Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([Br:12])[C:10]=1[NH2:11])=[O:5])[CH3:2].[CH:13](=O)[CH:14]([CH3:16])[CH3:15].[BH3-]C#N.[Na+].CC(O)=O.[OH-].[Na+]>C(Cl)Cl.CO>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([Br:12])[C:10]=1[NH:11][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:5])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1[nH]cc(Br)c1N
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]cc(Br)c1NCC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.8 %

Procedure:
3-Amino-4-bromo-1H-pyrrole-2-carboxylic acid ethyl ester (0.136 g, 0.58 mmol) and isobutyraldehyde (0.067 g, 0.93 mmol) were stirred in CH2Cl2/MeOH (1:1, 3 mL) at r.t. for 2 h. NaCNBH3 (0.065 g, 1.04 mmol) and HOAc (0.035 g, 0.58 mmol) were added and the mixture was stirred at r.t. for 2 h and then stirred at 50° C. for 16 h. Additional isobutyraldehyde (1 equiv.) and NaCNBH3 (0.5 equiv.) were added and the mixture was continued stirring at 50° C. overnight. The reaction mixture was neutralized with 2 M NaOH solution and the solvents were removed in vacuo. The residue was taken up in ethyl acetate and extracted with water. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (heptane/ethyl acetate gradient, 0 to 30% ethyl acetate), obtaining the title compound (0.040 g, 24%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])=[O:9])=[CH:4][C:3]=1I.[C:30]([C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])#[CH:31].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])=[O:9])=[CH:4][C:3]=1[C:31]#[C:30][C:32]1[CH:38]=[CH:37][CH:36]=[C:34]([NH2:35])[CH:33]=1
Reactant: C#Cc1cccc(N)c1
Reactant: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(I)c1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To the degassed mixture of dimethyl 5,5′-{N-[(6-amino-5-iodopridin-3-yl)carbonyl]sulfonimidoyl}dipentanoate (1.16 g, 2.15 mmol, 1.0 equiv.), 3-ethynylaniline (0.34 mL, 3.25 mmol, 1.5 equiv.), and triethylamine (1.2 mL, 8.61 mmol, 4.0 equiv.) in anhydrous DMF (7 mL) under nitrogen atmosphere was added CuI (81.5 mg, 0.42 mmol, 0.2 equiv.) and PdCl2(Ph3P)2 (150.6 mg, 0.21 mmol, 0.1 equiv.). The reaction mixture was stirred at room temperature for 15 minutes. The reaction was then diluted with EtOAc, washed with sat. aq. NaHCO3, aq. NH4Cl, and brine, and lastly dried with anhydrous Na2SO4. The solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (from EtOAc-Hex 1:3 to neat EtOAc) to give the title compound as a white foam (1.0 g).
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=O.[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:18]3[C:19]4[CH2:20][NH:21][CH2:22][CH2:23][C:24]=4[S:25][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:12][CH2:11]1.[CH2:31]([N:33](CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CN.C1COCC1>C1COCC1.C(Cl)Cl>[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:11][CH2:12][CH:13]([O:16][C:17]2[C:18]3[C:19]4[CH2:20][N:21]([C:3]([NH:33][CH3:31])=[O:5])[CH2:22][CH2:23][C:24]=4[S:25][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:14][CH2:15]1
Reactant: CN(C)C1CCC(Oc2ncnc3sc4c(c23)CNCC4)CC1
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(CC)CC
Agent: CN
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)N1CCc2sc3ncnc(OC4CCC(N(C)C)CC4)c3c2C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 3-necked round-bottom flask containing a solution of N,N-dimethyl-4-[8-thia-4,6,12-triazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yloxy]cyclohexan-1-amine trifluoroacetate (300 mg, 1.00 equiv, 30% purity) in THF (50 mL) was added triethylamine (0.4 mL). The solution was stirred at 0° C. for 10 min under nitrogen. Then triphosgene (300 mg, 1.0 mmol) in 10 mL of DCM was added via syringe at 0° C. and stirred for 2 h at room temperature. Then methanamine-THF (2 M, 1.8 mL) was added at 0° C. and the resulting solution was stirred overnight at room temperature. The reaction was quenched by the addition of methanol and concentrated under vacuum. The residue was pre-purified by a silica gel column with DCM/MeOH (30:1-10:1) to give the crude product, which was purified by preparative HPLC under the following conditions (Waters): Column: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase, water with 0.05% NH4HCO3 and CH3CN (9% CH3CN up to 21% in 12 min, up to 95% in 2 min, down to 9% in 2 min); flow rate: 20 mL/min; UV detection at 254/220 nm. After concentration in vacuo and lyophilization overnight, the corresponding 3-[[4-(dimethylamino)cyclohexyl]oxy]-N-methyl-8-thia-4,6,12-triazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraene-12-carboxamide (30 mg) was obtained as a white solid. MS (ES): m/z 390 (M+H)+ and 412 (M+Na)+. 1H NMR (300 MHz, CD3OD): δ 8.50 (1H, s), 5.30-5.21 (1H, m), 4.78 (2H, s), 3.75 (2H, t), 2.95 (2H, t), 2.78 (3H, s), 2.50-2.30 (9H, m), 2.07 (2H, d), 1.8-1.62 (2H, m), 1.60-1.50 (2H, m).
Reaction SMILES: [CH3:1][CH:2]([C@H:7]([O:10]C(=O)CCCCCCCCCCC)[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].CO.S(=O)(=O)(O)O>O>[CH3:1][CH:2]([C@H:7]([OH:10])[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCCCCCCCCCCC(=O)O[C@H](CC)C(C)C(=O)OC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: CC[C@@H](O)C(C)C(=O)OC
Yield: 38.5 %

