Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[C:12]([Cl:19])[CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:31][CH2:32][CH2:33][CH2:34]Br>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:17]#[N:18])[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:12]([Cl:19])[CH:11]=1
Reactant: N#CCc1ccc(-c2nc3ccccc3o2)cc1Cl
Reactant: BrCCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(-c3nc4ccccc4o3)cc2Cl)CCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of [4-(1,3-benzoxazol-2-yl)-2-chlorophenyl]acetonitrile (270 mg, 1.0 mmol) and THF (20 mL) was cooled to −78° C. A solution of NaHMDS (3.7 mL, 2.2 mmol, 0.6M solution in PhMe) was added dropwise via syringe to the reaction. After 15 min at −78° C., 1,4-dibromobutane (143 μL, 1.2 mmol) was added dropwise via syringe. The cooling bath was removed, and the reaction was allowed to warm to rt. The reaction was quenched by the addition of silica gel (600 mg) and concentrated to dryness. The residue was purified by flash chromatography on silica gel (EtOAc:hexanes 1:5) to afford the desired 1-[4-(1,3-benzoxazol-2-yl)-2-chlorophenyl]cyclopentanecarbonitrile as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.34 (s, 1H), 8.12 (dd, 1H), 7.77–7.80 (m, 1H), 7.56–7.62 (m, 2H), 7.35–7.42 (m, 2H), 2.71–2.78 (m, 2H), 2.14–2.26 (m, 2H), 1.89–2.01 (m, 4H). MS (ESI) 323 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[K+]>CO.O>[O:12]1[C:13]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=2[N:10]=[CH:11]1
Reactant: COC(=O)c1cccc2ncoc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc2ncoc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 0.21 g (1.18 mmol) of methyl-7-benzoxazole carboxylate in 6 mL of CH3OH at 0° C. was added 2.9 mL of a 1N solution of KOH in water and the reaction mixture was stirred at rt for 1 h. The reaction mixture was partitioned between water and CH2Cl2. The aqueous fraction was made acidic with 1N HCl solution and extracted with CH2Cl2. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated to give 0.17 g of the title compound as a yellow solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]([CH2:31][CH3:32])[C:20]3[C:25]([C:26]=2[C:27]#[N:28])=[CH:24][CH:23]=[C:22]([O:29][CH3:30])[CH:21]=3)=[CH:14][CH:13]=1)[S:8]([CH3:11])(=[O:10])=[O:9])(=O)C.O.[OH-].[Li+].C(OCC)(=O)C>C1COCC1>[C:27]([C:26]1[C:25]2[C:20](=[CH:21][C:22]([O:29][CH3:30])=[CH:23][CH:24]=2)[N:19]([CH2:31][CH3:32])[C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([N:7]([CH2:6][CH2:5][OH:4])[S:8]([CH3:11])(=[O:10])=[O:9])=[CH:17][CH:16]=1)#[N:28]
Reactant: CCn1c(-c2ccc(N(CCOC(C)=O)S(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1c(-c2ccc(N(CCO)S(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 60 °C
Yield: 91.9 %

Procedure:
A mixture of N-(2-acetoxyethyl)-N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide (compound 815, 164 mg, 0.360 mmol) and lithium hydroxide hydrate (45 mg, 1.07 mmol) in 5 mL THF/1 mL water was warmed to 60° C. overnight. The mixture was cooled and poured into ethyl acetate (50 mL). This was washed with water (50 mL) and brine (20 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to afford a solid. The solid was triturated with ether, collected by filtration and dried under high vacuum to afford N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-(2-hydroxyethyl) methanesulfonamide, compound 828 (137 mg, 0.331 mmol, 92%).
Reaction SMILES: Cl[C:2]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]=[C:5]1Cl)=[O:3].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]#[CH:22])=[CH:14][C:13]=1[NH:23][NH:24]C=O.C(N(CC)CC)C.O>C(#N)C>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]#[CH:22])=[CH:14][C:13]=1[N:23]1[C:2](=[O:3])[N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]2=[N:24]1
Reactant: C#CCOc1cc(NNC=O)c(Cl)cc1Cl
Reactant: O=C(Cl)N1CCCC=C1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#CCOc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl
Reaction time: 1 h

