Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[NH:28][S:29]([CH3:32])(=[O:31])=[O:30]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:8](=[O:14])[CH:9]=[CH:10][C:11]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[C:20]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[CH:21]=3)=[CH:12]2)=[CH:4][CH:3]=1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1
Reactant: COc1ccc(B(O)O)cc1NS(C)(=O)=O
Product: COc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1NS(C)(=O)=O
Yield: 17.2 %

Procedure:
According to Scheme 3 Method A: The title compound was prepared from 1-(4-chlorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 1.80 mmol, 0.55 g, Example 2 Step 1) and 4-methoxy-3-(methylsulfonamido)phenylboronic acid (1.1 eq, 2.00 mmol, 0.49 g) according to the procedure described for Example 1 Step 3. Reaction conditions: 4 hours at 80° C. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt (90/10) then recrystallized from pentane/Et2O to afford N-(5-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-2-methoxyphenyl)methanesulphonamide (0.31 mmol, 0.32 g, 41%) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[NH:8][C:9]([C:12]([O:14]C)=[O:13])=[N:10][N:11]=2)[CH2:3][CH2:2]1.[Li+].[OH-].O>C1COCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[NH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][N:11]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)c1nnc(N2CCOCC2)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nnc(N2CCOCC2)[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 5-morpholino-4H-1,2,4-triazole-3-carboxylate (0.090 g, 0.398 mmols†) in THF (1 mL) was added 1 N LiOH (0.800 mL, 0.80 mmol) and H2O (1 mL). The reaction was stirred at rt for 12 h. The reaction mixture was concentrated and lypholized to get 5-morpholino-4H-1,2,4-triazole-3-carboxylic acid quantative yield and used as it is in next step.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][NH:19][CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:25])[N:11]3[C:21]([O:23][CH3:24])=[O:22])[CH2:4][CH2:3][CH2:2]1.CS(O[CH:31]1[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH:1]1([O:5][C:6]2[C:15]([C:16]3[CH:20]=[N:19][N:18]([CH:31]4[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]4)[CH:17]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:25])[N:11]3[C:21]([O:23][CH3:24])=[O:22])[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)N1c2ccc(-c3cn[nH]c3)c(OC3CCC3)c2CC[C@@H]1C
Reactant: CS(=O)(=O)OC1CCS(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N1c2ccc(-c3cnn(C4CCS(=O)(=O)CC4)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 110 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
A mixture of (S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.160 g, 0.47 mmol), 1,1-dioxidotetrahydro-2H-thiopyran-4-yl methanesulfonate (0.320 g, 1.40 mmol) and cesium carbonate (0.457 g, 1.40 mmol) in N,N-dimethylformamide (5 mL) stirred overnight at 110° C. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 50% ethyl acetate/petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, Xbridge RP18 5 um, 19×150 mm; Mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (40% to 80% acetonitrile in 10 min; flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded of methyl (2S)-5-cyclobutoxy-6-[1-(1,1-dioxo-1λ6-thian-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (0.040 g, 18%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.18 (d, J=6.40 Hz, 3H), 1.29-1.31 (m, 1H), 1.47-1.49 (m, 1H), 1.60-1.62 (m, 1H), 2.01-2.08 (m, 4H), 2.11-2.24 (m, 1H), 2.45-2.47 (m, 1H), 2.63-2.68 (m, 4H), 2.90-2.94 (m, 1H), 3.10-3.17 (m, 2H), 3.45-3.47 (m, 2H), 3.78 (s, 3H), 4.06-1.10 (m, 1H), 4.45-4.58 (m, 2H), 7.22 (d, J=8.40 Hz, 1H), 7.31 (d, J=8.40 Hz, 1H), 7.81 (s, 2H). MS (ESI, pos. ion) m/z 474 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](C=C[CH:32]=1)[CH:7]=[CH:8][C:9]([CH2:11][C:12]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1)=[O:13])=O)([O-:3])=[O:2].[NH2:33]/[C:34](/[CH3:40])=[CH:35]\[C:36]([O:38][CH3:39])=[O:37].[CH2:41](O)[CH3:42]>>[CH3:41][C:42]1[NH:33][C:34]([CH3:40])=[C:35]([C:36]([O:38][CH3:39])=[O:37])[CH:9]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:32]=2)[C:11]=1[C:12]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:29])[C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:23][CH:24]=1)=[O:13]
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)Nc1ccc(C(=O)OCCOC(=O)CC(=O)C=Cc2cccc([N+](=O)[O-])c2)cc1
Reactant: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOC(=O)c2ccc(NC(C)=O)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 94 %

