Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:13](=[O:32])[N:12]2[CH2:33][C:34]([O:36]C)=[O:35])=[CH:7][CH:6]=1)#[N:4].O>O1CCOCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:13](=[O:32])[N:12]2[CH2:33][C:34]([OH:36])=[O:35])=[CH:9][CH:10]=1)#[N:4]
Reactant: COC(=O)CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aqueous sodium hydroxide solution (1 M, 7.27 mL, 7.27 mmol) is added to a solution of methyl 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-yl)acetate (example 31, 1.76 g, 3.64 mmol) in 1,4-dioxane (15 mL) and the mixture is stirred at room temperature for 1 h. Water (80 mL) is added and the mixture is extracted twice with diethyl ether. The organic phase is discarded and the aqueous phase is acidified with aqueous hydrogen chloride (1 M) and extracted three times with diethyl ether. The combined organic layers are washed with water and saturated aqueous sodium chloride, and concentrated under reduced pressure. Yield: 1.69 g; ESI mass spectrum [M+H]+=470; Retention time: 0.88 min (Z018_S04).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Br[CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1.[OH-].[Na+]>CO>[CH2:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH:17]1[N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: BrC1Cc2ccccc2C1
Reactant: COC(=O)c1ccnc(-c2c[nH]cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccnc(-c2cn(C3Cc4ccccc4C3)cn2)c1
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield from methyl 2-(1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 5) and 2-bromo-2,3-dihydro-1H-indene according to the procedure for the preparation of Example 44, followed by saponification using NaOH in MeOH. 1HNMR (400 MHz, DMSO): δ 2.21 (2H, d), 3.52 (2H, d), 5.22 (1H, m), 7.23 (2H, m), 7.32 (2H, m), 7.45 (1H, t, J=5.4 Hz), 7.59 (1H, s), 7.82 (1H, s), 8.21 (1H, s), 8.35 (1H, d). [M+H] Calc'd for C18H15N3O2, 306. Found, 306.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:33](=[O:34])[CH:32]=[N:31]C5C=CC(OC)=NC4=5)[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:41].[C:42]([O-:45])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO.O1CCOCC1>[ClH:41].[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:33](=[O:34])[CH:32]=[N:31][C:6]5[N:7]=[CH:8][C:9]([O:45][CH3:42])=[CH:10][C:5]4=5)[CH2:24][CH2:25]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C([O-])O
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1cnc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Yield: 23 %

Procedure:
A solution of 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)(1-{2-[6-(methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]ethyl}-4-piperidinyl)carbamate (1.408 g, 2.551 mmol) in chloroform (20 ml) and MeOH (5 ml) was added 4M HCl in 1,4-dioxane (10 ml) and the reaction was stirred at rt for 0.5 h before evaporation, treatment with sat. aq NaHCO3 (50 ml). The reaction was then extracted with 20% MeOH in DCM (3×100 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the free base of the title compound as a yellow solid (266 mg, 23%).
Reaction SMILES: N[C:2]1[NH:3][C:4](=[O:19])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1.N([O-])=[O:21].[Na+]>C(O)(=O)C.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:6]2[C:5]3[C:4](=[O:19])[NH:3][C:2](=[O:21])[NH:10][C:9]=3[N:8]=[CH:7]2)=[CH:13][CH:14]=1
Reactant: O=N[O-]
Reactant: Nc1nc2ncn(Cc3ccc(Cl)cc3)c2c(=O)[nH]1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2c(ncn2Cc2ccc(Cl)cc2)[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of 2-amino-7-(4-chlorobenzyl)-1H-purin-6(7H)-one (6.8 g, 24.7 mmol) in acetic acid (80 mL) and water (10 mL) was added a solution of sodium nitrite (3.4 g, 24.7 mmol) in water (10 mL) dropwise at 50° C. The reaction was stirred at 50° C. for 1 h. The mixture was cooled to room temperature and stirred for another 1.5 h. The precipitate was collected, washed with water and ethanol, and dried in vacuo to give 7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione (6.5 g, 95.3% yield) as yellow solid. LCMS retention time 0.635 min; LCMS MH+ 277.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([N:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]1=[O:20])[CH2:10][CH2:11][CH3:12].C1(CN2C=CC(O)=CC2=O)CC1>CN(C=O)C>[CH2:9]([N:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([Cl:1])[C:14]1=[O:20])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCn1ccc(O)cc1=O
Reactant: O=C1CCC(=O)N1Cl
Agent: O=c1cc(O)ccn1CC1CC1
Solvent: CN(C)C=O
Product: CCCCn1ccc(O)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
N-Chlorosuccinimide (1.6 g, 11.96 mmol) was added to a solution of 1-butyl-4-hydroxy-1H-pyridine-2-one (2.0 g, 11.96 mmol), which was prepared as described for description D2, in DMF (30 ml). The reaction was stirred at room temperature overnight and then it was concentrated in vacuo. The crude product was purified by column chromatography (silica gel; 0-5% methanol/DCM as eluent) to yield intermediate D3 (2.0 g, 83%).
