Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([N:13]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]2)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[NH2:26][NH2:27]>C(O)C(C)C>[F:10][C:9]([F:12])([F:11])[C@H:8]([N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]1)[C:5]1[CH:6]=[N:7][C:2]([NH:26][NH2:27])=[CH:3][CH:4]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C1
Solvent: CC(C)CO
Product: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Temperature: 25 °C
Yield: 100.6 %

Procedure:
A solution of tert-butyl (S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (68.5 g, 180.4 mmol) and anhydrous hydrazine (56.61 mL, 1804 mmol) in i-BuOH (80 mL) was stirred at 106° C. in a sealed flask for 16 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was partitioned in ethyl acetate (800 mL) and water (100 mL). The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (68.1 g, 95.6%) as white foam solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexane/10% (1:1 MeOH/EtOH) at 1.0 mL/min, >99% d.e. (R,S)-diastereomer).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]([O:15]CC3C=CC=CC=3)=[O:14])[CH:12]=1)[NH:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25]CC1C=CC=CC=1)=[O:24])#[N:2].[OH-:33].[Na+].Cl>C(O)C.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]([OH:15])=[O:14])[CH:12]=1)[NH:9][CH2:8][CH2:7][CH:6]2[C:23]([OH:25])=[O:24])(=[O:33])[NH2:2]
Reactant: [OH-]
Reactant: N#Cc1cc(C(=O)OCc2ccccc2)c2c(c1)C(C(=O)OCc1ccccc1)CCN2
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1cc(C(=O)O)c2c(c1)C(C(=O)O)CCN2
Yield: 60.4 %

Procedure:
A mixture of dibenzyl 6-cyano-1,2,3,4-tetrahydroquinoline-4.8 dicarboxylate (5 g), sodium hydroxide (4 g) in ethanol (50 ml) and water (500 ml) was refluxed for 18 hours. After cooling, water (100 ml) was added thereto. The mixture was adjusted to pH 2 by the addition of concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound (1.87 g, 60.5%) which was recrystallized from DMF-ethanol to white crystals, mp 265° C.-266 ° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Reactant: OB(O)c1ccccc1
Product: CCCNC(=O)c1nnc2c(-c3ccccc3)c(F)ccc2c1N
Yield: 25.7 %

Procedure:
Using method F, 4-amino-7-fluoro-8-iodo-N-propyl-cinnoline-3-carboxamide (291 mg, 0.78 mmol) and phenylboronic acid (379 mg, 3.11 mmol) were reacted (reflux 4 hours) to afford the title compound (65 mg, 26% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.52 (bs, 1H), 7.89 (dd, J=9.2, 4.6 Hz, 1H), 7.42-7.60 (m, 6H), 3.45 (apparent q, J=6.6 Hz, 2H), 1.65 (apparent sextet, J=7.2 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). MS APCI, m/z=325 (M+H) HPLC 1.92 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([C:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH2:15][C:14]=3[CH:18]=2)=[O:9])[CH:7]=1.[BH4-].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH2:15][C:14]=3[CH:18]=2)[OH:9])[CH:7]=1
Reactant: O=C(c1ccc2c(c1)CCO2)c1cc(Br)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Product: OC(c1ccc2c(c1)CCO2)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
(5-bromo-2-chloro-phenyl)-(2,3-dihydrobenzofuran-5-yl)methanone 5b (10.47 g, 31.0 mmol) was dissolved in 100 mL of mixed solution (THF and MeOH, v:v=1:1) and cooled to 0° C., followed by addition of sodium borohydride (2.35 g, 62.0 mmol) in batch. The reaction mixture was stirred for 30 minutes at 0° C. Thereafter, the reaction mixture was concentrated under reduced pressure after 20 mL acetone were added. The resulting residue was dissolved in 250 mL ethyl acetate and partitioned. The organic extract was washed with water (100 mL×2), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (5-bromo-2-chloro-phenyl)-(2,3-dihydrobenzofuran-5-yl)methanol 5c (10.5 g, pale yellow grease), yield: 99.7%. 1H NMR (400 MHz, CDCl3): δ 7.88 (d, 1H), 7.34 (dd, 1H), 7.18 (d, 1H), 7.16 (s, 1H), 7.11 (dd, 1H), 6.73 (d, 1H), 6.05 (s, 1H), 4.56 (t, 2H), 3.18 (t, 2H), 2.27 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>Br>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: COc1ccc(Cl)c(-n2ccnc2)c1
Agent: Br
Product: Oc1ccc(Cl)c(-n2ccnc2)c1
Yield: 95.1 %

