Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:41])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[NH:28]C(C1C2C(=CC=CC=2)C=CC=1)=O.C([O-])(O)=O.[Na+]>O=S(Cl)Cl.CC(C)=O>[CH3:18][O:19][C:20](=[O:41])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[NH:28][C:9](=[O:11])/[CH:8]=[CH:7]/[C:4]1[CH:3]=[CH:2][C:1]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1NC(=O)c1cccc2ccccc12
Reactant: O=C(O)C=Cc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Product: COC(=O)c1ccc(O)cc1NC(=O)/C=C/c1ccc(-c2ccccc2)cc1
Reaction time: 18 h
Yield: 79.2 %

Procedure:
A mixture of 3-biphenyl-4-yl-acrylic acid (0.449 g, 2.004 mmol) in SOCl2 (5 ml) was refluxed for 2 h. After cooling, the solvent was removed. The residue was dissolved in acetone and added into a stirred solution of 4-hydroxy-2-(naphthoylamino)-benzoic acid methyl ester (0.335 g, 2.004 mmol) in acetone (10 ml) with NaHCO3 (0.202 g, 2.405 mmol). After 18 h, the reaction mixture was concentrated. The residue was triturated with water, filtered and the solids rinsed with ether and dried to give 2-{[(2E)-3-(1,1′-biphenyl-4-yl)prop-2-enoyl]amino}-4-hydroxybenzoic acid methyl ester (0.593 g, 1.588 mmol, 79%) as an off-white solid, mp 292-296° C. 1H NMR (DMSO-d6) δ 3.88 (s, 3H), 6.57 (dd, 1H), 6.95 (d, 1H), 7.37-7.54 (m, 3H), 7.67 (d, 1H), 7.70-7.80 (m, 4H), 7.80-7.90 (m, 3H), 8.20 (dd, 1H), 10.55 (s, 1H), 11.20 (s, 1H); mass spectrum [ES(−)], m/z 372 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7](=[CH2:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:14]([OH:17])(=[S:16])[CH3:15]>>[C:14]([S:16][CH2:11][CH:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9])(=[O:17])[CH3:15]
Reactant: CC(O)=S
Reactant: C=C(Cc1ccc(Cl)cc1)C(=O)O
Product: CC(=O)SCC(Cc1ccc(Cl)cc1)C(=O)O
Yield: 47 %

Procedure:
By working in a way similar to that described in example 8 and by using 2-(4-chlorobenzyl)-propenoic acid (6.7 g; 0.034 moles), prepared as described in example 13, and thioacetic acid (3.64 ml; 0.051 moles), a crude was obtained which chromatographed on silica gel (eluent ligroin:ethyl acetate=1:1) afforded 3-acetylthio-2-(4-chlorobenzyl)-propionic acid (4.36 g; 47% yield) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14]/C=C/C)[C@@H:12]([O:18]/C=C/C)[C@H:11]([O:22]/C=C/C)[C@@H:10]([CH2:26][O:27]/C=C/C)[NH:9]2)=[CH:4][C:3]=1[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH3:40])=[CH:34][CH:33]=1>C1COCC1.CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:18])[C@H:11]([OH:22])[C@@H:10]([CH2:26][OH:27])[NH:9]2)=[CH:4][C:3]=1[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH3:40])=[CH:36][CH:37]=1
Reactant: C/C=C/OC[C@H]1N[C@@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)[C@H](O/C=C/C)[C@@H](O/C=C/C)[C@@H]1O/C=C/C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOc1ccc(Cc2cc([C@@H]3N[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 70 °C
Yield: 46.2 %

Procedure:
Compound from Step G (15 mg, 0.026 mmol) was dissolved in a solution of THF/AcOH/1NHCl (0.2 ml:0.3 ml:0.15 ml) and heated to 70° C. for 30 minutes. The mixture was concentrated to give a pale yellow oil. Purification by preparative HPLC (sunfire C18, 30×100 mm, 5 μm, 10%-100% B over 15 minutes) afforded (2S,3S,4R,5R,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-piperidine-3,4,5-triol (5 mg, 0.012 mmol, 46%) as a white solid. MS (ES+) [M+H]+=408.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([C:12](OC)=[O:13])=[CH:10][N:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C=O>O>[CH:1]1([N:7]2[C:11]([CH2:12][OH:13])=[CH:10][N:9]=[CH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cncn1C1CCCCC1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCc1cncn1C1CCCCC1

