Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([N:21]5[CH2:25][CH2:24][C@@H:23]([NH:26][C:27](=O)OC(C)(C)C)[CH2:22]5)=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH:37]([OH:39])C>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([N:21]5[CH2:25][CH2:24][C@@H:23]([NH:26][CH2:27][CH2:37][OH:39])[CH2:22]5)=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)I
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCN[C@@H]1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 0.6 %

Procedure:
To a solution of tert-butyl {(3R)-1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidin-3-yl}carbamate (300 mg, 0.672 mmol) in anhydrous DMF (2.0 ml) was added 95% NaH (25.4 mg, 1.01 mmol). After stirring at R.T. for 10 mins, to the reaction mixture was added iodoethanol (288.9 mg, 1.68 mmol). After stirring at 70° C. for 16 h, to the reaction mixture was added iodoethanol (288.9 mg, 1.68 mmol). After stirring at 90° C. for 7 h, 105° C. for 32 h, the reaction mixture was quenched with water and filtered. The eluent was extracted with 2:1 EtOAc:toluene (2×30 ml). The organic layer was dried with K2CO3, filtered and concentrated. The resulting residue was dissolved in CH2Cl2 (10 ml) and TFA (0.5 ml) and MeOH (1 pipet drop) were added. After stirring at R.T for 16 h, the reaction mixture was concentrated. The resulting residue was purified via reversed phase column eluted with 0.1% TFA CAN: water to give the desired product (1.6 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 99 using 1-chloro-3-(lH-indole-4-oxy)propane (0.446 g, 2.15 mmol) and 6-chloro-3-(piperidin-4-yl)-1H-indole ( 0.500 g, 2.13 mmol) in the presence of 2.0 equivalents of potassium carbonate (0.593 g, 4.3 mmol) in dimethylformamide at 90° C. Yield 0.330 g (37%) of a colorless foam. FDMS m/e=407 (M+ of free base).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:43][CH:44]([CH2:63][CH3:64])[C@@H:45]([C:47]1[O:48][C:49]([C:52]2[CH:57]=[CH:56][C:55]([O:58][C:59]([F:62])([F:61])[F:60])=[CH:54][CH:53]=2)=[N:50][N:51]=1)[OH:46].[F:65][C:66]([F:84])([CH2:81][CH2:82][CH3:83])[CH2:67][C@H:68]([NH:72][C:73]([N:75]1[CH2:80][CH2:79][O:78][CH2:77][CH2:76]1)=[O:74])[C:69](O)=[O:70]>C(Cl)Cl>[F:84][C:66]([F:65])([CH2:81][CH2:82][CH3:83])[CH2:67][C@H:68]([NH:72][C:73]([N:75]1[CH2:76][CH2:77][O:78][CH2:79][CH2:80]1)=[O:74])[C:69](=[O:70])[NH:43][C@H:44]([CH:45]([OH:46])[C:47]1[O:48][C:49]([C:52]2[CH:53]=[CH:54][C:55]([O:58][C:59]([F:61])([F:60])[F:62])=[CH:56][CH:57]=2)=[N:50][N:51]=1)[CH2:63][CH3:64]
Reactant: CCC(N)[C@H](O)c1nnc(-c2ccc(OC(F)(F)F)cc2)o1
Reactant: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)N[C@@H](CC)C(O)c1nnc(-c2ccc(OC(F)(F)F)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
PyBOP (68.69 mg, 0.13 mmol), diisopropylethylamine (0.023 mL, 0.13 mmol) and (S)-2-Amino-1-[5-(4-trifluoromethoxy-phenyl)-1,3,4-oxadiazol-2-yl]-butan-1-ol (38.0 mg, 0.12 mmol) are added to a solution of (S)-4,4-Difluoro-2-[(morpholine-4-carbonyl)-amino]-heptanoic acid (34 mg, 0.12 mmol) in dry methylene chloride (4 mL) and the reaction mixture is stirred overnight at room temperature. The reaction is quenched with aqueous NaHCO3, extracted twice with methylene chloride, the organic extracts are dried over Na2SO4 and evaporated under reduced pressure. Column chromatography on silica eluting with a mixture of methylene chloride and ethyl acetate gives morpholine-4-carboxylic acid [(S)-3,3-difluoro-1-((S)-1-{hydroxy-[5-(4-trifluoromethoxy-phenyl)-1,3,4-oxadiazol-2-yl]-methyl}-propylcarbamoyl)-hexyl]-amide as a solid (61 mg). LC/MS 71%, M+1=594
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]2[CH2:27][C:26]([CH3:29])([CH3:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]#[N:31])[CH:24]=3)[NH:19]2)[CH:15]=[CH:16][CH:17]=1.N1C=CC=CC=1>ClCCl>[C:30]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]([C:14]1[CH:13]=[C:12]([NH:11][S:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)(=[O:9])=[O:8])[CH:17]=[CH:16][CH:15]=1)[CH2:27][C:26]2([CH3:29])[CH3:28])#[N:31]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3cccnc3)c2)Nc2ccc(C#N)cc21
Reaction time: 8 h
Yield: 44.2 %

