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: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
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: [NH2:1][C@H:2]([CH2:21][F:22])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)=[CH:7][CH:6]=1)[OH:4].C(N(C(C)C)CC)(C)C.[F:32][CH:33]([F:37])[C:34](Cl)=[O:35].O>CN(C)C=O>[F:32][CH:33]([F:37])[C:34]([NH:1][C@H:2]([CH2:21][F:22])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH:12]=2)=[CH:7][CH:6]=1)=[O:35]
Reactant: CS(=O)(=O)Cc1cc(-c2ccc([C@@H](O)[C@H](N)CF)cc2)on1
Reactant: O=C(Cl)C(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
(1R,2S)-2-amino-3-fluoro-1-(4-(3-(methylsulfonylmethyl)isoxazol-5-yl)phenyl)propan-1-ol (75 mg, 0.21 mmol) in dimethylformamide (2 mL) at 5° C. is treated with diisopropylethylamine (0.055 mL, 0.62 mmol) and then difluoroacetylchloride (0.026 mL, 0.25 mmol) is added and the mixture stirred at room temperature for 1 hour. Water is added (10 mL) and extracted with ethyl acetate (10 mL) and the organics washed with brine (10 mL), dried over MgSO4, filtered, concentrated and purified by reverse phase preparative HPLC to give the title compound (35 mg). 1H NMR (400 MHz, DMSO-d6) δ: 3.10 (s, 3H), 4.33 (m, 1H), 4.40-4.60 (m, 1H), 4.65-4.80 (m, 3H including 2H singlet at 4.75), 4.92 (bs, 1H), 6.17 (t, 1H), 7.08 (s, 1H), 7.51 (d, 2H), 7.86 (d, 2H), 8.80 (d, 1H); m/z (Cl) 407 [M+H].
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].CS([Cl:12])(=O)=O.C(OC([N:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([CH2:29][OH:30])[CH:26]=2)[CH2:21]1)=O)(C)(C)C.Cl.O1CCOCC1>O1CCOCC1.O.O1CCCC1>[ClH:12].[CH2:1]([O:30][CH2:29][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[CH2:21][NH:20][CH2:28]2)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(CO)cc2C1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: CCOCc1ccc2c(c1)CNC2

Procedure:
0.84 ml of triethylamine and 0.37 ml of methanesulfonyl chloride were added to 10 ml of a tetrahydrofuran solution containing 0.99 g of 2-tert-butoxycarbonyl-5-(hydroxylmethyl)isoindoline under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. After the extract was dried over sodium sulfate, the solvent was removed under reduced pressure. To the residue were added 20 ml of ethanol and 1.02 ml of diisopropylethylamine, and the mixture was refluxed for 30 minutes. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and an aqueous 5% hydrochloric acid solution were added to the residue, followed by the extraction. After the extract was dried over sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (solvent: hexane-ethyl acetate=4:1) to obtain an oily product. This oily product was dissolved in 5 ml of dioxane, then, 8 ml of 4N hydrochloric acid-dioxane was added thereto, and the mixture was stirred at room temperature. The precipitates precipitated by addition of 20 ml of ether were collected by filtration and washed with ether to obtain 5-(ethoxymethyl)isoindoline-hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[CH2:32]([OH:35])[C:33]#[CH:34].C(NCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:3][C:2]=2[C:34]#[C:33][CH2:32][OH:35])[CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2C#CCO)CC1
Temperature: 120 °C
Yield: 44.2 %