Procedure:
To a suspension of 2.1 g (0.01 mol) of 1-cyclohexyl-5-carbmethoxyimidazole in 6 ml of water are added 0.8 g (0.02 mol) of sodium hydroxide and 4 ml of ~37% aqueous formaldehyde solution. The resultant mixture is heated at 80°-90° C. for about 2 hours. After completion of the reaction, the solvent is stripped off, and the remaining residue is extracted with ethyl acetate. The ethyl acetate extracted is concentrated to give 1-cyclohexyl-5-hydroxymethylimidazole as a solid, m.p. 133°-134° C.
Reaction SMILES: [CH3:1][CH:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][CH:4]([C:14]([O:16]CC)=[O:15])[CH2:3]1.O[Li].O.O>C1COCC1>[CH3:11][C:10]([O:9][C:7]([N:6]1[CH:2]([CH3:1])[CH2:3][CH:4]([C:14]([OH:16])=[O:15])[CH2:5]1)=[O:8])([CH3:12])[CH3:13]
Reactant: CCOC(=O)C1CC(C)N(C(=O)OC(C)(C)C)C1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC1CC(C(=O)O)CN1C(=O)OC(C)(C)C

Procedure:
1-(1,1-Dimethylethyl) 3-ethyl 5-methyl-1,3-pyrrolidinedicarboxylate (1.0 g, 3.89 mmol, an estimated 3:1 mixture of cis/trans isomers) and LiOH.H2O (228 mg, 5.44 mmol, 1.4 equiv) was stirred in THF (5 mL) and water (2 mL) as a two-phase mixture at room temperature for 18 hours. The mixture was concentrated in vacuo, and the resulting residue was taken up in 15 mL of water, acidified with cold 2N HCl, and extracted with 2×50 mL of EtOAc. The organic were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (1.03 g) as an oil. LC-MS (ES) m/z=230 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:21]([CH3:23])[CH3:22])[CH3:20].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([Br:24])[C:3]1([CH:21]([CH3:22])[CH3:23])[CH3:20]
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C(C)C)C2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C(C)C)C2Br

Procedure:
A solution of ethyl (1-oxo-2-isopropyl-2-methyl-6,7-dichloro-5-indanyloxy)acetate (3.6 g., 0.01 mole, N-bromosuccinimide (2.4 g., 0.0134 mole) and benzoyl peroxide (20 mg.) in carbon tetrachloride is refluxed 4 hours, cooled and filtered free of succinimide. The solvent is evaporated and the crude product is purified by column chromatography and then recrystallized from cyclohexane to afford substantially pure ethyl (1-oxo-2-isopropyl-2-methyl-3-bromo-6,7-dichloro-5-indanyloxy)acetate, m.p. 83°-85° C.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2I)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:23]1([C:26]#[CH:27])[CH2:25][CH2:24]1>C(N(CC)CC)C.[Cu]I.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>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:27]#[C:26][CH:23]2[CH2:25][CH2:24]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C#CC1CC1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ccccc2I)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ccccc2C#CC2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [4-(tert-butyldimethylsilanyloxy)cyclohexyl]-(2-iodophenyl)amine (4.47 g, 10.4 mmol) in triethylamine (70 mL) was added copper(I) iodide (198 mg, 1.04 mmol), followed by bis(triphenylphosphine)palladium(II) chloride (730 mg, 1.04 mmol) and cyclopropylacetylene (1.73 mL, 20.8 mmol). The reaction was stirred under nitrogen at room temperature overnight. After the reaction mixture was concentrated, the residue was dissolved in ether and filtered through Celite. Concentration gave the crude product, which was used without further purification in quantitative yield. LC-MS (C23H35NOSi calc'd 369) m/z 370 (M+H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)=[O:15].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:18][CH:17]=1)(=[O:15])[CH3:13]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 9.13 g (0.05 moles) of 2-chloro-5-nitrobenzonitrile, 7.01 g (0.0515 moles) of 4-hydroxyacetophenone, 7.10 g (0.0515 moles) of anhydrous K2CO3, and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was then cooled to room temperature and diluted with 150 ml of water. The product separated as a solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized twice from 300 ml of absolute ethanol to give 4.95 g (35% yield) of purified 2-(4-acetylphenoxy)-5-nitrobenzonitrile, mp 135°-136.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][CH2:13][OH:14])[C:5]#[N:6].[N:15]([O-])=O.[Na+]>Cl.O>[OH:14][CH2:13][CH2:12][CH2:11][N:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[N:15]1
Reactant: N#Cc1ccc(NCCCO)c(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc2c(c1)nnn2CCCO
Yield: 98.9 %

