Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([C:32](=[O:36])[N:33]([CH3:35])[CH3:34])[NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.O>[CH3:35][N:33]([CH3:34])[C:32]([CH:20]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:23])=[O:24])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:11][CH:10]=2)=[CH:18][CH:17]=1)=[O:36]
Reactant: COC(=O)CCc1ccc(Oc2ccc(CC(NS(=O)(=O)c3ccc(C)cc3)C(=O)N(C)C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(Cc2ccc(Oc3ccc(CCC(=O)O)cc3)cc2)C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
The sulfonamide compound 24 (0.9 g, 1.72 mmol) was dissolved in THF (10 mL) and diluted with water (10 mL). Lithium hydroxide (0.16, 6.86 mmol) was added and the reaction mixture was stirred at room temperature for about 2 h. The THF was evaporated and the resulting aqueous layer was acidified with 2.0 M HCl and extracted into EtOAc (2×25 mL). The organic layer was washed with water (1×25 mL) and brine (1×25 mL), dried and concentrated to yield the desired acid compound 25 (0.9 g, quantitative). 1H NMR (400 MHz, DMSO-d6): 12.2 (br, 1H), 8.05 (d, J=9.2 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.29 (d, J=7.6 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 7.10 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 4.28 (m, 1H), 2.75-2.81 (m, 3H), 2.69 (s, 3H), 2.60 (dd, J=13.2 and 7.6 Hz, 1H), 2.52 (t, J=8.0 Hz, 2H), 2.35 (s, 3H). LCMS (m/e): Obsd. 526, Calcd. 525.62
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:4]=1.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>CN(C)C=O>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[C:11]([C:9]([C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)=[O:10])=[CH:12]1
Reactant: Fc1ccccc1CBr
Reactant: O=C(c1cccnc1)c1c[nH]c2ccccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cccnc1)c1cn(Cc2ccccc2F)c2ccccc2c1=O

Procedure:
Compound 4ii was prepared following the procedure outlined in Step 3 of Example 1 using 16 mg (0.40 mmol) of sodium hydride (60%), 75 mg (0.30 mmol) of 3-(pyridine-3-carbonyl)-1H-quinolin-4-one, 3 mL of anhydrous dimethylformamide, and 75.6 mg (0.4 mmol) of 2-fluorobenzylbromide. The crude product was purified by flash chromatography to yield 35 mg of a colorless solid 4ii: LC-MSD, m/z for C22H15FN2O2, [M+H]+=359.4, [M+2H]+=360.4; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=1.432 min; 1H NMR (400 MHz, CDCl3HCl): δ 5.46 (s, 2H), 7.02-7.20 (m, 3H), 7.32-7.38 (m, 2H), 7.40-7.46 (m, 2H), 7.64 (t, 1H), 8.08 (d, 1H), 8.45 (d, 2H), 8.71 (d, 1H), 8.98 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[CH:14])[CH:6]=[CH:7][C:8]=1[O:9][C:10](=[O:12])[CH3:11].[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18][SH:19].[Na]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][C:10](=[O:12])[CH3:11])/[CH:13]=[CH:14]\[CH:18]([S:19][CH:18](/[CH:14]=[CH:13]\[C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10](=[O:12])[CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:17]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:16]=1[Cl:15])[C:17]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:16]=1[Cl:15]
Reactant: SCc1ccc(Cl)cc1Cl
Reactant: C#Cc1ccc(OC(C)=O)c(OC)c1
Agent: [Na]
Product: COc1cc(/C=C\C(SC(/C=C\c2ccc(OC(C)=O)c(OC)c2)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2Cl)ccc1OC(C)=O

Procedure:
A solution of 3-methoxy-4-acetoxyphenylacetylene (0.02 mol), 2,4-dichlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-3-methoxy-4-acetoxystyryl-2,4-dichlorobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)=[CH:12][C:11]=1[NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)=[CH:12][C:11]=1[NH:31][C:32](=[O:40])[C:33]1[CH:34]=[CH:35][C:36]([O:39][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)=[CH:37][CH:38]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1ccc(Oc2cc(Cl)ncn2)cc1
Yield: 53.2 %

