Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][NH2:23])[CH:18]=3)[C:13]([C:24]#[N:25])=[CH:12]2)=[CH:7][C:6]=1[O:26][CH2:27][O:28][CH3:29])[CH3:2].C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[CH2:1]([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][NH:23][C:38](=[O:40])[CH3:39])[CH:18]=3)[C:13]([C:24]#[N:25])=[CH:12]2)=[CH:7][C:6]=1[O:26][CH2:27][O:28][CH3:29])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(OCCN)cc32)cc1OCOC
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(OCCNC(C)=O)cc32)cc1OCOC
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.3 %

Procedure:
To a solution of 4-[6-(2-aminoethyloxy)-3-cyanoindol-1-yl]-2-methoxymethoxybenzoic acid ethyl ester (0.10 g) and triethylamine (0.076 g) in dichloromethane (5 mL) was added acetyl chloride (0.049 g) at room temperature, and this mixture was stirred at room temperature for 12 hours. This reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane:methanol=10:1) to give the title compound (0.083 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[N:27]1[C:35]2[C:30](=[CH:31][C:32]([OH:36])=[CH:33][CH:34]=2)[C:29]([C:37]([F:40])([F:39])[F:38])=[N:28]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[N:27]1[C:35]2[C:30](=[CH:31][C:32]([O:36][CH2:2][C:3]3[CH:4]=[N:5][C:6]([NH:9][C:10]4[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=4)=[N:7][CH:8]=3)=[CH:33][CH:34]=2)[C:29]([C:37]([F:40])([F:38])[F:39])=[N:28]1
Reactant: FC(F)(F)Oc1ccc(Nc2ncc(CCl)cn2)cc1
Reactant: Oc1ccc2c(c1)c(C(F)(F)F)nn2C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(Nc2ncc(COc3ccc4c(c3)c(C(F)(F)F)nn4C3CCCCO3)cn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
To a solution of 5-(chloromethyl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine (0.04 g, 0.132 mmol) in DMF (2 mL), 1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazol-5-ol (0.045 g, 0.158 mmol) and Cs2CO3 (0.086 g, 0.263 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, then diluted in EtOAc and washed sequentially with 10% NaOH and brine. The organic layer was dried over Na2SO4 and concentrated to afford 5-(((1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazol-5-yl)oxy)methyl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine (38 mg, 52%). LCMS: RT 2.33 min; 554.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:11]=1)[C:6]([OH:8])=O)#[N:2].[NH2:19][C:20]1[C:21]([F:28])=[C:22]([OH:27])[CH:23]=[CH:24][C:25]=1[F:26].C([O-])(O)=O.[Na+]>O=S(Cl)Cl.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:11]=1)[C:6]([NH:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([OH:27])[C:21]=1[F:28])=[O:8])#[N:2]
Reactant: N#Cc1cc(C(=O)O)cc(-c2cccc(F)c2)c1
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: N#Cc1cc(C(=O)Nc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
3-Cyano-5-(3-fluorophenyl)benzoic acid (500 mg, 2.1 mmol, 1 eq) was dissolved in SOCl2 (15 mL) and heated at reflux overnight. The excess SOCl2 was removed under reduced pressure and the residue that remained dissolved in THF (10 mL) and added dropwise to a mixture of 3-amino-2,4-difluorophenol (280 mg, 2 mmol, 0.95 eq) and NaHCO3 (880 mg, 10.5 mmol, 5 eq) in THF (40 mL). The reaction was stirred at room temperature for 3 h, then filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 10:1) to give the title compound as a white solid (500 mg, 64%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21](O)=[CH:20][C:19]=2[CH3:25])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>C(OCC)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:29])=[CH:20][C:19]=2[CH3:25])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(O)ccc1NC(=O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: Cc1cc(Cl)ccc1NC(=O)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 2-(4-benzyl-piperidin-1-yl)-N-(4-hydroxy-methyl-phenyl)-2-oxo-acetamide (Example 117) and thionyl chloride according to the method described in Example 115. Melting Point: 105-108° C. (diethylether)
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[OH2:16]>O.O.O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O>[CH:2]([C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:16]
Reactant: O
Reactant: COc1ccc(CC(=O)O)cc1CBr
Agent: [Cu+2]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Product: COc1ccc(CC(=O)O)cc1C=O