Procedure:
N-Chlorocarbonyl-2-chloro-1,4,5,6-tetrahydro-pyridine (4.32 g, 0.024 mol) dissolved in 20 ml acetonitrile are added to a stirred suspension of formic acid N'-(2,4-dichloro-5-(2-propinyloxy)-phenyl) hydrazide (5.18 g, 0.02 mol) in 250 ml acetonitrile at 0°-10° C. for 20 minutes. This is then reacted at the same temperature with triethylamine (4.04 g, 0.04 mol) and dissolved in 20 ml acetonitrile. This is stirred for one hour at 5°-10° C. and a colourless precipitate precipitates out. This is heated for 4 hours to 50°-55° C. and then stirred for one night at room temperature. The batch is reacted with 30 ml 6N hydrochloric acid and stirred for 1 hour at 50° C. The solvent is drawn off under reduced pressure and the residue digested with iced water. The resultant pale grey precipitate is separated by filtration, washed with water and dried at 50°-60° C. Yield: 6.6 g (=97.6%) Melting point: 160°-162° C.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[C:17]([NH:25][CH3:26])[N:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([NH:4][CH:1]([CH3:3])[CH3:2])[C:18]([N+:22]([O-:24])=[O:23])=[C:17]([NH:25][CH3:26])[N:16]=1
Reactant: CNc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNc1nc(Cl)nc(NC(C)C)c1[N+](=O)[O-]
Yield: 82.1 %

Procedure:
Isopropylamine (4.5 ml) and N,N-diisopropylethylamine (13.2 ml) were dissolved into 150 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitro-6-methylaminopyrimidine (11.5 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for half an hour. Purification was conducted by a column chromatography to obtain a yellow solid (10.4 g) in a yield of 82.1%. 1H NMR (400 MHz, CDCl3): δ8.17 (s, 1H), 4.48 (m, 1H), 2.78 (s, 3H), 1.31 (d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]([C:12](Cl)=[O:13])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[CH2:22]([OH:28])[CH2:23][CH2:24][CH2:25][C:26]#[CH:27].O>CCOCC>[CH2:1]([C:9]1[CH:10]([C:12]([OH:13])=[O:28])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:27][CH2:26][CH2:25][CH2:24][C:23]#[CH:22]
Reactant: CCCCCCCCC1=CC1C(=O)Cl
Reactant: C#CCCCCO
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: C#CCCCC
Product: CCCCCCCCC1=CC1C(=O)O
Temperature: 25 °C
Yield: 9.6 %

Procedure:
To a solution of 2-octylcycloprop-2-ene-1-carbonyl chloride (330 mg, 1.5 mmol) in 5 ml of ether is added 1.5 ml of triethylamine. 5-Hexyn-1-ol (0.18 g, 1.8 mmol) was added to the reaction mixture, which was stirred at room temperature over the weekend. Water and additional ether were added, and the resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was washed with water and brine, dried over MgSO4, filtered and stripped. The product was chromatographed on silica gel to give 40 mg of 60% pure hex-5-yne 2-octylcycloprop-2-ene-1-carboxylate containing roughly 40% 2-octylcycloprop-2-ene-1-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+].CN(C)C=O>O>[C:17]1([S:23][C:2]2[CH:15]=[CH:14][C:13]3[S:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5](=[O:16])[C:4]=3[CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1c2ccccc2sc2ccc(Cl)cc12
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ccccc2sc2ccc(Sc3ccccc3)cc12
Temperature: 25 °C
Yield: 45 %

