Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][NH:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=2[N+:29]([O-])=O)[C:24]#[N:25])[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]2)[CH2:4]1)[CH3:2].[CH:32](OC)(OC)OC.C(O)=O.C(O)(C(F)(F)F)=O>CO.CC#N.[Fe]>[CH2:1]([C:3]1([CH2:19][N:20]2[C:21]3[CH:22]=[C:23]([C:24]#[N:25])[CH:26]=[CH:27][C:28]=3[N:29]=[CH:32]2)[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]2)[CH2:4]1)[CH3:2]
Reactant: CCC1(CNc2cc(C#N)ccc2[N+](=O)[O-])CCCC2(CN(CC(C)(C)C)C(=O)O2)C1
Reactant: COC(OC)OC
Agent: [Fe]
Solvent: CO
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCC1(Cn2cnc3ccc(C#N)cc32)CCCC2(CN(CC(C)(C)C)C(=O)O2)C1
Temperature: 65 °C
Reaction time: 21 h
Yield: 116.5 %

Procedure:
To an orange solution containing 3-(((7-ethyl-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile (0.125 g, 0.292 mmol) in MeOH (2.48 mL) was added iron (325 mesh) (0.163 g, 2.92 mmol), trimethyl orthoformate (0.322 mL, 2.92 mmol), and formic acid (0.112 mL, 2.92 mmol). The reaction mixture was stirred at 65° C. for 21 h. Additional trimethyl orthoformate ((0.322 mL, 2.92 mmol) and formic acid (0.112 mL, 2.92 mmol) were added, and the reaction was stirred at 65° C. for another 4 h. The reaction was cooled to rt, diluted with MeCN (2 mL), and filtered through a Acrodisc CR 25 mm syringe filter with 0.2 μm PTFE membrane. The filtered solution was purified by reverse-phase HPLC (Sunfire Prep C18 column (30×150 mm); 15 min run; 25 mL/min elution; Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1% TFA, gradient: 30-60% solvent A) to afford the title compound (0.139 g, 88% yield) as the TFA salt. 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.06 (d, J=8.53 Hz, 1H), 7.85 (s, 1H), 7.73 (dd, J=1.25, 8.53 Hz, 1H), 4.13 (s, 2H), 3.31 (dd, J=8.78, 22.84 Hz, 2H), 3.00 (dd, J=14.31, 38.15 Hz, 2H), 2.01 (d, J=13.55 Hz, 2H), 1.81-1.97 (m, 2H), 1.58-1.75 (m, 3H), 1.10-1.29 (m, 3H), 1.06 (t, J=7.40 Hz, 3H), 0.96 (s, 9H); MS (m/z) 409.2 (M+H+).
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])=[CH:9][CH:8]=1)=[O:5].[OH:21]S(O)(=O)=O>>[O:20]=[C:16]1[N:15]([CH2:14][CH2:13][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[NH:6][C:4](=[O:5])[C:3]3=[O:21])[CH2:19][CH2:18][O:17]1
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccc(CCN2CCOC2=O)cc1
Product: O=C1Nc2ccc(CCN3CCOC3=O)cc2C1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Concentrated H2SO4 (20 ml) is heated to 50° C. The compound obtained in Step D (25.24 mmoles) is added slowly in solid form, maintaining the temperature between 60 and 70° C. The reaction mixture is then stirred for one hour at 80° C. The mixture is brought to ambient temperature and then poured onto 200 g of crushed ice. After 30 minutes, the red solid formed is filtered off and washed intensively with ice-cold water; it is then dried in vacuo in the presence of P2O5 and at 40° C. overnight to yield the title product, which is used directly in the next Step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[CH2:12][C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[CH:16]1([NH:15][C:13](=[O:14])[CH2:12][O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:18][CH2:17]1
Reactant: O=C(CCl)NC1CC1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(COc1cccc([N+](=O)[O-])c1)NC1CC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
A mixture of 3-nitrophenol (4 g, 28.8 mmol), 2-chloro-N-cyclopropylacetamide (4.61 g, 34.5 mmol), K2CO3 (7.95 g, 57.5 mmol) and 18-CROWN-6 (0.228 g, 0.863 mmol) in N,N-Dimethylformamide (30.0 ml) was stirred under N2 atmosphere for 18 hrs at 50° C. After cooling to RT, the reaction mixture was partitioned between EtOAc (250 ml) and water (250 ml). Aq. phase was re-extracted with EtOAc (200 ml). Combined organic layer was washed with brine (100 ml), dried over sodium sulphate and the solvent was evaporated under vacuum. Crude residue was purified by flash chromatography to obtain N-cyclopropyl-2-(3-nitrophenoxy)acetamide (4.21 gm).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](OC)=[O:4].C(N(CC)CC)C.[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].Cl>CO.C(OCC)(=O)C>[F:8][C:2]([F:1])([F:7])[C:3]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4]
Reactant: COC(=O)C(F)(F)F
Reactant: NCCCCCCCCCCCC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)CCCCCCCCCCCNC(=O)C(F)(F)F
Reaction time: 18 h
Yield: 97 %