Procedure:
A mixture of 3.5 g of methyl (3R)-2-methyl-3-dodecanoyloxypentanoate, 12 ml of methanol and 0.5 ml of concentrated sulfuric acid was refluxed for 8 hours, and 20 ml of water was added thereto followed by ether extraction. The ether phase was dried over anhydrous sodium sulfate and ether was distilled away, and then the residue was distilled to give 0.6 g of methyl (3R)-2-methyl-3-hydroxypentanoate of the following formula, b.p. 52.5° C. (2.5 mm Hg), [α]D30 =-10.7° (C=0.61, CHCl3). ##STR82##
Reaction SMILES: C[S:2][C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.Cl[C:11]([O:13][CH:14]([Cl:18])[CH:15]([CH3:17])[CH3:16])=[O:12].[CH3:19]N1CCOCC1>ClCCl>[CH3:19][C:6]1[CH:7]=[CH:8][C:3]([S:2][C:11]([O:13][CH:14]([Cl:18])[CH:15]([CH3:17])[CH3:16])=[O:12])=[CH:4][CH:5]=1
Reactant: CN1CCOCC1
Reactant: CSc1ccc(O)cc1
Reactant: CC(C)C(Cl)OC(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(SC(=O)OC(Cl)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4-(Methylthio)phenol (28 g) and dichloromethane (100 mL) were charged to a vessel. The vessel was cooled to approximately 0° C. 1-Chloro-2-methylpropyl chloroformate (14 mL) was added. A solution of 4-methylmorpholine (24 g) in dichloromethane (100 mL) was then slowed added using an addition funnel, keeping the temperature below 15° C. The reaction mixture was then stirred at approximately 0° C. for 10 minutes. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was washed with water (2×100 mL) followed by evaporation to an oil. Fifty-four grams (54 g) of the title compound D4 was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:31](=[O:32])[O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)Oc3ccccc3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
83 mg (0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 26 mg (0.17 mmol, 1.1 eq.) of phenyl chloroformate were reacted according to General Method 5. Yield: 25 mg (39% of theory)
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12](O)(=[O:14])=[O:13])[CH:10]=2)[C:5]([C:16]([OH:18])=[O:17])=[CH:4][NH:3]1.[Cl:19]S(O)(=O)=O>>[Cl:19][S:12]([C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:16]([OH:18])=[O:17])=[CH:4][NH:3][C:2]2=[O:1])=[CH:7][CH:8]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)O)ccc12
Product: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)Cl)ccc12
Temperature: 100 °C