Procedure:
1-chloro-2-(1H-imidazol-1-yl)-4-methoxybenzene (7.5 g, 0.036 m) was mixed with 40 ml 48% hydrobromic acid. The solution was distilled until the head temperature reached 120° C. and the reaction was then heated at reflux for two hours. The reaction was concentrated under reduced pressure. The residue was triturated in isopropyl alcohol-isopropyl ether and the solid was collected. The solid was dissolved in water and poured into a saturated solution of sodium bicarbonate. The solid was collected and rinsed with water, isopropyl alcohol-isopropyl ether, and isopropyl ether to give 6.65 g of solid. A small portion of this solid was recrystallized by dissolving in methanol-isopropyl alcohol, treated with charcoal, filtered, and evaporated to remove most of the methanol. A white solid was obtained which was dried at 70° C. under vacuum overnight, mp 204°-205° C.
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[O+]=1.[CH2:30]([NH2:44])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].C(N(CC)CC)C.N>C(Cl)(Cl)Cl.C(O)(=O)C>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N+:44]=1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCCCCCc1cc(C)cc(C)[o+]1
Reactant: CCCCCCCCCCCCCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCc1cc(C)cc(C)[n+]1CCCCCCCCCCCCCC
Yield: 26 %

Procedure:
2,4-Dimethyl-6-tetradecylpyrylium hexafluorophosphate (10, n=13, 1.5 g, 3.33 mmol) was dissolved in 15 mL chloroform and treated with 0.71 g (3.33 mmol) of tetradecylamine (11, m=13). Triethylamine (0.5 mL) was then added to the brown-yellow solution, which was subsequently refluxed for 5 minutes, treated with 1 mL of acetic acid and refluxed for another hour. The homogenous mixture was treated with 0.2 mL of concentrated aqueous ammonia, refluxed for 5 min., cooled and extracted with 10 mL of water to solve the precipitated inorganic salts. After separation, the chloroform layer was dried on sodium sulfate and evaporated to dryness to yield 2.00 g of crude product. This product was purified by means of flash chromatography (Silica gel 60) using a 20/80 methanol/chloroform (v/v) mobile phase to yield 0.56 g (22%) of pure product, which was recrystallized from ethanol to yield 0.54 g of crystalline compound (12, m=n=13).
Reaction SMILES: C([C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:24]=[N:23][C:22]=1OC)(C)C.[OH-:35].[Na+]>C(O)C>[CH2:8]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:21]1[C:22](=[O:35])[NH:23][N:24]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[CH:26]=1)[CH:9]([CH3:13])[CH3:10]
Reactant: [OH-]
Reactant: COc1nnc(-c2ccncc2)cc1-c1[nH]c2cc(CN3CCN(C)CC3)ccc2c1C(C)C
Agent: [Na+]
Solvent: CCO
Product: CC(C)Cc1c(-c2cc(-c3ccncc3)n[nH]c2=O)[nH]c2cc(CN3CCN(C)CC3)ccc12
Temperature: 150 °C
Yield: 41 %

Procedure:
98 mg 3-Isopropyl-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-6-(4-methyl-piperazin-1-ylmethyl)-1H-indole are dissolved in 1.23 mL ethanol. 1.18 mL 1 N aqueous sodium hydroxide are added. The reaction mixture is heated to 150° C. in a microwave oven for 15 minutes. Purification by HPLC affords 39 mg (41%) 4-[3-isobutyl-6-(4-methyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-6-pyridin-4-yl-2H-pyridazin-3-one as its trifluoroacetate salt.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:14][CH2:15][CH3:16].[Na+].O>C(O)C>[CH2:15]([O:14][C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:16]
Reactant: CC[O-]
Reactant: CCc1cc(Cl)nn2c(N)nnc12
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1cc(CC)c2nnc(N)n2n1
Temperature: 45 °C
Yield: 91.3 %

