Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:19])[CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:11][C:4]=2[CH:3]=1.C(O)(=O)/C=C\C(O)=O.ClC1[N:34]=[N:33]C2CCNCC=2C=1.C1(C(Cl)=O)CCCCC1>C(O)C>[NH:33]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:19])[CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:11][C:4]=2[CH:3]=1)[NH2:34]
Reactant: Clc1cc2c(nn1)CCNC2
Reactant: O=C(C1CCCCC1)N1CCc2nnc(Cl)cc2C1
Agent: O=C(Cl)C1CCCCC1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: NNc1cc2c(nn1)CCN(C(=O)C1CCCCC1)C2

Procedure:
The 3-chloro-6-hexahydrobenzoyl-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be produced in a manner analogous to that described in Example 8 (g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and cyclohexanecarboxylic acid chloride. M.P. 144°-146° (decomp., from absolute ethanol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4]([CH3:14])[N:3]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21].[OH-].[Na+]>C(Cl)Cl>[CH3:14][C:4]1[N:3]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)(=[O:21])=[O:22])=[O:25])[N:7]=[C:6]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=1
Reactant: COC(=O)COc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccs2)n1
Reaction time: 3 h

Procedure:
To a dry stirred solution of 18 parts of methyl (2-amino-6-methylpyrimidin-4-yloxy)acetate in 300 parts of methylene chloride at ambient temperature was added 20 parts of 2-thiophenesulfonylisocyanate. The solution was allowed to stand for 3 hours and was then poured onto ice. The pH of the aqueous layer was adjusted to 11 with sodium hydroxide solution and the methylene chloride layer was separated therefrom. The aqueous layer was neutralized with aqueous hydrochloric acid and then extracted with methylene chloride. The extract was dried and stripped of solvent to yield 8 parts of methyl [6-methyl-2-[(2-thienylsulfonyl)aminocarbonylamino]pyrimidin-4-yloxy]acetate, m.p. 114°-120°.
Reaction SMILES: [Na].[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH:5](P(OCC)(=O)OCC)[NH:4]1.[N+:17]([C:20]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:21]=1[CH:22]=O)([O-:19])=[O:18]>C(O)C>[N+:17]([C:20]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:21]=1[CH:22]=[C:5]1[NH:4][C:3](=[O:2])[NH:7][C:6]1=[O:8])([O-:19])=[O:18]
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Reactant: O=Cc1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cc(N3CCCCC3)ccc2[N+](=O)[O-])N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
Sodium (0.6 g, 0.026 g atom) was dissolved in absolute ethanol (200 mL) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (6.0 g, 25 mmol) added. After 10 minutes, 2-nitro-5-(1-piperidinyl)benzaldehyde (5.0 g, 21 mmol) was added in one portion and the mixture stirred at room temperature for 5 hours. The yellow precipitate was filtered off, washed with water and dried in air to give 5-[[2-nitro-5-(1-piperidinyl)phenyl]methylene]-2,4-imidazolidinedione (6.17 g, 92%), m.p. 273°-276° C. A sample dried in vacuo in 110° C. had m.p. 280° C. (dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:23]=[CH:22][C:10]([CH2:11][NH:12][C:13]3[S:14][C:15]([C:18]([O:20]C)=[O:19])=[CH:16][N:17]=3)=[CH:9][CH:8]=2)[CH:2]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1.[H-].[Na+].[OH-].[Na+]>CN(C)C=O.O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:12]([CH2:11][C:10]2[CH:22]=[CH:23][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=2)[C:13]2[S:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][N:17]=2)=[CH:27][CH:28]=1
Reactant: COC(=O)c1cnc(NCc2ccc(-c3cccnc3)cc2)s1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(N(Cc2ccc(F)cc2)Cc2ccc(-c3cccnc3)cc2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 250 mL round-bottomed flask was added methyl 2-(4-(pyridin-3-yl)benzylamino)thiazole-5-carboxylate (3 g, 9.22 mmol) and 1-(bromomethyl)-4-fluorobenzene (1.264 ml, 10.14 mmol) in dimethylformamide (46.1 ml). The mixture was cooled to 0° C., sodium hydride (0.738 g, 18.44 mmol) was added carefully; and the mixture was warmed to room temperature. After the mixture was stirred for about 30 minutes, it was found to be predominantely carboxylic acid. 1 N NaOH was added to complete the conversion; and a water work up followed by chromatography provided the title compound.
Reaction SMILES: Cl.C([O:4][C:5](=O)[CH2:6][NH:7][CH3:8])C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15]([N:17]=[C:18]=[S:19])[CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15]([N:17]2[C:5](=[O:4])[CH2:6][N:7]([CH3:8])[C:18]2=[S:19])[CH:16]=1
Reactant: COc1ccc(Cl)cc1N=C=S
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1N1C(=O)CN(C)C1=S
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (7.68 g), 5-chloro-2-methoxyphenyl-isothiocyanate (10.0 g), triethylamine (10.0 g) and chloroform (150 mL) was heated at reflux for 4.5 hours. The mixture was cooled to ambient temperature. The precipitated solid was collected, washed with chloroform and air dried to give the title compound (11.8 g) as an off-white solid, m.p. 245°-247° C. Anal. Calcd. for C11H11Cl N2O S: C, 48.80; H, 4.10; N,10.35. Found: C, 48.42; H, 3.96; N, 10.33. Mass spectrum (El, M.+) m/z 270.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH:7][C@H:8]([C:13]([O:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[CH:29]=[C:28]([F:30])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[C@H:19]([OH:31])[C@@H:18]1[OH:32])=[O:14])[C@H:9]([CH2:11][CH3:12])[CH3:10])=[O:6])[CH3:4].[CH2:33]([O:40][C:41]([NH:43][C@H:44]([C:52](O)=[O:53])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C.C(N(CC)C=O)C>CN(C)C=O>[CH2:33]([O:40][C:41]([NH:43][C@H:44]([C:52]([NH:2][C@H:3]([C:5]([NH:7][C@H:8]([C:13]([O:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[CH:29]=[C:28]([F:30])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[C@H:19]([OH:31])[C@@H:18]1[OH:32])=[O:14])[C@H:9]([CH2:11][CH3:12])[CH3:10])=[O:6])[CH3:4])=[O:53])[CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:42])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)N)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCN(C=O)CC
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Reaction time: 17 h
Yield: 35 %

