Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 108 %

Procedure:
To (2R,3R)-3-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (51B) (6.70 g, 20.24 mmol) in CH2Cl2 (100 mL) at 0° C. was added Dess-Martin periodinane. The ice bath was removed and the reaction was warmed to rt. After 2 h, saturated aqueous Na2S2O3 and NaHCO3 (ca. 100 mL each) were added and the reaction mixture was stirred vigorously for 0.5 h. The layers were separated, the organic layer was washed with a mixture of saturated aqueous Na2S2O3 and NaHCO3 followed by brine, dried (MgSO4), and was then filtered and concentrated to obtain the title compound (7.20 g) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CN(C)C=O>[Cl:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(OCCCCl)cc1

Procedure:
Following the procedure described in example 1§E, but starting from 4-hydroxyphenylacetonitrile (4.65 g), potassium carbonate (24 g) and 1-bromo-3-chloropropane (17.3 mL) in N,N-dimethylformamide (23 mL) affords 6.86 g of 4-(3-chloropropoxy)phenylacetonitrile as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([F:20])=[CH:4][C:5]2[CH:17]3[CH2:18][CH:15]([CH2:16]3)[C:8]3[NH:9][C:10]([C:12]([NH2:14])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:19]=1.CN(C)C=O.C(N(CC)CC)C.[CH3:33][C:34]([OH:38])([C:36]#[CH:37])[CH3:35]>C(#N)C.[Cu]I.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>[F:20][C:3]1[C:2]([C:37]#[C:36][C:34]([OH:38])([CH3:35])[CH3:33])=[CH:19][C:6]2[C:7]3[N:11]=[C:10]([C:12]([NH2:14])=[O:13])[NH:9][C:8]=3[CH:15]3[CH2:16][CH:17]([C:5]=2[CH:4]=1)[CH2:18]3
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1nc2c([nH]1)C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1cc2c(cc1F)C1CC(C1)c1[nH]c(C(N)=O)nc1-2
Temperature: 80 °C
Reaction time: 0.03 h
Yield: 27.1 %

Procedure:
Into a pressure tube containing a solution 9-bromo-8-fluoro-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide (47 mg, 0.14 mmol) in 1:1 N,N-dimethylformamide/triethylamine (0.8 mL) was introduced 2-methyl-3-butyn-2-ol (235 mg, 2.80 mmol), copper(I) iodide (2 mg, 0.01) and nitrogen gas bubbled through the solution for 3 minutes. Bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.01 mmol) was added and nitrogen bubbling continued a further two minutes before the pressure tube was closed under nitrogen. The reaction mixture was warmed to 80° C. for 8 hr. After cooling to room temperature, the reaction mixture was evaporated in vacuo and the residue re-dissolved in ethyl acetate (15 mL). This solution was washed with water (2×5 mL) and brine (5 mL). The organic extract was dried over sodium sulfate, filtered and the filtrate absorbed onto silica gel. Purification by silica gel flash column chromatography (eluent: dichloromethane containing a 0-8% gradient of methanol) furnished partially purified product as a brown oil. After several acetonitile solubilisation-evaporation (in vacuo) cycles, a grey-brown solid was obtained which was slurried in acetonitrile (0.4 mL) and collected by filtration to furnish the title compound (13 mg, 0.038 mmol, 27%) as a grey solid: 1H NMR (500 MHz, d4-methanol) δ 1.59 (s, 6H), 1.63 (d, J=11.03 Hz, 2H), 2.85-2.95 (m, 2H), 3.44 (td, J=6.94, 3.78 Hz, 1H), 3.63 (td, J=8.04, 3.78 Hz, 1H), 6.86 (d, J=10.40 Hz, 1H), 8.25 (d, J=7.57 Hz, 1H); M+1=340.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:18][C:19]2[C:20]([NH:29][S:30]([C:33]3[CH:34]=[C:35]([NH:39][C:40](=[O:51])[C@@H:41]([NH:43]C(=O)OC(C)(C)C)[CH3:42])[CH:36]=[CH:37][CH:38]=3)(=[O:32])=[O:31])=[N:21][C:22]3[C:27]([N:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=[C:14]([O:16][CH3:17])[CH:15]=1>C(Cl)Cl>[ClH:1].[NH2:43][C@@H:41]([CH3:42])[C:40]([NH:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([S:30](=[O:31])(=[O:32])[NH:29][C:20]2[C:19]([NH:18][C:12]3[CH:11]=[C:10]([O:9][CH3:8])[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=3)=[N:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH:34]=1)=[O:51]
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c2)cc(OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(NC(=O)[C@H](C)N)c2)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4 N HCl is dioxane (10 mL) was added to a solution of (S)-tert-butyl 1-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenylamino)-1-oxopropan-2-ylcarbamate (160 mg) and DCM (15 mL). The mixture was stirred at room temperature for 3 hours. The solvent decanted and ether added to the solid, ether decanted to gave 80 mg product as HCl salt. 1H NMR (400 MHz, CD3OD) δ 8.50-8.49 (t, 1H), 7.89-7.87 (m, 1H), 7.74-7.72 (m, 1H), 7.61-7.5 (m, 3H), 7.40-7.36 (m, 2H), 7.21-7.20 (d, 2H), 6.23-6.21 (t, 1H), 4.09-4.03 (q, 1H), 3.78 (s, 6H), 1.60-1.58 (d, 3H); MS (EI) m/z for C25H26N6O5S.HCl: 523.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1.C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:23]=[C:22]([NH:21][C:7]([C:5]5[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])[CH:43]=[CH:42][CH:41]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cc1cc(C(=O)O)n(CC(F)(F)F)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(CC(F)(F)F)n1
Yield: 87.1 %

