Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:15][C:14](=[O:16])[NH:13][C:12]=3[CH:17]=2)=[CH:4][CH2:3]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[O:16]=[C:14]1[NH:13][C:12]2[CH:17]=[C:8]([CH:5]3[CH2:6][CH2:7][CH:2]([N:18]4[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=5)=[O:24])[CH2:19]4)[CH2:3][CH2:4]3)[CH:9]=[CH:10][C:11]=2[S:15]1
Reactant: O=C1CC=C(c2ccc3sc(=O)[nH]c3c2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc4sc(=O)[nH]c4c3)CC2)C1

Procedure:
The title compounds were prepared as white solids from hydrogenation of 5-(4-oxo-cyclohex-1-enyl)-3H-benzothiazol-2-one (as prepared in the previous step) followed by reductive amination of the corresponding ketone with N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedures described in Step C of Example 5 and Step C of Example 4.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[CH:3]=1.[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C)C=O>[N:12]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[CH:3]=1)=[N+:13]=[N-:14]
Reactant: OCCOc1cc(Cl)ncn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1cc(OCCO)ncn1
Temperature: 70 °C
Reaction time: 20 h
Yield: 28.9 %

Procedure:
To a solution of 2-(6-chloropyrimidin-4-yloxy)ethanol (5.61 g) in dimethylformamide (60 ml) is added sodium azide (4.18 g), and the mixture is stirred at 70° C. for 20 hours. After cooling, the reaction solution is treated with water, and extracted with ethyl acetate. The ethyl acetate layer is dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane/ethyl acetate=1:1) to give 2-(6-azidopyrimidin-4-yloxy)ethanol (1.68 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[Br:15][Si](C)(C)C.O.BrN1C(=O)CCC1=O>ClCCl.C(N(CC)CC)C>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:8][CH:9]=1)=[O:3]
Reactant: C[Si](C)(C)Br
Reactant: CC(=O)c1ccc(-n2cncn2)nc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CBr)c1ccc(-n2cncn2)nc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
480 mg (corresponding to 2.55 mmol) of 5-acetyl-2-(1H-1,2,4-triazole-1-yl)pyridine was dissolved in 10 mL of dichloromethane and 1.07 mL of triethylamine, and then 662 μL (corresponding to 5.10 mmol) of bromotrimethylsilane was dropped under ice cooling. The resulting solution was stirred over night at room temperature under argon gas atmosphere, and then supplemented with water and extracted 3 times with dichloromethane. The combined dichloromethane layer was washed with water and a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off, the resulting residue was dissolved in 10 mL of tetrahydrofuran, and 454 mg (corresponding to 2.55 mmol) of N-bromosuccinimide was added thereto under ice cooling. The resulting solution was stirred at room temperature for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent: dichloromethane/ethyl acetate=2/1), to obtain 657 mg (corresponding to 2.46 mmol) of 5-(2-bromoacetyl)-2-(1H-1,2,4-triazole-1-yl)pyridine (FIG. 4, step 2).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:45])[CH2:21][NH:22][C:23]([CH3:44])([CH3:43])[CH2:24][CH2:25][N:26]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[C:29]([CH2:39][CH2:40][CH3:41])([CH2:36][CH2:37][CH3:38])[O:28][C:27]2=[O:42])[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:45][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[CH2:21][NH:22][C:23]([CH3:43])([CH3:44])[CH2:24][CH2:25][N:26]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([CH2:39][CH2:40][CH3:41])([CH2:36][CH2:37][CH3:38])[O:28][C:27]1=[O:42]
Reactant: [H][H]
Reactant: CCCC1(CCC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CCCC1(CCC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(O)cc3c2OCC(=O)N3)c2ccccc21

Procedure:
A suspension of 270 mg (0.438 mmol) 1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 27 mg Pd/C (10%) in MeOH (8 mL) is hydrogenated at RT and 1 bar hydrogen pressure for 3 hours. The catalyst is filtered off through CELITE® filter aid and washed with MeOH (5 mL) and the filtrate is concentrated by evaporation in vacuo. The residue is dissolved in EtOAc/dichloromethane (1:1, 10 mL), acidified to pH 2 by the addition of HCl solution (saturated in EtOAc) and concentrated by evaporation in vacuo. The residue is triturated with ether, filtered and dried in vacuo. Yield: 80 mg (33%; hydrochloride), HPLC-MS: Rt=12.8 min. (method A), ESI-MS: [M+H]+=526.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:3].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25]CNC[CH2:21]1>C1(C)C=CC=CC=1>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:1][N:2]([CH2:4][C:5]2[C:13]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH2:3][CH2:21]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Solvent: Cc1ccccc1
Product: c1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)nc1
Yield: 96.9 %