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C:3]([NH:5][NH:6][C:7]([CH:9]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:12][N:11]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:10]1)=O)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>>[N:28]1([C:26]([N:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:14][CH:9]([C:7]3[S:44][C:3]([CH:2]([CH3:34])[CH3:1])=[N:5][N:6]=3)[CH2:10]2)=[O:27])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)C(=O)NNC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CC(C)c1nnc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)s1

Procedure:
79 mg (0.155 mmol) of the compound from Example 122A and 126 mg (0.310 mmol) of Lawesson reagent were reacted according to the General Method 9. Yield: 17 mg (22% of theory)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([NH2:24])[CH2:19]2)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[CH3:25][N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][CH:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[CH2:19]2)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1cnccc1N1CCCC(N)C1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCC(NC2CCCN(c3ccncc3NC(=O)c3nc(Br)cnc3N)C2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
To a solution of 3-amino-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-bromopyrazine-2-carboxamide in CH2Cl2 at room temperature was added 1-methylpiperidin-4-one (1.5 eq) followed by sodium triacetoxyborohydride (5.0 eq). The reaction was stirred at room temperature for 12 hours, concentrated, purified by reverse phase HPLC and lyophilized to provide 3-amino-6-bromo-N-(4-(3-(1-methylpiperidin-4-ylamino)piperidin-1-yl)pyridin-3-yl)pyrazine-2-carboxamide, (66%). LCMS (m/z): 489.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13](Cl)=[O:14].[CH3:16][NH2:17]>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([NH:17][CH3:16])=[O:14]
Reactant: O=C(Cl)/C=C1\CCc2c(Cl)cc(F)cc21
Reactant: CN
Solvent: ClCCl
Product: CNC(=O)/C=C1\CCc2c(Cl)cc(F)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.2 %

Procedure:
A solution of (E)-2-(4-chloro-6-fluoro-1-indanylidene)acetyl chloride (4.0 g, 0.015 mol) in dichloromethane (36 ml) was added dropwise to an ice-cold mixture of 40% aqueous methylamine (2.6 ml, 0.03mol) and dichloromethane (100 ml) and the mixture was stirred at ambient temperature for 18 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between 5% aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate solution was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate:hexanes (1:1) as eluent to give 1.59 g (44%) of (E)-2-(4-chloro-6-fluoro-1-indanylidene)-N-Methylacetamide as a white solid: mp 173°-175° C.; NMR (CDCl3): δ7.10-7.30 (m, 2H), 6.16 (s, 1H), 5.64 (br, 1H), 3.42-3.48 (m, 2H), 3.01-3.07 (m, 2H), 2.95 (s, 3H).