Procedure:
After mixing 11.0 parts of 2-chlorothioxanthone, 4.9 parts of thiophenol, 2.5 parts of potassium hydroxide, and 162 parts of N,N-dimethylformamide uniformly and then making them react at 130° C. for 9 hours, the reaction solution was cooled to room temperature (about 25° C.) and then was poured into 200 parts of distilled water, so that the product was precipitated. This was filtered and the residue was washed with water until the pH of the filtrate became neutral. Then the residue was dried under reduced pressure, affording a yellow powdery product. The product was purified by column chromatography (eluate:toluene/hexane=1/1:volume ratio) to afford 2-(phenylthio)thioxanthone in a yield of 45%. The product was identified by 1H-NMR {d6-dimethyl sulfoxide, δ (ppm) 8.43 (1H, d), 8.25 (1H, s), 7.75-7.90 (3H, m), 7.66 (1H, d), 7.60 (1H, t), 7.42-7.46 (5H, m)}.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[CH3:29][NH:30][CH3:31].[BH4-].[Na+]>>[CH3:29][N:30]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([CH:13]2[NH:12][C:7]3[C:6]4[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=4[CH:10]=[CH:9][CH:8]=3)[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:22][CH:23]=1)[CH3:31]
Reactant: CNC
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
4-(3-Oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (59 mg, 0.16 mmol) and dimethylamine (5 mL) were added and the mixture was stirred at room temperature for 2 h. Then 20 mg of sodium borohydride was added and stirred for another 2 h. The resulting mixture was evaporated under reduced pressure and purified by prep-HPLC to give 8-(4-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (20 mg, yield 32%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.18 (s, 6H), 4.28-4.30 (d, J=8 Hz, 1H), 4.72-4.74 (d, J=8 Hz, 1H), 7.06-7.08 (m, 2H), 7.13-7.20 (m, 6H), 7.23-7.25 (m, 2H), 7.54-7.65 (m, 2H). LC-MS (ESI) m/z: 397 (M+1)+.
Reaction SMILES: CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.Cl.[N:32]1([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:59]=[CH:58][C:45]([C:46]([N:48]3[CH2:56][C:55]4[C:50](=[CH:51][CH:52]=[C:53]([NH2:57])[CH:54]=4)[CH2:49]3)=[O:47])=[CH:44][CH:43]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.Br[CH2:61][CH2:62][CH2:63][C:64]([Cl:66])=[O:65]>C(Cl)Cl>[ClH:66].[N:32]1([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:43]=[CH:44][C:45]([C:46]([N:48]3[CH2:56][C:55]4[C:50](=[CH:51][CH:52]=[C:53]([N:57]5[CH2:61][CH2:62][CH2:63][C:64]5=[O:65])[CH:54]=4)[CH2:49]3)=[O:47])=[CH:58][CH:59]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Nc1ccc2c(c1)CN(C(=O)c1ccc(OCCCN3CCCCC3)cc1)C2
Reactant: O=C(Cl)CCCBr
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Agent: Cl
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1ccc(OCCCN2CCCCC2)cc1)N1Cc2ccc(N3CCCC3=O)cc2C1
Reaction time: 2 h

Procedure:
A stirred mixture of diethylaminomethyl polystyrene (247 mg, 3.2 mmol/g) and N-[4-(3-piperidin-1-ylpropoxy)-benzoyl]-5-aminoisoindoline hydrochloride (E13) (150 mg) in DCM (5 ml) at rt was treated with 4-bromobutanoyl chloride (0.05 ml) for 30 mins. The mixture was filtered and evaporated. The residue was redissolved in DMF (5 ml) and treated with sodium hydride (18 mg of a 60% suspension in mineral oil) and stirred for 2 h. A further portion of sodium hydride (18 mg) was added and the mixture stirred for 1 h. The reaction was partitioned between EtOAc (10 ml) and saturated sodium hydrogen carbonate solution (10 ml). The organic layer was washed with water (2×10 ml), brine (10 ml), dried (MgSO4) and evaporated. After chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)] fractions containing the required product were evaporated, then redissolved in DCM, treated with excess 4M HCl in dioxan and evaporated. Crystallisation from EtOH/diethyl ether afforded the title compound (E15) (77 mg). MS electrospray (+ion) 448 (MH+). 1H NMR δ (DMSO-d6): 10.15 (1H, s), 7.60 (4H, m), 7.34 (1H, m), 7.0 (2H, d, J=8.5 Hz), 4.80 (4H, m), 4.13. (2H, t, J=6 Hz), 3.80 (2H, m), 3.05-3.58 (6H, m), 2.91 (2H, m), 2.21 (2H, m), 2.06 (2H, m), 1.28-1.90 (6H, m).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([OH:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][C:12]1=[C:13]([CH3:19])[C:14]([O:16][C:17]1=O)=[O:15]>C(O)(=O)CC>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([OH:10])=[CH:5][C:3]=1[N:4]1[C:14](=[O:15])[C:13]([CH3:19])=[C:12]([CH3:11])[C:17]1=[O:16]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: Nc1cc(O)c(Cl)cc1F
Solvent: CCC(=O)O
Product: CC1=C(C)C(=O)N(c2cc(O)c(Cl)cc2F)C1=O
Reaction time: 12 h
Yield: 101.6 %