Procedure:
Using 3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylic acid (175 mg, 0.84 mmol), N,N-dimethylformamide (1 drop), oxalyl chloride (91 μL, 1.01 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), triethylamine (196 mg, 1.94 mmol) and tetrahydrofuran (15 mL) as starting materials and in the same manner as in Example 109, the title compound (281 mg, 87%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([C@@H:7]([C@@H:18]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:19][C@H:20]([OH:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[O:41]1[CH:46]=[CH:45][CH2:44][CH2:43][CH2:42]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH2:1]([C@@H:7]([C@@H:18]([O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:36])[CH3:35])[CH2:19][C@H:20]([O:32][CH:42]1[CH2:43][CH2:44][CH2:45][CH2:46][O:41]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C1=COCCC1
Reactant: CCCCCCCCCCC[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CCCCCC)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CCCCCC)C(=O)OCc1ccccc1)OC1CCCCO1
Temperature: -15 °C

Procedure:
M)f) 350 mg of benzyl (2S,3S,5R)-2-hexyl-3-[(t-butyldimethylsilyl)oxy]-5-hydroxyhexadecanoate and 0.5 ml of freshly distilled 3,4-dihydro-2H-pyran were dissolved in 10 ml of methylene chloride and cooled to -15° C. A crystal of p-toluenesulfonic acid monohydrate was added thereto. The mixture was stirred until the reaction has finished. Thereupon, the solution was evaporated and the residue was chromatographed on silica gel. There were obtained 330 mg of benzyl (2S,3S,5R)-2-hexyl-3-[(t-butyldimethylsilyl)oxy]5-[(tetrahydro-2 H-pyran-2-yl)oxy]hexadecanoate, MS: 603 (M+ -t-butyl).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[ClH:19].[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([S:16]([N:29]3[CH2:30][CH2:31][N:26]([C:23]4[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=4)[CH2:27][CH2:28]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)o2)c(C)[nH]c1=O
Reactant: c1cc(N2CCNCC2)ccn1
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCN(c4ccncc4)CC3)o2)c(C)[nH]c1=O
Product: Cl
Yield: 72 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-sulfonyl chloride is reacted with 1-(pyridin-4-yl)piperazine as described in Step 5, Example 24 to give the title compound as a solid (72% yield). LC/MS: RT 2.13 min; m/e 429 (M+H).
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH:14]=[O:15])=[CH:7][C:6]=1[O:16][CH3:17].[CH2:18](OS(C1C=CC(C)=CC=1)(=O)=O)[C:19]#[C:20][CH2:21][CH3:22]>CO>[CH3:17][O:16][C:6]1[CH:7]=[C:8]([CH2:11][CH2:12][NH:13][CH:14]=[O:15])[CH:9]=[CH:10][C:5]=1[O:4][CH2:18][C:19]#[C:20][CH2:21][CH3:22]
Reactant: CCC#CCOS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc(CCNC=O)ccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC#CCOc1ccc(CCNC=O)cc1OC
Yield: 59.1 %

