Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[NH2:2][C@H:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.[O-]S(C(F)(F)F)(=O)=O.[N:29]1([S:34](N2C=C[N+](C)=C2)(=[O:36])=[O:35])[CH:33]=[CH:32][N:31]=[CH:30]1>CC#N>[Cl-:1].[N:29]1([S:34]([NH:2][C@H:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4][N+:5]([CH3:8])([CH3:6])[CH3:7])(=[O:36])=[O:35])[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: COC(=O)C[C@@H](N)C[N+](C)(C)C
Reactant: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C[C@H](C[N+](C)(C)C)NS(=O)(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (R)-2-amino-4-methoxy-N,N,N-trimethyl-4-oxobutan-1-aminium chloride (35 mg) in anhydrous MeCN (5 mL) is treated with triethyl amine (2.5 equiv.) and 3-(Imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium triflate (1.5 equiv.). The reaction mixture is stirred at ambient temperature for 16 h then concentrated under reduced pressure and the resulting residue is purified on silica gel using MeOH/DCM (0->80%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O.C([O:21][C:22](=O)[C:23](=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])C>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]2[N:9]([CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[C:22](=[O:21])[C:23]([OH:30])=[C:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: NCCCn1ccnc1
Reactant: CCCCCCC(=O)C(=O)OCC
Solvent: CCO
Product: CCCCCC1=C(O)C(=O)N(CCCn2ccnc2)C1c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 3-Chloro-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-octanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.Cl.[C:27]1([CH:33]([N:37]2[CH2:42][CH2:41][S:40][CH2:39][CH2:38]2)[C:34]([OH:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[N:43]12[CH2:50][CH2:49][CH:46]([CH2:47][CH2:48]1)[C@@H:45](O)[CH2:44]2>C1COCC1>[C:27]1([CH:33]([N:37]2[CH2:38][CH2:39][S:40][CH2:41][CH2:42]2)[C:34]([O:36][C@@H:45]2[CH:46]3[CH2:49][CH2:50][N:43]([CH2:48][CH2:47]3)[CH2:44]2)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(c1ccccc1)N1CCSCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCSCC1
Reaction time: 8 h
Yield: 43.9 %

Procedure:
PS-DCC (loading: 1.25 mmol/g; 0.73 g, 0.91 mmol) was suspended in dry THF (9 ml). HOBT (0.14 g, 0.91 mmol), 2-phenyl-2-thiomorpholinoacetic acid hydrochloride (0.12 g, 0.46 mmol) and (R)-quinuclidin-3-ol (0.17 g, 1.37 mmol) were sequentially added. The mixture was shaken overnight. PS-DCC was filtered off and washed with EtOAc and THF. The solution was evaporated and the residue was portioned between EtOAc and water. The organic phase was washed with sat. NaHCO3, dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5 to 85/15) to obtain (R)-quinuclidin-3-yl 2-phenyl-2-thiomorpholinoacetate (70 mg, 44.2% yield) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH:2]([C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:7][CH2:8]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a dichloromethane (30 mL) solution of the compound (1.6 g) obtained in Example 22, a Dess-Martin reagent (3.97 g) was added at 0° C. The reaction solution was stirred at room temperature for 16 hours. To the reaction solution, an aqueous saturated sodium hydrogen carbonate solution (50 mL) was added, and then aqueous layer was extracted with dichloromethane. The combined organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After removing the anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0→8:2) to obtain the title compound (1.60 g) having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[O:7])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](=[O:30])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH2:21].O.CO>C1(OC)C=CC=CC=1.[Pd]>[CH3:17][O:18][C:19](=[O:30])[CH:20]([NH:21][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)C2CCCCC2=O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: COc1ccccc1
Product: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 37.9 %

