Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[CH:6]=[CH:7][C:8](=[N:10][OH:11])[NH2:9])([O-:3])=[O:2].[CH:16]([O-])([O-])OCC>B(F)(F)F.CCOCC>[N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1/[CH:6]=[CH:7]/[C:8]1[N:9]=[CH:16][O:11][N:10]=1)([O-:3])=[O:2]
Reactant: CCOC([O-])[O-]
Reactant: NC(C=Cc1ccccc1[N+](=O)[O-])=NO
Agent: FB(F)F
Solvent: CCOCC
Product: O=[N+]([O-])c1ccccc1/C=C/c1ncon1
Reaction time: 8 h
Yield: 64 %

Procedure:
o-Nitrocinnamamidoxime (1.84 g.) was refluxed for 1 hr. in ethyl orthoformate (15 ml.) containing boron trifluoride etherate (4 drops). The mixture was refrigerated overnight and filtered to give trans-3-o-nitrostyryl-1,2,4-oxadiazole (1.24 g., 64%), m.p. 128°. Evaporation of the filtrate gave an additional 0.51 g. (26%) of the title compound. A sample recrystallised from aqueous acetone has m.p. 120°- 121°, λmax. 247 nm, ε 18900 (Found: C, 55.2; H, 3.3; N, 19.4. C10H7N3O3 requires C, 55.3; H, 3.25; N, 19.35%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:21]=[C:20]([CH:22]=[O:23])[N:19]([CH3:24])[N:18]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH:25]12CC(C=C1)C=[CH:26]2>O1CCOCC1>[CH3:24][N:19]1[C:20]([CH:22]=[O:23])=[CH:21][C:17]([C:14]2[CH:15]=[CH:16][C:11]([N:7]3[CH2:6][C@H:5]([CH2:4][N:1]4[CH:26]=[CH:25][N:3]=[N:2]4)[O:9][C:8]3=[O:10])=[CH:12][CH:13]=2)=[N:18]1
Reactant: C1=CC2C=CC1C2
Reactant: Cn1nc(-c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2)cc1C=O
Solvent: C1COCCO1
Product: Cn1nc(-c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2)cc1C=O
Temperature: 90 °C
Yield: 47.3 %

Procedure:
3-{4-[(5R)-5-(Azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-1-methyl-1H-pyrazole-5 carbaldehyde (Intermediate 13, 50 mg, 0.15 mmol), bicyclo[2.2.1]hepta-2,5-diene (0.17 ml, 1.58 mmol) and dioxane (1 ml) were combined and warmed to 90° C. for 4.5 hours. The mixture was evaporated and purified by chromatography on silica gel, eluting with ethyl acetate to give the title compound as a white solid (25 mg).
Reaction SMILES: [NH3:1].[C:2]12([C:12]3[CH:13]=[C:14]([C:25]#[C:26][C:27]4[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.O>C1COCC1>[C:2]12([C:12]3[CH:13]=[C:14]([C:25]#[C:26][C:27]4[CH:35]=[CH:34][C:30]([C:31]([NH2:1])=[O:32])=[CH:29][CH:28]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: N
Reactant: COCCOCOc1ccc(C#Cc2ccc(C(=O)Cl)cc2)cc1C12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOc1ccc(C#Cc2ccc(C(N)=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 3 h

Procedure:
500 μl (9.1 mmol) of an aqueous ammonia solution (32%) and 20 ml of THF were introduced into a round-bottomed flask. A solution of 1.1 g (2.3 mmol) of 4-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl]benzoyl chloride dissolved in 30 ml of THF was added dropwise and stirring was carried out at room temperature for three hours. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: [CH2:1]([NH:4][C:5](=O)[O:6]C1C=CC([N+]([O-])=O)=CC=1)[C:2]#[CH:3].[Cl:17][C:18]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][NH2:28])[CH2:22]1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:17][C:18]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][NH:28][C:5]([NH:4][CH2:1][C:2]#[CH:3])=[O:6])[CH2:22]1
Reactant: NC[C@H]1CN(Cc2cccc(Cl)c2Cl)CCO1
Reactant: C#CCNC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C#CCNC(=O)NC[C@H]1CN(Cc2cccc(Cl)c2Cl)CCO1
Reaction time: 16 h
Yield: 51.5 %