Procedure:
100 mg (0.52 mmol) of 3-amino-4-[(3-hydroxypropyl)amino]benzonitrile (Intermediate 12) are suspended in 0.5 ml of 5N aqueous HCl. After cooling externally with an ice/water bath, a solution of 54.12 mg (0.78 mmol) of sodium nitrite in 0.4 ml water is added dropwise with stirring. After 3.5 hr excess water is added and the solid is extracted with dichloromethane, washed with water, dried and concentrated to give 104 mg of pure title compound (96% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:25])[CH3:22]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCCO
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCCO)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 4-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamino]-pentan-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([N:4]1[C:24](=[O:25])[C:7]2=[CH:8][N:9]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]2=[N:5]1)[CH:2]=[CH2:3]>CO.[Pd]>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]3=[N:5][N:4]([CH2:1][CH2:2][CH3:3])[C:24](=[O:25])[C:7]3=[CH:8]2)=[CH:22][CH:21]=1
Reactant: C=CCn1nc2c3ccccc3n(Cc3ccc(F)cc3)cc-2c1=O
Agent: [Pd]
Solvent: CO
Product: CCCn1nc2c3ccccc3n(Cc3ccc(F)cc3)cc-2c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Allyl-5-(4-fluorobenzyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 764, 20 mg, 0.060 mmol) was dissolved in methanol (3 mL), treated with palladium on carbon (2 mg, 10 wt % on activated carbon, 0.1 wt equiv) sparged under an atmosphere of hydrogen (1 atm) and stirred for 4 hours at ambient temperature. The mixture was sparged under an atmosphere of nitrogen, filtered through a pad of Celite and the filtrate was concentrated in vacuo, providing the titled compound: 1H-NMR (400 MHz, CD3OD) δ 9.07 (1H, s), 8.42 (1H, d, J=7.7 Hz), 7.96 (1H, d, J=8.5 Hz), 7.78-7.68 (2H, m), 7.38-7.37 (2H, m), 7.16-7.11 (2H, m), 5.85 (2H, s), 4.10 (2H, t, J=7.0 Hz), 1.95-1.89 (2H, m), 0.99 (3H, t, J=7.5 Hz), ppm; low resolution mass spectrometry (ES+) m/z 336.0 [(M+H)+; calculated for C20H18FN3O: 336.1].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+]([O-])=O)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][SH:21]>CN(C=O)C>[CH3:24][O:23][C:19]([C:20]1[S:21][C:4]2[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=2[CH:6]=1)=[O:22]
Reactant: COC(=O)CS
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(Cl)cc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 600 mg (3.23 mmol) of 4-chloro-2-nitro-benzaldehyde in DMF (7 ml) were added 559 mg (4.04 mmol) of potassium carbonate and 294 μl (3.23 mmol) of methyl thioglycolate at 0° C. The reaction mixture was stirred for 30 min at 0° C. and then for 24 h at RT. Then the mixture was poured into ice-water and the precipitate was collected by filtration and dissolved in ethyl acetate. The solution was dried (MgSO4) and concentrated to yield 630 mg (86%) of 6-chloro-benzo[b]thiophene-2-carboxylic acid methyl ester as a white solid. 1HNMR (CDCl3, 300 MHz): δ 3.95 (s, 3H), 7.88 (dd, J=8.6 and 1.9 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H), 8.02 (s, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36]C)=[O:35])=[CH:29][CH:28]=3)[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:38]([F:41])([F:40])[F:39])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:42]=O>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([N:25]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:31][CH:32]=3)[CH3:42])[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:38]([F:39])([F:40])[F:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Reactant: C=O
Product: CN(Cc1ccc(CC(=O)O)cc1)c1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from methyl {4-[({3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amino)methyl]phenyl}acetate and 37% aqueous formaldehyde followed the procedures of Example 66 as an orange solid MS (EI) m/z 555.3 (M+H)+; 1H NMR (DMSO-d6): δ 2.86 (s, 3H), 3.55 (s, 2H), 4.44 (s, 2H), 6.50 (d, J=7.5 Hz, 1H), 6.60-6.65 (m, 2H), 6.98 (d, J=8.1 Hz, 2H), 7.09 (t, J=7.9 Hz, 1H), 7.18 (d, J=8.0 Hz, 2H), 7.36 (t, J=7.4 Hz, 2H), 7.55 (t, J=6.2 Hz, 1H), 7.64 (d, J=7.0 Hz, 2H), 7.73 (t, J=7.8 Hz, 1H), 8.01 (d, J=7.7 Hz, 1H), 8.30 (d, J=7.0 Hz, 1H), 9.10 (s, 1H), 12.31 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: NCc1ccc(F)cc1
Reactant: CCc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(4-fluorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](O)=[O:14])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:38][C:39]1[NH:43][N:42]=[N:41][N:40]=1.Cl>O1CCCC1.O>[NH:40]1[C:39]([NH:38][C:13]([C:11]2[S:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=2)=[O:14])=[N:43][N:42]=[N:41]1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(=O)O)sc2-c2ccc(F)cc2)cc1
Reactant: Nc1nnn[nH]1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc(C(=O)Nc3nnn[nH]3)sc2-c2ccc(F)cc2)cc1
Yield: 78.9 %