Reaction SMILES: C([CH:3](O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)C.P(Br)(Br)[Br:27]>CCOCC.CO.O>[C:13]1([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][Br:27])=[CH:5][CH:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(O)c1ccc(OCC(c2ccccc2)c2ccccc2)cc1
Reactant: BrP(Br)Br
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: BrCc1ccc(OCC(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
7-4 (0.572 g, 1.9 mmol) was dissolved in ether (10 ml). The solution was cooled in ice and phosphorus tribromide (0.204 g, 0.75 mmol) was added. After 1/2 hr. the reaction was diluted with methanol (2 ml) and water (5 ml). The ether layer was separated, washed with sodium bicarbonate and water, dried and filtered. Concentration of the filtrate in vacuo gave 7-5 as a white solid. mp: 70°-73° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@H:14]([C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[CH2:40]([O:39][CH:38]([O:42][CH2:43][CH3:44])[C@@H:37]([N:25]([CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)[C:23](=[O:24])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH3:45])[CH3:41]
Reactant: CCNC(=O)NN(C)CC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 57 mg (0.33 mmol) was coupled with (S)-tert-butyl 3-amino-4-(((S)-1,1-diethoxypropan-2-yl)(naphthalen-1-ylmethyl)amino)-4-oxobutanoate (Compound IV-16) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[N:4]=1.C(N1C=CN=C1)([N:25]1[CH:29]=[CH:28]N=C1)=O.C(N)C>ClCCl.O1CCCC1>[CH2:29]([NH:25][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:22])[F:21])=[N:4]2)=[CH:13][CH:14]=1)[CH3:28]
Reactant: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
A suspension of 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid (310 mg, 1.0 mmol) in dichloromethane (5 ml) was treated with 1,1′-carbonyldiimidazole (162 mg, 1.0 mmol) at room temperature under argon. This mix was stirred for 30 minutes and then treated with a 2M solution of ethylamine in tetrahydrofuran (0.5 ml). The whole mix was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate. The organic layer was separated, dried over sodium sulphate and reduced to minimum volume by rotary evaporation to give a beige solid (250 mg) which was purified by column chromatography on a 5 g pre-packed silica column, eluting from 0-50% ethyl acetate in petroleum ether to give the title compound as a colourless solid (128 mg, 38%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNS(=O)(=O)c3ccc(C(C)(C)C)cc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 4-tert-butylbenzenesulfonyl chloride: ESMS m/e: 500.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([CH2:23][OH:22])=[CH:25][CH:26]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccc(CCBr)cc1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(CO)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.24 g-see Preparation 3), 4-hydroxymethylphenethyl bromide (0.19 g), anhydrous potassium carbonate (0.5 g) and acetonitrile (20 ml) was heated under reflux for 4 hours. The mixture was partitioned between dichloromethane (50 ml) and 5% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.14 g.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.F[C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH:31]=[O:32].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:36]4[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=4)[CH:31]=[O:32])[CH2:23]3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: Clc1ccc(-c2ccc(COC3CCCNC3)cc2)cc1
Reactant: O=Cc1ccccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(N2CCCC(OCc3ccc(-c4ccc(Cl)cc4)cc3)C2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
Tetrabutylammonium iodide (26.9 mg, 0.0729 mmol) and potassium carbonate (206 mg, 1.46 mmol) were added to a solution of 3-[(4′-chlorobiphenyl-4-yl)methoxy]piperidine (220 mg, 0.729 mmol) and 2-fluorobenzaldehyde (0.159 mL, 1.46 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at 100° C. for 8 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate and washed with brine. The washed product was dried over magnesium sulfate and the solvent was evaporated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=40:1->10:1) gave 156 mg (53%) of the desired compound as a pale yellow powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C@H:23]4[CH2:28][CH2:27][C@H:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)[CH3:2]>O1CCCC1.[Pd]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C@H:23]4[CH2:24][CH2:25][C@H:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28]4)=[CH:19][C:18]=3[F:34])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C=Cc4ccc(CC)cc4)cc3)c(F)c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(CCc4ccc(CC)cc4)cc3)c(F)c2)CC1

Procedure:
A solution of 3.2 g of 1-(p-ethylphenyl)-2-[4'-(trans-4-n-pentylcyclohexyl)-2'-fluorobiphenyl-4-yl]ethene [obtained by Heck coupling of p-ethylstyrene with 4'-(trans-4-n-pentylcyclohexyl)-2'-fluoro-4-bromobiphenyl] in 100 ml of tetrahydrofuran is hydrogenated in the presence of Pd/C. Customary work-up gives 1-(p-ethylphenyl)-2-[4'-(trans-4-n-pentylcyclohexyl)-2'-fluorobiphenyl-4-yl)ethane.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][OH:8])[C:4]([CH3:9])=[N:3]1.C[N+]1([O-])CCOCC1.C([N+](CCC)(CCC)CCC)CC>>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[O:8])[C:4]([CH3:9])=[N:3]1
Reactant: Cc1nn(C)cc1CO
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: Cc1nn(C)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a solution of 1,3-dimethyl-1H-pyrazol-4-methanol (0.33 g, 2.63 mmol), N-methyl morpholine N-oxide (0.37 g, 3.16 mmol), and crushed, dried, and activated 4 Å sieves (1.5 g) in anhydrous dichloromethane (20 ml), is added tetrapropyl ammonium peruthenate (0.09 g, 0.26 mmol). The reaction mixture is stirred for one hour at room temperature, then filtered through a silica gel plug and eluted with ethyl acetate. The filtrate is concentrated in vacuo to give 1,3-dimethyl-1H-pyrazole-4-carboxaldehyde (0.26 g, 81%) which is used without further purification. 1H NMR (CDCl3): δ=9.83 (1H, s), 7.78 (1H, s), 3.86 (3H, s), 2.46 (3H, s).
