Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:21])([C:14]2[S:15][C:16]([CH2:19]O)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.CS([Cl:32])(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[S:15][C:16]([CH2:19][Cl:32])=[CH:17][N:18]=2)([F:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(CO)s2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(CCl)s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-fluoro-4-(5-hydroxymethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.34 g, 4.24 mmol) and pyridine (426 mg, 1.3 eq.) in CH2Cl2 (30 mL) at 0° C. was added MsCl (631 mg, 1.3 eq.). The mixture was warmed to room temperature and stirred overnight. The reaction mixture was washed with saturated NaHCO3 solution and dried over Na2SO4. Removal of the solvent afforded the desired product, which was used directly in the following reaction without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O)#[N:2].Cl.Cl.[CH2:14]([NH:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)C>[CH2:14]([N:21]1[C:1]([NH2:2])=[CH:3][C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NNCc1ccccc1
Reactant: N#CCC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1cc(-c2ccccc2)nn1Cc1ccccc1
Yield: 82.3 %

Procedure:
2.9 g of α-cyanoacetophenone and 3.9 g of benzyl hydrazine dihydrochloride were suspended in 50 mL of ethanol. The reaction solution was added with 6.0 ml of triethylamine at room temperature, and heated under reflux for 4 hours. The solvent was evaporated, and the residue was added with water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:4), to afford 4.1 g of the title compound as a yellow needle powder.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(COC)OC.CCOCC>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(CCNCc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOCC
Product: COC(=O)COc1ccc(CCNCc2ccccc2)cc1
Reaction time: 8 h
Yield: 125.4 %

Procedure:
The starting material was obtained as follows: N-Benzyltyramine (9.08 g) was added to a stirred solution of potassium t-butoxide (4.5 g) in dimethoxyethane (80 ml). To the clear solution was added methyl bromoacetate (6.2 g) and the mixture was stirred overnight. The mixture was diluted with ether (250 ml) and washed with water (2×25 ml). The ethereal solution was dried (MgSO4) and evaporated, to give methyl 4-[2-(benzylamino)ethyl]phenoxyacetate (15.0 g) as an oil, which was dissolved in isopropanol and teated with phenylglycidyl ether (7.5 g). The solution was heated to reflux for 1 hour, and then evaporated. The residue was dissolved in toluene and volatile material evaporated before being purified by chromatography on K60 silica (220 g) using 1% methanol in dichloromethane. Methyl 4-[2-(N-benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]phenoxyacetate was obtained as an oil (9.5 g), NMR: 2.55-2.85[m,6H, CH2NHCH2CH2 ]; 3.65-4.05[m,8H, PhOCH2CHOH and PhCH2 and OCH3 ]; 4.67]s, 2H, OCH2CO]; 6.73-7.40[m, 14H, aromatic H].
Reaction SMILES: [CH2:1]([CH:8]([CH2:14][S:15](Cl)(=[O:17])=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1)([CH3:22])([CH3:21])[CH3:20]>C(N(CC)CC)C>[C:19]([O:23][C:24](=[O:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[S:15]([CH2:14][CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:17])=[O:16])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
In an analogous manner to that described above, by reacting ethyl 2-benzyl-3-chlorosulphonylpropionate with L-proline tert-butyl ester in the presence of triethylamine there is obtained 1-[[(RS)-2-(ethoxycarbonyl)-3-phenylpropyl]sulphonyl]-L-proline tert-butyl ester which is converted into (S)-α-[[[(S)-2-(tert-butyloxycarbonyl)-1-pyrrolidinyl]sulphonyl]methyl]hydrocinnamic acid by enzymatic hydrolysis using α-chymotrypsin.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][CH:20]=1>N1C=CC=CC=1>[C:32]1([S:29]([NH:28][CH:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][S:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)(=[O:12])=[O:11])[CH:16]=2)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:30])=[O:31])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(N)c1
Solvent: c1ccncc1
Product: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Yield: 84.8 %

Procedure:
382 mg of 3-nitrobenzenesulphonyl chloride were added at 0° C. to a solution of 500 mg of (1d) in 4 ml of pyridine. After a reaction time of 1 h at 0° C. and 2 h at room temperature, the mixture was concentrated, treated with 1 N HCl and extracted with dichloromethane. After drying over MgSO4, the solvent was removed and 649 mg of a solid were obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=1)[O:31][CH2:32][C:33](Cl)=[O:34]>C(Cl)Cl>[CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:33](=[O:34])[CH2:32][O:31][C:30]2[CH:36]=[CH:37][CH:38]=[C:28]([O:27][CH3:26])[CH:29]=2)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: CC(C)CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: COc1cccc(OCC(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OCC(=O)Nc2ccc(OCCC(C)C)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A 1 L 3-neck flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with aniline 46b (12.0 g, 53.5 mmol) and CH2Cl2 (200 mL). The resultant solution was cooled in an ice bath and iPr2NEt (20.7 g, 28 mL, 161 mmol) was added followed by acid chloride 47b (12.9 g, 64.2 mmol) in CH2Cl2 (120 mL) over 10 min. The mixture was stirred at rt overnight. The red solution was diluted with CH2Cl2 (250 mL) and washed with saturated aqueous NH4Cl (200 mL), saturated NaHCO3 (200 mL), and brine (200 mL). The solution was filtered through phase separation paper and concentrated in vacuo to a red-brown solid. The solid was collected with EtOH (30 mL), pressed with rubber dam, and rinsed with EtOH (3×15 mL). The solid dried to give 15.0 g of 48b as a yellow solid (71%). 1H NMR (300 MHz, CDCl3): δ 9.78 (d, 1H), 7.73 (d, 1H), 7.29-7.22 (m, 2H), 6.68-6.60 (m, 3H), 4.65 (s, 2H), 4.05 (t, 2H), 3.86 (s, 3H), 1.86 (nonet, 1H), 1.72 (qt, 2H), 1.00 (d, 6H) ppm. HPLC analysis (0:10:90 H2O:A1:MeOH) showed a purity of 97% with a retention time of 6.2 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]([N:16]([CH3:18])[CH3:17])=[C:11]1[C:6]=2[CH:7]=[CH:8][C:9]([NH2:19])=[CH:10]1.P(Cl)(Cl)(Cl)=O.[CH2:25]([N:27]([CH2:30][CH3:31])[CH:28]=O)[CH3:26]>CC(C)=O>[CH2:25]([N:27]([CH:28]=[N:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]([N:16]([CH3:17])[CH3:18])=[C:11]1[C:6]=2[CH:7]=[CH:8][C:9]([N:19]=[CH:28][N:27]([CH2:30][CH3:31])[CH2:25][CH3:26])=[CH:10]1)[CH2:30][CH3:31])[CH3:26]
Reactant: CN(C)c1nc2cc(N)ccc2c2ccc(N)cc12
Reactant: CCN(C=O)CC
Solvent: CC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(C=Nc1ccc2c(c1)nc(N(C)C)c1cc(N=CN(CC)CC)ccc12)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A suspension of 3,8-diamino-6-dimethylaminophenanthridine (500 mg) in N,N-diethylformamide (2 ml) was added to a mixture of phosphorus oxychloride (1.5 ml) and N,N-diethylformamide (5 ml), the temperature of the mixture being kept at 5° C. The resulting mixture was stirred for 30 minutes at room temperature, heated at 75°-80° C. for 2 hours, cooled, and diluted with acetone. The precipitate formed was filtered off and dissolved in water. The pH of the clear solution was adjusted to a value of 9 with aqueous ammonia. The solid thus obtained was filtered off, washed with water, dried, and purified by column chromatography over a neutral aluminum oxide column using benzene as the mobile phase. The product crystallized out from chloroform/diisopropyl ether. Yield 71%, melting point 124°-126° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[C:5]=2[N:6]=1.[OH-].[Li+]>C1COCC1.CO>[CH3:1][C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[C:5]=2[N:6]=1
Reactant: CCOC(=O)C1CCc2sc(C)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(s1)CCC2C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 31.5 g (149 mmol) of ethyl 2-methyl-5,6-dihydro-4H-cyclopenta[d][1,3]thiazole-4-carboxylate from step A in a mixture of 450 mL of anhydrous THF and 100 mL of methanol was added a solution of 149 mL of a 1.0 M solution (149 mmol) of lithium hydroxide. The resulting mixture stirred at room temperature for 3 h and then the volatile organics were evaporated in vacuo. The aqueous residue was extracted with Et2O (2×250 ml.) and then acidified to pH=3 with 170 mL of a 1.0 N hydrochloric acid solution. The solution was saturated with solid sodium chloride and then extracted with dichloromethane (3×250 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was then triturated with acetonitrile, filtered and dried under vacuum to give the title compound as an off white solid. 1HNMR (500 MHz, CDCl3) δ: 11.75 (br s, 1H), 4.02 (m, 1H), 3.00 (m, 1H), 2.90-2.66 (m, 6H).