Procedure:
20 g (0.05 moles) of 2-(4-acetylaminobenzoyloxy)ethyl 2-(3-nitrobenzylidene)acetylacetate and 5.23 g (0.05 moles) of methyl 3-aminocrotonate are heated under reflux in 45 ml of ethanol for 8 hours. The solution is then cooled to room temperature to obtain 2-(4-acetylaminobenzoyloxy)ethyl 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate as a yellow powder melting at 190°-193° C. The yield is 94% of the theoretical yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>CN(C=O)C>[ClH:24].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:24])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Product: Cl

Procedure:
A mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (2.82 g, 0.01 mol), thionyl chloride (40 ml) and DMF (0.28 ml) was stirred and heated at reflux for 1 hour. The mixture was evaporated and azeotroped with toluene to give 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (3.45 g).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]([F:51])[F:50])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:52]=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:54]=[O:55].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH:49]([F:50])[F:51])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:54][OH:55])[CH:52]=[O:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 70 °C
Reaction time: 25 h

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 12i (1.10 g, 1.48 mmol) was dissolved in 20 mL 1,4-dioxane, followed by addition of 2.5 mL of 37% formaldehyde solution and dropwise addition of 4 mL of 2.9 M sodium hydroxide solution. The reaction mixture was stirred for 25 hours at 70° C. Thereafter, the reaction mixture was concentrated under reduced pressure before 20 mL water and 10 mL saturated sodium chloride solution were added. The aqueous phase was extracted with ethyl acetate (30 mL×3) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 12j (1.09 g, yellow grease), which was used directly in the next step without purification.
Reaction SMILES: O.NN.P(Cl)(Cl)(Cl)(Cl)Cl.Br.F[C:12]1C=CC(OC)=CC=1C#N.[F:22][C:23]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>CO>[F:22][C:23]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:24]=1[C:25]([O:27][CH3:12])=[O:26]
Reactant: COc1ccc(F)c(C#N)c1
Reactant: O=C(O)c1cc(O)ccc1F
Agent: Br
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(O)ccc1F

Procedure:
In the presence of hydrazine hydrate/glacial acetic acid, phthalic anhydride (3a) with substituent R was transformed into R-substituted phthalhydrazide (3b), which subsequently generated substituted dichlorophthalazine compounds (3c) under the action of phosphorus pentachloride. In another aspect, under the action of hydrobromic acid, 2-fluoro-5-methoxybenzonitrile (3d) was converted to 2-fluoro-5-hydroxybenzoic acid (3e), which was esterificated with methanol to give methyl 2-fluoro-5-hydroxybenzoate (3f). Under the action of sodium hydride, the prepared dichlorophthalazine compounds with substituent R (3c) was reacted with methyl 2-fluoro-5-hydroxybenzoate (3f) to give methyl 5-((4-chloronaphthyridine-1-yl)oxy)-2-fluorobenzoate with substituent R (3g), 3g was transformed into methyl 2-fluoro-5-((4-oxo-3,4-dihydro-phthalazin-1-yl)oxy)benzoate (3h) in the presence of AcOH/NaOAc under the reflux condition, 3h was then hydrolyzed under alkali condition into substituent-contained 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (3i), which finally condensated with R′ substituted nitrogen heterocycles, e.g. piperazine, piperidine, 4-hydroxypiperidine, tetrahydropyridine and 1,4-diazacycloheptane in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), triethylamine and 1-hydroxy-7-azabenzotriazole (HOAt) to generate target compounds, wherein the definition of R and R′ is as described above.
Reaction SMILES: O([C:8]([NH:10][C:11]1[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][N:12]=1)=[O:9])C1C=CC=CC=1.[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.CN(C)C=O>O>[CH2:18]([NH:17][C:15]1[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][N:12]=[C:11]([NH:10][C:8]([NH:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[O:9])[N:16]=1)[CH2:19][CH3:20]
Reactant: Nc1ccncc1
Reactant: CCCNc1nc(NC(=O)Oc2ccccc2)ncc1C(=O)OCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCNc1nc(NC(=O)Nc2ccncc2)ncc1C(=O)OCC
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 28.7 %