Procedure:
Copper(II) nitrate trihydrate (3.3 g) was added to (3-bromomethyl-4-methoxy-phenyl)-acetic acid (1.4 g) in water (50 mL) and heated to reflux for 75 minutes. On cooling the reaction mixture was acidified with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was separated and washed sequentially with 2M aqueous hydrochloric acid (2×50 mL), brine (50 mL), dried (magnesium sulfate) and concentrated. Purification on silica, eluting iso-hexane/ethyl acetate [4:1 to 1:1 to 0:1], to give the subtitle compound as a solid (0.26 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:10]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: O=S1(=O)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=S1(=O)CCN(Cc2cccc(Br)n2)CC1

Procedure:
The title compound was prepared as described in Example 2, Step 1 using 6-bromopyridine-2-carbaldehyde (3.0 g, 16.13 mmol), thiomorpholine 1,1-dioxide (2.18 g, 16.13 mmol), and sodium triacetoxyborohydride (4.79 g, 22.58 mmol) as starting materials. 1H NMR (600 MHz, d6-DMSO) δ 7.72 (t, 1H), 7.51 (d, 1H), 7.50 (d, 1H), 3.74 (s, 2H), 3.10 (m, 4H), 2.90 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH2:22][CH3:23].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:22]([N:10]1[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:9]1)[CH3:23]
Reactant: CCI
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2ncccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1nc(-c2cccc(Cl)c2)c2ncccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 8-(3-chlorophenyl)pyrido[2,3-d]pyridazin-5-one (0.32 g, 1.24 mmoles) in tetrahydrofuran (50 ml) was added sodium hydride (0.06 g, 1.4 mmoles). The mixture was stirred for 1 hour at room temperature. Iodoethane (0.48 g, 3.1 mmoles) was added and the solution was refluxed for 18 hours under an inert atmosphere. The mixture was cooled and acidified by the addition of 50 ml of 1N HCl. The desired compound was isolated by extraction with ethyl acetate (extracted until no product detected in aqueous layer), washed with sodium bicarbonate, brine and dried over magnesium sulfate. The solution was filtered and the solvent removed yielding 0.85 g of the crude desired product. The product was purified by recrystallization from methanol to yield 0.24 g of 6-ethyl-8-(3-chlorophenyl)pyrido-[2,3-d]pyridazin-5-one (67.8%), mp. 117°-118° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]([CH:27](O)[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[C:25]([CH:39]([CH3:41])[CH3:40])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:44])[CH2:20][C:21]([CH3:43])([CH3:42])[O:22]3)=[CH:13][CH:12]=1.O>ClCCl>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]([CH:27]([F:7])[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][CH:29]=3)=[C:25]([CH:39]([CH3:41])[CH3:40])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:44])[CH2:20][C:21]([CH3:42])([CH3:43])[O:22]3)=[CH:13][CH:12]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 2.5 h
Yield: 45 %

Procedure:
At −78° C., a solution of 51 μl (380 μmol) of diethylaminosulfur trifluoride in 1 ml of dichloromethane is slowly added dropwise to a solution of 170 mg (350 μmol) of rac-5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethyl)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 21A) in 4.5 ml of dichloromethane, and the mixture is stirred at this temperature for 2.5 h. The mixture is then allowed to thaw slowly to −20° C. Water is then added, and the mixture is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. Crystallization of the residue from cyclohexane/ethyl acetate (10:1) gives 77 mg of the target product. Column chromatography of the concentrated mother liquor on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1) gives a further 60 mg of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:5]=1[C:6]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:8])[CH3:2]
Reactant: NCc1ccccn1
Reactant: CCOc1ccc(OCC(F)(F)F)cc1C(=O)O
Product: CCOc1ccc(OCC(F)(F)F)cc1C(=O)NCc1ccccn1

