Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.[N+](=[CH2:28])=[N-]>CCOCC>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([O:21][CH3:28])=[O:20])=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: CC(C)(Cc1cc2cc(O)ccc2n1Cc1ccc(Cl)cc1)C(=O)O
Solvent: CCOCC
Product: COC(=O)C(C)(C)Cc1cc2cc(O)ccc2n1Cc1ccc(Cl)cc1

Procedure:
The acid from Step 1 (0.84 g) was dissolved in 10 mL of Et2O and a solution of diazomethane in Et2O was added portionwise until all the acid had been consumed. Excess diazomethane was removed by addition of 1 mL HOAc, the solvent was then removed and the residue chromatographed (hexane/EtOAc 4:1) to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CO.C1COCC1.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccccc1Oc1ccccc1N
Yield: 61.8 %

Procedure:
To a solution of 1-tert-butyl-2-(2-nitrophenoxy)benzene (20 g, crude) in MeOH/THF (1:1, 200 mL) was added 10% Pd/C (2 g). The mixture was hydrogenated under 75 psi overnight. The mixture was filtered through Celite® cake and the filtrate was evaporated to give the crude product as a black oil. Purification by flash chromatography (0-30% EtOAc/hexane) provided 135a (11 g) as a brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH2:15])[CH3:14])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:16]([N:26]([CH3:34])[C@H:27]([C:31](O)=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:18][C:16]([N:26]([CH:27]([CH:28]([CH3:30])[CH3:29])[C:31]([NH:15][CH:13]([CH3:14])[CH2:12][C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:32])[CH3:34])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CC(N)Cc1ccc(O)c(C(C)(C)C)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)C(C(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.31 g (1.50 mmol) of 2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethylamine, 0.40 g (1.50 mmol) of Z-N-Me-Val-OH and 0.30 g (2.25 mmol) of HOBT in DMF (5 ml), 0.35 ml (2.25 mmol) of DIC was added under cooling with ice. After being stirred at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous NaHCO3, water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; chloroform:methanol=125:1) to give 2-[N-(benzyloxycarbonyl)-N-methylamino]-N-[2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethyl]-3-methylbutanamide in the amount of 0.55 g (81%).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:6][CH:5]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29](O)=O)[N:23]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:6][CH:5]=4)[N:14]=3)[N:23]=2)=[CH:20][CH:21]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(C(=O)O)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2nc(-c3ccc(S(N)(=O)=O)cc3)no2)n1

Procedure:
The title compound was prepared from N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (0.16 g, 0.75 mmol) and 4-(4-chloro-phenyl)-6-methyl-pyrimidine-2-carboxylic acid (example D.10) (0.124 g, 0.5 mmol) according to the general procedure V. Obtained as an off-white solid (0.032 g, 15%). MS (ISN) 426.1 [(M−H)−]; mp 297° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]5[CH2:28][CH2:27][CH2:26][O:25][C:24]5=[O:29])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1.[N:33]([CH:36]([CH3:38])[CH3:37])=[C:34]=[O:35]>C(Cl)Cl>[F:32][C:4]1[CH:3]=[C:2]([NH:1][C:34]([NH:33][CH:36]([CH3:38])[CH3:37])=[O:35])[CH:31]=[CH:30][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][O:25][C:24]4=[O:29])=[CH:20][N:21]=3)[S:15][C:8]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCOC5=O)cn4)sc23)c(F)c1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CC(C)NC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCOC5=O)cn4)sc23)c(F)c1
Temperature: 80 °C
Yield: 29.4 %

