Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([NH2:30])=[O:29]>CN(C)C=O.ClCCl>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:27][C:28]([NH2:30])=[O:29])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Oc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)COc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reaction time: 216 h

Procedure:
A mixture of 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenol (0.28 g, Example 30), potassium carbonate (0.16 g) and 2-bromoacetamide (0.16 g) was stirred together at ambient temperature in dry dimethyl formamide (5 ml) for 4 days and then allowed to stand at ambient temperature for 9 days. The mixture was diluted with dichloromethane (50 ml) and washed with 1M aqueous sodium hydroxide solution and then with water. Some insoluble material which remained throughout the extractions was collected by filtration. The solid was purified by flash column chromatography on silica using ethyl acetate as the mobile phase. Appropriate fractions were collected, combined and evaporated to give 2-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxy]acetamide, m.p. 247-248° C.
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([Br:9])[NH:4][C:3]=1[C:10]#[N:11].[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CC(C)=O>[Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([Br:9])[N:4]([CH3:12])[C:3]=1[C:10]#[N:11]
Reactant: N#Cc1[nH]c(Br)c(C#N)c1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: Cn1c(Br)c(C#N)c(Br)c1C#N

Procedure:
A sample (1.0 g, 0.0036 mol) of 3,5-dibromopyrrole-2,4-dicarbonitrile is readily soluble in 20 mL of acetone. Anhydrous potassium carbonate (0.64 g, 0.0046 mol) is added, and while the slurry is stirred, methyl iodide (0.68 g, 0.0047 mol) is added. The reaction can be followed by Tlc. When the reaction is complete, the mixture is poured into water precipitating a white solid. The product (0.77 g, 74%) has mp 175°-178° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[CH:5]=[C:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)[O:7]2.I.C(O)(=O)C>O>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[CH:5]=[C:6]([C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)[O:7]2
Reactant: COc1ccc(-c2cc(=O)c3c(F)cc(F)cc3o2)cc1
Agent: I
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(-c2ccc(O)cc2)oc2cc(F)cc(F)c12
Temperature: 110 °C
Yield: 54.6 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 5,7-Difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (0.425 g, 1.47 mmol), hydroiodic acid (10 mL) and acetic acid (5 mL). The reaction mixture was heated 110° C. for 4 h. The reaction mixture was cooled to room temperature and diluted with water. The precipitate was filtered off, washed with water and dried to give the title compound (220 mg, 54%). Selected data for the title compound: MS (ES) m/z: 275.10 (M+1); 19F-NMR (DMSO-d6): δ −106.2, −113.4.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[C:4]([NH:7][C:8]1[C:9](CC)=[C:10]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[C:11]([O-])=[O:12])(=O)[CH3:5]>C(O)(=O)C>[CH2:1]([O:3][C:11]([C:10]1[CH:14]=[CH:15][C:16]2[N:17]=[C:4]([CH3:5])[NH:7][C:8]=2[CH:9]=1)=[O:12])[CH3:2]
Reactant: CCc1c(C(=O)[O-])ccc([N+](=O)[O-])c1NC(C)=O
Reactant: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2nc(C)[nH]c2c1

Procedure:
Reduced iron (6.64 g), ethanol (48 ml) and acetic acid (24 ml) are added to 3-acetylamino-4-nitro-ethylbenzoate (3.00 g), and the solution is refluxed by heating for 12 hours. Solid materials are removed using filter aid, and the filtrate is concentrated under reduced pressure. Ethanol (100 ml) and 35% hydrochloric acid (5.2 g) are added to the residue and the solution is refluxed by heating for five hours. The reaction solution is neutralized with sodium bicarbonate (6.3 g). The filtrate obtained through filtration is concentrated under reduced pressure. Ethyl acetate (70 ml) and water (70 ml) are added to the obtained residue, and the solution is separated. The organic layer is washed with water three times and extraction is performed on the aqueous layer using ethyl acetate three times. By concentrating the obtained organic layer under reduced pressure, 5-ethoxycarbonyl-2-methylbenzimidazole (1.53 g ) powder is obtained. 1H-NMR (CDCl3, δ): 1.41 (3H, t, J=6.9 Hz), 2.67 (3H, s), 4.40 (2H, q, J=7.1 Hz), 7.55 (1H, d, J=8.4 Hz), 7.96 (1H, dd, J=8.4 and 1.5 Hz), 8.27 (1H, d, J=1.4 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([C:16](C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:15]=3)=[CH:9][N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:5]2=[N:6][CH:7]=1.[C:43]1([SH:49])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CN(C)CC(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[CH3:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([S:49][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:3]=3)[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:40])[CH3:41])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Sc1ccccc1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c2cc(Br)cnc21
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(Sc4ccccc4)cc23)cn1
Temperature: 120 °C