Procedure:
To a mixture of 2-(4-methylbenzoyl)cyclohexanone (97.2 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on carbon (20 g), then the mixture is heated to reflux for 2 h while the resulting water is removed by a Dean-Stark apparatus. The mixture is cooled to 80° C., and the Pd/C is filtered and washed with anisole (3×60 ml). The mixture is cooled to 40° C., hexane (1000 ml) is added and the mixture kept at −20° C. for 48 h. The solid is filtered and washed with hexane (5×200 ml) to yield the crude 2-[(2-(4-methyl benzoyl)phenyl)-amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester. The crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2×50 ml), and dried under a vacuum to give the title compound (59.1 g, 38%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]1[C:10]2[NH:14][C:13]([C:15]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:16]3[N:39]=[C:19]([CH:20]=[C:21]4[NH:38][C:24](=[C:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:26]5[CH:27]=[CH:28][C:29]=1[N:30]=5)[CH:23]=[CH:22]4)[CH:18]=[CH:17]3)=[CH:12][CH:11]=2.CO.C([O-])(=O)C.[Zn+2:53].C([O-])(=O)C>C(Cl)(Cl)Cl>[Zn:53].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]1[C:10]2[NH:14][C:13]([C:15]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:16]3[N:39]=[C:19]([CH:20]=[C:21]4[NH:38][C:24](=[C:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:26]5[CH:27]=[CH:28][C:29]=1[N:30]=5)[CH:23]=[CH:22]4)[CH:18]=[CH:17]3)=[CH:12][CH:11]=2
Reactant: [Zn+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCc1c2nc(c(-c3cc(O)ccc3O)c3ccc([nH]3)c(CCCCCCC)c3nc(cc4ccc1[nH]4)C=C3)C=C2
Solvent: CO
Solvent: ClC(Cl)Cl
Product: [Zn]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A starting compound (9)(14.0 mg, 22.8 μmol) was dissolved in 1 mL of chloroform. A saturated methanol solution of zinc acetate (0.3 mL) was added thereto and stirred at room temperature for 30 minutes. The chloroform solution was washed with water and solvent was removed by distillation. As a result, the compound (10) (14.6 mg) was obtained in a yield of 95%.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:19][CH2:20]Cl)[C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]=1[CH3:16].[CH3:22][N:23]1[C:27]([NH2:28])=[CH:26][CH:25]=[N:24]1>>[CH3:22][N:23]1[C:27]([N:28]2[CH2:20][CH2:19][N:4]([C:5]3[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]4[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=4[C:15]=3[CH3:16])[CH2:3][CH2:2]2)=[CH:26][CH:25]=[N:24]1
Reactant: Cc1c(C)c(N(CCCl)CCCl)c(C)c2c1OC(C)(C)C2
Reactant: Cn1nccc1N
Product: Cc1c(C)c(N2CCN(c3ccnn3C)CC2)c(C)c2c1OC(C)(C)C2
Yield: 3.7 %

Procedure:
By using N,N-bis(2-chloroethyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (660 mg, 2.0 mmol) synthesized in Reference Example 146 and 1-methyl-1H-pyrazole-5-amine (233 mg, 2.4 mmol), the reaction was carried out in the same manner as Example 117 to obtain 26 mg of the title compound as a colorless solid (yield 4%). Melting point was 126 to 128° C. (ethanol-water).
Reaction SMILES: C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:18]([O:20][C:21](=[O:41])/[CH:22]=[C:23](\[CH3:40])/[CH2:24][CH2:25][S:26]([C:29]1[N:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:32]=[N:31][N:30]=1)(=O)=O)C.C[C@H]([C@@H](O[Si](CC)(CC)CC)CC)C=O>C1COCC1.COCCOC>[CH3:18][O:20][C:21](=[O:41])/[CH:22]=[C:23](\[CH3:40])/[CH2:24][CH2:25][S:26][C:29]1[N:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:32]=[N:31][N:30]=1
Reactant: CCOC(=O)/C=C(\C)CCS(=O)(=O)c1nnnn1-c1ccccc1
Agent: CC[C@H](O[Si](CC)(CC)CC)[C@@H](C)C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: COC(=O)/C=C(\C)CCSc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114 %

