Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[C:21](/[CH3:26])=[CH:22]/[C:23]([OH:25])=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.P([N:52]=[N+:53]=[N-:54])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(O)(C)C>[F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[C:21](/[CH3:26])=[CH:22]/[C:23]([N:52]=[N+:53]=[N-:54])=[O:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: C/C(=C\C(=O)O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C/C(=C\C(=O)N=[N+]=[N-])c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To (E)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-2-enoic acid (C28) (1.14 g, 2.93 mmol) in isopropanol (9.8 mL) was added triethylamine (0.53 mL, 3.81 mmol) and diphenyl phosphorazidate (0.68 mL, 3.23 mmol). The reaction was stirred at room temperature overnight. The white precipitate was vacuum-filtered and dried in a vacuum oven to afford the title compound as a white solid (0.978 g, 80%): 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.25-8.19 (m, 2H), 7.85-7.78 (m, 2H), 7.65-7.58 (m, 2H), 7.44-7.37 (m, 2H), 6.16 (d, J=1.3 Hz, 1H), 2.68 (d, J=1.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 387 ([M+H]+) (isocyanate).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[C:12]3[CH:13]=[CH:14][S:15][C:16]=3[CH2:17][C:10]=2[C:9]([C:18]2[CH:19]=[CH:20][C:21]([NH:24]C(=O)C)=[N:22][CH:23]=2)=[N:8]1.[ClH:30]>CO>[ClH:30].[S:15]1[CH:14]=[CH:13][C:12]2[C:11]3[NH:7][N:8]=[C:9]([C:18]4[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=4)[C:10]=3[CH2:17][C:16]1=2
Reactant: CC(=O)Nc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sccc2-3)cn1
Agent: Cl
Solvent: CO
Product: Nc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cn1
Temperature: 100 °C
Yield: 90 %

Procedure:
N-{5-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-pyridin-2-yl}-acetamide (0.21 g, 0.5 mmol) was dissolved in MeOH and treated with concentrated HCl (0.16 mL, 5 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 5-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-pyridin-2-ylamine hydrochloride (0.13 g, 0.45 mmol) as yellow solid in 90% yield.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[Br:17][C:18]1[C:22]([Br:23])=[C:21](Br)[N:20]([CH3:25])[N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:23][C:22]1[C:18]([Br:17])=[N:19][N:20]([CH3:25])[C:21]=1[C:13]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]2=[N:15][C:14]=1[CH3:16]
Reactant: Cn1nc(Br)c(Br)c1Br
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3c(Br)c(Br)nn3C)c(C)nc12
Temperature: 130 °C
Yield: 32 %

Procedure:
8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (300 mg, 1.4 mmol), 3,4,5-tribromo-1-methyl-1H-pyrazole (700 mg, 2.1 mmol) and cesium carbonate (900 mg, 2.8 mmol) are stirred in DMF (5 ml) and degassed by bubbling a stream of nitrogen through the mixture. PdCl2(PPh3)2 (14 mg) is added and the mixture heated to 130° C. overnight. The mixture is added to water and extracted twice with EtOAc. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography using a hexane-ethyl acetate gradient (100% hexane to 20% ethyl acetate in hexane) to elute the title product (204 mg, 32% yield). ES-MS (m/z): calc'd for C17H21Br2N5: 455.2. found 455.9 (M+H)+. 1H NMR (400 mHz, CDCl3): δ 6.75 (s, 1H), 3.72 (s, 3H), 3.33 (m, 1H), 2.51 (s, 3H), 2.45 (s, 3H), 1.84 (m, 4H), 0.88 (t, 6H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@:11]([CH3:15])([OH:14])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:18](OC)([CH3:20])[CH3:19].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][C@@:11]1([CH3:15])[CH2:12][O:13][C:18]([CH3:20])([CH3:19])[O:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@](O)(CO)CCOCc1ccccc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OC[C@](C)(CCOCc2ccccc2)O1

