Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[C:11]1([N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>O>[C:24]1([N:17]([C:11]2[CH:12]=[CH:13][C:14]([CH:8]=[O:9])=[CH:15][CH:16]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(C)C=O
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
Phosphorus oxychloride (MW 153, 0.129M, 19.7 g) was added dropwise to dimethylformamide ("DMF") (MW 73, 0.774M, 56.5 g) maintaining the temperature at <10° C. with external cooling. Triphenylamine (MW 245, 0.129M, 31.5 g) was added and the reaction mixture stirred at 100° C. for 1 hour. After cooling to room temperature and pouring into water (500 ml), the suspension was neutralised to pH 6 with saturated sodium acetate solution. The suspension was filtered off and washed with water, then redissolved in dichloromethane and dried over MgSO4 before screening through Silica gel (MERCK 60H Art 7736) and solvent removed under reduced pressure to give 27.5 g of 4-(N,N-diphenylamino) benzaldehyde (78% yield) as a yellow solid, m.p. 132°-133° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[OH:10]O>CC(O)=O.O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][N+:3]=1[O-:10]
Reactant: OO
Reactant: Cc1cnc(C)c(C)c1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)c(C)[n+]([O-])c1
Temperature: 100 °C

Procedure:
To a solution of 3,5-lutidine (42.86, 0.400 mol) in toluene (240 ml) in a three-neck flask, under N2 atmosphere, was added dropwise MeLi [0.33M in ether, 1330 ml (0.44 mol), prepared from CH3I and Li or obtained from Aldrich]. The reaction was stirred and heated at 60°-80° C. for 6 h, after which time the ether was distilled off. The remaining solution was poured into water/crushed ice (200 ml), acidified with conc. HCl and extracted with ethyl acetate (2×100 ml). The aqueous solution then was basified with aq. NaOH and extracted with CH2Cl2 (3×100 ml). The CH2Cl2 extracts were combined, washed with sat. NaCl solution (1×50 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was distilled under reduced pressure to give 2,3,5-trimethylpyridine (35.24 g, 72%) as a pale oil; bp 65°-71° C./11 mmHg. A solution of 2,3,5-trimethylpyridine (36.35 g, 0.30 mol) in AcOH (120 ml) was treated with 30% H2O (45 ml) and the mixture heated at 100° C. for 3 h. An additional aliquot of 30% H2O2 (15 ml) was added and the mixture was heated for an additional 10 h at 100° C. The reaction was cooled to rt, diluted with water (100 ml) and concentrated in vacuo. The residue again was diluted with water (200 ml), neutralized with KOH pellets and extracted with CH2Cl2 (3×100 ml). The extracts were combined, washed with sat. NaCl (1×50 ml), dried (MgSO4) and the solvent removed in vacuo to give 2,3,5-trimethylpyridine-N-oxide as a pale yellow solid, (50 g, quant.); mp 41°-42° C. (hexanes, colorless needles).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH:18]([C:22](=O)[CH3:23])[C:19](=O)[CH3:20])=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:2]2[N:1]=[C:22]([CH3:23])[C:18]([S:17][C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=3)=[C:19]([CH3:20])[C:3]=2[C:4]([OH:9])=[CH:5][CH:6]=1
Reactant: Nc1cc(O)ccc1Cl
Reactant: CC(=O)C(Sc1ccc(Cl)cc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc2c(Cl)ccc(O)c2c(C)c1Sc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-amino-4-chlorophenol (5.0 g), 3-(4-chlorophenylsulfanyl)pentane-2,4-dione (8.4 g), p-toluenesulfonic acid monohydrate (3.20 g) and toluene (150 mL) was heated at reflux for 2 days. The mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and cyclohexane (1:9 by volume) gave title compound as a pale yellow solid, 0.99 g.
Reaction SMILES: COC1C=CC(C[S:8][C:9]2[C:14](=[O:15])[N:13]3[C:16]4([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[NH:17][C:18](=[O:19])[C:12]3=[C:11]([CH3:25])[CH:10]=2)=CC=1.CS(O)(=O)=O.O>C(Cl)(Cl)Cl>[SH:8][C:9]1[C:14](=[O:15])[N:13]2[C:16]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:17][C:18](=[O:19])[C:12]2=[C:11]([CH3:25])[CH:10]=1
Reactant: COc1ccc(CSc2cc(C)c3n(c2=O)C2(CCCCC2)NC3=O)cc1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(S)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 6′-((4-methoxybenzyl)thio)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (3, 3.3 g, 8.58 mmol) in chloroform (40 mL) is added methanesulfonic acid (3 mL, 46.23 mmol). The reaction is stirred at 50° C. overnight. The resulting mixture is cooled to room temperature, poured into water and extracted with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated. The crude is purified via column chromatography to afford 6′-mercapto-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (4).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Yield: 88.6 %