Procedure:
0.5M Toluene solution (64.2 ml) of potassium bis(trimethylsilyl)amide was added dropwise to a DME (280 ml) solution of ethyl-(2E)-3-methyl-5-[(1-phenyl-1-H-tetrazol-5-yl)sulfonyl]pent-2-enoate (9.0 g, 25.7 mmol) at −60° C. and the reaction solution was stirred at the same temperature for 30 minutes. Subsequently a THF (50 ml) solution of (2R,3S)-2-methyl-3-[(triethylsilyl)oxy]pentanal (12.0 g, 52.1 mmol) was added dropwise at −78° C. and the reaction solution was stirred for one hour. After the reaction solution was warmed to room temperature, distilled water was added. The reaction solution was diluted with ethyl acetate and washed with brine. After the organic layer was dried over anhydrous sodium sulfate and 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, 230-400 mesh; hexane: diethyl ether=100:1) to obtain the title compound (8.92 g) as a colorless oil. The title compound was determined to be a mixture of E:Z=18:1 by 1H-NMR.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH3:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:4][CH2:3][CH2:2][N:9]1[CH2:10][CH2:11][N:6]([CH3:5])[CH2:7][CH2:8]1
Reactant: CN1CCNCC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(CCO)CC1
Yield: 46.4 %

Procedure:
2-Bromoethanol (2.36 g, 19 mmol) was added dropwise to a mixture of 1-methylpiperazine (1.26 g, 13 mmol) and potassium carbonate (5.0 g, 36 mmol) in absolute ethanol (150 ml) and the mixture heated at reflux for 18 hours. The mixture was allowed to cool and the precipitates were removed by filtration and the solvent volatiles were removed by evaporation. The residue was treated with acetone/methylene chloride, the insolubles were removed by filtration and the solvent was removed from the filtrate by evaporation to give 1-(2-hydroxyethyl)-4-methylpiperazine (870 mg, 48%) as a light brown oil.
Reaction SMILES: CC1OCC[S:6][C:7]=1[C:8](NC1C=CC=CC=1)=[O:9].[OH:17][CH2:18][CH2:19][S:20][CH:21]([C:31](=[O:33])[CH3:32])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>>[OH:17][CH2:18][CH2:19][S:20][S:6][CH2:7][CH2:8][OH:9].[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:23])[CH2:21][C:31]([CH3:32])=[O:33]
Reactant: CC1=C(C(=O)Nc2ccccc2)SCCO1
Reactant: CC(=O)C(SCCO)C(=O)Nc1ccccc1
Product: CC(=O)CC(=O)Nc1ccccc1
Product: OCCSSCCO

Procedure:
A method for making 5,6-dihydro-2-methyl-N-phenyl-1,4-oxathiin-3-carboxamide by cyclization of the intermediate 2-[(2-hydroxyethyl)thio]-3-oxo-N-phenyl-butanamide, in which this intermediate is obtained by the reaction of di-(2-hydroxyethyl) disulfide with acetoacetanilide.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][CH2:13]Cl.C(OC(=O)C)C.O>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
5 g (22.7 mmol) of 4-iodophenol are added to a suspension of 75% sodium hydride (872 mg; 27.25 mmol) in 20 ml of dimethylformamide. The mixture is stirred for 30 minutes at room temperature and 2.59 ml (34.1 mmol) of methoxymethyl chloride are then added. The solution is stirred for 2 h and the medium is then poured into an ethylacetate/water mixture. After separation of the phases by settling, the organic phase is washed twice with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. 5.74 g (96%) of a colourless oil are obtained.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:1]([NH:5][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CNS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.14 g of isobutylamine (56.6 mmol) and 2.86 g of triethylamine (28.3 mmol) in 40 mL of CH2Cl2 was slowly added 5.0 g of benzenesulfonyl chloride (28.3 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 30 min and then at rt for 1 hr. 150 mL of CH2Cl2 were added, and the organic layer was washed with saturated aqueous solution of NH4Cl and brine (30×2 mL), dried over MgSO4, filtered, and the filtrate was concentrated to give the title compound. 1H NMR (CDCl3) δ 0.87 (d, J=6.6 Hz, 6H), 1.71 (tsept, J=6.7, 6.5 Hz, 1H), 2.76 (dd, J=6.5, 6.7 Hz, 2H), 4.61 (t, J=6.5 Hz, 1H), 7.49–7.88 (m, 5H). Mass Spectrum (CI+) m/e=214 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[NH:32][C:31](=[O:41])[CH:30]=2)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:33]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[NH:32][C:31](=[O:41])[CH:30]=4)=[CH:25][CH:24]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)cc1-c1ccc(N)cc1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(-c2cc(=O)[nH]n2C(=O)OC(C)(C)C)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
120 mg (purity 93%, 0.37 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of tert-butyl 5-(4-aminophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate were reacted according to General Method 5A. Yield: 110 mg (53% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C:11]1([C:14]#[N:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:17]=[N+:18]=[N-:19].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C:11]1([C:14]2[NH:19][N:18]=[N:17][N:15]=2)[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC1(NC(=O)OCc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1(c2nnn[nH]2)CC1)OCc1ccccc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 63.4 %

