Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@H:10]([O:14][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]/[CH:27]=[CH:26]\[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Reactant: CCCCCC/C=C\CCCCCCCCCCOS(C)(=O)=O
Product: CCCCCC/C=C\CCCCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCCCC/C=C\CCCCCC

Procedure:
Compound VI-14 (244 mg, 60.8%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 112 mg, 0.577 mmol) and (Z)-octadec-11-enyl methanesulfonate (Nu-Chek Prep, Inc; 500 mg, 1.44 mmol).
Reaction SMILES: I[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:6]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:5]2[CH:6]=[C:2]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[N:4]2)=[CH:9][CH:10]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: COc1ccc(Cn2cc(I)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3ccncc3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1

Procedure:
To a solution of 100 mg (0.23 mol) of 4-iodo-1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazole in 16 ml of dioxane and 4 ml of water, 90 mg (0.46 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 52 mg (0.046 mmol) of palladium tetrakis and 150 mg (0.46 mmol) mg of cesium carbonate were added successively. The mixture was submitted to microwave irradiation at 120° C. for 30 minutes in a sealed vial. The reaction was filtered through a celite pad and the solvent evaporated to dryness. The crude was then partitioned between dichloromethane and water, the organic layer dried over sodium sulphate and the solvent removed in vacuo. After purification by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3) 78 mg (88%) of the title compound were obtained.
Reaction SMILES: [CH3:1][S:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14](N)=[O:15])=[C:7]2[N:6]=[N:5]1.N([O-])=[O:18].[Na+]>C(O)(C(F)(F)F)=O.O>[CH3:1][S:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]([OH:15])=[O:18])=[C:7]2[N:6]=[N:5]1
Reactant: CSCn1nnc2c(C(N)=O)ncn2c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CSCn1nnc2c(C(=O)O)ncn2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 3-(methylthiomethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (12.43 mmol, 3 g, 1 eq.) in TFA (12 mL) was added sodium nitrite (43.5 mmol, 3 g, 3.5 eq.) dissolved in water (6 mL) portion-wise keeping exothermic effervescence under control and the mixture was stirred at room temperature for over 3 hours. The reaction mixture was poured into ice and it was gently stirred until the ice melted. The resulted suspension was filtered, washed with water and ether and dried under vacuum to give the title compound. Yield=61%. δH (DMSO-d6) 8.85 (1H, s), 5.44 (2H, s), 2.25 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]3[CH3:25])[CH:12]=[C:11]([CH3:26])[N:10]=2)=[CH:4][CH:3]=1.[CH3:27][O:28][CH2:29][Cl:30]>C(OCC)C>[ClH:30].[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]3[CH3:25])[C:12]([CH2:27][O:28][CH3:29])=[C:11]([CH3:26])[N:10]=2)=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: Cc1cc(N2CCc3ccccc3C2C)nc(Nc2ccc(F)cc2)n1
Solvent: CCOCC
Product: COCc1c(C)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C
Product: Cl
Temperature: 80 °C
Reaction time: 24 h
Yield: 0.05 %

Procedure:
2-(4-Fluorophenylamino)-6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquino-line-2-yl)pyrimidine (0.9 g, 2.58 mmol) was added to chloromethyl methyl ether (3 ml) in a sealed tube. The mixture was stirred at 80° C. for 1 day. After cooling to room temperature, ethyl ether was added to mixture. Resulting solid was removed by filtration. Filtrate was washed with aqueous 2N NaOH solution, dried over sodium sulfate, and concentrated under reduced pressure. Crude product was purified with a silica gel column chromatography (eluent: ethyl acttate:hexane=1:3). Purified compound was treated with HCl solution in ethyl ether. Precipitated solid was isolated by filtration, washed with ethyl ether, and dried in vacuum. It gave 0.6 mg of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[CH:13][C:14]([F:27])=[C:15]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=4)=[O:19])[CH:16]=3)=[CH:6][N:5]2[CH:28]=1.[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>O1CCCC1.O>[CH2:29]([NH:31][C:32]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[CH:13][C:14]([F:27])=[C:15]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=4)=[O:19])[CH:16]=3)=[CH:6][N:5]2[CH:28]=1)=[O:33])[CH3:30]
Reactant: CCN=C=O
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4c3)ccc2F)n(C)n1
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)Nc1cn2cc(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.3 %