Procedure:
Using the general method of Example XXIII Part D, 15.4 g (0.058 mole) of 2-ethoxy-5-(2,2,2-trifluoroethoxy)benzoic acid was converted to the acid chloride and then reacted with 2-aminomethylpyridine to provide 14.1 g of crystalline 2-ethoxy-5-(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide, m.p. 110°-111° C. Analysis: Calculated for C17H17F3N2O3 : %C, 57.6; %H, 4.85; %N, 7.9; Found: %C, 57.1; %H, 4.8; %N, 7.8.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.C([O:9][C:10](=O)[CH:11]([Cl:15])[C:12](=O)[CH3:13])C.C(O)(=O)C>CCO>[Cl:15][C:11]1[C:12]([CH3:13])=[N:1][C:2]2[N:3]([N:4]=[CH:5][CH:6]=2)[C:10]=1[OH:9]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1cc[nH]n1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc2ccnn2c(O)c1Cl
Temperature: 120 °C
Yield: 93.7 %

Procedure:
A mixture of 3-aminopyrazole (10.0 g, 120.3 mmol), 2-chloro-3-oxo-butyric acid ethyl ester (16.7 mL, 120.3 mmol), and glacial acetic acid (103 mL) was heated to 120° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOH and concentrated. Trituration with Et2O gave 20.7 g (94%) desired product. MS APCI (+) m/z 184, 186 (M+, Cl pattern) detected; 1H NMR (400 mHz, CD3OD) δ 7.90 (d, 1H), 6.17 (d, 1H), 2.53 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[N:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[CH:22][N:21]=3)[N:19]=2)=[C:11]([F:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]1[CH2:33][CH2:32]OC1=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:32][CH2:33][OH:29])[CH:17]=[C:18]([C:20]3[N:24]([CH:25]([CH3:26])[CH3:27])[N:23]=[CH:22][N:21]=3)[N:19]=2)=[C:11]([F:28])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCO1
Reactant: CC(C)n1ncnc1-c1c[nH]c(-c2ccc(OCc3ccccc3)cc2F)n1
Solvent: Cc1ccccc1
Product: CC(C)n1ncnc1-c1cn(CCO)c(-c2ccc(OCc3ccccc3)cc2F)n1
Temperature: 130 °C
Yield: 70.3 %

Procedure:
A suspension of 5-[2-(4-benzyloxy-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazole (84 g, 0.22 mol) and [1,3]dioxolan-2-one (48 g, 0.55 mol) in toluene (100 mL) was heated at 130° C. for 7.5 h allowing some solvent to evaporate until reaction was initiated. The cooled reaction mixture was concentrated in vacuo and the residue treated with acetonitrile (50 mL), stirred, sonicated and cooled in an ice bath. The resultant solid was collected by filtration, washed with cold acetonitrile then diethyl ether and dried in vacuo at 60° C. to give 2-[2-(4-Benzyloxy-2-fluoro-phenyl)-4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol (65.2 g, 70%). 1H NMR (400 MHz, CDCl3): 8.04 (1H, s), 7.80 (1H, d, J=0.71 Hz), 7.43-7.41 (6H, m), 6.89 (1H, dd, J=8.59, 2.50 Hz), 6.79 (1H, dd, J=11.73, 2.47 Hz), 5.93-5.92 (1H, m), 5.11 (2H, s), 4.02 (2H, t, J=4.93 Hz), 3.89 (2H, t, J=4.96 Hz), 1.49 (6H, d, J=6.61 Hz). LCMS: RT=3.30 min, [M+H]+=422.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[S:61][C:60]([CH3:62])=[N:59][C:58]=2[C:63](O)=[O:64])=[CH:53][CH:52]=1>CN(C=O)C>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:63]([C:58]1[N:59]=[C:60]([CH3:62])[S:61][C:57]=1[C:54]1[CH:55]=[CH:56][C:51]([F:50])=[CH:52][CH:53]=1)=[O:64]
Reactant: c1ccc2sc(CC3CCCCN3)nc2c1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3ccccc3s2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Piperidin-2-ylmethylbenzothiazole, D30 (0.135 g), HATU (0.228 g), diisopropylethylamine (0.300 ml) and 5-(4-fluorophenyl)-2-methylthiazol-4-carboxylic acid (0.144 g) were dissolved in dry DMF and shaken at room temperature for 16 hours. The solvent was then evaporated and the residue partitioned between dichloromethane and brine. The organic layer was dried (MgSO4), evaporated and the residue chromatographed over silica gel. Elution with diethyl ether provided the title compound as a foam (220 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.CI.[C:22](=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([N:12]3[CH2:17][CH2:16][N:15]([CH3:22])[CH2:14][CH2:13]3)[NH:8][S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=S1(=O)NC(N2CCNCC2)=Nc2ccc(Cl)cc21
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCN(C2=Nc3ccc(Cl)cc3S(=O)(=O)N2)CC1
Reaction time: 2 h
Yield: 38.2 %