Procedure:
Methyl trifluoroacetate (200 μL, 1.99 mmoles) and triethylamine (184 μL, 1.32 mmoles) were added to a suspension of 12-aminododecanoic acid (300 mg, 1.32 mmoles) in methanol (2 mL). After the mixture was stirred vigorously for 18 h, 1 N HCl was added dropwise until the a pH of 2 was obtained. The reaction was added to ethyl acetate (20 mL) was washed with 1 N HCl (2×5 mL), dried over MgSO4, and concentrated in vacuo to yield the amide as a white solid (398 mg, 1.28 mmoles, 97%). LRMS: not performed. 1H NMR: spectrum is consistent with the predicted structure.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([C:25]1[N:30]=[C:29]([NH:31][NH2:32])[C:28]([F:33])=[C:27]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)[N:26]=1)[CH3:24].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C.O>[CH:1]1([CH2:6][C@@H:7]([C:8]([NH:32][NH:31][C:29]2[C:28]([F:33])=[C:27]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[N:26]=[C:25]([CH2:23][CH3:24])[N:30]=2)=[O:10])[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: CCc1nc(NN)c(F)c(N2CCN(C)CC2)n1
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCN(C)CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
A solution of (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (12.4 g, 40.6 mmol) in DMF (120 mL) was added to a mixture of 2-ethyl-5-fluoro-4-hydrazino-6-(4-methyl-1-piperazinyl)pyrimidine (9.6 g, 37.8 mmol), HOAt (5.66 g, 41.58 mmol), and EDC (7.97 g, 41.58 mmol). The resulting solution was treated with NMM (9.1 mL, 83.2 mmol) and stirred at room temperature for 3 h. After the reaction was complete, 200 mL of water was added and the solution was extracted three times with 200 mL of ether. The combined organic layers were washed with water (200 mL) and brine (100 mL), and then dried over anhydrous Na2SO4. Evaporation of the solvent provided a light yellow glassy solid as the pure product (17.1 g, 84%).
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[NH:21][N:20]=3)[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>C1COCC1.CO>[F:33][C:30]([F:31])([F:32])[C:27]1[CH:28]=[CH:29][C:24]([C:22]2[NH:21][N:20]=[C:19]([CH2:18][O:17][C:14]3[CH:15]=[C:16]4[C:11]([CH:10]=[CH:9][N:8]4[CH2:7][C:6]([OH:34])=[O:5])=[CH:12][CH:13]=3)[CH:23]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(C(F)(F)F)cc4)[nH]n3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cn1ccc2ccc(OCc3cc(-c4ccc(C(F)(F)F)cc4)[nH]n3)cc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 70 %