Procedure:
41 ml NaOMe 30% in methanol are added to a solution of 31.5 g (180 mmol) N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-formamide in 880 ml methanol. 48.1 g (184 mmol) toluene-4-sulfonic acid pent-2-ynyl ester are added and the mixture is refluxed for 4 hours. After evaporation the residue is taken up in ethyl acetate and washed with water. After evaporation the residue is submitted to flash-chromatography and crystallisation in ether to give 27.8 g (61%) of the N-[2-(3-methoxy-4-pent-2-ynyloxy-phenyl)-ethyl]-formamide. 1H-NMR (300 MHz, CDCl3): 1.14 (t, 3 H, CH2CH3), 2.22 (m, 2 H, CH2CH3), 2.81 (t, 2 H, CH2CH2), 3.48 and 3.57 (2 q (17:83), 2 H, CH2CH2), 3.88 (s, 3 H, OCH3), 4.70 (m, 2 H, OCH2), 5.58 (b, 1 H, NH), 6.73 (m, 2 H, arom.), 6.98 (m, 1 H, arom.), 8.14 (s, 1 H, CHO).
Reaction SMILES: [NH2:1][CH:2]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[Cl:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1C=CC=CC=1>[ClH:16].[ClH:16].[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][CH:2]([NH:1][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: CC(C)CCC(N)C(O)c1ccccc1
Reactant: ClCCCN1CCCCC1
Solvent: c1ccccc1
Product: CC(C)CCC(NCCCN1CCCCC1)C(O)c1ccccc1
Product: Cl
Yield: 113.5 %

Procedure:
A mixture of (1RS,2SR)-2-amino-5-methyl-1-phenylhexan-1-ol (1.04 g, 5 mmol) and 1-(3-chloropropyl)piperidine (0.81 g, 5 mmol) in benzene (10 ml) was refluxed for 40 hours. After being cooled, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethanol (10 ml), followed by addition of 6N-HCl in EtOH (2 ml). Precipitated crystals were collected by filtration and then recrystallized from ethanol to obtain 1.15 g of the title compound as white crystals (yield: 57%).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH:5]1[C:18]2[NH:17]C3C(=CC=CC=3)SC=2C=C[CH:6]=1.[C:19](O)([CH3:22])([CH3:21])[CH3:20].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[C:1](#[N:4])[CH:2]=[CH2:3].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[C:19]([NH:17][C:18](=[O:27])[CH:5]=[CH2:6])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)O
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Solvent: C=CC#N
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)NC(C)(C)C
Reaction time: 6 h

Procedure:
84 g of acrylonitrile are added dropwise to a solution of 1 g of phenothiazine in 90 g of trifluoroacetic acid at 20° C., whilst stirring. Thereafter, 43 g of tert.-butanol are added dropwise at 35° C. The reaction mixture is kept at 60° to 70° C. for 6 hours and then worked up by distillation. Acrylonitrile, trifluoroacetic acid and some of the N-tert.-butylacrylamide formed are distilled off under reduced pressure. 36 g of N-tert.-butylacrylamide (melting point 120° to 122° C.) remain as the distillation bottom product. The distillate can be re-used in the reaction with the same result.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[N:7]=1)=[O:5].[CH3:19][Mg+].[Br-].O>C1COCC1>[N:13]1([C:8]2[N:7]=[C:6]([C:4](=[O:5])[CH3:19])[CH:11]=[C:10]([CH3:12])[N:9]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: CON(C)C(=O)c1cc(C)nc(-n2ccnc2)n1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(C)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.4 %

