Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:21]=[C:22](OS(C(F)(F)F)(=O)=O)[C:23]4[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26][C:24]=4[N:25]=3)=[CH:15][CH:14]=2)=[CH:11][N:10]=[CH:9]1.Cl>CS(C)=O>[O:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:21]=[C:22]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:23]4[CH2:29][NH:28][CH2:27][CH2:26][C:24]=4[N:25]=3)=[CH:15][CH:14]=2)=[CH:11][N:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CS(C)=O
Product: c1ccc(Nc2nc(Nc3ccc(-c4cnco4)cc3)nc3c2CNCC3)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
Aniline (0.017 mL, 0.18 mmol) was added to tert-butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.1 g, 0.18 mmol, Example 1b) in DMSO (4 mL). The solution was heated in a microwave reactor at 80° C. for 1 h. HCl (2M aq, 1.5 mL) was added and the reaction was stirred in an open vessel at 76° C. for 30 min. The reaction was allowed to cool and DMSO was added to the solution. The product was purified by preparative HPLC to give N2-(4-(oxazol-5-yl)phenyl)-N4-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (0.017 g, 24%).
Reaction SMILES: N[C:2]1[C:15]2C(=S)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([C:18]2C=CC=CC=2)=[CH:4][C:3]=1Br.[OH:25]CCS(C1C=C(O)C=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CO>CN(C)C=O.OS(O)(=O)=O.O=S(=O)=O>[CH:12]1[C:13]2[C:18](=[O:25])[C:5]3[C:6](=[CH:15][CH:2]=[CH:3][CH:4]=3)[C:7](=[O:17])[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=S(=O)(CCO)c1cccc(O)c1
Reactant: Nc1c(Br)cc(-c2ccccc2)c2c1C(=S)c1ccccc1C2=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-2-bromo-4-phenylthioanthraquinone (4.1 parts) and 3-β-hydroxyethylsulfonylphenol (2.1 parts) were allowed to react with each other at 100° to 120° C. in dimethylformamide in the presence of potassium carbonate. After completion of the reaction, methanol was added to the reaction mixture to deposit crystals, which were then collected on a filter, well washed with water and then dried at 80° C. The product obtained was subjected to both sulfonation and esterification at 20° to 40° C. in 10% oleum. Ice was added to the reaction mixture to deposit crystals, which were then collected on a filter to obtain an anthraquinone compound of the following formula (free acid form). ##STR182##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][NH:11]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:23]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1.O>C(Cl)Cl>[CH:23]1([CH2:28][CH2:29][C:30]([N:11]2[C@@H:12]3[C@@H:8]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:15]=4[CH2:14][CH2:13]3)[CH2:9][CH2:10]2)=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: COc1cccc2c1CC[C@@H]1NCC[C@H]21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1C(=O)CCC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
4.06 g (0.020 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole were dissolved in 80 ml of CH2Cl2, 3.35 ml (0.024 mol) of triethylamine were added thereto and a solution of 3.7 ml (0.024 mol) of 3-cyclopentylpropionyl chloride in 40 ml of CH2Cl2 was added dropwise thereto at 20° under argon. The mixture was stirred at room temperature for 1 hour, then poured into water and extracted with CH2Cl2. The organic phase was washed with saturated aqueous NaHCO3 and NaCl solutions, dried with MgSO4, filtered and concentrated. By chromatography of the residue over silica gel with n-hexane/ethyl acetate 1:1 there were obtained 4.75 g (72.5%) of rac-cis-3-(3-cyclopentyl-propionyl)-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole as a pale yellow, oily material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([NH2:8])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([NH2:8])=[S:17]
Reactant: COc1cc(C(N)=O)cc(OC)c1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccccc1
Product: COc1cc(C(N)=S)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 122.7 %