Procedure:
6-Chloro-8-ethyl-[1,2,4]-triazolo[4,3-b]pyridazin-3-ylamine (W2.003; 700 mg) was dissolved in ethanol (100 ml) while stirring. Thereafter, the reaction mixture was admixed with sodium ethoxide (724 mg) and stirred at RT for 2 h. Subsequently, the mixture was heated to 45° C. for 3 h. After the solvent had been drawn off, the residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 670 mg of the title compound were obtained.
Reaction SMILES: C1N(CCO)CCN(CCS(O)(=O)=O)C1.[Cl-].[K+].[Mg+2].[Cl-].[Cl-].C(S)[C@@H](O)[C@H](O)CS.O([CH2:38]/[CH:39]=[C:40](\[CH2:42][CH2:43]/[CH:44]=[C:45](\[CH2:47][CH2:48][CH:49]=[C:50]([CH3:52])[CH3:51])/[CH3:46])/[CH3:41])P(OP([O-])([O-])=O)(=O)[O-].O(C/C=C(/CC/C=C(/CCC=C(C)C)\C)\C)P(OP([O-])([O-])=O)(=O)[O-].O(C/C=C(/CCC=C(C)C)\C)P(OP([O-])([O-])=O)(=O)[O-].O(C/C=C(\CCC=C(C)C)/C)P(OP([O-])([O-])=O)(=O)[O-].O(C/C=C(/CC/C=C(\C)/CC/C=C(/CCC=C(C)C)\C)\C)P(OP([O-])([O-])=O)(=O)[O-]>OCC(CO)O>[CH3:41][C:40]1[CH:42]=[CH:43][C@@H:44]([C@H:45]([CH2:47][CH2:48][CH:49]=[C:50]([CH3:52])[CH3:51])[CH3:46])[CH2:38][CH:39]=1
Reactant: CC(C)=CCC/C(C)=C\CC/C(C)=C\COP(=O)([O-])OP(=O)([O-])[O-]
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COP(=O)([O-])OP(=O)([O-])[O-]
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/COP(=O)([O-])OP(=O)([O-])[O-]
Agent: CC(C)=CCC/C(C)=C/COP(=O)([O-])OP(=O)([O-])[O-]
Solvent: OCC(O)CO
Product: CC(C)=CCC[C@H](C)[C@@H]1C=CC(C)=CC1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Activity assays were performed in 20 mL glass vials in a total volume of 500 μL 50 mM HEPES, pH7.2, 100 mM KCl, 7.5 mM MgCl2, 20 μM MgCl2, 5% (v/v) glycerol, 5 mM DTT with 50 μL protein and either 2 mM cis-FPP (2Z-6Z-farnesyl diphosphate), trans-FPP (E-E-farnesyl diphosphate), GPP (geranyl diphosphate), NDP (neryl diphosphate), or GGPP (geranylgeranyl diphosphate) as a substrate (Echelon Biosciences Incorporated, Salt Lake City, USA). Vials were closed with a teflon lined crimp cap immediately and incubated under moderate shaking for 1 hour at 30° C.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=O)=[C:7]([F:26])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[OH-].[Na+]>C1COCC1>[C:1]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:7]([F:26])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)NCCc2cccc(C(F)(F)F)c2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)c(F)c1
Yield: 89.8 %

