Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>CN(C=O)C>[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[C:3](=[O:19])[N:4]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:5](=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(N)cc1
Reactant: COCCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Solvent: CN(C)C=O
Product: COCCCN1C(=O)C(Nc2ccc(OC)cc2)=C(c2ccccc2)C1=O
Temperature: 150 °C
Yield: 15 %

Procedure:
3-Chloro-1-(3-methoxypropyl)-4-phenyl-1H-pyrrole-2,5-dione (0.20 mmol, 56 mg) and 4-methoxyaniline (0.48 mmol, 59 mg) were dissolved in DMF (1 mL). The mixture was heated in a microwave reactor at 150° C. for five min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 11 mg (15%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.17 (bs, 1H), 7.14-7.05 (m, 3H), 7.01-6.95 (m, 2H), 6.63-6.52 (m, 4H), 3.71 (t, J=7.0 Hz, 2H), 3.70 (s, 3H), 3.45 (t, J=6.2 Hz, 2H), 3.34 (s, 3H), 1.94 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)[CH2:22][C:23]1[CH:32]=C2C(C=CC=C2)=C[CH:24]=1.CC(CCl)=C>CCCCCC.CC(C)=O>[CH:22]([O:13][C:3]1[C:4]([C:9]([CH3:10])([CH3:12])[CH3:11])=[CH:5][C:6]([Br:8])=[CH:7][C:2]=1[Br:1])=[C:23]([CH3:32])[CH3:24]
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1O
Agent: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC(C)=COc1c(Br)cc(Br)cc1C(C)(C)C
Temperature: 23 °C
Reaction time: 56 h

Procedure:
In a 3000 mL 3-neck flask, equipped with Ar inlet and magnetic stirrer, is placed 2,4-dibromo-6-tert-butylphenol (70.0 g, 226 mmol), K2CO3 (37.6 g, 276 mmol, 1.2 eq), Nal (3.38 g, 22.6 mmol, 0.1 eq), β-methallyl chloride (33.9 mL, 339 mmol, 1.5 eq), and acetone (1500 mL). The reaction mixture is vigorously stirred at 23° C. for 56 hrs, and monitored by TLC analysis (pet. ether). The solids are removed by filtration, washed with acetone, and the filtrates rotoevaporated (bath temperature kept below 35° C.) to give an oil. The oil is dissolved in hexane (100 mL), and stirred with silica gel (80 g). The slurry is filtered through a pad of Celite, and eluted with additional hexane (6×100 mL). The filtrate is evaporated to give 2,4-dibromo-6-tert-butylphenyl isobutenyl ether as a yellow oil. The material is stored in the freezer and is used as soon as possible.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])C)=[CH:4][CH:3]=1.C(=O)([O:21][CH2:22][CH:23]1[CH2:27]OC(=O)[O:24]1)OC.[F-].[K+].[CH2:32](OCCO)CCC.[Al]>>[CH3:32][C:4]([CH3:3])=[C:5]1[CH:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:27][CH:23]([OH:24])[CH2:22][OH:21])=[CH:15][CH:16]=2)[CH:10]=[CH:2][CH:7]=[CH:6]1
Reactant: CCCCOCCO
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: COC(=O)OCC1COC(=O)O1
Agent: [Al]
Agent: [F-]
Agent: [K+]
Product: CC(C)=C1C=CC=CC1c1ccc(OCC(O)CO)cc1
Temperature: 170 °C
Yield: 90 %

