Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].[N:35](C(OCC)=O)=NC(OCC)=O.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>C1COCC1>[NH2:35][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1O
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
Triphenylphosphine (14.3 g) was added to a THF (190 ml) solution containing tert-butyl ((1S,2S)-2-hydroxycyclohexyl)carbamate (10.0 g), followed by ice cooling. Diethyl azodicarboxylate (40% in toluene) (24.3 g) and DPPA (15.3 g) were added dropwise to the reaction solution, followed by stirring at room temperature for 1 hour. The reaction solution was left overnight. The solvent was distilled away under reduced pressure. Water was added and then a 20% sodium hydroxide aqueous solution was added. Then, the organic layers were collected. Water (30 ml) was added to the obtained organic layers, followed by heating to 60° C. A THF (40 ml) solution containing triphenylphosphine (14.3 g) was added dropwise, followed by reflux for 2.5 hours. The solvent was distilled away under ordinary pressure. Toluene was added and the pH was adjusted with 3M hydrochloric acid to pH=1 or less. Then, the resulting aqueous layers were collected, ethyl acetate was added, and the pH was adjusted with a 20% sodium hydroxide aqueous solution to pH 12. The organic layers were collected and dried over anhydrous sodium sulfate. Light yellow oily matter of tert-butyl ((1S,2R)-2-aminocyclohexyl)carbamate (5.24 g) was thus obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]=1[CH3:23])=[O:5])C.[OH-].[Na+]>CO.O>[CH3:23][C:7]1[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9](=[O:16])[C:10]2[C:15]([C:6]=1[C:4]([OH:5])=[O:3])=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CCOC(=O)c1c(C)n(-c2ccccc2)c(=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)c2ccccc2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
3-Methyl-1-oxo-2-phenyl-1,2-dihydro-isoquinoline-4-carboxylic acid ethyl ester (4.2 g, 13.7 mmol) was dissolved in 100 ml of hot methanol and a solution of NaOH (6 g) in water (20 ml) was added. The reaction mixture was heated at reflux for 2 hrs, diluted with water (200 ml) and stirred overnight at ambient temperature. Organic volatiles were removed under reduced pressure and the obtained aqueous solution was extracted with ethyl acetate (2×50 ml). The aqueous solution was poured into ice/2M HCl (150 ml). The obtained suspension was sonicated, and the product was separated by filtration, washed with water and dried in vacuo to give 2.9 g of a colourless solid, yield 76%. LC-MS (m/z) 280.2 (MH+); tR=0.9. 1H NMR (500 MHz, DMSO-d6): 2.01 (s, 3H), 7.36 (d, 2H), 7.50 (t, 1H), 7.56 (q (overlapping m), 3H), 7.72 (d, 1H), 7.81 (t, 1H), 8.22 (d, 1H), 13.5 (br, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:21]C)[N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N>Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:21])[N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOc1nc(N)c2nc(OC)n(Cc3ccccc3)c2n1
Agent: Cl
Agent: N
Product: CCOc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Yield: 64.3 %

Procedure:
6-Amino-9-benzyl-2-ethoxy-8-methoxypurine (18 mg, 0.06 mmol) in concentrated hydrochloric acid (5 ml) was stirred for 3 hours at room temperature. The reaction mixture was made basic with 28% aqueous ammonia, and the resulting crystals were filtered and washed with water to give the subject compound (11 mg, yield 64%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:21][C:22]1[CH:43]=[CH:42][C:25]([CH2:26][N:27]([CH2:38][CH:39]([CH3:41])[CH3:40])[S:28]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C@@H:12]([O:37][C:34]2[CH:35]=[CH:36][C:31]([S:28](=[O:29])(=[O:30])[N:27]([CH2:26][C:25]3[CH:42]=[CH:43][C:22]([Cl:21])=[CH:23][CH:24]=3)[CH2:38][CH:39]([CH3:41])[CH3:40])=[CH:32][CH:33]=2)[C@H:10]([OH:11])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2OC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)cc1
Temperature: 25 °C
Yield: 26.3 %