Procedure:
To the mixture of compound 2 and 2,2-dimethoxypropane in DCM was added p-TSA. After TLC monitoring showed the disappearance of the starting material, aqueous NaHCO3 solution was added and then extracted with ethyl acetate three times. The combined organic phase was washed with brine and dried (Na2SO4). The solid was filtered and the solvent was removed. The residue was purified by column chromatography to give compound 3.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:12])=[O:13])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(OC)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (0.906 g, 22.67 mmol) in dimethylformamide (50.0 mL), is added ethyl 2-[[4-methoxybenzenesulfonyl]amino]acetate (4.13 g, 15.11 mmol) and 4-methoxybenzyl chloride (2.17 mL, 15.87 mmol), and the reaction is stirred overnight at room temperature. The reaction is cooled to 0° C., quenched with 1N hydrochloric acid, and extracted well with ether. The combined organic layers are washed with brine, dried (Na2SO4), and the solvent is evaporated. The product is recrystallized from ether/hexanes to give ethyl 2-[[4-methoxybenzenesulfonyl](4-methoxybenzyl)amino]acetate.
Reaction SMILES: [C:1]([O:9]C=C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=COC(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), (PPh3)2PdCl2 (0.05 mmol), L-menthoxyethanol (0.5 mmol), and vinyl benzoate (0.5 mmol). The reactor is sealed, pressurized to 1000 psig with CO, and stirred for 24 hours at 100° C. The product mixture, isolated after removal of gas from the reactor vessel, contains a diastereomeric mixture of L-menthoxyethyl benzoyl-L-lactate and L-menthoxyethyl benzoyl-D-lactate. The diastereomers are separated by preparative gas chromatography using an SE-30 liquid phase column. Each diastereomer is hydrolyzed separately by treatment with 2N HCl (aq) for 2 hours at 100° C. to give pure L- and D-lactic acid, benzoic acid, and L-menthoxyethanol, which is thereafter recycled to a repeat of the foregoing hydrocarboxylation reaction.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O>[C:17]([Si:21]([CH3:24])([CH3:23])[O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCOc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a solution of 4-(2-hydroxy-ethoxy)-phenol (4.2 g, 27 mmol) in anhydrous N,N-dimethylformamide (30 mL) at 0° C. was added imidazole (2.1 g, 31 mmol) and tert-butyldimethylchlorosilane (4 g, 27 mmol). The reaction mixture was then stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and water. Organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1;4) to give 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenol as a colorless oil (5.1 g, 70%)
Reaction SMILES: [H-].[Na+].[Si]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2)(C(C)(C)C)(C)C.CS(O[CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)(=O)=O.O>CN(C=O)C>[OH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[N:15]=[CH:14]2
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3cc(O)ccc32)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
To a solution of NaH (60% in mineral oil) (43.5 mg, 1.81 mmol) in DMF at 0° C. was added 5-((tert-butyldimethylsilyl)oxy)-1H-indazole (300 mg, 1.21 mmol), and the mixture was stirred at 0° C. for 15 min. Tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (243 mg, 1.21 mmol) was then added to the mixture at 0° C. After addition, the mixture was stirred at 85° C. for 12 h. The mixture was poured into water, and the product extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by TLC (Pet.Ether:EtOAc=2:1) to give tert-butyl 4-(5-hydroxy-1H-indazol-1-yl)piperidine-1-carboxylate (250 mg, yield 65%) as a colorless oil. LCMS (m/z): 318.2 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:6][N:7]=1.[CH2:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:27]([NH:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:28])[CH:9]=2)=[CH:6][N:7]=1
Reactant: O=C=NCc1ccccc1
Reactant: CNC(=O)c1nc(-c2cccc(N)c2)cnc1N
Solvent: C1CCOC1
Product: CNC(=O)c1nc(-c2cccc(NC(=O)NCc3ccccc3)c2)cnc1N
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of 3-amino-6-(3-aminophenyl)-N-methylpyrazine-2-carboxamide (0.25 g, 1.03 mmol) in dry tetrahydrofuran (2 mL) was added benzyl isocyanate (0.15 g, 1.12 mmol). The mixture was allowed to stir overnight. The solid product was filtered from the reaction mixture and triturated with hexane/ethyl acetate (9:1). The solid was collected by filtration and dried to afford 3-amino-N-methyl-6-[3-({[(phenylmethyl)amino]carbonyl}amino)phenyl]pyrazine-2-carboxamide (0.26 g, 70% yield) as light yellow solid. 1H NMR (400 MHz, d6-DMSO): 8.80 (m, 1H), 8.64 (s, 1H), 8.02 (s, 1H), 7.68 (d, 1H), 7.58 (d, 1H), 7.30 (m, 8H), 4.30 (d, 2H), 2.80 (d, 3H); MS (EI) for C20H20N6O2: 377 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](O)=O)=[CH:2]1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:31][C:32]1[CH:50]=[CH:49][C:35]2[N:36]=[C:37]([NH:40][C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:48])[N:38]([CH3:39])[C:34]=2[C:33]=1[C:51]([NH2:53])=[O:52]>CN(C=O)C.CCOC(C)=O>[Cl:48][C:42]1[CH:43]=[CH:44][CH:45]=[C:46]([Cl:47])[C:41]=1[NH:40][C:37]1[N:38]([CH3:39])[C:34]2=[C:33]3[C:32](=[CH:50][CH:49]=[C:35]2[N:36]=1)[N:31]=[C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[NH:53][C:51]3=[O:52]
Reactant: O=C(O)c1ccoc1
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc(N)c(C(N)=O)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc3nc(-c4ccoc4)[nH]c(=O)c3c21
Reaction time: 24 h