Procedure:
Pyridine-3-sulfonyl chloride (144 mg, 0.81 mmol) was added dropwise to a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (77 mg, 0.97 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. Filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=3:1) to afford pyridine-3-sulfonic acid [3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide as off-white solid (100 mg, yield: 44.2%). MS (ESI+APCI) M+1=419.1.
Reaction SMILES: C1(C)C=CC=CC=1.C[Al](C)C.C1C[O:15][CH2:14]C1.Cl.CNOC.C([C@@H]1CO[C:31](=O)[N:30]1[C:35](=[O:42])[C@H:36]([CH3:41])[C@@H:37]([OH:40])[CH2:38][CH3:39])C1C=CC=CC=1>ClCCl.C1COCC1.ClCCl>[OH:40][C@@H:37]([CH2:38][CH3:39])[C@@H:36]([CH3:41])[C:35]([N:30]([O:15][CH3:14])[CH3:31])=[O:42]
Reactant: C1CCOC1
Reactant: CC[C@H](O)[C@@H](C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC[C@H](O)[C@@H](C)C(=O)N(C)OC
Temperature: 0 °C

Procedure:
2M trimethylaluminum toluene solution (90 ml, 180 mmol) was added to a THF (180 ml) solution of N,O-dimethylhydroxyamine hydrochloride (18.3 g, 187.6 mmol) at −10° C. under stirring. After the reaction solution was warmed to 0° C. and stirred for 10 minutes, it was warmed to room temperature and further stirred for 30 minutes. The reaction solution was cooled to −10° C. again, and a THF-dichloromethane solution (4:5, 180 ml) of (4R)-4-benzyl-3-[(2R,3S)-3-hydroxy-2-methylpentanoyl]-1,3-oxazolidin-2-one (21.85 g, 75 mmol) was added dropwise to the reaction solution. After the reaction solution was warmed to 0° C. and stirred for two hours, a mixed solution of dichloromethane −0.5N hydrochloric acid (1:1, 80 ml) was added slowly, and the mixture was stirred for one hour at 0° C. The reaction solution was filtered through celite and the filtrate was dried over anhydrous sodium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60; heptane:ethyl acetate=1.5:1) to obtain (2R,3S)-3-hydroxy-N-methoxy-N,2-dimethylpentanamide (13.0 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.CN[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.O.[CH3:21][N:22](C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:14]=[C:13]([CH2:21][NH2:22])[CH:12]=[CH:11][CH:16]=2)=[N:3][CH:4]=1
Reactant: CNc1cccc(B(O)O)c1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: NCc1cccc(-c2ccc(Br)cn2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
2.2 g (9.5 mmol, 1.2 eq) of 2,5-dibromopyridine are dissolved in 3 mL of an 8/2 mixture of dimethylformamide/2M potassium phosphate. 1.2 g (7.9 mmol, 1 eq) of N-methyl-3-aminophenylboronic acid are added along with 456 mg (0.39 mmol, 5 mol %) of tetrakis(triphenylphosphine)palladium. The mixture is stirred for 3 hours at 90° C. The reaction is stopped by adding 30 mL of water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and the residue is then chromatographed on silica gel (80/20 to 70/30 heptane/ethyl acetate). 1.07 g of [3-(5-bromopyrid-2-yl)phenyl]methylamine are obtained. Yield 52%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.Cl.[CH:20](=[NH:24])OCC>C1COCC1>[NH:24]=[CH:20][NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCOC=N
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(NC=N)cc2)cs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