Procedure:
4,6-Dichloropyrimidine (0.103 g) was added to a stirred mixture of N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-4-hydroxybenzamide (0.3 g), caesium carbonate (0.453 g) and DMA (7.5 ml) and the resultant solution was stirred at ambient temperature for 18 hours. The mixture was poured into water (200 ml) and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. The material so obtained was triturated under diethyl ether. The resultant solid was isolated, washed with diethyl ether and dried under vacuum at 60° C. There was thus obtained the title compound (0.2 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 3.2 (t, 4H), 3.74 (t, 4H), 7.12 (m, 1H), 7.23 (m, 1H), 7.41 (m, 6H), 7.58 (m, 1H), 7.82 (d, 3H); 8.06 (d, 2H), 8.67 (s, 1H), 9.93 (s, 1H), 10.12 (s, 1H); Mass Spectrum: M+H+ 544.
Reaction SMILES: S(=O)(=O)(O)O.C(C1C=CC=CC=1[N:16](C(=O)N)[C@H:17]([C:25]([NH2:27])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(OC)=O.[C:31]([O:34][CH2:35]C)(=[O:33])[CH3:32]>>[N:16]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:32]=2[C:31](=[O:33])[O:34][C:35]=1[NH:27][C:25](=[O:26])[C@H:17]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:16]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccccc1N(C(N)=O)[C@@H](Cc1ccccc1)C(N)=O
Agent: O=S(=O)(O)O
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1nc2ccccc2c(=O)o1
Reaction time: 3 h

Procedure:
5 ml of concentrated sulfuric acid was added to 400 mg of 1-N-(2-carbomethoxyphenyl)-carbamoylphenylalanine amide (Preparation IX). The mixture was stirred for 3 hours and poured onto a mixture of ethyl acetate and ice-cold sodium bicarbonate solution. The mixture was extracted with ethyl acetate after neutralization. The organic extract, dried over magnesium sulfate, was evaporated to a solid. Recrystallization from ethyl acetate-hexane yielded 250 mg of N-(4H-3,1-benzoxazin-4-on-2-yl)-phenylalaninamide; m.p. 215°-216° C. 'H NMR 3.0 (m, 2H, PhCH2), 4.5 (m, 1H, NCH), 7.8-8.2 (overlapping peaks, 9H, ArH). IR: 3380, 3180, 1750, 1730, 1660, 1640 cm-1.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][C:4]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([Li])CCC.[F:41][C:42](=[C:45]([CH:53]1[CH2:55][CH2:54]1)[C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[CH:43]=O>O1CCCC1>[Cl:52][C:49]1[CH:48]=[CH:47][C:46]([C:45]([CH:53]2[CH2:55][CH2:54]2)=[C:42]([F:41])[CH:43]=[CH:7][C:6]2[CH:27]=[CH:28][C:3]([F:2])=[C:4]([O:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:5]=2)=[CH:51][CH:50]=1
Reactant: O=CC(F)=C(c1ccc(Cl)cc1)C1CC1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1Oc1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC(C=Cc1ccc(F)c(Oc2ccccc2)c1)=C(c1ccc(Cl)cc1)C1CC1
Temperature: -57.5 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
A mixture of (4-fluoro-3-phenoxybenzyl)triphenyl phosphonium bromide (41.77 g, 0.077 mol) in tetrahydrofuran is cooled to -55 to -60° C., treated dropwise with a 2.5M solution of butyllithium in hexanes (32.15 mL, 0.080 mol), warmed to and stirred at room temperature for 2 hours, cooled to -55 to -60° C., treated dropwise with a solution of 2-fluoro-3-cyclopropyl-3-(p-chlorophenyl)acrylaldehyde (15.7 g, 0.070 mol) in tetrahydrofuran, warmed to and stirred at room temperature overnight, and quenched with ethyl acetate and 2N hydrochloric acid. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water, 2N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and an ethyl acetate/hexanes solution (1:9) gives the title product as an oil (26.0 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([S:15]([C:18]2[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:23]([C:21]1[S:22][C:18]([S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])=[CH:19][CH:20]=1)(=[O:24])=[O:25]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(S(=O)(=O)c2ccccc2)s1
Product: Cc1noc(NS(=O)(=O)c2ccc(S(=O)(=O)c3ccccc3)s2)c1Br
Yield: 59 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(benzenesulfonyl)thiophene-2-sulfonamide was prepared: in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-benzenesulfonylthiophene-2-sulphonyl chloride in 59% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 139°-142° C.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.CO.BrBr.[NH2:13][C:14]([NH2:16])=[S:15]>O>[NH2:16][C:14]1[S:15][C:2]2[CH2:3][C:4](=[O:7])[CH2:5][CH2:6][C:1]=2[N:13]=1
Reactant: NC(N)=S
Reactant: O=C1CCC(=O)CC1
Agent: BrBr
Solvent: O
Solvent: CO
Product: Nc1nc2c(s1)CC(=O)CC2

Procedure:
8.8 g of 1,4-cyclohexanedione was dissolved with 40 mL of methanol. Solution was cooled to 10C and 4.2 mL of bromine was dropwise added at this temperature during 15 minutes. The temperature was kept at 10C for one hour and then allowed to rise to 20C. When bromine colour faded, 7.2 g of thiourea was added. The reaction mixture was then diluted with 20 mL of water and heated under reflux for 2 h. White precipitate was removed by filtration and filtrate was concentrated in vacuo and cooled. The crystals of product (6) were filtered off and washed with a cold water.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.[CH3:22][CH:23]([CH3:26])[C:24]#[CH:25]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:25]#[C:24][CH:23]([CH3:26])[CH3:22]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: C#CC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 70 °C

