Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.C1(C[N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C.O>[NH:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1
Reactant: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: C1CC(N2CCOCC2)CCN1

Procedure:
10.00 kg (30.00 mol) 4-[1-(phenylmethyl)-4-piperidinyl]-morpholine-dihydrochloride (M) were suspended in 50.0 L tert-butanol and 10.0 L water and heated to 45° C. At 45° C. a solution of 10.37 kg (75.01 mol) potassium carbonate in 24.0 L water was metered in. Then the aqueous phase was separated off at 45° C. and 20.0 L solvent were distilled off in vacuo. The mixture was then hydrogenated at a pressure of 4 bar and an internal temperature of 60° C. until no further uptake of hydrogen could be detected. After the reaction was complete, the catalyst was filtered off and the residue was washed with 20.0 L tert-butanol.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>O.[Pd]>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Oc1cccc(I)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Oc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 170 °C

Procedure:
To a mixture of 10% Pd/C (cat), 3-iodophenol (220 mg, 1.00 mmol) and 4-(trifluoromethyl)phenylboronic acid (284 mg, 1.49 mmol) was added a solution of K2CO3 (415 mg, 3.01 mmol) in water (10 mL) and the reaction mixture was heated in a Biotage microwave (170° C., absorption high, pre-stirring 10 s) for 20 min. The crude reaction mixture was then extracted into EtOAc (40 mL×3) and dried over MgSO4 to yield 3-(4-(trifluoromethyl)phenyl)phenol as a yellow solid (212 mg, 89%, 99% purity by HPLC) which was used without further purification.
Reaction SMILES: CN(C)C=O.[OH:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:17][N:16]=2)=[CH:11][CH:10]=1)[CH3:8].[H-].[Na+].[C:34]1(C)[CH:39]=[CH:38][C:37](S(OCCCCCC)(=O)=O)=[CH:36][CH:35]=1>O>[CH2:38]([O:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:17][N:16]=2)=[CH:13][CH:14]=1)[CH3:8])[CH2:39][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(C)O)cc2)nc1
Reactant: CCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCOc1cnc(-c2ccc(C(C)OCCCCCC)cc2)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Into 20 ml of anhydrous dimethylformamide were dissolved 1.78 g (5 millimole) of the (+)-2-{4-(1-hydroxyethyl)phenyl}-5-decyloxypyrimidine obtained in Preparation Example [starting material compound (VI)] 70, and then 0.24 g (6 millimole) of 60% sodium hydride was added thereto, followed by stirring at 40° C. for 1 hour. Subsequently, 1.79 g (7 millimole) of hexyl p-toluenesulfonate were added thereto, to subject to reaction at the same temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into 200 ml of water, extracted with 200 ml of toluene, followed by separation thereof, and the organic phase was washed with water sufficiently, followed by drying over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent; toluene:ethyl acetate) to obtain 1.81 g (yield: 82%) of (+)-2-{4-(1-hexyloxyethyl)phenyl}-5-decyloxypyrimidine.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:32]=4[Cl:39])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:40]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:40])=[O:26])=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:32]=4[Cl:39])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccc(C#N)cc1Cl
Reactant: N
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccc(C#N)cc1Cl
Temperature: 125 °C
Reaction time: 5 h

Procedure:
1.50 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[-1-(2-chloro-4-cyanophenyl)ethoxy]thiophene-2-carboxylate are dissolved in 60 ml of a 7 N solution of ammonia in methanol. The reaction mixture is stirred for 5 hours at 125° C. under microwave radiation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:12][CH:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=2)[CH2:11][CH2:10]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CCN(Cc2cccc(F)c2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2cccc(F)c2)CC1)c1ccccc1
Yield: 66.8 %

