Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][C:21]([NH:26]C(=O)OC(C)(C)C)([CH2:24][CH3:25])[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)(=[O:3])[NH2:2].[ClH:34]>ClCCl>[ClH:34].[NH2:26][C:21]1([CH2:24][CH3:25])[CH2:20][CH2:19][CH:18]([O:17][C:8]2[C:7]3[C:6]4[C@@H:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH2:16][CH2:15][C:14]=4[S:13][C:12]=3[N:11]=[CH:10][N:9]=2)[CH2:23][CH2:22]1
Reactant: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CCC1(N)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Reaction time: 1 h

Procedure:
To a 50-mL round-bottom flask containing a solution of tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]-1-ethylcyclohexyl)carbamate (60 mg, 0.13 mmol, 1.00 equiv) in dichloromethane (4 mL) was added hydrochloric acid (8 M, 0.5 mL) at 0° C. The resulting solution was stirred for 1 hr at the same temperature. The reaction mixture was concentrated in vacuo to give the 2-[(3R)-12-[(4-amino-4-ethylcyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]acetamide hydrochloride (50 mg, crude) as a white solid. The solid (50 mg, crude) was dissolved in 5 mL of methanol, HCHO (37%, 0.5 mL) was added and the solution was stirred at room temperature for 30 min. NaBH3CN (22 mg) was added to the mixture and stirred overnight. The reaction was then quenched by the addition of 30 mL of water, extracted with 3×40 mL of chloroform/isopropanol. The combined organic layers were concentrated under vacuum. The crude product (50 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 50 mM NH4HCO3 and CH3CN (6.0% CH3CN up to 52.0% in 14 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[(3R)-12-[[4-(dimethylamino)-4-ethylcyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide (25.1 mg) as a white solid. MS (ES): m/z 403 [M+H]+. 1H NMR (300 MHz, CD3OD): 8.47 (1H, s), 5.29 (1H, m), 3.85-3.89 (1H, m), 2.9-3.20 (3H, m), 2.70-2.88 (1H, m),2.22-2.46 (8H, m), 2.06-2.17 (2H, m), 1.65-1.93 (8H, m), 0.98-1.07 (3H, m).
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.C([Li])CCC.[C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH3:20].Br[C:28]1[CH:29]=[C:30]([CH3:35])[CH:31]=[CH:32][C:33]=1[F:34]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[C:23]([O:22][C:19](=[O:21])[CH2:20][C:28]1[CH:29]=[C:30]([CH3:35])[CH:31]=[CH:32][C:33]=1[F:34])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(=O)OC(C)(C)C
Reactant: Cc1ccc(F)c(Br)c1
Agent: [Pd]
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(F)c(CC(=O)OC(C)(C)C)c1
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
In analogy to the procedure described in M. Jorgensen et al., J. Am. Chem. Soc. 124 (2002), 12557-12565, in a first flask, dicyclohexylamine (3.06 g, 16.9 mmol) was dissolved in toluene and cooled in an ice bath. n-Butyllithium (6.14 ml, 2.5 M solution in hexane) was added. After 5 min, tert-butyl acetate (1.78 g, 15.3 mmol) was added slowly. A second flask was charged with tri-(tert-butyl)phosphonium tetrafluoroborate (83 mg, 0.30 mmol) and tris(dibenzylideneacetone)dipalladium(0) (146 mg, 0.153 mmol) and thoroughly flushed with argon. Toluene (100 ml) was added, followed by 3-bromo-4-fluoro-toluene (2.90 g, 15.3 mmol) and by the contents of the first flask. After stirring overnight, the formed suspension was filtered over a small plug of silica gel which was washed repeatedly with diethyl ether. The filtrates were evaporated in vacuo and the residue was purified by silica gel chromatography (HEP/EA gradient) to give 2.81 g of (2-fluoro-5-methyl-phenyl)-acetic acid tert-butyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]ccc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 43 %

Procedure:
The title compound is prepared from 1H-indole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 43% of theory; LC (method 4): tR=1.97 min; Mass spectrum (ESI+): m/z=317 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH3:12])=[CH:11][C:7]=2[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CC(C)=O>[CH3:16][O:14][C:13]([C:6]1[C:7]2[CH:11]=[C:10]([CH3:12])[O:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:15]
Reactant: COc1ccc(C(=O)O)c2cc(C)oc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc(OC)c2oc(C)cc12
Temperature: 25 °C
Yield: 75 %

