Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[N:28]([CH3:30])[CH3:29])[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH:33]([C:37]([NH2:39])=[O:38])[CH2:32]1>O1CCOCC1>[CH3:29][N:28]([CH3:30])[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:20]=1[CH2:19][N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:31]3[CH2:36][CH2:35][CH2:34][CH:33]([C:37]([NH2:39])=[O:38])[CH2:32]3)[N:11]=2)[CH2:14][CH2:15]1
Reactant: COc1cccc(N(C)C)c1CN1CCC(Nc2nc(Cl)nc3ccccc23)CC1
Reactant: NC(=O)C1CCCNC1
Solvent: C1COCCO1
Product: COc1cccc(N(C)C)c1CN1CCC(Nc2nc(N3CCCC(C(N)=O)C3)nc3ccccc23)CC1

Procedure:
Compound 47 (50 mg, 0.12 mmol) and piperidine-3-carboxamide (45 mg, 0.36 mmol) in 1,4-dioxane (5 mL) were heated to 117° C. for 24 h in a sealed tube. The product (AGN-219171) was purified by basic alumina flash column chromatography using 3% MeOH and 97% CH2Cl2 solution as eluent.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:30])[C@@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][C:39]=1[S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:30])[C@@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:22][S:48]([C:39]1[CH:40]=[CH:41][C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=1)(=[O:50])=[O:49])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 93.1 %

Procedure:
A solution of 10 g of (D)-phenylalanine benzyl ester p-toluenesulphonate in 150 ml of methylene chloride is treated with 8.2 ml of triethylamine and cooled to 0° C. 5.8 g of 2-naphthylsulphonyl chloride are added thereto and the mixture is stirred at room temperature for 12 hours. The reaction mixture is evaporated, the residue is taken up in 200 ml of ethyl acetate, the precipitated triethylammonium chloride salt is filtered off under suction and the mother liquor is washed with water. After evaporation of the organic phase and crystallization from hexane there are obtained 9.7 g of N-(2-naphthylsulfonyl) -3-phenyl-D-alanine benzyl ester, m.p. 107° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]2.[H-].[Na+].[CH3:24]I.[BrH:26]>CN(C)C=O.CC(C)=O>[BrH:26].[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:24])[C:16](=[O:21])[CH2:15][CH2:14]2
Reactant: Cc1c(-c2ccc3c(c2)CCC(=O)N3)nc2ccccn12
Reactant: CI
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc3c(c2)CCC(=O)N3C)nc2ccccn12

