Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7](C)=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[CH3:14]N(C)C=O>C(OCC)(=O)C>[N:10]([C:7]1[C:2]([CH3:14])=[N:3][CH:4]=[C:5]([CH3:9])[N:6]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cnc(Cl)c(C)n1
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cnc(C)c(N=[N+]=[N-])n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 42 %

Procedure:
To a stirred solution of 2-chloro-3,5-dimethyl pyrazine (1.0 mL; 8.3 mmol) in dimethylformamide (10 ml,) was added sodium azide (539 mg; 8.3 mmol). The reaction was heated to 100° C. and stirred for 12 hours. The reaction was cooled to room temperature, diluted with 50 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×50 mL), brine (50 mL), then dried (MgSO4), and filtered. The material was purified using a biotage 12L cartridge eluting with hexanes and ethyl acetate (3: 1) to yield an off white solid (42% yield).
Reaction SMILES: FC(F)(F)CCC([N:7]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11][C:8]21[CH2:10][CH2:9]2)=O.C(N(CC)CC)C.[CH2:33]([S:36](Cl)(=[O:38])=[O:37])[CH2:34][CH3:35]>C1COCC1>[CH2:33]([S:36]([N:7]1[CH:8]2[CH2:10][CH2:9][CH:14]1[CH2:13][N:12]([C:15]1[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=1)[CH2:11]2)(=[O:38])=[O:37])[CH2:34][CH3:35]
Reactant: CCCS(=O)(=O)Cl
Reactant: O=C(CCC(F)(F)F)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCS(=O)(=O)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Reaction time: 16 h

Procedure:
4-(3,8-Diaza-bicyclo[3.2.1]oct-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 4) (0.05 mmol) was dissolved in THF (1.0 mL). Triethylamine (0.12 mmol) and propane-1-sulfonyl chloride (0.06 mmol) was added. The reaction mixture was left at it for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>CCOCC>[C:11]1([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCc2ccccc21
Reactant: [Li]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C1=CC(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.82 %

Procedure:
To a solution of 1-indanone (23.78 g, 0.18 mol) in 250 ml of ether at 0° C. was added dropwise over 30 min., 100 ml of phenyllithium in ether (1.8M in ether) and the mixture was allowed to warm to room temperature and stirred 1 h. The reaction mixture was poured into a cold saturated ammonium chloride solution, extracted with ether (2×200 ml), and the combined organic layer was washed with brine and dried over sodium sulfate. The organic solvent was removed under reduced pressure, 70 ml of 20% sulfuric acid in acetic acid was added to the residue and stirred 2 min. To the above solution water (100 ml) and ether (3×200 ml) were added, The organic layer was washed with sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated. Toluene (300 ml) was added to the residue and the mixture was distilled (azeotropic removal of acetic acid) to afford a brown oil. The brown oil was purified by chromatography (silica; (2:1 hexane/methylene chloride)) to afford 15.58 g (45.82%) of 1-phenyl-indene as a colorless oil. In addition 11 g of 1-phenyl-1-acetoxy-indane was isolated as a by-product.
Reaction SMILES: CNCC(C1C=CC(OC)=C(OC)C=1)C.BrCCC[N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:24]1(=[O:25])[NH:20][C:21](=[O:30])[C:22]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: CNCC(C)c1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1NC(=O)c2ccccc21