Procedure:
A mixture of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylic acid (1.0 g) and 1,1'-carbonyldiimidazole (0.45 g) in tetrahydrofuran (15 ml) was refluxed for 1.5 hours. 5-Aminotetrazole (0.226 g) was added and the mixture was refluxed for 3 hours. The mixture was diluted with water (50 ml), acidified with hydrochloric acid, and cooled in an ice-water bath. The precipitates were collected and recrystallized from ethanol to give colorless crystals of N-(5-tetrazolyl)-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxamide (0.93 g).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1([S:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([OH:17])=[C:12]([CH3:18])[C:11]=2[CH3:19])[CH2:8][CH2:7][CH2:6]1.O.Cl>[OH-].[Na+].CO>[OH:17][C:13]1[C:14]([CH3:16])=[C:15]2[C:10](=[C:11]([CH3:19])[C:12]=1[CH3:18])[S:9][C:5]1([CH2:6][CH2:7][CH2:8]1)[CH2:4][C:3]2=[O:2]
Reactant: COC(=O)CC1(Sc2cc(C)c(O)c(C)c2C)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)C(=O)CC1(CCC1)S2
Reaction time: 1 h
Yield: 87.1 %

Procedure:
[1-(4-Hydroxy-2,3,5-trimethyl-phenylsulfanyl)-cyclobutyl]-acetic acid methyl ester (1.16 g) was suspended in 50 mL of 1N NaOH in MeOH and water (1:1, v/v), and the mixture was allowed to stir for 1 hour. The mixture was then acidified with 1 N HCl and extracted 3 times with ethyl acetate. The organic layer was washed with water and dried over anhydrous MgSO4, and concentrated in vacuo. The resulting acid was dissolved in 50 mL of concentrated sulfuric acid to form a homogeneous dark red solution. After 1 hour at room temperature the solution was poured into crushed ice. The resulting green mixture was extracted 3 times with ethyl acetate. The organic layer was washed with water and dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with 10% ethyl acetate in hexane to give 0.9 g of 6′-hydroxy-5′,7′,8′-trimethylspiro[cyclobutane-1,2′-thiochromen]-4′(3′H)-one as a yellow solid.
Reaction SMILES: C(OC(=O)NC[C@H]1CC[C@H](C2N3C(C(N)=NC=N3)=C([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)N=2)CC1)C1C=CC=CC=1.[CH3:42][O:43][C:44]([C@H:46]1[CH2:51][CH2:50][C@H:49]([C:52]2[N:60]3[C:55]([C:56]([NH2:61])=[N:57][CH:58]=[N:59]3)=[C:54](I)[N:53]=2)[CH2:48][CH2:47]1)=[O:45]>>[CH3:42][O:43][C:44]([C@H:46]1[CH2:47][CH2:48][C@H:49]([C:52]2[N:60]3[C:55]([C:56]([NH2:61])=[N:57][CH:58]=[N:59]3)=[C:54]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:30][CH:29]=3)[N:53]=2)[CH2:50][CH2:51]1)=[O:45]
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(N)ncnn32)CC1
Reactant: Nc1ncnn2c1c(-c1ccc(Oc3ccccc3)cc1)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Product: COC(=O)[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnn32)CC1

Procedure:
Prepared according to the procedure analogous to that described above for trans-{4-[4-amino-5-(4-phenoxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexylmethyl}-carbamic acid benzyl ester, except using trans-4-(4-amino-5-iodo-imidazo[5,1-f][1,2,4]triazin-7-yl)-cyclohexanecarboxylic acid methyl ester.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[N:11]([CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:10][C:9](=[O:19])[NH:8][C:5]2=[N:6][CH:7]=1.C[Sn](C)(C)[C:22]1[CH:23]=[CH:24][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[N:26][CH:27]=1.ClCCl>CN(C)C=O>[OH:31][C:28]([C:25]1[N:26]=[CH:27][C:22]([C:2]2[N:3]=[C:4]3[N:11]([CH2:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[CH2:10][C:9](=[O:19])[NH:8][C:5]3=[N:6][CH:7]=2)=[CH:23][CH:24]=1)([CH3:30])[CH3:29]
Reactant: O=C1CN(CC2CCOCC2)c2nc(Br)cnc2N1
Reactant: CC(C)(O)c1ccc([Sn](C)(C)C)cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(-c2cnc3c(n2)N(CC2CCOCC2)CC(=O)N3)cn1
Temperature: 125 °C
Yield: 35.7 %