Procedure:
To a solution of {6-[5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester (5 mg, 10 μmol) in THF/methanol 2/1 (750 μl) was added 1 N aqueous LiOH solution (600 μl). The reaction mixture was stirred for 14 h at ambient temperature and concentrated under reduced pressure. The residue was dissolved in 1 N HCl/ice water 1/1 and ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound (3 mg, 7 μmol, 68%) as brown crystals.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:54]1[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=1)CCC>CN(C)C=O.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>[CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:54]2[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(-c2cccnc2)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 100 °C
Yield: 73.4 %

Procedure:
To a solution containing the product from Example 92D (0.50 g, 0.70 mmol) in N,N-dimethylformamide (7.0 mL) were added lithium chloride (0.30 g, 7.08 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.150 g, 0.214 mmol), and 3-tributylstannylpyridine (0.776 g, 2.11 mmol), and the mixture was heated to 100° C. for 18 hours. The reaction was filtered, diluted with ethyl acetate and washed with water, and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with chloroform and ending with 25% ethyl acetate in chloroform to give the title compound (0.365 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([Br:9])[C:3]=1[F:10].[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:9][C:4]1[C:3]([F:10])=[C:2]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: O=C1CCCN1
Reactant: Fc1ccc(Br)c(F)c1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C1CCCN1c1ccc(F)c(Br)c1F
Temperature: 85 °C

Procedure:
1,3-dibromo-2,4-difluoro-benzene (5 g, 18.5 mmol) and pyrrolidin-2-one (1.56 g, 18.5 mmol) in dioxane (160 ml) were stirred under argon. Cs2CO3 (7.19 g, 22 mmol), xantphos (1.27 g, 2 mmol) and Pd2(dba)3 (0.675 g, 0.5 mmol) were added and the reaction was heated to 85° C. for 16 h. The reaction was quenched by the addition of 150 ml of H2O. After extraction with ethyl acetate (three times), the combined organic layers were washed with water, dried with Na2SO4, evaporated to dryness and the product was purified by silica gel chromatography (ethyl acetate/cyclohexane 0 to 20% ethyl acetate). Yield: 1 g, 20
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:39]=[CH:40][N:41]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:36]=[CH:37][CH:38]=3)[C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=3)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:39]=[CH:40][N:41]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:36]=[CH:37][CH:38]=3)[C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=3)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(NC(=O)c2cccc(-c3cc(Nc4ccc(OC)c(OC)n4)c4nccn4n3)c2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(NC(=O)c2cccc(-c3cc(Nc4ccc(OC)c(OC)n4)c4nccn4n3)c2)ccc1C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
A mixture of methyl 4-(3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamido)-2-methoxybenzoate (100 mg, 0.18 mmol) and NaOH (100 mg, 2.5 mmol) in 1,4-dioxane (5 mL) and water (5 mL) was stirred for 2 h at 50° C. The mixture was concentrated and adjusted to pH=2 with 3M HCl. The precipitate was filtered and the solid was washed with MeOH (1 mL) and dichloromethane (1 mL) to give 4-(3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamido)-2-methoxybenzoic acid (24 mg, 25%) as a brown solid. 1H NMR (300 MHz, DMSO): δ 10.62 (s, 1H), 10.01 (s, 1H), 8.63 (s, 1H), 8.53 (s, 1H), 8.26-8.21 (m, 2H), 8.09 (d, 1H, J=7.5 Hz), 7.75-7.67 (m, 4 h), 7.50 (dd, 1H, J1=8.4 Hz, J2=1.8 Hz), 7.41 (d, 1H, J=8.4 Hz), 7.10 (d, 1H, J=8.4 Hz), 4.03 (s, 3H), 3.84 (s, 3H), 3.77 (s, 3H). LC-MS: [M+H]+, 541, tR=1.548 min, HPLC: 95.24% at 214 nm, 95.03% at 254 nm, tR=7.943 min.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[NH2:7][C@@H:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[C:9]([N:11]([CH3:13])[CH3:12])=[O:10]
Reactant: CN(C)C(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 2.00 g of the compound obtained in Step 86-2 in CHCl3 (30 ml) was added TFA (6 ml) under ice cooling, then, the reaction solution was stirred at room temperature for 13 hours. The reaction solution was concentrated under reduced pressure to obtain 3.47 g of the title compound (yellow oil form, crude form).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10](=[O:12])[OH:11].[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17]O>>[C:3]1([CH2:8][O:12][C:10](=[O:11])[NH:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1][CH2:17][CH2:16][CH2:15][N:14]([CH3:19])[CH3:13])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CN(C)CCCO
Reactant: O=C(O)NCc1ccccc1O
Product: CN(C)CCCOc1ccccc1CNC(=O)OCc1ccccc1