Procedure:
A mixture of 1.55 g of N-methyl-N-(2-(3,4-dimethoxyphenyl)propyl)amine, 1.98 g of N-(3-bromopropyl)phthalimide, 1.0 g of anhydrous potassium carbonate and 10 ml of acetonitrile was refluxed under heating for 6 hours. They were allowed to cool and then concentrated after filtering out insoluble matters. The residue was purified on silica gel column chromatography (solvent: chloroform:methanol=100:1), to obtain 2.71 g of N-(3-(N'-(2-(3,4-dimethoxyphenyl)propyl)-N'-methyl)amino)propyl)phthalimide as yellow oil. The product was dissolved in 20 ml of ethanol, to which 0.4 ml of hydrazine monohydrate was added and refluxed under heating for 2 hours. Deposited matters were filtered out and diluted aqueous solution of sodium hydroxide was added, which was extracted with chloroform. After drying with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified on silica gel column chromatography (solvent: chloroform:methanol:concentrated aqueous ammonia: 100:10:1) to obtain 1.54 g of the above-captioned compound as yellow oil (yield: 78%).
Reaction SMILES: [CH:1]1([CH:4]([OH:6])[CH3:5])[CH2:3][CH2:2]1.[N+](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][O:6][CH:4]([CH:1]1[CH2:3][CH2:2]1)[CH3:5])[CH3:14]
Reactant: CC(O)C1CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCCCCCC
Product: CCOC(=O)COC(C)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a solution of cyclopropyl-1-ethanol (860 mg, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at rt for 30 min. The reaction mixture is diluted with heptane, filtered through celite, and the filtrate is evaporated and the residue is vacuum distilled at 130° C. to give 1.11 g of the product 471. 1H NMR (CDCl3) δ 4.12 (s, 2H), 4.10 (q, 2H), 2.86 (m, 1H), 1.25-1.15 (m, 6H), 0.8-0.7 (m, 1H), 0.55-0.3 (m, 3H), 0.05-0.02 (m, 1H); MS: m/z 173 (M++i).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[ClH:22]>C(#N)C.[Cu]>[Cl:22][C:9]1[S:10][C:11]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Reactant: Cl
Agent: [Cu]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: FC(F)(F)c1ccc2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
In a three-necked flask fitted with a condenser, a suspension of copper II chloride (370 mg, 2.75 mmol) in acetonitrile (5 mL) was treated with tert-butyl nitrite (0.41 mL, 3.44 mmol) and stirred at rt for 10 minutes. A solution of 2-amino-6-trifluoromethylbenzthiazole (500 mg, 2.29 mmol) in acetonitrile (1 mL) was then added dropwise. The mixture was heated at 65° C. for 30 minutes, then cooled and diluted with an excess of 1 N aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate. The organic phase was separated, dried (MgSO4), and concentrated under reduced pressure. An orange semi-solid (501 mg, 92%) was obtained and used without further purification. 1H NMR (300 MHz, CDCl3) δ 8.10-8.05 (m, 2 H), 7.74 (d, 1 H); LC-MS m/z 238.2 (MH+), ret. time 3.76 min TLC Rf=0.50 (9:1 hexanes/ethyl acetate).
Reaction SMILES: Cl.[CH:2]1([CH:5]([NH2:9])[CH:6]2[CH2:8][CH2:7]2)[CH2:4][CH2:3]1.[C:10]([NH:12][C:13]([NH2:15])=[NH:14])#[N:11]>CCCCCCCCCC.C1(C)C=CC=CC=1>[CH:2]1([CH:5]([NH:9][C:10]([NH:12][C:13]([NH2:15])=[NH:14])=[NH:11])[CH:6]2[CH2:8][CH2:7]2)[CH2:4][CH2:3]1
Reactant: N#CNC(=N)N
Reactant: NC(C1CC1)C1CC1
Agent: Cl
Solvent: CCCCCCCCCC
Solvent: Cc1ccccc1
Product: N=C(N)NC(=N)NC(C1CC1)C1CC1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