Procedure:
To a solution of 6-(3-methylimidazo[1,2-a]-pyridine-2-yl)-3,4-dihydrocarbostyril (3 g) in dimethylformamide (50 ml) was added 50% oily sodium hydride (590 mg) and the mixture was reacted for 2 hours at room temperature. Then, after adding methyl iodide (1.85 g), the mixture was further reacted for 3 hours at room temperature. After completion of reaction, dimethylformamide was evaporated. Chloroform and 0.5 N sodium hydroxide were added to the residue for extraction. The chloroform layer was washed with water thoroughly and dried followed by evaporation of chloroform. The residue was purified using silica gel column chromatography and the oily product thus obtained was dissolved in acetone. The solution was adjusted to pH of about 1 by the addition of 48% hydrobromic acid and crystals which formed were collected by filtration. The crude crystals thus obtained were recrystallized from water to give 2.9 g of 6-(3-methylimidazo[1,2-a]pyridine-2-yl)-1-methyl-3,4-dihydrocarbostyril monohydrobromide.
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]1[NH:19][C:20](=[N:23][C:24]([O:26][CH3:27])=[O:25])[S:21][CH3:22].ClC1C=C(C=CC=1)C(OO)=[O:33]>C(Cl)Cl>[NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH3:11])=[O:33])=[C:4]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]1[NH:19][C:20](=[N:23][C:24]([O:26][CH3:27])=[O:25])[S:21][CH3:22]
Reactant: CCCSC1=C(Cc2ccccc2)C(NC(=NC(=O)OC)SC)C(=N)C=C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCS(=O)C1=C(Cc2ccccc2)C(NC(=NC(=O)OC)SC)C(=N)C=C1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-iminophenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-4-n-propylthiobenzene (4.02 g.; 0.01 mol) in methylene chloride (50 ml.), cooled to -5° C., is added 85% of m-chloroperoxybenzoic acid (2.02 g.; 0.01 mol). The mixture is stirred at -5° C. for 30 minutes and is washed with aqueous sodium bicarbonate solution. The methylene dichloride is evaporated from the organic solution to afford 1-iminophenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-4-n-propylsulfinylbenzene.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:28][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN=Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Under a nitrogen atmosphere, p-hydroxybenzaldehyde (99.6 g), n-octadecylamine (200.0 g) and p-toluenesulfonic acid (13.4 g) were added to toluene (1200 ml) and the mixture was refluxed with heating and simultaneously the azeotropic water was removed. After about 2 hours, the reaction mixture was cooled to room temperature to precipitate a crystal, which was filtered off under reduced pressure. This crystal was recrystallized from isopropanol to obtain the desired product (207.9 g). Yield 75%; m.p. 101° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][O:25]C3CCCCO3)=[O:23])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[ClH:34].CC#N>CO>[ClH:34].[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][OH:25])=[O:23])=[CH:18][CH:19]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)cc1)NOC1CCCCO1
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (500 mg) in MeOH (5 mL) was added hydrogen chloride methanol reagent 10 (2.38 mL, Tokyo Kasei), and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added CH3CN and the solvent was removed in vacuo. Obtained colorless solid was triturated with CH3CN to give (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamide hydrochloride (257.4 mg) as colorless powder.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[Na+]>CN(C=O)C.O>[CH3:6][O:5][C:3](=[O:4])[CH2:2][S:14]([C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: COC(=O)CBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CS(=O)(=O)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 77.7 %

Procedure:
A mixture of methyl bromoacetate (11.25 ml, 116 mmol) and sodium 4-chloro-benzenesulfinate (25.2 g, 116 mmol) in DMF (120 ml) was stirred and heated at 80° C. for 2 h. The solution was diluted with water (360 ml). The separated oil was extracted with chloroform (200 ml) and washed with water (3×80 ml). The organic phase was evaporated in vacuo to obtain 22.4 g of the title compound in 77.7% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Li])CCC.[C:23]1([CH2:29]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:5]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NC(C)(C)CO2)cc1OC
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2=NC(C)(C)CO2)c(Cc2ccccc2)c1OC
Reaction time: 2 h

Procedure:
A solution of 2-[3,4-Dimethoxyphenyl]-4,5-dihydro 4,4-dimethyloxazole (15 g) in dry tetrahydrofuran (100 ml) under a nitrogen atmosphere was cooled to -45° in a chlorobenzene/dry ice bath. Butyl lithium (45.9 ml 1.6 M solution) was added dropwise and the mixture stirred at -45° for 2 hours. Phenylmethyl bromide (38 ml) was then added dropwise and the mixture allowed to stir at 20° for 16 hours. The mixture was quenched with brine and the aqueous phase extracted with ether. The organic phase was separated, dried over magnesium sulphate, filtered and evaporated to leave a solid. Purification by flash chromatography (30% ether/40/60 petrol) gave the title compound as a colourless solid (10.58 g); mp 81°-82°.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: O=S1(=O)CCN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC1
Product: O=S1(=O)CCN(c2nc(N3CCNCC3)nc3c(SCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8 -benzylthio-2-chloro-4-(1,1-dioxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 238°-239° C.) and piperazine.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C@H:6]2[O:12][C@H:11]([CH2:13]O)[C@@H:10]([OH:15])[C@H:9]([OH:16])[C@H:7]2[N:8]=1)[CH3:2].[Cl:17]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[Cl:17][CH2:13][C@H:11]1[O:12][C@H:6]2[C@H:7]([N:8]=[C:4]([NH:3][CH2:1][CH3:2])[S:5]2)[C@@H:9]([OH:16])[C@@H:10]1[OH:15]
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CCl)O[C@@H]2S1
Temperature: 50 °C
Reaction time: 2 h
Yield: 16.9 %

