Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:17][C:18](=[O:22])[CH:19]=[N+]=[N-])[CH3:16]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][O:11][CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Solvent: ClCCCl
Product: CCOC(=O)COC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 65.4 %

Procedure:
To a solution of N-t-butyloxycarbonyl-(S)-prolinol (5.0 g, 25 mmol) in 1,2-dichloroethane (500 ml) rhodium(II)acetate (180 mg) was added and the mixture was heated to 80° C. Ethyldiazoacetate (3.9 ml, 37 mmol) in 1,2-dichloroethane (180 ml) was added over a period of 90 min and the mixture was heated at 80° C. for 3 hours. Then another portion of ethyldiazoacetate (1.3 ml, 12 mmol) in 1,2-dichloroethane (40 ml) was added and the mixture was refluxed for 6 hours. The mixture was cooled to room temperature and washed with saturated sodium bicarbonate (2×100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (300 g) with petrol ether/ethyl acetate 4:1 as eluent to give 4.7 g of (2S)-2-(((ethoxycarbonyl)methoxy)methyl)pyrrolidin-1-carboxylic acid tert-butylester. The obtained product was taken up in 50 ml of 1 M lithium hydroxide in water/methanol 1:3 and stirred at room temperature overnight. The mixture was concentrated in vacuo, water (20 mL) was added and washed with ether (20 mL). The aqueous phase was acidified to pH 4 with I M aqueous hydrogen chloride and extracted with ethyl acetate (200 ml), dried over magnesium sulfate and concentrated in vacuo to give 3.6 g of (2S)-2-(((carboxy)methoxy)methyl)pyrrolidin-1-carboxylic acid tert-butylester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:16][CH3:17].CC(OC([NH:25][C@H:26]([CH2:30][CH3:31])[C:27](O)=[O:28])=O)(C)C.CCN(CC)CC.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[NH2:25][C@H:26]([CH2:30][CH3:31])[C:27]([NH:15][C:12]1[CH:13]=[N:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:16][CH3:17])[CH:4]=2)=[CH:10][CH:11]=1)=[O:28]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(Oc2ccc(N)cn2)ccc1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Temperature: 0 °C
Yield: 119.3 %

Procedure:
6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinamine (Intermediate 50, 500 g), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (530 g) and Et3N (905 mL) are mixed together in ethyl acetate (2 L) and stirred at 0° C. until complete dissolution. ®T3P (2.15 L) was added dropwise in 30 minutes maintaining the temperature at ˜0° C. Ethyl acetate (500 mL) was added for washing the line. Work-up: 10% w/w sodium carbonate aqueous solution (2.5 L) was added and the mixture was stirred for 20 minutes. Then water (1.5 L) and ethyl acetate (1 L) were added and the two phases separated. The organic layer was washed with 10% w/w sodium carbonate aqueous solution (2.5 L), stirring the mixture for 10 minutes before separation of phases, then with 28% malic acid aqueous solution (2.5 L) and finally with 20% NaCl aqueous solution (2.5 L). The organic solution was concentrated to the lowest volume (<2 L), acetonitrile (5 L) was added, the solution was concentrated to the lowest volume (<2 L) and acetonitrile was added up to 12.5 L (it is a solution of Intermediate 64 in acetonitrile). To this solution, 5-6N HCl solution in Isopropanol (2.5 L) was added at 20° C. and the resulting reaction mixture was stirred at 45° C. for 1.5 hours. The obtained suspension was cooled to 20° C., stirred for 1 hour and then filtered. The collected solid was washed with 5/1 acetonitrile/Isopropanol (3×1.5 L), then dried under vacuum at 40° C., until constant weight, obtaining the title compound (817 g).
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6]2.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:31]([CH3:30])(=[O:33])=[O:32])[CH:20]=[CH:21][CH:22]=2)[CH:3]2[CH:7]1[CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]2
Reactant: CC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCCc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 8, 28 mg, 0.09 mmol) in dichloromethane (2 ml), at 0° C. under nitrogen was added pyridine (20 μl, 0.24 mmol) and then methanesulfonylchloride (25 μl, 37 mg , 0.32 mmol) over 5 minutes. The mixture was allowed to warm to room temperature and was then stirred for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica (5 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (18 mg, 52%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[S:14][CH2:13][C:12]([C:18]([O:20]CC)=[O:19])=[CH:11]3)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.C(#N)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[S:14][CH2:13][C:12]([C:18]([OH:20])=[O:19])=[CH:11]3)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(C)cc3)ccc2SC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CS3)cc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 94.8 %