Procedure:
0.2 g (0.000956 mol) of 1-(3-fluoro-benzyl)-piperidin-4-ol and 0.16 ml (0.00147 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.122 ml (0.00105 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.2 g (67%) of 1-(3-fluoro-benzyl)-piperidin-4-yl benzoate was obtained as yellow crystals.
Reaction SMILES: ClC1C=CC(C2NC(C3C=CC([O:19]C)=CC=3OCC)=NC2CC(C)C)=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[N:39]([C:40]([N:42]3[CH2:47][CH2:46][N:45](C)[CH2:44][CH2:43]3)=[O:41])[C:38]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=3[O:57][CH2:58][CH3:59])=[N:37][CH:36]2[CH2:60][CH:61]2[CH2:65]CC[CH2:62]2)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH:35]2[N:39]([C:40]([N:42]3[CH2:43][CH2:44][NH:45][C:46](=[O:19])[CH2:47]3)=[O:41])[C:38]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=3[O:57][CH2:58][CH3:59])=[N:37][CH:36]2[CH2:60][CH:61]([CH3:65])[CH3:62])=[CH:33][CH:34]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC(C)C)C(c2ccc(Cl)cc2)N1
Product: CCOc1cc(OC)ccc1C1=NC(CC(C)C)C(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-isobutyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-isobutyl-4,5-dihydro-1H-imidazole (Example 10) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 513.2267, calculated for C27H33N4O3Cl [(M+H)+]513.2263.
Reaction SMILES: BrC[C:3]1[C:4]([NH:10][C:11](=[O:17])[O:12][C:13](C)(C)C)=[N:5][CH:6]=[CH:7][C:8]=1[F:9].O>CS(C)=O>[F:9][C:8]1[C:3]2[CH2:13][O:12][C:11](=[O:17])[NH:10][C:4]=2[N:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc(F)c1CBr
Solvent: O
Solvent: CS(C)=O
Product: O=C1Nc2nccc(F)c2CO1
Yield: 29.7 %

Procedure:
The solution of the product of Step C (120 mg, 0.4 mmol) in DMSO (1 mL) was stirred at 60° C. for 4 hours under N2. Then water (10 mL) was added and extracted with ethyl acetate (3×15 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC (EtOAc:PE=1:1) to give the title compound (20 mg, 30%) as a solid. 1H-NMR (600 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.21-8.18 (m, 1H), 6.97-6.94 (m, 1H), 5.37 (s, 2H) ppm. MS: M/e 169 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH:24]([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH2:23]1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH:21][C:30](=[O:31])[CH2:29][CH2:28][CH:24]3[CH2:25][CH2:26][CH2:27][NH:22][CH2:23]3)(=[O:19])=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(N)c1
Reactant: O=C(Cl)CCC1CCCNC1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCC2CCCNC2)cc1-c1cccc(N)c1

Procedure:
Proceeding as in Reference 21, but substituting 3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-piperidin-3-ylpropanoyl chloride, gave 3′-amino-5-formyl-6-methoxy-N-(3-piperidin-3-ylpropanoyl)-biphenyl-3-sulfonamide.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][C:19](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[C:14]([F:38])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].ClC[S:41][C:42]#[N:43]>CN1CCCC1=O>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH2:19][S:41][C:42]#[N:43])=[C:14]([F:38])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: N#CSCCl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Solvent: CN1CCCC1=O
Product: CC(=O)NC[C@H]1CN(c2ccc(SCSC#N)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
Prepared according to Method B of the General Procedures for Preparation of 5-(S)-(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazolidine-2-ones from 5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)thio-3′-fluorophenyl]oxazolidine-2-one with chloromethyl thiocyanate (0.041 g, 0.38 mmol) in N-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t. for 2 h. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.022 g (35%). MS (m/z): 324 [M+H]+. 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.O>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Cl)ccc1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
Under nitrogen atmosphere, a solution of 4-chloro-2-nitro-benzoic acid (4.00 g) in THF (15 mL) was cooled to 0° C., and thereto was added dropwise dimethylsulfideborane (2.51 mL), and the mixture was stirred at room temperature for 16 hours. To the reaction solution were added water and a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=2/1) to give (4-chloro-2-nitrophenyl)methanol (1.32 g, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11](Cl)[N:10]=[C:9]([S:18][CH3:19])[N:8]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:29]2[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]2)[N:10]=[C:9]([S:18][CH3:19])[N:8]=1
Reactant: COC(=O)c1c(Cl)nc(SC)nc1NCc1ccc(OC)c(Cl)c1
Reactant: OC1CCNCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(SC)nc1N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-chloro-2-methylthiopyrimidine (prepared in the above (3)) 100 mg, 4-hydroxypiperidine 78 mg, triethylamine 0.11 ml and N,N-dimethylacetamide 3 ml is stirred at room temperature for 1 hour. The reaction mixture is diluted a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-methylthiopyrimidine as a colorless caramel 132 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.[CH:22]12[CH2:27][CH:26]1[CH2:25][N:24]([C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][N:29]=1)[CH2:23]2>>[CH:26]12[CH2:27][CH:22]1[CH2:23][N:24]([C:28]1[N:29]=[CH:30][C:31]([NH:34][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:21])=[CH:32][CH:33]=1)[CH2:25]2
Reactant: Nc1ccc(N2CC3CC3C2)nc1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Product: O=C(Nc1ccc(N2CC3CC3C2)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 73.6 %