Procedure:
To a solution of N-{5-[(2-aminoimidazo[1,2-a]pyridin-6-yl) oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (70.0 mg, 0.184 mmol) in tetrahydrofuran (3 mL) was added ethyl isocyanate (17.5 μL, 0.221 mmol), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate-ethanol to give the title compound (21.0 mg, 25%) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1(O)[CH2:7][S:6][C:5]([CH2:8][N:9]([CH3:11])[CH3:10])=[N:4]1.ClCCCl.P(Cl)(Cl)(Cl)=O>O>[ClH:1].[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:8][N:9]([CH3:11])[CH3:10])[S:6][CH:7]=1
Reactant: CN(C)CC1=NC(O)(CCl)CS1
Solvent: O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)Cc1nc(CCl)cs1
Product: Cl
Reaction time: 0.5 h

Procedure:
A 1.9 g. portion of 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline and 19 ml. of 1,2-dichloroethane were added to a 100 ml. flask, and the mixture was cooled while 1.53 g. of phosphorus oxychloride dissolved in 10 ml. of 1,2-dichloroethane was added dropwise. The mixture was stirred for 30 minutes at 23°, and then at 50° for 1 hour. It was cooled, and 25 ml. of water was added. The layers were separated, and both layers were examined by the tlc system described above in Example 1. No product or starting compound was in the organic layer. The aqueous layer contained all of the product and there was no indication of remaining starting material.
Reaction SMILES: C([NH:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([CH3:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>Cl>[NH2:9][CH:10]1[CH2:11][C:12]([CH3:19])([CH3:20])[N:13]([CH3:18])[C:14]([CH3:17])([CH3:16])[CH2:15]1
Reactant: CN1C(C)(C)CC(NC(=O)c2ccccc2)CC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1C(C)(C)CC(N)CC1(C)C

Procedure:
750 Parts of 4-benzoylamino-1,2,2,6,6-pentamethylpiperidine are dissolved in 1000 parts of concentrated hydrochloric acid and the solution is boiled under reflux for 10 hours. Sodium hydroxide solution is added after cooling until the reaction is alkaline, and the mixture is repeatedly extracted with methylene chloride. The residue left after evaporation of methylene chloride is distilled under vacuum; 300 parts of 1,2,2,6,6-pentamethyl-4-amino-piperidine boiling at 98° C./15 Torr are thereby distilled over.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[N:8]=[CH:7]2.[N:23]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].S(NN)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([N:9]2[N:8]=[CH:7][C:6]3[C:11](=[C:2]([NH:1][CH2:29][C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)[CH:3]=[CH:4][CH:5]=3)[C:10]2=[O:12])=[CH:18][CH:17]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(-n2ncc3cccc(N)c3c2=O)cc1
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-n2ncc3cccc(NCc4ccncc4)c3c2=O)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of the amine (Step E, 45 mg, 0.15 mmol) and CH2Cl2 (10 mL) was added 4-pyridinecarboxaldehyde (0.04 mL, 0.39 mmol) and NaBH(OAc)3 (95 mg, 0.45 mmol). The reaction was stirred at RT for 7 h then quenched with H2O and extracted with CH2Cl2. The organic layer was washed with H2O and brine, dried (MgSO4) and concentrated in vacuo to give the crude product as an orange oil. The crude product was dissolved in 10 mL CH2Cl2 and stirred with PS-TsNHNH2 resin to remove un-reacted aldehyde. After 1 h, the mixture was filtered through Celite® and concentrated in vacuo. The residue was purified by silica flash chromatography (20-75% EtOAc:hexane) to give the desired product as a light-yellow crystalline solid. MS m/e 385 (M+H)+. Calc'd for C24H24N4O-384.47.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:25]/[O:26][C:27]2([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:29][CH2:28]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][OH:24])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:25]/[O:26][C:27]2([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH2:28][CH2:29]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][O:24][S:47]([CH3:46])(=[O:49])=[O:48])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CO)cs1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2COS(C)(=O)=O)cs1
Reaction time: 2 h

Procedure:
To a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2S,3S)-2-(hydroxymethyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (1 g, 1.57 mmol) at 0° C. in THF (15.7 ml) was added TEA (0.66 ml, 4.7 mmol) and MsCl (25 μl, 0.32 mmol). After 2 h, the reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo, affording the title compound (assumed quantitative). LCMS: R=0.99 min, m/z=714.1 (M+1), Method 2m_acidic.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:10]([O:21]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2OC2C1
Reaction time: 8 h
Yield: 55.6 %