Procedure:
To a solution of 7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (354 mg, 1.8 mmol) in EtOH (5 mL) was added K2CO3 (246 mg, 1.8 mmol) and a solution of N-(4-chloro-benzyl)-4-hydroxy-N-isobutyl-benzenesulfonamide (629 mg, 1.78 mmol) in EtOH (5 mL) and the reaction was heated at 95° C. for 16 hours. The reaction was left to cool to room temperature and concentrated. Water and EtOAc were added, extracted, washed with brine, dried with Na2SO4 then concentrated and purified by silica gel column chromatography (0-100% EtOAc in cyclohexane) to give (+/−)trans-4-{4-[(4-chloro-benzyl)-isobutyl-sulfamoyl]-phenoxy}-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (259 mg, 26%). LCMS (m/z, Method A) ES+ 553 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:23][OH:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:14][CH2:13][CH:12]2[CH:23]=[O:24])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C(CO)CCCC1c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=CC1CCCC(c2ccccc2)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of the 1-(4-chloro-benzenesulfonyl)-6-phenyl-piperidin-2-yl-methanol prepared according to Example 53 Preparation C Step 1 (300 mg; 0.82 mmol) in DCM (8 ml) was added Dess-Martin periodinane (850 mg; 2.0 mmol) followed by sodium bicarbonate (100 mg) and two drops of water. The mixture was stirred overnight at room temperature, then quenched with Et2O (20 mL), saturated NaHCO3 and sodium thiosulfite (2.0 g) for 20 minutes. The reaction was extracted with Et2O, dried over Na2SO4 and concentrated to provide 232 mg (78%) of 1-(4-chloro-benzenesulfonyl)-6-phenyl-piperidine-2-carbaldehyde as an oil.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)#[N:4].Cl[CH2:15][CH2:16][O:17][CH2:18]Cl>CN1CCCC1=O.C1COCC1>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([C:5]2([C:3]#[N:4])[CH2:15][CH2:16][O:17][CH2:18]2)=[CH:7][CH:8]=1)#[N:11]
Reactant: N#CCc1ccc(C#N)cc1
Reactant: ClCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(C#N)CCOC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.4 %

Procedure:
To a suspension of NaH (60% by weight, 1.2 g, 30 mmol) in 1-methylpyrrolidin-2-one (20 mL) was added a solution of 4-(cyanomethyl)benzonitrile (1.42 g, 10 mmol) and 1-chloro-2-(chloromethoxy)ethane (1.29 g, 10 mmol) in THF (10 mL) at −20° C. The mixture was allowed to warm to room temperature after completion of addition and stirred for 24 hours. The reaction was quenched by ice water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (3×50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to afford the crude product which was purified by Prep-TLC (EtOAc/hexane=1:5) to provide the title compound as a yellow oil (345 mg, 17.4%). LC-MS: m/z 172 (M−CN).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:22]1([C:25]([NH:1][C:2]2[O:3][C:4]3[CH:10]=[C:9]([O:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:26])[CH2:24][CH2:23]1
Reactant: COC(=O)c1cccc(Oc2ccc3nc(N)oc3c2)c1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution (100 mL) of methyl 3-[(2-amino-1,3-benzooxazol-6-yl)oxy]benzoate (6.84 g, 24.1 mmol) in pyridine were added N,N-dimethylpyridine-4-amine (129 mg, 1.05 mmol) and cyclopropanecarbonyl chloride (2.5 mL, 27.5 mmol), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added cyclopropanecarbonyl chloride (2.5 mL, 27.5 mmol), and the mixture was further stirred at room temperature for 1.5 hr. Cyclopropanecarbonyl chloride (1.5 mL, 16.5 mmol) was further added to the reaction mixture, and the mixture was continuously stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate (200 mL). This suspension was washed with 0.1N hydrochloric acid (150 mL) and saturated aqueous sodium hydrogencarbonate solution (150 mL), successively. The diluted hydrochloric acid layer was extracted with ethyl acetate (100 mL×2), and the combined organic layers were washed with saturated aqueous sodium hydrogencarbonate solution (150 mL) and saturated brine (150 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated to give a brown amorphous substance (8.2 g).
Reaction SMILES: [CH2:1]([N:8]([CH3:24])[C@@H:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([Br:21])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][C@@H:10]1[CH2:22][OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:23][CH2:22][C@H:10]1[CH2:11][N:12]2[C:20]3[CH:19]=[CH:18][C:17]([Br:21])=[CH:16][C:15]=3[CH:14]=[C:13]2[C@H:9]1[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:24])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1ccccc1)[C@@H]1c2cc3cc(Br)ccc3n2C[C@@H]1CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccccc1)[C@@H]1c2cc3cc(Br)ccc3n2C[C@@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Step 2 (690 mg, 1.8 mmol) was dissolved in CH2Cl2 (10 mL) with N,N-diisopropylethylamine (0.94 mL, 5.4 mmol). The mixture was cooled to 0° C., before adding methanesulfonyl chloride (0.21 mL, 2.7 mmol). After 30 min, the mixture was washed with water, dried over Na2SO4 and concentrated. The crude mixture was carried on without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[CH:23]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: COc1cccc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)c1