Procedure:
Furan-3-carboxylic acid (20 mg, 0.18 mmol), hydroxybenzotriazole (24 mg, 0.18 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (35 mg, 0.18 mmol) were stirred together in DMF (1 mL) for 15 min. 5-Amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzoimidazole-4-carboxylic acid amide (Example 7)(50 mg, 0.15 mmol) was added, and stirring continued for 24 h. The solution was diluted with EtOAc and washed in turn with aqueous Na2CO3, water and brine. The organic layer was evaporated and the residue dissolved in MeOH (2 mL). Sodium methoxide in MeOH (25%, 0.1 mL) was added and the solution heated to reflux for 45 min. The cooled solution was partitioned between water and CH2Cl2. The organic layer was evaporated and the crude product stirred with MeOH (1 mL) for 1 h. The solid was filtered, washed with a few drops of MeOH and dried to yield the title compound, 8 (14 mg, 22%). mp>300° C. MS (ES) 428, 426 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[I:11].S(Cl)(Cl)=O.O1CCOCC1.C([N:25](C(C)C)CC)(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:25])=[O:7])=[CH:4][C:3]=1[I:11]
Reactant: O=C(O)c1ccc(Cl)c(I)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc(Cl)c(I)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
4-chloro-3-iodobenzoic acid (2.09 g, 7.40 mmol) was suspended in thionyl chloride (0.540 mL, 7.40 mmol) and heated to 70° C. for 3 h before it was concentrated and azeotropically dried with toluene. The concentrate was dissolved in ammonia, 0.5 M in 1,4-dioxane (92.5 mL, 37.0 mmol) to which diisopropylethylamine (6.44 mL, 37.0 mmol) was added and it was stirred at RT for 3 h. The mixture was diluted with 100 mL of ethyl acetate, added to a separation funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 4 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated in vacuo to give the title compound. MS (ES+): 282 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]#[C:13][C:14]([CH3:17])(O)C)=[N:7]2.[OH-].[K+].Br[C:21]1[CH:26]=[CH:25]C=C[N:22]=1.CCOC(C)=O.CCCCCC>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]#[C:13][C:14]1[CH:17]=[CH:25][CH:26]=[CH:21][N:22]=1)=[N:7]2
Reactant: Brc1ccccn1
Reactant: CC(C)(O)C#Cc1ccc2c(Cl)cccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: Clc1cccc2nc(C#Cc3ccccn3)ccc12
Temperature: 110 °C
Reaction time: 0.08 h