Procedure:
A reaction mixture consisting of amine 200 (100 mg, 0.222 mmol) and 2-isocyanatopropane (434 mg, 5.10 mmol) in DCM (3 mL) was heated to 80° C. in a sealed flask overnight. The mixture was then cooled to RT and purified by Biotage (SiliaFlash 12 g cartridge, 0-12% MeOH/CHCl3) to afford after the separation title compound 201 (35 mg, 29.4% yield) as beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.67 (s, 1H), 8.55 (d, 1H, J=1.8 Hz), 8.50 (d, 1H, J=5.3 Hz), 8.33 (s, 1H), 8.25 (d, 1H, J=8.2 Hz), 7.84 (dd, 1H, J1=2.2 Hz, J2=8.2 Hz), 7.69 (dd, J1=2.5 Hz, J2=13.7 Hz), 7.35 (t, 1H, J=9.0 Hz), 7.12-7.10 (m, 1H), 6.62 (d, 1H, J=5.1 Hz), 6.14 (d, 1H, J=7.4 Hz), 4.50 (s, 2H), 4.21 (t, 2H, J=5.1 Hz), 3.77-3.72 (m, 1H), 3.30-3.28 (m, 2H), 1.97-1.92 (m, 2H), 1.10 (s, 3H), 1.08 (s, 3H). MS: 536.4 (MH)+
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19](OC)=[O:20].CCCCCC>O1CCCC1>[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19](=[O:20])[CH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccn1
Reactant: COC(=O)c1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Cc1ncccn1)c1ccc(F)cc1F
Yield: 17.3 %

Procedure:
Treatment of 2-methylpyrimidine (8.50 g) with lithium diisopropylamide (0.09 mole) in dry tetrahydrofuran followed by methyl 2,4-difluorobenzoate (15.5 g) according to the method of Example 11(i) gave the title compound (3.65 g), m.p. 86°-88° (from hexane).
Reaction SMILES: C([O:4][CH:5]1[C:13]2[C:8](=[C:9]([N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=O)C.[OH-].[K+]>O.C(O)C>[N:14]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[CH2:7][CH2:6][CH:5]3[OH:4])[CH:15]=[CH:16][CH:17]=[CH:18]1
Reactant: CC(=O)OC1CCc2c1cccc2-n1cccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC1CCc2c1cccc2-n1cccc1
Yield: 27 %

Procedure:
In the manner of Example 1, step H, hydrolysis of 13.0 g (0.054 mole) of 4-(1-pyrrolyl)-1-indanyl acetate with 4.3 g of potassium hydroxide in 77 mL of water and 154 mL of ethanol gave 2.9 g of 4-(1-pyrrolyl)-1-indanol, m.p. 80°-81° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([OH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:25]([CH3:27])[CH3:26]>CN(C=O)C>[Br:16][C:13]1[CH:14]=[CH:15][C:8]2[O:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:10]([CH3:11])[C:9]=2[C:12]=1[O:17][CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)Br
Reactant: CCOC(=O)c1oc2ccc(Br)c(O)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2ccc(Br)c(OC(C)C)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To 0.50 g (1.7 mmole) of ethyl 5-bromo-4-hydroxy-3-methyl-1-benzofuran-2-carboxylate (Example 119, Step 1) in 7 mL DMF was added 0.51 g (3.75 mmole) of potassium carbonate and 0.48 mL (3 mmole) of 2-bromopropane and the reaction was stirred at room temperature overnight. The solvent was concentrated in vacuo, and the residue was extracted with ethyl acetate and water. The organic layer washed with water and brine, dried over sodium sulfate, filtered, and concentrated to provide 0.58 g of ethyl 5-bromo-4-isopropoxy-3-methyl-1-benzofuran-2-carboxylate. Yield: 100%; m.p. 48-50° C.; MS: 341.0 (M+H)+.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: Fc1ccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-fluorobenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-fluorophenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: CC(C)(OC([NH:7][CH2:8][C:9]([NH:11][CH:12]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])=O)C.[ClH:26]>O1CCOCC1>[ClH:26].[ClH:26].[NH2:7][CH2:8][C:9]([NH:11][CH:12]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10]
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)OC(C)(C)C)c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CC(NC(=O)CN)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl β-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-acetyl]amino]pyridine-3-propanoate (from Step C) (232 g, 0.66 mole) was dissolved in warm dioxane (1 liter). After cooling to room temperature, 4M HCl in dioxane (1.6 liters) (Aldrich) was slowly added. A white precipitate formed after several minutes and then turned to a thick goo. After 2 hours, the solvent was decanted off. The goo was slurried in ether and the ether decanted off until a white solid resulted. This was dried under vacuum to yield ethyl β-[(2-aminoacetyl)amino]pyridine-3-propanoate, bis hydrochloride salt (224.2 g) as a white hygroscopic solid.
Reaction SMILES: C(OC(=O)[CH2:5][NH:6][CH2:7][C@H:8]([NH:12][C:13]([O:15]CC1C=CC=CC=1)=O)[CH:9]([CH3:11])[CH3:10])C.[H][H]>CO.[Pd]>[CH:9]([C@H:8]1[NH:12][C:13](=[O:15])[CH2:5][NH:6][CH2:7]1)([CH3:11])[CH3:10]
Reactant: CCOC(=O)CNC[C@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H]1CNCC(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
To a Parr vessel charged with (R)-(2-benzyloxycarbonylamino-3-methyl-butylamino)-acetic acid ethyl ester (4.2 g, 13.0 mmol) in MeOH (130 mL) is added Pd-on-C (10%, 396 mmol). The reaction vessel is pressurized with 40 PSI hydrogen pressure and shaken for 4 h at ambient temperature. The reaction mixture is then filtered through celite and the filtrate is concentrated to provide 1.77 g (95%) of (R)-6-isopropyl-piperazin-2-one as an off-white solid which is used without further purification. 1H NMR (300 MHz, CDCl3) δ0.93 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H), 1.68 (sept, J=6.7 Hz, 1H), 2.67 (dd, J=12.8, 8.9 Hz, 1H), 3.09-3.22 (m, 2H), 3.46 (ABq, ΔAB=34.3 Hz, JAB=17.5 Hz, 2H), 5.97 (br s, 1H) ppm.
Reaction SMILES: ClC1N=C(C)N([CH2:8][C:9]2[S:24][C:12]3[N:13]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:14](=[O:19])[N:15]([CH3:18])[C:16](=[O:17])[C:11]=3[C:10]=2[C:25]([N:27]2[CH2:31][C@H:30]([OH:32])[CH2:29][O:28]2)=[O:26])C=1Cl.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][N:41]=2)[CH:36]=[CH:35]1>>[OH:32][C@@H:30]1[CH2:29][O:28][N:27]([C:25]([C:10]2[C:11]3[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[N:13]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:12]=3[S:24][C:9]=2[CH2:8][N:34]2[C:42]3=[N:41][CH:40]=[CH:39][CH:38]=[C:37]3[CH:36]=[CH:35]2)=[O:26])[CH2:31]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: Cc1nc(Cl)c(Cl)n1Cc1sc2c(c1C(=O)N1C[C@H](O)CO1)c(=O)n(C)c(=O)n2CC(C)C
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)N3C[C@H](O)CO3)c(Cn3ccc4cccnc43)sc21