Procedure:
To a solution of 2-imidazol-1-yl-6-methyl-pyrimidine-4-carboxylic acid methoxy-methyl-amide (162 mg, 0.800 mmol) in THF (10 mL) at 0° C. was added MeMgBr (0.8 mL, 3M in Et2O, 2.40 mmol). The solution was warmed to rt and stirred for 20 min. Water was added and the mixture was extracted with ethyl acetate, washed with brine and dried over Na2SO4. Evaporation of the solvent gave 143 mg (88%) of 1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-ethanone as a yellow solid. [M+H]+ 203.17.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][CH:15]1[C:19](=[O:20])[N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH2:17][CH:16]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(CC)CC)C>C(Cl)Cl>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:18]1[C:19](=[O:20])[C@H:15]([NH:14][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:12])[C@H:16]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17]1
Reactant: CC(C)(C)OC(=O)C1CN(c2ccccc2F)C(=O)C1N
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H]1CN(c2ccccc2F)C(=O)[C@@H]1NC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
To a solution of 2-naphthoyl chloride (178 mg, 0.934 mmol) in CH2Cl2 (3 ml) was added a solution of aminopyrrolidinone of Example W (250 mg, 0.849 mmol) and triethylamine (146 mg, 1.44 mmol) in CH2Cl2 (3 ml) and the resulting solution was stirred at room temperature for 18 h. The solvent was then removed in vacuo and the resulting foam was purified by radial chromatography on a silica gel plate (4 mm) eluting with 2/98 EtOH/CH2Cl2 to give the title compound (380 mg, 100%) as a colorless foam. MS M+1 calcd for C26H25N2O4F 449, found 449. DSC =142.2°-151.5° C.@55.9 J/g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:25]=[C:24]([C:26]#[N:27])[C:19]([C:20]([O:22]C)=O)=[C:18]([C:28]2[CH:29]=[N:30][N:31]([CH2:33][CH3:34])[CH:32]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CO.[Pd].C(Cl)Cl>[CH2:33]([N:31]1[CH:32]=[C:28]([C:18]2[C:19]3[C:20](=[O:22])[NH:27][CH2:26][C:24]=3[CH:25]=[C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[N:17]=2)[CH:29]=[N:30]1)[CH3:34]
Reactant: CCn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc(C#N)c2C(=O)OC)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a flask containing methyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexyl-amino)-4-cyano-2-(1-ethyl-1H-pyrazol-4-yl)nicotinate (62 mg, 0.132 mmol) in MeOH (2 mL) was added HOAc (1 mL) to give a yellow solution. Palladium on carbon was added (14.08 mg, 0.132 mmol). The flask was evacuated and filled with H2 three times, after which the mixture was stirred vigorously at RT under a H2 atmosphere overnight. The mixture was filtered through Celite, and the solvent was removed in vacuo to give a residue, which was dissolved in DCM (10 mL) and MeOH (10 mL). Potassium carbonate was added and the mixture was stirred for 5 h. The solids were filtered out and the filtrate concentrated to give the title compound (50 mg, 86%). [M+H] calc'd for C23H32N6O3, 441; found, 441.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[CH2:27][CH:28]=C.F[P-](F)(F)(F)(F)F.N1([O:46][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.Cl.[NH2:66][C:67]1[CH:72]=[CH:71][C:70]([CH2:73][NH2:74])=[C:69]([CH3:75])[N:68]=1>CN(C=O)C.C(Cl)Cl>[NH2:66][C:67]1[N:68]=[C:69]([CH3:75])[C:70]([CH2:73][NH:74][C:28](=[O:46])[CH2:27][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([NH:8][S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=3)(=[O:11])=[O:10])[C:4]=2[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:71][CH:72]=1
Reactant: C=CCc1c(C)ccc(NS(=O)(=O)c2cccc(C)c2)c1OCc1ccccc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1nc(N)ccc1CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(S(=O)(=O)Nc2ccc(C)c(CC(=O)NCc3ccc(N)nc3C)c2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
The product of Example 9, step 7 (0.18 g, 0.42 mmol), BOP (0.21 g, 0.47 mmol), triethylamine (0.25 mL, 1.80 mmol), and 2-amino-5-aminomethyl-6-methylpyridine dihydrochloride (Sanderson, P. E., et al. WO 97/01338 (1997)) (0.10 g, 0.48 mmol), were dissolved in DMF (10 mL) and stirred at ambient temperature for 2 hours. The reaction was concentrated in vacuo and the crude product purified by flash column chromatography (gradient elution: 10% to 15% methanol in DCM) giving an impure product that was dissolved in DCM, washed with saturated sodium bicarbonate, water, and brine, dried over sodium sulfate, and filtered. The evaporated filtrate then gave the title compound as a pale yellow solid (0.23 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.64 (m, 1H), 7.56 (m, 1H), 7.35 (m, 1OH), 7.11 (d, 1H, J=8.3 Hz), 6.94 (d, 1H, J=8.5 Hz), 6.22 (d, 1H, J=8.1 Hz), 5.60 (br t, 1H, J=5.3 Hz), 4.49 (s, 2H), 4.37 (br s, 2H), 4.19 (d, 2H, J=5.5 Hz), 3.56 (s, 2H), 2.34 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H). Mass spectrum (LCMS, ESI pos.) calc'd. for C30H32N4O4S: 545.2 (M+H). Found: 545.2.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[C:13]([O:20][CH3:21])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:19]=[CH:18][CH:17]=[C:14]([CH:15]=[O:16])[C:13]=2[O:20][CH3:21])[CH:3]=1
Reactant: COc1c(O)cccc1C=O
Reactant: N#Cc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C=O)cccc1Oc1cc(Br)ccc1C#N
Yield: 82.8 %

