Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([C:42]3[N:46]([CH3:47])[CH:45]=[N:44][CH:43]=3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([C:42]3[N:46]([CH3:47])[CH:45]=[N:44][CH:43]=3)[C:11]=12
Reactant: COc1ccc(Cn2nc(-c3cncn3C)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1-c1n[nH]c2nccc(Oc3ccc(NC(=O)c4ccnn(-c5ccc(F)cc5)c4=O)cc3F)c12
Temperature: 100 °C
Yield: 81.2 %

Procedure:
N-(4-(1-(4-Methoxybenzyl)-3-(1-methyl-1H-imidazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (0.201 g, 0.3043 mmol) and CF3COOH (2 mL) were charged in a 25 mL, single-neck, round-bottomed flask. The reaction mixture was stirred at 100° C. until the starting material had been consumed (7 days). Then the CF3COOH was removed under reduced pressure. The residue was partitioned between DCM (50 mL) and saturated NaHCO3 (50 mL). The phases were separated and the aqueous phase was extracted with DCM (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (133.5 mg, 81.18%). LRMS (APCI pos): >98% purity, 254 nm, m/e 541 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 9.31 (s, 1H), 8.46 (d, 1H), 8.39 (d, 1H), 8.26 (d, 1H), 8.10 (s, 1H), 8.07 (d, 1H), 7.68 (m, 2H), 7.62 (m, 2H), 7.42 (m, 2H), 6.46 (d, 1H), 4.07 (s, 3H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3([C:18]([NH:20][C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:24]5)=[O:19])[CH2:17][CH2:16]3)=[CH:14][C:9]=2[O:8][CH2:7]1.CN([CH:37]=[O:38])C>>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3([C:18]([NH:20][C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])=[C:24]5[CH:37]=[O:38])=[O:19])[CH2:17][CH2:16]3)=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
POCl3 (12 g, 80 mmol) was added dropwise to DMF (40 mL) held at −20° C. After the addition was complete, the reaction mixture was allowed to MUM to 0° C. and was stirred for 1 h. 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclopropanecarboxamide (3.0 g, 8.0 mmol) was added and the mixture was warmed to 25° C. After stirring for 30 minutes the reaction mixture was poured over ice and stirred for 2 h. The mixture was then heated at 100° C. for 30 min. The mixture was cooled and the solid precipitate was collected and washed with water. The solid was then dissolved in 200 mL dichloromethane and washed with 200 mL of a saturated aq. NaHCO3. The organics were dried over Na2SO4 and evaporated to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-formyl-1H-indol-5-yl)cyclopropane-carboxamide (2.0 g, 61%). ESI-MS m/z calc. 404.5. found 405.5 (M+1)+; retention time 3.30 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 10.39 (s, 1H), 8.72 (s, 1H), 8.21 (s, 1H), 7.35-7.31 (m, 2H), 7.04-7.03 (m, 1H), 6.97-6.90 (m, 2H), 6.03 (s, 2H), 1.53 (s, 9H), 1.42-1.39 (m, 2H), 1.05-1.03 (m, 2H).
Reaction SMILES: [CH:1]12[CH2:14][CH:7]([CH:8]3[CH:10]1[CH:9]3[C:11](O)=[O:12])[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[CH:1]12[CH2:14][CH:7]([CH:8]3[CH:10]1[CH:9]3[C:11]([Cl:18])=[O:12])[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1C2C3CC(C4CCCC43)C12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1C2C3CC(C4CCCC43)C12
Reaction time: 2 h

