Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C.C(OCC)C>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH3:7])[CH3:23])[CH3:22]
Reactant: CCOC(=O)C(C)Br
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccccc1OC
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 91.6 %

Procedure:
Cesium carbonate (53.86 g, 165.3 mmol) was added to a solution of 2-methoxyphenol (10.26 g, 82.6 mmol) in anhydrous DMF (500 mL) at room temperature under an atmosphere of nitrogen. After five minutes, ethyl 2-bromopropionate (10.7 mL, 82.6 mmol, d=1.394) was added rapidly dropwise and the resultant mixture was allowed to stir at 90° C. for 18 h. The reaction mixture was diluted with diethyl ether, then extracted twice with 1N HCl and twice with water. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (25% ether in hexanes) to provide the titled compound (16.97 g, 92%) as a light yellow oil.1H NMR (400 MHz, CDCl3): δ 6.96–6.80 (m, 4H), 4.73 (q, 1H, J=7.04 Hz), 4.23–4.12 (m, 2H), 3.82 (s, 3H), 1.62 (d, 3H, J=6.65 Hz), 1.21(t, 3H, J=7.04 Hz). MS [ES+] m/z exact mass calcd for C12H17O4 225.1127, found 225.1110. Rf=0.19 in 25% ether in hexanes.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:30]=[C:29]([F:31])[C:28]([N:32]2[C:37](=[O:38])[CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]([CH3:43])[C:33]2=[O:44])=[CH:27][C:11]=1[O:12][C:13]1[C:14]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1.[ClH:45]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:45][C:10]1[CH:30]=[C:29]([F:31])[C:28]([N:32]2[C:37](=[O:38])[CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]([CH3:43])[C:33]2=[O:44])=[CH:27][C:11]=1[O:12][C:13]1[C:14]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1
Reactant: COC(=O)COc1nc(OC)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1nc(OC)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
First, isoamyl nitrite is added dropwise to a mixture of methyl [3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-methoxy-2-pyridyloxy]acetate, copper(I) chloride, copper(II) chloride, and acetonitrile at room temperature, and the mixture is stirred for 1 hour. The reaction mixture is poured into 2% hydrochloric acid, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue is subjected to silica gel column chromatography to give methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-methoxy-2-pyridyloxy]acetate (compound a-118).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:24]([Li])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([C:20]1([OH:23])[CH2:21][CH2:22][N:17]([CH2:16][C:13]23[CH2:15][CH:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=42)[C:5]2[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:18][CH2:19]1)[CH2:25][CH2:26][CH3:27]
Reactant: [Li]CCCC
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: CCCCC1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in example 49 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing n-butyllithium, the title compound was formed as a white solid, mp 194°-196° C. TLC analysis on the free base (Rf 0.22, 30% ethyl acetate in hexane). free base: 1H NMR (CDCl3, 250 MHz) 7.20 (m, 4H), 6.94 (m, 4H), 4.26 (s, 1H), 3.41 (s, 2H), 2.73 (m, 2H), 2.60 (d, J=2.0 Hz, 2H), 1.53 (m, 10H), 0.9 (t, 3H) MS (CI, CH4) m/z 362 (M+1,100), 390 (M+29,13), 344 (47), 304 (44) hydrochloride salt:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[C:16]([CH3:17])=[CH:15][NH:14][C:13]=1[CH:18]=O>N1CCCCC1>[CH3:11][C:12]1[C:16]([CH3:17])=[CH:15][NH:14][C:13]=1[CH:18]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: Cc1c[nH]c(C=O)c1C
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Product: Cc1c[nH]c(C=C2C(=O)Nc3ccccc32)c1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A reaction mixture of 67.0 mg (0.5 mmoles) of oxindole, 73.0 mg (0.6 mmoles) of the 3,4-dimethylpyrrole-2-carboxaldehyde, and 2 drops of piperidine in 2 was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 87.7 mg (37%) of the title compound as a yellow solid.
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:37][C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[CH2:20][C@@H:21]3[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:16][CH:15]=4)[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Si:30]([O:29][C@@H:21]1[C@@:22]2([CH3:23])[C:17](=[CH:16][CH:15]=[C:14]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[CH:8]([CH:5]=[O:4])[CH3:9])[CH2:18][C@@H:19]([O:37][C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[CH2:20]1)([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:32])[CH3:31]
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)N(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)N(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 66.6 %