Procedure:
By following a procedure analogous to Preparation XCVI starting from the benzyl ester of [(2-hydroxyphenyl)methyl]carbamic acid and 3-(dimethylamino)propanol, the expected product is obtained in the form of a colorless oil (yield=81%).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:21])[N:17]=[C:18](Cl)[CH:19]=[C:11]12)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:22][C:23]1[CH:24]=[C:25]([CH2:30][OH:31])[CH:26]=[CH:27][C:28]=1[F:29]>CN(C)C=O>[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:21])[N:17]=[C:18]([O:31][CH2:30][C:25]3[CH:26]=[CH:27][C:28]([F:29])=[C:23]([F:22])[CH:24]=3)[CH:19]=[C:11]12)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: O=c1nc(Cl)cc2n1CCCN2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1nc(OCc2ccc(F)c(F)c2)cc2n1CCCN2Cc1ccccc1
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a suspension of NaH (21.76 mg, 0.54 mmol) in N,N-dimethylformamide (DMF) (2 mL), 1-benzyl-8-chloro-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (50 mg, 0.18 mmol) was added (3,4-difluorophenyl)methanol (0.026 mL, 0.22 mmol) at r.t., and stirred for 30 mins. The reaction mixture was quenched by water. Purification via reverse phase column (0.3% trifluoroacetate acid in acetonitrile/water) afforded the title compound (22 mg).
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:18]([C:23]3[S:27][C:26]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)=[N:25][C:24]=3[CH3:38])[CH2:19][CH2:20][CH2:21][OH:22])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[OH:22][CH2:21][CH2:20][CH2:19][CH:18]([C:23]1[S:27][C:26]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)=[N:25][C:24]=1[CH3:38])[O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:39])=[O:5])=[CH:12][CH:13]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(CCCO)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(CCCO)Oc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], [rac]-(6-{4-hydroxy-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-butoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with LiOH to obtain [rac]-(6-{4-hydroxy-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-butoxy}-indol-1-yl)-acetic acid as brown crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[CH2:12](Br)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15].O>CN(C=O)C>[CH3:15]/[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:13]\[CH2:12][NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: Nc1ccc(C(=O)O)c(O)c1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCC/C(C)=C/CNc1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 7.5 %

Procedure:
In 30 ml of DMF was dissolved 2.12 g (13.8 mmol) of 4-amino-2-hydroxybenzoic acid, and 3.0 g (13.8 mmol) of geranyl bromide was added thereto. After the mixture was stirred at room temperature for 4 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by column chromatography and recrystallized from ethyl acetate/hexane to obtain 0.30 g (yield: 7.6%) of N-{(2E)-3,7-dimethylocta-2,6-dienyl}-4-amino-2-hydroxybenzoic acid represented by the following structural formula (hereinafter referred to as compound 47) as white crystals. The analytical results are shown below. ##STR68##
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[C:8]([NH2:13])[CH:9]=[C:10]([OH:12])[CH:11]=1)(=[O:4])[CH3:3].[C:14]([C:17]1[C:18](=[O:28])[O:19][C:20]([OH:27])=[C:21]([C:24](=O)[CH3:25])[C:22]=1[OH:23])(=[O:16])[CH3:15]>>[C:2]([NH:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([NH:13][C:24](=[C:21]2[C:22]([OH:23])=[C:17]([C:14](=[O:16])[CH3:15])[C:18](=[O:28])[O:19][C:20]2=[O:27])[CH3:25])[CH:7]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: CC(=O)Nc1cc(N)cc(O)c1
Agent: Cl
Product: CC(=O)Nc1cc(O)cc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)c1