Procedure:
5.31 ml (5.31 mmol) of a 1M borane-THF complex solution in THF were added under nitrogen at rt to 650 mg (1.77 mmol) of 4-tert-butyl-2-fluoro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide dissolved in 8.9 ml THF. The reaction mixture was heated to reflux over night. At rt 15 ml 2N aqueous HCl solution were added and the reaction mixture was heated to reflux for 3 h. The reaction mixture was basified with 17 ml of 2N aqueous NaOH solution and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (60 g silica gel; DCM/methanol 19:1) to yield 562 mg (89%) of (4-tert-butyl-2-fluoro-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine as a light yellow oil. 1H NMR (DMSO-d6, 300 MHz): δ 7.50-7.46 (m, 2H), 7.22 (t, 1H), 7.08-7.01 (m, 2H), 3.63 (s, 2H), 2.72 (m, 4H), 1.19 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@H:8]2[NH2:11])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([Cl:31])[N:23]=1>>[Cl:31][C:24]1[N:23]=[C:22]([NH:11][C@H:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[CH2:6][CH2:7]2)[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: N[C@@H]1CCc2ccc(F)cc21
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Cl)nc1N[C@@H]1CCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
Purge a 12 L 3-necked flask with nitrogen, and then assemble thermocouple, heating mantle and condenser. Charge (1R)-6-fluoro-2,3-dihydro-1H-inden-1-amine (386 g, 2.55 mol) to the flask, add 3A-EtOH (3.9 L), diisopropylethylamine (1.34 L, 7.68 mol), and 2,6-dichloro-3-nitropyridine (643 g, 3.07 moles). Stir the reaction mixture at ambient temperature for eight hours followed by heating to 70° C. for 12 hours. Cool the reaction mixture to 8° C. over 1.25 h, then filter onto a polypropylene pad. Wash the solids with 3A-EtOH (760 mL), transfer to a tared dish and further dry in a vacuum oven (45° C.) to afford the title compound as an orange solid (786 g, 71%, 98.0% ee). GC/MS (m/z): 307 (M+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26](Cl)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)C1OC=CC=1)CCC>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[CH:26][N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2cn1
Agent: Cl[Pd]Cl
Agent: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5cnccc45)ccc32)cc1

Procedure:
A stirred solution of (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (0.165 g), 2-(tri-n-butylstannyl)furan (0.139 g) and bis-(triphenylphosphine)palladium (II) chloride (30 mg) in dioxane (10 ml) was heated at reflux under nitrogen for 65 hr (Procedure B). The cooled mixture was absorbed onto silica and chromatographed to give the title compound as an orange solid; δH CDCl3 9.34(1H,s), 8.82(1H,s), 8.70(1H,d), 8.15(1H,d), 8.10(1H,s), 7.65(1H,d), 7.60(1H,s), 7.53(1H,dd), 7.40(1H,d), 7.25(6H,m), 5.60(2H,s); m/z (M+1)+353.
Reaction SMILES: [CH2:1]([C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9]([NH2:11])=O)=[CH:7][N:6]=1)[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9]#[N:11])=[CH:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(C(N)=O)cnc1CC(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C#N)cnc1CC(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
To a solution of 6-isobutyl-5-methyl-nicotinamide (1.89 g, 9.85 mmol) in DCM (40 mL) and pyridine (2.83 g, 39.4 mmol), TFA anhydride (5.17 g, 24.6 mmol) is added portionwise at 0° C. The mixture is stirred at rt for 24 h, diluted with DCM and washed with water, 4% aq. citric acid solution followed by sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 6-isobutyl-5-methyl-nicotinonitrile (1.35 g) as a white solid; LC-MS: tR=0.89 min, [M+1]+=175.11.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].CC1C=CC(S(O)(=O)=O)=CC=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.[OH-].[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.7 %