Procedure:
A mixture of 22 (50 mg, 0.079 mmol), benzenethiol (13.0 mg, 0.118 mmol), copper (I) iodide (3.0 mg, 0.016 mmol), N,N-dimethylglycine (1.62 mg, 0.016 mmol) and potassium phosphate (41.8 mg, 0.197 mmol) in DMF (0.5 mL) were heated at 120° C. for 69 h. The reaction mixture was cooled and partitioned between AcOEt/brine, the layers separated and the aqueous phase extracted with more AcOEt (2×). The combined organic extracts were dried (MgSO4) and concentrated. The resulting crude residue containing 23 was used for the subsequent deprotection step.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][NH2:30].C(NC(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CS(C)=O.C(#N)C>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][NH:30][C:4](=[O:6])[C@@H:3]1[CH2:7][CH2:8][C:9](=[O:10])[N:2]1[CH3:1]
Reactant: CN1C(=O)CC[C@H]1C(=O)O
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CN1C(=O)CC[C@H]1C(=O)NCc1ccc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
1-Methyl-5-oxo-proline (0.057 g, 0.4 mmol, prepared as described below) was dissolved in anhydrous dichloromethane (6 ml) and to this was added 1-hydroxybenzotriazole (0.060 g, 0.4 mmol), [(2,4-dichloro-phenyl)methyl]amine (0.055 ml, 0.4 mmol), diisopropylamine (0.140 ml, 0.8 mmol) and 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.152 g, 0.4 mmol). The mixture was stirred at room temperature (20° C.) under argon for 3 hrs and then overnight. The mixture was diluted with more dichloromethane (25 ml) and washed sequentially with 2M aqueous hydrogen chloride (20 ml), saturated aqueous sodium hydrogen carbonate (20 ml), 10% aqueous sodium carbonate (20 ml) and brine (20 ml). The organic layer was filtered through a hydrophobic frit and then evaporated to give the crude product. The crude material was dissolved in a mixture of dimethylsulphoxide (0.9 ml) and acetonitrile (0.9 ml) and then purified by mass-directed automated HPLC to give pure N-[(2,4-dichlorophenyl)methyl]-1-methyl-5-oxo-prolinamide (0.085 g) as a white solid. LC/MS [M+H]+=301, retention time=2.16 minutes.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH2:28][CH:29]([C:37]1[S:41][CH:40]=[N:39][C:38]=1[Cl:42])[O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)(C(C)(C)C)(C)C>C1COCC1>[Cl:42][C:38]1[N:39]=[CH:40][S:41][C:37]=1[CH:29]([O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[CH2:28][CH2:27][OH:26]
Reactant: CC(C)(C)[Si](C)(C)OCCC(OC1CCCCO1)c1scnc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCC(OC1CCCCO1)c1scnc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., a soln. of TBAF in THF (1 M, 19.2 mL, 19.2 mmol) was added to a. soln. of 5-(3-((tert-butyldimethylsilyl)oxy)-1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-4-chlorothiazole (6.27 g, 16.0 mmol) in THF (80 mL). The mixture was allowed to warm to RT and stirred overnight. Then, the mixture was quenched by the addition of aq. sat. NaHCO3 and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. Purification by means of CC (20-85% EtOAc/Hept) provided the product as a yellow oil as an isomeric mixture.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2ccccc2c1=O
Reactant: Cc1cccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O
Yield: 74.7 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 2.87 g (13.2 mmol) of 4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester, 0.64 g (15.9 mmol) of 60% sodium hydride, 2.95 g (15.9 mmol) of 2-bromomethyl-6-methyl-pyridine in 30 mL DMF to give 3.18 g of the product as an off-white solid.
Reaction SMILES: BrC1C=N[C:5]2[N:6]=[C:7]([O:14][CH2:15][CH2:16][CH3:17])[N:8]([CH2:11][CH2:12][CH3:13])[C:9](=[O:10])[C:4]=2C=1.BrC1C=NC2N=C(SCCC)N(CCC)C(=O)C=2C=1.IC1C=C2C(=CC=1)N=C(OCCC)N(CC1CCCO1)C2=O.BrC1C=C2C(=CC=1)N=C(OCCC)N(CC1CCCO1)C2=O.BrC1C=C2C(=CC=1)N=C(OCCC)N(CC1ON=C(Br)C1)C2=O.Br[C:107]1[S:115]C2C(=O)N(CCC)C(OCCC)=NC=2[C:108]=1[Br:124].IC1C=C2C(=C(I)C=1)N=C(SCCC)N(CC1CCCO1)C2=O.C1(CN2C(=O)C3C=C(I)C=NC=3N=C2SCCC)CC1>>[Br:124][C:108]1[C:5]2[N:6]=[C:7]([O:14][CH2:15][CH2:16][CH3:17])[N:8]([CH2:11][CH2:12][CH3:13])[C:9](=[O:10])[C:4]=2[S:115][CH:107]=1
Reactant: CCCOc1nc2ncc(Br)cc2c(=O)n1CCC
Reactant: CCCOc1nc2c(Br)c(Br)sc2c(=O)n1CCC
Agent: CCCOc1nc2ccc(Br)cc2c(=O)n1CC1CC(Br)=NO1
Agent: CCCOc1nc2ccc(Br)cc2c(=O)n1CC1CCCO1
Agent: CCCOc1nc2ccc(I)cc2c(=O)n1CC1CCCO1
Product: CCCOc1nc2c(Br)csc2c(=O)n1CCC

