Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10](CC)=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[H-].[CH2:16]([Al+]CC(C)C)[CH:17](C)C.C([O-])(O)=O.[Na+]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:16][CH3:17])[C:3]=1[CH2:4][OH:6]
Reactant: CCOC(=O)c1cc(CC)ccc1Cl
Reactant: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cccc(Cl)c1CO
Temperature: -10 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
The required (2-chloro-5-ethylphenyl)methanol was prepared as follows: To a nitrogen purged solution of ethyl 5-bromo-2-chlorobenzoate (4.3 mL, 25.1 mmol) in THF (100 mL) was added lithium chloride (2.12 g, 50.1 mmol) and Pd(dppf)Cl2 (0.82 g, 1 mmol). Subsequently, the mixture was cooled to −78° C., and a solution of diethylzinc in heptane (37.6 mL; 1.00 mol/l; 37.6 mmol) was added dropwise. The reaction mixture was allowed to come to RT overnight. The resulting reaction mixture was cooled to −10° C. and diluted with Et2O (300 mL). Subsequently, a 1 M aqueous HCl solution (150 mL) was added carefully. The layers were separated, and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 5:95) to afford ethyl 2-chloro-5-ethylbenzoate (4.61 g). To a nitrogen purged solution of ethyl 2-chloro-5-ethyl-benzoate (1 g, 4.70 mmol) in THF (25 mL), was added diisobutylaluminiumhydride (14.11 mL; 14.11 mmol) in toluene, at −5° C. The reaction mixture was allowed to come to RT and stirred overnight. The resulting reaction mixture was cooled to −10° C. and a 5% aqueous NaHCO3-solution (10 mL) was added. The layers were separated, and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:3 followed by Et2O:hexanes 1:1) to afford (2-chloro-6-ethylphenyl)methanol (0.59 g) which was used as such.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20](Br)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1>>[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:6]3[S:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: O=Cc1ccc(-c2ccc(Cn3ccnc3)cn2)s1

Procedure:
Synthesized using 5-formyl-2-thiophenylboronic acid (197 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 78 mg, 0.28 mmol, 46%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.18 (s, 2H), 6.92 (t, J=1.3 Hz, 1H), 7.13 (t, J=1.3 Hz, 1H), 7.47 (dd, J=8.2, 2.2 Hz, 1H), 7.56 (brs, 1H), 7.66 (d, J=4.1 Hz, 1H), 7.71 (dd, J=8.2, 0.6 Hz, 1H), 7.76 (d, J=4.1 Hz, 1H), 8.52 (dd, J=2.2, 0.6 Hz, 1H), 9.93 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 119.0, 119.8, 125.5, 130.5, 131.7, 135.8, 136.7, 137.3, 144.6, 148.7, 151.4, 152.8, 183.0; MS (ESI): m/z=270.22 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10](=[O:12])[CH:11]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:10](=[O:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1cn[nH]c(=O)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(COCC[Si](C)(C)C)c(=O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
The title compound from Example 18.4 (0.90 g, 5.35 mmol) was stirred in dimethylformamide (20 mL) and diisopropyl ethylamine (1.39 mL, 8.025 mmol) at 0° C. and (2-chloromethoxy-ethyl)-trimethyl-silane (1.88 mL, 10.70 mmol) was added and the reaction was allowed to continue to stir at 0° C. for 2 hours and then overnight at r.t. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated onto silica gel. The product was purified by column chromatography (0-20% EtOAc/hexanes) to afford the title compound as a clear oil (0.85 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:20]=1[O:21]C)[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6].[Cl-].[Li+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:20]=1[OH:21])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6]
Reactant: COc1c(Cl)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)c(O)c(C(F)(F)F)c1)N1CS(=O)(=O)c2ccccc21
Temperature: 70 °C
Reaction time: 22 h
Yield: 91 %

Procedure:
3-(3-chloro-4-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (74 mg) was dissolved in N,N-dimethylformamide (2 mL), lithium chloride (77 mg) was added to the solution, and then the mixture was stirred at 70° C. for 22 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from diethylether to obtain the title compound (65 mg) as a colorless crystal.
Reaction SMILES: O[C@@H:2]1[CH2:25][C@H:24]2[C@:19]([CH3:27])([CH2:20][CH2:21][C:22](=[O:26])[CH2:23]2)[C@@H:18]2[C@@H:3]1[C@H:4]1[C@:15]([CH3:29])([C:16](=[O:28])[CH2:17]2)[C@@H:7]([C@H:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.Cl>N1C=CC=CC=1>[O:26]=[C:22]1[CH2:21][CH2:20][C@@:19]2([CH3:27])[CH:24]([CH2:25][CH2:2][C@@H:3]3[C@@H:18]2[CH2:17][C:16](=[O:28])[C@@:15]2([CH3:29])[C@H:4]3[CH2:5][CH2:6][C@@H:7]2[C@H:8]([CH3:14])[CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH2:23]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC(=O)[C@]12C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: C[C@H](C=CC(=O)O)[C@H]1CC[C@H]2[C@@H]3CCC4CC(=O)CC[C@]4(C)[C@H]3CC(=O)[C@]12C
Yield: 87.2 %