Procedure:
6-Bromo-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (35.98 g, 110 mmol), 2-(5-(trimethylstannyl)pyridin-2-yl)propan-2-ol (See Example 5.E) (33.0 g, 110 mmol) and [1,1′-bis(diphenyl-phosphino)ferrocene]dichloro-palladium(II) complex with dichloromethane (1:1) (8.05 g, 11.00 mmol) were combined in a sealed tube and suspended in N,N-dimethylformamide (288 mL). The reaction was then heated to 125° C. for 2 h. The reaction was cooled slightly and poured while still warm onto a silica gel column and purified using an Biotage SP1 (0-100% (5% methanol in ethyl acetate) in hexanes). The desired fractions were combined and organic volatiles removed under reduced pressure. The residue was triturated with 20% ethyl acetate in hexanes followed by several washes with denatured ethanol. The slightly yellow solid was dried under reduced pressure to afford the desired compound (15.08 g, 39.3 mmol, 35.8% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.32 (s, 1H), 9.07 (d, J=1.56 Hz, 1H), 8.29 (dd, J=8.59, 2.34 Hz, 1H), 8.05 (s, 1H), 7.72 (d, J=8.20 Hz, 1H), 5.26 (s, 1H), 4.21 (s, 2H), 3.83 (d, J=2.73 Hz, 2H), 3.51 (d, J=7.42 Hz, 2H), 3.27 (t, J=11.32 Hz, 2H), 2.09 (br. s., 1H), 1.61 (d, J=11.3 Hz, 2H), 1.46 (s, 6H), 1.24-1.38 (m, 2H); MS (ESI) m/z 384.2 [M+1]+; mp 268-269° C.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Cl:26][C:27]1[N:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([C:40]([CH:42]2[CH2:44][CH2:43]2)=[O:41])[C:36]([O:38]C)=O)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[N:32]=[C:31]2[C:30](=[CH:29][CH:28]=1)[N:33]=[CH:34][C:35]([C:40]([CH:42]1[CH2:44][CH2:43]1)=[O:41])=[C:36]2[OH:38]
Reactant: COC(=O)C(=CNc1ccc(Cl)nc1)C(=O)C1CC1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C(c1cnc2ccc(Cl)nc2c1O)C1CC1
Temperature: 25 °C
Reaction time: 0.62 h

Procedure:
To a flask containing Dowtherm™ A (500 mL) at 250° C. was added methyl 3-(6-chloropyridin-3-ylamino)-2-(cyclopropanecarbonyl)acrylate (4.2 g, 15 mmol) portion wise over 3 to 5 min and the reaction mixture was stirred for an additional 30 to 45 min. The reaction mixture was removed from the heat source, cooled to room temperature and diluted with hexanes to facilitate precipitation. The solids were filtered, washed with hexanes and dried under vacuum to afford the intermediate (6-chloro-4-hydroxy-1,5-naphthyridin-3-yl)(cyclopropyl)methanone which was stirred with heat at 70° C. in neat phosphorus oxychloride (10 mL) with catalytic N,N-dimethylformamide for 4 h. The reaction was cooled and poured slowly into a vigorously stirring mixture of ice-cold satd. aq. sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica, methylene chloride/ethyl acetate) to provide the desired product (0.78 g, 20% over two steps) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 8.93 (s, 1H), 8.39 (d, J=8.7 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 2.65 (t, J=7.7, 4.5 Hz, 1H), 1.52-1.42 (m, 2H), 1.32-1.22 (m, 2H); ESI MS m/z 268 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:13](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:13][O:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc([N+](=O)[O-])c1O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C=O)cccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 72 %

Procedure:
To a solution of 2-hydroxy-3-nitrobenzaldehyde in DMF was added portionwise cesium carbonate (3 eq), followed by iodomethane (1.2 eq.). The solution was warmed to 60° C. for 2 hours, then cooled to room temperature and filtered. The filtrate was concentrated under vacuum and purified by column chromatography on SPE cartridge (Silica) using as eluent cyclohexane-ethyl acetate (8:2) to give the product in 72% yield.