Procedure:
1-Oxo-7-sulfo 1,2-dihydroisoquinoline-4-carboxylic acid (5 g) was added to chlorosulphonic acid (25 ml). The mixture was heated at 100° C. for 84 h and then slowly dripped onto ice with sting. The mixture was filtered and the residue was washed with water and ether and dried to yield 7-(chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as a buff solid (7.5 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:6][C:5]=2[C:4]([CH2:22][CH2:23][CH3:24])=[N:3]1.[ClH:25].[CH2:26]=O>O>[Cl:25][CH2:26][C:16]1[CH:15]=[CH:14][C:13]([O:18][CH2:19][CH2:20][CH3:21])=[C:12]([C:7]2[NH:8][C:9](=[O:11])[C:10]3[N:2]([CH3:1])[N:3]=[C:4]([CH2:22][CH2:23][CH3:24])[C:5]=3[N:6]=2)[CH:17]=1
Reactant: Cl
Reactant: C=O
Reactant: CCCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Solvent: O
Product: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Temperature: 120 °C
Reaction time: 22 h
Yield: 70 %

Procedure:
1-Methyl-5-(2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (0.80 g, 0.00246 mol) was added portionwise to stirred concentrated hydrochloric acid (10 ml) at room temperature. Paraformaldehyde (0.20 g, 0.00246 mol) was then added and the resulting solution stirred at 120° C. for 22 hours. The reaction mixture was cooled and poured into ice and water (50 g), then the resulting mixture extracted with ethyl acetate (3×30 ml). The organic extracts were combined, dried (Na2SO4) and evaporated under vacuum to give a white solid. Trituration with ether, followed by crystallisation from ethyl acetate-hexane, gave the title compound as colourless crystals (0.65 g, 70%), m.p. 102°-104° C. Found: C,60.91; H,6.14; N,14.94. C19H23CIN4O2 requires C,60.88; H,6.18; N,14.95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[N:16][NH2:17])[CH2:11]1)=[O:9].C(N(CC)CC)C.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]2[C:30]([C:26]3[O:25][CH:29]=[CH:28][CH:27]=3)=[N:17][N:16]=[C:12]2[CH2:11]1)=[O:9]
Reactant: NN=C1CN(C(=O)c2ccccc2Cl)CCN1
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1Cl)N1CCn2c(nnc2-c2ccco2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-[(2-chlorophenyl)carbonyl]-2-piperazinone hydrazone (140) (715 mg, 2.83 mmol) and triethylamine (0.986 mL, 7.08 mmol) were dissolved in Dichloromethane (DCM) (10 mL). 2-furancarbonyl chloride (0.306 mL, 3.11 mmol, commercially available from e.g. Sigma-Aldrich, Apollo or Acros) was added and the solution stirred at 25° C. for 4 hr. Solvents were removed in vacuo and the residue was dissolved in n-butanol (10.00 mL). The solution was heated at reflux for 4 hours and the solvents were removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was extracted with ethyl acetate (3×25 mL), the combined extracts were washed with water (3×50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated to a crude solid in 925 mg. The product was purified by flash chromatography (Isolera, 100 g, 0-100% Methanol:Dichloromethane (1:9)/Dichloromethane) to afford product in 260 mg. This was further purified by MDAP to afford product in 85 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:5]=[N:6][CH:7]=1.Cl.[NH2:19][CH2:20][CH:21]1[CH2:23][CH2:22]1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:19][CH2:20][CH:21]2[CH2:23][CH2:22]2)=[O:13])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cccnc1Oc1cncc(Cl)c1
Reactant: NCC1CC1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)c1cccnc1Oc1cncc(Cl)c1
Yield: 61 %

Procedure:
To a stirred solution of 2-(5-chloro-pyridin-3-yloxy)-nicotinic acid (0.200 grams, 0.88 mmole), aminomethylcyclopropane hydrochloride (0.094 grams, 0.88 mmole), triethylamine (0.089 grams, 0.88 mmole) and 1-hydroxybenzotriazole hydrate (0.119 grams, 0.88 mmole) in dry dimethylformamide (3 ml) was added 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (0.164 grams, 0.96 mmole) and stirred over night. The mixture was poured into 100 ml water and extracted with ethyl acetate. The combined organics were washed with 1 N NaOH, water and brine, dried over MgSO4, filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 2.5% methanollmethylene chloride. Recrystalization from ethyl acetate/hexane gave a white solid (0.163 g). M.P. 105-107° C.; Anal. calcd. for C15H14N3O2Cl: C, 59.31;H, 4.65; N, 13.83. Found: C, 59.41;H, 4.68; N, 13.44.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:28])C(=O)C1.C(Cl)Cl>C(Cl)(Cl)(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][Br:28])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncc(Br)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: BrCc1ncc(Br)cn1
Temperature: 70 °C
Reaction time: 30 h
Yield: 25.5 %