Procedure:
To a solution of tetracyclo[5.3.1.02,6.08,10]undecane-9-carboxylic acid (0.43 g, 2.2 mmol, Bennani, Y. L., et al., US2004077617) in dichloromethane (11 mL) was added oxalyl chloride 0.21 mL, 2.4 mmol) and a catalytic amount of dimethylformamide (2 drops). The mixture was stirred for 2 hours and then concentrated under reduced pressure to afford tetracyclo[5.3.1.02,6.08,10]undecane-9-carbonyl chloride. To a suspension of the product of Example 46A (0.30 g, 1.1 mmol) and triethylamine (0.46 mL, 3.3 mmol) in tetrahydrofuran (5 mL) was added a solution of tetracyclo[5.3.1.02,6.08,10]undecane-9-carbonyl chloride (0.23 g, 1.2 mmol) in tetrahydrofuran (1 mL). The mixture was heated at reflux for 14 hours, then cooled to room temperature and diluted with water and CH2Cl2. The layers were separated and tile organic extract was washed with water and brine, dried (Na2SO4), and concentrated. Purification by column chromatography (SiO2, 10-35% ethyl acetate/hexanes gradient) afforded the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 0.94 (d, J=10.5 Hz, 1 H), 1.22 (d, J=11.9 Hz, 1 H), 1.45-1.76 (m, 6 H), 1.87-1.98 (m, 2 H), 2.17 (s, 3 H), 2.20 (s, 3 H), 2.32 (s, 2 H), 2.35-2.43 (m, 3 H), 3.30 (s, 3 H), 3.70 (t, J=5.3 Hz, 2 H), 4.20-4.33 (m, 2 H); MS (DCI/NH3) m/z 361 (M+H)+. Anal. Calculated for C20H28N2O2S: C, 66.63; H, 7.83; N, 7.77. Found. C, 66.49; H, 7.91; N, 7.53.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8](OC)=[O:9])[C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23].[CH:24]1(B(O)O)[CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:24]1([C:2]2[CH:7]=[C:6]([CH2:8][OH:9])[C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH2:26][CH2:25]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cc(Br)c(-c2ccc(F)cc2F)cc1OC(C)C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(-c2ccc(F)cc2F)c(C2CC2)cc1CO
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of methyl 2-bromo-2′,4′-difluoro-5-isopropoxybiphenyl-4-carboxylate (4.90 g), cyclopropylboronic acid (3.28 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.783 g), a 2 M aqueous sodium carbonate solution (19.1 mL), tris(dibenzylideneacetone)dipalladium(0) (0.815 g), and toluene (50 mL) was stirred overnight at 100 C. The organic layer was separated from the reaction mixture, washed with saturated saline, and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate). A THF (50 mL) solution of this purified product was added to a THF (50 mL) suspension of lithium aluminum hydride (0.474 g) under ice cooling. After stirring at the same temperature as above for 30 minutes, water (0.5 mL) and a 15% aqueous sodium hydroxide solution (0.5 mL) were added thereto, and the mixture was stirred for 5 minutes. Water (1.5 mL) was further added to the reaction mixture, and the mixture was stirred for 30 minutes and then filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (3.97 g).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][N:14]=[C:13]([OH:16])[C:12]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].FC1C=C[C:28]([C:31]2[C:32](O)=[N:33]NC=2C2C=CC(S(C)(=O)=O)=CC=2)=[CH:27]C=1>O>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]3[O:16][C:31]([C:32]#[N:33])=[C:28]([CH3:27])[N:14]3[N:15]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: NS(=O)(=O)c1ccc(-c2[nH]nc(O)c2-c2ccc(F)cc2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2[nH]nc(O)c2-c2ccc(F)cc2)cc1
Solvent: O
Product: Cc1c(C#N)oc2c(-c3ccc(F)cc3)c(-c3ccc(S(N)(=O)=O)cc3)nn12

Procedure:
The desired compound was prepared according to the method of Example 54C, substituting 5-(4-(aminosulphonyl)phenyl)-4-(4-fluorophenyl)-3-hydroxypyrazole prepared according to the method of Example 55C in place of 4-(4-fluorophenyl)-3-hydroxy-5-(4-(methylsulphonyl)phenyl)pyrazole (yield: 35 mg, 13%). MP 231-232° C.; MS (APCI+) m/z 397 (M+H)+; (APCI−) m/z 395 (M−H)−, 431 (M+Cl)−; 1H NMR (300 MHz, DMSO-d6) δ2.65 (s, 3H), 7.30 (m, 4H), 7.47 (s, 2H), 7.67 (d, J=9 Hz, 2H), 7.88 (d, J=9 Hz, 2H); Anal. calc. for C19H13FN4O3S.1.5 H2O: C, 53.89; H, 3.80; N, 13.23. Found: C, 53.82; H, 3.93; N, 11.38.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=O)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>>[N:4]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH:29][C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[O:28])=[CH:23][CH:24]=3)[N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Nc1cccnc1
Reactant: O=C(O)Cc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Product: O=C(Cc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1)Nc1cccnc1
Yield: 44 %