Procedure:
To a solution of ethyl 6-(4-methylphenyl)-2H-thiochromene-3-carboxylate (2.12 g, 6.84 mmol) in tetrahydrofuran (20 ml) and acetonitrile (20 ml) was added dropwise 1N sodium hydroxide (7 ml), and the mixture was stirred at 60° C. for 2.5 hours. The solvent was evaporated, and the residue was dissolved in diethylether. The mixture was extracted with water. The organic layer was extracted with 0.5N sodium hydroxide, and both of the aqueous layers were made pH 3 with 6N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated to give 6-(4-methyl-phenyl)-2H-thiochromene-3-carboxylic acid (1.83 g, 95%) as yellow powder.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:12]O>[Pd]>[CH3:12][C:2]1[C:3]([NH2:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: CO
Reactant: Nc1c(Cl)ccc2[nH]ncc12
Agent: [Pd]
Product: Cc1ccc2[nH]ncc2c1N
Yield: 6 %

Procedure:
Analogously to the production of 5-chloro-1H-indazol-4-ylamine, the regioisomeric mixture of the previous reaction (1.0 g, 5.64 mmol)) is reacted with 100 mg of palladium on carbon in methanol under hydrogen atmosphere for 16 hours at room temperature. After purification on silica gel with hexane/ethyl acetate (33% hexane, then 100% ethyl acetate), 53 mg (6% of theory) of 5-methyl-1H-indazol-4-ylamine is obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[O:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.C(O)(=O)C>[CH3:4][C:3]([OH:5])([CH3:6])[CH2:2][NH:1][CH:10]1[CH2:11][CH2:12][O:7][CH2:8][CH2:9]1
Reactant: O=C1CCOCC1
Reactant: CC(C)(O)CN
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(O)CNC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.75 g of 1-amino-2-methylpropan-2-ol are dissolved in 20 ml of MeOH. 1.71 ml of glacial acetic acid are added dropwise under an inert atmosphere. 2 g of tetrahydropyran-4-one in 10 ml of MeOH are added, the mixture is stirred for 30 minutes at room temperature and 1.98 g of sodium cyanoborohydride are added. The resulting mixture is stirred under an inert atmosphere for 15 hours. The reaction medium is poured into saturated aqueous NaHCO3 solution (100 ml). The resulting mixture is stirred for 30 minutes and then extracted with 4 times 100 ml of DCM. The organic phase is dried over Na2SO4, filtered and evaporated without heating. The MeOH contained in the aqueous phase is evaporated off and the extraction, drying, filtration and evaporation operation is repeated 3 times. 2.8 g of 2-methyl-1-((tetrahydro-2H-pyran-4-yl)amino)propan-2-ol are recovered in total.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=O.[S:9]1([C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13](=[O:14])[NH:12]1)(=[O:11])=[O:10].[Na].C(Cl)(Cl)(Cl)Cl.[C:27](Cl)(Cl)=[O:28]>ClCCl>[O:6]1[CH2:7][CH2:8][N:3]([CH:1]=[N:12][S:9]([C:20]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:27]([N:12]2[C:13](=[O:14])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[S:9]2(=[O:10])=[O:11])=[O:28])(=[O:11])=[O:10])[CH2:4][CH2:5]1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: O=CN1CCOCC1
Reactant: O=C(Cl)Cl
Agent: [Na]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1S(=O)(=O)N=CN1CCOCC1)N1C(=O)c2ccccc2S1(=O)=O
Temperature: -30 °C
Yield: 73.4 %