Procedure:
500 mg of 3,4,5-trimethoxybenzamide was suspended in 15 ml of benzene. Thereto was added 526 mg of phosphorus pentasulfide. The mixture was refluxed for 30 minutes with heating. The solvent was removed by distillation. To the residue were added 5 ml of 10% sodium hydroxide and 5 ml of water. The mixture was stirred for 30 minutes. The reaction mixture was filtered, and the resulting solid was washed with small amounts of water and ethanol and dried to obtain 330 mg of 3,4,5-trimethoxythiobenzamide as a yellow powder.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1>>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CC(C)c1cc(NN)nc2ccccc12
Product: CC(C)c1cc(NNC(=O)Nc2cc(Cl)cc(Cl)c2)nc2ccccc12

Procedure:
A solution of 2-hydrazinyl-4-isopropylquinoline (97 mg, 0.48 mmol) and 91 mg (1.0 eq) of 3,5-dichlorophenyl isocyanate was reacted as outlined in Scheme 1 above to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.29 (d, J=6.74 Hz, 6 H) 3.53-3.71 (m, 1 H) 6.83 (s, 1 H) 7.09 (t, J=1.90 Hz, 1 H) 7.28 (td, J=7.47, 1.46 Hz, 1 H) 7.45-7.62 (m, 2 H) 7.69 (br. s., 2 H) 7.94 (d, J=7.62 Hz, 1 H) 8.50 (br. s., 1 H) 8.70 (s, 1 H) 9.23 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]N(C)C)[C:12]=2[S:21][CH3:22])[CH:3]=1.C1(C)C=CC=CC=1.[Cl:30]C(OCC)=O.O>C(OCC)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][Cl:30])[C:12]=2[S:21][CH3:22])[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: CSc1c(CN(C)C)cccc1Oc1cc(Cl)ccc1C#N
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CSc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Temperature: 0 °C
Reaction time: 17 h
Yield: 80.6 %

Procedure:
Under a nitrogen atmosphere, 4-chloro-2-(3-dimethylaminomethyl-2-methysulfanyl-phenoxy)-benzonitrile (1.02 g, 3.06 mmol) was dissolved in anhydrous-toluene (10 mL). The solution was cooled to 0° C. and ethyl chloroformate (900 μL, 9.2 mmol) was slowly added. The reaction mixture was stirred for 17 h, allowing it to reach room temperature. Water (5 mL) and diethyl ether (5 mL) were added and the organic layer was separated and dried with MgSO4. After filtration, the solution was absorbed onto silica gel (1.5 g) and the solvent was removed in vacuo. This material was chromatographed on an ISCO CombiFlash Chromatography System to yield 4-chloro-2-(3-chloromethyl-2-methysulfanyl-phenoxy)-benzonitrile as a clear oil (800 mg, 81%).
Reaction SMILES: [CH3:1][CH:2]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4].[H-].[Na+].[Si:17]([O:24][C@@H:25]([C@H:27]1[C@H:30](SC2C=CC=CC=2)[NH:29][C:28]1=[O:38])[CH3:26])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].[Cl-].[NH4+]>O1CCCC1>[Si:17]([O:24][C@@H:25]([C@@H:27]1[C@@H:30]([C:2]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])([C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4])[CH3:1])[NH:29][C:28]1=[O:38])[CH3:26])([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:18])[CH3:19]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)N[C@H]1Sc1ccccc1
Reactant: C=CCOC(=O)C(C)C(=O)OCC=C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCOC(=O)C(C)(C(=O)OCC=C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 92.1 %

