Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[C:15]([CH2:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]2.[N:35]1([CH2:40][CH:41](O)[CH:42]([CH3:44])[CH3:43])[CH:39]=[CH:38][N:37]=[CH:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N:35]1([CH2:40][CH:41]([O:13][C:14]2[C:15]([CH2:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]3)[CH:42]([CH3:44])[CH3:43])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: CC(C)C(O)Cn1ccnc1
Reactant: O=C1CCCc2c1ccc(O)c2CS(=O)(=O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C(Cn1ccnc1)Oc1ccc2c(c1CS(=O)(=O)c1ccccc1)CCCC2=O
Reaction time: 72 h
Yield: 10 %

Procedure:
Diethyl azodicarboxylate (0.16 mL, 0.99 mmol) was added over 10 min to a mixture of 6-Hydroxy-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone (300 mg, 0.99 mmol), 1-(1H-imidazol-1-yl)-3-methyl-2-butanol (167 mg, 1.08 mmol), triphenylphosphine (259 mg, 0.99 mmol) and tetrahydrofuran (2 mL) under nitrogen. The resulting mixture was stirred for 3 d, whereupon it was concentrated and the residue was purified by dry-flash column chromatography (SiO2, 1-9% 2-propanol-dichloromethane) to give 6-[1-(1H-imidazol-1-ylmethyl)-2-methylpropoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1 (2H)-naphthalenone as a colorless solid, 46 mg, 10% yield. NMR spectrum was consistent with structure. Calcd. for C25H28N2O4S.¼H2O: Theory: C, 65.69; H, 6.28; N, 6.13. Found: C, 65.77; H, 6.67; N, 6.11.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C([Li])CCC.CCCCCC.[Cl:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH:26]=[CH:27][CH:28]=[O:29].C(=O)(O)[O-].[Na+]>CCOCC.O1CCCC1>[Br:8][C:6]1[CH:7]=[C:2]([CH:28](/[CH:27]=[CH:26]/[C:25]2[CH:30]=[CH:31][C:32]([Cl:33])=[C:23]([Cl:22])[CH:24]=2)[OH:29])[C:3]([O:9][CH3:10])=[N:4][CH:5]=1
Reactant: O=CC=Cc1ccc(Cl)c(Cl)c1
Reactant: COc1ncc(Br)cc1Br
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ncc(Br)cc1C(O)/C=C/c1ccc(Cl)c(Cl)c1
Temperature: -78 °C

Procedure:
A solution of 60.6 g of 3,5-dibromo-2-methoxypyridine in 900 ml of anhydrous ether was stirred under nitrogen and cooled to -78° C. to give a thick slurry. Efficient stirring was used to prevent the solid starting material from adhering to the wall of the reaction vessel. While the temperature was maintained below -65° C., 85 ml of 2.67M n-butyllithium/hexane was added dropwise. The reaction mixture was homogeneous upon completion of the addition and it was stirred for 15 minutes at -78° C. Then, a solution of 45.6 g of 3,4-dichlorocinnamaldehyde in 200 ml of anhydrous tetrahydrofuran was added dropwise while keeping the temperature below -65° C. When the addition was complete, 100 ml of aqueous saturated sodium bicarbonate solution was added to the cold reaction mixture. It was then allowed to warm to about -40° C. and then partitioned between ether and aqueous saturated sodium bicarbonate solution. The aqueous layer was extracted with ether and the combined ether layers were washed with aqueous saturated sodium chloride solution, dried over potassium carbionate, filtered and concentrated to leave a pale yellow solid. This was recrystallized from a mixture of 2-propanol/ethyl acetate/hexane (1:3:5) to give (E)-5-bromo-α-[2-(3,4-dichlorophenyl)ethenyl]-2-methoxy-3-pyridinemethanol melting at about 149°-150° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].Cl.[NH2:27][CH2:28][C:29]1[C:30]([O:40][CH3:41])=[C:31]([CH:37]=[CH:38][CH:39]=1)[C:32]([O:34]CC)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Li+].[OH-]>>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:27][CH2:28][C:29]3[C:30]([O:40][CH3:41])=[C:31]([CH:37]=[CH:38][CH:39]=3)[C:32]([OH:34])=[O:33])=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: CCOC(=O)c1cccc(CN)c1OC
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cccc(C(=O)O)c3OC)cn2)C1