1.6 g (10.8 mmol) of 1,1-dicyclopropylmethylamine hydrochloride were admixed with 0.91 g (10.8 mmol) of cyanoguanidine in a mixture of 6 ml of decane and 20 ml of toluene. The mixture was heated to a temperature of 140° C. for 5 h, in the course of which toluene distilled off. The flask contents were cooled to room temperature, then acetone was added. The precipitate was decanted off and freed of residual solvent under reduced pressure. 1.7 g of the crude product (purity approx. 80%) were obtained, which were used for the next synthesis stage without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@:5]([CH3:9])([CH:7]=O)[CH2:4][O:3]1.Cl.[NH2:12][OH:13].C([O-])([O-])=O.[Na+].[Na+]>O.CO>[CH3:1][C:2]1([CH3:10])[O:6][C@:5]([CH3:9])([CH:7]=[N:12][OH:13])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@](C)(C=O)O1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)OC[C@@](C)(C=NO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
(S)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde (5.8 g, 40 mmol) was dissolved in 1:1 methanol water (100 mL) and hydroxylamine hydrochloride (2.8 g, 40 mmol) and Na2CO3 (2.4 g, 20 mmol). The reaction was stirred at ambient temperature overnight, then concentrated in vacuo. The aqueous layer was extracted with CH2Cl2, and the organic layer was dried over sodium sulfate, filtered and concentrated to afford (R)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde oxime (4.8 g, 30 mmol, 75% yield).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:8][CH2:9][C:10]([CH3:13])([CH3:12])[N:11]=1.C([Li])CCC.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=1>CCOCC.CCCCCC>[CH3:13][C:10]1([CH3:12])[CH2:9][O:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH2:14][C:23]2[N:24]=[C:25]([Cl:27])[CH:26]=[C:21]([Cl:20])[N:22]=2)=[N:11]1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1ccccc1C1=NC(C)(C)CO1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(C)COC(c2ccccc2Cc2nc(Cl)cc(Cl)n2)=N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 1.25 g of 2-o-tolyl-4,4-dimethyl-oxazoline in 20 ml of ether under N2 atmosphere at -30° C. is added by syringe 4.2 ml of 1.6M n-butyllithium in hexane with stirring which is continued for 1 hr at -10° C. 0.98 g of 4,6-dichloropyrimidine in 20 ml of ether are added slowly to the reaction mixture which is then stirred at -45° to -30° C. for 30 min and at 0° C. for a further 30 min. The reaction mixture is quenched with acetic acid (0.4 ml) and water (0.1 ml) in THF (1.3 ml) and then treated with 1.5 g of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in 6 ml of THF. The temperature is brought to RT and the mixture stirred for 5 min after cooling to 0° C. 7.6 ml of 1N NaOH (cooled) are added and the mixture stirred for 5 min. The organic phase is separated and dried over Na2SO4 filtered and the solvent removed. Following chromatography (10/90 ether/hexane) the title product is obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]3[CH:17]=[N:18][C:19]([C:20](OCC)=[O:21])=[C:9]3[N:8]=2)[CH2:3][CH2:2]1.C([NH2:28])(=O)C.C[O-].[Na+]>CN(C)C=O.CO.C(O)(C)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]3[CH:17]=[N:18][C:19]([C:20]([NH2:28])=[O:21])=[C:9]3[N:8]=2)[CH2:3][CH2:2]1
Reactant: CC(N)=O
Reactant: CCOC(=O)c1ncn2c1nc(N1CCOCC1)c1ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: NC(=O)c1ncn2c1nc(N1CCOCC1)c1ccccc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A stirred mixture of ethyl 5-morpholino-imidazo[1,5-a]quinazoline-3-carboxylate (2.0 g) and acetamide (1.2 g) in 20 ml of dry dimethylformamide was heated to 80° C. 30% sodium methoxide in methanol (1 ml) was added and the mixture was stirred at 100° C. for 2 hours, cooled to room temperature and diluted with isopropanol (20 ml). Crystals were filtered off, washed with isopropanol (15 ml), water (20 ml) and diethyl ether (10 ml), and dried to give the title compound as yellow crystals, m.p. >300° C. Yield 1.3 g.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl.[Cu].C1CCCCC1.C(Cl)Cl>[Br:14][C:15]1[CH:16]=[C:17]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:18]=[CH:19][CH:20]=1
Reactant: Brc1cccc(I)c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: O
Product: Brc1cccc(-n2c3ccccc3c3ccccc32)c1
Temperature: 150 °C
Reaction time: 48 h
Yield: 79.2 %