Procedure:
In a 5 mL seal vial equipped with a stir bar was added (3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol (30.00 mg; 0.12 mmol; 1.00 eq.) and 1-chloropyrrolidine-2,5-dione (24.20 mg; 0.18 mmol; 1.50 eq.) in N,N-dimethylformamide (1.00 ml) followed by triphenylphosphine (63.38 mg; 0.24 mmol; 2.00 eq.). After the clear solution was stirred at 50° C. for 2 h, color became wine red. The reaction was stirred for overnight before it is concentrated and dissolved in 2 mL MeOH. Yamazen HPLC Channel1 (acidic condition, 220 nm, 55 g Interchim column, product efflux at H2O/ACN=75/25) was used to isolate 5.4 mg (12%) of the title compound as a white solid once lyophilized.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)=[O:16])=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[NH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)=[O:16]
Reactant: O=C(CCCNC(=O)OCc1ccccc1)Nc1ccc2[nH]ccc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCCCC(=O)Nc1ccc2[nH]ccc2c1

Procedure:
4.56 of 4-(Benzyloxycarbonylamino)-N-(1H-indol-5-yl)butanamide, 1.1 g palladium (10%) on charcoal and 100 ml methanol are added together at room temperature in the presence of hydrogen until about 90% of theoretical hydrogen uptake is obtained (maximum uptake). The suspension is filtered through talc and the solvent evaporated off giving an oily residue of 4-amino-N-(1H-indol-5-yl)butanamide which is recrystallised from methanol/ether (M.P. 124°-136°).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:11][C@H:10]1[OH:21])C1C=CC=CC=1>[OH-].[Pd+2].[OH-].CO>[NH2:8][C@@H:9]1[CH2:13][N:12]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:11][C@H:10]1[OH:21]
Reactant: O[C@@H]1CN(c2ccc(F)cc2)C[C@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: N[C@@H]1CN(c2ccc(F)cc2)C[C@H]1O
Temperature: 50 °C
Reaction time: 24 h
Yield: 122 %

Procedure:
A methanol suspension (4.6 mL) of (3R,4R)-4-(dibenzylamino)-1-(4-fluorophenyl)pyrrolidin-3-ol (230 mg, 0.61 mmol) synthesized in Reference Synthesis Example 73 and palladium hydroxide-activated carbon catalyst (23 mg) was stirred under hydrogen atmosphere at 50° C. for 1 day. After completion of the reaction, the suspension was filtered with Celite and the filtrate was concentrated under reduced pressure to obtain a crude product (146 mg) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:22][C:23]3[N:28]=[C:27]([C:29]([O:31]C)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[C:7]([CH:19]3[CH2:21][CH2:20]3)[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:22][C:23]3[N:28]=[C:27]([C:29]([OH:31])=[O:30])[CH:26]=[CH:25][CH:24]=3)=[C:7]([CH:19]3[CH2:20][CH2:21]3)[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: CCn1cc(-n2c(C3CC3)c(Sc3cccc(C(=O)OC)n3)c3ccc(Cl)c(F)c32)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1cc(-n2c(C3CC3)c(Sc3cccc(C(=O)O)n3)c3ccc(Cl)c(F)c32)cn1
Temperature: 60 °C
Yield: 103.7 %

Procedure:
To a stirred solution of compound 9 (2.81 g, 5.97 mmol) in THF:water (4:1) (40 mL) was added 1M aq. NaOH solution (6.03 mL, 6.03 mmol) and the mixture was heated at 60° C. for 1 h. After completion of the reaction, the solvent was removed to afford Compound 1-92 (2.83 g, 100%) as a light brown solid. LC-MS: 457 (M++1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Oc2ccc(N)c([N+](=O)[O-])c2)cc1

