Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16]>C(Cl)Cl.[I-].[K+]>[O:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[N:3]1
Reactant: Clc1noc2ccccc12
Reactant: NCCCCO
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: OCCCCNc1noc2ccccc12
Temperature: 80 °C
Reaction time: 96 h
Yield: 93.3 %

Procedure:
A mixture of 3-chloro-1,2-benzisoxazole (0.08 mol), 4-amino-1-butanol (0.24 mol) and potassium iodide (1 g) was stirred for 4 days at 80° C. The reaction mixture was cooled, dissolved in CH2Cl2 and purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 15.4 g (93%)of 4-(1,2-benzisoxazol-3-ylamino)-1-butanol (interm. 7). b) SOCl2 (0.048 mol) was cooled to 0° C. A solution of intermediate 7 (0.048 mol) in CHCl3 (20 ml) was added dropwise and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated. The residue was washed with water. The reaction mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered, and the solvent was evaporated, yielding 10.4 g of N-(4-chlorobutyl)-1,2-benzisoxazol-3-amine (interm. 8).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>ClCCl>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19]([N:2]2[C:1]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:5][CH2:4][CH2:3]2)=[O:20])=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Reaction time: 3 h
Yield: 65.9 %

Procedure:
To a solution of tetrahydroisoquinoline (3.99 g, 30 mmol) in triethyl amine(6 g, 60 mmol) and dichloromethane(150 mL) cooled in ice bath was added p-nitrophenyl chloroformate (6.06 g, 30 mmol) drop wise over a period of 1 h. The reaction mixture was srirred at room temperature for 3 h and then washed with water (3×100 mL), dried over sodium sulfate and concentrated to afford an oil which was triturated with ether:hexane to afford the titled compound as yellow solid (5.9 g, 65%).
Reaction SMILES: CO[C:3](=[O:34])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[N:29])=[C:22]([O:30][CH3:31])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:35]([C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[NH2:36].C(N(CC)CC)C>CN(C=O)C>[CH3:31][O:30][C:22]1[CH:21]=[C:20]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:10][CH:9]=2)[C:5]2[NH:4][C:3](=[O:34])[N:35]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:36]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH2:27][C:28]#[N:29]
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(OCC#N)c(OC)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)ccc1OCC#N
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a solution of 535 mg of {2-(4-cyanomethoxy-3-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 8 ml of DMF there were added 123 mg of 2-hydrazinopyrimidine and 312 μl of triethylamine, and the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 6 ml of a methanol:THF=1:1 mixed solvent. Next, 229 μl of acetic acid and 357 mg of sodium cyanotrihydroborate were added to the solution and the mixture was stirred at room temperature for 3 hours and 30 minutes. After adding ethyl acetate to the reaction mixture, it was filtered through a small amount of NAM silica gel, and the silica gel was washed with ethyl acetate-methanol. The filtrate was concentrated under reduced pressure, and the residue was crudely purified by NAM silica gel column chromatography (methanol-ethyl acetate), to give (2-methoxy-4-{[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl}phenoxy)acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([CH2:15][CH3:16])[CH2:13][NH2:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C(O)C>[Cl:1][C:2]1[C:3]([CH:12]([CH2:15][CH3:16])[CH2:13][NH:14][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[C:18]([F:17])([F:28])[F:29])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CCC(CN)c1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(O)c1ccccc1C(F)(F)F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCC(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(C(F)(F)F)cc1Cl

Procedure:
100 mg of 2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-1-butanamine (0.0004 mol), 58 μL of 2-(trifluoromethyl)benzoic acid(0.0004 mol), 0.109 g of 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (0.0004 mol) are stirred in 2 mL of ethanol at room temperature overnight.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH3:20][C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([NH2:32])[CH:22]=1>CN(C=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:32][C:23]2[CH:22]=[C:21]([CH3:20])[N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:24]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(N)nn1-c1ccccc1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Nc2cc(C)n(-c3ccccc3)n2)=C(c2ccccc2)S1(=O)=O
Temperature: 140 °C
Yield: 61.8 %

