Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:5]([C@@H:6]2[O:9][C@H:8]([CH2:10][OH:11])[C@H:7]2[CH2:12][OH:13])[C:4]2[N:14]=[C:15]([NH2:19])[N:16]=[C:17](N)[C:3]=2[N:2]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1[OH:22]>P([O-])([O-])([O-])=O>[CH:1]1[N:5]([C@@H:6]2[O:9][C@H:8]([CH2:10][OH:11])[C@H:7]2[CH2:12][OH:13])[C:4]2[NH:14][C:15]([NH2:19])=[N:16][C:17](=[O:22])[C:3]=2[N:2]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@H]3CO)c2n1
Agent: O=P([O-])([O-])[O-]
Product: Nc1nc(=O)c2ncn([C@@H]3O[C@H](CO)[C@H]3CO)c2[nH]1
Temperature: 37 °C
Reaction time: 70 h

Procedure:
After 2.0 g of 2-amino-OXT-A was dissolved in 300 ml of 1/10M phosphate buffer (pH 6.5), 8.0 g of 5'-adenylic acid deaminase (manufactured by Amano Pharmaceutical Co., Ltd., DEAMIZYME®) was added to the solution followed by stirring at 37° C. for 70 hours. After insoluble matters of the reaction solution were removed by filtration, the filtrate was passed through a column packed with 50 ml of activated charcoal powders (manufactured by Wako Pure Chemical Industry K.K., for chromatography). After washing with water, elution was performed with 50% aqueous methanol. By concentrating the desired fraction to dryness, crude OXT-G was obtained. The crude powders were dissolved in 50 ml of water and the OXT-G in the solution was adsorbed onto MCI® GEL CHP 20 (300 ml) followed by elution with water. The desired fraction was concentrated and evaporated to dryness under reduced pressure to give 1.5 g of OXT-G as colorless crystals (yield, 75%).
Reaction SMILES: [F:1][C:2]([F:12])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]OCC(C1C=CC=C(OC)C=1)(F)F>>[F:1][C:2]([F:12])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][O:4][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Br:13]
Reactant: OCC(F)(F)Cc1ccccc1
Reactant: COc1cccc(C(F)(F)COCCCCCCBr)c1
Product: FC(F)(COCCCCCCBr)Cc1ccccc1
Yield: 36 %

Procedure:
Obtained from Intermediate 91 (0.75 g, 4.36 mmol) by the procedure described in Intermediate 69. Purification by column chromatography with silica gel eluting with n-hexane/ethyl acetate (from pure n-hexane to 40:1) gave the title compound (0.53 g, 36%) as oil.
Reaction SMILES: CO[C:3]([NH2:7])([CH3:6])[CH2:4][OH:5].[C:8](=[O:15])([O-])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:16](=O)([O-])OC(C)(C)C>C([O-])(O)=O.[Na+].C(O)(C)(C)C>[C:8]([NH:7][C:3]([CH3:6])([CH3:16])[CH2:4][OH:5])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:15]
Reactant: COC(C)(N)CO
Reactant: CC(C)(C)OC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(CO)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
2-Methoxy-2-amino-1-propanol is dissolved in saturated aqueous NaHCO3 at room temperature. Di-tert-butyl di-carbonate is added in tert-butanol. The contents are stirred overnight and then extracted with ethyl acetate. The organic layer is dried over MgSO4 and filtered. The filtrate is evaporated to give N-Boc-2-amino-2-methyl-1-propanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[O:20][C:19]([CH2:21][NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:18][CH:17]=4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: CS(=O)(=O)CCN
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1