Procedure:
To an ice-cold solution of 5-bromo-2-methylpyrimidine (3.5 g, 20.23 mmol) in CCl4 (20 mL) was added AIBN (0.14 g, 2.02 mmol) followed by portion wise addition of NBS (3.6 g, 20.23 mmol) and the mixture stirred at 70° C. for 30 h. After completion of reaction (by TLC), DCM (150 mL) was added and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 2% EtOAc:hexane to obtain the desired product (1.30 g, 25% yield). 1H NMR (CDCl3): δ 4.68 (s, 2H) and 9.03 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20](=[O:21])[NH:19][N:18]=[N:17]3)=[C:12]([F:22])[CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][F:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20](=[O:21])[N:19]([CH2:24][CH2:25][CH2:26][F:27])[N:18]=[N:17]3)=[C:12]([F:22])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nnn1-c1ccc(OCc2ccc(F)cc2)cc1F
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(CCCF)nnn1-c1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 70 °C
Yield: 75.8 %

Procedure:
A mixture of 7.0 g (0.023 mole) of 1-[4-(4-fluorophenylmethoxy)-2-fluorophenyl]-1,4-dihydro-5H-tetrazol-5one, 4.23 g (0.030 mole) of 1-bromo-3-fluoropropane, and 4.14 g (0.030 mole) of anhydrous potassium carbonate in 60 mL of N,N-dimethylformamide was heated at 70° C. for approximately seventeen hours. The mixture was allowed to cool to room temperature before being poured over ice. The solid that formed was removed by filtration and dried. This solid was then placed on a silica gel column and eluted with with methylene chloride. The product-containing fractions were combined and the solvents evaporated under reduced pressure, leaving 6.35 g of 1-[4-(4-fluorophenylmethoxy)-2-fluorophenyl]-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one, m.p. 86°-88° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[CH3:31][C@@H:32]1[O:36][C:35](=[O:37])[NH:34][CH2:33]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[CH2:33][C@H:32]([CH3:31])[O:36][C:35]4=[O:37])=[CH:3][C:4]=3[N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: C[C@H]1CNC(=O)O1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)OC4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 62.9 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (493 mg) described in Preparation Example 118 and (S)-5-methyloxazolidin-2-one (121 mg) described in Preparation Example 42, the title compound (323 mg) was obtained.
Reaction SMILES: N1C=CC=N1.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][N:8]=1.S(Cl)([Cl:18])=O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([Cl:18])=[O:15])[CH:10]=[CH:9][N:8]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: O=S(Cl)Cl
Agent: c1cn[nH]c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)c1ccnc(Cl)c1

Procedure:
Scheme III shows the synthesis of a pyrazole, compound 13, analogs of compound 5 in which the pyridine 10 ring bears a chlorine atom at position 2. 2-Chloropyridine-4-carboxylic acid, compound 9, is treated with thionyl chloride in a solvent such as toluene, and heated to reflux to give 2-chloropyridine-4-carboxylic acid chloride, compound 10, which is then converted to methyl 2-chloroisonicotinate, compound 11. Compound 11 is treated with a ketone 2 in the presence of a base such as sodium methoxide in a solvent such as tetrahydrofuran, at temperatures ranging from 25° C. up to reflux to provide a diketone, compound 12. Treatment of the diketone, compound 12, with an arylhydrazine derivative 4 in ethanol or other suitable solvent at a temperature ranging up to reflux, provides pyrazole compound 13. When R2 of ketone 2 is hydrido, then R2 of 13 is hydrido.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[C:5]([N+:9]([O-:11])=[O:10])[C:6](=[O:8])[N:7]=1.C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:8][C:6]2[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:3]=[C:2]([NH2:1])[N:7]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Nc1nc(=O)c([N+](=O)[O-])c(-c2ccco2)[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc(-c3ccco3)c2[N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 24.2 %