Procedure:
The subtitle compound was prepared using the procedure described in example 3 part c) from the product of example 3 part b) and 7-azaindole. MS (APCI) 427 [M+H]+. δ 1HCDCl3 0.85 (3H,s), 0.92 (3H,s), 2.15-2.25 (1H,m), 3.38 (3H,s), 3.66 (3H,d), 4.03 (3H,s), 4.97 (s,2H), 5.61 (2H,s), 6.49-6.91 (1H,d), 7.06-7.14 (1H,m), 7.38 (1H,d), 7.91 -7.95 (1H,m) and 8.31-8.37 (1H, m).
Reaction SMILES: Cl.[CH:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[CH3:21])[NH:17][C:16]([C:22]([OH:24])=O)=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[CH:2]([N:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[CH3:21])[NH:17][C:16]([C:22]([N:32]2[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]2)=[O:24])=[CH:15]3)[CH2:9][CH2:10]1)([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Cc1cc2[nH]c(C(=O)O)cc2cc1OC1CCN(C(C)C)CC1
Agent: Cl
Product: Cc1cc2[nH]c(C(=O)N3CCN(S(C)(=O)=O)CC3)cc2cc1OC1CCN(C(C)C)CC1
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(1-isopropyl-piperidin-4-yloxy)-6-methyl-1H-indole-2-carboxylic acid hydrochloride and 1-methanesulfonylpiperazine to afford the title compound as a light-yellow solid (49%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]2=[O:22])=[CH:11][C:10]=1[F:23])C1C=CC=CC=1>C1COCC1.CO.[Pd]>[F:23][C:10]1[CH:11]=[C:12]([N:15]2[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]2=[O:22])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: O=C1O[C@@H](CO)CN1c1ccc(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1O[C@@H](CO)CN1c1ccc(O)c(F)c1
Yield: 69.6 %

