Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C-]#[C-].[Na+].[Na+].[C:12]1(C)C(C)=CC=C[CH:17]=1>O1CCCC1>[CH:12]#[C:17][CH:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Cc1ccccc1C
Reactant: CCCCCC=O
Agent: [C-]#[C-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(O)CCCCC
Reaction time: 2 h

Procedure:
A 750-mL reactor is loaded with 40.1 g (400 mmoles) i.e. 49.2 mL of hexanal (RN 66-25-1) and 400 mL of anhydrous tetrahydrofuran and 100 g of a suspension of 18% sodium acetylide (RN 1066-26-8) in xylene (375 mmoles) is added by portions accompanied by stirring. An exothermic reaction takes place. Stirring is then continued for another 2 hours at no particular temperature. After hydrolysis, extractions and concentration, fractionation is carried out under reduced pressure.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([O:11]C)=[O:10])[CH:2]=[CH2:3].O1CCCC1.[OH-].[Li+]>CO>[CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([OH:11])=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCn1cccc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCn1cccc1C(=O)O
Temperature: 60 °C
Reaction time: 5 h
Yield: 102.4 %

Procedure:
A mixture of methyl 1-allyl-1H-pyrrole-2-carboxlate (4.52 g, 27.4 mmol), tetrahydrofuran (30 ml), methanol (30 ml) and an aqueous 1N lithium hydroxide solution was stirred for 3 hours at room temperature, and for 5 hours at 60° C. Thereto was added additional lithium hydroxide (0.5 g) and the mixture was stirred for 5 hours at 60° C. Methanol and tetrahydrofuran were removed under reduced pressure and the residue was acidified with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate and the organic layer was washed with water and an aqueous saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed to give the subject compound (4.24 g, 100%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[C:22]([C:23](=[O:25])[NH2:24])=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[N:18]=[CH:19][CH:20]=[CH:21][C:22]=2[C:23]([NH2:24])=[O:25])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ncccc2C(N)=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(Oc2ncccc2C(N)=O)cc1
Yield: 101.9 %

Procedure:
Dissolve {2-[4-(3-carbamoylpyridin-2-yloxy)phenyl]ethyl}carbamic acid tert-butyl ester (0.518 g, 1.45 mmol) in dichloromethane (8.4 mL). Add TFA (8.4 mL) and stir at room temperature for 4 hours. Concentrate the reaction mixture. Load the product onto an SCX column with methanol. Wash the column with methanol then elute with 50% (2.0 M NH3 in methanol) in methanol to give the title compound (0.38 g, 100%): TOF MS ES+ 258.1 (M+H)+, base peak TOF ES+ 241.1 (M-NH2)+, HRMS calcd for C14H16N3O2 258.1243 (M+H)+, found 258.1228, time 0.34 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min], tR=13.4 min, 100% purity.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=1>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Cc1ccnc(Br)c1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3cc(C)ccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and 2-bromo-4-methylpyridine
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)([OH:3])=[O:2].[Br:17]Br.CCCCCC>CC(O)=O>[Br:17][C:14]1[C:5]([CH2:4][C:1]([OH:3])=[O:2])=[CH:6][C:7]([O:15][CH3:16])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(CC(=O)O)cc1OC
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COC(=O)c1cc(Br)c(CC(=O)O)cc1OC
Temperature: 22.5 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
Methyl 4-carboxymethyl-2-methoxybenzoate 10c (12.7 g, 0.0567 mol) was dissolved in glacial AcOH (100 mL) and bromine (3.2 mL, 0.0624 mol, 1.1 eq) was added drop wise via a syringe, while maintaining the internal temperature between 20-25° C. After stirring for 4 h at RT, the AcOH was evaporated and the orange oil co-evaporated twice with toluene to give an orange solid. This material was triturated with CH2Cl2 and some of the precipitated product was removed by filtration. The rest of the product which remained in the filtrate was then concentrated, loaded on a silica gel column and eluted with 1% AcOH in EtOAc:hexane (6:4 ratio). The product was further purified by a second chromatography and re-crystallization from EtOAc:hexane to give pure methyl 5-bromo-4-carboxymethyl-2-methoxybenzoate as white solid 10d (total amount 9 g, 52% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=2[CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH3:22][C:15]1[CH:16]=[C:17]([CH2:20][OH:21])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1cc(CO)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(CO)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.9 %