Procedure:
Prepared according to Procedure D from 5-(4-{3-chloro-4-(3-fluorobenzyloxy)-anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 400 MHz (DMSO-d6) 9.60 (bs, 1H); 9.32 (bs, 1H); 8.82 (bs, 1H); 8.34 (d, 1H); 8.0 (s, 1H); 7.88 (d, 1H); 7.74 (d, 1H); 7.45 (m, 1H); 7.34-7.23 (m, 4H); 7.17 (m, 1H); 6.83 (d, 1H); 5.27 (s, 2H); 4.42 (s, 2H); 3.59 (m, 2H); 3.40 (m, 2H, obscured by waterpeak); 3.12 (s, 3H); MS m/z 581 (M+H+).
Reaction SMILES: [NH2:1][C:2](=[O:21])[C@@H:3]([NH:10]C(=O)OCC1C=CC=CC=1)[CH2:4][O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[ClH:22].[H][H]>CO.[Pd]>[ClH:22].[NH2:10][C@@H:3]([CH2:4][O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[C:2]([NH2:1])=[O:21]
Reactant: [H][H]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(N)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC[C@H](N)C(N)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of Example 31A (784 mg, 2.67 mmol) in methanol (9 mL) at ambient temperature was treated with 10% Pd/C (75 mg) and sufficient 1M HCl to solubilize the substrate (ca. 0.50 mL). The system was equipped with a hydrogen balloon and stirred for 4 hours at ambient temperature. The reaction mixture was purged with nitrogen, filtered through diatomaceous earth (Celite®), rinsed with methanol and water, and the aqueous filtrate was washed with diethyl ether (2×40 mL). The aqueous layer was lyophilized providing 467 mg of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:21][CH2:20]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:33].[H-].[Na+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39].O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([O:25][Si:26]([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:27])[CH3:28])[CH2:23][CH2:24]3)=[N:14][CH:15]=2)[N:10]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:9]1=[O:33]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)CN1C(=O)N(c2ccccc2Cl)Cc2cnc(N[C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(Chlorophenyl)-7-(trans-4-tert-butyldimethylsilyloxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (972 mg, 2 mmol) (prepared as described in Example 81) was suspended in 1-methyl-2-pyrrolidinone (15 mL), and sodium hydride (88 mg, 2.2 mmol (60% oil dispersion)) was added. The reaction mixture was stirred at room temperature for 30 minutes, methyl bromoacetate (0.190 mL, 2 mmol) was added. The mixture was stirred for 6 hours. The reaction mixture was added to water and extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. :The residue was purified by column chromatography on silica gel using 70:30 hexane/acetone as eluant. The fractions containing the product were combined and evaporated under reduced pressure to give 425 mg of 3-(2-chlorophenyl)-7-(trans-4-tert-butyldimethylsilyloxycyclohexylamino)-1-methoxycarbonylmethyl-3,4-dihydropyrimido-[4,5-d]pyrimidin-2(1H)-one as a white solid ((M+H)+560, m.p.165.7-167.4° C.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH2:40])(=[O:39])=[O:38])([O-:30])=[O:29]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:40][S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N+:28]([O-:30])=[O:29])(=[O:38])=[O:39])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 2-nitrobenzenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (22%); 1H NMR (d6-DMSO) δ 8.18 (d, J=5.2 Hz, 1H), 7.99 (d, J=5.9 Hz, 1H), 7.94-7.84 (m, 2H), 7.44-7.08 (m, 13H), 6.86 (d, J=8.1 Hz, 2H), 6.50 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.4 Hz, 2H), 0.82 (t, J=7.4 Hz, 3H); APcI m/z: 539 (M+H+).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2O[C:16](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)=[N:17][N:18]=2)=[CH:9][CH:8]=1>C(O)(=O)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[NH:5][C:16](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)=[N:17][N:18]=2)=[CH:9][CH:8]=1
Reactant: COc1cc(/C=C/c2nnc(Nc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2nnc(Nc3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 150 °C
Reaction time: 12 h
Yield: 53.9 %

Procedure:
Acetic acid (10 mL) and ammonium acetate (6.8 g) were added to (4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazol-2-yl}amine (692 mg), and the reaction solution was stirred at 150° C. for 12 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The insoluble matter generated during separation was added to the resulting extract, and THF and ethanol were further added to provide a mixed solution. The mixed solution was concentrated under reduced pressure and solidified with ethyl acetate and diethyl ether to obtain 372 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=1.[H][H]>CO.CCOC(C)=O.[Pd]>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]2)[CH:5]=1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(N)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 83.7 %

Procedure:
A solution of tert-butyl 4-(2-methoxy-5-nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (1.30 g, 3.90 mmol) and 10% Pd/C (200.0 mg) in MeOH:EtOAc (1:4, 100 mL) was hydrogenated at room temperature for 72 h using the hydrogen balloon method. The reaction mixture was filtered through Celite and washed with ethanol (3×100 mL). The combined organic filtrates were concentrated in vacuo to afford tert-butyl 4-[5-amino-2-methoxyphenyl]-1-piperidinecarboxylate (1.00 g, 84%): ESMS m/e: 307.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:27][CH:28]1[CH2:30][C:29]1([F:32])[F:31].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:31][C:29]1([F:32])[CH2:30][CH:28]1[CH2:27][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:3][C:2]=1[F:1]
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Reactant: FC1(F)CC1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4(F)F)c(F)c3)oc2c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
A suspension of N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide (290 mg), 1-bromomethyl-2,2-difluorocyclopropane (288 mg) and potassium carbonate (175 mg) in DMF (10 mL) was stirred at 70° C. for 1 hr and 30 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine, and the organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. The obtained solid was washed with diethyl ether to give the title compound (279 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:9](=O)[C:8]2=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:20]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:9](=[O:11])[C:8]2=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Reactant: CC(C)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)CN1C(=O)c2ccc(C(C)(C)C)cc2C1=O
Temperature: 75 °C