Procedure:
4-(5-Chloroquinoline-2-yl)-2-methylbut-3-yn-2-ol (24.5 mg, 0.0997 mmol), PdCl2(PPh3)2 (3.4 mg, 0.00484 mmol), CuI (1.2 mg, 0.00875 mmol), and KOH (44.6 mg, 0.795 mmol) were dissolved in diisopropylamine (0.2 mL) in a vial. The resulting mixture was stirred for 5 min under nitrogen atmosphere, followed by adding 2-bromopyridine (9.6 uL, 0.0997 mmol) thereto. After the vial was capped, it was heated to 110° C. The completion of the reaction was confirmed by TLC (EtOAc/Hexane=1:1). When the reaction was completed, the reactant was cooled down to room temperature and filtered through Celite and ethyl acetate. The thus obtained filtrate was extracted with ethyl acetate, to thereby obtain an organic layer. The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (EtOAc/Hexane=1:1, R.f: 0.3), to thereby obtain 5-chloro-2-(pyridine-2-ylethynyl)quinoline (6.2 mg, 25%) as a brown solid.
Reaction SMILES: CS(O)(=O)=[O:3].[F:6][C:7]([F:19])([F:18])[C:8]1[CH:9]=[C:10]([CH:14](O)[CH:15]=[CH2:16])[CH:11]=[CH:12][CH:13]=1.C1(C)C=CC=CC=1>O1CCCC1.O>[F:6][C:7]([F:19])([F:18])[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH2:16][OH:3])[CH:11]=[CH:12][CH:13]=1
Reactant: C=CC(O)c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: OCC=Cc1cccc(C(F)(F)F)c1

Procedure:
Methanesulphonic acid (59.4 g) was added to a solution of 1-[3-(trifluoromethyl)phenyl]prop-2-en-1-ol (50 g) in tetrahydrofuran (200 mL) and de-ionized water (100 mL) at room temperature. Reaction mixture was refluxed at 65° C. to 70° C. for about 20-22 hours. After completion of the reaction, de-ionized water (50 mL) and toluene (200 mL) were added to organic layer. Organic layer was separated and neutralized to pH 7.5-8.0 using solution of sodium bicarbonate (7%), and concentrated under vacuum to give 3-[3-(trifluoromethyl)phenyl]prop-2-en-1-ol as oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH:25][CH2:26][C@@H:27]3[C@H:32]([CH3:33])[CH2:31][CH2:30][CH2:29][NH:28]3)=[N:22][C:21]=2[CH:34]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH:25][CH2:26][C@@H:27]3[C@H:32]([CH3:33])[CH2:31][CH2:30][CH2:29][N:28]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)=[O:9])=[N:22][C:21]=2[CH:34]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: Cc1ccc(-n2cncn2)c(C(=O)O)c1
Product: Cc1ccc(-n2cncn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(1H-1,2,4-triazol-1-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 465 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([NH2:9])[CH:5]=1.[OH:10][C:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14](=[O:22])(=[O:21])[N:13]([CH3:23])[C:12]=1[C:24](OC)=[O:25]>C1(C)C(C)=CC=CC=1>[OH:10][C:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14](=[O:22])(=[O:21])[N:13]([CH3:23])[C:12]=1[C:24]([NH:9][C:6]1[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[O:8][N:7]=1)=[O:25]
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: COCc1cc(N)no1
Solvent: Cc1ccccc1C
Product: COCc1cc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)no1
Reaction time: 8 h
Yield: 22.3 %

Procedure:
A mixture of 0.52 g (4 mmole) of 5-(methoxymethyl)-3-isoxazolamine, 1.08 g (4 mmole) of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide, and 100 ml of xylene is heated at reflux for six hours in a soxhlet apparatus, the thimble of which contains 20 g of Linde type 4A molecular sieve. The reaction mixture is filtered to clarify it and is allowed to stand at room temperature overnight when the product crystallizes out. The product is filtered, washed with methanol-ether mixture, and then recrystallized from methanol to give 0.326 g of white crystals, mp 218°-223° C. dec.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15]>C(Cl)Cl>[Cl:19][C:18]([Cl:21])([Cl:20])[CH2:17][O:16][C:14](=[O:15])[NH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](=[O:7])[N:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)c1ccc(N)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a 250 mL round bottom flask, 4-amino-N,N-dimethyl-benzamide (20 g, 0.1219 mol; prepared as described in Preparation 1) and 2,2,2-trichloroethyl chloroformate (30 g, 0.1463 mol), TEA (34 mL, 0.2438 mol) and DCM (100 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product. The crude product was washed with diethyl ether and dried under reduced pressure to afford the title compound [30 g, 73%]. LC-MS (ESI): Calculated mass: 338.0; Observed mass: 341.0 (RT: 1.38 min). The compound was directly taken to the next step.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[NH:15][CH:16]=2)=[CH:6][CH:5]=1.O>C(O)(=O)C.CCOC(C)=O>[Br:1][C:16]1[NH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=1[CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: O=C(O)c1cc(CCc2ccc(Cl)cc2)c[nH]1
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(CCc2ccc(Cl)cc2)c(Br)[nH]1
Yield: 57.7 %