Procedure:
In 10 ml of acetone was dissolved 110 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(tert-butyldimethylsilyl)oxy- 3β-(N,N-dimethylcarbamoyl)oxypregna-5,7diene, followed by addition of 10 mg of p-toluenesulfonic acid. The mixture was refluxed in an atmosphere of argon gas for 4 hours. The reaction mixture was then worked up in the same manner as Example 156 to give 63 mg of 1α-(tert-butyldimethylsilyl)oxy-3β-(N,N-dimethylcarbamoyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: [C:1]1(=[O:8])O[C:5](=[O:6])[CH:4]=[C:2]1[CH3:3].[CH2:9]([NH2:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>N1C=CC=CC=1>[CH3:3][C:2]1[C:1](=[O:8])[N:17]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5](=[O:6])[CH:4]=1
Reactant: CC1=CC(=O)OC1=O
Reactant: CCCCCCCCN
Solvent: c1ccncc1
Product: CCCCCCCCN1C(=O)C=C(C)C1=O
Temperature: 90 °C

Procedure:
A solution of citraconic anhydride (0.1 M) in pyridine (20 ml)was treated with octylamine (0.1 M). The reaction mixture was heated to 90° C. for six hours. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: N1CCCCC1.C(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([CH2:18][C:19]([NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])=[O:20])(O)=O.Cl>C1(C)C=CC=CC=1>[O:20]=[C:19]([NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])/[CH:18]=[CH:15]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C(/C=C/c1ccccc1)Nc1ccccc1C(=O)O
Yield: 96.1 %

Procedure:
Piperidine (0.42 mL, 4.2 mmol) was added to a suspension of benzaldehyde (0.43 mL, 4.2 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.83 g, 3.7 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[(1-oxo-3-phenyl-2-propenyl)amino]benzoic acid (0.95 g, 96%) was obtained as a pale yellow crystalline solid; mp 188-189° C., lit. [23] 196-197° C.; δH (500 MHz, DMSO-d6) 6.88 (d, J=16.0 Hz, 1H, CH═CHCO), 7.18 (t, J3,4=J4,5=8.0, 1H, H4), 7.41-7.45 (m, 3H, H3′, H4′, H5′), 7.62 (td, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 7.62 (d, J=16.0 Hz, 1H, CH═CHCO), 7.72-7.74 (m, 2H, H2′, H6′), 8.00 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.59 (d, J5,6=8.0 Hz, 1H, H6), 11.32 (s, 1H, NH).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][C:16]1[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+]>C1COCC1.CO>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccnc4cc(OC)c(OC)cc34)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2nccc(Oc3ccc4[nH]c(C(=O)O)cc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(6,7-dimethoxy-quinolin-4-yloxy)-1H-indole-2-carboxylic acid ethyl ester (0.2 g, 0.51 mmol, from step a) in 1:1 THF/MeOH (4 mL) was added 1.53 mL of 1N NaOH. The reaction was stirred at RT for 16 h then concentrated in vacuo. The remaining solution was acidified with 10% HCl to pH ˜5. The white precipitate was collected, dried in vacuo to afford white solid as desired acid. MS (ESI pos. ion) m/z: 365 (M+H). Calc'd Exact Mass for C20H16N2O5: 364.35.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:14][CH3:15])[CH:3]=1.C(Cl)(=O)OCC.[NH2:22][C@H:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][C@H:24]1[O:34][CH3:35]>ClC(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][C@H:24]2[O:34][CH3:35])=[O:8])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: CCOC(=O)N1CC[C@H](N)[C@H](OC)C1
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CC[C@H](NC(=O)c2cc([N+](=O)[O-])c(Cl)cc2OC)[C@H](OC)C1
Reaction time: 1 h
Yield: 75 %

Procedure:
To a stirred and cooled (5° C.) suspension of 81 parts of 4-chloro-2-methoxy-5-nitrobenzoic acid in 1350 parts of trichloromethane were added first 35.4 parts of N,N-diethylethanamine and then 38 parts of ethyl carbonochloridate at a temperature below 5° C. The whole was stirred for 2 hours in an ice bath. A solution of 65 parts of ethyl cis-4-amino-3-methoxy-1-piperidinecarboxylate in 1125 parts of trichloromethane was added while the temperature was kept below 10° C. Stirring was continued first for 1 hour in an ice bath and then overnight at room temperature. The mixture was washed successively once with water, twice with a sodium hydroxide solution 5% and three times with water, dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 100 parts (75%) of ethyl cis-4-[(4-chloro-2-methoxy-5-nitro-benzoyl)amino]-3-methoxy-1-piperidinecarboxylate; mp. 181.3° C. (interm. 13).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C[Al](C)C.CCCCCC.C[O:20][C:21]([C:23]1[C:28]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:27][CH:26]=[C:25]([CH3:37])[N:24]=1)=O>O1CCOCC1>[C:33]([O:32][C:30](=[O:31])[NH:29][C:28]1[C:23]([C:21](=[O:20])[NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)=[N:24][C:25]([CH3:37])=[CH:26][CH:27]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)c1nc(C)ccc1NC(=O)OC(C)(C)C
Reactant: Nc1ccnc(Cl)c1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: CCCCCC
Product: Cc1ccc(NC(=O)OC(C)(C)C)c(C(=O)Nc2ccnc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 2-chloro-4-aminopyridine (0.97 g, 7.5 mmol, 4.0 equiv.) in dry dioxane (20.0 ml) were added 3.75 ml of a 2M solution of trimethyl aluminium in hexane (7.5 mmol, 4.0 equiv.) and the mixture was stirred for 1 h at r.t.. Then 3-tert-Butoxycarbonylamino-6-methyl-pyridine-2-carboxylic acid methyl ester (0.50 g, 1.88 mmol) were added and the reaction was refluxed for 2 h. After allowing the reaction to cool to r.t., the reaction was quenched with water (0.5 ml), stirred for 5 min, dried by addition of magnesium sulfate and filtered over Dicalite which was further washed with methylene chloride. The filtrate was concentrated in vaccuo. The residue was purified by flash chromatography (heptane/ethyl acetate 2:1) to yield the title compound as a white solid (total 0.50 g, 73%), MS (ISP): m/e=363.1, 365.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:28]=1[CH:29]=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:4])/[CH:5]=[CH:29]/[C:28]1[C:27]([O:26][CH3:25])=[CH:34][CH:33]=[CH:32][C:31]=1[O:35][CH3:36]
Reactant: COc1cccc(OC)c1C=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1c(OC)cccc1OC
Temperature: 0 °C
Yield: 93.5 %