Procedure:
4-tert-Butyl-N-isobutylphthalimide is prepared as described in Example 2, starting with 10 g of 4-tert-butylphthalic anhydride and 4.9 cm3 of isobutylamine in 100 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 75° C. for 10 minutes, followed by addition of a catalytic amount of para-toluenesulfonic acid and the mixture is heated at a temperature in the region of 140° C. for 3 hours. After cooling to a temperature in the region of 60° C., the reaction mixture is concentrated to dryness under reduced pressure (2 kPa). The residue is taken up in a mixture of 50 cm3 of water and 30 cm3 of saturated aqueous sodium bicarbonate solution and the aqueous phase is extracted twice with 200 cm3 of dichloromethane. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 10.4 g of 4-tert-butyl-N-isobutylphthalimide are thus obtained in the form of a viscous yellow oil. (Rf=0.75, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][N:7]([C@@H:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13]C(C)(C)C)=[O:12])[C:6]1=[O:22].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][N:7]([C@@H:10]([C:18]([CH3:20])([CH3:21])[CH3:19])[C:11]([OH:13])=[O:12])[C:6]1=[O:22]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2F)C1=O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2F)C1=O
Yield: 72.7 %

Procedure:
A solution of Example 135B (199 mg, 0.54 mmol) in dichloromethane (1.5 mL) was treated with trifluoroacetic acid (1.5 mL) at 25° C. for 16 h. The solvents were evaporated, and the crude residue was purified using reverse phase chromatography using 95% water (0.1% trifluoroacetic acid)/5% acetonitrile-100% acetonitrile to give the title compound (0.121 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[C:9]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[CH:6]=1)([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=O)c1ccc(F)c(F)c1
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(c1ccc(F)c(F)c1)c1ccc(F)c(F)c1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
The Grignard reagent is prepared from 2.24 g (0.092 mol) of magnesium chips, a few granules of iodine, and 17.80 g (0.092 mol) of 1-bromo-3,4-difluorobenzene in 100 mL of THF at 50° C. After the halide has all been added, the mixture is stirred for another hour. The Grignard reagent thus obtained is added dropwise to 18.81 g (0.088 mol) of ethyl 3,4-difluorophenylglyoxylate in 80 mL of THF at 10° C.-15° C. and the mixture obtained is stirred for 2 hours at 5° C. The white suspension is poured onto ice/sulfuric acid for working up, extracted with ethyl acetate, the organic phase is washed with water, dried over MgSO4, and evaporated to dryness. The crude product is purified by column chromatography (eluent: toluene). Yield: 10.80 g of oil 4.1. (38% of theory).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: NC(=O)c1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
According to the recently released paper in line with the direct manufacture of amide compound formed by the NASH reaction, it is reported that benzamide is reacted with nitrobenzene in the presence of TMA(OH) to isolate N-(4-nitrophenyl)benzamide, a relatively stable intermediate, and then methanol and ammonia are added to the mixture and reacted under a pressure reactor to prepare 4-nitroaniline as a final product, while regenerating benzamide (J. Org. Chem., 1993, 58(24), 6883-8; WO No. 93/24447).
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH3:37][C:38]1[S:39][C:40]([C:44](=O)[CH3:45])=[C:41]([CH3:43])[N:42]=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:44]([C:40]2[S:39][C:38]([CH3:37])=[N:42][C:41]=2[CH3:43])[CH:45]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1sc(C)nc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)s1
Yield: 12 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(2,4-dimethyl-thiazol-5-yl)-ethanone (40 mg, 0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (14 mg, 12% yield).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[Br:29][C:30]1[C:31]([CH3:38])=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>O1CCCC1>[CH3:2][O:3]/[CH:4]=[CH:33]/[C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([Br:29])[C:31]=1[CH3:38]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c(Br)cccc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CO/C=C/c1cccc(Br)c1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of [(methyloxy)methyl](triphenyl)phosphonium chloride (2.1 g, 6.13 mmol) in Tetrahydrofuran (THF) (40 mL) stirred under nitrogen at 0° C. was added BuLi (4.08 mL, 6.53 mmol) dropwise. The reaction mixture was stirred at −78° C. for 30 min. Then a solution of 3-bromo-2-methylbenzaldehyde (D93) (1 g, 5.02 mmol) in Tetrahydrofuran (THF) (40 mL) was added dropwise. The reaction mixture was continuously stirred overnight. The reaction was quenched with sat. aq. NH4Cl. The aqueous layers were separated and extracted with EA for 3 times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated, and purified by ISCO column chromatography (PE: EA=8:2) to afford (E)-2-(3-bromo-2-methylphenyl)ethenyl methyl ether (D94) (938 mg) as a yellow oil. MS (ES): C10H11BrO requires 255.9. found 227 (M+H+)
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].C/[C:12](=[CH:17]\[CH2:18][CH2:19]/[C:20](/C)=[CH:21]/[CH2:22][O:23]C1CCCCO1)/[CH2:13][CH2:14][CH:15]=O.CC(=CC)C>O.C(O)(C)(C)C>[C:22]([OH:23])(=[O:6])[CH2:21][CH2:20][CH:19]=[CH:18][CH2:17][CH2:12][CH:13]=[CH:14][CH3:15]
Reactant: C/C(=C\CC/C(C)=C/COC1CCCCO1)CCC=O
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC=CCCC=CCCC(=O)O