Procedure:
The title compound was prepared by following the procedure of example 473 step 3 using 2-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)acetic acid and 3-aminopyridine. Yield 21 mg, 44% yield; HPLC: Rt=1.91 min; MS 462 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9](Cl)(=[O:11])[CH3:10].O>N1C=CC=CC=1>[C:9]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)(=[O:11])[CH3:10]
Reactant: Nc1ccc(Br)cn1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Br)cn1
Yield: 85 %

Procedure:
In 29 ml of pyridine was dissolved 1 g of 2-amino-5-bromopyridine which was then acetylated through reaction with 0.61 ml of acetyl chloride at room temperature for 15 hours with stirring. Following the addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer thus obtained was washed with brine. Dehydration, filtration and concentration under vacuum of the organic layer provided a solid which was then recrystallized in ethanol and hexane to obtain the title compound. 1.06 g. Yield 85%.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]1=[O:11].[Br:12]N1C(=O)CCC1=O>CN(C)C=O.ClCCl>[Br:12][C:4]1[C:3](=[O:11])[N:2]([CH3:1])[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1cc([N+](=O)[O-])ccc1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cc([N+](=O)[O-])cc(Br)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution containing 0.55 g (3.57 mmol) of 1-methyl-5-nitropyridin-2(1H)-one in 10 ml of N,N-dimethylformamide under a nitrogen atm. was added 0.76 g (4.27 mmol) of N-bromosuccinimide. The reaction was allowed to stir at 25° C. overnight. The reaction was diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 70% ethyl acetate/hexanes gave 0.60 g (72.15%) of product as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[N:16]=[C:10]([C:6]1[N:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=1)[CH3:11]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1cc(C)c(N)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Yield: 5.1 %

Procedure:
10 g of 2,6-diacetylpyridine (0.0613 mol), 9.54 g of 2-chloro-4,6-dimethylaniline (0.0613 mol) and 0.6 g of p-toluenesulfonic acid were heated under reflux on a water separator in 400 ml of methanol for 90 min. The solvent was distilled off completely and the residue was recrystallized twice from 50 ml of isopropanol. 0.92 g (0.0031 mol) of 1-{6-[1-(2-chloro-4,6-dimethyl-phenylimino)ethyl]pyridin-2-yl}ethanone was obtained in a yield of 5%.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:20]1[CH2:21][C:16]2[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])=[N:14][C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=3)=[N:18][C:17]=2[CH2:19]1)(=[O:38])[CH3:37]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(C)=O)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
To a stirred solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 7) (60 mg, 0.16 mmol) in DCM (1.5 mL) was added triethylamine (42 uL, 0.31 mmol) and acetyl chloride (71 uL, 0.31 mmol). The reaction mixture was stirred overnight at room temperature, concentrated in vacuo, then diluted with water and ethyl acetate. The organic layer was concentrated and purified by prep HPLC (low pH) to give an off-white solid (5.7 mg, 0.013 mmol, 9% yield).
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[C:9]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:18])[CH:2]=[CH2:3].[Cl:19]N1C(=O)CCC1=O>C1(C)C=CC=CC=1.[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[CH2:1]([N:4]1[C:8]2[C:9]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][CH:11]=[C:12]([Cl:19])[C:7]=2[NH:6][C:5]1=[O:18])[CH:2]=[CH2:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=CCn1c(=O)[nH]c2cccc(C(CC)CC)c21
Agent: [Zr+4]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C=CCn1c(=O)[nH]c2c(Cl)ccc(C(CC)CC)c21
Reaction time: 15 h
Yield: 38.3 %