Procedure:
To a solution of 1.67 g (19.14 mmol) of morpholine in 50 ml of dry pyridine was added 3.26 g (12.76 mmol) of 4-bromobenzenesulfonyl chloride in an atmosphere of argon, and the mixture was allowed to react at 0° C for 3 hours. To the solution was added water followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane yielded 3.45 g (11.3 mmol) of N-(4-bromobenzenesulfonyl)morpholine.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([OH:18])[CH:14]=[CH:15][C:16]=1[F:17].C([O-])([O-])=O.[K+].[K+]>>[F:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=1[F:17])[O:18][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1
Temperature: 25 °C

Procedure:
4-Fluorobenzaldehyde (5.32 mL, 49.6 mmol), 3,4-difluorophenol (7.10 g, 54.6 mmol) and K2CO3 (8.31 g, 60.1 mmol) were combined in a flask, which was immediately flushed with argon. DMF (50.0 mL) was added and the mixture was heated at reflux under argon for 6 h. Upon cooling to room temperature, EtOAc (100 mL) and H2O (100 mL) were added; the ethyl acetate layer was separated and washed with H2O (2×100 mL). The combined organic layers were washed with brine, dried over MgSO4, and the solvent was removed in vacuo. The desired product was obtained (11.4 g, 98.0%): 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 7.88 (dd, 2H, J=0.8 Hz, 8.8 Hz) 7.24–7.17 (m, 1H), 7.07 (d, 2H, J=8.8 Hz), 6.97–6.92 (m, 1H), 6.86–6.82 (m, 1H); ESMS m/e: 235.0 (M+H)+.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:4]([C:15]#[N:16])=[C:5]([C:9]([Cl:14])=[C:10]([Cl:13])[C:11]=1[Cl:12])[C:6]([OH:8])=[O:7].S(OC)(O[CH3:21])(=O)=O.[OH-].[Na+]>C(C(C)=O)C.O>[Cl:2][C:3]1[C:4]([C:15]#[N:16])=[C:5]([C:9]([Cl:14])=[C:10]([Cl:13])[C:11]=1[Cl:12])[C:6]([O:8][CH3:21])=[O:7]
Reactant: COS(=O)(=O)OC
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: O
Product: COC(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N
Yield: 93 %