Procedure:
The process is carried out according to the method described in example 2, using 0.15 g (0.52 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid and 0.1 g (0.57 mmol) of 2-(3-azabicyclo[3.1.0]hex-3-yl)-5-aminopyridine, prepared in step 12.2. 0.17 g of the expected product is thus isolated.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.C([O-])(=O)C.[Na+].S(=O)(=O)(O)O>C(O)(=O)C.O>[Br:1][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[C:8]=1[OH:11]
Reactant: BrBr
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (16.0 g, 100 mmol) in acetic acid (20 mL) was added into a mixture of 4-methoxy-2-nitrophenol (16.9 g, 100 mmol, sodium acetate (16.4 g, 200 mmol) and acetic acid (100 mL). The mixture was stirred for 30 min at room temperature, and then at 70° C. for 2 h and poured into water (1.5 l) containing concentrated sulfuric acid (10 mL). The precipitated solid filtered and crystallized from (chloroform/hexane) to give a brownish solid, m.p. 116–118° C.; MS m/e 246 (M−H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:22])(=O)=O)=CC=1.C(NC(C)C)(C)C.C([Li])CCC>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][C:7]([F:22])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: Cc1csc2ccc(Br)cc12
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1c(F)sc2ccc(Br)cc12
Yield: 22.3 %

Procedure:
Using analogous reaction condition and workup as described in Example 20 above from the preparation of I-20a, 5-bromo-3-methyl-benzo[b]thiophene (I-24b: 500 mg, 2.192 mmol) in dry THF was reacted with N-fluoro benzene sulfonimide (1.2 g, 3.94 mmol), diisopropyl amine (266.2 mg, 2.6315 mmol), n-butyl lithium (1.3 mL, 2.6315 mmol) to afford crude product. Purification by column chromatography on silica gel (hexane) afforded 120 mg of the product (22% yield).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH3:14][C:15]1[CH:16]=[CH:17][C:18]2[CH:22]=[C:21]([CH:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)O)[S:20][C:19]=2[CH:31]=1>>[OH:6][C:5]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3](=[O:7])[C:4]=1[CH:23]([C:21]1[S:20][C:19]2[CH:31]=[C:15]([CH3:14])[CH:16]=[CH:17][C:18]=2[CH:22]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Reactant: Cc1ccc2cc(C(O)c3ccccc3)sc2c1
Product: Cc1ccc2cc(C(C3=C(O)C(C)(c4ccccc4)C3=O)c3ccccc3)sc2c1

Procedure:
Using general procedure D, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with (6-methyl-benzo[b]thiophen-2-yl)-phenyl-methanol to give the title compound as a pale yellow solid. MS: 409.3 ([M−H]−).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[CH2:13][CH2:12][C:11]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:10][C:9]3=[O:21])[N:3]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC1(c2ccccc2)CCN(c2nccc(Cl)n2)C(=O)O1
Product: CC1(c2ccccc2)CCN(c2nccc(-c3ccc(F)cc3)n2)C(=O)O1

Procedure:
The title compound was prepared following procedures analogous to those in Example 56 using 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 4-fluorophenylboronic acid. LC-MS Method 3, tR=1.193 min, m/z=363.9. 1H NMR (CDCl3) 1.60 (s, 1H), 1.80 (s, 3H), 2.48-2.53 (m, 1H), 2.62-2.71 (m, 1H), 3.60-3.67 (m, 1H), 4.30-4.40 (m, 1H), 7.20-7.55 (m, 10H), 7.60-7.62 (m, 1H), 8.05-8.15 (m, 3H), 8.80-8.85 (m, 1H).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1.I[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[OH:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COCOc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2cccc(O)c2)cc1
Temperature: 90 °C

Procedure:
2 g of 3-methoxymethoxyphenylboronic acid (13.3 mmol) and 1.86 mL (11 mmol) of ethyl 4-iodobenzoate are dissolved in 20 mL of DME. 13.3 mL of 2M potassium carbonate solution (26.6 mmol) are then added and the reaction medium is degassed with a stream of argon for 10 minutes. 640 mg of Pd(PPh3)4 are then added and the mixture is heated at 90° C. for 14 hours. After treatment with saturated ammonium chloride solution, extraction with ethyl acetate and then drying and evaporation of the solvents from the organic phase, the residue is dissolved in 25 mL of anhydrous methanol and 0.5 mL of sulphuric acid is then added; The reaction medium is refluxed for 15 h and then cooled and finally treated by addition of water. After extraction with ethyl acetate, the organic phase is separated out by settling, dried and then concentrated under reduced pressure. After purification by chromatography on a column of silica, a colourless oil is obtained (m=2 g; Y=75%). (
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:23](=[C:24]3[CH2:29][CH2:28][N:27](C)[CH2:26][CH2:25]3)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH2:16][CH2:15][C:14]=2[CH:31]=1)#[N:9].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(N(CC)CC)C>[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:23](=[C:24]3[CH2:29][CH2:28][N:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:26][CH2:25]3)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH2:16][CH2:15][C:14]=2[CH:31]=1)#[N:9]
Reactant: CN1CCC(=C2c3ccc(C#N)cc3CCc3cccnc32)CC1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(=C2c3ccc(C#N)cc3CCc3cccnc32)CC1
Yield: 75.2 %