Procedure:
To a well stirred suspension of 7-methoxy-2-methylbenzo[b]furan-4-carboxylic acid (from step 4) (4.5 g, 24.21 mmol) and powdered potassium carbonate (7.5 g, 54.61 mmol) in acetone (740.0 mL) was added dimethyl sulfate (4.1 g, 32.76 mmol) and refluxed for 2-3 hours. Reaction mixture was cooled to room temperature and water (500 mL) was added to it. The organic material separated was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water ((2×100 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave product (4.0 g) as brown viscous oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH2:34]([O:36][C:37](=[O:42])[C:38](Br)([CH3:40])[CH3:39])[CH3:35]>>[CH3:39][C:38]([N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:6]=[C:5]([N:24]2[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:26]=[C:25]2[CH3:33])[N:4]=3)[CH2:13][CH2:14]1)([CH3:40])[C:37]([O:36][CH2:34][CH3:35])=[O:42]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Product: CCOC(=O)C(C)(C)N1CCC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1

Procedure:
Following General Procedure C, 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine was alkylated with 2-bromo-2-methyl-propanoic acid ethyl ester to give 456. LCMS m/z: 561.3 (MH+)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:18]([Mg]Br)#[CH:19]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[C:18]#[CH:19])[CH:10]=[CH:11][C:12]=1[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)ccc1N1CCCC1
Reactant: C#C[Mg]Br
Product: C#CC(O)c1ccc(N2CCCC2)c(C(C)(C)C)c1

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 1 g (4 mmol) of 3-tert-butyl-4-pyrrolidin-1-ylbenzaldehyde with 11 ml (5.5 mmol) of a 0.5M solution of ethynylmagnesium bromide. 640 mg of 1-(3-tert-butyl-4-pyrrolidin-1-ylphenyl)prop-2-yn-1-ol are obtained in the form of a colourless oil (yield=62%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:10]2=[N:11][C:12]([NH:15][C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)=[N:13][CH:14]=[C:9]2[CH:8]=[N:7]1.[O:25]1[CH2:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.CO>[O:25]1[CH2:26][CH:27]=[C:28]([C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[CH2:5][N:6]2[C:10]3=[N:11][C:12]([NH:15][C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)=[N:13][CH:14]=[C:9]3[CH:8]=[N:7]2)[CH2:29][CH2:30]1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(I)c4)c3n2)cn1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(C5=CCOCC5)c4)c3n2)cn1

Procedure:
1-(3-iodobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (50 mg, 0.12 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (29 mg, 1.2 eq), sodium carbonate (31 mg, 2.5 eq) and bis(diphenylphosphino)-ferrocenedichloropalladium(II)-DCM-complex (5 mg, 0.05 eq) in ACN/water (1:1, 2 mL) were heated in the microwave for 30 min at 130° C. The reaction mixture was diluted with methanol, passed through a thiol column, washed with methanol and evaporated. The residue was dissolved in DCM, the organic phase washed with water, dried over sodium sulfate and concentrated in vacuo to afford 1-(3-(3,6-dihydro-2H-pyran-4-yl)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH:4]=1.[CH3:23][O:24][CH2:25][C:26]([OH:28])=[O:27]>>[OH:22][C@@:12]1([C@:13]2([CH3:14])[C@H:9]([C@H:8]3[C@H:17]([CH2:16][CH2:15]2)[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH2:20][CH2:19]2)=[CH:6][CH2:7]3)[CH2:10][CH2:11]1)[CH:25]([O:24][CH3:23])[C:26]([OH:28])=[O:27]
Reactant: COC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Reactant: COCC(=O)O
Product: COC1=CC2=CC[C@@H]3[C@H](CC[C@@]4(C)[C@H]3CC[C@@]4(O)C(OC)C(=O)O)[C@@]2(C)CC1

Procedure:
Under the conditions described in Example 1, 15 g. of 3-methoxy-3,5-androstadien-17-one is reacted with the lithium enolate of the methyl ester of methoxyacetic acid. After recrystallization of the crude product from methylene chloride/ether, 17.8 g. of the methyl ester of 17β-hydroxy-3,20-dimethoxy-3,5-pregnadiene-21-oic acid is obtained, m.p. 182°-185°.
Reaction SMILES: [CH:1]([N:3]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]=[O:5])=[CH2:2].C(O)C[OH:15].C[O-].[Na+].C(O)C>CO>[CH:1]([N:3]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][OH:15])=[O:9])[CH:4]=[O:5])=[CH2:2]
Reactant: C=CN(C=O)CCC(=O)OCC
Reactant: OCCO
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: C=CN(C=O)CCC(=O)OCCO
Temperature: 90 °C
Reaction time: 2 h