Procedure:
A mixture of 5.58 g (0.03 mole) of bisphenol A, 5.28 g (0.03 mole) of methyl 2-oxo-1,3-dioxolan-4-ylmethyl carbonate, 0.174 g (0.003 mole) of KF, and 5 ml of 2-(n-butoxy)ethanol is placed in a 50-ml resin pot equipped with a mechanical stirrer and a distillation head and warmed with stirring to 170° C. After heating at 170° C. for 4 hours, the gas evolution appeared to cease and the reaction mixture becomes viscous. The hot reaction mixture is poured into 8 aluminum cups and the solvent is evaporated in a vacuum oven (150° C.) for 24 hours to give 6.8 g (90 percent yield) of a yellow, brittle polymer with 12,000 molecular weight and m.p.=116° C. "p" can be calculated to be about 40. The above structure of the polymer is confirmed by nuclear magnetic resonance spectra data.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([CH3:26])[C@@H:6]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][OH:9])=[N+:2]=[N-:3].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.CCOCC.C(OCC)(=O)C>[CH3:27][S:28]([O:9][CH2:8][C@@H:7]([NH:10][C:11]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:17])[C@H:6]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[C@@H:5]([CH3:26])[CH2:4][N:1]=[N+:2]=[N-:3])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of tert-butyl (2R,3R,4S)-5-azido-3-(tert-butyldimethylsilyloxy)-1-hydroxy-4-methylpentan-2-ylcarbamate (1.0 equiv.) in pyridine (0.2 M) was added MsCl (1.3 equiv.) followed by DMAP (catalytic amount) at 0° C. The mixture was stirred at that temperature for 1 hour. The solution was diluted with ether and ethyl acetate (4:1), washed with aq. NaHSO4, sat. NaHCO3, brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate and hexanes (1:3) to give (2R,3R,4S)-5-azido-2-(tert-butoxycarbonylamino)-3-(tert-butyldimethylsilyloxy)-4-methylpentyl methanesulfonate as the major isomer (5:2) in 90% yield. LC/MS=367.3 (M+H-Boc), Rt=0.81 min (Frac 65%-95% method).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:34][N:35]([CH3:40])[S:36]([Cl:39])(=[O:38])=[O:37]>>[ClH:39].[CH3:34][N:35]([CH3:40])[S:36]([N:31]1[CH2:32][CH2:33][CH:28]([C:25]2[N:24]=[C:23]([NH:22][C:10]3[C:9]([O:8][C:7]4[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[CH:14][C:13]([S:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:12][N:11]=3)[S:27][N:26]=2)[CH2:29][CH2:30]1)(=[O:38])=[O:37]
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CCNCC2)ns1
Reactant: CN(C)S(=O)(=O)Cl
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CCN(S(=O)(=O)N(C)C)CC2)ns1
Product: Cl
Yield: 60.5 %

Procedure:
Following the procedure in Example 1, Step G, and using N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(piperidin-4-yl)-1,2,4-thiadiazol-5-amine (150 mg, 0.314 mmol) and dimethylsulfamoyl chloride (45.1 mg, 0.314 mmol) provided N,N-dimethyl-4-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-sulfonamide hydrochloride (118 mg, 0.190 mmol, 60.5% yield). Mass spectrum (apci) m/z=585.1 (M+H—HCl).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[C:22]([F:31])[C:23]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].ClC1C=CC=C(C(OO)=[O:40])C=1.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:20][C:19]3[CH:21]=[C:22]([F:31])[C:23]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:24][C:18]=3[N:17]=2)=[O:40])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:11])([F:13])[F:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2cc(N3CCCCC3)c(F)cc2[nH]1
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2cc(N3CCCCC3)c(F)cc2[nH]1
Yield: 76.5 %

Procedure:
The title compound (0.18 g, 78%) was prepared by the above general procedure using 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio]-6-fluoro-5-(piperidin-1-yl)-1H-benzimidazole (0.23 g, 0.5 mmol) (obtained in example 16), m-chloroperbenzoic acid (50%, 0.2 g, 0.6 mmol) and chloroform (20 mL). mp 99-100° C.; IR (KBr) 3413, 1070 cm- 1; 1H NMR (DMSO-d6) δ 1.52 (m, 2H, CH2), 1.70 (m, 4H, (CH2)2), 2.20 (s, 3H, CH3) 3.98 (t,J=4.5 Hz, 4H, N(CH2)2), 4.80 (ABq,J=12.9 Hz, Δv=9.1 Hz, 2H, SOCH2), 4.94 (q,J=8.1 Hz, 2H, OCH2CF3), 7.12 (d,J=5.8 Hz, 1H), 7.18 (d,J=7.8 Hz, 1H), 7.44 (d,J=12.7 Hz, 1H), 8.32 (d,J=5.5 Hz, 1H); Mass (m/z) 454 (M -16).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]([NH:15][NH2:16])=[O:14])[O:4]1.[CH2:17]([N:24]=[C:25]=[S:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]([NH:15][NH:16][C:25](=[S:26])[NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[O:4]1
Reactant: S=C=NCc1ccccc1
Reactant: CO[C@@H]1O[C@H](C(=O)NN)[C@H]2OC(C)(C)O[C@@H]12
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](C(=O)NNC(=S)NCc2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Yield: 89.9 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbohydrazide (Preparation 16) (4 g, 17.2 mmol) and benzyl isothiocyanate (2.38 ml, 18 mmol) in dichloromethane (50 ml) was stirred at room temperature for 12 hours. The solvent was removed by evaporation under reduced pressure and the residue was partioned between dichloromethane (100 ml) and water (100 ml). The organic layer was separated, dried (anhydrous magnesium sulphate) and evaporated under reduced pressure to give the title compound (5.90 g) which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C:13]1([CH3:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1[CH:22]=[CH:23]C2N(O)N=[N:27][C:25]=2[CH:26]=1.N1CCCCC1.CCN(CC)CC>C(Cl)Cl>[CH3:19][C:13]1([CH3:20])[C@H:14]([C:16]([N:27]2[CH2:23][CH2:22][CH2:21][CH2:26][CH2:25]2)=[O:18])[CH2:15][C@@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)O
Reactant: On1nnc2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.6 %