Procedure:
35.6 g of (methoxycarbonylmethylene)-triphenylphosphorane is added to a solution of 8.48 g of 2,6-dimethoxybenzaldehyde in 450 ml of tetrahydrofuran under nitrogen and refluxed for 16 hours. It is poured on 200 ml of ice water, extracted three times with ethyl acetate, the combined organic phases are washed once with saturated sodium chloride solution, dried on sodium sulfate and after filtration, concentrated by evaporation in a vacuum. The thus obtained residue is purified by chromatography on silica gel. With hexane/0-40% ethyl acetate, a solid is obtained, which is recrystallized from hexane/toluene. 10.6 g of the title compound is obtained in this-way as crystalline substance (melting point: 76°-78° C).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1.Cl[CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:27][N:26]([CH3:28])[C:24](=[O:25])[CH2:23][N:2]([CH3:1])[CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1
Reactant: CN(C)C(=O)CCl
Reactant: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN(C)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
Note: For the preparation of the starting material compound 1, see Example 147. To a solution of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]cyclohexane-1,4-diamine (90 mg, 0.30 mmol, 1.00 equiv) in DMF (10 mL) was added 2-chloro-N,N-dimethylacetamide (54.45 mg, 0.45 mmol, 1.50 equiv) and potassium carbonate (83 mg, 0.60 mmol, 2.00 equiv) at room temperature under nitrogen. The resulting solution was stirred overnight at ambient temperature. After completion of the reaction, the solids were removed by filtration and the filtrate was concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (5.0% CH3CN up to 49.0% in 13 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired N,N-dimethyl-2-[methyl[4-([7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino)cyclohexyl]amino]acetamide (31.8 mg) as a white solid. MS (ES, m/z): 388 (M+H+). 1H NMR (400 MHz, DMSO): δ 8.25 (s, 1H), 5.98 (d, 1H), 4.01-4.04 (m, 1H), 3.22 (s, 2H), 3.08 (t, 2H), 3.03 (s, 3H), 2.93 (t, 2H), 2.80 (s, 3H), 2.42-2.44 (m, 3H), 2.20 (s, 3H), 1.97-2.00 (m, 2H), 1.78-1.81 (m, 2H), 1.24-1.48 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13](Cl)=[O:14].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[C:23]1([NH:22][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:10]([S:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH:11]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A solution of 3-(2,4-difluorophenylthio)-4-nitrobenzoyl chloride (1 g) in tetrahydrofuran (3 ml) was added to a stirred mixture of aniline (0.306 g) and sodium bicarbonate (0.51 g) in tetrahydrofuran (2 ml) and water (5 ml) at 5° C. The mixture was stirred at 5° C. for 1 hour and at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with water, dried and evaporated. The residue was washed with ethanol to give yellow crystals of N-phenyl3-(2,4-difluorophenylthio)-4-nitrobenzamide (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:15][C:16]1[C:21]2[NH:22][C:23](=[O:25])[O:24][C:20]=2[CH:19]=[CH:18][CH:17]=1>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:18]2[CH:17]=[C:16]([CH3:15])[C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)=[O:9])[CH:3]=1
Reactant: Cc1cccc2oc(=O)[nH]c12
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
2.34 g (13.2 mmol) 6-chloropyrimidine-4-carbonyl chloride, 8.00 g (60.0 mmol) aluminium trichloride and 1.79 g (12.0 mmol) 4-methyl-3H-benzoxazol-2-one were heated to 130° C. for 1.5 h. After cooling to RT the mixture was mixed with ice water, then extracted with ethyl acetate, the organic phase was dried on sodium sulphate and evaporated down i.vac. The crude product left as a solid was triturated with diethyl ether, suction filtered and dried in the air.
Reaction SMILES: FC1C=CC(C(C2C=CC(F)=CC=2)=C(C2N(C)N=NN=2)C=[O:11])=CC=1.[C:25]1([P:31](=CC=O)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1C=CC=CC=1>[C:25]1([P:31](=[O:11])([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: c1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a mixture of 3,3-bis (4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal (71.6 g, 0.22 mole) and triphenylphosphoranylidene acetaldehyde (66.8 g, 0.22 mole) was added 1.1 liters of dry benzene and the suspension was heated to reflux temperature over a period of 30 minutes. The reaction was allowed to proceed at reflux temperature for 2 hrs. Analytical TLC eluted five times with 30% (v/v) ethyl acetate in hexanes showed only one major spot at Rf =0.37 for the desired product. The crude hot reaction mixture was diluted with an equal volume of hexane and the warm mixture was quickly filtered through a bed of activated charcoal. The filtrate was allowed to stand at room temperature from which 58.12 g (75.2%) of the desired product was collected. A second crystallization from the filtrate yielded mostly triphenylphosphine oxide. Concentration of the filtrate yielded an additional amount of the desired product to give a total of 71 g (91.1%) of the title compound. The combined material was recrystallized from ethyl acetate-hexane to give pure title compound; m.p.=164°-165° C. A 1H NMR of the recrystallized material showed no detectable double homologated product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([F:16])[CH:5]=1.[CH:17](OCC)=[O:18].Cl>O1CCCC1.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:17]=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([F:16])[CH:5]=1
Reactant: CCOC(=O)Cc1ccc(Cl)cc1F
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C=O)c1ccc(Cl)cc1F
Reaction time: 0.5 h