Procedure:
To a solution of 1.0 g of 7-chloro-3-(1-piperazinyl)-2H-1,2,4-benzothiadiazine 1,1-dioxide in 15 ml of dimethylformamide is added dropwise at 0° C. 0.56 g of 93% methyl iodide, in the presence of 0.7 g of anhydrous sodium carbonate. The mixture is stirred for 2 hours, while the temperature is kept at 0° C. After removal of dimethylformamide by distillation under reduced pressure, the resulting residue is triturated with 10 ml of water to precipitate the crystals. The collected precipitate is recrystallized from a mixture of dimethylformamide and water to give 0.4 g of the desired product, m.p. above 300° C.
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[CH:8][C:7](=[O:11])[CH2:6][S:5]1(=[O:13])=[O:12])([CH3:3])[CH3:2].[NH3:14]>CO>[NH2:14][C:9]([CH3:10])=[CH:8][C:7](=[O:11])[CH2:6][S:5]([NH:4][CH:1]([CH3:3])[CH3:2])(=[O:13])=[O:12]
Reactant: N
Reactant: CC1=CC(=O)CS(=O)(=O)N1C(C)C
Solvent: CO
Product: CC(N)=CC(=O)CS(=O)(=O)NC(C)C

Procedure:
A suspension of 10 g of 2-isopropyl-3-methyl-1,2-thiazin-5(6H)-one 1,1-dioxide in 100 ml of methanol was reacted with ammonia in accordance with the procedure described in Example 1. The solution obtained was concentrated to dryness under reduced pressure and the solid residue was recrystallized from isopropanol. There were obtained 10.1 g of 4-amino-N-isopropyl-2-oxo-3-pentenesulfonamide in the form of colorless crystals, m.p. 119°-121°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:31]1([NH2:34])[CH2:33][CH2:32]1>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:34][CH:31]4[CH2:33][CH2:32]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: NC1CC1
Solvent: CCO
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)NC4CC4)c3)C(C)(C)C2=O)cc1
Temperature: 50 °C

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 200 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 4 mL of ethanol and 32.3 mg of cyclopropanamine. After heating for one hour at a temperature of 50° C., and chromatography on a column of silica, eluting with a mixture of heptane/ethyl acetate (gradient from 100/0 to 0/100 by volume), 76.1 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-3-cyclopropylurea are obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][CH2:11][NH2:12])([O-:7])=[O:6].[O:13]=[C:14]1[NH:18][CH:17]([C:19](O)=[O:20])[CH2:16][S:15]1>>[N+:5]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:19]([CH:17]1[CH2:16][S:15][C:14](=[O:13])[NH:18]1)=[O:20])([O-:7])=[O:6]
Reactant: NCCCO[N+](=O)[O-]
Reactant: O=C1NC(C(=O)O)CS1
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCCO[N+](=O)[O-])CS1
Yield: 35.4 %

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 1.25 g of N-(3-nitrooxypropyl)amine nitrate and 1.0 g of 2-oxothiazolidine-4-carboxylic acid, to obtain 0.60 g of the title compound as pale yellow crystals, melting at 83°-850° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH3:5])[CH3:2].C([Li])CCC.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)C(C)C)(C)C>[Cu]I>[CH2:1]([O:3][CH:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:5])[CH3:2]
Reactant: CCOC(C)Oc1cccc(OC)c1
Reactant: CCOC(=O)CBr
Agent: [Cu]I
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1c(OC)cccc1OC(C)OCC
Yield: 96 %