Procedure:
A solution of Intermediate 22 (0.024 g) in dichloromethane (1 ml) was stirred with Intermediate 20 (0.033 g) and N,N-diisopropylethylamine (0.022 ml) for 3 h at 23° C. The solvent was removed in vacuo and the residue was purified by solid phase extraction (Isolute SCX sulphonic acid column) eluting with methanol followed by 10% 0.880 ammonia solution in methanol. The basic fraction was concentrated in vacuo, and the residue was dissolved in dichloromethane (5 ml), and the solution shaken with polystyrene methyl isocyanate resin (Argonaut technologies, 0.256 g, 1.43 mmol/g) for 16 h. The solution Was drained from the resin and the resin washed with dichloromethane (8 ml); the combined filtrate and washings were concentrated in vacuo to give the title compound as a pale yellow gum (0.02 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17].CCO.C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:13]([CH3:20])([CH3:19])[CH3:12])=[CH:15][C:16]([NH2:17])=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(-n2nc(N)cc2C(C)(C)C)cc1

Procedure:
A mixture of 4-methoxyphenylhydrazine hydrochloride (3.5 g), 4,4-dimethyl-3-oxopentanenitrile (2.5 g), EtOH (30 mL), and AcOH (1 mL) was heated at the reflux temperature for 3 h, cooled to room temp., and poured into a mixture of EtO (100 mL) and a 10% Na2CO3 solution (100 mL). The organic layer was washed with a saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The solid residue was washed with pentane to afford the desired pyrazole as a pale brown solid. (4.25 g): 1H-NMR (DMSO-d6) δ 1.18 (s, 9H); 3.78 (s, 3H); 5.02 (br s, 2H); 5.34 (s, 1H); 6.99 (d, J=8 Hz, 2H); 7.42 (d, J=8 Hz, 2H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[SH:25][C:26]1[N:30]([CH2:31][C:32]([OH:34])=[O:33])[N:29]=[N:28][N:27]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8](=[O:9])[NH:7][C:5]2[S:6][C:2]([S:25][C:26]3[N:30]([CH2:31][C:32]([OH:34])=[O:33])[N:29]=[N:28][N:27]=3)=[CH:3][N:4]=2)=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)Cn1nnnc1S
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3nnnn3CC(=O)O)s2)c(C(=O)C2CCCC2)c1
Yield: 27.9 %

Procedure:
(5-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-tetrazol-1-yl)-acetic acid (136 mg, 28%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and (5-mercapto-tetrazol-1-yl)-acetic acid (320 mg, 2 mmol) following the general procedure Y.
Reaction SMILES: CN(C)C=CC(C1C=COC=1)=[O:6].[O:13]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]3[CH:24]=[N:25][C:26]([C:27]#[N:28])=[C:22]3[N:21]=[CH:20][CH:19]=2)=[CH:14]1>>[O:13]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]3[CH:24]=[N:25][C:26]([C:27]([NH2:28])=[O:6])=[C:22]3[N:21]=[CH:20][CH:19]=2)=[CH:14]1
Reactant: N#Cc1ncn2c(-c3ccoc3)ccnc12
Reactant: CN(C)C=CC(=O)c1ccoc1
Product: NC(=O)c1ncn2c(-c3ccoc3)ccnc12

Procedure:
3-Dimethylamino-1-(3-furyl)-2-propen-1-one (prepared as described in Example 4) can be substituted for 3-dimethylamino-1-(2-thienyl)-2-propen-1-one (prepared as described in Example 4) in the procedure of Example 6, to produce 4-(3-furyl)imidazo[1,5-a]pyrimidine-8-carboxamide.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8](OCC)=[O:9])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:9][CH2:8][CH:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCC(O)CC1