Reaction SMILES: NC(C)(C)C/C=C/C(N([C@H](CC1C=CC2C(=CC=CC=2)C=1)[C:11]([N:13]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23]CCO)C)=O)C)=O.O.[OH:41]N1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN>CN(C)C=O.ClCCl.C(OCC)(=O)C>[OH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][C:15]([NH:13][CH3:11])=[O:41]
Reactant: On1nnc2ccccc21
Reactant: CN(CCc1ccccc1OCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)Cc1ccccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methyl-3-(2-naphthyl)propionamide ##STR130## 2-(2-Hydroxyphenyl)-N-methylacetamide ##STR131## (2-Hydroxyphenyl)acetic acid (9.89 g, 63.7 mmol) and 1-hydroxybenzotriazole hydrate (8.61 g, 63.7 mmol) were dissolved in N,N-dimethylformamide (50 ml) and dichloromethane (200 ml). The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (8.67 g, 63.7 mmol) was added. The reaction mixture was stirred for 30 min at 0° C. A 8.0M solution of methyl amine (39 ml, 318 mmol) was added. The reaction mixture was stirred for 16 h, while it was slowly warming up to room temperature. It was diluted with ethyl acetate (600 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate (2×300 ml). The combined aqueous phases were extracted with ethyl acetate. The combined organic layers were washed with saturated sodium hydrogen carbonate solution (300 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (180 g), using ethyl acetate/heptane (1:1) as eluent to give 4.90 g of 2-(2-hydroxyphenyl)-N-methylacetamide.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[CH2:11]([Si:13]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:14]#[C:15][CH2:16][CH2:17][OH:18])[CH3:12].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][C:8]=1[Cl:9])[NH:6][C:14]([Si:13]([CH2:19][CH3:20])([CH2:21][CH3:22])[CH2:11][CH3:12])=[C:15]2[CH2:16][CH2:17][OH:18]
Reactant: CC[Si](C#CCCO)(CC)CC
Reactant: Nc1cc(Cl)c(Cl)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(Cl)cc2c1CCO
Temperature: 100 °C
Reaction time: 15 h
Yield: 111.5 %

Procedure:
4,5-Dichloro-2-iodoaniline (1.50 g; 5.21 mmol), 4-(triethylsilyl)but-3-yn-1-ol (1.65 mL; 7.81 mmol), bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.212 g; 0.260 mmol), lithium chloride (0.221 g; 5.21 mmol) and sodium carbonate (1.10 g; 10.42 mmol) were suspended in DMF (14 mL) and the mixture was stirred at 100° C. for 15 hours. The solution was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was successively washed with brine, sodium thiosulfate, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to afford 2.0 g (quantitative yield) of the title compound as a brown oil.
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]([C:11]3[CH:16]=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)[CH:3]2[C:20]([OH:22])=[O:21])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Ethyl (RS)-1-(4-Methoxyphenyl)-3-(3,4-methylene-dioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1-hydroxy-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (0.80 g, 1.9 mmol) in CH2Cl2 (10 ml) at 0° C. under an argon atmosphere was added triethylsilane (0.28 g, 2.4 mmol), followed by boron trifluoride etherate (1 ml, 8.1 mmol). The resulting solution was stirred at 0° C. for 10 min, and was then partitioned between EtOAc and 3M HCl. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacua, and the residue was filtered through a pad of silica gel, eluting with CH2CH2. The title compound (mixture of Δ1 and Δ2 double bond isomers) was obtained as a glassy, yellow solid (0.72 g, 94%).