Procedure:
(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-2-methoxybenzoic acid was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid and ethyl 3-(aminomethyl)-2-methoxybenzoate hydrochloride using Amidation Method 1 (HATU) and Ester Hydrolysis Method 1 (LiOH). 1H NMR (300 MHz, DMSO-d6) δ 12.6 (s, 1H), 8.78 (s, 3H), 7.88 (d, 1H), 7.78 (s, 1H), 7.10 (d, 1H), 7.05 (d, 1H), 6.90 (m, 3H), 4.45 (d, 2H), 4.36 (m, 1H), 4.18 (d, 1H), 3.90 (m, 8H), 2.05 (m, 1H), 1.87 (m, 2H), 1.52 (m, 1H), 1.21 (t, 3H). MS (ES+) 507.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:22][CH2:23][CH:24]1[CH2:26][O:25]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][CH2:23][CH:24]3[CH2:26][O:25]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: BrCCC1CO1
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCC2CO2)CC1

Procedure:
In analogy to the procedure described for example 166A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A) and (rac)-2-(2-bromo-ethyl)-oxirane (Journal of Organic Chemistry (1969), 34(12), 4060-5) gave after extraction with Et2O instead of EtOAc the title compound as yellow oil. MS: 383.2 (MH+, 2Cl).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[OH:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].OO.Cl>[OH-].[Na+].C(O)C>[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]2[O:8][C:16]3[C:15]([C:13](=[O:14])[C:12]=2[OH:11])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: O=C(CO)c1ccccc1
Reactant: C=Cc1ccc(C=O)cc1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: C=Cc1ccc(-c2oc3ccccc3c(=O)c2O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
13 gms of 4-vinyl benzaldehyde 0.955 moles) was added to a flask containing 13.9 gms of 2-hydroxyacetophenone (0.955) in 150 ml alcohol. In a separate RB flask, 13 gms of NaOH was dissolved in 100 ml of aqueous ethyl alcohol (75%). The NaOH solution was added to the reaction mixture at once. The color of the solution immediately changed from colorless to yellow to pink, and then, finally, to a dark red precipitate. The solution was allowed to sit at room temperature overnight. The next morning, 6 gms of NaOH in 200 ml of aqueous ethyl alcohol (75%) was added to the Precipitate and the reaction mixture was cooled in an icebath for 15 mins. In a separate RB flask, a solution of 50 ml of 30% hydrogen peroxide solution in 50 ml of aqueous ethyl alcohol (75%) was added to the reaction flask at once at 0°-5° C. The red colored precipitate dissolved immediately and the color of the solution slowly changed from red to yellow. The solution was gradually warmed to room temperature and was stirred for 6 hrs. The reaction mixture was neutralized with dil. HCl at 0°-4° C. A white precipitate formed and was filtered and washed with distilled water until it was free from acid. The color of the product slowly changed from colorless to light pink or to light brown during filtration.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=CC=1.P(=O)(O)(O)O.C1CC=CC=1>C(C(C)=O)C(C)C.O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH:10]2[CH2:15][CH2:14][CH:13]=[CH:16]2)[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1ccccc1
Reactant: Cc1cccc(C)c1O
Agent: C1=CCC=C1
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Solvent: CC(=O)CC(C)C
Product: Cc1cc(C2C=CCC2)cc(C)c1O

Procedure:
Into a 2-liter flask having a stirrer, a condenser and a thermometer, 366 g of 2,6-dimethylphenol, 360 g of toluene and 102 g of phosphoric acid were introduced, and a solution of mixture of 247 g of cyclopentadiene and 200 g of toluene was added dropwise over a period of 3 hours while stirring the mixture under ice cooling, followed by further stirring for 4 hours at room temperature. To the reaction solution thus obtained, tetrahydrofuran (hereinafter “THF”) and methyl isobutyl ketone (hereinafter “MIBK”) were added, and the resultant solution was washed with water until it turned neutral, followed by distillation under reduced pressure. After the reaction solvent had evaporated, unreacted 2,6-dimethylphenol evaporated. A fraction at 3 mmHg and 140° C. was 2,6-dimethyl-4-(2-cyclopenten-1-yl)phenol. The results of analysis by GPC thereof are shown in FIG. 1. Its yield determined by GPC was 94% (area ratio).
Reaction SMILES: O.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[C@@H:17]([OH:18])[C:16](=[O:19])[N:15]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:14]3[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:13]=3[S:12]2)=[CH:7][CH:6]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(O)(=O)C>[OH2:4].[ClH:29].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[C@@H:17]([O:18][C:30](=[O:32])[CH3:31])[C:16](=[O:19])[N:15]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:14]3[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:13]=3[S:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc([C@@H]2Sc3c(Cl)cccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc([C@@H]2Sc3c(Cl)cccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 110 °C
Reaction time: 6.5 h
Yield: 89.4 %