Procedure:
A solution of diallyl 2-methylmalonate (396 mg, 2 mmol) in tetrahydrofuran (2 ml) was added dropwise to a suspension of sodium hydride (80 mg, 2 mmol) in tetrahydrofuran (5 ml) under an argon stream at 0° C., and the solution mixture was stirred for 5 min and admixed with cuprous bromide dimethylsulfide complex (411 mg, 2 mmol), followed by stirring for 30 min at the same temperature, addition of a solution of (3R,4S)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-phenylthio-2-azetidinone (338 mg, 1 mmole) in tetrahydrofuran (3 ml) and stirring for 1 hour. The reaction solution was admixed with aqueous saturated ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography (10 g of silica gel; a 8/1 mixture of n-hexane/ethyl acetate) to give 392 mg (92%) of the subject compound in the form of colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]=[CH:3][C:2]=1[C:12]([O:14]CC)=O.O.[NH2:18][NH2:19]>C(O)C>[NH:18]([C:12]([C:2]1[N:1]=[CH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][CH:3]=1)=[O:14])[NH2:19]
Reactant: CCOC(=O)c1cnc(C(=O)OCC)cn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnc(C(=O)NN)cn1
Temperature: 75 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A mixture of diethyl pyrazine-2,5-dicarboxylate (1.75 g, 7.81 mmol) and ethanol (15 mL) was heated to 75° C. to obtain a homogeneous solution. After cooling to room temperature, a solution of hydrazine monohydrate (0.281 g, 7.03 mmol) in ethanol (3.5 mL) was added to the solution dropwise over 4 hours. After stirring at room temperature overnight, a solid had precipitated out of the reaction mixture. The solid was collected by filtration and dried under vacuum to give the title compound (1.05 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:20]1([CH:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:27]2[CH2:30][CH:29](OS(C)(=O)=O)[CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:29]2[CH2:30][N:27]([CH:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:28]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
A mixture of N-tert-butoxycarbonylpiperazine (14.08 g), potassium carbonate (26.1 g), and 1-diphenylmethyl-3-methanesulphonyloxyazetidine (WO 96/05193) (20 g) in dry acetonitrile (600 mL) was heated under reflux for 32 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic phase was dried over sodium sulphate and evaporated to dryness in vacuo. The residue was purified by column chromatography over silica (dichloromethane/methanol 97/3 by volume) to afford the title compound as a solid (22.53 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[C:3]=1[N+:9]([O-:11])=[O:10].CS(C)=[O:14]>O>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:14])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CS(C)=O
Reactant: Nc1ccnc(Cl)c1[N+](=O)[O-]
Solvent: O
Product: Nc1ccnc(O)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A solution of 18.0 g (104 mmol) of 4-amino-2-chloro-3-nitropyridine in 120 ml dimethylsulphoxide and 30 ml of water was stirred for four hours at 130° C. The solution was then cooled and left to stand overnight while cooling with ice. The product that crystallised out was suction filtered, washed with a little water and dried at 50° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:24][CH:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH:26]([F:28])[F:27])=[C:13]([CH:23]=1)[CH2:14][NH:15]C(=O)OC(C)(C)C>C(Cl)Cl>[NH2:15][CH2:14][C:13]1[CH:23]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]=1[CH2:24][CH:25]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[CH:26]([F:28])[F:27]
Reactant: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)OC(C)(C)C)C(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NC(Cc2ccc(Cl)cc2CN)C(F)F)cc1
Yield: 137.9 %

Procedure:
TFA (5.2 mL) was added to a stirred solution of tert-butyl 5-chloro-2-{3,3-difluoro-2-[(4-methoxyphenyl)amino]propyl}benzylcarbamate (0.516 g, 1.17 mmol) in CH2Cl2 (5.2 mL). After 1 h the solvent was evaporated in vacuo and the residue was partitioned between EtOAc and saturated aqueous Na2CO3. The EtOAc layer was dried (Na2SO4) and evaporated in vacuo to give N-{1-[2-(aminomethyl)-4-chlorobenzyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine (0.550 g) as a foam; MS m/z=341.1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][C@@H:12]([NH:14][CH2:15][C@H:16]([O:23][Si](C(C)(C)C)(C)C)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:13])=[CH:8][CH:7]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][C@@H:12]([NH:14][CH2:15][C@@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:23])[CH3:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: COC(=O)Cc1ccc(OC[C@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC[C@H](C)NC[C@H](O)c2ccccc2)cc1
Yield: 66.6 %