Procedure:
Toluene (40 ml) was added to 1 g of 8-cyano-11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine to dissolve the latter, followed by the addition of 0.52 g of triethylamine and 1.92 g of ethyl chloroformate. The resulting mixture was refluxed for 2.5 hours. The mixture was cooled and washed with water. The organic layer was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column. The substance eluted with chloroform was recrystallized from n-hexane, whereby 0.89 g of 8-cyano-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine was obtained (yield: 75%).
Reaction SMILES: [Zn:1].[F:2][C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][C@@H:9]([OH:29])/[CH:10]=[CH:11]/[C:12]#[C:13]/[CH:14]=[CH:15]/[CH:16]=[CH:17]/[C@@H:18]([OH:28])[C@@H:19]([OH:27])[CH2:20][O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:5][CH:4]=1.O>CO>[Zn:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C@@H:9]([OH:29])/[CH:10]=[CH:11]/[CH:12]=[CH:13]\[CH:14]=[CH:15]\[CH:16]=[CH:17]\[C@@H:18]([OH:28])[C@@H:19]([OH:27])[CH2:20][O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:30][CH:31]=1
Reactant: COC(=O)COC[C@H](O)[C@H](O)/C=C/C=C/C#C/C=C/[C@H](O)COc1ccc(F)cc1
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COC(=O)COC[C@H](O)[C@H](O)/C=C/C=C/C=C\C=C\[C@H](O)COc1ccc(F)cc1
Reaction time: 42 h
Yield: 10.8 %

Procedure:
Activated zinc was prepared from 10 g of zinc and the reduction carried out using the procedure described in Helv. Chim. Acta (1987), Vol. 70, p. 1025). A solution of (5S,6R,7E,9E,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid, methyl ester, (0.8 g, 1.2 mmol) in methanol (4 mL) was added to a slurry of activated zinc in 1:1 methanol:water (45 mL). The flask was stirred vigorously under nitrogen for 24-60 hours. The mixture was filtered through a pad of Celite 545 and rinsed with methanol (3x25 mL). Purification by chromatography on a reverse phase semi-prep column using a gradient of acetonitrile and water afforded 55 mg of (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxa-7,9,11,13-hexadecatetraenoic acid, methyl ester, as an oil; 1H-NMR (400 mHz, methanol-d4) δ3.62 (m, 2H), 3.75 (s, 3H), 3.93 (m, 2H), 4.13 (m, 3H), 4.58 (m, 1H), 5.85 (m, 2H), 6.14 (m, 2H), 6.36 (m, 2H), 6.77 (m, 1H), 6.96 (m, 5H) ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH2:16][N:17]([CH:21]3[CH2:23][CH2:22]3)[CH:18]([CH3:20])[CH3:19])[CH:15]=1)[O:12][C:11]([CH3:25])([CH3:24])[CH2:10][C:9]2([CH3:27])[CH3:26])=[O:5])C.[OH-].[Na+]>C(O)C.O1CCCC1>[CH:21]1([N:17]([CH2:16][C:14]2[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([CH3:24])([CH3:25])[CH2:10][C:9]3([CH3:27])[CH3:26])[CH:18]([CH3:20])[CH3:19])[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1cc(CN(C(C)C)C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)N(Cc1cc(C(=O)O)cc2c1OC(C)(C)CC2(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of 8-[(cyclopropyl-isopropyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-carboxylic acid ethyl ester (Intermediate 38, 0.09 g, 0.26 mmol) in ethanol (3 mL) and tetrahydrofuran (1 mL) was treated with a 1M solution of sodium hydroxide (3 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The volatiles were evaporated in vacuo, the residue was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water and brine and dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound (0.079 g, 96%). It was used as such for the next step.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:17](I)[CH3:18]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][O:16][CH2:17][CH3:18])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: COC(=O)c1cc(CO)cc(C(C)(C)C)c1
Product: CCOCc1cc(C(=O)OC)cc(C(C)(C)C)c1

Procedure:
Methyl 3-tert-butyl-5-hydroxymethylbenzoate (2.0 g) was alkylated with ethyl iodide analogously to the conditions of O5.043. 1.18 g of the title compound were obtained.