Procedure:
2-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (110 mg, 0.330 mmol) was dissolved in dry DMF (0.5 mL) under nitrogen atmosphere. 5-Methyl-1-phenyl-1H-pyrazol-3-amine (172 mg, 0.991 mmol) was added and the reaction mixture was heated in a microwave reactor for 25 mins at 140° C. The crude product was purified by preparative HPLC affording the title compound (89 mg, 58.6%). 1H NMR (500 MHz, CD3CN): δ 0.99 (t, 3H), 1.42-1.51 (m, 2H), 1.76-1.84 (m, 2H), 2.14 (s, 3H), 3.73 (t, 2H), 5.87 (s, 1H), 6.87-6.90 (m, 2H), 7.27-7.38 (m, 8H), 7.74 (bs, 1H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Cl>CN(C=O)C>[CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])[CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1cnc2[nH]cc(-c3ccnc(NC4CCCCC4)n3)c2c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(-c2ccnc(NC3CCCCC3)n2)c2cccnc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
Compound 13 (25 mg) was dissolved in DMF (1 mL) and NaH (5 mg) was added. The mixture was stirred for 1 hr, followed by addition of 2-(dimethylamino)ethyl chloride hydrochloride (10 mg). After being warmed to 45° C. for 2 hrs, the solution was concentrated and the residue was purified by flash chromatography [silica gel, DCM:MeOH/9.5:0.5] to afford 13 mg (42%) of the desired product. 1H NMR (400 MHz, CDCl3) δ 8.72 (d, 1 H), 8.35 (d, 1 H), 8.18 (d, 1 H), 7.92 (s, 1 H), 7.15 (dd, 1 H), 6.80 (d, 1 H), 5.01 (d, 1 H), 4.45 (t, 2 H), 3.95 (m, 1 H), 2.80 (t, 2 H), 2.32 (s, 6 H), 2.15 (m, 2 H), 1.80 (m, 2 H), 1.70 (m, 2 H), 1.45 (m, 2 H), 1.30 (m, 2 H). MS (ESI) m/z: 365 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([SH:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>C(COC)OC>[C:1]([C:5]1[CH:9]=[C:8]([S:10][CH2:15][CH:14]=[CH2:13])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCBr
Reactant: CC(C)(C)c1cc(S)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=CCSc1cc(C(C)(C)C)n[nH]1
Yield: 88 %

Procedure:
To a slurry of 3-t-butylpyrazole-5-thiol (10 g) in dry dimethoxyethane (100 ml) was added portionwise, with stirring, sodium hydride (1.6 g). Stirring at room temperature was continued for a few minutes, and then allyl bromide (7.8 g) was added. The reaction mixture was stirred for 2 hours, filtered, and evaporated. The residue was dissolved in ether and washed with water, and the ether layer separated, dried, and evaporated to give 3-t-butyl-5-(allylthio)pyrazole, as a pale brown oil (11.0 g), 88% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:24]1[CH2:25][CH2:26][CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23]1)=[O:15]
Reactant: c1ccc(C2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
5-(2-chlorophenyl)-isoxazole-4-carboxylic acid (51.6 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/Acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C20H17ClN2O2: 352.0979, found 352.0980.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=1)[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[OH-].[Na+]>CO>[CH3:1][N:2]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:21][CH:22]=1)[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10]
Reactant: CCOC(=O)c1ccc(N(C)C(=O)c2ccccc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1C(=O)N(C)c1ccc(C(=O)O)cc1
Yield: 67.5 %

Procedure:
A sample of 1.51 g of sodium hydride (60% in oil) is washed with hexane under argon to remove the oil. To the washed sodium hydride is added 5 ml of N,N-dimethylformamide. To this mixture is added dropwise a solution of 8.69 g of ethyl 4-[(2-methylbenzoyl)amino]benzoate in 20 ml of N,N-dimethylformamide. The mixture is stirred at room temperature for 0.5 hour and then 5.23 g of methyl iodide is added. The mixture is stirred at room temperature for 16 hours. The mixture is diluted with water and extracted with dichloromethane. The extract is dried (Na2SO4), concentrated to reduce the volume and the solution filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give 11 g of an oil (1:1 mixture of product and N,N-dimethylformamide). The preceding product, ethyl 4-[N-methyl-N-(2-methylbenzoyl)amino]benzoate, (11 g) is dissolved in 30 ml of methanol and 25 ml of 2N NaOH added. The mixture is refluxed for 2 hours and the solvent removed. The residue is extracted with ether (discard) and the remaining residue dissolved in 50 ml of water. The basic solution is acidified with 2N citric acid and the solid filtered off and washed with water. The product is air dried to give 6.72 g of crystals, m.p. 187°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C([O-])([O-])=O.[K+].[K+].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: N#Cc1ccc(F)cc1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 120 °C

Procedure:
The mixture of 4-chloro-3-(trifluoromethyl)phenol (2 g, 10.18 mmol), K2CO3 (2.109 g, 15.26 mmol) and 4-fluorobenzonitrile (1.232 g, 10.18 mmol) in DMF (20 ml), was heated at 120° C. overnight. It was diluted with water and extracted with EtOAc. The organic phases were collected, washed with water and brine, dried over Na2SO4 and concentrated to afford the title compound as a brown oil. LCMS: rt=3.81 min, [M+H+]=298
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[C:13]([O:15][CH3:16])=[O:14])(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[N:17]([CH2:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[C:13]([O:15][CH3:16])=[O:14])=[N+:18]=[N-:19]
Reactant: COC(=O)[C@@H]1CCCC[C@H]1COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCC[C@H]1CN=[N+]=[N-]
Temperature: 100 °C
Yield: 99.6 %