Procedure:
0.46 Gram of 5'-O-(N-alanylisoleucyl)-5-fluorouridine hydrochloride obtained in Example 4 was dissolved in dimethylformamide (20 ml), and 1.51 g (5.30 mmol) of N-benzyloxycarbonylphenylalanine and 1.10 g (6.74 mmol) of diethylphosphoryl cyanide were then added. To this solution was added dropwise under ice-cooling a solution of 2.40 g (23.8 mmol) of triethylamine in diethylformamide (3 mmol), and the reaction liquid was kept for 17 hours at -20° C. and then concentrated under reduced pressure. The residue was dissolved in chloroform (200 ml) and the solution was washed with a 3% aqueous solution of potassium hydrogen carbonate (100 ml). The aqueous layer was further extracted with chloroform (100 ml). These organic layers were dried (over Na2SO4) and then concentrated under reduced pressure, and the residue was subjected to separation/purification by way of silica gel column chromatography (first time: a linear gradient of chloroform containing 3%→6% methanol; second time: a linear gradient of chloroform containing 3%→6% methanol) whereby 1.25 g (35%) of 5'-O-[N-{(N-benzyloxycarbonylphenylalanyl)alanyl}isoleucyl]-5-fluorouridine was obtained as a colorless powdery solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH3:12].[CH:13]1([NH2:20])[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:9]([NH:19][CH:16]3[CH2:17][CH2:18][CH:13]([NH2:20])[CH2:14][CH2:15]3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH3:12]
Reactant: Cc1sc2ncnc(Cl)c2c1Br
Reactant: NC1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1sc2ncnc(NC3CCC(N)CC3)c2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A solution of 5-bromo-4-chloro-6-methylthieno[2,3-d]pyrimidine (79 mg, 0.30 mmol, 1.00 equiv) in anhydrous DMF (5 mL) was added cyclohexane-1,4-diamine (171 mg, 1.50 mmol, 5.00 equiv) and triethylamine (91 mg, 0.90 mmol, 3.00 equiv) successively at room temperature. The resulting solution was stirred overnight at ambient temperature and then quenched with water. The resulting solution was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to provide the resulted 1-N-[5-bromo-6-methylthieno[2,3-d]pyrimidin-4-yl]cyclohexane-1,4-diamine (90 mg, 88%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Yield: 99 %