N-(4-[2-(4-Aminophenyl)ethyl]-1,3-thiazol-2-yl)acetamide (150 mg) was dissolved in THF (2 ml) and pH=7 buffer (2 ml). Then, ethyl imidoformate hydrochloride (1.26 g) was added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 2 hours, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with CH3CN/water (7:3) as an eluent. The oil was purified again by preparative silica gel chromatography with CHCl3/MeOH (5:1) as an eluent to give N-[4-(2-{4-[(iminomethyl)amino]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide (110 mg) as pale brown oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].CCN(CC)CC.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19].O>ClCCl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:18]([O:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)N1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
A solution of 1-acetylpiperazine (1.30 g) and Et3N (1.23 g) in dichloromethane (10 ml) was added dropwise to a solution of 4-nitrophenyl chloroformate (2.05 g) in dichloromethane (20 ml) under ice-cooling. After stirring at 0° C. for 30 minutes and at room temperature for 1 hour, water was added to the reaction solution, and the reaction solution was extracted with dichloromethane. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (1.70 g) as colorless crystals.
Reaction SMILES: [I-:1].[Na+].[CH3:3][C:4]1([CH3:13])[O:9][C:8](=[O:10])[CH:7]=[C:6]([CH2:11]Cl)[O:5]1>CC(C)=O>[I:1][CH2:11][C:6]1[O:5][C:4]([CH3:13])([CH3:3])[O:9][C:8](=[O:10])[CH:7]=1
Reactant: CC1(C)OC(=O)C=C(CCl)O1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)OC(=O)C=C(CI)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
Sodium iodide (2.16 g) was dissolved in 16 mL of acetone, 2.00 g of 2,2-dimethyl-6-chloromethyl-1,3-dioxin-4-one diluted with 4 mL of acetone was added, and the mixture was stirred at room temperature for 2 hours. The insoluble matter was removed from the reaction mixture by filtration and the filtrate was concentrated. The residue was dissolved in 20 mL of chloroform, the insoluble matter was again filtered off and the filtrate was concentrated. The thus-obtained residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate=1/1 (volume ratio)) to give 2.65 g of 6-iodomethyl-2,2-dimethyl-4H-1,3-dioxin-4-one as a yellow liquid. The NMR spectrum of this compound is shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([Li])CCC.N1C=[CH:18][C:17]([CH:20]=[O:21])=[CH:16]C=1.C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:21])[C:17]([CH3:9])([CH3:18])[CH3:16])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: [Li]CCCC
Reactant: O=Cc1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2 g of pivaloyl protected 4-chloroaniline in 50 mL of THF was cooled to −78° C. under nitrogen. A solution of n-butyl lithium (14 mL of 2 N in hexane) was added dropwise. The mixture was allowed to warm 0° C. and stirring continued at 0° C. for one hour. A pyridine 4-carboxaldehyde was added to the solution and the reaction was stirred at 0° C. for one hour. The reaction mixture was poured into ethyl acetate and washed with water. The organic layer was separated and dried over MgSO4. Removal of the solvent followed by chromatography on silica gel (hexane:ethyl acetate 2:1 as eluent) afforded 1 g of the desired product.
Reaction SMILES: [N+]([O-])(O)=O.[C:5]([NH:8][C:9]1[C:10]([Cl:17])=[N:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=1)(=[O:7])[CH3:6].[O-:18][Mn](=O)(=O)=O.[K+]>O.CC(C)=O>[C:15]([C:12]1[N:11]=[C:10]([Cl:17])[C:9]([NH:8][C:5](=[O:7])[CH3:6])=[CH:14][CH:13]=1)(=[O:18])[CH3:16]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCc1ccc(NC(C)=O)c(Cl)n1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: O=[N+]([O-])O
Product: CC(=O)Nc1ccc(C(C)=O)nc1Cl
Temperature: 20 °C

