Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.[CH:20]([Mg]Br)=[CH2:21]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]2[C:3]=1[NH:17][CH:21]=[CH:20]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)c(F)cc1Br
Solvent: C1CCOC1
Product: Fc1cc(Br)c2[nH]ccc2c1OCc1ccccc1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 34.7 %

Procedure:
A solution of 1-bromo-5-fluoro-2-nitro-4-[(phenylmethyl)oxy]benzene (D4) (10.58 g, 32.4 mmol) in THF was cooled to −40° C. under argon and vinylmagnesium bromide (97 mL of 1M solution in THF, 97 mmol) was added quickly via syringe. The temperature reached ˜−30° C. before cooling down to −40° C. The mixture was stirred at −40° C. for 40 mins and then quenched by the addition of NH4Cl solution. The mixture was allowed to reach room temperature and the layers were separated. The aqueous layer was reextracted with ethyl acetate and the combined organic layers were dried (Na2SO4) and evaporated. Chromatography on silica gel (elution with 0-50% ethyl acetate in hexane) gave the title compound as an orange oil (D5), (3.6 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1.[CH3:11][N:12]1[CH:16]=[C:15]([C:17](O)=[O:18])[N:14]=[CH:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(#N)C>[OH:10][CH2:9][CH2:8][N:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:17]([C:15]1[N:14]=[CH:13][N:12]([CH3:11])[CH:16]=1)=[O:18]
Reactant: Cn1cnc(C(=O)O)c1
Reactant: OCCNC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1cnc(C(=O)N(CCO)C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
A mixture of 2-(tetrahydro-2H-pyran-4-ylamino)ethanol (3.45 g), 1-methyl-1H-imidazole-4-carboxylic acid (3.00 g), HATU (13.6 g), diisopropylethylamine (12.4 mL) and acetonitrile (52 mL) was stirred at room temperature for 2 hours. The solvents were distilled off under reduced pressure and the resulting residue was purified by column chromatography (silica gel cartridge; chloroform/methanol=98:2 to 96:4) to give the titled compound (2.34 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[C:23]([F:30])=[CH:24][C:25]([F:29])=[C:26]([OH:28])[CH:27]=1.C(=O)([O-])O.[Na+]>C(Cl)(=O)C(Cl)=O.O1CCCC1.O>[Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][C:22]1[CH:27]=[C:26]([OH:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])=[O:6]
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Reactant: Nc1cc(O)c(F)cc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(C(=O)Nc3cc(O)c(F)cc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (4.42 g, 20 mmol) produced in Example C62(ii) in oxalyl chloride (10 mL) was added N,N-dimethylformamide (100 μL)), and the mixture was stirred at room temperature for 1 hr, and concentrated to dryness under reduced pressure. This was dissolved in tetrahydrofuran (10 mL), and the solution was added dropwise with vigorous stirring to a two-layer mixture of a solution of 5-amino-2,4-difluorophenol (2.90 g, 20 mmol) in tetrahydrofuran (5 mL) and a solution (10 mL) of sodium hydrogen carbonate (2.70 g, 30 mmol) in water under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50) to give the title compound (4.90 g, 70%) as white crystals.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]3[O:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].C(O)(C(F)(F)F)=O.C(C1C=NC(N2CCC(OC3SC4C=C(C5CCNCC=5)C=CC=4N=3)CC2)=NC=1)CC>>[CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]3[O:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH:27]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1cnc(N2CCC(Cc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4o3)CC2)nc1
Agent: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cnc(N2CCC(Cc3nc4ccc(C5=CCNCC5)cc4o3)CC2)nc1