Procedure:
2,5-Dihydro-pyrrole-1-carboxylic acid tert-butyl ester (46 g, 65% purity) was dissolved in CH2Cl2 (500 mL). The solution was cooled to 0° C. mCPBA (122 g, 2 eq, 77% purity) was slowly added to the solution at 0° C. The reaction mixture was stirred at 0° C. to RT for overnight. The mixture was concentrated to 200 ml, and filtered. The organic phase was washed with 1 N NaOH solution (4×100 mL), dried over Na2SO4. The resulting oil was purified by column chromatography (hexane:ethyl acetate 3:1) to give 28 g of desired product as a colorless oil (87% yield). 1H-NMR (300 MHz, CDCl3): δ 1.41 (s, 9H), 3.26 (dd, 2H), 3.25-3.80 (m, 4H)
Reaction SMILES: [OH:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])N1CCCC.Cl.[OH2:24]>>[OH:24][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[O:1]1
Reactant: CCCCN1C(=O)c2cccnc2C1(O)c1cccc(Cl)c1
Reactant: O
Agent: Cl
Product: O=C1OC(O)(c2cccc(Cl)c2)c2ncccc21

Procedure:
To the 7-hydroxy-7-(3-chlorophenyl)-6-(n-butyl)-6,7-dihydropyrrolo[3,4-b]pyridin-5-one was added 500 mL of water, 250 mL of concentrated hydrochloric acid and the mixture was heated under reflux for 24 hours. The solution was then filtered, cooled and made basic with sodium hydroxide. An ethyl acetate extraction removed unhydrolyzed starting material and the pH of the resulting aqueous fraction was adjusted to pH 2 with hydrochloric acid. The resulting aqueous fraction was extracted twice with ethyl acetate (250 mL). The solvent was removed yielding 16 g of 7-hydroxy-7-(3-chlorophenyl)-7H-furo[3,4-b]pyridin-5-one, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.Br[CH2:11][CH2:12][CH2:13][OH:14]>ClCCl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:11][CH2:12][CH2:13][OH:14])=[C:4]([CH3:9])[CH:3]=1
Reactant: OCCCBr
Reactant: Cc1cc(Cl)ccc1N
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1NCCCO
Temperature: 100 °C
Yield: 143.2 %

Procedure:
A mixture of 4-chloro-2-methylaniline (35.7 g) and 3-bromo-1-propanol (8.75 g) was heated at 100° C. under nitrogen for 1 hour. After cooling, a solid mass formed which was partitioned between dichloromethane and 1N sodium hydroxide. The organic layer was washed with brine, dried over anhydrous potassium carbonate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 100% dichloromethane to 95:5 dichloromethane-methanol) provided the title product (18.0 g, 90%) as a brown oil, which was used as such in the next step.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][C:35]3[S:36][CH:37]=[CH:38][N:39]=3)[CH:29]=2)[C:25](=[O:27])[CH3:26])=[CH:18][CH:17]=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][CH3:14].C[I:41].[CH3:42]COCC>C1(C)C=CC=CC=1>[I-:41].[CH3:42][N+:39]1[CH:38]=[CH:37][S:36][C:35]=1[CH2:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([N:24]([C:25](=[O:27])[CH3:26])[CH2:23][CH2:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][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][CH3:14])=[CH:21][CH:20]=2)[CH:29]=1
Reactant: CI
Reactant: CCCCCCCCCCCCCCOc1ccc(CCN(C(C)=O)c2cccc(Cc3nccs3)c2)cc1
Reactant: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOc1ccc(CCN(C(C)=O)c2cccc(Cc3scc[n+]3C)c2)cc1
Product: [I-]
Temperature: 140 °C

Procedure:
A mixture of 300 mg of N-[2-[4-(tetradecyloxy)phenyl]ethyl]-N-[3-(2-thiazolylmethyl)phenyl]acetamide and 1.4 g of methyl iodide in 5 ml of toluene is heated at 140° C. in a closed vessel for 4.5 hours then cooled. Ether is added, the solid collected by centrifugation and then washed several times with ether. The solid is vacuum dried to give 235 mg of the desired product as a tan solid, m.p. 130°-134° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.C(OCC)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:32]([NH:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:33])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)Nc2ccccc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 80 %