Procedure:
6-bromo-2-propoxy-3-propylpyrido[2,3-d]pyrimidin-4(3H)-one; 6-bromo-3-propyl-2-(propylthio)pyrido[2,3-d]pyrimidin-4(3H)-one; 6-iodo-2-propyloxy-3-[(tetrahydro-2-furanyl)methyl]-4(3H)-quinazolinone; 6-bromo-2-propyloxy-3-[(tetrahydro-2-furanyl)methyl]-4(3H)-quinazolinone; 6bromo-3-[(3-bromo-4,5-dihydro-5-isoxazolyl)methyl]-2-propoxy-4(3H)-quinazolinone; 6,7-dibromo-2-propoxy-3-propylthieno[3,2-d]pyrimidin-4(3H)-one; 6,8-diiodo-2-(propylthio)-3-[(tetrahydro-2-furanyl)methyl]-4(3H)-quinazolinone; and 3-(cyclopropylmethyl)-6-iodo-2-(propylthio)pyrido[2,3-d]pyrimidin-4(3H)-one.
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15]3[NH:19][C:18]([CH3:20])=[N:17][N:16]=3)=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([C:5]2[C:14]([C:15]3[NH:19][C:18]([CH3:20])=[N:17][N:16]=3)=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cc(-c2nnc(C)[nH]2)c(C2CCC2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Temperature: 50 °C
Yield: 113.8 %

Procedure:
To a solution of methyl 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoate (compound 152.7, 240 mg, 0.842 mmol) in methanol (5 mL) was added aqueous NaOH (6 mL, 1M). The resulting mixture was heated to 50° C. for 6 hours. After cooling to ambient temperature, the reaction mixture was acidified with 1N HCl to pH 2 and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to afford 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid (260 mg, quantitative) as a white solid. m/z (ES+) 272 (M+H)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.[NH4+:12].[OH-]>CC(C)=O>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH2:12])(=[O:10])=[O:9])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CC(C)=O
Product: NS(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-pyridinesulfonyl chloride hydrochloride (5.00 g) in acetone (8.5 ml) was added ammonia aqueous solution (28%, 8.5 ml) at 0° C. dropwise and stirred at room temperature for 3 hours. The solution was evaporated and poured into water (ca. 10 ml), ethyl acetate (100 ml) and tetrahydrofuran (100 ml). The organic layer was washed with brine twice and the aqueous layer was extracted with ethyl acetate (90 ml) and methanol (10 ml). The combined organic layer was dried over magnesium sulfate, evaporated and crystallized in hexane and ethyl acetate to give 3-pyridinesulfonamide (3.45 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]([NH:6][C@@H:7]1[C@@H:14]2[C@@H:10]([CH2:11][NH:12][CH2:13]2)[CH2:9][CH2:8]1)=[O:5].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:29]([N:12]1[CH2:13][C@@H:14]2[C@@H:7]([NH:6][C:4](=[O:5])[CH:3]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:2]([CH3:21])[CH3:1])[CH2:8][CH2:9][C@@H:10]2[CH2:11]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(C(=O)c3ccccc3)C[C@@H]21)c1ccccc1
Reaction time: 0.08 h