Procedure:
Under nitrogen, carbazole (24.3 g, 1 eq.) is added to a flask together with 1-bromo-3-iodobenzene (98%; 75.3 g, 1.9 eq.), potassium carbonate (48.2 g, 2.5 eq.) and copper (1.77 g, 0.1 eq.). The reaction is heated to 150° C. and stirred at 150° C. for 48 h. The mixture is cooled to room temperature and diluted with 150 mL of methylene chloride. 100 mL of demineralized water are added to the mixture, which is stirred. Removal of the aqueous phase is followed by washing a further 2× with demineralized water (100 mL). The organic phase is dried over sodium sulfate and concentrated. The excess 1-bromo-3-iodobenzene is distilled off under reduced pressure. LC (SiO2; cyclohexane/methylene chloride 95:5) gives 37.1 g of product (82.4% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C:12]([O:14][CH3:15])=[O:13])[CH2:3][CH2:2]1.[O:16]=[C:17]1[N:23]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C@@H:33]([C:46](O)=[O:47])[CH2:34][C:35]3[CH:44]=[C:43]([CH3:45])[C:38]4[NH:39][C:40](=[O:42])[O:41][C:37]=4[CH:36]=3)=[O:31])[CH2:26][CH2:25]2)[CH2:22][CH2:21][C:20]2[CH:49]=[CH:50][CH:51]=[CH:52][C:19]=2[NH:18]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:16]=[C:17]1[N:23]([CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C@H:33]([CH2:34][C:35]3[CH:44]=[C:43]([CH3:45])[C:38]4[NH:39][C:40](=[O:42])[O:41][C:37]=4[CH:36]=3)[C:46]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[CH2:11][CH2:10][CH2:9][C@H:8]4[C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH2:6]3)=[O:47])=[O:31])[CH2:28][CH2:29]2)[CH2:22][CH2:21][C:20]2[CH:49]=[CH:50][CH:51]=[CH:52][C:19]=2[NH:18]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Reactant: COC(=O)[C@@H]1CCCN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(C)c3[nH]c(=O)oc3c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
93 mg (0.44 mmol) methyl (S)-1-piperidin-4-yl-pyrrolidine-2-carboxylate were added to a solution of 200 mg (0.39 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenzoxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 140 mg (0.44 mmol) TBTU and 61 μL (0.44 mmol) triethylamine in 2 mL DMF and the reaction mixture was shaken overnight at RT. The reaction solution was purified by HPLC without working up; the fractions containing the product were concentrated by evaporation and lyophilised.
Reaction SMILES: C[C:2]([O:4]Cl)=[O:3].[CH2:6]1[O:30][C:29]2[C:8](=[CH:9][C:10]3[N:14]=[C:13]([S:15]([CH2:17][C:18]4[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=4)=[O:16])[NH:12][C:11]=3[CH:28]=2)[O:7]1.[CH2:31](N(CC)CC)C>C(Cl)Cl>[CH3:31][O:4][C:2]([N:12]1[C:11]2[CH:28]=[C:29]3[O:30][CH2:6][O:7][C:8]3=[CH:9][C:10]=2[N:14]=[C:13]1[S:15]([CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=1)=[O:16])=[O:3]
Reactant: CC(=O)OCl
Reactant: CCN(CC)CC
Reactant: COc1c(C)cnc(CS(=O)c2nc3cc4c(cc3[nH]2)OCO4)c1C
Solvent: ClCCl
Product: COC(=O)n1c(S(=O)Cc2ncc(C)c(OC)c2C)nc2cc3c(cc21)OCO3
Temperature: 25 °C
Reaction time: 19 h
Yield: 6 %