Procedure:
To ethyl 2-((phenoxycarbonyl)amino)-4-(propylamino)pyrimidine-5-carboxylate (E7, 2.89 g) and 4-aminopyridine (3.16 g), N,N-dimethylformamide (30 mL) was added at room temperature, and the mixture was stirred at 70° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then the reaction mixture was poured into water (300 mL). The solid matter was taken by filtration, and purified by silica gel column chromatography (eluent, ethyl acetate) to obtain ethyl 4-(propylamino)-2-(3-(pyridin-4-yl)ureido)pyrimidine-5-carboxylate (E8, 830 mg) as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7](C#N)=[C:6](C)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:17])[N:3]=1.[OH-:18].[K+].[CH2:20]([OH:23])[CH2:21]O>>[NH2:1][C:2]1[C:21]([C:20]([OH:23])=[O:18])=[C:6]([CH3:7])[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:17])[N:3]=1
Reactant: OCCO
Reactant: Cc1nc(N)c(C#N)c(C)c1-c1ccccc1
Reactant: [OH-]
Agent: [K+]
Product: Cc1nc(N)c(C(=O)O)c(C)c1-c1ccccc1
Temperature: 0 °C

Procedure:
2-Amino-4,6-dimethyl-5-phenyl-3-pyridinecarbonitrile (0.5 gram) and potassium hydroxide (1.0 gram) were heated in 15 ml ethylene glycol at approximately 165° C. for about 6 hours. The reaction mixture was poured into ice water and then made acidic to a pH of 4-5. A solid formed which was collected, washed with water and identified as the desired product by TLC and NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([NH:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])=[O:16])([CH3:13])([CH3:12])[CH3:11]>CO.O>[C:10]([O:14][C:15]([NH:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[N:7]=[C:6]([NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:18]([NH:17][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH:19]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:22]=[CH:23][CH:24]=1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2ncc(F)c(Nc3cccc(NC(=O)OC(C)(C)C)c3)n2)c1
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (75 mg, 0.45 mmol) was dissolved in a mixture of MeOH (2 ml) and H2O (0.2 ml). 3-tert-butoxycarbonylaminoaniline (374 mg, 1.8 mmol) was added and the mixture was refluxed for 40 hours (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 9:1) to give N2,N4-bis[3-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6+CD3OD): δ 7.96 (d, 1H, J=4.1 Hz), 7.83 (m, 1H), 7.60 (m, 1H), 7.34-7.42 (m, 2H), 7.15-7.19 (m, 2H), 7.06 (t, 1H, J=8.2 Hz), 6.93 (d, 1H, J=8.2 Hz), 1.43 (s, 9H), 1.40 (s, 9H); LCMS: purity: 93.2%; MS (m/e): 511.06 (M+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C>C([O-])(O)=O.[Na+].[Cu]I>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:14]#[C:13][CH2:12][OH:15])[CH:3]=1
Reactant: C#CCO
Reactant: Brc1cnc2ccccc2c1
Agent: [Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: OCC#Cc1cnc2ccccc2c1
Yield: 88.3 %