Procedure:
A.a) A solution of 105 g of 80% sodium chlorite and 100 g of sodium dihydrogen phosphate in 1 l of water is added within 30 min. to 50 g of (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca-4,8-dienal in 1.5 l of tert-butanol and 1.5 1 of 2-methyl-2-butene. After 2 1/2 hrs. at room temperature the mixture is concentrated and the residue is taken up in methylene chloride, washed with ice-water and 10% potassium hydrogen sulphate solution and dried. 46.5 g of (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy])-deca-4,8-dienoic acid are obtained. The acid obtained is dissolved in 590 ml of methylene chloride and treated at 0° C. with 14.9 ml of N-allyl-methyl-amine, 32.0 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and 1.88 g of dimethylaminopyridine. After 3 hrs. at room temperature and working up with methylene chloride/10% potassium hydrogen sulphate and subsequently saturated sodium hydrogen carbonate solution the organic phase is dried and concentrated. 52.3 g of crude (4E,8E)-(RS)-4,8-dimethyl-1 0-(tetrahydro-pyran-2-yloxy)-deca-4,8-dienoic acid allyl-methylamide are obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[CH3:13][C:14]([CH3:16])=O.[Na]>ClCCCl>[CH:14]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=1)([CH3:16])[CH3:13]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)=O
Agent: [Na]
Solvent: ClCCCl
Product: CC(C)Nc1ccc(OC(F)(F)F)cc1

Procedure:
A solution of 9.33 g of p-trifluoromethoxyaniline, 4.1 mL of acetone, and 14.53 g of sodium triacetoxyborohydryde in 50 mL of 1,2-dichloroethane were stirred overnight at RT. The reaction mixture is then poured onto ice-water and product extracted with 100 mL of dichloromethane. The organic layer is washed with water, sat NaHCO3, dried with Na2SO4 and solvent evaporated to afford 12 g of Isopropyl-(4-trifluoromethoxy-phenyl)-amine: 1H NMR (300 MHz, CDCl3) δ7.06 (d, 2H, J=8.5), 6.56 (d, 2H, J=8.5), 3.63(m, 1H), 1.25 (d, 6H, J=6.8).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]([F:27])([F:26])[F:25])=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:7]=1.O.NN>C(O)C.[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:13][CH2:14]2)[C:5]([NH2:21])=[CH:4][C:3]=1[C:24]([F:26])([F:25])[F:27]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1cc(C(F)(F)F)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
N-(5-Chloro-4-trifluoromethyl-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D51) (0.64 g, 1.57 mmole) was dissolved in ethanol (25 ml) and Raney nickel (50% aqueous suspension, 100 mg) was added at room temperature; the mixture was heated to 60° C. and hydrazine monohydrate (0.8 ml) was added over 30 min. After 2 hr more, the reaction mixture was cooled to room temperature, filtered through Celite and the solvent was evaporated to dryness. The residue was purified by silica gel chromatography eluting with 2 to 20% methanol in dichloromethane to yield the title compound as a cream solid, 0.34 g, 58%. MH+=378 and 380.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32](=[O:33])[NH:1][C:2]2[S:3][C:4]3[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=3[N:6]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cl)CC1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C3CCN(C(=O)OC(C)(C)C)CC3)nc12

Procedure:
Using 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol and 4-chlorocarbonyl-piperidine-1-carboxylic acid tert-butyl ester the title compound was obtained as a white solid (3%), MS: m/e=477(M+H+).