Procedure:
To a stirred solution of (1R,3S)-3-(benzyloxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (Intermediate 1-Step 3, 0.650 g, 2.346 mmol) in DCM (5 ml) EDCI (0.674 g, 3.519 mmol) and HOBt (0.475 g, 3.519 mmol) were added at 0° C., after 10 minutes piperidine (0.46 ml, 4.692 mmol) and Et3N (0.65 ml, 4.692 mmol) were added drop wise and the reaction mixture was stirred at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, 1N HCl, water and saturated brine and the organic layer was concentrated under reduced pressure. The resulting crude was purified by a silica gel column (100-200 mesh, elution 20% EtOAC in hexane) to afford the title compound as an off white solid. Wt: 0.393 g; Yield: 48.6%; 1H NMR (300 MHz, CDCl3): δ 7.40-7.28 (m, 5H), 5.18-4.99 (m, 3H), 3.97-3.87 (m, 1H), 3.77-3.67 (m, 1H), 3.49-3.28 (m, 3H), 2.83 (t, 1H, J=8.4 Hz), 2.47-2.20 (m, 2H), 3.65-3.41 (m, 6H), 1.35 (s, 3H), 0.87 (s, 3H); Mass: [M+1]+ 345 (10%), [M+Na]+ 367 (100%); IR (KBr, cm−1): 3315, 3013, 2931, 2855, 1719, 1622, 1534, 1443, 1369, 1255, 1236, 1219, 1125, 1040, 853, 746, 697; M.R: 145.2° C.-150.8° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27].C(Cl)CCl.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:18][C:19]([F:28])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][C:15]([C@@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:14][CH2:13]1)=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)NCc2ccccc2C(F)(F)F)CC1
Reaction time: 8 h

Procedure:
To a solution of cis-4-({[(1,1-dimethylethyl) oxy]carbonyl}amino)cyclohexanecarboxylic acid (3.0 g, 12 mmol, 1.0 equiv) and 1-[2-(trifluoromethyl)phenyl]methanamine (1.9 mL, 14 mmol, 1.0 equiv) in CH2Cl2 (82 mL) at room temperature, DMAP (301 mg, 2.47 mmol, 0.2 equiv) was added. EDC (2.95 g, 15.4 mmol, 1.25 equiv), and diisopropylethylamine (DIEA, 2.7 ml, 15 mmol, 1.25 equiv) were added. Stirring was continued overnight at room temperature. The solution was diluted with CH2Cl2 (100 ml), washed with saturated sodium bicarbonate (200 mL), water (200 mL), and brine (200 mL). The CH2Cl2 extracts were dried with MgSO4, filtered, and concentrated under reduced pressure to yield the title compound. MS (ES+): m/e 400.8 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[CH:16]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23].N>O.CC(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:8][N:5]1[C:6]([CH3:7])=[C:2](/[N:1]=[C:18]2\[C:17]([CH3:23])=[CH:16][C:21](=[O:22])[CH:20]=[CH:19]\2)[C:3](=[O:15])[N:4]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Reactant: Cc1cccc(O)c1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC1=CC(=O)C=C/C1=N/c1c(C)n(C)n(-c2ccccc2)c1=O