Procedure:
The title compound, MS: m/e=324.8 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-methoxy-benzene boronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:11][CH2:10][O:9][C:8]2=[O:12])=[CH:4][CH:3]=1.II.[CH3:17][OH:18]>>[CH3:17][O:18][C:8](=[O:12])[CH:7]([O:6][C:5]1[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:11][CH2:10][OH:9]
Reactant: CO
Reactant: O=C1OCCC1Oc1ccc(Cl)cc1
Agent: II
Product: COC(=O)C(CCO)Oc1ccc(Cl)cc1
Yield: 33 %

Procedure:
3-(4-chlorophenoxy)dihydrofuran-2(3H)-one, (Example 473a), 1.136 g), iodine (30.0 mg) and methanol (28.9 mL) were stirred at 65° C. for 24 hr. The reaction mixture was concentrated in vacuo. Exces of iodine was eliminante by adding an aqueous solution of sodium sulfite (10% w/w, 15 mL). The mixture was extracted with ethyl acetate. The organic layers were washed with brine (10 mL), dried over sodium sulfate and filtered. The crude mixture was concentrated to dryness and purified by chromatography on silica gel to yield the title compound as a colorless oil (433 mg; 33%). MS (ESI): m/z=244 [M]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][SH:19])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>C1COCC1>[C:27]([S:19][CH2:18][CH2:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])(=[O:29])[CH3:28]
Reactant: O=C(CCNC(=O)OCc1ccccc1)NCCS
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)SCCNC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To the stirred solution of 3-(benzyloxycarbonylamino)-N-(2-mercaptoethyl)propionamide (2 g) and triethylamine (0.8 g) in anhydrous THF (15 ml), acetyl chloride (0.6 g) is added dropwise under ice-water cooling. After the addition, the mixture is stirred for 30 minutes under ice-water cooling and additional 30 minutes at room temperature. The solution is filtered and the filtrate is concentrated in vacuo. The residue is dissolved in ethyl acetate (30 ml) and the solution is washed with saturated sodium bicarbonate solution, N hydrochloric acid and then saturated sodium chloride solution. The ethyl acetate solution is dried over anhydrous magnesium sulfate and concentrated in vacuo to give 1.6 g (70%) of the titled compound.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:22][C:23](=O)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[C:9]([NH:22][C:23](=[S:43])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CC(=O)Nc2ncc(-c3ccc(OC)cc3)nc2Cc2ccccc2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CC(=S)Nc2ncc(-c3ccc(OC)cc3)nc2Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
Under an argon atmosphere, 3-benzyl-5-(4-methoxyphenyl)-2-[(4-methoxyphenyl)acetylamino]pyrazine (c-43) (prepared by the method described in Inouye, S. & Hosoya, T., Biochem. Biophys. Res. Commun., 386, 617-622 (2009)) (1.00 g, 2.28 mmol) was suspended in anhydrous toluene (30 mL) and to this was added Lawesson's reagent (552 mg, 1.37 mmol) while stirring at room temperature, and then heated to reflux for 17 h. After refluxing, it was cooled to room temperature, and concentrated under reduced pressure with a rotary evaporator. The residue was purified by silica gel column chromatography (100 g, dichloromethane/ethyl acetate=49/1) to give 3-benzyl-5-(4-methoxyphenyl)-2-[(4-methoxyphenyl)thioacetylamino]pyrazine (c-44) as a yellow oily substance (823 mg, 79.4%). Rf=0.43 (dichloromethane/ethyl acetate=19/1). 