Procedure:
The apparatus of Example 2 was charged with 17.1 grams (0.1 mol) of ethyl 3-(N-vinylformamido)propionate, 6.2 grams (0.1 mol) of ethylene glycol, and 0.15 gram of 25% sodium methoxide in methanol solution. The mixture was stirred at 90° C. for 2 hours. No evolution of ethanol was observed during the reaction period. Heating for an additional hour at 135° C. also failed to generate a volatile coproduct which indicated no conversion to the desired product.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:60][O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[NH:5][C:6](=[O:59])[C@H:7]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:47][CH:46]=1)[NH:8][C:9](=[O:43])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:42])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:41])[C@H:22]([CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1)[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].[CH2:70]([NH2:72])[CH3:71]>CO>[CH2:70]([NH:72][C:3](=[O:2])[C@H:4]([CH2:60][O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[NH:5][C:6](=[O:59])[C@H:7]([CH2:44][C:45]1[CH:46]=[CH:47][C:48]([O:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[CH:49][CH:50]=1)[NH:8][C:9](=[O:43])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:42])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:41])[C@H:22]([CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1)[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH3:71]
Reactant: CCN
Reactant: COC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Solvent: CO
Product: CCNC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C

Procedure:
Nα -t-Butoxycarbonyl-L-tryptophyl-L-prolyl-L-prolyl-O-benzyl-L-tyrosyl-O-benzyl-L-serine methyl ester, 1.0 g., is dissolved in 50 ml. of a mixture of methyl alcohol and ethylamine (50:50). The solution is let stand at room temperature for one day. After removal of the solvent, the crude product is purified by chromatography over silica gel in ethyl acetate-methanol (90:10) solution to give 0.6 g. of the above named product as a white glass [α]D23 -70° (c. 1.02 in methanol).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8](OCC)=[O:9])=[C:6]([OH:13])[C:5]2[S:14][C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=3[C:4]=2[S:3]1(=[O:23])=[O:22].[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1>>[CH3:1][N:2]1[C:7]([C:8]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[O:9])=[C:6]([OH:13])[C:5]2[S:14][C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=3[C:4]=2[S:3]1(=[O:22])=[O:23]
Reactant: CCOC(=O)C1=C(O)c2sc3cc(C)ccc3c2S(=O)(=O)N1C
Reactant: Cc1csc(N)n1
Product: Cc1ccc2c3c(sc2c1)C(O)=C(C(=O)Nc1nc(C)cs1)N(C)S3(=O)=O
Yield: 40 %

Procedure:
Prepared analogous to Example 1 from ethyl 2,7-dimethyl-4-hydroxy-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-4-methyl-thiazole with a yield of 40% of theory.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)([O-:3])=[O:2].Cl.Br[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.COCCOC>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Reactant: Brc1ccncc1
Agent: [Pd]
Agent: Cl
Agent: N#N
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccccc1-c1ccncc1

Procedure:
To a 1 L round-bottomed flask equipped with a reflux condenser was added 2-nitrobenzeneboronic acid (Lancaster) (10 g, 60 mmol), 4-bromopyridine hydrochloride (Fluka) (12 g, 60 mmol), Na2CO3 (25 g, 240 mmol), DME (300 in L) and H2O (100 mL). The mixture was stirred magnetically, degassed in vacuo and purged with N2. The process was repeated five times then tetrakis(triphenylphosphine)-palladium (0) (Strem Chemicals) (3.5 g, 3.0 mmol) was added and the reaction mixture was stirred at reflux under a slight positive pressure of N2 for 15 h. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc (100 mL) and satd NaCl (50 mL) diluted with H2O (50 mL). The aqueous phase was further extracted with EtOAc (2×100 mL). The combined organic fractions were extracted with 1 N HCl (3×100 mL). The combined acidic extract was washed with EtOAc (100 mL), cooled in an ice bath and adjusted to pH 10 with 5 N NaOH. The aqueous solution was saturated with NaCl and extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with satd NaCl (100 mL), dried over Na2SO4, filtered and concentrated to afford a brown oil. Purification by silica gel chromatography (5:30-65, 1 M NH3/MeOH-EtOAc-hexane) provided the title compound as a viscous, dark orange oil (6.0 g). MS (ESI, pos. ion) m/z: 201 (M+1). Calc'd for C11H8N2O2: 200.19.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:30]([F:33])([F:32])[F:31])=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:34]([O:36][C:37]([CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38])[CH3:35].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH2:34]([O:36][C:37]([CH:39]1[CH2:44][CH2:43][N:42]([C:27]([CH:24]2[CH2:25][CH2:26][N:21]([C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:12]([C:10]4[N:11]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[O:8][C:9]=4[C:30]([F:32])([F:31])[F:33])=[O:13])=[CH:20][CH:19]=3)[CH2:22][CH2:23]2)=[O:28])[CH2:41][CH2:40]1)=[O:38])[CH3:35]
Reactant: O=C(Nc1ccc(N2CCC(C(=O)O)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CCOC(=O)C1CCNCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)C2CCN(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)CC1
Reaction time: 8 h