Procedure:
Ethyl 4-oxocyclohexanecarboxylate (Aldrich Chemical Co., Milwaukee, Wis.) is reduced with excess lithium aluminum hydride in tetrahydrofuran to provide 4-(hydroxymethyl)cylohexan-1-ol.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[O:15][CH2:16][CH3:17].[OH-].[Li+].Cl>O1CCCC1.O>[CH2:16]([O:15][C:5]1[CH:6]=[C:7]([O:10][C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:9][C:4]=1[C:3]([OH:18])=[O:2])[CH3:17]
Reactant: CCOc1cc(OC(F)(F)F)ccc1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(OC(F)(F)F)ccc1C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
590 mg 2-Ethoxy-4-trifluoromethoxy-benzoic acid methyl ester was dissolved in a mixture of 30 ml tetrahydrofuran and 10 ml water. 367 mg lithium hydroxide were added and the reaction mixture stirred at 60° C. for two hours. The cooled reaction mixture was acidified by dropwise addition of concentrated hydrochloric acid, then the mixture was extracted three times with portions of 80 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was removed in vacuo to obtain 518 mg 2-ethoxy-4-trifluoromethoxy-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C[Si]([N-:18][Si](C)(C)C)(C)C.[Li+].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][NH2:18])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=Cc1cc(Cl)cc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCc1cc(Cl)cc2ccccc12
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
The 3-chloro-1-naphthalenecarbaldehyde (2 g) dissolved in dry THF (12 mL) was added dropwise to lithium bis(trimethylsilyl)amide 1M in THF (11.5 mL) previously cooled at −40° C. The resulting yellow mixture was stirred from −40° C. to −20° C. over 1.5 h; then it was cooled down at −50° C. and lithium aluminium hydride 1M in Et2O (10.6 mL) was added; the mixture was stirred at −40° C. for 2 h then it was quenched with HCl 2N (10 mL) and allowed to reach room temperature. The reaction mixture was diluted with further aqueous HCl 2N solution (20 mL) and extracted with CH/Et2O 1/1 (50 mL). The acidic aqueous phase was basified at 0° C. with NaOH pellets until pH=14, then it was extracted with diethyl ether (2×150 mL). The organic phase was dried and concentrated in vacuo to give the title compound (1.78 g) as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18](Cl)=[C:19]([CH3:21])[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:23]([Sn](CCCC)(CCCC)CCCC)[CH:24]=C>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([CH:23]=[CH2:24])=[C:19]([CH3:21])[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Cc1cc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1ncc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1C
Yield: 55 %

Procedure:
3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-6-chloro-5-methylpyridine (830 mg, 2.57 mmol) in toluene (10 mL) was added [1,1'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(U) (83 mg) and allyltributyltin (1.3 mL, 5.1 mmol). The mixture was stirred and refluxed for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 3:2) to afford an oil (450 mg, 57%): 1H NMR (CDCl3, 300 MHz) δ 1.47 (s, 9H), 1.62 (m, 1H), 1.86 (m, 1H), 2.00-2.10 (m, 2H), 2.34 (s, 3H), 3.30-3.46 (m, 2H), 3.90 (m, 1H), 4.04-4.20 (m, 2H), 5.37 (d, 1H, J=11.0 Hz), 6.20 (d, 1H, J=17.0 Hz), 6.94 (dd, 1H, J=11.0, 17.0 Hz), 7.02 (br s, 1H), 8.14 (d, 1H, J=2.5 Hz); MS (CI/NH3) m/z 319 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[S-:18][CH2:19][CH3:20].[Na+]>O1CCCC1>[CH2:19]([S:18][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1)[CH3:20]
Reactant: CC[S-]
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 0 °C
Yield: 67.9 %

Procedure:
Into a round-bottomed flask equipped with a condenser was placed 6-chloro-N-(4-fluoro-phenyl)-nicotinamide (0.20 g, 0.80 mmol), tetrahydrofuran (6 mL), and sodium thioethoxide (0.10 g, 1.2 mmol). The mixture was heated to reflux for 4 h at which time additional sodium thioethoxide (0.10 g, 1.2 mmol) was added and stirred for 2 additional hours. The reaction mixture was then cooled and poured into ice water and the solids isolated by vacuum filtration to provide 0.15 g (68%) of the product as a white solid. MS (EI) m/z 275.2 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24]>[N+](C)([O-])=O>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:34][CH:33]=3)[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc2O1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 46.2 %

Procedure:
200 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 10 ml of nitromethane and the solution was cooled to 0° C. under a nitrogen atmosphere. 240 mg of finely powdered aluminum chloride were added and, after stirring at 0° C. for 5 minutes, 388 mg of 4-nitrobenzoyl chloride were added. After 16 hours at room temperature 120 mg of aluminum chloride were added and the mixture was stirred at 100° C. for 45 minutes. After dilution with diethyl ether and washing with sodium hydroxide solution the organic phase was dried over sodium sulphate and evaporated. The residue crystallized and was triturated with diethyl ether to give 150 mg of 3,4-dihydro- 2,2-dimethyl-6-(4-nitrobenzoyl)-4-(2-pyridyl)-2H-1-benzopyran.
Reaction SMILES: Br.[NH2:2][C:3]1[NH:7][N:6]=[C:5]([CH3:8])[C:4]=1[Br:9].[C:10]([CH:13]1[CH2:18][CH2:17][O:16][C:14]1=[O:15])(=O)[CH3:11]>C(O)C>[Br:9][C:4]1[C:5]([CH3:8])=[N:6][N:7]2[C:14]([OH:15])=[C:13]([CH2:18][CH2:17][OH:16])[C:10]([CH3:11])=[N:2][C:3]=12
Reactant: Cc1n[nH]c(N)c1Br
Reactant: CC(=O)C1CCOC1=O
Agent: Br
Solvent: CCO
Product: Cc1nc2c(Br)c(C)nn2c(O)c1CCO
Temperature: 25 °C
Yield: 31.5 %