Procedure:
The intermediate 4-(4-methoxycarbonyl-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.42 g) described in Preparation Example 97 was dissolved in diethyl ether (18 mL), 0.99M diisobutylaluminum hydride (9 mL) was added under cooling to −78° C., and the mixture was stirred while rising the temperature to room temperature. The mixture was further stirred at room temperature for 2 hr, methanol (0.7 mL) was added, and aqueous solution (5 mL) of Rochelle salt was added. The precipitate was collected by filtration from the reaction mixture, and the filtrate was concentrated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give 4-(4-hydroxymethyl-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (720 mg). The obtained 4-(4-hydroxymethyl-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (720 mg) was dissolved in chloroform (6 mL), 4N hydrogen chloride/ethyl acetate solution (2.3 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (654 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[O:39]1[CH2:43][CH2:42][CH2:41][C@@H:40]1[CH2:44][NH2:45]>CN(C=O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:45][CH2:44][C@H:40]4[CH2:41][CH2:42][CH2:43][O:39]4)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: NC[C@H]1CCCO1
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NC[C@H]4CCCO4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol, example 69c) was dissolved in DMF (2 mL). (R)-(tetrahydrofuran-2-yl)methanamine (45.6 mg, 0.45 mmol) was added and the reaction mixture was stirred overnight at 85° C. The solvent was evaporated under reduced pressure and the crude crude was purified by flash column chromatography using dichloromethane and methanol as eluent and gave (R)-tert-butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-((tetrahydrofuran-2-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (75 mg, 33%). MS (ES+) m/z 506.4 (M+H)+
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([S:14][C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[N:18]=[CH:17][C:16]=2[C:30]([O:32]C(C)(C)C)=[O:31])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[CH:8]1([S:14][C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[N:18]=[CH:17][C:16]=2[C:30]([OH:32])=[O:31])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)OC(C)(C)C)c2SC2CCCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2ncc(C(=O)O)c2SC2CCCCC2)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 101.5 %

Procedure:
Trifluoroacetic acid (4.72 mL, 61.46 mmol) was added to tert-butyl 5-(cyclohexylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate (Intermediate #89) (2.56 g, 6.15 mmol) in CH2Cl2 (40 mL) The resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness, re-dissolved in dioxan (20 mL) and re-evaporated to dryness to afford 5-(cyclohexylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylic acid (2.25 g, 100%) as a white crystalline solid.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[C:14]([CH:16]([CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)#[N:15].S([O-])(O)(=O)=O.[Na+].C(OCC)C.Cl.[NH2:38][CH:39]([C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)[C:40]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)=[O:41]>ClCCl.O.N1C=CC=CC=1>[CH3:49][O:48][C:45]1[CH:46]=[CH:47][C:42]([C:40](=[O:41])[CH:39]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[NH:38][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([C:14]#[N:15])[CH3:25])=[CH:43][CH:44]=1
Reactant: CC(C#N)CCCCCC(=O)O
Reactant: COc1ccc(C(=O)C(N)c2ccc(OC)cc2)cc1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: COc1ccc(C(=O)C(NC(=O)CCCCCC(C)C#N)c2ccc(OC)cc2)cc1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 83.7 %

Procedure:
14.4 g of 7-cyanooctanoic acid dicyclohexylamine salt are added to a mixture of 45 cm3 of a molar solution of sodium hydrogen sulphate and 100 cm3 of diethyl ether. The mixture is stirred for 15 minutes at 20° C. and the organic phase is then separated. The latter is dried over magnesium sulphate and filtered and the solvent is evaporated off under reduced pressure. The residue, treated with 24.6 g of thionyl chloride is heated to 50° C. for 3 hours. The mixture is evaporated under reduced pressure. The residual oil is dissolved in 10 cm3 of dichloromethane, and the solution obtained is added to a suspension, stirred and cooled to 5° C., of 12.1 g of 2-amino-1,2-bis(4-methoxyphenyl)ethanone hydrochloride in 50 cm3 of dichloromethane containing 7.8 g of pyridine. The mixture is stirred for 20 hours at room temperature, 40 cm3 of water are then added and the organic phase is separated after settling has taken place and washed with 20 cm3 of normal hydrochloric acid and with water (3 times 20 cm3). The organic phase is dried over magnesium sulphate and filtered and the solvent is evaporated off under reduced pressure. The residue is chromatographed on a column 2.8 cm in diameter containing 100 g of silica gel (50 to 200μ). The column is eluted, collecting 200 cm3 fractions, with 4 liters of a diisopropyl ether/ethyl acetate (80:20 by volume) mixture. The fractions emerging at between 0.6 liter and 4 liters are concentrated under reduced pressure (0.2 kPa). 13.9 g (83%) of (RS)-1,2-bis(4-methoxyphenyl)-2-(7-cyanooctanamido)ethanone are obtained in the form of a yellowish oil, which is used directly in the subsequent reaction.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH:18]=[CH:19][C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:25][N:21]1[CH:22]=[CH:23][N:24]=[C:20]1[CH2:19][CH2:18][C:10]1[C:9]([OH:8])=[CH:17][C:13]2[CH2:14][CH2:15][O:16][C:12]=2[CH:11]=1
Reactant: Cn1ccnc1C=Cc1cc2c(cc1OCc1ccccc1)CCO2
Agent: [Pd]
Solvent: CCO
Product: Cn1ccnc1CCc1cc2c(cc1O)CCO2
Yield: 81.9 %