Reaction SMILES: Cl.[C:2]1([CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:15][C:16]1([CH3:29])[C:20]2([CH2:24][S:25](Cl)(=[O:27])=[O:26])[C:21]([CH2:23][CH:17]1[CH2:18][CH2:19]2)=[O:22]>C(Cl)(Cl)Cl>[CH3:15][C:16]1([CH3:29])[CH:17]2[CH2:18][CH2:19][C:20]1([CH2:24][S:25]([N:11]1[CH2:10][CH2:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:14])[CH2:13][CH2:12]1)(=[O:27])=[O:26])[C:21](=[O:22])[CH2:23]2
Reactant: Cc1ccccc1N1CCNCC1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)Cl)C(=O)C2
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1N1CCN(S(=O)(=O)CC23CCC(CC2=O)C3(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, 0° C. solution of 1-(o-tolyl) piperazine hydrochloride (50.0 g; 235 mmol) and TEA (83 mL; 590 mmol) in chloroform (1000 mL) was added (+)-10-camphorsulfonyl chloride (65.5 g; 260 mmol). The solution was stirred at 0° C. for 1 h and then at ambient temperature for 3 h. The solution was extracted with 5% aqueous HCl (2×500 mL), water (500 mL), and saturated aqueous NaHCO3 (2×500 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The resulting solid was recrystallized from methanol to give the title compound, mp 112°-114° C. (69 g; 75%).
Reaction SMILES: [O:1]=[C:2]=[N:3][CH:4]1[CH2:13][C:12](C)(C)[CH2:11][C:6](C)([CH2:7][N:8]=[C:9]=[O:10])C1.[N-]=C=O.O>>[CH2:7]([N:8]=[C:9]=[O:10])[CH2:6][CH2:11][CH2:12][CH2:13][CH2:4][N:3]=[C:2]=[O:1]
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: [N-]=C=O
Solvent: O
Product: O=C=NCCCCCCN=C=O
Temperature: 60 °C

Procedure:
The mixture was made to be at 70° C., and a mixture of 178 parts by mass of isophorone diisocyanate and 244 parts of hexamethylene-1,6-diisocyanate was added thereto, and a resultant mixture was stirred at 80° C. to 90° C. until a content of isocyanate thereof became 5.6% by mass. The prepolymer was cooled to 60° C., and 56 parts by mass of biuret polyisocyanate obtained from 3 mol of hexamethylene diisocyanate and 1 mol of water and 175 parts by mass of bisketimine obtained from isophorone diamine and acetone were sequentially added to obtain an aqueous dispersion of polyurethane.