Procedure:
To a solution of 3-(N,N-dimethylaminomethyl)-1H-pyrrolo[2,3-b]pyridine (258 mg, 1.39 mmol) (prepared in Example 1(a)) in toluene (10 mL) was added 1-(pyridin-2-yl)piperazine (233 mL, 250 mg, 1.53 mmol). The mixture was heated at reflux over night. Heating was discontinued and when the reaction temperature had reached room temperature the solid was filtered off and dried in vacuo to give 3-[4-(pyridin-2-yl)-piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine as a colourless solid (395 mg, 93%). δH (300 MHz, CDCl3) 2.50 (4H, m, piperazinyl), 3.46 (4H, m, piperazinyl), 3.68 (2H, s), 6.61 (1H, dd, J=5.1 and 6.9), 6.78 (1H, d, J=8.6), 7.06 (1H, dd, J=4.7 and 7.8), 7.39 (1H, s), 7.51 (1H, dd, 6.9 and 8.6), 8.10 (1H, d, J=8.1), 8.12(1H, d, J=7.8), 8.22(1H, d, J=4.6),11.49(1H, br s); ESMS 294 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:29])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]([CH2:27][CH3:28])=[CH:25][CH3:26])[C:5]2=[CH:4][CH:3]=1.[CH3:30][O:31][CH:32]([Si:34]([CH3:37])([CH3:36])[CH3:35])[CH3:33].[C:38]([O:42][C:43](=[O:46])[CH2:44]Br)([CH3:41])([CH3:40])[CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:38]([O:42][C:43]([CH2:44][N:12]1[C:13](=[O:23])[CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:29])[CH:11]1[C:24]([CH2:27][CH3:28])=[CH:25][CH3:26])=[O:46])([CH3:41])([CH3:40])[CH3:39].[CH3:30][O:31][CH:32]([Si:34]([CH3:37])([CH3:36])[CH3:35])[CH3:33]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC=C(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC=C(CC)C1N(CC(=O)OC(C)(C)C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 37 %

Procedure:
In a manner similar to the method described in example 55c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (1.6 g, 2.8 mmol) prepared in example 81a was reacted with bromo-acetic acid tert-butyl ester and cesium carbonate in N,N-dimethylformamide to give racemic (2′R,3R,4′S)-1′-[(tert-butoxycarbonyl)methyl]-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white foam (Yield 0.7 g, 37%).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:19]=[CH:18][CH2:17][C:16]2[C:9]=1[CH:10]=[C:11]1[C:15]=2[C:14]([CH3:20])=[N:13][N:12]1[CH2:21][C@@H:22](O)[CH3:23].C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:32]([CH:22]([CH3:23])[CH2:21][N:12]1[C:11]2=[CH:10][C:9]3[C:16]([CH2:17][CH:18]=[CH:19][C:8]=3[O:7][CH3:6])=[C:15]2[C:14]([CH3:20])=[N:13]1)=[N+:33]=[N-:34]
Reactant: COC1=C2C=c3c(c(C)nn3C[C@H](C)O)=C2CC=C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC1=C2C=c3c(c(C)nn3CC(C)N=[N+]=[N-])=C2CC=C1
Yield: 82.9 %

Procedure:
0.7 ml (8.52 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.1 g (4.26 mmol) of (S)-1-(7-methoxy-3-methyl-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 2.4 ml (17 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 130 ml of dichloromethane, washed twice with 60 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 50 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 60 ml of anhydrous dimethylformamide, treated with 0.55 g (8.46 mmol) of sodium azide and the reaction mixture was heated to 80° for 15 hours while stirring. After cooling, the solution was poured into 80 ml of semi-saturated sodium chloride solution and extracted twice with 80 ml of diethyl ether each time. The combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1 g (83%) of (RS)-1-(2-azido-propyl)-7-methoxy-3-methyl-1,4-dihydro-indeno[2,1-c]pyrazole was obtained as a dark brown oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl-]>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:11](=[O:16])[CH2:12][C:13]2([CH3:14])[CH3:15])([CH3:3])[CH3:2]
Reactant: CC(C)=CC(=O)Nc1ccc(C(C)C)cc1
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)c1ccc2c(c1)C(C)(C)CC(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-methyl-but-2-enoic acid (4-isopropyl-phenyl)-amide (Intermediate 1, 8.12 g, 37.4 mmol) in 100 ml of anhydrous CH2Cl2 under argon at 0° C. was slowly added aluninum chloride (20 g, 150 mmol) through a powder addition fumnel. The cooling bath was removed and the mixture was stirred at ambient temperature for 3 hours. The reaction was re-cooled to 0° C. and slowly quenched with ice. The product was extracted with diethyl ether. The organic layer was washed with water, saturated NaHCO3 and brine, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (silica, first using 25% ethyl acetate in hexane followed by 50% ethyl acetate in hexane) to give the title compound as a white solid.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH:8](O)([CH3:10])[CH3:9]>>[CH:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1)([CH3:10])[CH3:9]
Reactant: CC(C)O
Reactant: O=C1C=CC(O)N1
Product: CC(C)OC1C=CC(=O)N1
Reaction time: 3 h