Procedure:
10 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in 30 ml of water. This solution was admixed with 10 mmol of meta-cresol in solution in 30 ml of 2-propanol, 3 ml of 20% aqueous ammonia and 22 mmol of potassium ferricyanide at a temperature ranging from 5 to 10° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>N1C=CC=CC=1>[CH3:19][S:20]([O:11][C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH:3]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:2]([CH3:18])([CH3:1])[C:6]=2[CH:7]=1)(=[O:22])=[O:21]
Reactant: CC1(C)c2cc(O)ccc2OC1N1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1N1CCCCC1
Temperature: 10 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
To a stirred solution of 2,3-dihydro-3,3-dimethyl-5-hydroxy-2-piperidino-benzofuran (640 parts) in dry pyridine (1000 parts) at 5°-10° C. was added methanesulphonyl chloride (370 parts) over 1 hour. The mixture was stirred for a further 5 hours at about 10° C., then poured into water. The precipitated gum was washed with water (3×200 parts) by decantation, then triturated with ethanol (500 parts) when it set to a crystalline mass which was broken up, filtered, and the residue of crude ester was washed with aqueous ethanol (2:1) and sucked dry. Drying at 35° C. in vacuo over phosphoric oxide gave 2,3-dihydro-3,3-dimethyl-2-piperidinobenzofuran-5-yl methanesulphonate (660 parts, 78%) m.p. 97°-8° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[CH:13]2)[CH3:7].[I:17]I>O.C(O)C>[CH2:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[C:13]2[I:17])[CH3:7]
Reactant: CCc1cccc2cn[nH]c12
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1cccc2c(I)n[nH]c12
Yield: 48.2 %

Procedure:
To a stirred solution of sodium bicarbonate (1.67 g, 19.8 mmol) in water (4.65 mL) and ethanol (9.3 mL) was added 7-ethyl-1H-indazole (771 mg, 5.27 mmol) followed by iodine (1.87 g, 7.38 mmol). After 16 h the reaction mixture was quenched with sodium thiosulfate, diluted with ethyl acetate and washed with water. The organic layer was collected and dried (MgSO4). Purification by chromatography (silica, 5-25% ethyl acetate/hexanes) gave 7-ethyl-3-iodo-1H-indazole (690 mg, 2.54 mmol, 48%) as an off-white solid. MS (M+H)+=272.9; 1H NMR (CDCl3) δ: 7.39 (d, J=8.1 Hz, 1H), 7.30 (d, J=7.1 Hz, 1H), 7.22 (t, J=7.1 Hz, 1H), 2.95 (q, J=7.5 Hz, 2H), 1.41 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl.C([O:6][C:7]([C:9]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1)=[O:12])=[O:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:7]([C:9]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1)=[O:12])([OH:8])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(-c2ccncc2)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(-c2ccncc2)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 258 %

Procedure:
In dichloromethane (50 ml), 1-[2-tert-butoxycarbonyl-4-(pyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride (250 mg) was dissolved, followed by the dropwise addition of trifluoroacetic acid (50 ml) under ice cooling. After stirring at room temperature for 5 hours, the solvent was distilled off. The residue was dissolved in methanol and the resulting solution was allowed to stand in a refrigerator for one day. The colorless solid so precipitated was collected by filtration and dried, whereby the title compound (550 mg, 28%) was obtained as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[F:12].[NH3:13]>>[F:12][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([N+:8]([O-:10])=[O:9])[C:4]=1[NH2:13]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: N
Product: Nc1c([N+](=O)[O-])ccc(F)c1F
Temperature: 70 °C
Yield: 35.6 %

Procedure:
A solution of 1,2,3-trifluoro-4-nitrobenzene (1) (1.00 g, 5.64 mmol, 1.00 equiv) in methanolic ammonia (1.5 mL) was taken in microwave vial and heated to 70° C. for 90 min in the microwave. The solvent was evaporated under vacuum to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane 1:49) to furnish compound 2 (0.350 g, 35.6%) as yellow solid. TLC: 10% EtOAc/Hexane (Rf: 0.10); 1H NMR (500 MHz, DMSO-d6): δ 7.94-7.91 (m, 1H), 7.51 (s, 2H), 6.75-6.70 (m, 1H); LC-MS: m/z=173 (M+-1) at RT 3.15 (99.8% purity)
Reaction SMILES: Br.[NH2:2][C@@H:3]([CH2:8][C:9]([F:12])([F:11])[CH3:10])[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[C:19](Cl)(Cl)=[O:20].C1(C)C=CC=CC=1>ClCCl>[F:12][C:9]([F:11])([CH3:10])[CH2:8][C@H:3]([N:2]=[C:19]=[O:20])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@@H](N)CC(C)(F)F
Reactant: O=C(Cl)Cl
Agent: Br
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](CC(C)(F)F)N=C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
The compound from example 6 (6.76 g, 28.8 mmol) was initially charged and dissolved in 240 ml of dichloromethane and 9.46 ml (117 mmol, 4.05 eq) of pyridine, cooled down to 0° C. in an ice bath for 15 min and admixed with 19.86 ml of a 20% phosgene solution in toluene (37.54 mmol, 1.3 eq) within 20-30 seconds. The mixture was stirred at 0° C. for a further 2 h, then the reaction mixture was extracted with cold half-molar HCl and ice. The water phases were reextracted with dichloromethane, and the combined organic phases were washed with ice and saturated NaCl solution, then dried over MgSO4 and filtered off from the desiccant. Concentration by evaporation under reduced pressure left 5.21 g of brown oil (corresponded to a yield of 94%), which was reacted further directly.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH:5]=[CH:6][CH:7]=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH:5]=[CH:6][CH:7]=[N:12][NH:13][C:14]([NH2:16])=[S:15]
Reactant: NNC(N)=S
Reactant: O=CC=Cc1cccc(O)c1
Product: NC(=S)NN=CC=Cc1cccc(O)c1
Yield: 28 %