Procedure:
To a solution of (trans)-methyl 2-((methylsulfonyloxy)methyl)cyclohexanecarboxylate (1.4 g, 5.6 mmol) in DMF (6 mL) was added NaN3 (0.730 g, 11.0 mmol). The mixture was heated at about 100° C. for about 3 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (2×45 mL). The combined organic layers were washed with aqueous 1 N NaOH (1×40 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give (trans)-methyl 2-(azidomethyl)cyclohexanecarboxylate (1.1 g, 100%.): 1H NMR (400 MHz, CDCL3) δ 3.69 (d, J=6.0, 3H), 3.28-3.15 (m, 2H), 2.24-2.14 (m, 1H), 1.97-1.73 (m, 5H), 1.46 (dd, J=12.2, 3.2, 1H), 1.36-1.05 (m, 3H).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:19]1(O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.N1C=CC=CC=1.Cl>C(Cl)Cl>[CH:19]1([O:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][C:10]([CH:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH2:7][CH2:8][CH3:9])=[CH:11][CH:12]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: OC1CCCCC1
Reactant: CCCC(c1ccc(C(=O)O)cc1)n1ccnc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(c1ccc(C(=O)OC2CCCCC2)cc1)n1ccnc1
Yield: 78 %

Procedure:
1 g of 4-[1-(1-imidazolyl)-butyl]-benzoic acid is converted, analogously to example 20, into the acid chloride; it is dissolved in 10 ml of methylene chloride, mixed with 360 mg of cyclohexanol and 3 ml of pyridine, after 20 hours at room temperature it is added to excess 1M hydrochloric acid and extracted with ether. The water phase is alkalized with potassium carbonate and extracted with ethyl acetate. After drying and concentration by evaporation, the residue is distilled on a bulb tube. 915 mg of the title compound is obtained as oil with a boiling point of 200° C./0.03 mbar.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[Cl:17])[CH2:15][CH:16]=1
Reactant: C1=C(c2cc3ccccc3s2)CCNC1
Reactant: Clc1ccccc1CBr
Agent: Cl
Product: Clc1ccccc1CN1CC=C(c2cc3ccccc3s2)CC1
Yield: 11.9 %

Procedure:
4-(Benzothiophen-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (250 mg, 0.99 mmol) was reacted with 2-chlorobenzyl bromide (0.24 ml, 1.5 mmol) as exemplified in Example 1. The crude product was triturated with methanol to give the title compound as a pale yellow brown solid (40 mg, 12%) m.p. 105°-106° C.; (Found: C, 69.29; H, 5.17; N, 4.23. C20 H18ClNS. 0.5H2O requires C, 68.85; H, 5.49; N, 4.01%). δH (CDCl3), 2.66 (2H, m, NCH2CH2), 2.80 (2H, m, NCH2CH2), 3.27 (2H, m, NCH2CH2), 3.77 (2H, s, NCH2Ar), 6.20 (1H, m, NCH2CH), 7.13 (1H, s, ArH), 7.25 (4H, m, ArH), 7.36 (1H, d of d, J 7.7Hz, J 1.4Hz, ArH), 7.53 (1H, d of d, J 7.5Hz, J 1.6Hz, ArH), 7.66 (1H, d of d, J 6.9Hz, J 1.5Hz, ArH), 7.73 (1H, d of d, J 8.7Hz, J 1.7Hz, ArH). m/z (ES+) 340 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:8]=2[CH:24]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:8]=2[CH:24]=1
Reactant: O=C(NCCNc1nsc2ccc([N+](=O)[O-])cc12)c1ccccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2snc(NCCNC(=O)c3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.5 %