Procedure:
A mixture of 3 g of 1,5-dihydro-5-hydroxy-2H-pyrrol-2-one, 1.5 g of Amberlite IR 120 H and 60 cm3 of isopropanol is taken to 45°-50° C. for 3 hours. After cooling, filtering and evaporating to dryness, 1.8 g of the expected product is obtained, m.p. 79°-81° C., crystallized from isopropanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([C:14]1[CH2:15][CH2:16][O:17][CH2:18][CH:19]=1)([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:23]([F:40])=[C:24](/[CH:28]=[C:29](/[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[F:39])\[C:30]#[N:31])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[CH:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[C:23]=2[F:40])[C:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[F:39])([C:30]#[N:31])[CH:9]([CH2:10][C:11]([C:14]2[CH2:19][CH2:18][O:17][CH2:16][CH:15]=2)([CH3:13])[CH3:12])[NH:8]1)=[O:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C/N=C/CC(C)(C)C1=CCOCC1
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C1NC(CC(C)(C)C2=CCOCC2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Yield: 75 %

Procedure:
In a manner similar to the method described in Example 100b, [3-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 129a (4.3 g, 15.5 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (3.8 g, 12.4 mmol) prepared in Example 52a, AgF (2.4 g, 19 mmol), and triethylamine (4.3 mL, 31 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (19 ml) in tert-butanol (18 mL) at 100° C. for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester as a yellow gum (5.5 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26]([NH:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]2[N:4]([CH3:7])[N:5]=[CH:6][C:2]=2[F:1])[CH:9]=1)=[O:27]
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Reactant: O=C=Nc1ccc(F)cc1F
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(F)cnn1C
Yield: 58 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2,4-difluorophenylisocyanate, in a similar manner as described in Example 1.68, providing 21 mg (58% yield) of Compound 37: LCMS m/z (%)=377 (M+H, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.50 (s, 1H), 8.24 (m, 1H), 7.98 (s, 1H), 7.64 (dd, J1=9.0 Hz, J2=2.6 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.38 (d, JH,F=4.8 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.06 (ddd, J1=11.4 Hz, J2=8.6 Hz, J=2.8 Hz, 1H), 6.99 (dd, J1=9.6 Hz, J2=9.6 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −119.93 (m, 1F), −127.63 (m, 1F) −177.41 (d, JH,F=4.1 Hz, 1F).
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:19][C:20](=[O:33])[NH:21][C:22]2[CH:27]=[C:26]([Cl:28])[C:25]([O:29][CH3:30])=[CH:24][C:23]=2[O:31][CH3:32])[C:9]1=[O:34])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:28][C:26]1[C:25]([O:29][CH3:30])=[CH:24][C:23]([O:31][CH3:32])=[C:22]([NH:21][C:20]([CH2:19][N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[N:15][C:12]=3[C:13](=[O:14])[N:8]([CH2:7][C:6]([OH:35])=[O:5])[C:9]2=[O:34])=[O:33])[CH:27]=1
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)OC(C)(C)C)c(=O)c3ncccc32)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ncccc32)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirring solution of {1-[(5-chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl}-acetic acid tert-butyl ester (Intermediate R) (22.1 mg, 0.044 mmol) in DCM (1 ml) is treated with TFA (1 ml). The reaction mixture is stirred at RT and monitored by HPLC/LCMS until the starting material is consumed. After 3 hours, the reaction mixture is diluted with a minimal amount of DCM and concentrated in vacuo. The residue is taken up in a minimal amount of MeOH, concentrated in vacuo, the again in a minimal amount of EtOAc and concentrated in vacuo to afford the title compound as an off white solid; [M+H]+ 449
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]([C:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][C:7]=1[CH3:14])=[O:5].C(N(CC)CC)C.[CH3:22][SH:23]>CCOCC>[CH3:22][S:23][CH:2]([CH3:1])[CH2:3][C:4]([C:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][C:7]=1[CH3:14])=[O:5]
Reactant: C/C=C/C(=O)C1=C(C)C=CCC1(C)C
Reactant: CS
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CSC(C)CC(=O)C1=C(C)C=CCC1(C)C
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a 50-ml, three-necked, round-bottom flask equipped with a magnetic stirring assembly, a tube submerged for the introduction of gas, an immersion thermometer and a dry ice isopropanol condenser, the outlet of which leads through a 50% alkali trap to the hood sink, is placed 8.3 grams of beta-damascenone and approximately 1 gram of triethylamine. Gaseous methyl mercaptan is introduced into the stirred reaction mixture which is maintained at 10° C. Addition is continued for approximately one hour and then stopped. The stirred reaction mix is allowed to attain room temperature, and the reaction mix is stirred overnight at room temperature. The next morning the light yellow reaction mix is transferred to 50 ml of ether in a separatory funnel and washed twice with dilute sulfuric acid, twice with saturated sodium bicarbonate solution, and then with saturated saline solution until the wash is neutral. The dried ether layer is stripped of solvent on a `rotovap` and GLC of the residue on an 1/8'×10" stainless steel, 5% carbowax 20 M column isothermally at 190° C. shows one major late eluting peak which is trapped for infra-red and nuclear magnetic resonance/mass spectral analyses. Infra-red analysis suggests that the cyclohexadienyl ring structure is intact and in conjugation with the side chain ketone which is, however, now out of cross conjugation. Therefore, reaction appears to have occurred at the side chain olefinic site. Mass spectral analysis shows a molecular weight of 238, and the proper fragmentation for the proposed structure. The mass spectral analysis also is a satisfactory match with the scan for peak "A" as set forth in Example I. This peak has an IE on SE-30 of 13.00. A trap of the synthetic material is run for IE and the IE on SE-30 is 13.08.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:39]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH3:29]
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Reactant: CCCCCCCCCCCBr
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCOc1ccc(CCC(=O)OCC)cc1-c1cc(CCC(=O)OCC)ccc1O
Yield: 88 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 1179.8 μl (5.181 mmol) of undecyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated overnight at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 20 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1) to obtain 245.5 mg (0.456 mmol, 88%) of 2-undecyloxy-2'-hydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl as an oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH2:9]([OH:11])[CH3:10].[OH-].[Na+]>ClCCl>[CH2:9]([O:11][C:4]1[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1)[CH3:10]
Reactant: CCO
Reactant: Nc1cccc(Br)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOc1cccc(N)n1
Temperature: 170 °C