Procedure:
1-(4-Fluorophenyl)ethanone (1.79 g, 12.9 mmol), 4-amino-3-nitrophenol (2 g, 12.9 mmol) and Cs2CO3 (4.65 g, 14.3 mmol) were stirred in 50 mL of dimethylformamide at 80 degrees Centigrade for 24 hours. The solids were filtered away. The filtrate was diluted with ethyl acetate and washed with water and brine three times each. The aqueous layers were back extracted twice with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated onto basic alumina. The crude product was purified by silica gel column chromatography (hexanes to ethyl acetate gradient) to give 1-{4-[(4-amino-3-nitrophenyl)oxy]phenyl}ethanone. (M+1) 272.9, 2.42 min (LC/MS method B)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[S:23][CH2:24][C:25]([CH3:28])([CH3:27])[N:26]=4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:31]N(C)C=O.IC>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]=[C:22]4[N:26]([CH3:31])[C:25]([CH3:28])([CH3:27])[CH2:24][S:23]4)=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(N2CCN(c3ccc(NC4=NC(C)(C)CS4)cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(N=C4SCC(C)(C)N4C)cc3)CC2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 37 parts of 4,5-dihydro-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-4,4-dimethyl-2-thiazolamine, 5 parts of a sodium hydride dispersion 50% and 376 parts of N,N-dimethylformamide was stirred for 2 hours at 70° C. After cooling to room temperature, 14.1 parts of iodomethane were added slowly to the reaction mixture. The whole was stirred for 1 hour at room temperature. The reaction mixture was diluted with water. The precipitated product was filtered off, washed with water and 2-propanol and purified by column chromatography (HPLC) over silica gel using a mixture of dichloromethane and methanol (96:4 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was further purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume). The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 4-[4-(4-methoxyphenyl)-1-piperazinyl]-N-(3,4,4 -trimethyl-2-thiazolidinylidene)-benzenamine (int. 9). The second fraction was collected and boiled in 2-propanol. After cooling, the product was filtered off and dried, yielding 19.5 parts (51.0%) of 4,5-dihydro-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-N,4,4-trimethyl-2-thiazolamine; mp. 166.6° C. (int. 10)
Reaction SMILES: Br[CH2:2][C:3]1[C:11]([F:12])=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4]=1[F:13].[C:14]([O-:17])(=[O:16])[CH3:15].[K+].O.C(OCC)(=O)C>CN(C)C=O>[C:14]([O:17][CH2:2][C:3]1[C:11]([F:12])=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4]=1[F:13])(=[O:16])[CH3:15]
Reactant: Fc1cc2sccc2c(F)c1CBr
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1c(F)cc2sccc2c1F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 0.18 g of 5-bromomethyl-4,6-difluorobenzo[b]thiophene in 5 ml of N,N-dimethyl-formamide is added 0.23 g of potassium acetate, and the resulting mixture is stirred at 60° C. for one hour. The temperature of the thus stirred mixture is lowered to room temperature, and 10 ml of water and 10 ml of ethyl acetate are added thereto. Thereafter, the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure, to obtain 0.14 g of colorless, oily 5-acetoxymethyl-4 , 6-difluorobenzo[b]thiophene.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]([S:8]([N:11]1[CH2:14][CH2:13][CH2:12]1)(=[O:10])=[O:9])([CH3:7])[CH3:6])C.C[Si](C)(C)[O-].[K+]>O1CCCC1.Cl>[N:11]1([S:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:15])=[O:3])(=[O:10])=[O:9])[CH2:12][CH2:13][CH2:14]1
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)N1CCC1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)S(=O)(=O)N1CCC1
Reaction time: 1 h

Procedure:
To a solution of 2-(azetidine-1-sulfonyl)-2-methyl-propionic acid ethyl ester (5.0 g, 21 mmol) in tetrahydrofuran (200 mL) at room temperature is added potassium trimethylsilanolate (8.2 g, 64 mmol). The reaction is stirred for 1 h. After this time, the mixture is diluted with a solution of 1N aqueous hydrochloric acid (50 mL) and extracted with dichloromethane (250 mL). The organic phase is dried (MgSO4), filtered and concentrated under reduced pressure to provide the title compound as a white solid, m/z 208 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([OH:14])=[O:13])[CH2:4][CH2:3]1.[C:16]1(C)C=CC(S(O)(=O)=O)=C[CH:17]=1>>[CH2:16]([O:13][C:12]([CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:15])([CH3:1])[CH2:3][CH2:4]1)=[O:14])[CH3:17]
Reactant: CC1(C)CCC(C(=O)O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)C1CCC(C)(C)c2ccccc21
Yield: 63 %