Procedure:
854.0 g of 1-(1-ethoxyethoxy)-3-methoxybenzene (content: 717.4 g (3.66 mol)) was put into a 20 L reactor under a nitrogen atmosphere and rinsed in with 7174 mL of tetrahydrofuran and the mixture was stirred. A coolant which was set to 4° C. was circulated through the jacket of the reactor and 1156 g (4.41 mol) of n-butyllithium [2.71 M, n-hexane solution] was added dropwise for 41 minutes, and the reaction mixture was stirred at the same temperature for about 1.5 hours. The coolant temperature was set to −20° C., and after it was confirmed that the mixture's temperature lowered below −10° C., 417.8 g (2.19 mol) of copper (I) iodide was added portionwise divided into three to the reaction mixture and the reaction mixture was stirred at the same temperature for about 14 hours. The coolant temperature was changed to −90° C. and 702.1 g (4.20 mol) of ethyl bromoacetate was added dropwise to the reaction mixture over 26 minutes and rinsed in with 10 mL of tetrahydrofuran. After the dropwise addition was completed, the reaction mixture was stirred for 44 minutes, and the liquid cooling temperature was changed to −35° C. and the reaction mixture was further stirred for about 1.8 hours. The coolant temperature was changed to −20° C., and the reaction mixture was stirred for one hour after the time point when temperature of the mixture exceeded −20° C. and progress of the reaction was confirmed by HPLC. 1435 mL of 28% ammonium hydroxide solution was added to the reaction mixture at the same temperature for about 30 minutes and the coolant temperature was changed to 25° C. The reaction mixture was added and extracted with 7174 mL of toluene and the organic layer was washed with 1440 mL of 28% ammonium hydroxide solution and 1435 mL×3 water sequentially. The obtained organic layer was added with 127 mL (0.73 mol) of N,N-diisopropylethylamine and concentrated in vacuo to afford a pale orange oil containing the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.[O:14]1CCCC1.[OH-].[Na+].OO>CCOC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:13])([CH3:12])[CH2:6][CH:5]2[OH:14]
Reactant: C1CCOC1
Reactant: CC1(C)C=Cc2cc(Br)ccc2N1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CC(O)c2cc(Br)ccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-2,2-dimethyl-1,2-dihydroquinoline (4.50 g, 18.9 mmol) in tetrahydrofuran (37.8 ml, 18.9 mmol) was added BH3DMS (3.58 ml, 37.8 mmol) dropwise at 0 deg C. The resulting solution was allowed to warm to RT and stirred for 1 hour. The temperature was returned to 0 deg C. and sodium hydroxide (6N) (30.0 ml, 18.9 mmol) followed by Hydrogen peroxide (30.0 ml, 18.9 mmol) was slowly added to the reaction mixture. The resulting solution was stirred for 45 minutes and then transferred to a sep. funnel containing water and EtOAc. The layer were separated and the aqueous layer was subsequently washed 3× with DCM. The organic layers were dried with MgSO4, filtered and concentrated. The crude mixture was then purified with the MPLC (100% DCM to 10% 90:10:1 DCM:MeOH:NH4OH) to provide the desired product. MS m/z: 257 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][CH:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=O.[CH3:26][NH2:27].[O-]CC.[Na+].[Na]>C(O)C>[CH3:26][NH:27][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:3]1[CH:4]([CH:7]=[CH:8][CH:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:5][CH2:6][CH:2]1[OH:1]
Reactant: CN
Reactant: CCCCCC(O)C=CC1CCC(O)C1CCCCCCC(=O)OC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCCCC(O)C=CC1CCC(O)C1CCCCCCC(=O)NC
Yield: 25 %

Procedure:
To a solution of methyl 7-[2-hydroxy-5-(3-hydroxy-1-octenyl)cyclopentyl]heptanoate (0.8 g.) [prepared as described in Example 5] in ethanol (16 ml.) was added 33% methylamine in ethanol (4 ml.) followed by sodium ethoxide in ethanol [0.8 ml. of a solution prepared by dissolving sodium (0.2 g.) in ethanol (1 ml.)]. The resulting solution was refluxed for 1 day and the ethanol removed in vacuo. The residue was diluted with ice-cooled water and extracted twice with dichloromethane. The combined dichloromethane extracts were dried over magnesium sulphate and evaporated to give N-methyl-7-[2-hydroxy-5-(3-hydroxy-1-octenyl)cyclopentyl]heptanoamide (0.2g., 25%). Found: C, 71.9; H, 10.6. C21H39NO3 requires C, 71.4; H, 11.05%) νmax 3300 cm-1, 1650 cm-1, 1570 cm-1 and 980 cm-1 (liquid film).