Reaction SMILES: C[N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH:31][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][CH:10]=1
Reactant: CN(c1ccccc1)c1ccc(C(=O)O)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Nc2ccccc2)cc1
Yield: 14.2 %

Procedure:
A solution of 4-(methyl(phenyl)amino)benzoic acid (0.045 g, 0.198 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.046 g; 0.198 mmol), HATU (0.083 g; 0.217 mmol) and N,N-diisoproylethylamine (0.085 mL; 0.495 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.011 g (14%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=2)[C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[O:16])(=[O:10])=[O:9])[CH:7]=1.Cl[C:33]1C=CC(OC)=C(S(Cl)(=O)=O)[CH:38]=1>>[CH2:33]([O:23][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:27]=[CH:28][CH:29]=[C:12]([NH:11][S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:30][CH3:31])(=[O:9])=[O:10])[CH:13]=2)=[CH:19][CH:20]=1)[CH3:38]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(C(=O)O)cc2)c1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cc(Cl)ccc3OC)c2)cc1

Procedure:
4-[3-(5-Chloro-2-methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=459.0 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride and yielded 4-[3-(5-chloro-2-methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][S:21]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O)(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1)(=[O:22])=[O:23]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CS(=O)(=O)c1ccccc1C=O
Product: CS(=O)(=O)c1ccccc1CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-methylsulfonylbenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-methylsulfonylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C(#N)C.C1C(=O)N([Br:24])C(=O)C1>>[Br:24][C:9]1[C:10]([NH2:13])=[N:11][CH:12]=[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:8]=1
Reactant: Nc1ccc(C2CCOCC2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(C2CCOCC2)cc1Br
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To 5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine/acetonitrile solution (1.4 g, 7.85 mmol/30 mL) at 0-5° C. was added portionwise NBS (1.4 g, 7.85 mmol) with internal temperature controlled below 5° C. The resulting mixture was stirred at 0° C. for 1 hour 40 min. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with dilute aqueous NaOH/H2O (1 g/30 mL). The solid suspension was collected via filtration. The filtercake was washed with ice cold water (˜10 mL), and the filtrates were combined, and extracted with EtOAc (20 mL). The EtOAc extract was washed with brine (20 mL), dried over Na2SO4, and concentrated. A light yellow solid was combined with the filter cake, and dried under high vacuum as crude 3-bromo-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine. LCMS (m/z) 257.1/259.1 (MH+) 0.39 min. 1H NMR (CDCl3) δ ppm 7.90 (d, J=1.6 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 4.80 (br. s., 1H), 4.12-4.02 (m, 2H), 3.54-3.44 (m, 2H), 2.71-2.61 (m, 1H), 1.78-1.68 (m, 4H).
Reaction SMILES: [CH2:1]([CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]1=[O:13])[CH3:2].[H-].[Na+].Br[CH2:17][C:18]([O:20]CC)=[O:19]>CN(C=O)C.O>[CH2:1]([CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH2:17][C:18]([OH:20])=[O:19])[C:4]1=[O:13])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCC1Oc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1Oc2ccccc2N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (1.5 mmol, 260 mg) in DMF (2 ml) was added NaH (1.8 mmol, 43 mg) and the reaction mixture was stirred at room temperature for 1 h before the dropwise addition of ethyl bromoacetate (1.5 mmol, 250 mg). The reaction mixture was stirred at room temperature overnight, diluted with water and extracted with ethyl acetate. The organic layer was washed with 1N HCl, Sat. NaHCO3, dried over Na2SO4 and evaporated to dryness. The crude compound was dissolved in MeOH (3 ml) and 1 N NaOH (3 ml) and stirred for 2 h at room temperature. The MeOH was removed under reduced pressure and the resulting aqueous solution extracted with EtOAc. The aqueous layer was acidified to pH 2 with 1N HCl and extracted with EtOAc. The organic phase was dried over Na2SO4 and the solvent was evaporated to give the title compound. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=236; tR=2.4.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:8]=2)=[CH:4][CH:3]=1.[CH:30]([N:33]=[C:34]=[O:35])([CH3:32])[CH3:31]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:21][C:34]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:35])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH:8]=2)=[CH:28][CH:29]=1