Procedure:
2-(3-Bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (117 mg, 0.21 mmol, Example 69), propargyl alcohol (25 μL, 0.42 mmol, Sigma-Aldrich, St. Louis, Mo.), diethylamine (44 μL, 0.42 mmol, Sigma-Aldrich, St. Louis, Mo.), bis(triphenylphosphine) palladium(II) dichloride (15 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.), triphenylphosphine (11 mg, 0.04 mmol, Sigma-Aldrich, St. Louis, Mo.), and copper iodide (4 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.) were combined in DMF (1 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 30 min. The reaction was diluted with CH2Cl2 (10 mL) and water (10 mL). The organic extracts were separated, washed with water (10 mL), dried (Na2SO4), filtered, and concentrated. Purification via column chromatography (12 g silica gel, 0 to 1% MeOH in CH2Cl2) afforded 3-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-2-propyn-1-ol (49 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.09 (br s, 1H), 7.45-7.75 (m, 3H), 7.33 (br s, 1H), 7.09 (d, J=7.63 Hz, 1H), 5.29 (br s, 1H), 4.27 (br s, 2H), 3.24-3.36 (m, 4H), 3.07-3.17 (m, 4H); m/z (ESI, +ve ion) 529.1 (M+H)+. GK-GKRP IC50 (Binding)=0.712 μM. GK-GKRP EC50 (LC MS/MS-2)=0.557 μM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:35]1)=[O:31]
Reactant: O=C(Br)CBr
Reactant: NC1CC(c2ccccc2)c2ccccc21
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NC2CC(c3ccccc3)c3ccccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-3-phenyl-indane
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([C:5]3[C:6]([C:8]4[CH:13]=[CH:12][N:11]=[C:10]5[NH:14][CH:15]=[CH:16][C:9]=45)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=3)=[CH:18][CH:19]=2)=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3cccc(Cl)c3)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and 3-chlorophenyl isocyanate provided the title compound. ESMS [M+H]+: 457.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1.[CH2:30]([CH2:32][NH2:33])[OH:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:33][CH2:32][CH2:30][OH:31])=[O:26])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1
Reactant: NCCO
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)cc2)c2ccc(Cl)cc2F)ccc1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)NCCO)cc2)c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-[1-(4-chloro-2-fluoro-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-benzoic acid was coupled with ethanolamine using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a colourless foam, MS (ESI+): m/z=457.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[NH2:12][O:13][CH2:14][CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:12][O:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(O)cc1
Yield: 84.2 %

Procedure:
Following a procedure similar to that described in Example 40(f), but using 0.33 g of 4'-hydroxyacetophenone and 0.70 g of 5-[4-(2-aminooxyethoxy)benzyl]-thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)], 0.74 g of the title compound, melting at 157°-159° C., was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:19][CH2:18][C:13]4([O:17][CH2:16][CH2:15][O:14]4)[CH2:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1>[Pd].C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:19][CH2:18][C:13]4([O:14][CH2:15][CH2:16][O:17]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C1=C(c2ccc3c(c2)OCO3)CCC2(C1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: c1cc2c(cc1C1CCC3(CC1)OCCO3)OCO2
Yield: 91 %

Procedure:
A mixture of 8-(1,3-benzodioxol-5-yl)-1,4dioxaspiro[4,5]dec-7-ene and 10% palladium on charcoal in ethanol was reacted as described in example 3 to give the product (91%, mp: 115°-116° C.). Calc'd for C15H18O4 : C, 68.69%; H, 6.92%. Found: C, 68.35%; H, 6.84%.
Reaction SMILES: [CH:1]1([C:7]2[N:8]=[C:9]([C:15]3[C:16]([CH3:24])=[N:17][N:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=34)[S:10][C:11]=2[C:12]([NH2:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC(OC)[N:28]([CH3:30])C.O.[NH2:34]N>C(O)(=O)C>[CH:1]1([C:7]2[N:8]=[C:9]([C:15]3[C:16]([CH3:24])=[N:17][N:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=34)[S:10][C:11]=2[C:12]2[NH:28][CH:30]=[N:34][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nn2ccccc2c1-c1nc(C2CCCCC2)c(C(N)=O)s1
Reactant: NN
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CC(=O)O
Product: Cc1nn2ccccc2c1-c1nc(C2CCCCC2)c(-c2nnc[nH]2)s1
Yield: 68 %