Procedure:
A reaction vessel is charged in succession with 360 g of water, 475 g of methyl ethyl ketone and 307 g (1.0 mole) of the sodium salt (dry) of 3,4,5,6-tetrachloro-2-cyanobenzoic acid. With stirring, the mixture is heated to 72°-74° C. and to the suspension so obtained are added, at this temperature and over 1 hour, 189 g of dimethyl sulfate (1.5 moles), while keeping the pH at 5.0-5.5 by the gradual addition of 66 g (0.5 mole) of 30% sodium hydroxide solution. The reaction mixture is then stirred for 1 hour at reflux temperature (72°-74° C.). Conventional working up affords a yield of 93% of theory of methyl 3,4,5,6-tetrachloro-2-cyanobenzoate, based on the sodium salt of 3,4,5,6-tetrachloro-2-cyanobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:11]=1[N+:24]([O-:26])=[O:25].[CH3:27][O:28][CH2:29][CH:30]([NH2:32])[CH3:31]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:32][CH:30]([CH3:31])[CH2:29][O:28][CH3:27])[C:11]=1[N+:24]([O-:26])=[O:25]
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(Cl)c1
Reactant: COCC(C)N
Product: COCC(C)Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-]
Yield: 68.6 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.48 g, 1.16 mmol), prepared substantially as described in Part C of Example 19a, and 2-methoxy-1-methyl-ethylamine (0.21 g, 2.32 mmol) were treated substantially as described in Part C of Example 19a to produce 0.28 g (68%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine: MS (AP) m/z 351.8 [(M+H)+, 90].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10]>C(O)(=O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:10][CH2:9][C:8]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Nc1ccccn1
Reactant: C=CC(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)CCNc1ccccn1
Temperature: 88 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
200 g (2.12 mol) of 2-aminopyridine and 346 mL (3.18 mol) of ethyl acrylate were dissolved in 53 mL of acetic acid. The mixture was heated to 88° C. and stirred overnight at the same temperature. Solvent was removed under vacuum, and the title compound was purified by column chromatography, eluting with ethyl acetate, to obtain 358 g of ethyl 3-(2-pyridylamino)propionate as a pale red solid. Yield: 86.7%.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]([C:28]3[CH:36]=[C:35]([O:37][CH3:38])[C:31]4[O:32][CH2:33][O:34][C:30]=4[CH:29]=3)[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[O:26][CH3:27])(=[O:18])=[O:17])=[O:14])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CN(C)[CH:41]=[O:42]>CCCCCC.O1CCCC1>[CH:41]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]([C:28]3[CH:36]=[C:35]([O:37][CH3:38])[C:31]4[O:32][CH2:33][O:34][C:30]=4[CH:29]=3)[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[O:26][CH3:27])(=[O:18])=[O:17])=[O:14])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1)=[O:42]
Reactant: CN(C)C=O
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(Br)ccc12
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(C=O)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Butylithium (0.8 ml of 2.5M solution in hexane) was added to a stirred solution of 6-bromo-3-{1-(7-methoxy-1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-indole (from Example 92, 400 mg, 0.67 mmol) in anhydrous tetrahydrofuran at -75° C. under a nitrogen atmosphere. After 30 minutes dimethylformamide (0.15 ml) was added to the orange solution, and after a further 30 minutes the mixture was allowed to warm at 0° C. before quenching with excess 1N hydrochloric acid. Ethyl acetate was added and the organic layer was separated and washed with water. The organic layer was dried (magnesium sulphate), and the solvents removed in vacuo. The residue was flash chromatographed using 1% methanol in dichloromethane as eluant, and the product was crystallised from dichloromethane and diethyl ether mixture to give the title compound (187 mg).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[S:23]([O:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)([CH3:22])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylamine (8.8 ml) was added to a stirred mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (European Patent Application No. 0 495 750, Chem. Abstracts, Vol. 117, Abstract 191869g, 6.38 g), methanesulphonyl chloride (3.7 ml) and methylene chloride (70 ml) which had been cooled to 0° C. The mixture was stirred at 0° C. for 2 hours and then evaporated. The residue was partitioned between ethyl acetate and a concentrated aqueous citric acid solution. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using ethyl acetate as eluent to give tert-butyl 4-mesyloxypiperidine-1-carboxylate (7.82 g).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.[CH:10]1([CH:13]=[O:14])[CH2:12][CH2:11]1.O>C1COCC1>[Cl:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH:13]([CH:10]2[CH2:12][CH2:11]2)[OH:14])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)ccnc1Br