Procedure:
4.937 g (0.124 mol) of MgO are suspended in 112 ml of water and the suspension is brought to pH 6 with about 16.7 ml (0.242 mol) of 65% strength HNO3. 10 g (49.4 mmol) of 3-acetamido-2-chloro-6-ethylpyridine, dissolved in 112 ml of acetone, are then added, 19.5 g (0.124 mol of KMnO4 are introduced and the mixture is stirred at 20° C. until the reaction is complete (48 hours). The solid is then filtered off with suction and the filter cake is washed thoroughly with hot acetone. The filtrate is diluted with 500 ml of water and extracted three times with 200 ml of CHCl3 each time, and the combined extracts are washed with water, dried with Na2SO4 and evaporated. For purification, the product is recrystallized from toluene/petroleum ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:23][C:21]1[CH:20]=[CH:19][C:17]2=[N:18][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:15]=[C:16]2[CH:22]=1.[N:15]1[NH:14][N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=12
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1nc2ccc(F)cc2n1
Product: FCc1cccc(C#CCCn2nc3ccc(F)cc3n2)n1
Product: c1ccc2n[nH]nc2c1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (55 mg, 0.29 mmol) and 2-(but-3-ynyl)-5-fluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.26 mmol). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 50 mg (0.17 mmol, 64%) of 5-fluoro-2-(4-(6-fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: O=[C:2]([CH3:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.BrBr.[Cl:17][C:18]1[N:23]=[C:22]([NH:24][C:25]([NH2:27])=[S:26])[CH:21]=[N:20][CH:19]=1.[Br-]>O1CCOCC1.C(O)C>[Cl:17][C:18]1[N:23]=[C:22]([NH:24][C:25]2[S:26][C:3]([C:4]3[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=3)=[C:2]([CH3:14])[N:27]=2)[CH:21]=[N:20][CH:19]=1
Reactant: NC(=S)Nc1cncc(Cl)n1
Reactant: CC(=O)Cc1ccc(S(N)(=O)=O)cc1
Agent: BrBr
Agent: [Br-]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nc(Nc2cncc(Cl)n2)sc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88.2 %

Procedure:
4-(2-Oxo-propyl)-benzenesulfonamide (prepared as described in European patent specification EP 91749 A2) (0.63 g, 2.9 mmol) is dissolved in dry dioxan (70 ml) at 0° C. and bromine (0.121 ml, 2.4 mmol) is added dropwise. The mixture is stirred for 45 minutes at room temperature then the solvent is removed in vacuo. 6-Chloro-pyrazin-2-yl-thiourea (0.35 g, 1.87 mmol) is added to a solution of the above bromide (0.546 g, 1.87 mmol) in ethanol and the solution is heated at 60° C. for 4 hours. The reaction mixture is allowed to cool and the solvent removed under vacuum to give the title compound (0.63 g). MH+ (ES+): 382.1, 384.2 (3:1)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][C:11]([F:20])([F:19])[C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(O)CO.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.[Cu]I.C(O)(C)C>[F:20][C:11]([F:10])([F:19])[C:12]1[CH:13]=[CH:14][C:15]([S:18][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])=[CH:16][CH:17]=1
Reactant: FC(F)(F)c1ccc(S)cc1
Reactant: O=Cc1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: OCCO
Solvent: CC(C)O
Product: O=Cc1cccc(Sc2ccc(C(F)(F)F)cc2)c1
Temperature: 85 °C
Yield: 44.5 %

Procedure:
To a sealed tube flushed with nitrogen, was added 3-iodobenzaldehyde 31.1 (300 mg, 1.29 mmol), 4-(trifluoromethyl)benzenethiol (230 mg, 1.29 mmol), copper (I) iodide (24.6 mg, 0.129 mmol), ethylene glycol (0.144 mL, 2.59 mmol), potassium carbonate (357 mg, 2.59 mmol), and isopropanol (6.50 mL). The reaction mixture was heated at 85° C. for 48 hours. The reaction was then cooled and diluted with DCM and filtered over a pad of diatomaceous earth. The filtrate was concentrated, and the residue was purified by medium pressure chromatography (silica gel, 0 to 20% diethyl ether:hexanes) to give 31.2 (162 mg). 1H NMR (400 MHz, CDCl3) δ ppm 9.92 (1H, s), 7.85 (1H, s), 7.77 (1H, d, J=7.4 Hz), 7.59 (1H, d, J=7.8 Hz), 7.44-7.50 (3H, m), 7.29 (2H, d, J=8.2 Hz).
Reaction SMILES: I[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[N:7]([CH3:10])[N:6]=[N:5]1.[CH3:11][O:12][CH2:13][C:14]1([N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21](=[O:24])[CH2:22][CH3:23])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[C:31](=O)([O-:33])[O-:32].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[C:8]([OH:9])(=[O:12])[C:31]([OH:33])=[O:32].[CH3:10][N:7]1[C:8](=[O:9])[N:4]([CH2:3][CH2:2][N:17]2[CH2:18][CH2:19][C:14]([N:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21](=[O:24])[CH2:22][CH3:23])([CH2:13][O:12][CH3:11])[CH2:15][CH2:16]2)[N:5]=[N:6]1
Reactant: O=C([O-])[O-]
Reactant: Cn1nnn(CCI)c1=O
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCn2nnn(C)c2=O)CC1
Product: O=C(O)C(=O)O
Yield: 42 %