Procedure:
A solution of 5-amino-4-bromo-3-methylpyrazole hydrobromide (13 g, 51 mmol) and α-acetyl-γ-butyrolactone (6.8 g, 53 mmol) in ethanol (65 mL) was heated under reflux for nine hours. After cooling to room temperature, the resulting crystals were collected by filtration, to give the title compound (4.6 g) as white crystals.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[S:6][CH:7]=1)=O.[Br-].[C:13]([C:16]1[CH:17]=[C:18]([CH:39]=[CH:40][CH:41]=1)[CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:15])=[O:14]>>[C:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH:1]=[CH:19][C:18]2[CH:17]=[C:16]([CH:41]=[CH:40][CH:39]=2)[C:13]([OH:15])=[O:14])[N:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1nc(C=O)cs1
Reactant: O=C(O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Product: CC(=O)Nc1nc(C=Cc2cccc(C(=O)O)c2)cs1
Yield: 99.3 %

Procedure:
N-(4-Formyl-1,3-thiazol-2-yl)acetamide (1.702 g, 10.00 mmol) and (3-carboxybenzyl)(triphenyl)phosphonium bromide (5.251 g, 11.00 mmol) were condensed by a method similar to that of Production Example 4, step 3, to give 3-{2-[2-(acetylamino)-1,3-thiazol-4-yl]vinyl}benzoic acid (2.862 g, 9.926 mmol, yield 99.3%) as a pale-yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7]2[NH:11][O:10][C:9](=[O:12])[C:8]=2[CH:13]=1)([OH:3])=[O:2].[C:17](=O)([O-])[O-].[Na+].[Na+].COS(OC)(=O)=O.S(=O)(=O)(O)O>>[CH3:17][N:11]1[C:7]2[C:6]([C:14]([OH:16])=[O:15])=[CH:5][C:4]([C:1]([OH:3])=[O:2])=[CH:13][C:8]=2[C:9](=[O:12])[O:10]1
Reactant: O=C(O)c1cc(C(=O)O)c2[nH]oc(=O)c2c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Product: Cn1oc(=O)c2cc(C(=O)O)cc(C(=O)O)c21

Procedure:
Crude 1C is dissolved in a slight excess of aqueous sodium carbonate solution and treated with a 10% excess of dimethylsulfate. The reaction is warmed on a steam bath under nitrogen with swirling until the solution becomes homogeneous. The warm reaction mixture is immediately made acidic with concentrated sulfuric acid and allowed to cool. The precipitate which forms on cooling is collected, dried and used directly in the next step. Mass spectrum, m/e 237 (m+).
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.Br[CH2:32][CH2:33][CH2:34][C:35]#[N:36].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C>[OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:32][CH2:33][CH2:34][C:35]#[N:36])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: N#CCCCBr
Reactant: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OCCCC#N)cc1
Yield: 76.1 %