Reactant: O=CC1CC1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)ccnc1C(O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
A solution of 2-bromo-4-chloro-3-methylpyridine (7 g, 28.1 mmol) in dry THF (150 mL) was cooled down to 0° C. An isopropyl magnesium chloride-Lithium chloride complex (26 mL, 33.8 mmol) was added carefully so temperature would not rise above 5° C. during the addition. The mixture was allowed to warm up to room temperature and was stirred for 1 h. The reaction mixture was cooled down to 0° C. and cyclopropane carboxaldehyde (2.5 mL, 33.5 mmol) was added carefully so temperature would not rise above 5° C. during the addition. The mixture was allowed to warm up to room temperature and was stirred for 1 h. The reaction mixture was cooled to 0° C. and water (150 mL) was added carefully so temperature would not rise above 10° C. during the addition. The mixture was allowed to warm up to room temperature and was stirred for 1 h. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with brine (100 mL), dried over sodium sulfate and evaporated. The residue was purified by flash chromatography over silica gel (0-30% ethyl acetate in heptane) yielding a yellow oil (3.47 g, 16.8%).
Reaction SMILES: CNCCN(C)C.[Li]CCCC.[CH:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[Li]C1C=CC=CC=1.[Cl:30]C(Cl)(Cl)C(Cl)(Cl)Cl>C1(C)C=CC=CC=1.C1COCC1>[Cl:30][C:15]1[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]=[O:22]
Reactant: COc1cccc(C=O)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CNCCN(C)C
Agent: [Li]CCCC
Agent: [Li]c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cccc(C=O)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a sol. of N,N′,N′-trimethylethylendiamine (2.77 g, 21.4 mmol) in toluene (50 mL) was added BuLi (13.0 mL, 20.8 mmol) dropwise at 0° C. After stirring for 15 min at 0° C., m-anisaldehyde (2.44 g, 20 mmol) was added, and the mixture was stirred 30 min at 0° C. PhLi (30 mL, 60 mmol) was then added at 0° C., and the mixture was stirred at rt for 4 h. The mixture was cooled to −30° C., and 25 mL THF were added followed by hexachloroethane (14.2 g, 60 mmol) in THF (25 mL). The cooling bath was removed and the mixture was stirred for 3 h. Then it was poured with stirring onto aq. 5M HCl (20 mL). The aq. layer was extracted with EtOAc (2×). The combined org. extracts were washed successively with aq. 1M NaOH, aq. 1M HCl, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 5:95→1:9) afforded the desired aldehyde, which was further purified by crystallization (EtOAc/heptane, 0° C.) to give 1.50 g of pure title product. LC-MS: tR=0.88 min.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]N(C)C=O.CN(C1C=CC=CN=1)C.C(N=C=NCCCN(C)C)C>CO.C(Cl)(Cl)Cl>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:2]=1[Cl:1]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C)nc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Chloro-6-methylnicotinic acid (25.0 g) was suspended in a mixed solvent of dimethylformamide (100 mL) and chloroform (100 mL), and to this suspension were added dimethylaminopyridine (21.3 g) and methanol (4.67 g). Finally, 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (WSC) hydrochloride (33.5 g) was added to the mixture, followed by stirring at room temperature for 6 hours. After the reaction mixture was concentrated, ethyl acetate (300 mL) was added thereto. The mixture was washed successively with water, 10% ammonium chloride, water, and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:4, v/v) to give the title compound (24.6 g) as a colorless oil.
Reaction SMILES: NCCCN.[CH2:6]([OH:14])[CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]>CCCCCC>[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13]
Reactant: CCCCC#CCCO
Agent: NCCCN
Solvent: CCCCCC
Product: C#CCCCCCCO
Temperature: 25 °C