Procedure:
4-Bromo-2-fluorobenzonitrile (0.41 g, 2.0 mmol), 3-hydroxy-2-methoxybenzaldehyde (0.31 g, 2.0 mmol) and cesium carbonate (0.66 g, 2.0 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 18 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (2×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-bromo-2-(3-formyl-2-methoxyphenoxy)-benzonitrile (0.55 g, 81%) as a yellow solid.
Reaction SMILES: [N:1]([C@H:4]1[C@H:12]2[O:13][C@H:6]([C@@H:7]3[C@H:11]2[S:10](=[O:15])(=[O:14])[N:9]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=2)[CH2:8]3)[CH2:5]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][C@H:4]1[C@H:12]2[O:13][C@H:6]([C@@H:7]3[C@H:11]2[S:10](=[O:15])(=[O:14])[N:9]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:25])([F:26])[F:27])[CH:17]=2)[CH2:8]3)[CH2:5]1
Reactant: N#Cc1ccc(N2C[C@H]3[C@H]([C@@H]4O[C@H]3C[C@H]4N=[N+]=[N-])S2(=O)=O)cc1C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(N2C[C@H]3[C@H]([C@@H]4O[C@H]3C[C@H]4N)S2(=O)=O)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 2 h

Procedure:
The mixture of Examples 24i and 24ii was dissolved in a mixed solvent of THF (3 mL) and H2O (0.25 mL). To the mixture, PPh3 (147 mg, 0.56 mmol) was added. The mixture was stirred at 70° C. for 2 h, and then cooled down. The reaction mixture was purified by SCX cartridge to give a mixture of Examples 25i and 25ii.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[C:18](=O)[CH:17]([CH2:21][C:22]24[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]5)[CH2:23]2)[CH2:29]4)[CH2:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH2:18][C:17]([CH2:21][C:22]24[CH2:23][CH:24]5[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]5)[CH2:31]2)[CH2:29]4)=[CH:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cccc3c2C(=O)C(CC24CC5CC(CC(C5)C2)C4)C3)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(-c2cccc3c2CC(CC24CC5CC(CC(C5)C2)C4)=C3)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
94.0 g (228 mmole) 7-(4′-tert-Butyl-phenyl)-2-(1-adamantylmethyl)-indan-1-one were dissolved in 291 ml toluene in a 1 l-roundbottom flask equipped with a reflux condenser. 9.5 g (1.1 eq.) sodium borohydride were added. Then 40 ml (4.3 eq.) methanol were added at 50° C. and the mixture was stirred for 6 h at 50° C. 2M sulphuric acid was added until the gas evolution ceased. After addition of 100 ml water the layers were separated and the organic layer was washed two times with 2M sulphuric acid and once with a saturated sodium chloride solution. The solvent was evaporated and the crude indanol was dissolved in approx. 350 ml of toluene. After addition of 0.7 g p-toluene sulfonic acid the mixture was heated to reflux using a Dean-Stark-trap until TLC showed complete conversion (90 min). The solution was washed twice with a saturated NaHCO3-solution, once with water and once with a saturated sodium chloride solution. Drying over magnesium sulphate, evaporation of the solvent and crystallization from 900 ml ethanol afforded 76.9 g (85%) of the desired indene as white crystals. 1H-NMR (400 MHz, CDCl3): δ=7.44, 7.32, 7.23, 7.12 (4×m, 7H, aromatic), 6.63 (s, 1H, ═CH), 3.32 (s, 2H, benzylic), 2.29 (d, 2H, aliphatic), 1.69-1.15 (m, 15H, aliphatic), 1.38 (s, 9H, C(CH3)3) ppm.