Procedure:
Similarly reaction of 5-acetamido-3-aminophenol hydrochloride with 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one as described above furnishes 3-[1-(5-acetamido-3-hydroxyphenylamino)ethylidene]-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:15][C:16]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:17]=1[CH2:18][N:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22](=[O:30])(=[O:29])[N:21](CC2C=CC=CN=2)[C:20]1=[O:38]>>[Cl:15][C:16]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:17]=1[CH2:18][N:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22](=[O:30])(=[O:29])[N:21]([CH2:2][C:3]2[CH:7]=[C:6]([CH3:8])[O:5][N:4]=2)[C:20]1=[O:38]
Reactant: O=C1N(Cc2c(F)cccc2Cl)c2ccccc2S(=O)(=O)N1Cc1ccccn1
Reactant: Cc1cc(CBr)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(CN2C(=O)N(Cc3c(F)cccc3Cl)c3ccccc3S2(=O)=O)no1

Procedure:
The title compound (0.16 g, 0.37 mmol) was prepared from (IntE1) (0.3 g, 0.88 mmol), 3-(bromomethyl)-5-methyl-1,2-oxazole (0.11 g, 0.63 mmol) and Cs2CO3 (0.86 g, 2.64 mmol) using the methods of (128).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[CH:5][CH:4]=1.[CH3:17][N:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:19].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7](=[N:19][N:18]([CH3:17])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: CN(N)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CC(=NN(C)c1ccccc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
In 60 ml of acetic acid were dissolved 15 g of ethyl p-methoxybenzoylacetate and 8.25 g of 1-methyl-1-phenylhydrazine and the resulting solution was stirred at room temperature for 12 hours. The reaction mixture was poured into iced water and extracted with ethyl acetate. The extract was washed with aqueous solution of sodium hydrogen carbonate and water in that order, dried over anhydrous magnesium sulfate and concentrated to provide 21.8 g of the desired compound as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[N:16]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]=2[CH2:37][CH2:38][NH2:39])[CH3:11])=[CH:6][CH:5]=1.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49](Cl)(=[O:51])=[O:50]>>[CH:24]([N:16]1[C:17]2[C:22](=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]([CH2:13][CH2:12][N:10]([CH3:11])[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:40])=[CH:9][CH:8]=2)=[C:15]1[CH2:37][CH2:38][NH:39][S:49]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[O:42][CH3:41])(=[O:51])=[O:50])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)c1ccc(N(C)CCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: COc1ccccc1S(=O)(=O)NCCc1c(CCN(C)c2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 95 %

Procedure:
The intermediate from Example 147 step 7 was treated with 2-methoxy-benzenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 95% yield.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C1C=C[C:30]([C:31]#[N:32])=CC=1.N[C@H](C(O)=O)CS>>[CH3:25][O:24][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23])[C:12]([C:10]1[N:11]=[C:7]([C:1]2[CH:6]=[CH:5][C:4]([CH2:30][C:31]#[N:32])=[CH:3][CH:2]=2)[S:8][CH:9]=1)=[O:13]
Reactant: N#Cc1ccc(C#N)cc1
Reactant: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Agent: N[C@@H](CS)C(=O)O
Product: COc1cc(C(=O)c2csc(-c3ccc(CC#N)cc3)n2)cc(OC)c1OC

Procedure:
2-(4-(4-(3,4,5-Trimethoxybenzoyl)thiazol-2-yl)phenyl)acetonitrile (2n) was prepared using the same method as used of compound 1h from terephthalonitrile and cysteine. 1H NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 8.04 (d, 2H), 7.76 (s, 2H), 7.46 (d, 2H), 3.97 (s, 3H), 3.95 (s, 6H), 3.83 (s, 2H).