Procedure:
To a solution of (2R, 4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (3.17 g: 12.9 mmole) in dichloromethane (16 ml) in a nitrogen atmosphere under ice cooling, triethylamine (2.15 ml: 15.5 mmole) and methanesulfonyl chloride (1.19 ml: 15.5 mmole) are added. The mixture is stirred to react for 30 minutes to give (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine as oil (4.13 g). Yield: 99%.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][C:11]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)([CH:24]1[CH2:26][CH2:25]1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.O>CS(C)=O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:11]([CH:24]2[CH2:25][CH2:26]2)([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:32][CH:31]=1
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CSCc1cccc2c(C(CCC#N)(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
16 mg (0.25 mmol) of potassium cyanide were added to 57 mg (0.12 mmol) of the compound from Example 116A in 1 ml of DMSO. The mixture was stirred at 80° C. for 16 h, water was added to the reaction solution, and the crude product was purified directly by preparative HPLC (mobile phase: acetonitrile/water gradient). 29 mg (60% of theory) of the target compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[C:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:24].[CH3:25][NH:26][OH:27].Cl.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:26]([CH3:25])[O:27][C:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=3)([C:11]([F:14])([F:13])[F:12])[CH:9]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Reactant: CNO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1Br

Procedure:
300 mg 1-(4-Bromo-3-methyl-phenyl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-en-1-one (IVa), 80 mg MeNHOH.HCl and 100 mg triethylamine were refluxed in 2 ml of ethanol for 18 hours. After evaporation of the solvent the residue was purified on silica gel giving 210 mg (65%) of 3-(4-Bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazole (IIIa) as a colorless resin.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][C:8]3[N:9]2[CH:12]=[N:13][N:14]=3)=[CH:4][CH:3]=1.[CH2:21]([CH:23]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][SH:29])[CH3:22].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:21]([CH:23]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][S:29][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][C:8]3[N:9]2[CH:12]=[N:13][N:14]=3)=[CH:4][CH:3]=1)[CH3:22]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: Ic1ccc2c(-c3ccccc3)cc3nncn3c2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(CC)COC(=O)CCSc1ccc2c(-c3ccccc3)cc3nncn3c2c1
Temperature: 60 °C

Procedure:
8-Iodo-5-phenyl-[1,2,4]triazolo[4,3-a]quinoline (900 mg, 3.0 mmol), 3-mercaptopropionic acid 2-ethylhexyl ester (660 mg, 3.0 mmol), iPr2NEt (1.05 mL, 6.0 mmol), Pd2dba3 (69 mg, 0.08 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (87 mg, 0.15 mmol) were dissolved in 1,4-dioxane (15 mL) and degassed with N2 for 10 minutes. The reaction was heated to 60° C. for 1.5 hours, and then cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the desired product, 5w.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[CH:14]1([C@H:17]2[CH2:22][NH:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:18]2[OH:31])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)(C)C>[CH:14]1([C@H:17]2[CH2:22][N:21]([C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]4[CH2:11][CH2:12][CH2:13][C:3]=34)[CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C@@H:18]2[OH:31])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C2CC2)[C@H]1O
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@H](C2CC2)[C@H]1O
Temperature: 90 °C
Yield: 40.7 %