Procedure:
In a three-necked (round bottom) flask, 7α-hydroxy-3,12-diketo-5β-cholanic acid (3 g) obtained in the above examples was dissolved in pyridine (70 ml) and added thereto tosyl chloride (1 mol). The resulting mixture was reacted at 0° C. for 1 hour and then, refluxed for 5 hours. After reflux, 3 N aqueous hydrochloric acid was added and the reaction mixture was extracted with ether (100 ml). Ether was distilled off from the extract under a reduced pressure to give Δ6 - and/or Δ7 -3,12-diketo-cholenic acid (2.5 g). The resultant (2 g) was dissolved in 1 N aqueous sodium hydroxide (10 ml) and added thereto Raney nickel (0.1 g). After addition of hydrogen (0.01 mol), the mixture was reacted overnight to obtain 3α,12α-dihydroxy-5β-cholanic acid (deoxycholic acid) and 3α,12α-dihydroxy-5β-cholanic acid (yield: 90%).
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:9](=[O:26])[C:8]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:36]=[N+:37]=[N-:38])(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:38][N:37]=[N:36][N:25]=3)=[CH:14][CH:13]=2)[C:9](=[O:26])[C:8]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C(=O)OCC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCCc1ncc(C(=O)OCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
The title compound is prepared by heating one equivalent of 2-n-butyl-3-(2'-cyanobiphen-4-yl)methyl-5-ethoxycarbonylpyrimidin-4(3H)-one from (from Example 7) with one to four equivalents of trimethylstannyl azide in toluene. After completion of the reaction the trimethylstannyl moiety is removed from the tetrazole moiety by workup with an acidic aqueous solution such as saturated aqueous ammonium chloride.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].[H-].[Na+].[CH3:37]I.O>COCCOC>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH3:37])[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: CI
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CN(c2ccccc2Cl)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
8-(3,5-Bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (253 mg) was suspended in 1,2-dimethoxyethane (3 mL) and sodium hydride (24 mg, 60%) was added with stirring at room temperature. After 15 minutes methyliodide (78 mg) was added and stirring was continued overnight at room temperature. Water was added and the mixture was extracted with ethylacetate. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. Chromatography on silica gel (hexane/ethylacetate=1:1) yielded the desired product (152 mg, 59%), MS: m/e=520.1 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7](O)[C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:2]=1.O.O.[Sn](Cl)Cl.Cl>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:2]=1
Reactant: OC(c1cccnc1)c1cccs1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: c1cncc(Cc2cccs2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.5 %

Procedure:
To a solution of 2-(3-pyridylhydroxymethyl)thiophene (8.82 g, 46.2 mmol), prepared as in step 1, in acetic acid (50 mL) was added tin(II)chloride dihydrate (22.9 g, 101 mmol) and HCl gas was bubbled through the reaction mixture for about 10 min. The reaction mixture was stirred for 1.5 hours at ambient temperature, and the liquid was decanted, concentrated in vacuo to a volume of about 10 mL, and poured into H2O. The aqueous solution was made basic by the slow addition of saturated aqueous NaHCO3 and extracted with ethyl acetate/ether. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (5% methanol/CHCl3) gave 2-(3-pyridylmethyl)thiophene (2.63 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9]2[C:10](=[O:25])[N:11]([CH3:24])[CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)=[N:3]1.Cl[C:27]1[C:32]([CH:33]=[O:34])=[C:31]([N:35]2[CH2:47][CH2:46][C:45]3[N:44]4[C:39]([CH2:40][CH2:41][CH2:42][CH2:43]4)=[CH:38][C:37]=3[C:36]2=[O:48])[N:30]=[CH:29][CH:28]=1.C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9]2[C:10](=[O:25])[N:11]([CH3:24])[CH:12]=[C:13]([C:27]3[C:32]([CH:33]=[O:34])=[C:31]([N:35]4[CH2:47][CH2:46][C:45]5[N:44]6[C:39]([CH2:40][CH2:41][CH2:42][CH2:43]6)=[CH:38][C:37]=5[C:36]4=[O:48])[N:30]=[CH:29][CH:28]=3)[CH:14]=2)=[N:3]1
Reactant: O=Cc1c(Cl)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Reactant: Cc1cc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nn1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cc1cc(Nc2cc(-c3ccnc(N4CCc5c(cc6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nn1C
Temperature: 90 °C
Yield: 53.3 %