Procedure:
A mixture of 2.55 parts of 1,4-dihydro-1-(2-iodoethyl)-4-methyl-5H-tetrazol-5-one, 3.45 parts of N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide, 2 parts of sodium carbonate, 0.2 parts of potassium iodide and 160 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, 100 parts of water are added and the layers are separated. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the ethanedioate salt in 2-propanone. The salt is filtered off and crystallized from 2-propanone, yielding 2.1 parts (42%) of N-{1-[2-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(methoxymethyl)-4-piperidinyl}-N-phenylpropanamide ethanedioate (1:1); mp. 155.9° C.
Reaction SMILES: NC1N=NN=C(Cl)C=1N.[CH2:10]([NH2:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[Na+].[N:25]1[C:32]([NH2:33])=[N:31][C:29](N)=[N:28][C:26]=1[NH2:27]>O>[CH2:10]([NH:22][C:29]1[N:31]=[C:32]([NH2:33])[N:25]=[C:26]([NH2:27])[N:28]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCN
Reactant: Nc1nc(N)nc(N)n1
Agent: Nc1nnnc(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCNc1nc(N)nc(N)n1
Yield: 65 %

Procedure:
A mixture of 14.6 g (0.1 mol) of diaminochlorotriazine, 19.5 g (0.105 mol) of n-dodecylamine and 4.0 g (0.1 mol) of sodium hydroxide in 200 ml of water is refluxed for 5 hours. The solid formed is filtered off wich suction, washed until free of chloride and then treated with a mixture of methylene chloride/ether (1:1). The precipitate is filtered off and boiled in dimethylformamide. After filtration, the concentrated filtrate is poured into water with stirring. The precipitate formed is dried to constant weight. The yield is 65% of theory. The product contains 0.1 mol of hydrated water per mole of melamine and melts at 119° C.
Reaction SMILES: Cl.N1C=CC=CC=1C[N:9]1[C:13]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:12][C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:10]1.O1CCOCC1.[Se](=O)=O>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([C:13]2[NH:9][CH:10]=[C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:12]=2)=[O:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(C(=O)c2ccc(Cl)cc2)n(Cc2ccccn2)c1
Agent: Cl
Agent: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c[nH]c(C(=O)c2ccc(Cl)cc2)c1
Yield: 97.3 %

Procedure:
Ethyl 1-(2-pyridylmethyl)-5-(4-chlorobenzoyl)-pyrrole-3-carboxylate hydrochloride (4.05 g.) was combined with 150 ml. of dioxane, 5 ml. of water and 10 g. of selenium dioxide and refluxed for 18 hours. The reaction mixture was filtered, the filtrate diluted with 150 ml. of ether and 150 ml. of water, and equilibrated. The organic phase was separated, back-washed with two 100 ml. portions of water, and concentrated to yield solid ethyl 5-(4-chlorobenzoyl)pyrrole-3-carboxylate (2.7 g., Rf 0.55 on silica gel thin layer chromatography with ethyl acetate-1/hexane-5/5% acetic acid as eluant).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:20](O)[CH2:21][OH:22].O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:3][C:4]2([CH2:5][CH2:6][CH:7]=1)[O:22][CH2:21][CH2:20][O:8]2
Reactant: CC1=CC(=O)CCC1
Reactant: OCCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=CCCC2(C1)OCCO2
Yield: 62 %

Procedure:
A mixture of 3-methyl-2-cyclohexenone (4 g, 36.36 mmol), toluenesulfonic acid (100 mg) and ethylene glycol (7 mL) in 100 mL of toluene is refluxed overnight and water formed is removed by Dean- Stark trap. The residue after concentration is chromatographed on silica gel (10% ethyl acetate/hexane) to give 3.36 g (62%) of 7-methyl-1,4-dioxa-spiro[4.5]dec-7-ene.