Procedure:
To a solution of 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid (229.5 mg, 0.5 mmol) in DMF (4 mL) was added piperidine-4-carboxylic acid ethyl ester (79 mg, 0.5 mmol), PyBrop (233.1 mg, 0.5 mmol) and triethylamine (0.1 mL). The mixture was stirred overnight and solvents were evaporated. The residue was extracted with ethyl acetate and water. After the evaporation of solvents, the residue was purified through flash column chromatography using ethyl acetate and hexanes. The desired fraction was evaporated and triturated with ether and petroleum ether (2:1) to give a yellow solid as 1-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carbonyl)-piperidine-4-carboxylic acid ethyl ester. LC-MS showed a single peak with a retention time of 3.54 min. LRMS calcd for C31H33F3N4O5 (M+H) 599.24, obsd 599.3
Reaction SMILES: BrC1C=CC=C2C=1C=CN2.[NH:11]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14](=[O:15])[C:12]1=[O:13].BrCCCCC.Br[CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([O:32][CH2:31][CH2:30][CH2:29][N:11]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14](=[O:15])[C:12]1=[O:13])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCCCOCc1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: Brc1cccc2[nH]ccc12
Solvent: CCCCCBr
Product: O=C1C(=O)N(CCCOCc2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1A, and making non-critical variations to replace 4-bromoindole with isatin, and 1-bromopentane with benzyl 3-bromopropyl ether, the title compound was obtained (95%) as a pale yellow syrup: 1H NMR (300 MHz, CDCl3) δ 7.57-6.92 (m, 9H), 4.50 (s, 2H), 3.84 (t, 2H), 3.54 (t, 2H), 2.03-1.94 (m, 2H); MS (ES+) m/z 296.3 (M+1), 318.3 (M+23).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]([NH2:16])=[C:4]([F:17])[CH:3]=1.C[Al](C)C.[N:22]1([C:31]([O-])=[O:32])[CH:27]=[CH:26][CH:25]=[CH:24][N:23]1[C:28]([O-])=[O:29]>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:17])=[C:5]([N:16]2[C:28](=[O:29])[N:23]3[CH2:24][CH:25]=[CH:26][CH2:27][N:22]3[C:31]2=[O:32])[CH:6]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cc(OCc2ccccc2)c(Cl)cc1F
Reactant: O=C([O-])N1C=CC=CN1C(=O)[O-]
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=c1n(-c2cc(OCc3ccccc3)c(Cl)cc2F)c(=O)n2n1CC=CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
To a solution of 4.8 g of 4-chloro-2-fluoro-5-(phenylmethoxy)benzenamine (19.1 mmol) in 30 mL of toluene was added 11.5 mL of a 2.0M solution of trimethylaluminum (23.0 mmol) in toluene at room temperature. The mixture was stirred at the same temperature for 10 min. Then, 5.22 g of diethyl 1,2,3,6-tetrahydro-, 1,2-pyridazinedicarboxylate (22.9 mmol) was added at room temperature. The mixture was warmed under reflux overnight. The mixture was then cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel, eluting with a 1:1 v:v mixture of ethyl acetate and n-hexane to give 6.20 g of the title product of Step A as a yellow solid melting at 165°-166° C. 1H NMR (CDCl3, 300 MHz) δ 4.2 (s, 4H), 5.1 (s, 2H), 6.0 (s, 2H), 7.0 (d, 1H), 7.4 (m, 6H).
Reaction SMILES: O[CH:2]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[C:3]#[C:4][C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1.CC1(C)CCC(C)(C)C2C=C(C#CCC3C=C(C=CC=3)C(O)=O)C=CC1=2>>[CH3:15][C:11]1([CH3:16])[CH2:10][CH2:9][C:8]([CH3:17])([CH3:18])[C:7]2[CH:6]=[C:5]([C:4]#[C:3][CH2:2][C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[CH:14]=[CH:13][C:12]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C#CC(O)c3ccc(C(=O)O)cc3)ccc21
Agent: CC1(C)CCC(C)(C)c2cc(C#CCc3cccc(C(=O)O)c3)ccc21
Product: CC1(C)CCC(C)(C)c2cc(C#CCc3ccc(C(=O)O)cc3)ccc21