Procedure:
To a stirred solution of 2-amino-4-methylthiazole-5-carboxylic acid benzylamide (0.10 g, 0.40 mmol) in anhydrous tetrahydrofuran (5 mL), triethylamine (0.17 mL, 0.12 g, 1.22 mmol) and phenyl isocyanate (0.07 mL, 0.072 g, 0.61 mmol) were added dropwise at ambient temperature. The reaction mixture was stirred at ambient temperature for 25 h and then diluted with ethyl ether (20 mL). The white precipitate obtained was collected by filtration, washed with ethyl ether (3×6 mL) and dried under the reduced pressure to afford the title compound as a white solid in 80% yield (0.119 g); m.p.>300° C.; 1H NMR (DMSO-d6, 300 MHz) δ 9.00 (s, 1H), 8.47 (t, J=5.7 Hz, 1H), 7.46-7.17 (m, 10H), 7.03-6.98 (m, 1H), 4.35 (d, J=6.0 Hz, 2H), 2.43 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 162.2, 140.2, 140.0, 129.4, 129.2, 128.7, 127.7, 127.1, 123.3, 119.1, 118.6, 43.0, 39.1; MS (ES+) m/z 367.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]=[CH:9][N:10]([CH3:12])[CH3:11])[C:5]([C:13]#[N:14])=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O>[C:13]([C:5]1[C:6]([N:8]=[CH:9][N:10]([CH3:12])[CH3:11])=[N:7][C:2]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)=[C:3]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)[N:4]=1)#[N:14]
Reactant: CC(C)n1nc(-c2nc(C#N)c(N=CN(C)C)nc2Cl)ccc1=O
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)n1nc(-c2nc(C#N)c(N=CN(C)C)nc2-c2ccc(F)cc2)ccc1=O
Temperature: 90 °C
Reaction time: 15 h
Yield: 103.2 %

Procedure:
A mixture of N′-[6-chloro-3-cyano-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide (100 mg), 4-fluorophenylboronic acid (122 mg), tetrakistriphenylphosphine palladium (10 mg) and Na2CO3 (123 mg) in dioxane (5 ml) and water (1 ml) was stirred at 90° C. for 15 hours. Water and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain N′-[3-cyano-6-(4-fluorophenyl)-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide (121 mg) as white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7])([O-])=O.[H][H].C(#N)C>C(O)C.[Pt]>[NH2:1][C:4]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7]
Reactant: [H][H]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])cc1OC
Agent: [Pt]
Solvent: CC#N
Solvent: CCO
Product: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
In 10 ml of ethanol, 1 g (2.88 mmol) of 2-nitro-4,5,3',4'-tetramethoxybenzophenone (prepared according to Example 2) was hydrogenated on 100 mg of platinum/activated carbon (5 percent Pt, moist, H2O content 50 percent) at 40° C. and a hydrogen pressure of 2 bar. After 5 h, the reaction mixture was cooled to room temperature, and 10 ml of acetonitrile was added. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 0.88 g of 2-amino-4,5,3',4'-tetramethoxybenzophenone as a beige solid. The yield of the product was 96 percent of theory.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([OH:29])=[O:28].C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:27]([OH:29])=[O:28].[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=1)=[O:28]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: O=C(O)c1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1ccccn1
Product: O=CO
Yield: 156.3 %

Procedure:
To a solution of (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (80 mg, 0.259 mmol) in DMF (5 ml) was added 2-pyridinecarboxylic acid (31.9 mg, 0.259 mmol), HOBT.H2O (39.7 mg, 0.259 mmol), HBTU (98 mg, 0.259 mmol) and DIPEA (0.136 ml, 0.778 mmol) and the reaction mixture was stirred at room temperature overnight. DMF was evaporated in vacuo then 5 ml of DCM were added and washed with saturated NaHCO3 solution (5 ml), dried on a phase separation cartridge and evaporated in vacuo. The crude material was dissolved in MeCN/DMSO 1:1 and purified by MDAP. The desired fractions were collected and concentrated under vacuo giving the title compound (93 mg).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([NH:14][C@@H:15]([CH2:19][C:20]1[CH:27]=[C:25]([OH:26])[C:23]([OH:24])=[CH:22][CH:21]=1)[C:16]([OH:18])=[O:17])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(#N)C>[CH2:28]([O:26][C:25]1[CH:27]=[C:20]([CH2:19][C@H:15]([NH:14][C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[C:16]([O:18][CH2:19][C:20]2[CH:27]=[CH:25][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:21]=[CH:22][C:23]=1[O:24][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)OCc1ccccc1
Temperature: 55 °C
Yield: 163.3 %

Procedure:
K2CO3 (21.0 g, 150 mmol) was added to a solution of Boc-L-dopa (10.0 g, 33 mmol) in acetonitrile (100 mL) followed by addition of benzyl bromide (21.0 g, 123 mmol). The suspension was heated at 50-60° C. for 4 h and then cooled to ambient temperature. The mixture was filtered and the filtration cake was washed with acetonitrile (50 mL). The filtrate and washings were combined and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (Hexane/EtOAc=20:1) to afford (S)-benzyl 3-(3,4-bis(benzyloxy)phenyl)-2-(tert-butoxycarbonylamino)propanoate (15.3 g, yield 80%).