Procedure:
To a mixture of 1-allyl-7-(1-ethylpropyl)-1,3-dihydro-2H-benzimidazol-2-one (22.0 g, 89.8 mmol) and zirconium chloride (1.05 g, 4.49 mmol) in toluene (300 mL) was added N-chlorosuccinimide (12.4 g, 92.5 g) portionwise at 0° C. After stirring for 15 hr, the mixture was concentrated in vacuo to give a residue which was partitioned in aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate. Combined organic layer was washed with aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in hot ethyl acetate. n-Hexane was then added and the solution was cooled down. Resulting precipitate was collected by filtration to afford the title compound (9.60 g, 34.4 mmol, 38%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])[CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5].[CH3:30][O:31][CH2:32][CH2:33][NH2:34].CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[O:20])[CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5]
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(-c3cccc(C(=O)O)c3)ccc12
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1cccc(-c2ccc3c(C)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a solution of 3-[2-(2,4-dichloro-benzoyl)-3-methyl-benzofuran-6-yl]-benzoic acid (40 mg, 0.09 mmol) in dichloromethane (2 mL) was added 2-methoxyethylamine (0.02 mL, 0.19 mmol), EDCI (20 mg, 0.1 mmol), DMAP (1 mg, 0.01 mmol), and N,N-diisopropylethylamine (0.02 mL, 0.1 mmol). The reaction mixture was stirred at rt overnight, then concentrated in vacuo and purified by prep-HPLC to afford the desired product (11 mg, 25%). 1H-NMR (CDCl3) δ 8.05 (t, J=1.8 Hz, 1H), 7.77-7.75 (m, 3H), 7.69 (m, 1H), 7.60 (dd, J=8.3, 1.0 Hz, 1H), 7.51 (m, 2H), 7.47 (m, 1H), 7.40 (ddd, J=8.2, 1.9, 0.5 Hz, 1H), 6.62 (t, J=4.5 Hz, 1H), 3.70 (m, 2H), 3.60 (m, 2H), 3.40 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[CH:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([NH2:1])[CH:13]=2)[CH:8]=[CH:9][N:10]=1
Reactant: O=[N+]([O-])c1ccc2ccncc2c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2ccncc2c1
Yield: 73.5 %

Procedure:
7-Nitroisoquinoline (1.62 g, 9.25 mmol) in ethanol (150 ml) was hydrogenated on a Paar Hydrogenator Apparatus over 5% palladium on carbon (0.2 g) as catalyst for 3 h at 50 psi The reaction mixture was filtered and the solvent removed at reduced pressure. Recrystallization of the solid from ethanol (3 ml) gave isoquinolin-7-amine (0.98 g) as a tan solid. MS 145 (M+H), NMR (CDCl3) 9.02 (s, 1H), 8.29 (d, 1H), 7.63 (d, 1H), 7.47 (d, 1H),7.13 (dd, H), 7.03 (d, 1H), 4.00 (broad, 2H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([CH3:10])([CH3:9])[C:4](=[O:8])[CH2:5][C:6]#[N:7].S(O)(O)(=O)=O.[NH2:18]O.C(=O)([O-])O.[Na+].Cl>CO.O>[F:1][C:2]([F:11])([F:12])[C:3]([C:4]1[O:8][N:7]=[C:6]([NH2:18])[CH:5]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(C(=O)CC#N)C(F)(F)F
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CC(C)(c1cc(N)no1)C(F)(F)F
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
A mixture of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (3 g, 16:76 mmol), hydroxylamine sulfate (3.30 g, 20.11 mmol) and sodium hydrogencarbonate (3.52 g, 41.90 mmol) in a mixture of 10% methanol in water (60 mL), was heated at 65° C. for 15 h. After cooling to rt, a further 30 mL of 10% methanol in water was added, and the mixture was divided into 9×10 mL batches. Each batch was adjusted to pH 1 with concentrated hydrochloric acid and each placed into a 20 mL volume microwave vial fitted with a stirrer bar. After sealing, each batch was placed in a Biotage Microwave Synthesizer and heated (with stirring) at 140° C. for 5 min (maximum internal pressure attained was 7 bar). Each batch was cooled and neutralized with saturated aqueous sodium hydrogencarbonate solution. All processed batches were combined and concentrated in vacuo and the aqueous solution extracted with 10% isopropanol in chloroform (3×150 mL). The combined organic layers were washed with brine (200 mL), separated, dried over MgSO4 and filtered. Concentration in vacuo afforded 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (2.34 g, 71%) as a light yellow solid which taken on without further purification. 1H NMR (300 MHz, CDCl3) δ 5.80 (s, 1H), 3.98 (brs, 2H), 1.53 (s, 6H); LC-MS (ESI) m/z 195 (M+H)+.
Reaction SMILES: CO[C:3]1C=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[N:31]1C=CC=C(C=O)C=1>>[N:31]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])[CH:29]=1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: O=Cc1cccnc1
Product: O=C(NCCNCc1cccnc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 3-pyridinecarboxaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 393 (M+H) 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.51 (1H, d, J=2.20 Hz) 8.39 (1H, dd, J=4.91, 1.54 Hz) 8.00 (1H, d, J=5.66 Hz) 7.80 (1H, dt, J=7.83, 1.87 Hz) 7.64 (1H, d, J=5.42 Hz) 7.47 (1H, d, J=5.47 Hz) 7.33 (1H, dd, J=7.83, 4.91 Hz) 7.24 (1H, d, J=3.56 Hz) 6.87 (1H, d, J=5.66 Hz) 6.55 (1H, d, J=3.56 Hz) 3.80 (2H, s) 3.51 (2H, t, J=6.30 Hz) 2.79 (2H, t, J=6.22 Hz)
Reaction SMILES: P(=O)(O)(O)O.[Cl:6][CH:7]([Cl:23])[C:8]([NH:10][CH:11]([C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14])O)=[O:9]>O>[Cl:6][CH:7]([Cl:23])[C:8]([NH:10][CH2:11][C@H:13]([OH:14])[C@@H:15]([OH:16])[C@H:17]([OH:18])[C:19](=[O:20])[CH2:21][OH:22])=[O:9]
Reactant: O=C(NC(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)C(Cl)Cl
Agent: O=P(O)(O)O
Solvent: O
Product: O=C(NC[C@H](O)[C@@H](O)[C@H](O)C(=O)CO)C(Cl)Cl
Reaction time: 10 h