Procedure:
In a similar manner to Example 5(e), starting with 1.66 g (4.6 mmol) of 4-[1-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl]benzoic acid (prepared in Example 10(b) of patent EP 0,661,258), 310 mg (19.5%) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-2-propynyl]benzoic acid are obtained, with a melting point of 159-60° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16](=[O:22])[NH:17]4)[CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40](O)=[O:41])[C:35]2=[O:43])=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([N:4]3[C:5]4[CH:10]=[CH:9][C:8]([O:11][C:12]5[CH:21]=[CH:20][N:19]=[C:18]6[C:13]=5[C:14]5[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=5[C:16](=[O:22])[NH:17]6)=[CH:7][C:6]=4[O:1][CH2:2][CH2:3]3)=[O:41])[C:35]2=[O:43])=[CH:30][CH:29]=1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: O=c1[nH]c2nccc(Oc3ccc4c(c3)OCCN4)c2c2ccccc12
Product: O=C(c1cccn(-c2ccc(F)cc2)c1=O)N1CCOc2cc(Oc3ccnc4[nH]c(=O)c5ccccc5c34)ccc21
Yield: 80.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 181 using 218 (40 mg, 0.12 mmol) and 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (41 mg, 0.17 mmol) to provide 228 (54 mg, 83% yield) as a tan solid. LC-MS (M+H=561, obsd.=561).
Reaction SMILES: Br[C:2]1[C:3]([NH2:10])=[N:4][C:5]([CH3:9])=[C:6]([Br:8])[N:7]=1.[Na].[CH3:12][OH:13]>>[Br:8][C:6]1[N:7]=[C:2]([O:13][CH3:12])[C:3]([NH2:10])=[N:4][C:5]=1[CH3:9]
Reactant: CO
Reactant: Cc1nc(N)c(Br)nc1Br
Agent: [Na]
Product: COc1nc(Br)c(C)nc1N

Procedure:
A solution of 3,5-dibromo-6-methyl-2-pyrazinamine (Example 118b) (0.9 g) was added to a solution of sodium (0.39 g) in methanol (30 mL) was heated at reflux for 18 h. After removal of solvent in vacuo, the residue was partitioned between water and dichloromethane, and the organic phase dried (MgSO4), filtered and evaporated to give the title compound as a pale yellow solid (0.58 g).
Reaction SMILES: [CH2:1]([C:3](=[CH:7][C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)[C:4]([OH:6])=[O:5])[CH3:2]>CC(C)=O>[CH2:1]([C:3](=[CH:7][C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)[C:4]([O:5][C:4](=[O:6])[C:3]([CH2:1][CH3:2])=[CH:7][C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCC(=Cc1ccco1)C(=O)O
Solvent: CC(C)=O
Product: CCC(=Cc1ccco1)C(=O)OC(=O)C(=Cc1ccco1)CC

Procedure:
A fine-powder crystal of 2-ethyl-3-(2-furyl)acrylic acid anhydride was prepared from 2-ethyl-3-(2-furyl)acrylic acid in the same manner as in Example 1. Then, the fine-powder crystal was dissolved in acetone and the acetone was evaporated by circulating an argon gas in the same manner as in Example 1 to form a single crystal of 2-ethyl-3-(2-furyl)acrylic acid anhydride having a size of 5×2×1.5 mm. The single crystal was fixed on a goniohead and irradiated with Nd:YAG laser light (wavelength; 1064 nm). The output of the second harmonic wave in green was very low.