Procedure:
Then, 3.6 g of sodium hydride (60% in oil) was suspended in 120 ml of tetrahydrofuran, and the mixture was cooled to 5° C., to which a solution of 17.8 g of ethyl 4-chloro-2-fluorophenylacetate in 120 nm of tetrahydrofliran was slowly added dropwise. The mixture was stirred for 30 minutes with a gradual temperature increase to room temperature, to which 20 ml of ethyl formate was added at room temperature, followed by stirring for 3 hours. Then, the reaction mixture was cooled with ice, to which diluted aqueous hydrochloric acid was added. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 19.1 g of ethyl 2-(4-chloro-2-fluorophenyl)-2-formylacetate.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([O:15]CC=C)=[CH:7][C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:3])[CH3:2].CN(C)[C:25]1[CH:30]=CC=C[CH:26]=1>>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:9][C:8]([OH:15])=[C:7]([CH2:30][CH:25]=[CH2:26])[C:6]=1[C:19]([CH3:22])([CH3:20])[CH3:21])(=[O:3])[CH3:2]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Product: C=CCc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Temperature: 25 °C
Yield: 77 %

Procedure:
4-Acetoxy-3,5-di-tert-butyl-1-(2-propenyloxy)benzene (11.0 g) was dissolved in N,N-dimethylaniline (50 ml) and the solution was refluxed for 18 h under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (15% ethyl acetate in n-hexane) to afford 4-acetoxy-3,5-di-tert-butyl-2-(2-propenyl)phenol [8.84 g (yield, 77%)] as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15]>>[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][NH:15][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)=[O:9]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cn1nccc1C(=O)O
Product: COc1ccc(CNC(=O)c2ccnn2C)c(OC)c1

Procedure:
Prepared in a similar manner to example 4 using 2-methyl-2H-pyrazole-3-carboxylic acid and 2,4-dimethoxy-benzylamine. MS (M+H, 276.2).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]#[N:17])=[CH:10][C:9]=1[Cl:18])(=O)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:18][C:9]1[CH:10]=[C:11]([C:16]#[N:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=1[CH:7]=[CH2:6]
Reactant: COc1cc(CCOS(C)(=O)=O)c(Cl)cc1C#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=Cc1cc(OC)c(C#N)cc1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of 2-(2-chloro-4-cyano-5-methoxyphenyl)ethyl methanesulfonate (274 mg, 0.945 mmol) in DCM (4 mL) was treated with DBU (0.712 mL, 4.73 mmol) and stirred for 3 hours at 50° C., then at RT for 12 hours. TLC (50% ethyl acetate/hexanes) showed complete conversion to a faster intense UV band for the product. The reaction was then diluted with DCM and aq. citric acid and the mixture was extracted twice with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography (10-20% ethyl acetate/hexanes) afforded the title intermediate.