Procedure:
Using 4-cyclohexyl-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazole-5-carboxamide (200 mg, 0.6 mmol), N,N-dimethylformamide dimethyl acetal (15 mL), acetic acid (25 mL) and hydrazine monohydrate (0.3 mL) as starting materials and in the same manner as in Example 13-B (vi), the title compound (146 mg, 68%) was obtained as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([CH2:30][Br:31])[CH:27]=[CH:26][C:25]=1[N+:32]([O-:34])=[O:33])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[Br-:31].[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([CH:27]=[CH:26][C:25]=1[N+:32]([O-:34])=[O:33])[CH2:30][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[N+:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C1=C(N2CCCC2)CCc2ccccc21
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CC2C(=[N+]3CCCC3)CCc3ccccc32)cc1OCc1ccccc1
Product: [Br-]

Procedure:
A solution of 1-(3,4-dihydronaphthalen-2-yl)-pyrrolidine (Syn. Comm. 33, 2215 (2003)) (450 mg, 2.26 mmol) and 2-benzyloxy-4-bromomethyl-1-nitrobenzene (Example 83, step C) (730 mg, 2.26 mmol) in 20 mL CH3CN is stirred at RT for 1 h. The solvent is removed under reduced pressure to give the title compound as a red solid.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:19][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:17][CH:18]=1
Reactant: Cc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(CBr)cc1)c1ccc([N+](=O)[O-])cc1
Yield: 112.4 %

Procedure:
Benzoyl peroxide (0.012 g) was added to a mixture of 4-(4-methylbenzoyl)-nitrobenzene (1.20 g) and N-bromosuccinimide (0.89 g) suspended in carbon tetrachloride (63 mL). The reaction mixture was refluxed under argon for 4 hours while illuminated with an incandescent lamp. The mixture was filtered, and the yellow solution containing the crude product was evaporated, chromatographed on silica gel, eluting with hexane/ethyl acetate, to give 4-(4-bromomethylbenzoyl)-nitrobenzene (1.79 g, 81%) as a white solid, m.p. 112.7-113.1° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]2)=[C:35]([F:46])[C:34]=1[F:47])[CH3:31].O>C1COCC1.C1(C)C=CC=CC=1>[CH2:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][C:42](=[CH:2][O:3][CH3:4])[CH2:41][CH2:40]2)=[C:35]([F:46])[C:34]=1[F:47])[CH3:31]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ccc(C2CCC(=COC)CC2)c(F)c1F
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 130.9 %

Procedure:
Methoxymethyltriphenylphosphonium chloride (dried; 26.3 g) and THF (100 ml) were mixed under a nitrogen atmosphere and cooled to −30° C. Then, potassium t-butoxide (t-BuOK) (8.6 g) was added in twice in the temperature range of −30° C. to −20° C. The stirring was continued at −20° C. for 30 minutes, and the compound (16) (15.0 g) dissolved in THF (100 ml) was added dropwise in the temperature range of −30° C. to −20° C. The reaction mixture was stirred at −10° C. for 30 minutes, poured into a mixture of water (200 ml) and toluene (200 ml), and mixed. The mixture was allowed to separate into organic and aqueous phases, and the extraction into an organic phase was carried out. The organic phase obtained was washed with water, and dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure and the residue was purified by means of column chromatography (silica gel; toluene). The eluent obtained was concentrated under reduced pressure, giving 21.8 g of 1-(4-ethoxy-2,3-difluorophenyl)-4-methoxymethylenecyclohexane (17). The compound obtained (17) was colorless oil.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([C:23]([CH:25]3[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]3)=[O:24])[CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>CN(C)C=O>[CH3:43][C:42]([CH3:45])([CH3:44])[C:41]([O:40][CH2:39][O:13][C:12]([C:10]1[S:11][C:7]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:8][C:9]=1[N:15]([C:23]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])[CH:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1)=[O:14])=[O:46]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC1CCC(C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)C2CCN(C)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1CCC(N(c2cc(C3=CCCCC3)sc2C(=O)OCOC(=O)C(C)(C)C)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid (130 mg, 0.27 mmol) in 5.0 mL of dry dimethylformamide under nitrogen was added cesium carbonate (351 mg, 1.08 mmol) and 2,2-dimethyl-propionic acid chloromethyl ester (45 mg, 0.297 mmol). The mixture was stirred for 120 min at 60° C. The mixture was partitioned between ethyl acetate and water. The EtOAc layer was separated and was washed 3 times with water, dried over Na2SO4. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by HPLC purification afforded 120 mg (79%) of 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([CH3:24])[CH2:11][N:12]1[C:17]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:23])(C(C)(C)C)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCCCCCC.CCOC(C)=O>[F:22][C:19]1[CH:20]=[CH:21][C:16]2[O:15][CH2:14][C:13](=[O:23])[N:12]([CH2:11][C@H:10]([CH3:24])[CH2:9][OH:8])[C:17]=2[CH:18]=1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2ccc(F)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: O
Product: C[C@H](CO)CN1C(=O)COc2ccc(F)cc21
Yield: 94.8 %