Procedure:
A-100 mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 242a (282 mg, 0.82 mmol, 1.5 eq.), 4-chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)nicotinaldehyde 139a (180 mg, 0.55 mmol, 1.0 eq.), Pd(dppf)Cl2 (45 mg, 0.055 mmol, 0.1 eq.), sodium acetate (90 mg, 1.25 mmol, 2.0 eq.), K3PO4 (232 mg, 1.25 mmol, 2.0 eq.), acetonitrile (20 mL), and water (1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 1 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 242b (150 mg, 48%) as a yellow solid. MS-ESI: [M+H]+ 512.3.
Reaction SMILES: N1CCC2(C=CC3C=CC=CC=3O2)CC1.[OH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:25])[CH3:24].[C:26]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].N1CCCC1>CO>[C:26]([N:33]1[CH2:34][CH2:35][C:36]2([CH2:24][C:23](=[O:25])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16]2)[CH2:37][CH2:38]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1ccccc1O
Agent: C1=CC2(CCNCC2)Oc2ccccc21
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2

Procedure:
The compounds prepared in Examples Z1-Z14 and depicted in Table Z1 were prepared according to the Schemes Z1-Z6. The preparation of spiro[2H-1-benzopyran-2,4′-piperidine] derivatives 15 (Example Z1), 16 (Example Z2) and 18 (Example Z3) is outlined in Scheme Z1. The 2′-hydroxyacetophenone derivatives 1, 2 and 3 (commercially available from Aldrich Chemical Company) were condensed with 1-Boc-4-piperidone 4 in methanol in the presence of pyrrolidine to provide N-Boc-spiro[2H-1-benzopyran-2,4′-piperidine]-4(3H)-one derivatives 5-7 respectively. Compounds 12-14 were prepared by conversion of the ketones 5-7 to the enol triflate derivatives 8-10 and subsequent Suzuki coupling reaction with 4-(N,N-diethylaminocarbonyl)phenylboronic acid 11. The Boc protecting groups of 12-14 were subsequently removed using trifluoroacetic acid to generate the corresponding spiro[2H-1-benzopyran-2,4′-piperidine] derivatives 15 (Example Z1), 16 (Example Z2) and 17. Demethylation of the methyl ether 17 using boron tribromide in anhydrous dichloromethane afforded the phenolic derivative 18 (Example Z3). Hydrogenation of 15 in methanol in the presence of palladium hydroxide (Pearlman's catalyst) afforded the 3,4-dihydrospiro[2H,1-benzopyran-2,4′-piperidine] derivative 19 (Example Z4) (Scheme Z2). Treatment of 15 with formaldehyde in the presence of sodium cyanoborohydride gave the N-methyl derivative 20 (Example Z5) (Scheme Z2).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH3:27])[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH3:27])[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:11]1
Reactant: Cc1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@@H]1C)CO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1NC1CNC1)N1C(=NNC(=O)[C@@H]1C)CO2
Yield: 98 %

Procedure:
A solution of 3-(4(S),7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (enantiomer 2, SFC (Table 1, Method 8), Rt=4.151 min, 0.240 g, 0.60 mmol) in TFA (4 mL) and DCM (24 mL) was stirred at 25° C. for 3 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-4(S),7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (Example #54-2, Enantiomer 2, SFC (Table 1, Method 9), Rt=4.945 min, 0.246 g, 98%) as a yellow solid. LC/MS (Table 1, Method 5) Rt=2.048 min.; MS m/z: 302 [M+H]+.
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:9].C[O:18][C:19](=O)[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.O>C1COCC1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH2:7][C:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[O:18])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: CC(=O)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9.27 g KOtBu was added to 109 mg 18-Krone-6 and 5 mL 4-fluoracetophenone in 150 mL THF. After 30 min at RT 10.7 g 4-fluoro-benzoic acid methyl ester was added and stirred for 3 h at RT. The reaction was decomposed with water and filtered, the filtrate was concentrated and the residue was purified by chromatography on silica gel (cyclohexane/EE: 98:2). The solvent was removed and 3.9 g of the desired compound was obtained.
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3]>O1CCCC1.CO.O.O.[OH-].[Li+]>[CH2:22]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:23][CH3:24]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2nccs2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2nccs2)c1
Reaction time: 0.25 h