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.094 g, 0.47 mmol), tert-butyl [(3R,4R,5S)-5-cyclopropyl-4-hydroxypiperidin-3-yl]carbamate (0.13 g, 0.51 mmol), and triethylamine (0.26 mL, 1.9 mmol) in isopropyl alcohol (2 mL) was heated at 90° C. for 2 days. The desired product partially precipitated from the reaction mixture and was collected by filtration, washed with hexanes and dried under reduced pressure to afford pure sub-title compound (0.080 g). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (20 g silica gel column, eluting with 0-15% MeOH/DCM) to afford further sub-title compound (0.034 g, total 0.114 g, 58%). LCMS (ESI) m/z calc. for C21H31N4O5 419.2 [M+H]+. found 419.1.
Reaction SMILES: [OH:1][C:2]([CH3:33])([CH3:32])[CH2:3][C@@:4]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3([OH:25])[CH2:24][NH:23][CH2:22]3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:35]([O:37][CH3:38])=[O:36]>>[OH:25][C:21]1([C:20]#[C:19][C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:32])[CH3:33])([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)[CH2:24][N:23]([C:35]([O:37][CH3:38])=[O:36])[CH2:22]1
Reactant: C[C@@H](c1ccc(C#CC2(O)CNC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: COC(=O)Cl
Product: COC(=O)N1CC(O)(C#Cc2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)C1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-((3-hydroxyazetidin-3-yl)ethynyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one and methyl chloroformate following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.43 min, m/z=507, 449; 1H NMR (CDCl3) 1.12 (s, 3H), 1.19 (s, 3H), 1.52 (d, 3H), 2.10-2.45 (5H), 2.83 (m, 1H), 3.69 (s, 3H), 4.15 (d, 2H), 4.33 (d, 2H), 5.66 (q, 1H), 6.87 (d, 2H), 7.17 (d, 2H), 7.30-7.40 (5H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8].ClC(Cl)(Cl)[C:20]([N:22]=C=O)=[O:21].N>C(#N)C.CO>[NH2:22][C:20]([NH:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:21]
Reactant: Cc1c(-c2ccc(Cl)cc2)sc(N)c1C(N)=O
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: N
Solvent: CO
Solvent: CC#N
Product: Cc1c(-c2ccc(Cl)cc2)sc(NC(N)=O)c1C(N)=O
Reaction time: 0.17 h

Procedure:
2-Amino-4-methyl-5-(4-chlorophenyl)-3-thiophencarboxamide (0.44 g) was suspended in acetonitrile (25 mL) and trichloroacetylisocyanate (0.2 mL) added dropwise with stirring over 10 minutes. Stirring was continued for a further 3 h at room temperature and then a 2M solution of ammonia in methanol (10 mL) was added and stirring continued for a further 2 h. The solvent was evaporated and the residue treated with water. The resultant solid was filtered off and washed with more water. The crude product was chromatographed on silica gel eluting with dichloromethane/methanol mixtures. Trituration with ether gave the title urea (0. 1 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:10]([OH:12])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:14](O)([CH3:17])([CH3:16])[CH3:15].O>C(O)(=O)C>[C:14]([C:9]1[CH:8]=[CH:7][C:6]2[CH2:5][CH2:4][CH2:3][C:2]([CH3:13])([CH3:1])[C:11]=2[C:10]=1[OH:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)O
Reactant: CC1(C)CCCc2cccc(O)c21
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1ccc2c(c1O)C(C)(C)CCC2
Reaction time: 3 h
Yield: 71.4 %

Procedure:
To a solution of 8,8-dimethyl-5,6,7,8-tetrahydro-1-naphthol (10.1 g, 57.3 mmole) and tert-butanol (4.25 g, 57.3 mmole) in glacial acetic acid (30 ml) 90% aqueous sulphuric acid (3.0 ml) was added. The mixture was stirred at 40° for 3 hours, poured into water (100 ml) and extracted with diethylether (2×200 ml). The ethereal extract was washed with water and with aqueous saturated sodium chloride, dried and evaporated. The residue was chromatographed on silica gel using a n-pentane: dichloromethane (1:1) mixture to give 2-tert-butyl-8,8-dimethyl-5,6,7,8-tetrahydro-1-naphthol as a colourless oil (9.5 g, 71%).
Reaction SMILES: [NH:1]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH:2]1[CH3:3].[OH-].[Na+].[C:14](Cl)([Cl:16])=[O:15]>C(OCC)C.O>[Cl:16][C:14]([N:1]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH:2]1[CH3:3])=[O:15]
Reactant: CC1CCC2CCCCC2N1
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC1CCC2CCCCC2N1C(=O)Cl