Procedure:
To a round bottom flask was added (1-cyano-cyclopropyl)-carbamic acid benzyl ester (500 mg, 2.31 mmol) in DMF (4 ml), followed by the addition of NaN3 (195 mg, 3 mmol) and NH4Cl (161 mg, 3 mmol). The reaction mixture was stirred at 110° C. for 24 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc/water. The organic layer was separated, washed with brine, dried under any. Na2SO4, filtered and concentrated to afford 380 mg of [1-(1H-tetrazol-5-yl)-cyclopropyl]-carbamic acid benzyl ester as a off-white solid, m/z 260.8 [M+1]+.
Reaction SMILES: O[C:2]1[N:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C1(OC)C=CC=CC=1.P(Br)(Br)([Br:23])=O>>[Br:23][C:2]1[N:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: COc1cnc(O)c2[nH]ccc12
Reactant: O=P(Br)(Br)Br
Solvent: COc1ccccc1
Product: COc1cnc(Br)c2[nH]ccc12
Temperature: 160 °C
Yield: 27.4 %

Procedure:
To a flask containing 7-hydroxy-4-methoxy-6-azaindole (0.200 g, 1.22 mmol) was added anisole (3 mL) and then POBr3 (1.57 g, 6.09 mmol). The system was purged with Ar and then it was heated at 160° C. (oil bath temperature) for 1 h. The reaction mixture was then allowed to cool to room temperature, quenched with 2M HBr (5 mL) and extracted with methyl t-butyl ether. The aqueous phase was separated and the pH was adjusted to 6-7, after which it was extracted with EtOAc. The resulting organic phase was dried (MgSO4) and evaporated to give a solid residue which was chromatographed (SiO2/5% MeOH-DCM) to afford the title compound (0.076 g, 27%) as a white solid:
Reaction SMILES: [CH3:1]I.[H-].[Na+].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#N)=[C:8]([F:15])[CH:7]=1.C[N:17]([CH:19]=O)C>>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:1])([CH3:13])[C:19]#[N:17])=[C:8]([F:15])[CH:7]=1
Reactant: CN(C)C=O
Reactant: CI
Reactant: N#CCc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C#N)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of MeI (3.2 mL, 49.3 mmol) in anhydrous DMF (82 mL) at 0° C. was added NaH (60%, 2.0 g), followed by (4-bromo-2-fluorophenyl)acetonitrile (3.5 g, 16.4 mmol). The mixture was slowly warmed up to room temperature and stirred for 3 hours. The reaction was quenched by the addition of saturated NH4Cl and extracted with EtOAc (3×150 mL). The combined organic extracts were washed with brine, dried with Na2SO4 and evaporated to dryness. The mixture was purified by flash column chromatography (0-20% EtOAc in hexanes) to give the product (3.0 g, 77% yield). 1H NMR (300 MHz, CDCl3) δ: 1.78 (s, 6H), 7.26-7.42 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:17][CH:18]([CH3:20])[CH3:19])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15][CH3:16])[CH:10]=2)=[N:6][CH:7]=1.C[C:22]1[CH:27]=[CH:26][C:25]([S:28]([N-:31]Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O.O.O.[Na+].[C:37](#N)C>>[Br:1][C:2]1[C:3]([NH:17][CH:18]([CH3:20])[CH3:19])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([S:15]([CH3:16])=[N:31][S:28]([C:25]3[CH:24]=[CH:23][CH:22]=[CH:27][C:26]=3[CH3:37])(=[O:29])=[O:30])[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CC#N
Reactant: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Reactant: CSc1cccc(Nc2ncc(Br)c(NC(C)C)n2)c1
Agent: [Na+]
Solvent: O
Product: Cc1ccccc1S(=O)(=O)N=S(C)c1cccc(Nc2ncc(Br)c(NC(C)C)n2)c1