Procedure:
A mixture of 16.1 g of 2-fluoro-4-chloro-5-hydroxyaniline and 12.6 g of dimethylmaleic acid anhydride in 100 ml of propionic acid are heated to 150° and stirred for 12 hours at that temperature. The reaction mixture is then allowed to cool and concentrated. The residue is cristallized from methanol and yields 27.3 g of N-(2-fluoro-4-chloro-5-hydroxyphenyl)-2,3-dimethylmaleic acid imide melting at 170°-171°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[PH:22](=[O:24])[OH:23])([O-:3])=[O:2].[PH2](Cl)=O.O[N:29]=[C:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[PH:22]([O:23][N:29]=[C:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:24])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[PH](=O)O
Reactant: CCOC(=O)C(C)=NO
Agent: O=[PH2]Cl
Product: CCOC(=O)C(C)=NO[PH](=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 1, the phosphinic acid is halogenated to the corresponding phosphinic chloride, which is then reacted with ethyl 2-hydroxyiminopropionate to yield ethyl 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxyimino]propionate.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:40]([C:42]1[CH:51]=[C:50]2[C:45]([CH:46]=[C:47]([C:54]3[CH:55]=[C:56]([NH:61]/[C:62](/[NH2:65])=[N:63]/O)[CH:57]=[CH:58][C:59]=3[CH3:60])[C:48](=[O:53])[N:49]2[CH3:52])=[CH:44][N:43]=1)[CH3:41]>CN(C=O)C>[CH2:40]([C:42]1[CH:51]=[C:50]2[C:45]([CH:46]=[C:47]([C:54]3[CH:55]=[C:56]([NH:61][C:62]4[N:63]=[C:1]([CH:2]([CH3:4])[CH3:3])[O:6][N:65]=4)[CH:57]=[CH:58][C:59]=3[CH3:60])[C:48](=[O:53])[N:49]2[CH3:52])=[CH:44][N:43]=1)[CH3:41]
Reactant: CCc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: CC(C)C(=O)O
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: CCc1cc2c(cn1)cc(-c1cc(Nc3noc(C(C)C)n3)ccc1C)c(=O)n2C
Temperature: 100 °C

Procedure:
To a solution of isobutyric acid (8 μL, 0.09 mmol) in DMF (1 mL) were added DIPEA (16 μL, 0.09 mmol) and HATU (33 mg, 0.09 mmol). After stirring at rt for 15 min 17a (30 mg, 0.09 mmol) was added as a solution in DMF (0.5 mL). The reaction was stirred at rt until complete consumption of 17a was determined by LC/MS and then heated at 100° C. for 1 h. Subsequently the reaction was cooled to rt, filtered and purified by preparative LC/MS to give 7-ethyl-3-(5-(5-isopropyl-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (A104). 1H NMR (400 MHz, d6-DMSO) δ 9.91 (s, 1H), 9.10 (s, 1H), 8.05 (s, 1H), 7.78 (s, 1H), 7.41 (dd, J=8, 2 Hz, 1H), 7.33 (d, J=2 Hz, 1H), 7.23 (d, J=8 Hz, 1H), 3.72 (s, 3H), 3.19 (m, 1H), 3.01 (q, J=7.6 Hz, 2H), 2.08 (s, 3H), 1.36 (t, J=7.6 Hz, 3H), 1.31, (d, J=6.8 Hz, 6H). MS m/z 404.1 (M+1).
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[I:1]
Reactant: N#Cc1ccc(N)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: N#Cc1ccc(N)c(I)c1
Yield: 35.8 %

Procedure:
4-amino-3-iodobenzonitrile was prepared according to method D Step I with Iodine (0.645 g; 2.54 mmol), silver sulphate (0.791 g; 2.54 mmol) and 4-aminobenzonitrile (0.300 g; 2.54 mmol) in ethanol (10 mL). The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40% ethyl acetate in heptane) to yield 0.222 g (36%) of 4-amino-3-iodobenzonitrile as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][SH:12])=[CH:9][CH:8]=1)[CH2:4][CH3:5].[C:15]([N:19]1[C:24](=[O:25])[C:23]([CH3:26])=[C:22](Cl)[CH:21]=[N:20]1)([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O>[C:15]([N:19]1[C:24](=[O:25])[C:23]([CH3:26])=[C:22]([S:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:3][CH2:4][CH3:5])=[CH:14][CH:13]=2)[CH:21]=[N:20]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Reactant: CCCOc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2C)cc1
Yield: 46.3 %

