.91 Hz, 1 H), 7.11 (bs, 1 H), 7.47 (d, J=1.76 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH3:3].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[OH:14][C:15]1[C:10]2[C:8](=[CH:7][CH:6]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:11]=2)[N:9]=[CH:22][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCOc1ccc(N)cc1
Product: CCCOc1ccc2ncc(C(=O)OCC)c(O)c2c1

Procedure:
Prepared as in Example 1c from 4-propoxyaniline and diethyl 2-(ethoxymethylene)malonate as a white solid (65%). 1H NMR (400 MHz, DMSO-d6) δ 0.98 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.72-1.77 (m; 2H), 3.98 (t, J=6.0 Hz, 2H), 4.16-4.21 (m, 2H), 6.97-6.99 (m, 1H), 7.53-7.56 (m, 2H), 8.47 (d, J=5.2 Hz, 1H), 12.27 (s, 1H). MS 276 (MH+).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([NH:10][C:11]3[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=[C:15]([Br:17])[CH:16]=3)[CH:6]=2)[CH2:2]1.[CH2:20]=O.[BH4-].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[Br:17][C:15]1[CH:16]=[C:11]([NH:10][C:7]2[CH:6]=[C:5]([CH:3]3[CH2:4][N:1]([CH3:20])[CH2:2]3)[NH:9][N:8]=2)[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=1
Reactant: Cn1cc(Br)cc(Nc2cc(C3CNC3)[nH]n2)c1=O
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CC(c2cc(Nc3cc(Br)cn(C)c3=O)n[nH]2)C1
Yield: 50 %

Procedure:
To a solution of 3-(5-(azetidin-3-yl)-1H-pyrazol-3-ylamino)-5-bromo-1-methylpyridin-2(1H)-one 168a (crude, 2.36 mmol) in methanol (30 mL) and acetic acid (5 mL) at 0° C., was added CH2O (30% wt in H2O) (12 g, 120 mmol), followed by the addition of NaBH4 (1.8 g, 47.2 mmol) in small portions over the period of 1 h at 0° C. After the reaction was finished, the mixture was adjusted to pH>7 with 2N aq. NaOH. It was then extracted with methylene chloride (60 mL×3), dried over Na2SO4 and, concentrated to give a yellow solid, which was further purified on flash column eluting with 50:1 methylene chloride/methanol containing 0.5% triethylamine to afford 168b as a yellow solid (50%, two steps).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([OH:16])(=[O:15])[CH2:13][OH:14]>C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:14][CH2:13][C:12]([OH:16])=[O:15])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: O=C(O)CO
Solvent: CCO
Product: O=C(O)COc1ccc(Br)cc1[N+](=O)[O-]
Yield: 70 %

Procedure:
The reaction between 28.1 g of 2,5-dibromonitrobenzene and 7.6 g of glycolic acid was carried out by heating in a 70% aqueous ethanol solution under alkaline conditions to give 19.3 g of 4-bromo-2-nitrophenoxyacetic acid as precipitated crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[OH:26]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1cc2nccc(Oc3ccc4ccccc4c3)c2cc1OC
Temperature: 180 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (45 mg) and commercially available β-naphthol (144 mg) were mixed and stirred at 180° C. for 2 hours, and the reaction mixture was then purified in the same manner as described in Example 2 to obtain 45 mg of the title compound (yield: 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][C:40]=2[CH3:41])[CH:10]2[CH2:15][CH2:14][N:13]([C@H:16]([CH3:33])[CH2:17][CH2:18][NH:19][C:20](=[O:32])[C:21]3[C:29]([CH3:30])=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][C:22]=3[CH3:31])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C[CH2:43][N:44]=[C:45]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CNC.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][C:40]=2[CH3:41])[CH:10]2[CH2:15][CH2:14][N:13]([C@H:16]([CH3:33])[CH2:17][CH2:18][NH:19][C:20](=[O:32])[C:21]3[C:22]([CH3:31])=[CH:23][C:24]([C:25]([N:44]([CH3:45])[CH3:43])=[O:27])=[CH:28][C:29]=3[CH3:30])[CH2:12][CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(C(=O)O)cc3C)CC2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(C(=O)N(C)C)cc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
N-((R)-3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-terephthalamic acid (0.070 g, 0.12 mmol), EDCI (0.026 g, 0.13 mmol) and HOBT (0.019 g, 0.13 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added dimethylamine (2M in THF) (94 μL, 0.18 mmol) followed by DIPEA (33 μL, 0.18 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 93:5:2, v/v/v) afforded N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,6, N′,N′-tetramethyl-terephthalamide (0.028 g, 38%) as a white foam. 1H NMR (CDCl3) δ 0.99 (d, 3H, J=6.0 Hz), 1.26 (m, 1H), 1.37 (m, 1H), 1.62 (m, 2H), 1.78-1.85 (m, 3H), 2.14 (br t, 1H), 2.33 (s+m, 8H), 2.47 (br t, 1H), 2.74 (m, 3H), 2.94 (s, 3H), 3.06 (s, 3H), 3.32-3.46 (m, 2H), 3.66 (m, 1H), 3.72 (s, 3H), 4.10 (s, 2H), 6.66 (d, 2H, J=9.0 Hz), 6.73 (d, 2H, J=9.0 Hz), 6.93 (br t, 1H), 7.02 (d, 1H, J=3.0 Hz), 7.05 (s, 2H), 8.29 (s, 1H), 8.31 (d, 1H, J=6.0 Hz). 13C NMR (CDCl3) δ 13.8, 19.2, 19.6, 29.9, 30.7, 32.8, 39.0, 39.9, 44.8, 47.6, 51.8, 56.0, 58.8, 58.9, 114.8, 119.4, 125.3, 126.4, 133.8, 134.8, 143.0, 145.4, 148.3, 149.6. ES-MS m/z 586 (M+H), 608 (M+Na). Anal. Calcd. for C35H47N5O3.0.2 CH2Cl2: C, 70.14; H, 7.93; N, 11.62. Found: C, 70.06; H, 8.03; N, 11.54.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([N:22]([CH3:24])[CH3:23])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.O.O.O.O.O.O.O.S([O-])(O)(=O)=O.[Na+].CO>O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([N:22]([CH3:24])[CH3:23])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CN(C)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)c2ccccc12
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)c1ccc(N=Nc2ccc(N)cc2)c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 15 g of 1-(4-nitro-phenylazo)-4-(dimethylamino)naphtalene, 75 ml sodiumhydrogen sulphate nonahydrate (50% wt in water) and 80 ml of methanol was heated at reflux for 3 h. The reaction mixture was then cooled to room temperature and poured into 300 ml of water. The brownish precipitate was filtered off, washed with water (200 ml) and cold methanol-water (100 ml/100 ml) to give 12 g of nearly pure 1-(4-amino-phenylazo)-4-(dimethylamino)naphtalene as a brownish solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=3[N:15]=2)[C:7]([NH:24][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1cccc2oc(-c3cc([N+](=O)[O-])ccc3F)nc12
Reactant: CCCN
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2c(C)cccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-4-methylbenzoxazole (218 mg, 0.8 mmol) and propylamine (328 μL, 4.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][N:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1>ClCCCl.O=[Mn]=O>[N:1]1([C:6]2[CH:11]=[C:10]([CH:9]=[CH:8][N:7]=2)[CH:12]=[O:13])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: OCc1ccnc(-n2cccn2)c1
Agent: O=[Mn]=O
Solvent: ClCCCl
Product: O=Cc1ccnc(-n2cccn2)c1
Temperature: 25 °C