Procedure:
Bromine (0.049 mL, 0.962 mmol) was added dropwise over 5 minutes to a stirring solution of 39 (0.200 g, 0.802 mmol) in acetic acid (2.5 mL). When the reaction was judged complete by HPLC (30 min), H2O was added, and the solid that precipitated was filtered off and washed with H2O. The light purple solid that was obtained was dissolved in EtOAc, washed with Na2SO3 and H2O, then dried with Na2SO4, filtered, and concentrated. The product was purified by preparative reverse phase HPLC with 40:60 H2O:CH3CN (w/0.05% TFA); 20 mL/min.; λ=214 nM. 0.1520 g (57.7%) of 70 was obtained as a fluffy white solid. 1H (CD3OD, 400 MHz): δ 7.22 (2H, d, J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz), 6.65 (1H, s), 2.81 (2H, t, J=7.3 Hz), 2.67 (2H, t, J=7.3 Hz) ppm. Partial 13C (CD3OD, 100 MHz): δ 163.33, 141.42, 132.54, 131.03, 129.18, 124.73, 117.15, 105.84, 36.72, 29.04 ppm. DEPT (CD3OD, 100 MHz): CH2 carbons: 36.72, 29.04; CH carbons: 131.03, 129.18, 117.15 ppm. HPLC: 10.484 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[C:14]([O:16]CC)=[O:15])=[N:6][CH:7]=1.[H-].[Na+].CI.[CH3:23]CCCCC>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2([CH3:23])[C:14]([OH:16])=[O:15])=[N:4][CH:3]=1
Reactant: CCOC(=O)C1CCCCN1c1ncc(Br)cn1
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)O)CCCCN1c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 32 %

Procedure:
To an ice-cold solution of ethyl 1-(5-bromopyrimidin-2-yl)piperidine-2-carboxylate (0.37 g, 1.18 mmol) in THF (25 mL) was added NaH (60% dispersion in mineral oil, 0.06 g, 1.41 mmol) portion wise. The mixture was stirred at the same temperature for 45 min followed by addition of MeI (0.52 mL, 8.26 mmol) at 0° C. The temperature of the reaction was slowly raised up to rt and left to stir for 16 h. The reaction was then cooled to 0° C., quenched by drop wise addition of ice-cold water then extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 2% EtOAc: hexane to obtain the desired product as off-white solid (0.115 g, 32% yield). MS: 300.09 [M+H]+.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][S:10]([CH:13]=[CH2:14])(=[O:12])=[O:11].[C:16](=O)([O-])[O-].[Na+].[Na+].CI>CC(C)=O>[C:1]1([CH3:15])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]([CH3:16])[S:10]([CH:13]=[CH2:14])(=[O:12])=[O:11]
Reactant: C=CS(=O)(=O)Nc1c(C)cc(C)cc1C
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CS(=O)(=O)N(C)c1c(C)cc(C)cc1C
Yield: 100.3 %

Procedure:
22.5 g (0.1 mole) N-mesitylethenesulphonamide, 37.2 g anhydrous sodium carbonate, 52 ml methyl iodide and 1000 ml acetone were mixed and refluxed for 6 hours. The mixture was then filtered and evaporated to dryness. The residue was dissolved in diethyl ether and extracted with 2 N sodium hydroxide solution (to remove remaining starting material). The ether solution was dried over magnesium sulphate and evaporated to dryness. 24.0 g of the crude title compound was obtained as an oil, which solidifies slowly. M.p. c.a. 25° C.