Procedure:
N-formylmorpholine (3 ml) and 2.05 g of anhydrous sodium saccharin were added to 10 ml of dichloromethane. The mixture was cooled to -30° C., and with stirring, 1.65 ml (corresponding to about 5 millimoles of phosgene) of a carbon tetrachloride solution containing 30% of phosgene (W/V %) was added. The temperature of the mixture was raised to room temperature over a period of about 1 hour and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure. Water was added to the remaining oily product, and under ice cooling, the mixture was stirred until the oily product crystallized. The crystals were collected by filtration, thoroughly washed with water, and dried to afford 1.70 g of white crystals (yield 73.4%), decomposition point:160°-169° C. Recrystallization of the crude crystals from acetone yielded white needle-like crystals having a decomposition point of 173° to 175° C.
Reaction SMILES: C[CH:2]([C:13]([CH:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)C)=O)C1C=CC(OC)=C(OC)C=1.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)[OH:30].C(OC(C)C)(C)C>[Pt]=O.C(O)(C)C>[Cl:37][C:33]1[CH:32]=[C:31]([C@@H:29]([OH:30])[CH2:28][NH:27][C@H:13]([CH3:2])[CH2:15][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Reactant: COc1ccc(C(C)C(=O)C(C)c2ccc(OC)c(OC)c2)cc1OC
Agent: O=[Pt]
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Product: COc1ccc(C[C@@H](C)NC[C@H](O)c2cccc(Cl)c2)cc1OC
Reaction time: 24 h
Yield: 62 %

Procedure:
To a mixture of 5.83 g of methyl-3,4-dimethoxyphenylmethyl ketone, 5.15 g of (R)-2-amino-1-(3-chlorophenyl)ethanol and 50 mg of platinum oxide were added 15 ml of isopropyl alcohol and 30 ml of diisopropyl ether, and the reducing reaction was carried out at room temperature, at 1 atm under hydrogen atmosphere for 24 hours. After removing off platinum oxide by filtration, the solvent was distilled off under reduced pressure to give 6.51 g of white oil of (R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol (yield 62%). The optical purity of the (R,R)-isomer was 65%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([NH:7][CH3:8])=O.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:7]([CH3:8])[N:32]=[N:31][N:30]=2)[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: CNC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Cn1nnnc1-c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a solution of 3-bromo-N-methyl-5-nitro-benzamide (0.6 g) in DCM (15 ml) at −15° C. was added triflic anhydride (0.6 ml) and the reaction stirred for 30 min. Sodium azide (226 mg) was added and the reaction allowed to warm to room temperature and stirred further overnight. NaHCO3(aq) was added to neutralise the reaction and the mixture extracted into EtOAc. The organic layer was separated, dried and concentrated in vacuum and the residue purified by flash chromatography (9:1 to 2:8 cyclohexane:EtOAc) to give the title compound (290 mg). Rf=0.51 (3:2 cyclohexane:EtOAc).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[NH:5][C:4](=[O:28])[CH2:3]1.C([O-])(=O)C.[K+].Br[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.ClCCl>CS(C)=O>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[C:4](=[O:28])[CH2:3]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)Nc3ccccc32)C(C)C)cc1
Reactant: Brc1ccncc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccncc3)c3ccccc32)C(C)C)cc1
Temperature: 100 °C
Yield: 50.4 %