Procedure:
A solution of (2-(1H-pyrazol-1-yl)pyridin-4-yl)methanol (217 mg; 1.23 mmol) in anh. DCE (4 ml) was treated with MnO2 (861 mg; 9.91 mmol), and the resulting mixture was stirred at reflux, under nitrogen, for 1.5 h. After cooling to rt, the resulting reaction mixture was filtered over celite, and the separated solids were washed with DCM. The filtrate was concentrated to dryness under reduced pressure giving 2-(1H-pyrazol-1-yl)isonicotinaldehyde as a colorless solid. LC-MS (conditions C): tR=0.70 min.; [M+H]+: 173.76 g/mol.
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][C:17]([CH3:25])=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N+:14]=[N-:15]>>[ClH:1].[CH3:25][C:17](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][N:13]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]2[NH:8][C:9]([NH2:12])=[N:10][CH:11]=2)[N:15]=[N:14]1
Reactant: C#CCCCc1c[nH]c(N)n1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(CCCc2cnc(N)[nH]2)nn1
Yield: 41 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.096 g, 0.517 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.110 g, 0.635 mmol) following the general procedure for click reactions outlined above to produce 5-{3-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1H-imidazol-2-ylamine hydrochloride (0.076, 41%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.65 (s, 1H), δ 7.14-7.04 (m, 5H), δ 6.35 (s, 1H), δ 6.28 (s, 1H), δ 4.94 (s, 2H), δ 2.57 (t, 2H), δ 2.34 (t, 2H), δ 1.75 (m, 2H), δ 1.57 (s, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.5, 136.9, 132.5, 129.7, 128.8, 128.6, 128.4, 128.3, 128.2, 126.9, 122.5, 109.2, 58.1, 61.9, 28.0, 24.3, 24.3, 24.1, 14.6 ppm; HRMS (ESI) calcd for C18H22N6 (M+) 323.1978. found 323.1984.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH2:16][CH3:17])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[CH:18]1([NH:23][C:2]2[C:3]3[N:4]([C:12]([CH2:15][CH2:16][CH3:17])=[N:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCCc1nnc2c(Cl)nc3ccccc3n12
Reactant: NC1CCCC1
Solvent: CN(C)C=O
Product: CCCc1nnc2c(NC3CCCC3)nc3ccccc3n12
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.9 %

Procedure:
A reaction mixture of 4-chloro-1-propyl[1,2,4]triazolo[4,3-a]quinoxaline (1.0 g; 0.004 mole) and cyclopentanamine (1.0 g; 0.012 mole) in 15 ml of DMF was stirred at room temperature for 20 hours. The precipitated solid was filtered, washed with ethanol, and dried affording 0.98 g (82%) of N-cyclopentyl-1-propyl[1,2,4]triazolo[4,3-a]quinoxalin-4-amine having a mp of 186°-188° C.