Procedure:
A mixture of 15 g decahydro-quinaldine dissolved in 200 ml of diethylether and 4 g of sodium hydroxide in 50 ml of water is reacted while stirring and cooling at -5° to 0° with 10 g of phosgene. An ethereal solution of 1-chlorocarbonyl-2-methyl-decahydro-quinoline is obtained. When an aqueous solution of 8.4 g of sodium ethylmercaptide is added to the ethereal solution at room temperature with stirring, 16 g of an almost colorless oil are obtained. The physical constants of this oil coincide with those of the compound of Example 1.
Reaction SMILES: [OH-].[K+:2].[SH2:3].Cl[C:5]1[N:10]=[N:9][C:8](Cl)=[C:7]2[CH:12]=[N:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][C:6]=12.[SH-:22].[K+]>C(O)(=O)C.CO>[SH-:3].[K+:2].[SH:3][C:5]1[N:10]=[N:9][C:8]([SH:22])=[C:7]2[CH:12]=[N:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][C:6]=12
Reactant: Clc1nnc(Cl)c2cc(-c3ccccc3)ncc12
Reactant: S
Agent: [K+]
Agent: [OH-]
Agent: [SH-]
Solvent: CO
Solvent: CC(=O)O
Product: Sc1nnc(S)c2cc(-c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium hydrosulfide methanolic solution is prepared by reacting 7 parts by weight of potassium hydroxide, 150 parts by volume of methanol and hydrogen sulfide gas in accordance with the known method. 4.2 parts by weight of 1,4-dichloro-7-phenyl-pyrido (3,4-d) pyridazine is added to the potassium hydrosulfide solution, and the resulting mixture is stirred at room temperature for three hours. Methanol is evaporated under reduced pressure, and the residue is added to 50 parts by volume of water to obtain a solution. The solution is acidified by the addition of acetic acid to precipitate yellow crystals. The crystals are collected by filtration, washed with water and dried to obtain 1,4-dimercapto-7-phenyl-pyrido (3,4-d) pyridazine melting at 212° to 215° C (decomposition).
Reaction SMILES: Cl[CH:2]1[CH2:5][S:4](=[O:7])(=[O:6])[CH2:3]1.C(N(CC)CC)C.NC1N=CN=C([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)C=1>C(O)CCC>[O:6]=[S:4]1(=[O:7])[CH2:5][CH:2]([N:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)[CH2:3]1
Reactant: O=S1(=O)CC(Cl)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)ncn2)CC1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(C2CS(=O)(=O)C2)CC1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
3-Chlorothietane 1,1-dioxide 50-1 (0.50 g, 3.56 mmol) was dissolved in n-butanol (4 mL) then triethylamine (1.08 g, 10.67 mmol) was added followed by tert-butyl piperazine-1-carboxylate 12-1 (0.66 g, 3.56 mmol). This was then stirred at 150° C. for 5 hours. Upon cooling the solid was filtered off, washed with n-butanol, ethyl ether and then purified on a silica column to afford 50-2. 1H-NMR (CDCl3): 4.10(complex, 4H); 3.46(t, 4H); 3.19(m, 1H); 2.36(t, 4H); 1.46(s, 9H).
Reaction SMILES: O=[O+][O-].[CH2:4]([CH:7]([CH2:12][CH2:13][CH2:14][CH:15]=C)[C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH3:6].CC[O:19]CC.O>C(O)(=O)C.[Zn]>[CH:15]([CH2:14][CH2:13][CH2:12][CH:7]([CH2:4][CH2:5][CH3:6])[C:8]([O:10][CH3:11])=[O:9])=[O:19]
Reactant: C=CCCCC(CCC)C(=O)OC
Reactant: CCOCC
Agent: O=[O+][O-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCCC(CCCC=O)C(=O)OC

Procedure:
Ozone stream was bubled into a solution of methyl 2-propyl-6-heptenoate (2 g) in glacial acetic acid (80 ml) for 55 minutes at room temperature. Ether (100 ml) was added to the resulting mixture, followed by the portionwise addition of zinc powder (10 g) and water (1.1 ml) under cooling. The mixture was heated under reflux until KI-starch test became negative. After cooling, ether (100 ml) was added to the mixture, which was then filtered. The organic layer was separated, washed with water, dried and concentrated. The resulting residue was purified by silica gel column chromatography to give oil of methyl 5-formyl-2-propylpentanoate (1.1 g).
Reaction SMILES: O=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.[NH2:17][OH:18].C[O-].[Na+].CCOCC>CO>[OH:18][N:17]=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: NO
Reactant: O=C(O)CCC(=O)CCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=C(O)CCC(CCc1ccccc1)=NO
Yield: 89.7 %

Procedure:
The ketone 99 (3.0 g, 13.6 mmol) and hydroxylamine hydrochloride (1.98 g, 27 mmol) were dissolved in methanol (20 mL) then sodium methoxide (2.9 g) was added. The solution was stirred and refluxed for 2 hr then cooled. Ether was added and the organic layer was washed twice with 2M HCl, brine and dried over MgSO4. Removal of solvent gave the oximes 100 (2.7 g 90%) as a mixture of E:Z isomers in the ratio 1.5:1.