Procedure:
Following a procedure similar to that described in Example 27, but using 460 mg of N-[2-(4-methoxycarbonylmethylphenoxy)-1(S)-methylethyl]-2(R)-t-butyldimethylsilyloxy-2-phenylethanamine (prepared as described in Preparation 31), 15 ml of tetrahydrofuran and 780 mg of tetrabutylammonium fluoride, 0.23 g of the title compound was obtained as crystals, melting at 89°-90° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[CH:7]3)[CH2:24][CH2:23]2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: ClCCCCn1cnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCN(CCCCn3cnc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-methylphenyl piperazine (5.3 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 10-15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.4 g compound (I-11) with a yield of 60.7%. ESI-MS [M+H]+: m/z 349.2.
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1.[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].N1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(Cl)Cl>[C:9]([NH:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1)(=[O:12])[CH:10]=[CH2:11]
Reactant: C=CC(=O)Cl
Reactant: Nc1csc(Br)n1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(=O)Nc1csc(Br)n1
Yield: 12 %

Procedure:
4-Amino-2-bromothiazole hydrobromide (15.6g) and acryloylchloride (7g) were suspended in methylene chloride (100 ml) with stirring and treated with pyridine (16 ml.), maintaining reaction temperature at 0° C. with an ice bath. After addition was complete, the reaction mixture was stirred at room temperature for 3 hours, then poured onto 20% aqueous sodium acetate and stirred for 30 minutes. The mixture was filtered and separated and the organic layer washed with 2N hydrochloric acid, water, sodium carbonate solution and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo. The residue was recrystallised from carbon tetrachloride to give the title compound (0.7 g) m.p. 152°-4° C. (Found: C, 30.5; H, 2.2; N, 11.8. C6H5BrN2OS requires C, 30.9; H, 2.2; N, 12.0%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH3:14].[OH-].[Na+]>[Br-].C([N+](CC)(CC)CC)C.CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH2:13][CH3:14])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: CCCBr
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCC(C#N)c1ccc(F)cc1
Reaction time: 3 h
Yield: 35.1 %

Procedure:
To 50.0 gm (0.37 mol) of 4-fluorophenylacetonitrile, 0.6 gm of tetraethyl ammonium bromide, 50 gm (0.407 mol) of 1-bromopropane and 50 ml of DMSO was added 35.5 gm (0.44 mol) of 50% (w/w) sodium hydroxide at room temperature. After the addition was complete, the reaction was stirred at 50°-60° C. for 3 hours. The reaction mixture was extracted with ether, the organic phase washed with water and then 10% (w/w) hydrochloric acid. The ether was dried, filtered and distilled to give 23 grams of the product (b.p. 105°-110° C. at 5 mm).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br-:13].[C:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:50])[CH2:24][N+:25]23[CH2:32][CH2:31][CH:28]([CH2:29][CH2:30]2)[C@@H:27]([O:33][C:34](=[O:49])[C@@H:35]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:26]3)=[CH:19][CH:18]=1)([OH:16])=O.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>CN(C=O)C>[Br-:13].[N:51]1([C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:50])[CH2:24][N+:25]34[CH2:32][CH2:31][CH:28]([CH2:29][CH2:30]3)[C@@H:27]([O:33][C:34](=[O:49])[C@@H:35]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:26]4)=[CH:19][CH:18]=2)=[O:16])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1
Reactant: O=C(O)c1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cc1
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Solvent: CN(C)C=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1ccccc1)C2)c1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.4 %

Procedure:
1,1′-Carbonyldiimidazole (14.0 mg, 0.09 mmol) was added to a solution of (R)-1-(2-(4-carboxyphenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (diastereomer 1 of C67) (50 mg, 0.09 mmol) in dry DMF (2 ml). The reaction mixture was stirred at room temperature for 2 hours. Then morpholine (7.52 mg, 0.09 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 1 hour. DMF was evaporated and the crude was purified by preparative HPLC (eluents: CH3CN/H2O) to obtain (R)-1-(2-(4-(morpholine-4-carbonyl)phenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (18.9 mg, 33.8% yield).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][C:11]([C:14]#[N:15])=[CH:10][C:9](=[O:16])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[N+:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[NH:19][N:18]=[N:17][N:15]=3)=[CH:10][C:9](=[O:16])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(=O)c2cccc([N+](=O)[O-])c2o1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2nnn[nH]2)oc2c([N+](=O)[O-])cccc12
Temperature: 100 °C
Reaction time: 1.25 h
Yield: 68.3 %