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (447 mg, the compound of Example A1) in triethylamine (10 ml) at room temperature was added 3-methylbut-1-yne (0.5 ml), cuprous iodide (15 mg) and bis(triphenylphosphine)palladium(II) chloride (30 mg). The reaction mixture was heated at 70° C. for two hours. The reaction mixture was partitioned between ether (100 ml) and water (100 ml). The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane: hexane (1:1) to provide the title compound as a pale yellow solid m.p. 210-2° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:20])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C@@H:3]([OH:20])[CH2:2][NH:1][CH:44]2[CH2:43][CH2:42][N:41]([C:38]3[CH:37]=[CH:36][C:35]([S:32]([NH:31][C:25]4[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=4)(=[O:33])=[O:34])=[CH:40][CH:39]=3)[CH2:46][CH2:45]2)=[CH:7][CH:8]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCC(O)COc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Product: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(NC[C@H](O)COc4ccc(OCc5ccccc5)cc4)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from 1-Amino-3-(4-benzyloxy-phenoxy)-propan-2-ol and Reference Example 73, N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid; mp 113-121° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.15-1.35 (m, 2H), 1.75-1.90 (m, 2H), 5H), 2.89 (s, 3H), 3.61 (s, 3H), 3.64 (s, 3H), 3.64-3.80 (m, 5H), 5.02 (s, 2H), 6.70-7.00 (m, 9H), 7.30-7.70 (m, 7H); MS (ES) m/z: 648.1 (MH+); HRMS Calcd. for C35H42N3O7S (MH+): 648.2743. Found: 648.2710.
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1>[CH2:7]([O:8][CH2:9][CH:10]([O:13][CH3:14])[CH2:11][OH:12])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC1COC(c2ccccc2)OC1
Solvent: C1CCOC1
Product: COC(CO)COCc1ccccc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 61.3 %

Procedure:
4.2 g of 2b was dissolved in 10 ml of tetrahydrofuran at 0° C. A solution of BH3 in tetrahydrofuran (1M, 30 ml) was added slowly, under stirring. Stirring was continued for 48 hours at room temperature. The mixture was then cooled to 0° C., quenched with cold water and extracted with diethyl ether. The solvent was eliminated and the crude product was chromatographed (eluent petroleum ether/diethyl ether, successively 80:20 and 70:30 by volume), yielding 2.6 g of 3b (62%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:6]([OH:16])[C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)[CH2:3][CH2:2]1.[H-].[Na+].F[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1>CN(C=O)C>[CH:1]1([C:4]2[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:6]([O:16][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=3)[C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)[CH2:2][CH2:3]1
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(C3CC3)cc2c1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C3CC3)cc2c1
Yield: 86 %

Procedure:
3-Cyclopropyl-6-(methyloxy)-2-phenyl-1-naphthalenol (152) (0.18 g, 0.62 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.21 g (86%) of the title compound (153) as a yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.75-0.85 (m, 4H), 1.60-1.70 (m, 1H), 3.92 (s, 3H), 6.70 (d, J=8.6 Hz, 2H), 7.03 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 7.18-7.28 (m, 6H), 7.62 (d, J=8.7 Hz, 2H), 7.66 (d, J=9.1 Hz, 1H), 9.79 (s, 1H). LCMS (ESI): m/z 395 (M+H)+.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.C1(C)C=CC=CC=1.[Sn](Cl)(Cl)(Cl)Cl>CCCCCC>[NH2:17][C:16](=[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COC(=O)CC(=O)C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
75.09 g of methyl isobutyrylacetate (0.50 mol, concentration 96%) and 61.80 g of 4-fluorobenzonitrile (0.50 mol, concentration 98%) were introduced into [500 ml of toluene and treated with 144.7 g of tin tetrachloride (0.55 mol, concentration 99%) at room temperature over the course of 16 min. After half an hour at room temperature, the thick suspension was heated to 80° C. After 3 h, 175 ml of toluene were distilled off at normal pressure, and the mixture was cooled to room temperature and treated with 450 ml of saturated sodium carbonate and 300 ml of ethyl acetate. The organic phase was separated off and the aqueous phase (after dilution with 300 ml of water) was again extracted with 300 ml of ethyl acetate. After drying the combined organic phases over sodium sulphate, the solvent was removed in vacuo (40° C./25 mbar). 127.2 g of crude product were obtained in the form of a slightly yellowish solid, which was dissolved in 160 ml of n-hexane (slightly turbid solution). After hot filtration and subsequent cooling in an ice bath, 99.8 g of methyl 2-[1-amino-1-(4-fluorophenyl)-methylene]-4-methyl-3-oxopentanoate were obtained after filtration in the form of a pale yellow solid.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][C:24]2([CH2:32][O:33][CH3:34])[CH3:31])#[CH:20]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH3:34][O:33][CH2:32][C:24]1([CH3:31])[C:23]2[C:28](=[CH:29][CH:30]=[C:21]([C:19]#[C:20][C:2]3[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=3)[CH:22]=2)[O:27][CH2:26][CH2:25]1
Reactant: C#Cc1ccc2c(c1)C(C)(COC)CCO2
Reactant: COC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC1(C)CCOc2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Reaction time: 0.25 h