Procedure:
A mixture of the phenol prepared in example 91 (0.90 g, 2.2 mmol), 4-bromobutyronitrile (0.5 mL, 5.0 mmol), potassium carbonate (0.97 g, 7.0 mmol), potassium iodide (0.1 g) and methyl ethyl ketone (30 mL) was heated at reflux for 10 h. The reaction was concentrated in vacuo and the resulting residue partitioned between EtOAc and water. The layers were separated and the aqueous layer extracted with EtOAc (3×). The combined organic layers were washed with water (3×), brine, dried (MgSO4), and concentrated in vacuo to a light pink oil. The material was purified by flash chromatography over silica gel eluting with 5% MeOH/CHCl3 to provide 0.79 g (76%) of a clear oil. MS (FD+) 471.65. NMR.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].Cl[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=1.O>CS(C)=O>[CH3:1][C:2]1[N:3]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2ccnc2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
In DMSO (5 mL) was dissolved 2-methyl-1H-imidazole (575 mg, 7.00 mmol). To the solution 60% sodium hydride (in oil) (323 mg, 8.08 mmol) was added at 0° C. and the mixture was stirred at room temperature for 30 minutes. Ethyl 6-chloronicotinate (1.00 g, 5.39 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=97/3) to give ethyl 6-(2-methyl-1H-imidazol-1-yl)nicotinate (455 mg, 37% yield).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:14]1[NH:19][C:18]([NH2:20])=[N:17][CH:16]=[C:15]1[N+:21]([O-:23])=[O:22]>CN(C=O)C>[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:16]2[C:15]([N+:21]([O-:23])=[O:22])=[CH:14][N:19]=[C:18]([NH2:20])[N:17]=2)=[CH:4][CH:3]=1
Reactant: NC1=NC=C([N+](=O)[O-])C(Cl)N1
Reactant: Ic1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc([N+](=O)[O-])c(-n2ncc3ccc(I)cc32)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-iodo-1H-indazole (537 mg, 2.20 mmol) in DMF (16 mL) was added NaH (60% oil dispersion) (132 mg, 3.30 mmol) at 0° C. Mixture was stirred at RT for 10 min before addition of a portion of 6-chloro-5-nitro-1,6-dihydropyrimidin-2-amine (60% pure, 500 mg, 1.71 mmol). The mixture was stirred at RT for 20 min. Another portion of NaH (60% oil dispersion) (132 mg, 3.30 mmol) was added at RT. After 10 min, another portion of 6-chloro-5-nitro-1,6-dihydropyrimidin-2-amine (60% pure, 300 mg, 1.03 mmol) was added. Stirring continued for 30 min. The reaction mixture was cooled in an ice bath before quenching with water. The mixture was acidified by addition of 1 M aq HCl then the pH was adjusted to 8-9 by dropwise addition of saturated aq NaHCO3.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1C1C=CC=CC=1O.CC(C[AlH]C[CH:27]([CH3:29])[CH3:28])C>C1COCC1>[OH:20][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:28]2[CH:27]=[CH:29][CH:6]=[CH:7][C:8]=2[OH:9])=[O:9])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1-c1ccccc1O
Reactant: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of (2-hydroxyphenyl)-terephthalamic acid methyl ester (1.31 g, 4.8 mmol) in THF (50 mL) at −78° C. was added a solution of DIBAL-H (27 mL, 1.0 M in THF). The reaction was allowed to warm to room temperature, stirred for 1 h and quenched with a saturated potassium sodium tartrate solution (15 mL). The biphasic mixture was stirred vigorously for 1 h, the phases separated and the organic layer dried (MgSO4), filtered, concentrated and purified by column chromatography on silica gel (5% MeOH/CH2Cl2) to give 4-hydroxymethyl-N-(2-hydroxyphenyl)-benzamide (0.58 g, 50%). 1H NMR (CDCl3) δ 1.83 (t, 1 H (OH)), 4.82 (d, 2H, J=6.0 Hz), 6.93 (t, 1H, J=7.8 Hz), 7.08 (t, 1H, J=7.8 Hz), 7.19 (d, 2H, J=7.8 Hz), 7.53 (d, 2H, J=6.0 Hz), 7.92 (d, 2H, J=7.8 Hz), 8.07 (br, 1H), 8.62 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:12]([O:14][C:15](=[O:25])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:25])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:11])[CH:19]=1)[CH3:13]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1

Procedure:
5-Bromo-2-fluoro-benzoic acid (250 mg, 1.14 mmol) was coupled to aniline (60) (240 mg, 1.26 mmol) using Method D. The residue was purified by column chromatography eluting with a stepped gradient of 10-15% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[Na].O[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=O>C(O)(=O)C>[F:20][C:19]([F:21])([F:22])[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]2[N:3]3[N:4]=[CH:5][CH:6]=[C:2]3[N:1]=[CH:9][CH:10]=2)[CH:14]=1
Reactant: Nc1cc[nH]n1
Reactant: O=C(C=CO)c1cccc(C(F)(F)F)c1
Agent: [Na]
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1

Procedure:
A mixture of 0.83 g. of 3-aminopyrazole and 2.38 g. of 3-hydroxy-3'-(trifluoromethyl)acrylophenone sodium salt in 25 ml. of glacial acetic acid is refluxed for 15 hours and then concentrated to dryness. The residue is treated as described in Example 1, giving the desired product, m.p. 104°-106° C.