Procedure:
Approximately a 1:1 ratio of cis and trans isomers of 1-(5-benzyloxy-2,3-dihydrobenzofuran-6-yl)-2-(1-methylimidazol-2-yl)ethene (104 mg, 0.3 mmoles) was hydrogenated in ethyl alcohol (15 ml) at room temperature using 10% Pd/C (15 mg) as a catalyst which was removed by suction filtration of the reaction mixture through a bed of celite. The catalyst bed was washed with ethyl alcohol (2×10 ml) and the filtrate was evaporated in vacuo to afford a white solid. Recrystallization from methlene chloride/n-hexane produced 6-(2-(1-methylimidazol-2-yl)ethyl)-5-hydroxy-2,3-dihydrobenzofuran as fine white crystals (60 mg, 79%). m.p. 190°-191° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:36])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]2[N:7]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=4)[CH:24]=3)[CH2:20][C:19](=[O:36])[NH:18][C:9]=2[CH:10]=1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (4-chloro-5-ethoxy-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M164) (244 mg, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (157 mg, 82%).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[N:13]1([CH2:2][C:3]2[N:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNC1
Reactant: COC(=O)c1cnc(CBr)cn1
Product: COC(=O)c1cnc(CN2CCCC2)cn1
Yield: 85 %

Procedure:
By essentially following the procedure used to prepare Example 137, Part B, the title compound was prepared from methyl 5-(bromomethyl)pyrazine-2-carboxylate (Part A) and pyrrolidine in 85% yield as a pale yellow oil. The mixture was subjected to flash chromatography on silica gel, eluting with a gradient of EtOAc(100-95%)/Et3N(0-5%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:14]2=[CH:15][N:16]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[C:17]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:13]2[CH:12]=[N:11]1.O>CN(C)C=O>[Br:1][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[CH:24]=[C:17]1[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:13]3[CH:12]=[N:11][N:10]([CH3:9])[C:14]3=[CH:15][N:16]12
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1N=CN2C1=Cn1c(cc3ccccc31)-c1ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: CN1N=CN2C1=Cn1c(cc3c(Br)cccc31)-c1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
A solution of 2.41 g N-bromosuccinimide in 50 ml dimethylformamide was added dropwise to 3.53 g 1-methyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine in 108 ml dimethylformamide. After the addition was complete, the reaction mixture was stirred for one hour at room temperature. Upon addition of water, a solid precipitated, which was collected, washed with water and dried. Recrystallization from water/methanol yielded 2.55 g solid;
Reaction SMILES: CN(C=O)C.[H-].[Na+].[Si:8]([O:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[CH2:16][O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1CCCCN1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a DMF (4 ml) solution of 60% sodium hydride (0.21 g, 5.2 mmol) was dropwise added a DMF (4 ml) solution of 2-(tert-butyldimethylsilyloxymethyl)piperidine (1.00 g, 4.4 mmol) at room temperature. The mixture was stirred at room temperature for 30 min., to which was then dropwise added a THF (1 ml) solution of benzyl bromide (0.75 g, 4.4 mmol). After stirring at room temperature for additional 30 min., a reaction solution was poured onto water followed by extraction with diethyl ether (30 ml). The extract was washed successively with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 1.30 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[F:11][C:12]([F:19])([F:18])[CH:13]([OH:17])[C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[NH:9][C:14]([CH:13]([OH:17])[C:12]([F:19])([F:18])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: Cc1cc(N)c(N)cc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2nc(C(O)C(F)(F)F)[nH]c2cc1C
Temperature: 108 °C

Procedure:
4,5-Dimethyl-benzene-1,2-diamine (5.04 g; 37.0 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (8.01 g; 55.6 mmoles) were suspended in 6N HCl (9 mL; 54 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (100 mL) and with ethyl acetate (100 mL), then sodium bicarbonate (6.90 g; 81.00 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×40 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as an off-white solid.
Reaction SMILES: [C:1]([C@@H:5]1[C@@H:16]2[C:17]3[C:8](=[CH:9][C:10]([O:26][CH3:27])=[C:11]([O:24][CH3:25])[C:12]=3[CH2:13][C@@H:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15]2)[C:7](O)=[CH:6]1)([O:3][CH3:4])=[O:2].Cl.[H][H]>CO.C(OCC)(=O)C.[Pd]>[C:1]([C@H:5]1[C@@H:16]2[C:17]3[C:8](=[CH:9][C:10]([O:26][CH3:27])=[C:11]([O:24][CH3:25])[C:12]=3[CH2:13][C@@H:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:15]2)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1C=C(O)c2cc(OC)c(OC)c3c2[C@@H]1C[C@H](c1ccccc1)C3
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1CCc2cc(OC)c(OC)c3c2[C@@H]1C[C@H](c1ccccc1)C3