Procedure:
3-Methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A (25 mg, 0.087 mmol), triethylamine (0.018 mL, 0.131 mmol), and benzoyl chloride (10.12 μL, 0.087 mmol) were combined in dichloromethane (5 mL). After 5 minutes, TLC shows no more starting material. The crude reaction mixture was concentrated and applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS-4) eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 7.49-7.42 (m, 2H), 7.41-7.35 (m, 3H), 7.33-7.27 (m, 3H), 5.43 (d, J=6.7, 1H), 3.97 (m, 1H), 3.74 (m, 2H), 3.56 (m, 2H), 3.39 (m, 1H), 2.74 (m, 2H), 2.48 (m, 1H), 2.38 (m, 2H), 2.07 (dd, J=4.6, 10.8, 1H), 1.94 (m, 1H), 1.52-1.31 (m, 2H), 1.01 (d, J=6.3, 3H), 0.68 (d, J=6.6, 3H); MS (ESI+) m/z 391 (M+H)+.
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:8]1[C:17]([O:18][CH2:19][CH2:20][CH3:21])=[CH:16][C:15]2[C:14]([CH3:23])([CH3:22])[CH2:13][CH2:12][C:11]([CH3:25])([CH3:24])[C:10]=2[CH:9]=1)\[CH2:6]C)/[CH2:3][OH:4].C[N+]1([O-])CCOCC1>C(Cl)Cl.CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[F:1]/[C:2](=[C:5](/[C:8]1[C:17]([O:18][CH2:19][CH2:20][CH3:21])=[CH:16][C:15]2[C:14]([CH3:23])([CH3:22])[CH2:13][CH2:12][C:11]([CH3:24])([CH3:25])[C:10]=2[CH:9]=1)\[CH3:6])/[CH:3]=[O:4]
Reactant: CCCOc1cc2c(cc1/C(CC)=C(/F)CO)C(C)(C)CCC2(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88.1 %

Procedure:
A mixture of (E)-2-fluoro-3-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-pent-2-en-1-ol (Intermediate 7, 1.01 g, 3.04 mmol), NMO (0.89 g, 7.60 mmol), TPAP (catalytic amount), and 4 Å molecular sieves (200 mg) in CH2Cl2—CH3CN (40 mL, 8 mL) was stirred at ambient temperature for 45 min. The mixture was loaded onto a pad of silica gel and eluted with 10% EtOAc-hexane to give the tide compound as a pale yellow solid (890 mg, 89%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH3:15])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14].Cl.O.[OH-].[Na+]>CO>[CH3:1][O:2][NH:3][CH:4]([CH3:15])[CH2:5][C:6]1[C:7]([Cl:14])=[CH:8][C:9]([Cl:13])=[CH:10][C:11]=1[Cl:12]
Reactant: CON=C(C)Cc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CONC(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To 1-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime prepared as described in example P4 (53.9 g; assay 99%; 0.20 mol) in methanol (100 g) was added hydrogen chloride gas (22.0 g; 0.60 mol), whereas internal temperature in maintained at 20-30° C. by external cooling. A colourless suspension was obtained. The reaction mixture was cooled to 15° C. and triethylamino borane (borane triethylamine complex; 27.6 g; assay 96%; 0.23 mol) was dosed in during 60 min maintaining internal temperature at 15° C. The reaction mass was stirred for another 2 hours allowing the mixture to warm to ambient temperature. Thereafter almost no starting material can be detected by HPLC. The reaction mixture was then added to preheated (85° C.) water (126 g) during 30 min. A steady stream of gas was evolved; at the same time solvent was distilled. Heating was continued and the temperature maintained at 85-90° C. for another 1 hour. Finally gas was no longer produced. The resulting mixture was cooled to 20-25° C. Sodium hydroxide (30% aqueous solution; 56.5 g; 0.42 mol) was carefully added in order to bring pH to 7.2-7.7. The resulting mixture was extracted with tert-butyl methyl ether (125 ml). Phases were allowed to separate. The (lower) aqueous phase was split of. The (upper) organic phase was washed with water (2×100 g) and evaporated. Crude O-Methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (53.9 g; assay 97.8%; yield 98.0%) was obtained as clear oil.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9]([CH:12]2[CH2:17][CH2:16][CH2:15][NH2+:14][CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH3:3].[CH3:18][C:19]1[N:23]([CH2:24][C:25](O)=[O:26])[N:22]=[C:21]([C:28]([F:31])([F:30])[F:29])[CH:20]=1>>[CH3:18][C:19]1[N:23]([CH2:24][C:25]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:9]3[S:10][CH:11]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:8]=3)[CH2:13]2)=[O:26])[N:22]=[C:21]([C:28]([F:30])([F:29])[F:31])[CH:20]=1
Reactant: CCOC(=O)c1csc(C2CCC[NH2+]C2)n1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: [Cl-]
Product: CCOC(=O)c1csc(C2CCCN(C(=O)Cn3nc(C(F)(F)F)cc3C)C2)n1