Procedure:
To a stirring solution of 700 mg (1.89 mmol) 2-(2,4-Dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide in DMSO is added 370 mg of Cu powder (5.8 mmol, 3 equiv), 380 mg of potassium acetate (3.88 mmol, 2 equiv) and 500 mg of 4-bromopyridine (3.16 mmol, 1.7 equiv, freshly free-based from the hydrochloride salt). The reaction is heated to 100° C. for 16 h then poured onto ice. Dichloromethane is added, and the mixture is filtered through celite. The filtrate is poured into a separatory funnel containing 100 mL of H2O, and the layers separated. 2 mL of a 30% solution of NH4OH were added to the aqueous layer, and the resulting blue solution is extracted with dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel flash column chromatography to afford 437 mg of 2-(2,4-Dioxo-5-pyridin-4-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as a white solid: mp. 211°-213° C.; 1H NMR (CDCl3, 400 MHz) δ8.61 (d, br, 2H, J=5.4), 7.43 (d, 1H, J=8.1), 7.36-7.14 (m, 5H), 6.99-6.22 (m, 4H), 5.03 (m, 1H), 4.26 (dd, br, 2H, J=16.6, 28.5), 3.87 (s, 3H), 3.55 (dd, 2H, J=12.0, 36.4), 1.09 (d, 6H, J=6.8); low resolution MS (FAB)m/e 459 (MH+).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:17]4[CH:18]=[C:19]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[N:20]5[C:25]=4[C:24]([NH2:26])=[N:23][CH:22]=[N:21]5)[CH:13]=[CH:14]3)=[N:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:34][C:35](N(C)C)=[O:36]>>[C:35]([N:30]1[CH2:29][CH2:28][CH:27]([C:19]2[N:20]3[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]3)=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:16]=4)[CH:18]=2)[CH2:32][CH2:31]1)(=[O:36])[CH3:34]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(CC5CCCCC5)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Product: CC(=O)N1CCC(c2cc(-c3ccc4cn(CC5CCCCC5)nc4c3)c3c(N)ncnn23)CC1
Yield: 16 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 5-[2-(cyclohexylmethyl)-2H-indazol-6-yl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting acetyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 13 mg (16%) of the desired product was isolated. 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1 H) 7.82 (s, 1 H) 7.80 (d, 1 H) 7.64 (d, 1 H) 7.21 (dd, 1 H) 6.60 (s, 1 H) 4.65 (dd, 1 H) 4.26-4.31 (m, 2 H) 4.04 (dd, 1 H) 3.50 (dt, 1 H) 3.27 (dd, 1 H) 2.80 (dd, 1 H) 2.12-222 (m, 6H) 1.67-1.77 (m, 7 H) 1.06-1.29 (m, 5 H). LC-MS [M+H]+=472.3, RT=2.66 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12][C:13]1[CH:14]=[C:15]([N:19]2[C:24](=[O:25])[C:23](Cl)=[C:22](Cl)[CH:21]=[N:20]2)[CH:16]=[CH:17][CH:18]=1.[CH3:28][O-:29].[Na+].O.CC[O:34][CH2:35]C>C1(C)C=CC=CC=1.CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12][C:13]1[CH:14]=[C:15]([N:19]2[C:24](=[O:25])[C:23]([O:29][CH3:28])=[C:22]([O:34][CH3:35])[CH:21]=[N:20]2)[CH:16]=[CH:17][CH:18]=1
Reactant: CCOCC
Reactant: O=c1c(Cl)c(Cl)cnn1-c1cccc(Sc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: COc1cnn(-c2cccc(Sc3ccc(C(F)(F)F)cc3Cl)c2)c(=O)c1OC
Reaction time: 2 h
Yield: 80 %

Procedure:
A suspension of 20 g of 1-[3'-(2"-chloro-4"-trifluoromethylphenylthio)-phenyl]-4,5-dichloropyridaz-6-one, 5.3 g of sodium methylate and 0.1 g of N-methylpyrrolidone in 150 ml of absolute toluene was kept at 60° C. for 2 hours, while stirring. The solution formed was diluted with 200 ml of ether, treated with twice 100 ml of water, dried, filtered and evaporated down under reduced pressure. The oily residue was triturated with diisopropyl ether, and the product was filtered off under suction. 15.7 g (80% of theory) of 1-[3'-(2"-chloro-4"-trifluoromethylphenylthio)-phenyl]-4,5-dimethoxypyridaz-6-one of melting point 86° to 90° C. were obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].Cl[C:20]1C=CC(S(C(C)C)(=O)=O)=C[C:21]=1C(O)=O.N1CC[O:38]CC1>>[N:14]1([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH2:1][CH2:20][CH3:21])(=[O:4])=[O:3])=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH2:18][CH2:17][O:38][CH2:16][CH2:15]1
Reactant: CC(C)S(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: C1COCCN1
Product: CCCS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Yield: 62 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(propane-2-sulfonyl)-benzoic acid and morpholine and obtained in 62% yield. MS (m/e): 312.2 (MH−, 100%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26](Br)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:37][C:38]1([CH3:45])[C:42]([CH3:44])([CH3:43])[O:41][BH:40][O:39]1>O1CCCC1.C(N(CC)CC)C.CC#N>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([B:40]3[O:41][C:42]([CH3:44])([CH3:43])[C:38]([CH3:45])([CH3:37])[O:39]3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1Br
Reactant: CC1(C)OBOC1(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1B1OC(C)(C)C(C)(C)O1

Procedure:
A mixture of EXAMPLE 1D (1.2 g), 1.0 M 4,4,5,5-tetramethyl-1,3,2-dioxaborolane in tetrahydrofuran (4.24 mL), triethylamine (0.92 mL), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (0.087 g) in CH3CN (15 mL) was heated at 100° C. in a Biotage Initiator microwave reactor for 30 minutes. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to provide the title compound.
Reaction SMILES: CC(CSC[C@H]1[O:11][C@@H:10]([N:12]2C3NC=NC(=O)C=3N=C2)[C@H](O)[C@@H]1O)C.[C:24]1([OH:34])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(N(CC)C(Cl)=O)C>N1C=CC=CC=1>[C:10](=[O:11])([O:34][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[NH2:12]
Reactant: CC(C)CSC[C@H]1O[C@@H](n2cnc3c(=O)nc[nH]c32)[C@H](O)[C@@H]1O
Reactant: Oc1cccc2ccccc12
Agent: CCN(CC)C(=O)Cl
Solvent: c1ccncc1
Product: NC(=O)Oc1cccc2ccccc12