Procedure:
To a solution of 0.5 g (1.3 mmol) of [1 R,8 S,9a R]-1-carbomethoxy-5,6-dimethoxy-3-hydroxy-8-phenyl-7,8,9,9a-tetrahydrophenalene (182-3A) in 50 mL of methanol, 50 mL of ethyl acetate, and 0.1 mL of concentrated aqueous hydrochloric acid was solution was added 0.2 g of 5% palladium supported on carbon and the mixture was shaken under 4 atmospheres of hydrogen until the gas uptake had ceased. The palladium catalyst was removed by filtration through Celite® filter aid and the filtrate concentrated to give a white solid, which was carried on to the next step without purification.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH3:12][C:13]1([CH3:25])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[O:24])[CH:21]=2)[S:16][CH2:15][CH2:14]1.[Cl-].[NH4+]>C1COCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][CH:15]1[CH2:14][C:13]([CH3:12])([CH3:25])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][OH:24])[CH:21]=2)[S:16]1
Reactant: CC1(C)CCSc2ccc(C=O)cc21
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CC(C#C[Si](C)(C)C)Sc2ccc(CO)cc21
Temperature: 25 °C
Yield: 99.9 %

Procedure:
3 ml (21.3 mmol) of trimethylsilylacetylene and 50 ml of THF were introduced into a three-necked flask. A solution of 8.6 ml (21.3 mmol) of n-butyllithium (2.5M in hexane) was added dropwise at -78° C. under a stream of nitrogen and the reaction mixture was permitted to heat to room temperature. This solution was introduced dropwise into a solution of 4 g (19.4 mmol) of 4,4-dimethyl-6-thiochromancarboxaldehyde in 50 ml of THF at -78° C. The reaction mixture was permitted to heat to room temperature, was poured into an aqueous ammonium chloride solution and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. 5.9 g (100%) of the expected alcohol were obtained in the form of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([OH:17])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[O:40]1[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]1>O1CCCC1>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:46][CH:43]2[CH2:44][CH2:45][O:40][CH2:41][CH2:42]2)=[O:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: O=C(O)C1COCCN1c1nc(Cl)ncc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NC1CCOCC1)C1COCCN1c1nc(Cl)ncc1Br
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a 200 mL round-bottom flask were added 4-(5-bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (PREPARATION x30, 2.5 g, 7.75 mmol) and 1-hydroxybenzotriazole (1.257 g, 9.30 mmol) in tetrahydrofuran (30 mL) to give a beige suspension. To this suspension were added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.783 g, 9.30 mmol) and tetrahydro-2H-pyran-4-amine (0.802 mL, 7.75 mmol). After 1 hour at 0° C., HPLC showed the reaction was almost complete. The reaction mixture was subsequently partitioned between brine and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by normal phase column chromatography (˜50 g silica, 35-100% EtOAc gradient in hexanes) to give the title compound as a white foam (1.8 g, 57.2%).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:24])=[CH:6][C:7]2[O:11][CH:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]([CH3:22])[C:8]=2[CH:23]=1)[CH:2]=[CH2:3]>C(OCC)(=O)C.[Pd]>[OH:24][C:5]1[C:4]([CH2:1][CH2:2][CH3:3])=[CH:23][C:8]2[C@H:9]([CH3:22])[C@@H:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[O:11][C:7]=2[CH:6]=1
Reactant: C=CCc1cc2c(cc1O)OC(c1ccc(OC)c(OC)c1)C2C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc2c(cc1O)O[C@H](c1ccc(OC)c(OC)c1)[C@H]2C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
A solution of Rac-(2S,3S)-5-allyl-6-hydroxy-2-(3,4-dimethoxyphenyl)-3-methyl-2,3-dihydrobenzofuran (1.28 g) in ethyl acetate (30 ml) containing 10% palladium-on-charcoal (40 mg) was hydrogenated at 20 p.s.i. for 2 hours. The mixture was filtered and the filtrate was evaporated to give (2S,3S)-6-Hydroxy-2-(3,4-dimethoxyphenyl)-3-methyl-5-propyl-2,3-dihydrobenzofuran (1.2 g); n.m.r. (CDCl3): δ0.99 (t, CH2CH2CH3), 1.37 (d, CH3 --3), 1.65 (m, CH2CH2CH3), 2.55 (t, CH2CH2CH3), 3.38 (m, H-3), 3.90, 3.91 (s, s, 2OCH3), 4.69 (b, OH), 5.07 (d, J 9.0 Hz, H-2), 6.06-7.01 (Ar--H), 6.38 (s, H-7).