1H NMR (400 MHz, DMSO-d6) δ 2.84 (s, 3H), 3.82 (s, 3H), 3.92 (s, 2H), 4.07 (s, 2H), 6.90-6.96 (AA′BB′, 2H), 6.98-7.04 (AA′BB′, 2H), 7.05-7.11 (AA′BB′, 2H), 7.13-7.26 (m, 3H), 7.38-7.50 (m, 2H), 8.06-8.11 (AA′BB′, 2H), 8.99 (s, 1H), 12.12 (s, 1H). 13C NMR (67.8 MHz, DMSO-d6) δ 39.3, 50.8, 55.0, 55.3, 113.8 (2C), 114.5 (2C), 126.3, 127.6, 128.18 (2C), 128.21 (2C), 128.8, 128.9 (2C), 130.0 (2C), 137.8, 138.0, 145.0, 149.6, 152.1, 158.4, 160.8, 205.1. IR (KBr, cm−1) 704, 835, 1030, 1113, 1175, 1250, 1292, 1304, 1319, 1371, 1422, 1439, 1493, 1510, 1607, 2835, 2932, 2957, 3150. HRMS (ESI+) m/z 456.1747 ((M+H)+, C27H26N3O2S+ requires 456.1740).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([CH3:10])=[CH:4][N:3]=1.[CH2:11]([NH2:13])[CH3:12].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[C:7]([CH2:8][NH:13][CH2:11][CH3:12])=[CH:6][C:5]([CH3:10])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)c(C=O)c1
Reactant: CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNCc1cc(C)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-5-methyl-pyridine-3-carbaldehyde (0.22 g, 1.41 mmol), ethylamine (2M in THF; 1.06 mL, 2.12 mmol), and sodium cyanoborohydride (0.133 g, 2.12 mmol) were combined in MeOH (2.52 mL). Acetic acid (0.12 mL, 2.12 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was dissolved in CH2Cl2, washed with saturated aqueous NaHCO3, concentrated, and purified by silica gel chromatography (0-10% MeOH in CH2Cl2) to give the title compound.
Reaction SMILES: CO[CH:3](OC)[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].O>ClC1C=CC=CC=1>[CH3:12][C:7]1[C:6]2[S:5][CH:4]=[CH:3][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COC(CSc1ccccc1C)OC
Solvent: O
Solvent: Clc1ccccc1
Product: Cc1cccc2ccsc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.6 %

Procedure:
To a heated (130° C.) solution of polyphosphoric acid (59 g) in chlorobenzene (500 ml) is added a solution of 1-[(2,2-dimethoxyethyl)thio]-2-methyl-benzene (23.4 g, 110 mmol) in chlorobenzene (125 ml) slowly over several hours and when addition is complete the reaction mixture is heated for a further 8 hours. The reaction mixture is cooled to ambient temperature and stirred for an additional 24 hours. Water is added, the layers are separated, and the aqueous layer is extracted with dichloromethane. The combined organic extracts are dried over anhydrous MgSO4, filtered, and concentrated. The crude material thus obtained is purified via flash chromatography on silica gel eluting with 100% pentane then 100% hexanes to afford 7-methyl-benzo[b]thiophene (12.65 g, 69%). 1H NMR (CDCl3): δ=7.71 (1H, d), 7.45 (1H, d), 7.39 (1H, d), 7.33 (1H, dd), 7.17 (1H, d), 2.61 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C)=[O:10])=[CH:4][C:3]=1[NH:13][C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[NH:13][C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: COC(=O)Cc1ccc(Cl)c(NC(=O)NCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(Cl)c(NC(=O)NCc2ccccc2)c1