Procedure:
A mixture of 0.95 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride hydrate, 10 ml of acetic anhydride and 10 ml of acetic acid is stirred at 110° C. for 6.5 hours. After the reaction is completed, the reaction mixture is evaporated under reduced pressure to remove solvent. Toluene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent. The residue is recrystallized from a mixture of methanol and ether. 0.93 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride hydrate is obtained. Yield: 89.4%
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:21][OH:22])=[O:18])[C@@H:14]([CH3:16])[OH:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:21][OH:22])=[O:18])[C@@H:14]([CH3:16])[OH:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[F:34][C:35]([C:36]([OH:38])=[O:37])([F:40])[F:39]
Reactant: COC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccccc1)[C@@H](C)O
Temperature: 25 °C

Procedure:
BOC-Phe-Thr-Ser-OMe, 6.63 g., is suspended in 67 ml. of trifluoroacetic acid. The mixture is stirred at 25° C. until solution is complete. The solution is cooled to 0° C. and the product precipitated by the addition of 300 ml. of ether and 600 ml. of petroleum ether. The product is filtered, washed with ether:petroleum ether and dried in vacuo. The yield of substantially pure Phe-Thr-Ser-OMe.TFA is 6.4 g.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Cl)[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2].[O:30]1CCC[CH2:31]1.O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:31][OH:30])[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(CCl)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: C1CCOC1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)c1cccc(CCO)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 60 °C
Reaction time: 7 h
Yield: 66 %

Procedure:
4.24 g (25 mmol) of silver nitrate were added to a solution of 10.14 g (25.0 mmol) N-(2-isopropyl-6-chloromethylphenyl)-2-(9H-xanthen-9-yl)acetamide [prepared as described in step (iv) above] in a mixture of 500 ml of acetone, 100 ml of tetrahydrofuran and 200 ml of water, and the resulting mixture was stirred for 7 hours at 60° C. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was diluted with ethyl acetate. The diluted mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 6.41 g (yield 66%) of the title compound as crystals.
Reaction SMILES: [S:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[P:18](Cl)([O:35][C:36]1[C:41]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:40][C:39]([CH3:46])=[CH:38][C:37]=1[C:47]([CH3:50])([CH3:49])[CH3:48])[O:19][C:20]1[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][C:23]([CH3:30])=[CH:22][C:21]=1[C:31]([CH3:34])([CH3:33])[CH3:32].Cl>O1CCCC1.C(#N)C>[P:18]([O:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][C:9]2[CH:14]=[CH:13][C:12]([O:15][P:18]([O:35][C:36]3[C:37]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:38][C:39]([CH3:46])=[CH:40][C:41]=3[C:42]([CH3:45])([CH3:44])[CH3:43])[O:19][C:20]3[C:21]([C:31]([CH3:32])([CH3:33])[CH3:34])=[CH:22][C:23]([CH3:30])=[CH:24][C:25]=3[C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:11][CH:10]=2)=[CH:3][CH:4]=1)([O:35][C:36]1[C:41]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:40][C:39]([CH3:46])=[CH:38][C:37]=1[C:47]([CH3:50])([CH3:49])[CH3:48])[O:19][C:20]1[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][C:23]([CH3:30])=[CH:22][C:21]=1[C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1cc(C(C)(C)C)c(OP(Cl)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Reactant: Oc1ccc(Sc2ccc(O)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1cc(C(C)(C)C)c(OP(Oc2ccc(Sc3ccc(OP(Oc4c(C(C)(C)C)cc(C)cc4C(C)(C)C)Oc4c(C(C)(C)C)cc(C)cc4C(C)(C)C)cc3)cc2)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 0.65 gram of 4,4'-thiobisphenol (0.003 mol) in 50 ml of dry tetrahydrofuran was added to a reaction vessel equipped with stirring and heating means. While stirring the 4,4'-thiobisphenol solution under nitrogen, 0.14 gram (0.006 mol) of sodium hydride, as a 50 weight percent dispersion in mineral oil was added to the 4,4'-thiobisphenol solution and the resulting mixture was stirred at 55° C. for one hour. The reaction mixture was cooled to room temperature and a solution of bis(2,6-di-t-butyl-4-methylphenyl) phosphorochloridite (3.0 grams, 0.006 mol) in 25 ml of tetrahydrofuran was added to the reaction mixture and the mixture was stirred for three hours. The reaction product was then acidified with 1N HCl and filtered. The filtrate was heated to remove the solvent, and an oily reaction product was obtained. This oil was stirred with 50 ml of acetonitrile for one hour. The resulting white powder was recovered by filtration and dried. The product yield of tetrakis(2,6-di-t-butyl-4 -methylphenyl) 4,4'-thiobisphenyl diphosphite was 1.19 grams. The molecular weight, FD/MS was 1154. NMR data obtained was, (CDCl3): 1.44 (S, 72H), 2.24 (S, 12H), 6.06 (d, J=8.4, 4H), 6.85 (d, J=8.4, 4H), 7.30 (S, 8H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[H-].[Na+].[CH:9]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:20]1[C:21]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: BrCCCCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: BrCCCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
1,4-Dibromobutane (640.2 g, 30 mol) and sodium hydride (30.1 g, 0.60 mol, 55%) were mixed in 500 mL of DMF under an argon atmosphere. Carbazole (100.0 g, 0.60 mol) was slowly added and the reaction mixture was stirred for 6 hours at room temperature. DMF was removed by vacuum distillation. Then, 9-(4-bromobutyl)-9H-carbazole was purified in a fresh column. The resulting product was purified by silica gel column chromatography (eluent: ethyl acetate:hexane=1:50 v/v) to yield 112 g (62%) of 9-(4-bromobutyl)-9H-carbazole (Compound 8).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=[CH:14][C:15]1[CH:27]=[CH:26][C:18](/[CH:19]=[CH:20]/[C:21](OCC)=[O:22])=[CH:17][CH:16]=1.[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][C:18](/[CH:19]=[CH:20]/[CH2:21][OH:22])=[CH:26][CH:27]=1
Reactant: CCOC(=O)/C=C/c1ccc(C=Cc2nc(-c3ccccc3)oc2C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1oc(-c2ccccc2)nc1/C=C/c1ccc(/C=C/CO)cc1