Procedure:
Sibi et al (J. Org. Chem., 48 (11), 1935-1937, 1983) disclose reaction of 1-naphthol with diethyl carbamyl chloride in pyridine to produce a 1-naphthyl carbamate. Treatment of 1-naphthyl carbamate under the standard conditions for methylation of tertiary amides (1.1 equiv. sec-BuLi/TMEDA/THF/-78° C./1 hour) followed by quenching with methyl iodide, warming to room temperature (8 to 12 hours) and NH4Cl work-up, afforded 2-methyl-1-naphthyl carbamate in a yield of 90%. Carbamate removal was effected in a yield of 90% by reduction (LAH/THF/reflux;H+) or hydrolysis (NaOH/aqueous CH3OH or HO(CH2)2OH/reflux) to yield 2-methyl-1-naphthol.
Reaction SMILES: FC1C=CC2N(C(CC3N(C)C=CN=3)=C(C3C=CC(F)=CC=3)N=2)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]3[C:40]=2[CH:41]=O)=[CH:28][CH:27]=1.[CH3:43][N:44]1[CH:48]=[N:47][CH:46]=[N:45]1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]3[C:40]=2[CH2:41][C:48]2[N:44]([CH3:43])[N:45]=[CH:46][N:47]=2)=[CH:28][CH:27]=1
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: Cn1cncn1
Agent: Cn1ccnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Product: Cn1ncnc1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Yield: 89 %

Procedure:
The title compound was prepared according to Method C and the experimentals described for compound 199 from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and 1-methyl-1H-1,2,4-triazole. (0.22 g, 89% yield). M/e+ 324.1 for C17H14ClN5 (M+H)+; 1H-NMR (300 MHz, DMSO-d6, δ) 8.26 (d, J=6.9 Hz, 1H), 7.74-7.70 (m, 3H), 7.65-7.61 (m, 1H), 7.54-7.51 (m, 2H), 7.33-7.28 (m, 1H), 6.93 (td, J=6.8, 1.2 Hz, 1H), 4.68 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:13](=O)[CH3:14])[C:10](=O)[CH3:11])=[CH:5][CH:4]=1.Cl.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.O>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[C:13]([CH3:14])=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:10]([CH3:11])=[N:32]2)=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(C(C(C)=O)C(C)=O)cc1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2c(C)nn(-c3ccc(OCc4ccccc4)cc3)c2C)cc1
Yield: 61.8 %

Procedure:
A solution of 3-(4-methoxyphenyl)pentane-2,4-dione (50 mg, 0.24 mmol, prepared according to Ghosh et al, Bioorg. Med. Chem. 2003, 11, 629) and (4-benzyloxyphenyl)hydrazine hydrochloride (61 mg, 0.24 mmol) in ethanol (3 mL) was heated at 80° C. overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with 1 N HCl (2×) and saturated sodium bicarbonate (1×), dried (MgSO4), and concentrated to give 57 mg of the crude pyrazole. LC-MS (C25H24N2O2 calculated 384) m/z 385 (M+H).
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14][C:2]1=2.C(O)(=O)C>[Pd].CO>[NH:1]1[C:6](=[O:7])[CH2:5][CH2:4][C@@H:3]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14][C@H:2]12
Reactant: O=C1CCC2=C(Cc3ccccc32)N1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CC[C@@H]2c3ccccc3C[C@@H]2N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1,3,4,9-tetrahydro-indeno[2,1-b]pyridin-2-one (1.10 g), 10% palladium on carbon (0.15 g), acetic acid (0.75 mL), and methanol (20 mL) is shaken under hydrogen atmosphere (3 bar) at room temperature for 6 h. The catalyst is then separated by filtration and the filtrate is concentrated. The residue is triturated with tert-butyl methyl ether and dried to give the title compound as a colorless solid. Yield: 0.99 g (89% of theory); LC (method 1): tR=2.53 min; Mass spectrum (ESI+): m/z=188 [M+H]+.