Procedure:
A suspension of 2-amino-6-(2-furyl)-5-nitropyrimidine-4(1H)-one (1.00 g, 4.50 mmol) in dichloromethane (50 mL) was treated with triethylamine (0.941 mL, 6.75 mmol) and p-toluenesulfonyl chloride (944 mg, 4.95 mmol), stirred for 1 h, diluted with dichloromethane (50 mL), washed with 2-M HCl (20 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (2:1)] to give the title compound (410 mg, 24%) as a yellow solid; NMR δH (400 MHz, CDCl3) 7.95 (2H, d, J 8.5 Hz), 7.59-7.57 (1H, m), 7.39 (2H, d, J 8.5 Hz), 7.23-7.21 (1H, m), 6.59-6.51 (1H, m), 5.39 (2H, br s), 2.48 (3H, s); Retention time 5.68 min.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[F-:14].[Cs+].O.Cl>CS(C)=O>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([F:14])[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: [F-]
Agent: Cl
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=S1(=O)N=C(F)Nc2cc(Cl)sc21
Temperature: 155 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
A mixture of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (257 mg, 1.0 mmol) and cesium fluoride (456 mg, 3.0 mmol) in dry DMSO (1 ml) was stirred for 16 h at 155° C. in a sealed flask. Water (3 ml) was added to the cooled mixture followed by 4M hydrochloric acid to pH <2. The precipitated beige solid was isolated by filtration, washed with water and dried to give 193 mg (80%) of the title compound; 1H-NMR (DMSO-d6): δ7.09 (s, 1H), 7.34 (br s, 1H; MS: m/e 240/242 (M+).
Reaction SMILES: [CH2:1]([C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>ClCCl>[CH2:1]([C@@H:8]([N:25]([CH3:26])[C:41]([C:35]1([CH3:34])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:42])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: CN[C@H](Cc1ccccc1)CN1CCC(c2cc(F)ccc2OC)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1C1CCN(C[C@@H](Cc2ccccc2)N(C)C(=O)C2(C)CCCCC2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Under a N2 atmosphere, a solution of {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-ethyl}-methyl-amine (0.12 g, 0.33 mmole) and triethylamine (0.10 mL, 0.74 mmole) in dichloromethane (10 mL) was cooled to 0° C. To the solution, 1-methyl-1-cyclohexanecarboxylicacid chloride (93 mg, 0.58 mmole) in a minimal amount of dichloromethane was added. The resulting mixture was stirred at 0° C. overnight. The solvent was evaporated and the residue dissolved in EtOAc (50 mL) and water (50 mL). The layers were separated, the organics washed with water (2×50 mL) and brine and dried over Na2SO4, filtered and concentrated. Flash chromatography (elution with 1:3 EtOAc-hexane) gave 0.14 g (88% yield) of 1-methyl-cyclohexanecarboxylic acid {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-ethyl}-methylamide. An ethanolic solution of the product was heated to gentle reflux and 1 equivalent of fumaric acid in hot ethyl alcohol solution was added to afford the fumarate salt of the titled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])=[O:11].[NH2:24][C@@H:25]([CH3:44])[CH2:26][O:27][C:28]1[CH:43]=[CH:42][C:31]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[CH:30][CH:29]=1.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([NH:24][C@@H:25]([CH3:44])[CH2:26][O:27][C:28]2[CH:43]=[CH:42][C:31]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:33])=[CH:30][CH:29]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])=[O:11]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Br
Reactant: C[C@H](N)COc1ccc(C(=O)OCc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)N[C@@H](C)COc2ccc(C(=O)OCc3ccccc3)cc2)ccc1NC(=O)Nc1ccccc1Br
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-bromophenyl)ureido]phenylacetic acid (480 mg, 1.27 mmol), benzyl (S)-4-(2-amino-1-propoxy)benzoate (361 mg, 1.27 mmol), EDC(hydrochloride) (364 mg, 1.90 mmol), HOBt (256 mg, 1.89 mmol), and 4-DMAP (31 mg, 0.25 mmol) in DMF (8 mL) was stirred at room temp. overnight. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3 to 5% MeOH in CHCl3 as eluent to give 476 mg (58%) benzyl (S)-4-[2-[3-methoxy-4-[N′-(2-bromophenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as a brown solid. 1H-NMR (CDCl3) δ 1.25–1.28 (m, 3 H), 3.51 (s, 2 H), 3.74 (s, 3 H), 3.95–3.97 (m, 2 H), 4.36–4.39 (m, 1 H), 5.33 (s, 2 H), 6.75–6.94 (m, 5 H), 7.26–7.70 (m, 8 H), 7.99–8.26 (m, 5 H).