Procedure:
Ethyl (E)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)vinyl]cinnamate was reduced with diisobutylaluminum hydride in the same manner as in Reference Example 22 to yield (E,E)-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)vinyl]phenyl]-2-propenol, which was then recrystallized from ethyl acetate to yield light yellow prisms having a melting point of 165°-166° C.
Reaction SMILES: C[C:2](=[O:6])[C:3]([OH:5])=[O:4].[C:7]([C:15](OC)=O)(=O)[C:8]1C=C[CH:11]=[CH:10][CH:9]=1.C(O)CCCC=C>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[C:3]([O:5][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=[CH2:15])(=[O:4])[CH:2]=[O:6]
Reactant: CC(=O)C(=O)O
Reactant: COC(=O)C(=O)c1ccccc1
Agent: C=CCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: C=CCCCCOC(=O)C=O
Temperature: 120 °C
Yield: 147.3 %

Procedure:
A mixture of 25 g of methyl benzoylformate (methyl glyoxalate), 15.25 g of 5-hexen-1-ol and 1.02 g of p-toluenesulfonic acid is heated at 120° C. for 18 hours. The methanol formed is removed by distillation. The mixture is poured into water (70 ml) and extracted with ethyl acetate. The organic phases are washed with water and dried over magnesium sulfate. Filtration, evaporation of the solvent, chromatography (eluent: 3:1 hexanethyl acetate) and distillation (b.p.=115° C. at 0.006 mbar) give hex-5-enyl glyoxalate (22.8 g, 64%) as a pale yellowish liquid.
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][CH:12]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[N:16]=3)[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH2:33][CH2:34][O:35][CH2:36][CH:37]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[O:35]1[CH2:34][CH:33]=[C:32]([C:2]2[C:3]([O:8][CH:9]3[CH2:10][CH2:11][CH:12]([C:15]4[NH:19][C:18]5[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=5[N:16]=4)[CH2:13][CH2:14]3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:37][CH2:36]1
Reactant: Brc1cccnc1OC1CCC(c2nc3ccccc3[nH]2)CC1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C1=C(c2cccnc2OC2CCC(c3nc4ccccc4[nH]3)CC2)CCOC1
Temperature: 90 °C
Yield: 66.8 %