Reactant: CC(C)N=C=O
Reactant: NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: CC(C)NC(=O)NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-amine (635 mg, 1.61 mmol) in THF (10 mL) at room temperature was added isopropyl isocyanate (164 mg, 1.93 mmol) and the solution stirred 50° C. for 16 h. The volatiles were removed under vacuum and the residue was triturated with water to afford a white solid, 627 mg, 82%.1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J=6.55 Hz, 6 H), 1.08-1.21 (m, J=7.18, 7.18 Hz, 1 H), 1.23-1.39 (m, 1 H), 1.65-1.90 (m, 2 H), 2.81 (t, J=10.95 Hz, 1 H), 3.05-3.25 (m, J=11.33, 11.33 Hz, 1 H), 3.50-3.72 (m, 2 H), 3.80 (d, J=13.60 Hz, 1 H), 3.95 (s, 2 H), 4.07 (d, J=13.35 Hz, 1 H), 5.03-5.33 (m, 2 H), 5.58 (d, J=7.81 Hz, 1 H), 5.75 (d, J=7.81 Hz, 1 H), 6.56 (s, 1 H), 7.02-7.26 (m, 2 H), 7.22-7.40 (m, 2 H), 7.64-7.79 (m, 2 H), 8.56 (d, J=6.04 Hz, 2 H); m/z (APCI+) for C26H31FN6O2 479.6 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][NH2:19])[O:15][N:14]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:26](=[O:28])[CH3:27])[O:15][N:14]=3)=[CH:11][CH:12]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cc(-c2ccc(-c3ccncc3)cc2)no1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CC(c2ccc(-c3ccncc3)cc2)=NO1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a flame drived flask containing (R)-4,5-Dihydro[3-[4-(4-pyrdinyl)phenyl]-5-(hydroxymethyl)]isoxazole (440 mg, 1.73 mmol) in methylene chloride (20 mL) at 0° C. under an inert atmosphere is added triethylamine (0.36 mL, 2.60 mmol) and methanesulfonyl chloride (0.14 mL, 1.82 mmol). The reaction is slowly warmed to ambient temperature, stirred 3 hours, and quenched with water (25 mL). The organic phase is separated, washed with saturated NaHCO3 (25 mL) and saline (25 mL), dried over sodium sulfate and concentrated in vacuo to give crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-[[(methylsulfonyl)oxy]methyl]isoxazole. The crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-[[(methylsulfonyl)oxy]-methyl]isoxazole (580 mg, 1.73 mmol) is dissolved in tetrahydrofuran (4 mL), isopropanol (4 mL), and concentrated ammonium hydroxide (4 mL) in a thick wall resealable vessel and heated to 100-110° C. for 15 hours. The reaction is cooled to ambient temperature, diluted with ethyl acetate (50 mL), washed with saline (20 mL), dried over sodium sulfate and concentrated in vacuo to give crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-(aminomethyl)isoxazole. The crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-(aminomethyl)isoxazole (320 mg. 1.57 mmol) is dissolved in methylene chloride (15 mL) and cooled to 0° C. under an inert atmosphere. Pyridine (0.31 mL, 3.78 mmol) and acetic anhydride (0.15 mL, 1.57 mmol) are added to the cooled solution and stirred 20 hours at ambient temperature. The reaction is concentrated in vacuo, diluted with methylene chloride (50 mL), washed with saline (25 mL), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-240 mesh, 200 mL), eluting with chloroform/methanol (97/3). The appropriate fractions are combined (Rf =0.14, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 244-245° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]([CH2:9][NH2:10])([CH2:7][CH3:8])[CH2:5][CH3:6].[CH3:12][C:13]([CH3:15])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][C:3](=[O:11])[C:4]([CH2:5][CH3:6])([CH2:9][NH:10][CH:13]([CH3:15])[CH3:12])[CH2:7][CH3:8]
Reactant: CCC(CC)(CN)C(=O)OC
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(CNC(C)C)C(=O)OC
Reaction time: 8 h
Yield: 52.7 %

Procedure:
Methyl2-(aminomethyl)-2-ethyl-butanoate (Intermediate 201; 8 g, 50 mmol) and acetone (4.35 g, 75 mmol) were added to methanol (230 mL) and stirred for 10 minutes before the rapid addition of sodium triacetoxyborohydride (15.9 g, 75 mmol). The reaction was stirred overnight before being evaporated to dryness. The residue was quenched with saturated K2CO3(aq) (100 mL), extracted with DCM (3×150 mL), dried and solvent evaporated to yield a dark liquids. Purification was achieved via distillation (65 oC @ 0.18 mbar) to yield the title compound as clear oil (5.3 g, 53%)