Procedure:
The compound (S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one (111MF01) (4.09 g, 11.6 mmol) and tetrabutylammonium flouride monohydrate (4.30 g, 15.4 mmol) were mixed according to GP8. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF03) (2.63 g, 95%). 1H NMR (CDCl3) d 6.92 (dd, J=5.2 Hz, J=8.8 Hz, 1H), 6.80 (dd, J=2.8 Hz, J=10.0 Hz, 1H), 6.71-6.66 (m, 1H), 4.59 (d, J=0.8 Hz, 2H), 4.17-4.11 (m, 1H), 3.58-3.40 (m, 3H), 2.79 (s, 1H), 2.08-1.96 (m, 1H) 1.04 (d, J=7.2 Hz, 3H); 13C NMR (CDCl3) d 165.3, 158.4 (d, J=238.44 Hz), 141.5 (d, J=2.7 Hz), 129.5 (d, J=10.4 Hz), 117.9 (d, J=9.3 Hz), 110.2 (d, J=23.1 Hz), 103.1 (d, J=28.4 Hz), 67.5, 63.85, 43.8, 34.0, 14.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:21]([OH:23])=O)=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH:7]=2.C[CH2:25][N:26]=C=NCCCN(C)C.OC1C2N=NNC=2C=CC=1.CN.C(N(CC)CC)C.Cl>ClCCl>[CH3:1][O:2][C:3]1[C:4]([C:21]([NH:26][CH3:25])=[O:23])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH:7]=2
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cccc(-c2ccc3cc(OC)c(C(=O)O)cc3c2)c1
Agent: CN
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc2cc(-c3cccc(OC)c3)ccc2cc1OC
Temperature: 0 °C
Yield: 74 %

Procedure:
3-Methoxy-7-(3-methoxyphenyl)-2-naphthoic acid (323 mg, 1.05 mmol, 1 eq), EDCI (1 eq) and hydroxybenzotriazole (1 eq) are dissolved in 50 ml of dichloromethane. To this solution, cooled at 0° C., are added dropwise methylamine (1 eq) and triethylamine (1 eq) in 40 ml of dry dichloromethane. The reaction mixture is boiled under reflux for 1.5 h, and after cooling, the reaction is stopped by adding 20 ml of 0.1 M HCl. The organic phase is separated, washed with saturated sodium carbonate and chloride solutions, dried over magnesium sulfate, filtered and concentrated in vacuum on a rotary evaporator. Purification by column chromatography with hexane/ethyl acetate 8/2 as the eluent yielded the desired product in a yield of 74%, 250 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:17](Br)[C:18]#[CH:19].O>C1(C)C=CC=CC=1>[CH2:19]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:18]#[CH:17]
Reactant: C#CCBr
Reactant: N#Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: C#CCNc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
A solution of 4-aminobenzonitrile, 5 g (0.042 mol), triethylamine, 8.55 g (0.085 mol), and an 80% by weight solution of propargyl bromide in toluene, 12.6 g (0.085 mol), in toluene is refluxed overnight. The solution is cooled to room temperature and poured into water. The organic layer is separated, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue is purified by chromatography over silica gel to give 4-(2-propynylamino)benzonitrile.