Procedure:
The mixture of 2-[4-(3-bromo-pyridin-2-yloxy)-cyclohexyl]-1H-benzoimidazole (0.15 g, 0.40 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (0.09, 0.40 mmol), Pd(dppf)Cl2, Na2CO3, dioxane and H2O was heated at 90° C. for 10 h under N2 atmosphere. Then the mixture was concentrated and the obtained residue was purified by silica gel chromatography (DCM:MeOH=10:1) to give 2-{4-[3-(3,6-dihydro-2H-pyran-4-yl)-pyridin-2-yloxy]-cyclohexyl}-1H-benzoimidazole (0.10 g, 0.267 mmol, 75% yield) as light yellow oil.
Reaction SMILES: [CH:1](=[C:8]([C:10]([CH2:15][OH:16])([CH2:13][OH:14])[CH2:11][OH:12])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C:19](CC)([C:23](O)=[O:24])[C:20](O)=[O:21])C.C([C:30](CC)([C:34](O)=[O:35])[C:31](O)=[O:32])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH:1](=[C:8]([C:10]([CH2:11][OH:12])([CH2:13][OH:14])[CH2:15][OH:16])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([OH:24])[CH2:19][CH2:20][OH:21].[CH2:34]([OH:35])[CH2:30][CH2:31][OH:32]
Reactant: CCC(CC)(C(=O)O)C(=O)O
Agent: OCC(CO)(CO)C(O)=Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: OCCCO
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Bis-(diethyl malonate) monobenzalpentaerythritol (100 mmol) dissolved in diethyl ether (100 mL) is added dropwise to a lithium aluminium hydride in diethyl ether (100 mL) suspension. The mixture is stirred for 2 h at reflux temperature and 20 h at 20° C. After cooling at 5° C., water (5 mL), 2 N aqueous solution of sodium hydroxide (10 mL) and water (5 mL) is successively added. The suspension is filtered, the solid is washed with diethylether and the combined filtrates are dried (Na2SO4) and concentrated under vacuum. The crude product is chromatographed on silica gel using a solvent ethyl acetate as eluent to give the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])=[C:4]2[N:3]=1.C[O-].[Na+].[C:27](OCC)(=[O:29])C.Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:29][CH3:27])[N:5]2[N:9]=[CH:10][C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])=[C:4]2[N:3]=1
Reactant: CCOC(C)=O
Reactant: Cc1c(Cc2cnn3c(Cl)cc(Cl)nc23)cccc1C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)nc2c(Cc3cccc(C(F)(F)F)c3C)cnn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,7-dichloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidine (247 mg, 0.69 mmol) in methanol (2 ml) stirred under nitrogen at room temp was added a 25% sodium methoxide solution in methanol (163 mg, 0.75 mmol) dropwise. The reaction mixture was stirred at 25° C. for 30 minutes. Reaction mixture was diluted ethyl acetate (30 mL) and 5% HCl (10 mL). Two layers were separated. Organic layer was dried and concentrated. The titled product was obtained and used in next step. (193 mg, 79%); LC/MS: MS (ES+) m/e 356 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[NH2:16][C:17]1[NH:21][N:20]=[CH:19][C:18]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(OCC)(=O)C>CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[N:21]3[N:20]=[CH:19][C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]3[N:16]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn[nH]c1N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn2c(O)cc(-c3ccc(Cl)cc3)nc12
Temperature: 160 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
A mixture of ethyl 3-(4-chloro-phenyl)-3-oxo-propionate (18.1 g, 0.080 mol) and ethyl 5-amino-1H-pyrazole-4-carboxylate (13.7 g, 0.088 mol) was stirred at for 3 h 160° C. Ethyl acetate (40 mL) and hexane (40 mL) were successively added to the cooled mixture and stirring was continued at 0° C. for 0.5 h. The crystals were isolated by filtration and triturated for 1.2 h with 0.2 N HCl (80 mL). The solid was filtered off, washed with water and dried to give ethyl 5-(4-chloro-phenyl)-7-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylate (13.3 g, 52%). White solid. MS (ISN) 316.3 [(M−H)−]; mp 190-192° C.