Procedure:
A solution of (R)-3-(4-benzyloxy-3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (6.34 g, prepared according to WO 2004/096221) in THF/MeOH (1:1; 200 mL) was hydrogenated over Pd/C 10% (1 g) overnight. The catalyst was filtered off, the filtrate evaporated under reduced pressure and the residue stirred in EA. The crystals were collected by filtration, affording 3.16 g (70% yield) of a colorless solid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH2:19]Cl.C(N(CC)CC)C>ClCCl>[CH3:17][O:18][CH2:19][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCCl
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOC(=O)C(c1ccccc1)c1ccccc1
Temperature: -5 °C
Reaction time: 8 h

Procedure:
Diphenylacetic acid methoxymethyl ester was prepared in the following manner: to a mixture of 10.0 g (47.1 mmol) diphenylacetic acid and 4.0 ml (4.16 g, 51.8 mmol) of chloromethyl methyl ether in 50 ml of dichloromethane cooled to -5° C. was added 7.2 ml (5.24 g, 51.8 mmol) of triethylamine in 50 ml dichloromethane. The mixture was allowed to warm to room temperature and stir overnight at which point the reaction mixture was washed with aqueous sodium bicarbonate, dried with MgO-MgSO4, and concentrated in vacuo. The residue was distilled to give 7.25 g (28.3 mmol, 60% yield) of the corresponding methoxymethyl ester, bp 135°-140° C./0.1 mm Hg.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][C:8]([CH3:10])=[CH:9][N:4]2[N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[CH:15][C:14]=1[OH:28].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([C:2]2[S:6][C:5]3=[N:7][C:8]([CH3:10])=[CH:9][N:4]3[N:3]=2)[CH:16]=[CH:15][C:14]=1[OH:28]
Reactant: Cc1cn2nc(Br)sc2n1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(-c2nn3cc(C)nc3s2)ccc1O
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole (1.53 g, 7.02 mmol, 1 eq) in dioxane (30 mL), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.76 g, 7.02 mmol, 1 eq) was added followed by 2M aq. Na2CO3 (15 mL, 30 mmol, 4.3 eq). The suspension was degassed (N2, 15 min) and equipped with an argon balloon. Pd(Ph3P)2Cl2 (1.23 g, 1.75 mmol, 0.25 eq) was quickly added, and the reaction flask was placed in a pre-heated bath (115° C.). After stirring at reflux temperature for 2 h the reaction mixture was cooled to RT and concentrated. The residue was taken in water and extracted with DCM; the organic phase was washed with water, dried and concentrated to give 2-methoxy-4-(6-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)phenol as a crude product (brown solid, 3 g) that was used in the next step without further purification. HPLC-MS (10-95% B in 4 min +2 min 100% B, flow 0.5 mL/min, 50° C.): tR=3.27 min, [M+H]+ m/z 262.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[CH3:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Ba+2].[OH-].COCCOC>O>[Cl:1][C:2]1[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(I)cc1Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccccc2)cc1Cl

Procedure:
A mixture of 2-chloro-4-iodotoluene(2.94 g, 11.63 mmol), phenyl boronic acid (1.56 g, 12.79 mmol), barium hydroxide (5.50 g, 17.44 mmol), DME (3 mL) and water (15 mL) was purged with dry argon. Tetrakis(triphenyl-phosphine)palladium(O) (672 mg, 0.58 mmol) was added, and the resultant solution was stirred at 80° C. for 4 hours. The solvents were evaporated in vacuo, and the residue partitioned between EtOAc and water and acidified with 1M aq. HCl. The aqueous extract was separated, and extracted with EtOAc. The organic extracts were combined, washed with NaHCO3 and 5% aq. Na2S2O3, dried, (Na2SO4) filtered and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, 10% EtOAc in hexanes) to afford the title compound. 1H NMR (CDCl3 400 MHz) δ 7.62-7.54 (3H, m), 7.48-7.25(5H, m) and 2.43(3H, s) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:12]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)[CH:12]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2C(COS(=O)(=O)c3ccc(C)cc3)c3ccc(OC)cc3C3CCCCC32)cc1
Reactant: C1CCNC1
Solvent: c1ccccc1
Product: COc1ccc(C2C(CN3CCCC3)c3ccc(OC)cc3C3CCCCC32)cc1
Reaction time: 18 h
Yield: 84.5 %