Procedure:
Chloro methylformate (0.24 g, 0.0026 mol) dissolved in CH2Cl2 (5 ml) was added dropwise to a stirred solution of 5,6-methylenedioxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (0.80 g, 0.0022 mol) and triethylamine in CH2Cl2 (10 ml). The mixture was then stirred at room temperature for 19 h. The CH2Cl2 -solution was washed with water, dried (MgSO4) and the solvent was evaporated giving the desired product as an oil (0.06 g, 6%). NMR data for the final product is given below.
Reaction SMILES: Cl.[C:2]([N:9]1[CH2:13][C@@H:12]([S:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:11]([N:19]([CH3:36])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:10]1)(OC(C)(C)C)=[O:3].C([N:39](CC)CC)C.[Si](N=C=O)(C)(C)C>C(OCC)(=O)C>[C:2]([N:9]1[CH2:13][C@@H:12]([S:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C@H:11]([N:19]([CH3:36])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)(=[O:21])=[O:22])[CH2:10]1)(=[O:3])[NH2:39]
Reactant: CN([C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1SC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CN([C@@H]1CN(C(N)=O)C[C@H]1SC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Yield: 94.9 %

Procedure:
To a stirred solution of 1.5 M HCl in ethyl acetate (5 mL) was added (±)-N-Boc-trans-3-(N-methyl-4-phenoxybenzenesulfonamido)-4-tertbutylmercaptopyrrolidine (130 mg, 0.25 mmol) and stirring was continued at room temperature until no starting material was detected by TLC. The solvent was evaporated under reduced pressure and the residue was dissolved in CH2Cl2. The solution was cooled to 0° C. and triethylamine (46 μL, 0.33 mmol) and TMSNCO (100 μL, 0.74 mmol) were added successively. The solution was stirred at room temperature overnight. The reaction mixture was extracted with water and saturated brine, and was dried over Na2SO4 and filtered. The solvent was evaporated and the residue was purified by flash chromatography (5% MeOH in ethyl acetate) to give (±)-N-carbamoyl-trans-3-(N-methyl-4-phenoxybenzenesulfonamido)-4-tert-butylmercaptopyrrolidine as a white powder (110 mg, 95%): 1H NMR (300 MHz, CD3OD) δ 7.85 (m, 2H), 7.42 (m, 2H), 7.22 (m, 1H), 7.10 (m, 4H), 4.24 (m, 1H), 3.96 (m, 1H), 3.42 (m, 2H), 3.08 (m, 2H), 2.87 (s, 3H), 1.28 (s, 9H); MS (ESI) m/e 463.2 (M+); HRMS (ESI) calcd for C22H29N3O4S2Na+ 486.1479. found 486.1481.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][C:15]([CH3:17])=O.Cl.[CH3:22][NH2:23]>N1C=CC=CC=1>[CH3:22][N:23]1[C:15]([CH3:17])=[C:14]([C:13]([O:19][CH3:20])=[O:18])[CH:7]([C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)[C:14]([C:13]([O:19][CH3:20])=[O:18])=[C:15]1[CH3:17]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CN
Reactant: COC(=O)CC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)C1=C(C)N(C)C(C)=C(C(=O)OC)C1c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 5.22 g (0.03 mol) of 4-trifluoromethylbenzaldehyde, 7.04 g (0.06 mol) of methyl acetoacetate and 2.07 g (0.03 mol) of methylamine hydrochloride in 20 ml of pyridine is stirred under reflux for 5 hours. After removing the pyridine by distillation, the mixture is partitioned between water and methylene chloride, and the organic phase is washed with water, dried over sodium sulphate and evaporated. The residue is recrystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([O:13][CH2:14][CH3:15])[C:6]([CH3:12])=[N:7]2.[CH3:16][O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>>[ClH:1].[CH2:14]([O:13][C:5]1[C:6]([CH3:12])=[N:7][C:8]2[C:3]([CH:4]=1)=[C:2]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[O:17][CH3:16])[CH:11]=[CH:10][N:9]=2)[CH3:15]
Reactant: COc1ccccc1N
Reactant: CCOc1cc2c(Cl)ccnc2nc1C
Product: CCOc1cc2c(Nc3ccccc3OC)ccnc2nc1C
Product: Cl

Procedure:
In a similar manner to Example 1, a mixture of 5-chloro-3-ethoxy-2-methyl-1,8-naphthyridine (2.0 g) and 2-methoxyaniline (1.05 g) in IMS (30 ml) was boiled under reflux for 6 hours then cooled and filtered to give 3-ethoxy-5-(2-methoxyanilino)-2-methyl-1,8-naphthyridine hydrochloride, m.p. 250°-252° C. (with decomposition). Active (1/1) at 30 mg/kg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Se](=O)=[O:16]>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:16])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Se]=O
Reactant: Cc1ccc(-c2ncccc2Cl)cc1
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2ncccc2Cl)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
100 g (0.49 mol) of 3-chloro-2-para-tolylpyridine was dissolved in 1 L of 1,4-dioxane in a reactor. 163.4 g (1.47 mol) of selenium dioxide was added, and the mixture was refluxed for 4˜6 hours. The reaction solution was cooled to 25° C., and floating matter was filtered off with celite. A 10% sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure, yielding 4-(3-chloropyridin-2-yl)benzaldehyde as represented below in a 85% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C>C(OCC)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:15][CH:16]=1
Reactant: COC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)Oc1ccc(N)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-(4-nitrophenoxy)propionate (10 g, 0.044 mol) in ethyl acetate is added dropwise to a mixture of iron dust (7.37 g, 0.132 mol) in a 5% acetic acid solution at 65° C. The reaction mixture is stirred at 65° C. for 30 minutes, cooled to room temperature and filtered through diatomaceous earth. The resultant filtrate is diluted with water and extracted with ethyl acetate. The organic extracts are combined, washed sequentially with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as an oil which is identified by NMR spectral analyses.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][CH2:9]1)C1C=CC=CC=1.C1CCCCC=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCN1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCCCCCCCCN1CCNCC1

Procedure:
A mixture of 1-benzyl-4-nonylpiperazine (0.54 g, 1.80 mmol) (prepared by reacting 1-benzylpiperazine, Aldrich, with 1-bromononane, Aldrich, and Nail in DMF), palladium hydroxide on carbon (0.14 g) and cyclohexene (7 mL) in ethanol (15 mL) was heated at reflux overnight. After filtration, the filtrate was concentrated in vacuo to dryness to give the title compound as an oil, 0.38 g, 100%.