Procedure:
In analogy to Example 1, 0.15 g (0.42 mmol) of 5-bromo-N4-isopropyl-N2-(3-methylsulphanylphenyl)pyrimidine-2,4-diamine is reacted with 0.132 g (0.47 mmol) of chloramine-T trihydrate in 3.0 ml of acetonitrile (24 hours). Purification by chromatography (silica gel, ethyl acetate/hexane with ethyl acetate 0-100%, then ethyl acetate/methanol with methanol 5-10% results in 0.14 g (63% of theory) of the product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(-c2ccc(F)cc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-Fluorobenzene boronic acid. MS (M+H) 371.2
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1.[C:11](Cl)(=[O:13])[CH3:12]>C1(C)C(C)=CC=CC=1>[C:11]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: Nc1nc(C(F)(F)F)ns1
Solvent: Cc1ccccc1C
Product: CC(=O)Nc1nc(C(F)(F)F)ns1
Yield: 27.5 %

Procedure:
A solution of 4.3 grams (0.05 mole) 5-amino-3-trifluoromethyl-1,2,4-thiadiazole and 7.0 grams (0.09 mole) acetyl chloride in 50 milliliters xylene was refluxed at about 140° C. for 20 hours. Upon cooling to room temperature 2.9 grams (55% yield) pure product precipitated; m.p. 178.1° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Br:16])[CH:3]=1.NC1C=CC(C#N)=CC=1OC1C=CC=CC=1Br.[CH3:34][N:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1.C(OC(N1CCC(=O)CC1)=O)(C)(C)C>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Br:16])[CH:3]=1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ccc(Br)cc1Sc1ccccc1Br
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: N#Cc1ccc(N)c(Oc2ccccc2Br)c1
Product: CN1CCC(Nc2ccc(Br)cc2Sc2ccccc2Br)CC1

Procedure:
Using an adaptation of the method described in Procedure 3, substituting 4-bromo-2-(2-bromophenylsulfanyl)-aniline, 2e for 4-amino-3-(2-bromophenoxy)-benzonitrile, 2a, and 1-methylpiperidin-4-one for 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, the title compound [4-bromo-2-(2-bromophenylsulfanyl)-phenyl]-(1-methyl-piperidin-4-yl)-amine, 3e was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.COC1C=CC(C(=O)CBr)=CC=1.[Cl:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25]Cl)=[CH:22][CH:21]=1>N1C=CC=CC=1>[Cl-:19].[Cl:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25][N+:1]2[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=2)=[CH:22][CH:21]=1
Reactant: O=C(CCl)c1ccc(Cl)cc1
Reactant: c1ccnnc1
Agent: COc1ccc(C(=O)CBr)cc1
Solvent: c1ccncc1
Product: O=C(C[n+]1ccccn1)c1ccc(Cl)cc1
Product: [Cl-]

Procedure:
Employing the procedure of Example I but replacing pyridine with a substantially equimolecular amount of pyridazine and replacing 4-methoxyphenacyl bromide with a substantially equimolecular amount of 4-chlorophenacyl chloride there is obtained N-(4-chlorophenacyl) pyridazinium chloride, a solid soluble in water.