Procedure:
The compound is prepared according to the method described in example 1A from 3-hydroxycinnamaldehyde (6 mmoles) and from thiosemicarbazide (6 mmoles). Yield 28%.
Reaction SMILES: [CH2:1]([OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>O1CCCC1>[CH3:24][S:25]([O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:27])=[O:26]
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCCCCCOS(C)(=O)=O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
247.4 g of behenyl alcohol (1-docosanol) was dissolved in 640 mL of tetrahydrofuran, 116.1 mL of methanesulfonyl chloride was gradually added, and 64.7 mL of triethylamine was then added dropwise under ice cooling over 30 minutes. After stirring for one hour, the mixture was heated at 40° C. and further stirred for 30 minutes. The reaction mixture was poured into 3.5 L of ice water, and the resulting mixture was ultrasonically dispersed for 15 minutes and further stirred at room temperature for 4 hours. The dispersion was filtered under reduced pressure, and a crystal was washed with 2 L of water. The resulting white crystal was stirred in 1.5 L of acetonitrile for one hour, filtered under reduced pressure and then washed with 0.5 L of acetonitrile. The resulting crystal was dried under reduced pressure to obtain 303.4 g of a white crystal.
Reaction SMILES: [CH3:1][C:2]([CH3:18])=[CH:3][CH2:4][O:5][CH2:6][CH:7]([OH:17])[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[N+:14]([O-:16])=[O:15].[N:19]([O:21]CCC(C)C)=O.[ClH:27]>>[Cl:27][C:2]([CH3:18])([CH3:1])[CH:3]([N:19]=[O:21])[CH2:4][O:5][CH2:6][CH:7]([OH:17])[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[N+:14]([O-:16])=[O:15]
Reactant: CC(C)=CCOCC(O)Cn1ccnc1[N+](=O)[O-]
Reactant: CC(C)CCON=O
Reactant: Cl
Product: CC(C)(Cl)C(COCC(O)Cn1ccnc1[N+](=O)[O-])N=O

Procedure:
To a cooled (0°-5° C.) stirred slurry of 1-[2-hydroxy-3-(2 -nitro-1H-imidazol-1-yl)propyl dimethylallyl ether (7.0 g, 0.0275 mol) in isoamyl nitrite (43 g, 50 mL, 0.042 mol) was added concentrated hydrochloric acid (2.5 mL, 0.03 mol) with stirring. The reaction mixture was maintained below 5° C. during the addition and stirred at 5° C. for an additional 2 hrs. The solid formed was stirred with cold ether-ethanol (3:1, 150 mL), filtered, and dried under vacuum. Yield: 5.8 g (67%). mp: 116°-117° C. dec. 1H NMR (DMSO) δ1.55 and 1.62 (s, 6H, CH3), 3.35 (m, 4H, CH2OCH2CHOH), 3.82 (m, 1H, CHOH), 4.1-4.52 (m, 2H, CHOHCH2N<), 5.3 (m, 1H, CHOH), 6.0 (dd, 1H, CHNO), 7.15 and 7.42 (s, 2H, imi H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:3]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](B(O)O)=[CH:21][N:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)[CH:3]=2)=[CH:21][N:20]=1
Reactant: Cc1cccc(-c2cc(Cl)c3cccnc3n2)n1
Reactant: OB(O)c1cncc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(-c2cc(-c3cncc4ccccc34)c3cccnc3n2)n1
Yield: 68 %

Procedure:
190 mg 4-chloro naphthyridine from example 3, 341 mg 4-isoquinoline boronic acid pinacole ester, 473 mg sodium carbonate were dissolved with 20 ml dioxan and 5 ml water, flushed with nitrogen, and 86 mg tetrakistriphenylphosphine palladium(0) were added. After 90 min reflux, workup as in example 20 yielded a grey-brownish oil, which was crystallized with ether to give 176 mg correct product as a brownish powder with correct LC_MS: M+H+ 349 and Rf˜1.76 min.