Procedure:
A mixture of N-(2-(5-nitrobenzo[d]isothiazol-3-ylamino)ethyl)picolinamide (100 mg, 0.29 mmol), iron powder (100 mg, 1.75 mmol) and ammonium chloride (31 mg, 0.29 mmol) in ethanol (5 mL) and water (2.5 mL) was allowed to stir at room temperature for 15 min. The mixture was then heated at 80° C. for 20 min. The reaction mixture was cooled to room temperature and passed through a plug of Celite. The filtrate was concentrated under reduced pressure and the resulting residue was diluted with water. The aqueous solution was extracted several times with ethyl acetate and then concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 2% methanol in dichloromethane, and selected fractions were combined and concentrated under reduced pressure to yield N-(2-(5-aminobenzo[d]isothiazol-3-ylamino)ethyl)picolinamide (95 mg) as a pale yellow solid. 1H NMR (300 MHz, CDCl3): 8.56 (d, 1H), 8.25 (d, 1H), 8.20 (d, 2H), 7.80 (t, 1H), 7.40 (m, 1H), 7.18 (d, 1H), 6.01 (s, 1H), 5.98 (d, 1H), 4.80 (broad s, 1H), 3.70 (m, 2H), 3.40 (m, 2H). MW=313 confirmed by LC-MS, tr=9.21 min (Method Y) MH+=314.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([C:2]2[C:3]([N:22]3[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)[CH:32]=[N:33][CH:34]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncc(F)c2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 128.1) and (5-fluoropyridin-3-yl)boronic acid. HPLC (Condition 4) tR=5.15 min, UPLC-MS (Condition 3) tR=1.04 min, m/z=463.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.29 (s, 3H) 3.57 (m, J=2.70 Hz, 4H) 5.48 (s, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.84 (d, J=8.99 Hz, 3H) 8.01-8.10 (m, 1H) 8.53 (s, 1H) 8.61 (d, J=2.74 Hz, 1H) 8.72-8.84 (m, 1H) 10.20 (s, 1H).
Reaction SMILES: O.[OH:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]([OH:11])[C:8]([O-:10])=[O:9])=[CH:5][CH:4]=1.[Na+].[OH-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O>[CH2:17]([O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]([OH:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C([O-])C(O)c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(O)c1ccc(OCc2ccccc2)cc1
Yield: 68.9 %

Procedure:
A solution of 41.6 g (0.20 mol) of sodium 4-hydroxymandelate monohydrate, 9.6 g (0.24 mol) of sodium hydroxide and 27.9 g (0.22 mol) of benzyl chloride in 50 ml of water is stirred for 17 hours at 70° C. It is then diluted using 50 ml of water, and a further 4.0 g (0.10 mol) of sodium hydroxide are added. The reaction mixture is refluxed for one hour, then cooled and acidified using concentrated hydrochloric acid, and the product which has precipitated is filtered. The residue is washed with cold water and subsequently dried under a high vacuum. 35.6 g (69%) of 4-benzyloxymandelic acid, m.p. 148°-155° C., result.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:2]1([CH2:1][N:8]2[CH2:12][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@@H:10]([CH2:19][N:30]3[CH2:31][CH2:32][CH:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:28][CH2:29]3)[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: c1ccc(CN2C[C@H](CN3CCC(c4ccccc4)CC3)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.68 g (10 mmol) of 1-benzyl-3-(R)-formyl-4-(S)-phenylpyrrolidine in 10 mL of 1,2-dichlorethane was added 2.0 g (12 mmol) of 4-phenylpiperidine. To this was added 3.2 g (15 mmol) of sodium triacetoxyborohydride and the solution was stirred at room temperature for 1 h. The reaction was poured into 50 mL of saturated NaHCO3 solution and the mixture was extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel using ethyl acetate-hexane (1:1) to afford the title compound. 1H NMR (CDCl3) δ 1.6-1.85 (m, 4H), 1.98 (dq, J=7 Hz, J=2 Hz, 2H), 2.4-2.56 (m, 4H), 2.62 (m, 1H), 2.72 (m, 1H), 2.83 (m, 1H), 3.04 (m, 4H), 3.69 (d, AB, J=7 Hz, 1H), 3.77 (d, AB, J=7 Hz, 1H), 7.2-7.6 (m, 15H); Mass Spectrum (ESI) m/e 411 (M+1); [α]D =+26.0 (c.=1.56, CHCl3)
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>>[CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([Cl:18])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(COCc1ccccc1)C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(C)(COCc1ccccc1)C(=O)Cl

Procedure:
The obtained carboxylic acid (3.0 g) was reacted with 4 ml of thionyl chloride, and 3-benzyloxy-2,2-dimethylpropionyl chloride was obtained quantitatively as an oily material.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([NH:15][C:16]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19])[CH3:14]>O1CCOCC1>[CH2:13]([N:15]1[C:16]2[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:17]=2[C:18](=[O:20])[O:19][C:2]1=[O:4])[CH3:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCNc1cc(I)ccc1C(=O)O
Solvent: C1COCCO1
Product: CCn1c(=O)oc(=O)c2ccc(I)cc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 283 %

Procedure:
0.785 g (2.65 mmol) of triphosgene were added at room temperature to 2.2 g (7.55 mmol) of 2-ethylamino-4-iodo-benzoic acid in 30 ml of dioxane. The reaction mixture was then heated and stirred at 110° C. during 2 hours. The solution was evaporated to dryness and reevaporated twice after 2 additions of 20 ml of toluene to give 2.39 g (7.5 mmol) of a solid.