Procedure:
For ester cleavage, analogously to the above instructions, 2.47 mmol (790 mg) of methyl 4-chloro-3-[[[(phenylmethyl)amino]carbonyl]amino]benzeneacetate is saponified with 1N-NaOH. Product 5 is obtained without recrystallization. Yield: 693 mg of yellowish solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[C:4]([N+:20]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:20][C:4]1[CH:3]=[C:2]([F:1])[CH:19]=[CH:18][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([N:12]([CH3:13])[CH3:14])=[O:11]
Reactant: CN(C)C(=O)c1cccc(Oc2ccc(F)cc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: CN(C)C(=O)c1cccc(Oc2ccc(F)cc2N)c1
Yield: 94.4 %

Procedure:
The product from Example 181d (1.1 g, 3.4 mmol) was reduced with SnCl2 as described in Example 1f to give the title compound (0.88 g, 88%).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]([NH2:27])[CH3:26].CCN(C(C)C)C(C)C>>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]([NH:27][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH3:26]
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: CC(N)c1cccs1
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1)c1cccs1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 1-thiophen-2-yl-ethylamine and DIEA to give 2-(1-thiophen-2-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 366 (MH+).
Reaction SMILES: [C:1]([O:10]CC)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:13][C:14]([CH3:18])=[CH:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:13][C:14]([CH3:18])=[CH:15][CH2:16][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)=CCOc1ccccc1C(=O)O

Procedure:
The reaction of ethyl salicylate and 3,3-dimethylallyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-(3-Methyl-but-2-enyloxy)-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.50 (s, —CO2H); 7.55 (m, 1 arom. H); 7.41 (m, 1 arom. H); 7.07 (m, 1 arom. H); 6.92 (m, 1 arom. H); 5.36 (m, CH═C(CH3)2); 4.54 (d-like, CH2CH═C(CH3)2); 1.72, 1.68 (2s, CH═C(CH3)2). 13C-NMR (100 MHz, d6-DMSO): 167.42 (C═O); 157.06; 136.97; 132.70; 130.44; 121.91; 119.99; 119.82; 113.79; 65.23; 25.42; 18.03.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[O:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29]Cl)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[O:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:23][CH:24]=1)[CH3:26]
Reactant: CCN(CC)CCCl
Reactant: O=C(c1ccc(O)cc1)c1oc2ccccc2c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCOc1ccc(C(=O)c2oc3ccccc3c2-c2ccccc2)cc1

Procedure:
(0.005 mol.) of 2-(4-hydroxybenzoyl)-3-phenylbenzofuran with 2.7 g. (0.02 mol.) of 2-diethylaminoethyl chloride in 50 ml. of acetone containing 2.7 g. (0.02 mol.) of potassium carbonate for 3 hours according to the procedure described in Example 1 gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]12[CH2:10][CH2:9][CH:6]([CH:7]=[CH:8]1)[CH2:5][C:4]2=[O:11]>CO.[Ni]>[CH3:1][O:2][C:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH2:5][C:4]2=[O:11]
Reactant: COC12C=CC(CC1)CC2=O
Agent: [Ni]
Solvent: CO
Product: COC12CCC(CC1)CC2=O
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 88.4 %

Procedure:
To a solution of 1-methoxybicyclo[2.2.2]oct-5-en-2-one (16.5 g, 0.11 mol) in MeOH (250 mL) was added Raney-Ni (3.3 g). The reaction mixture was stirred at 40° C. and 45 psi under H2 atmosphere for 2-3 h (8.0 g, 40%). The resulting mixture was filtered, the filtrate was concentrated in vacuo to produce 1-methoxybicyclo[2.2.2]octan-2-one (15.0 g, 90%). 1H NMR (CDCl3, 400 MHz) δ 3.33 (s, 3H), 2.32 (d, 2H), 2.09 (m, 1H), 1.49-1.95 (m, 8H).