Procedure:
A suspension of 5-nitro-1H-indazole (24.4 g, 150 mmol) and p-TSA (2.58 g, 14.98 mmol) in DCM (1000 mL) was treated with 3,4-dihydro-2H-pyran (41.0 mL, 449 mmol) over 5 min to provide a solution that was stirred at RT for 6 hr. The resulting dark reaction mixture was added to 2 M NaOH (250 mL) and the organic layer was separated, dried and then concentrated in vacuo to afford a black oil. This material was purified by filtering through a plug of silica (˜700 g), loading and eluting with DCM (>12 L) to yield 5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole as a pale yellow solid (34.02 g, 133 mmol, 89% yield); Rt 2.06 min, no ionisation observed; 1H NMR (400 MHz, CDCl3) δ: 1.70-1.78 (3H, over-lapping m), 2.14 (2H, m), 2.51 (1H, m), 3.76 (1H, ddd), 4.01 (1H, m), 5.77 (1H, dd), 7.69 (1H, d), 8.21 (1H, d), 8.27 (1H, dd), 8.71 (1H, dd).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:3]=1[CH2:4][NH:5]C(=O)OC(C)(C)C.C(=O)(O)[O-].[Na+]>Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:3]=1[CH2:4][NH2:5]
Reactant: CC(C)(C)OC(=O)NCc1c(F)cccc1CC=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NCc1c(F)cccc1CC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
34 mg of t-butyl N-(2-fluoro-6-cinnamylbenzyl)carbamate was dissolved in a 4N hydrochloric acid/ethyl acetate solution, followed by stirring at room temperature for 1 hour. After completion of the reaction, to the reaction liquid was added an aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate, and the organic layer was then washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 24 mg of a crude composition of 2-fluoro-6-cinnamylbenzylamine as a light yellow oily substance. The obtained crude composition, 19 mg of 2-methoxycarbonylethylsulfonylchloride, and 21 mg of sodium carbonate were dissolved in 1 mL of methylene chloride and 1 mL of water, followed by stirring under ice-cooling for 1 hour. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was then washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using PLC (n-hexane:ethyl acetate=2:1) to obtain 29 mg (yield 79%) of a title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13][CH2:14]O>>[CH2:13]([O:10][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:12])[CH3:14]
Reactant: CC(C(=O)O)c1ccc(O)cc1
Reactant: CCO
Product: CCOC(=O)C(C)c1ccc(O)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixture of 13.0 g (78.2 mmol) of 2-(4-hydroxyphenyl)propionic acid in 250 ml EtOH 5.82 ml (78.2 mmol) thionyl chloride are added slowly at 0° C. The reaction mixture is stirred at 70° C. for 2 h. After cooling to r.t. the solvent is removed in vacuo. The residue is mixed with toluene and the solvent is removed again.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]>FC(F)(F)C(O)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(CC2CCNC2)CC1

Procedure:
tert-Butyl 3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)methyl]pyrrolidine-1-carboxylate (440 mg) was stirred in a mixture of trifluoroacetic acid (5 ml) and dichloromethane (10 ml) for one hour at room temperature. The reaction mixture was concentrated in vacuo to give the title compound as a trifluoro acetate salt (350 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[C:10]([S:17][CH3:18])[N:9]=1.[NH:19]1[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:24][CH:21]1[CH2:22][CH2:23][N:19]([C:14]([C:13]2[C:8]([NH:7][CH2:6][C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[N:9][C:10]([S:17][CH3:18])=[N:11][CH:12]=2)=[O:16])[CH2:20]1
Reactant: CSc1ncc(C(=O)O)c(NCc2ccco2)n1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CSc1ncc(C(=O)N2CCC(N)C2)c(NCc2ccco2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
To a solution of 4-[(2-furylmethyl)amino]-2-(methylthio)pyrimidine-5-carboxylic acid (19.1 mg) and tert-butyl pyrrolidin-3-ylcarbamate (13.4 mg) in DMF (1.0 ml) was added a solution of HOBt (9.7 mg) and WSC.HCl (13.8 mg) in DMF (0.5 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 2% aqueous sodium hydrogen carbonate, the mixture was extracted with ethyl acetate, and the extract was concentrated by a nitrogen gas blower. The residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated by a nitrogen gas blower. The residue was dissolved in trifluoroacetic acid/acetonitrile solution (20% (V/V), 1.0 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was passed through a column of MP-TsOH resin (manufactured by Argonaut) to fix the object compound on the resin, and the resin was washed with methanol (6 ml). 2 M Ammonia-methanol solution (6 ml) was passed through the column, and the eluate was concentrated by a nitrogen gas blower to give the object compound (6.3 mg).