Procedure:
Methyl 3-[(dipropylamino)carbonyl]-5-(1,3-thiazol-2-yl)benzoate (4.4 g, 12.8 mmol) is dissolved in 1:1:1 tetrahydrofuran/methanol/water (60 mL), and lithium hydroxide monohydrate is added (1.1 g, 25.6 mmol), and the reaction stirred 15 min. The solution is concentrated under reduced pressure and diluted in chloroform. The solution is washed with water and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to give the title compound. ESI MS m/z 333.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][CH:14]=[C:13]2[C:17]#[N:18])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:24]([O:26]C)Cl>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([CH:24]=[O:26])[CH:14]=[C:13]2[C:17]#[N:18])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cccc2C#N)cc1
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1ccc(-n2cc(C=O)cc2C#N)cc1
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a mixture of 1-(4-ethoxycarbonylphenyl)pyrrole-2-carbonitrile (5.16 g) and aluminum chloride (5.72 g) in 1,2-dichloroethane (51 ml) was added a solution of dichloromethylmethyl ether (2.97 g) in 1,2-dichloroethane (5 ml) in one portion at -15° C. The mixture was stirred for one hour at the same temperature and then dichloromethylmethyl ether (0.6 g) was added therein. After stirring for 3 hours at 5° C., the reaction mixture was quenched with 10% hydrochloric acid. The separated organic layer was washed with 10% hydrochloric acid three times, dried, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted by 1% methanol in dichloromethane to yield 1-(4-ethoxycarbonylphenyl)-4-formylpyrrole-2-carbonitrile (2.96 g) as a pale yellow solid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][C:11]([CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OC(=O)CC)(=O)CC>[O:12]=[C:11]([CH2:13][CH3:14])[CH:13]([C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])[C:11](=[O:12])[NH:10][C@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][CH3:9]
Reactant: CC[C@H](NC(=O)Cc1ccccc1C(=O)O)c1ccccc1
Agent: CCC(=O)OC(=O)CC
Product: CCC(=O)C(C(=O)N[C@@H](CC)c1ccccc1)c1ccccc1C(=O)O
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A sealed mixture of 2-[((S)-1-phenyl-propylcarbamoyl)-methyl]-benzoic acid (409 mg, 1.38 mmol), propionic anhydride (10 ml) and 4-N,N-dimethylaminopyridine (15 mg) was heated under microwave irradiation at 150° C. for 20 min and partitioned between 1M HCl (50 ml) and ethyl acetate (100 ml). The organic layer was washed with sat. aq. NaHCO3 (2×50 ml) and brine and concentrated in vacuo. To the obtained residue methanol (25 ml) tetrahydrofurane (25 ml) and 2M aq. NaOH (50 ml) was added and stirred at r.t. for 1 hour. The organic volatiles were removed in vacuo and the pH was adjusted to 1 with 3M aq. HCl. The crude title product (495 mg) was separated by extraction with ethyl acetate (150 ml) and used in the next step without further purification. 1H NMR (500 MHz, DMSO-d6): a mixture of tautomers and diastereoisomers.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([C:14]([C:20]#[N:21])=[C:15](SC)[S:16][CH3:17])#[N:13]>>[C:12]([C:14]([C:20]#[N:21])=[C:15]([S:16][CH3:17])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])#[N:13]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: Cc1nc[nH]c1CSCCN
Product: CSC(NCCSCc1[nH]cnc1C)=C(C#N)C#N

Procedure:
Reaction of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole with 1,1-dicyano-2,2-bis methylthioethylene by the procedure of Example 8(i) yields 1,1-dicyano-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([C:13](Cl)=[O:14])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26][NH2:27]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([C:13]([NH:27][CH2:26][CH:25]([O:28][CH3:29])[O:24][CH3:23])=[O:14])[CH:5]=1
Reactant: COC(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Reactant: COC(CN)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)NCC(OC)OC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under ice cooling a solution of 22.1 g (90.7 mmol) of 3-chlorocarbonyl-5-nitro-benzoic acid methyl ester (U.S. Pat. No. 4,120,891) in 200 ml of DCM is added dropwise to a stirred suspension of 11.2 g (181 mmol) of K2CO3 and 11.7 ml (109 mmol) of aminoacetaldehyde dimethylacetal in 200 ml of DCM. The mixture is stirred at ambient temperature for 2 days, diluted with ethyl acetate and extensively washed with water. The organic phase is dried over sodium sulfate and evaporated to yield the product in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:17]=1[CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:22]3[CH2:21][CH2:20][CH:19]([CH2:18][C:17]4[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:16]=4[F:15])[CH2:24][CH2:23]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(F)c(CC2CCNCC2)c1
Reactant: O=C1CCC(c2ccc(F)cc2)CC1
Product: Fc1ccc([C@H]2CC[C@H](N3CCC(Cc4cc(F)ccc4F)CC3)CC2)cc1

Procedure:
4-(4-Fluorophenyl)cyclohexanone and 4-(2,5difluorobenzyl)piperidine were reacted as described in example 9 to give the product (36%, mp: 80°-81° C.). Calc'd for C24H28F3N: C, 74.40%; H, 7.29%; N, 3.18%. Found: C, 74.25%; H, 7.29%; N, 3.56%.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[Br:1][C:2]1[C:3]([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][CH:11]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: c1ccc2[nH]ccc2c1
Product: Clc1ncc(Br)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 5-bromo-2,4-dichloropyrimidine and 1H-indole. m/z 309.