Procedure:
Introduced into a microwave tube are 500 mg (2.89 mmol) of 2-amino-6-bromopyridine, to which 2 ml of ethanol and 231 mg (5.78 mmol, 2 eq) of sodium hydroxide are added. The mixture is heated for 10 hours in a microwave oven at 170° C. The reaction medium is diluted with 50 ml of dichloromethane and then washed twice with 50 ml of water. The organic phase is concentrated to dryness and the residue is purified by chromatography over silica with, as eluent, heptane/ethyl acetate (1/1). The expected product is obtained in the form of a colourless oil.
Reaction SMILES: C[CH:2]([CH2:6][C:7]1[O:8][C:9]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:11]=1)[C:3](O)=[O:4].[NH3:29]>CO>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:11]=[C:7]([CH2:6][CH2:2][C:3]([NH2:29])=[O:4])[O:8][C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:13][CH:14]=1
Reactant: N
Reactant: CC(Cc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)o1)C(=O)O
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2oc(CCC(N)=O)nc2-c2ccc(F)cc2)cc1

Procedure:
3-[4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)oxazol-2-yl]propanamide was prepared by treating methyl 3-[4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)oxazol-2-yl]propanoic acid, (Example 12) with excess ammonia in methanol for 5 days. Melting point: 193°-195° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH2:15]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)[CH2:16][CH2:17][CH3:18].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.O>[CH2:15]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:26]=[CH:27][C:28]([C:29]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=4[O:13][CH3:14])[N:1]=3)=[CH:31][CH:32]=2)[CH2:23][CH2:24]1)[CH2:16][CH2:17][CH3:18]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CCCCN1CCN(c2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCN1CCN(c2ccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)cc2)CC1
Temperature: 155 °C
Yield: 13 %

Procedure:
To a solution of 2-amino-4,6-dimethoxybenzamide (6) (1.19 mmol) in DMA (10 mL) was added 4-(4-butylpiperazin-1-yl)benzaldehyde (5) (1.09 mmol), NaHSO3 (1.30 mmol), and p-TsOH (0.10 mmol). The resulting solution was heated to 155° C. for 4 hours and cooled to room temperature. The solution was diluted with water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was purified by flash chromatography on silica gel eluting with 10% to 50% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the compound 7 (0.06 g, 13%). 1H NMR (300 MHz, DMSO-d6): δ 11.76 (s, 1H), 8.09 (d, J=8.9 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.17-3.42 (m, 4H), 2.39-2.58 (m, 4H), 2.23-2.37 (m, 2H), 1.37-1.56 (m, 2H), 1.26-1.37 (m, 2H), 0.84-0.94 (m, 3H). APCI MS m/z 423 [M+H]+.