Procedure:
A mixture of 8-nitro-4-oxo-4H-1-benzopyran-2-carbonitrile (1.094 g, 5.06 mmol), sodium azide (1.638 g, 25.3 mmol), ammonium chloride (1.349 g, 25.3 mmol) and dry N,N-dimethylformamide (50 ml) was left under stirring at 100° C. for 1.25 h. After that the mixture was cooled at room temperature and poured onto a 1M hydrochloric acid solution (50 ml) recovering the formed precipitate by filtration. The resulting solid was suspended in concentrated hydrochloric acid (12 ml) stirring at room temperature for 2.5 h. After this time the acid mixture was diluted with water (50 ml) and extracted with ethyl acetate (4×30 ml). The organic phase was dried and the solvent was evaporated off under reduced pressure, thereby obtaining 0.896 g of the title product (69% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:13]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[NH2:13][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:5]=1[O:4][C:3]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:2]=1[Cl:1])[C:9]#[N:10]
Reactant: N#Cc1ccc(Oc2cc(Cl)ccc2Cl)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2cc(Cl)ccc2Cl)c(N)c1
Yield: 103.7 %

Procedure:
The coupled product 34 was reduced with sodium hydrosulfite ((49.76 g, 268.56 mmol) in a mixture of THF (200 mL) and water (100 mL). After the reaction was complete, THF was removed in vacuo. The product was precipitated out from the remaining reaction mixture, and was collected via vacuum filtration to yield compound 35 (12.961 g, 103.7% yield, 97.3% pure). 1H NMR (500 MHz, DMSO-d6): δ 7.64 (d, J=9 Hz, 1H), 7.31 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.13 (d, J=2 Hz, 1H), 7.08 (d, J=2 Hz, 1H), 6.93 (dd, J1=8 Hz, J2=2 Hz, 1H), 6.74 (d, J=8 Hz, 1H), 5.63 (s, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C.C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.[Pd]>[C:2]1([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccccc1
Reactant: Ic1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 79.9 %

Procedure:
In a 60 ml miniautoclave, 85 mg of palladium in sol-gel matrix (cf. Example 71, metal content 0.1%) are suspended in 20 ml of DMF. After 2 mmol of iodobenzene, 2 mmol of styrene, and 4 mmol of tetrabutylammonium acetate have been added, heating at 60° C. is performed with shaking. After 12 h, 288 mg of stilbene can be isolated from the reaction solution. This corresponds to an 80% yield.
Reaction SMILES: CN([CH:4]=[C:5]1[C:9](=O)[CH2:8][CH:7]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]1)C.Cl.[NH2:16][C:17]([NH2:19])=[NH:18].C[O-].[Na+]>CO>[NH2:18][C:17]1[N:19]=[CH:4][C:5]2[CH2:6][CH:7]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:9]=2[N:16]=1
Reactant: COC(=O)C1CC(=O)C(=CN(C)C)C1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1Cc2cnc(N)nc2C1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 3-[(dimethylamino)methylidene]-4-oxocyclopentanecarboxylate (71.7 mg, 0.36 mmol) in anhydrous methanol (2.5 mL) was added guanidine hydrochloride (124.7 mg, 1.3 mmol) followed by sodium methoxide in methanol (0.24 mL, 1.27 mmol). The mixture was heated to 90° C. in a sealed tube overnight. The crude reaction was quenched with 2 N HCl and concentrated in vacuo. The aqueous residue was purified by HPLC (30×100 mm Waters Sunfire column; 5 micron; 35 mL/min.; 210 nM; 0% to 40% CH3CN+0.05% TFA/water+0.05% TFA over 15 min.; the compound eluted at 10% CH3CN+0.05% TFA/water+0.05% TFA) to afford the title compound after lyophilization.