Procedure:
35% KH in mineral oil (27 g, 240 mmol) under an argon atmosphere was washed with hexane and treated dropwise with 1,3-diaminopropane. The mixture was stirred at room temperature until it became homogeneous. The flask was cooled to 0° C. and 3-octyn-1-ol (10 g, 79 mmol, Lancaster Synthesis) was slowly added. The reaction was then stirred at room temperature for 18 hours. The reaction was quenched with H2O (50 mL) and the product was extracted into ether. The organic layer was washed with 10% HCl and brine and dried (MgSO4). Evaporation gave a colorless oil which was used without further purification: 1H NMR (90 MHz, CDCl3) δ 3.65 (t, J=5 Hz, 2H, O--CH2), 2.23 (m, 2H, CH2), 2.0 (m, 1H, acetylenic), 1.7-1.2 (m, 8H, (CH2)4); IR (neat) nmax 3350, 2930, 2125 cm-1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:8][NH:9][O:10][CH3:11].C1(C)C=CC=CC=1.[C:19](Cl)(=[O:23])[CH2:20][CH2:21][CH3:22]>O>[CH3:11][O:10][N:9]([CH3:8])[C:19](=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(=O)Cl
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC(=O)N(C)OC

Procedure:
Potassium carbonate (62.4 g) was added in portions at 0° C. over 10 minutes to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (250 g) in water (250 ml), then toluene (250 ml) was added and the mixture was stirred until the internal temperature reached 2° C. Butyryl chloride (26 ml) was added dropwise over 10 minutes, then the mixture was stirred at 0° C. for 5 minutes and at ambient temperature for 1 hour. The aqueous phase was separated and shaken with toluene (2×100 ml), then the combined toluene solutions were dried (Na2SO4) and the solvent was removed in vacuo to give N-methoxy-N-methylbutyramide (21.0 g) as a pale-yellow oil which was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)=[CH:5][CH:4]=1)=[O:2].[CH3:29][Mg]Br>>[OH:2][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)=[CH:5][CH:4]=1)[CH3:29]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C=O)cc1)CO2
Reactant: C[Mg]Br
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)O)cc1)CO2
Yield: 93 %

Procedure:
Using N-(3-(4-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 174 and methylmagnesium bromide, the title compound was synthesized in the same manner as Example 22.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:35][N:34]=[C:33]([CH3:36])[N:32]=2)[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:25][CH:26]=[C:27]([C:31]5[O:35][N:34]=[C:33]([CH3:36])[N:32]=5)[CH:28]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Reactant: Cc1noc(-c2cccc(I)c2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(-c4nc(C)no4)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C

Procedure:
To a solution of the compound from Example 3 (E1) (0.125 g, 0.4 mmol) and 1-iodo-3-(3-methyl-[1,2,4]oxadiazol-5-yl)benzene (0.09 g, 0.32 mmol) in triethylamine (3mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, followed by trituration from hexanes/ethyl acetate, to provide the title compound as a white solid, m.p. 122-123° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH2:7][Cl:8])[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[CH2:13][N:14]=[C:15]=[O:16].O>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1>[F:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[CH2:13][NH:14][C:15]([NH:1][C:2]1[S:6][N:5]=[C:4]([CH2:7][Cl:8])[N:3]=1)=[O:16]
Reactant: O=C=NCc1cccc(F)c1
Reactant: Nc1nc(CCl)ns1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(NCc1cccc(F)c1)Nc1nc(CCl)ns1
Temperature: 25 °C

Procedure:
A solution of 5-Amino-3-(chloromethyl)-1,2,4-thiadiazole (Intermediate XXIV) (1 equivalent) and the 3-fluoro-benzyl isocyanate (1.2 equivalents) and DMAP (150 μmol) in NMP (12 ml) was heated in a microwave oven for 30 minutes at 150° C. After cooling to ambient temperature, the brown solution is poured into water (60 ml) and the mixture was extracted with ethyl acetate (5×20 ml). The combined organic layers were partitioned with water (2×20 ml), then brine, and dried over sodium sulphate, filtered and volatiles removed in vacuo. The crude material was first purified by normal phase column chromatography (silica gel, 12-75% ethyl acetate in heptane), followed by reversed phase column chromatography (C18, 10-100% methanol in water) to give a white solid. 1H NMR (300 MHz, d6-DMSO) δ 4.36 (d, 2H), 4.69 (s, 2H), 7.03-7.13 (m, 3H), 7.33-7.38 (m, 1H), 7.45 (t, br, 1H).