Procedure:
248 g of 1,1-dimethyl-tetralin-4-carboxylic acid in 1.740 liters of absolute alcohol are held at reflux temperature for 6 hours with 24.8 g of paratoluenesulphonic acid in a 3-liter flask provided with a thermometer, stirrer and reflux condenser. The excess alcohol is then distilled off under a slight vacuum and the residue is poured into ice/water. The mixture is extracted with ether, washed neutral, dried, filtered, evaporated and distilled, there being thus obtained 177 g of 1,1-dimethyl-tetralin-4-carboxylic acid ethyl ester of boiling point 74° C./0.03 mmHg; nD20 =1.5153; yield 63%. Odour: faint, jasmone-like.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH2:12][CH3:13].CN(C(ON1N=[N:29][C:24]2[CH:25]=[CH:26][CH:27]=[N:28][C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.CN1CC[C@@H](N)C1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:29][C@@H:24]2[CH2:25][CH2:26][N:28]([CH3:27])[CH2:23]2)=[O:8])=[CH:4][C:3]=1[O:11][CH2:12][CH3:13]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOc1cc(C(=O)O)ccc1N
Agent: CN1CC[C@@H](N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1N
Reaction time: 2 h
Yield: 68 %

Procedure:
4-amino-3-ethoxybenzoic acid (Intermediate 164; 400 mg, 2.21 mmol), HATU (1.26 g, 3.31 mmol) and (3R)-1-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 453 mg, 3.31 mmol) were stirred in DMF (5 mL) and diisopropylethylamine (1.7 ml, 9.95 mmol) added. The mixture was stirred for 2 hours and then absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (2.5% ammonia in methanol/DCM) to yield the title compound as a yellow foam (396 mg, 68%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5]([C:7]1[C:11](=[O:12])[C@@H:10]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C@:9]([OH:25])([C:18]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[O:19])[C:8]=1[OH:26])=[O:6])[CH3:3].[H][H].S(=O)(=O)(O)O>CO.[Pd]>[CH3:17][CH:15]([CH2:14][CH2:13][C@@H:10]1[C@@:9]([OH:25])([C:18]([CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])=[O:19])[C:8]([OH:26])=[C:7]([C:5]([CH2:4][CH:2]([CH3:3])[CH3:1])=[O:6])[C:11]1=[O:12])[CH3:16]
Reactant: CC(C)=CCC(=O)[C@]1(O)C(O)=C(C(=O)CC(C)C)C(=O)[C@H]1CC=C(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(C)CCC(=O)[C@@]1(O)C(O)=C(C(=O)CC(C)C)C(=O)[C@@H]1CCC(C)C
Reaction time: 0.08 h

Procedure:
96.3 mg of the dry Mg salt of (+)-cis isohumulone ((+)-VIII) was dissolved in 1 mL of methanol. 3.1 mg (0.3 eq) of MgO was added, and the reaction mixture was stirred for five minutes. 30 mg of 10% Pd/C was added to the solution, and stirring was resumed. A hydrogen atmosphere was introduced by bubbling hydrogen gas into the solution. After 45 minutes the reaction was judged to be complete by HPLC, the stirring was stopped, and the hydrogen atmosphere was removed by opening the vial. 1 equivalent of sulfuric acid was added to the reaction mixture (pH˜1), and the reaction was filtered through a 0.2 mm syringe filter. The reaction vessel and filter were washed 2 times successively with ethyl acetate. The filtrate was concentrated in vacuo, redissolved in hexanes, dried over Na2SO4, filtered via a cotton pipette, and concentrated in vacuo and dried overnight at 0.070 mbar. 58.1 mg of (+)-KDT-500 was produced. Further purification was carried out via chromatography and crystallization.