Procedure:
To 5 ml of dry N,N-dimethylformamide was added 0.24 g of 55% sodium hydride. The resulting mixture was kept at 0° C. and added dropwise with a solution of 0.91 g of p-propoxybenzyl mercaptan dissolved in 5 ml of N,N-dimethylformamide. After ten minutes passed, the resulting mixture was added dropwise with a solution of 1.0 g of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone dissolved in 5 ml of N,N-dimethylformamide. After completion of dropwise addition, the resulting mixture was reacted at room temperature for four hours. The resulting solution was poured into 50 ml of water and extracted twice with 50 ml of diethyl ether. The resulting organic layer was dried over anhydrous sodium sulfate, and freed of solvent by distillation under reduced pressure to give 1.7 g of crude product. The crude product was fractionated on thin layer chromatography to obtain 0.8 g of 2-t-butyl-4-methyl-5-(p-propoxybenzylthio)-3(2H)-pyridazinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH3:26][N:27]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:23])([F:24])[F:25])[CH:16]=2)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1cccc(C)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N(C)C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)n1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (100 mg, 0.24 mmol), methyl-(6-methyl-pyridin-2-yl)-amine (88 mg, 0.72 mmol), BOP (137 mg, 0.31 mmol), DIEA (265 L, 1.44 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methyl-(6-methyl-pyridin-2-yl)-amide: MS m/z: 519.0 (M+H).
Reaction SMILES: NO.[CH:3](=[O:7])[CH:4]([CH3:6])[CH3:5].C([Zn][CH2:11][CH3:12])C.[C:13](OC(=O)C)(=[O:15])[CH3:14]>CCCCCC.C1(C)C=CC=CC=1.ClC1C=CC=CC=1>[C:13]([O:7][CH:3]([CH2:11][CH3:12])[CH:4]([CH3:6])[CH3:5])(=[O:15])[CH3:14]
Reactant: CC(C)C=O
Reactant: CC[Zn]CC
Reactant: CC(=O)OC(C)=O
Agent: NO
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Solvent: CCCCCC
Product: CCC(OC(C)=O)C(C)C
Reaction time: 48 h
Yield: 100 %

Procedure:
A vial was charged with aminoalcohol 1 (0.0067 g, 0.023 mmol) prepared as in Example 1. To the vial was added 1.45 mL of a stock solution containing freshly distilled isobutyraldehyde (0.22 g), chlorobenzene internal standard (0.22 g), 1 M diethylzinc in hexane (6.0 mL), and toluene (3.0 mL). After 48 h, acetic anhydride (0.200 mL) was added. After an additional 72 h, a sample of the solution was analyzed by gas chromatography at 70° C. on a Cyclodex B stationary phase. The product 3-acetoxy-2-methylpentane was formed in 100% yield and 97% enantiomeric excess. The identity and yield of the product was established by comparison with an authentic sample prepared by treatment of racemic 2,2-dimethyl-3-pentanol with acetic anhydride.
Reaction SMILES: [C:1]([C:3]12[CH2:10][N:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2)#[CH:2].[N:11]([Si](C)(C)C)=[N+:12]=[N-:13].[CH3:18]O>O1CCCC1>[CH3:18][N:12]1[N:13]=[C:1]([C:3]23[CH2:10][N:7]([CH2:8][CH2:9]2)[CH2:6][CH2:5][CH2:4]3)[CH:2]=[N:11]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#CC12CCCN(CC1)C2
Reactant: CO
Solvent: C1CCOC1
Product: Cn1ncc(C23CCCN(CC2)C3)n1
Reaction time: 0.25 h

Procedure:
A solution of 5-ethynyl-1-azabicyclo[3.2.1]octane (D6) (1 g, 0.0074 mol) in tetrahydrofuran (5 ml) was treated with azidotrimethylsilane (1.27 g, 0.011 mol) at 140° C. for 8 h in a PTFE lined autoclave. The reaction was then cooled and treated with methanol (30 ml). The solution was then concentrated in vacuo to a brown gum. The gum was then taken up in methanol (30 ml) and treated with diazomethane in ether (excess) and allowed to stand for 15 min at 20° C. The reaction mixture was then concentrated in vacuo to a gum and chromatographed on neutral alumina in a gradient of 10-40% methanol in ethyl acetate. Elution with 15% methanol in ethyl acetate afforded the required product as a gum which slowly crystallised on standing. Recrystallisation from petrol afforded the title compound (EI, 99mg, 7%) as needles.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([OH:15])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.CN(C=O)C.N1C=CN=C1.[CH:27]([Si:30](Cl)([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28]>O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([OH:15])=[CH:11][C:12]([O:14][Si:30]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:27]([CH3:29])[CH3:28])=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COC(=O)Cc1csc2cc(O)cc(O)c12
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1csc2cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(O)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of methyl(4,6-dihydroxy-1-benzothiophen-3-yl)acetate (7.7 g) and DMF (dry) (150 mL) was added imidazole (4.40 g) at room temperature, and the mixture was added slowly triisopropylsilyl chloride (7.61 mL) over a period of 20 min, and the mixture was stirred at room temperature for 48 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (8.10 g).