Procedure:
3-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-2, 5.32 g) is reacted analogously to Example IV-1 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (4.00 g). This gives, after chromatographic purification, ethyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-3-yl)-1,3-thiazole-4-carboxylate (5.7 g, 69%).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([NH:10][CH3:11])[N:7]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O[C:25](=[O:27])[CH3:26])(=O)C>>[C:25]([N:10]([C:8]1[N:7]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:9]=1)[CH3:11])(=[O:27])[CH3:26]
Reactant: CNc1nc(C(C)(C)C)nn1-c1c(Cl)cc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(C)c1nc(C(C)(C)C)nn1-c1c(Cl)cc(Cl)cc1Cl
Yield: 73.2 %

Procedure:
6.7 g (0.02 mol) of 3-(tert-butyl)-5-(N-methylamino)-1-(2,4,6-trichlorophenyl)-1H-1,2,4-triazole was added to 51 g (0.5 mol) of acetic anhydride, and the mixture was stirred under reflux for 1 hour. Then, excess acetic anhydride was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5.5 g (yield: 73.3 g) of the desired compound as white powder. Melting point: 93°-94° C.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[C:5](I)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(NC(C)C)(C)C.[Si:30]([C:34]#[CH:35])([CH3:33])([CH3:32])[CH3:31]>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[C:5]([C:35]#[C:34][Si:30]([CH3:33])([CH3:32])[CH3:31])=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccccc3)noc2c1O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2c(-c3ccccc3)noc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (500 mg, 1.22 mmol), copper iodide (93 mg, 0.49 mmol), and PdCl2(PPh3)2 (171 mg, 0.24 mmol) were added to a flask and the flask evacuated. After refilling with nitrogen, THF (20 mL), diisopropylamine (1 mL) and TMS acetylene (0.35 mL, 2.44 mmol) were added and the resulting mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was partitioned between 25 mL of 1M hydrochloric acid and 25 mL of EtOAc. The aqueous layer was extracted with additional EtOAc and the combined organic layer was dried over MgSO4 and concentrated. The residue was purified flash chromatography (0-100% CH2Cl2/hexanes) to afford 405 mg of the title compound. MS: (+) m/z 381.35 (M+1).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]([F:25])([F:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[C:9]([CH3:26])[CH:8]=1.[B:27](OC)([O:30]C)[O:28]C>C1COCC1>[Si:17]([O:16][CH2:15][C:14]([C:10]1[C:11]([CH3:13])=[CH:12][C:7]([B:27]([OH:30])[OH:28])=[CH:8][C:9]=1[CH3:26])([F:25])[F:24])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: Cc1cc(Br)cc(C)c1C(F)(F)CO[Si](C)(C)C(C)(C)C
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)cc(C)c1C(F)(F)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.5 %

Procedure:
n-BuLi (1.6 M in hexanes, 1.236 ml, 1.977 mmol) was added to a solution of Intermediate 7C (500 mg, 1.318 mmol) in THF (5 ml) at −78° C. After 45 min, trimethyl borate (0.295 ml, 2.64 mmol) was added and the cooling bath was removed. The reaction mixture was warmed to rt, diluted with diethyl ether (300 mL), washed with 1.0 HCl, water and brine and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0 to 100% ethyl acetate in hexane over 30 min using a 12 g Isco column). Intermediate 7D (370 mg, 82% yield) was obtained as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm −0.03-0.02 (m, 6H) 0.82-0.88 (m, 9H) 2.57-2.63 (m, 6H) 4.10 (t, J=12.92 Hz, 2H) 7.86 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9](=[C:10]([C:21]4C=CC=CC=4)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.CC1C=CC=C2C=1NC(=O)C2=O.C(OCC(=O)CC1C=CC(Cl)=CC=1)(=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9](=[C:10]([CH3:21])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:27][CH:28]=1
Reactant: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c(-c3ccccc3)cccc12
Agent: CC(=O)OCC(=O)Cc1ccc(Cl)cc1
Agent: Cc1cccc2c1NC(=O)C2=O
Product: Cc1cccc2c(C(=O)O)c(O)c(Cc3ccc(Cl)cc3)nc12
Yield: 38 %

Procedure:
This compound was synthesized by the procedure described above for Compound 2, reacting 7-methyl-1H-indole-2,3-dione (1.00 g, 6.21 mmol) with intermediate 2 (1.76 g, 7.76 mmol). The crude acid was purified as described above for Compound 3 to give Compound 6 as a bright yellow powder (0.774 g, 38% yield): 1H NMR (400 MHz, DMSO-D6) δ 2.65 (s, 3H) 4.33 (s, 2H) 7.35 (m, 4H) 7.44 (m, 2H) 8.30 (dd, J=8.1, 1.3 Hz, 1H).