Procedure:
Combine toluene-4-sulfonic acid 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-ylmethyl ester (0.087 g, 0.175 mmol), pyrrolidine (0.09 mL, 1.05 mmol), and benzene (5 mL), and reflux under nitrogen atmosphere. After 18 hours, concentrate reaction under vacuum then add ethyl acetate and wash with sodium bicarbonate solution (aq). Separate the organic phase and wash with brine. Dry the organic phase with anhydrous sodium sulfate and flash chromatograph using 2% to 4% (2M NH3 methanol)/methylene chloride to yield the titled compound (0.060 g, 86%) as a white solid. TLC Rf=0.25 in 4% 2M NH3 methanol:DCM. 1H NMR (CDCl3): 7.95 (d, 1H, J=8.4 Hz), 7.24 (d, 2H, J=8.4 Hz), 6.91 (m, 3H), 6.79 (dd, 1H, J=8.6, 2.4 Hz), 3.85 (s, 6H), 3.34 (t, 1H, J=9.2 Hz), 3.22 (s, 1H), 3.07 (dd, 1H, J=11.7, 3.3 Hz), 2.74 (dd, 1H, J=12.3, 7.5 Hz), 2.42 (m, 4H), 2.20 (m, 2H), 1.89 (m, 1H), 1.66 (m, 6H), 1.43 (m, 2H), 1.17 (m, 3H); MS m/z 406 (M+1).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH3:9][C:10](O)([CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:11][CH3:12].S(=O)(=O)(O)O>COCCO>[CH2:11]([C:10]([C:3]1[CH:4]=[C:5]([OH:6])[C:7]([C:10]([CH3:9])([CH2:11][CH3:12])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])=[CH:8][C:1]=1[OH:2])([CH3:9])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:12]
Reactant: CCC(C)(O)CCCC(C)CCCC(C)C
Reactant: Oc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: COCCO
Product: CCC(C)(CCCC(C)CCCC(C)C)c1cc(O)c(C(C)(CC)CCCC(C)CCCC(C)C)cc1O
Temperature: 0 °C

Procedure:
55 g of hydroquinone and 120 ml of 3,7,11-trimethyldodecan-3-ol were dissolved in 120 ml of methyl Cellosolve. Then, 50 ml of concentrated sulfuric acid (36 N) was added dropwise thereto under stirring and cooling so as to maintain the temperature at 40° C. or less. Subsequently, the reaction mixture was maintained at 50° to 55° C. for 4 hours. The resulting reaction mixture was added to ice-water, and extracted with 500 ml of benzene. The benzene layer was washed with water and, after drying over anhydrous sodium sulfate, benzene and unreacted 3,7,11-trimethyldodecan-3-ol were distilled off under reduced pressure. The residual oil was chromatographed on silica gel using benzene as a developing solvent. Thus, 41 g of 2,5-bis(1-ethyl-1,5,9-trimethyldecyl)hydroquinone (the same compound as obtained in Synthesis Example 1) was first eluted, and then 20 g of 2-(1-ethyl-1,5,9-trimethyldecyl)hydroquinone was eluted. The results of elemental analysis of the above-described monoalkyl hydroquinone are shown below.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].O1CCCC1.[Cl:14][CH2:15][CH2:16][N:17]([N:23]=[O:24])[C:18](N=[N+]=[N-])=[O:19]>C(=O)([O-])[O-].[K+].[K+]>[Cl:14][CH2:15][CH2:16][N:17]([N:23]=[O:24])[C:18]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:19]
Reactant: [N-]=[N+]=NC(=O)N(CCCl)N=O
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)N(CCCl)N=O)C(=O)O
Reaction time: 2 h
Yield: 64.3 %

Procedure:
Dissolved in a 5% aqueous potassium carbonate solution was 2.1 g of L-valine, and a tetrahydrofuran solution containing 3.2 g of (2-chloroethyl)-nitrosocarbamoyl azide was added at 0° C. The mixture was stirred for two hours. The reaction solution was washed with ether, neutralized with hydrochloric acid, and extracted with ether to obtain 2.9 g (Yield 64%) of N-{(2-chloroethyl)-nitrosocarbamoyl}-L-valine as a slightly yellow oil.