Procedure:
In 11 ml of abs. DMF was successively dissolved 1.061 g (1.25 eq.) of methyl 4-iodo-benzoate, 114 mg (0.05 eq.) of bis (triphenylphosphine)palladium(II) chloride, 74.1 mg (0.12 eq.) of CuI, and 1.13 ml (2.5 eq.) of triethylamine. 701 mg (3.24 mmol) of the above prepared 6-ethynyl-4-methoxymethyl-4-methyl-chroman, dissolved in 2.7 ml of abs. DMF, was added within 1 h via dropping funnel. After 0.25 h, the reaction was quenched by pouring the reaction mixture onto crushed ice/ HCl. Extraction with diethylether, washing the organic phase twice with water, drying it over magnesium sulfate, filtration and evaporation of the solvent yielded after flash chromatography (SiO2, hexane/ ethylacetate 92/8) 630 mg of the title compound as yellowish oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][CH2:26][CH2:25][C:24]=3[CH:28]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:30]([Cu])#[N:31]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:30]#[N:31])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][CH2:26][CH2:25][C:24]=3[CH:28]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc4c(c3)CCO4)cc2c1O
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4c(c3)CCO4)cc2c1O

Procedure:
Prepared in analogy to example 31g from 1-bromo-6-(2,3-dihydro-benzofuran-5-yloxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and CuCN. ESI MS (m/z): 405 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:34]=[C:35]([O:43][S:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[Cl:53])(=[O:46])=[O:45])[CH:36]=[C:37]([C:39]([O:41][CH3:42])=[O:40])[CH:38]=1.[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][CH:64]([CH2:67]O)[CH2:63][CH2:62]1)=[O:60])([CH3:57])([CH3:56])[CH3:55]>O1CCCC1>[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][CH:64]([CH2:67][O:32][C:33]2[CH:34]=[C:35]([O:43][S:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])(=[O:46])=[O:45])[CH:36]=[C:37]([C:39]([O:41][CH3:42])=[O:40])[CH:38]=2)[CH2:63][CH2:62]1)=[O:60])([CH3:57])([CH3:55])[CH3:56]
Reactant: COC(=O)c1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
A solution of triphenylphosphine (0.249 g, 0.95 mol) in tetrahydrofuran (20 mL) was treated with diethyl azodicarboxylate (0.131 mL, 0.83 mol) and allowed to stir at ambient temperature for 15 min. before the addition of 2-chlorobenzenesulfonic acid 3-hydroxy-5-carbomethoxyphenyl ester (0.25 g, 0.73 mol), as prepared in the preceding step, in tetrahydrofuran (5 mL) and N-tert-butoxycarbonyl-4-piperidinemethanol (0.165 g, 0.77 mol), as prepared in step f of Example 1. The reaction mixture was allowed to stir at ambient temperature overnight. The solvent was evaporated and treated with ether/hexane to produce a crystalline material, which was separated by filtration. The filtrate was evaporated to an oil, placed on a silica gel column, and eluted with 20% ethyl acetate/hexane. The appropriate fractions were evaporated to give 0.14 g of material. 1H-NMR (CDCl3 ; 300 MHz): δ 1.25 (m, 3H), 1.47 (s, 9H), 1.78 (m, 2H), 2.74 (t, 2H), 3.77 (d, 2H), 3.88 (s, 3H), 4.12 (m, 2H), 6.90 (t, 1H), 7.38 (m, 3H), 7.62 (m, 2H), 7.97 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@H:15]([OH:16])[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]1[C@H:15]([O:16][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][O:17]2)[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: O[C@@H]1CCCO[C@H]1COCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: c1ccc(COC[C@@H]2OCCC[C@H]2OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.22 g of dl-trans-2-benzyloxymethyltetrahydropyran-3-ol (prepared as described in Preparation 2), 2.65 ml of dihydropyran and 0.05 g of pyridinium p-toluenesulfonate were dissolved in 40 ml of methylene chloride, and the mixture was stirred at room temperature for 4 hours. The solvent was then distilled off to give a residue, which was subjected to column chromatography through 80 g of silica gel. Those fractions eluted with mixtures of hexane and diethyl ether ranging from 6:1 to 5:1 by volume were worked up, to afford 2.93 g of the title compound as a colorless oil.