Procedure:
To a dry 2-L three-necked flask previously purged with nitrogen, was charged 3-bromoquinoline (118.77 g, 570 mmol), propargyl alcohol (71.9 g, 1.28 mol, 2.25 equiv), triethylamine (1500 mL), copper(I) iodide (3.62 g, 19 mmol, 0.033 equiv) and dichlorobis(triphenylphosphine) palladium(II) (6.67 g, 9.5 mmol). The resulting mixture was mechanically stirred and heated to reflux for 3 hours. Upon cooling, the triethylamine solution was filtered and washed with triethylamine (300 mL). The filtrate was then concentrated under reduced pressure to provide solids which were suspended in 5% aq. NaHCO3 (600 mL) and extracted with ethyl acetate (1×600 mL). The solids which were left after filtration were treated in the same manner (i.e., suspend in aq. 5% NaHCO3 and extracted with ethyl acetate). The combined ethyl acetate extracts were stirred with silica gel (15 g) and decolorizing carbon (3 g) before being filtered through a bed of diatomaceous earth. The filtrate was concentrated under reduced pressure to provide a tan colored solid which was dried in the vacuum oven at 45° C. overnight. The 3-(3-quinolyl)-2-propyn-1-ol was thus isolated. 92.14 g, 88.3% yield. MS(Cl): (M+H)+ at 184; NMR (300 MHz CDCl3) δ: 4.58 (s, 2H), 4.70 (s, broad, 1H), 7.57 (m,1H), 7.70 (m, 1H), 7.77 (d, 1H), 8.10 (d, 1H), 8.10 (s, H), 9.05 (s, 1H).
Reaction SMILES: [C:1]([Cl:4])(=[O:3])C.CO.[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>C1(C)C=CC=CC=1>[ClH:4].[CH3:1][O:3][C:10](=[NH:11])[C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[OH:7]
Reactant: CC(=O)Cl
Reactant: N#Cc1ccccc1O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=N)c1ccccc1O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
Acetyl chloride (6.0 g, 76.4 mmol) was added drop-wise to methanol (10 mL) over 30 min. The temperature was kept at 20° C. by cooling the mixture in a water bath. After the addition of acetyl chloride, the solution was stirred for 2 h at room temperature. o-Hydroxybenzonitrile (4.0 g, 33.61 mmol) was added followed by toluene (20 mL). The mixture was stirred at room temperature under an argon atmosphere for 4 days. The precipitate was filtered and washed with toluene. After drying under high vacuum, 2-hydroxy-benzimidic acid methyl ester hydrochloride (2.2 g, 35%) was isolated as a white solid.
Reaction SMILES: [C:1]1([S:7][CH:8](S(C2C=CC=CC=2)(=NC)=O)[C:9](O)([C:11]2[CH2:15][CH2:14][CH2:13][CH:12]=2)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C(O)(=O)C>C1COCC1>[C:11]1([C:9]([CH2:8][S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH2:10])[CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: CN=S(=O)(c1ccccc1)C(Sc1ccccc1)C(C)(O)C1=CCCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C=C(CSc1ccccc1)C1=CCCC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of S-[1-phenylthio-2-hydroxy-2-(cyclopent-1-enyl)propyl]-N-methyl-S-phenylsulfoximine (1.05 g, 2.7 mmol) in a mixture of THF (20 mL), H2O (8 mL) and acetic acid (8 mL) is added freshly prepared Al/Hg (1.3 g) in an ice-bath. After stirring at 0° C. for 5 hours, the mixture is filtered through a pad of Celite and the Celite is washed with EtOH (10 mL). The filtrate is concentrated in vacuo to ca. 5 mL. The residue is diluted with H2O (100 mL) and extracted with pentane (40 mL×5). The combined extracts are dried (Na2SO4), and evaporated in vacuo to dryness. The residue is chromatographed over a silica gel column (2×40 cm) using pentane as the eluent. The product is obtained as a syrup, 486 mg (83%). 1H NMR (CDCl3): δ1.73-2.08 (2H, m, CH2 -4), 2.49 (4H, t, J=6.72 Hz, CH2 -3 and -5), 3.78 (2H, s, CH2 --S), 5.01 (2H, d, J=6.86 Hz, CH2 =), 5.90 (1H, brs, CH=), 7.11-7.53 (5H, m, pH).
Reaction SMILES: [N+]([O-])([O-])=[O:2].[NH4+].[Ce].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25]C)[C:17]=3[N:18]=2)=[CH:10][CH:9]=1>C(OCC)(=O)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[C:22](=[O:2])[C:21]([O:23][CH3:24])=[CH:20][C:19](=[O:25])[C:17]=3[N:18]=2)=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cc(OC)c2nc(-c3ccc(F)cc3)sc2c1
Agent: [Ce]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COC1=CC(=O)c2nc(-c3ccc(F)cc3)sc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
63 ml of a freshly prepared 0.65 M cerium ammonium nitrate solution is added, dropwise, to 3.8 g (13.1 mmol) of 2-(4-fluorophenyl)-4,6-dimethoxy-1,3-benzothiazole in solution in 100 ml of ethyl acetate. The reaction mixture is maintained under stirring at ambient temperature for 3 hours then the aqueous phase is separated and washed with 3 times 75 ml of ethyl acetate. The organic phases are combined, dried over sodium sulphate and the solvents are evaporated off under reduced pressure. The residue is purified by chromatography on a silica column (eluent: ethyl acetate/heptane mixture 1:3) in order to provide 0.6 g (16% yield) of expected product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:25][C:26]1[CH:30]=[C:29]([Br:31])[S:28][C:27]=1[C:32]([NH2:34])=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[Br:31][C:29]1[S:28][C:27]([C:32](=[O:33])[NH2:34])=[C:26]([NH:25][C:10]([C@@H:9]2[CH2:13][C@H:14]([CH3:16])[CH2:15][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])[CH:30]=1
Reactant: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1C[C@@H](C(=O)Nc2cc(Br)sc2C(N)=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of (4S)-1-(tert-butoxycarbonyl)-4-methyl-L-proline (491 mg) and triethylamine (0.353 mL) in tetrahydrofuran (5 mL) was added 2-methylpropyl chlorocarbonate (0.292 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. Thereafter, to the reaction system was added 3-amino-5-bromothiophene-2-carboxamide (225 mg) produced in Example 1, step D, and the mixture was stirred at 60° C. for 24 hr. Ethyl acetate (20 mL) and aqueous sodium hydrogen carbonate (10 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was crystallized from ethanol (5 mL). The obtained colorless solid was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm i.d.×500 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (850/150), flow rate: 80 mL/min, column temperature: 30° C.) to give the title compound (302 mg) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:5].[CH2:31]([NH2:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C[CH2:41][OH:42]>>[CH2:31]([NH:39][C:41](=[O:42])[NH:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:5])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCN
Reactant: CCO
Reactant: Nc1ccccc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: CCCCCCCCNC(=O)Nc1ccccc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 72.1 %