Procedure:
To a suspension of 40 g of Gluconobacter oxidans ssp. suboxidans (DSM 50049) in 1 l of tap water, brought to pH 4.5 with phosphoric acid, are added at 32° C. and 700 rpm with venting of 3 l of air/hour 20 g of N-dichloroacetylaminosorbitol. The reaction has ended after 10 hours, and the cells are then centrifuged off, washed twice with 100 ml of methanol each time and discarded. The methanol extracts are combined with the aqueous supernatant and concentrated to dryness in vacuo.
Reaction SMILES: Cl.[CH2:2]([C:8]1[N:9]=[C:10]([NH2:13])[NH:11][CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]#[CH:7].[N:14]([CH2:17][C:18]([CH3:26])=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N+:15]=[N-:16]>>[CH3:26][C:18](=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][N:14]1[CH:7]=[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][C:8]2[N:9]=[C:10]([NH2:13])[NH:11][CH:12]=2)[N:16]=[N:15]1
Reactant: C#CCCCCc1c[nH]c(N)n1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(CCCCc2c[nH]c(N)n2)nn1
Yield: 88 %

Procedure:
4-Hex-5-ynyl-1H-imidazol-2-ylamine hydrochloride (0.089 g, 0.4.47 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.085 g, 0.491 mmol) following the general procedure for click reactions outlined above to produce 4-{4-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-butyl}-1H-imidazol-2-ylamine (0.132 g, 79%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.36 (s, 1H), 7.03 (m, 5H), 6.49 (s, 1H), 6.25 (s, 1H), 5.05 (s, 2H), δ 2.67 (t, 2H), δ 2.73 (t, 2H), δ 1.56 (s, 3H), δ 1.42 (m, 4H) ppm; 13C (75 MHz, CD3O) δ 147.3, 144.7, 136.4, 132.7, 129.9, 128.9, 128.6, 128.5, 128.3, 127.5, 127.2, 126.9, 108.7, 61.2, 27.4, 27.3, 23.8, 22.8, 14.8 ppm; HRMS (ESI) calcd for C19H24N6 (M+) 336.2135. found 336.2134.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([C:21](=[O:23])[NH2:22])=[CH:19][C:18]([N+:24]([O-])=O)=[C:17]([CH3:27])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([C:21](=[O:23])[NH2:22])=[CH:19][C:18]([NH2:24])=[C:17]([CH3:27])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(N)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(N)=O)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-5-carbamoyl-2-methylnitrobenzene (4.7 g) in methanol (120 ml) was added palladium on carbon (0.5 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered. The filtrate was concentrated in vacuo to give the desired compound (4.0 g, yield 93%) as a yellow amorphous solid.