Procedure:
{2-amino-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide and n-octylamine}: yield 72.1%; mp 155°-157° C. (EtOH); 1H NMR (DMSO-d6)ppm: 0.86 (3H, t), 1.25-1.83 (19H, m), 2.79 (2H, d), 3.01 (2H, dd), 3.15 (2H, t), 4.26 (1H, s), 6.91 (1H, t), 7.13-7.41 (12H, m), 7.57 (1H, d), 8.21 (1H, d), 8.58 (1H, t), 9.95 (1H, s).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Br[CH2:39][C:40]1[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[C:44]([O:51][CH3:52])[CH:43]=[CH:42][CH:41]=1>CC#N>[CH2:49]([O:48][C:46](=[O:47])[C:45]1[C:44]([O:51][CH3:52])=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:39][N:18]([CH2:17][C:9]1[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH3:50]
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Reactant: CCOC(=O)c1c(CBr)cccc1OC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cccc1OC
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.409 g, 1.08 mmol) in CH3CN (5 mL) was added N,N-diisopropylethylamine (0.38 mL, 2.18 mmol) followed by a solution of ethyl 6-(bromomethyl)-2-methoxybenzoate (0.454 g, 1.66 mmol) in CH3CN (6 mL). The resultant mixture was heated to 60° C. for 22 hours then cooled to room temperature. The mixture was concentrated and the residue was partitioned between CH2Cl2 (50 mL) and brine (10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (25:1 CH2Cl2—CH3OH) followed a further chromatographic purification by column chromatography on silica gel (2:1 hexanes-EtOAc) and radial chromatography on silica gel (2 mm plate, 100:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.38 g (62%) of a white solid.