Procedure:
Compound 29E was prepared from Compound 29D and TFA in a similar manner to the procedure described for Compound 1E in Example 1. LCMS (m/z)=418 (M+H)+.
Reaction SMILES: [CH:1]1([CH:8]([C:12](=O)[CH3:13])[C:9](=O)[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1.Cl.[NH:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=1)[NH2:17]>>[CH:1]1([C:8]2[C:12]([CH3:13])=[N:17][N:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][OH:26])=[CH:22][CH:23]=3)[C:9]=2[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CC(=O)C(C(C)=O)C1C=CC=CC=C1
Reactant: NNc1ccc(CCO)cc1
Agent: Cl
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1C1C=CC=CC=C1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 3-cyclohepta-2,4,6-trien-1-ylpentane-2,4-dione and 2-(4-hydrazinophenyl)ethanol hydrochloride: MS (EI) m/z 306 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[N:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[C:22]1[C:26]([NH2:27])=[CH:25][NH:24][N:23]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:27][C:26]3[C:22]([C:16]4[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=4[CH3:14])=[N:23][NH:24][CH:25]=3)=[O:12])=[C:4]2[N:3]=1
Reactant: Cc1ccc(C)c(-c2n[nH]cc2N)c1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C)c(-c2n[nH]cc2NC(=O)c2cnn3ccc(Cl)nc23)c1
Reaction time: 14 h

Procedure:
To a solution of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (400.4 mg, 1.853 mmol, 1.16 equiv) in dichloromethane (6 mL) was added 3-(2,5-dimethylphenyl)-1H-pyrazol-4-amine (300.0 mg, 1.602 mmol, 1.0 equiv) and triethylamine (0.70 mL, 5.0 mmol, 3.1 equiv) at room temperature. After 14 hours, the reaction mixture was partitioned between dichloromethane and half-saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted once with dichloromethane. The combined organic portions are dried over magnesium sulfate, filtered, and concentrated to yield 5-chloro-N-(3-(2,5-dimethylphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was carried forward without purification. LCMS (ESI) m+H=367.1.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[C@@H:5]([OH:8])[C@H:4]([OH:9])[C@@H:3]([OH:10])[C@@H:2]1O>O.C(O)(=O)C>[OH:10][C@@H:3]1[C@@H:4]([OH:9])[C@H:5]([OH:8])[C:6](=[O:7])[CH:1]=[CH:2]1
Reactant: O=C1C[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: O
Solvent: CC(=O)O
Product: O=C1C=C[C@H](O)[C@@H](O)[C@@H]1O
Yield: 48 %

Procedure:
0.05 g of 2-deoxy-scyllo-inosose synthesized according to the method described in WO 2006/112000 was added to 1 mL of 5 N acetic acid water, and the resulting mixture was heated at 100 degrees centigrade for 2 hours. After the completion of the reaction, a quantitative analysis was carried out using HPLC and as a result, (4S,5R,6S)-4,5,6-trihydroxy-2-cyclohexene-1-one was obtained at a yield of 48%. At this time, 35% of the raw material of 2-deoxy-scyllo-inosose was collected.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[C:5]([Cl:11])=[CH:6][C:7]=1[N+:8]([O-])=O.Cl[Sn]Cl.O>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:13])[F:14])[C:5]([Cl:11])=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c(C(F)(F)F)cc1N
Temperature: 90 °C
Yield: 70.3 %

Procedure:
To a stirred mixture of 3-amino-6-chloro-4-nitrobenzotrifluoride (300 mg, 1.25 mmol) in ethanol (5 mL) was added SnCl2.2 H2O (1.40 g, 6.20 mmol) in one portion. The mixture was refluxed at 80° C. (oil bath, 90° C.) for 1 h and the solution was cooled to room temperature and ice water (20 g) was added. It was adjusted to pH=7 and extracted with ethyl acetate. The extract was dried over Mg2SO4 and evaporated to give 185 mg (71%) of 3,4-diamino-6-chlorobenzotrifluoride as a brown solid. 1H NMR (CDCl3): δ 3.404 (s, 2H); 3.717 (s, 2H); 6.754 (s, 1H); 6.974 (s, 1H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl:12][C:13]1[CH:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:24][CH2:23]2)[C:19]([N+:35]([O-:37])=[O:36])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].IC>O>[CH3:1][O:16][C:15](=[O:17])[C:14]1[CH:18]=[C:19]([N+:35]([O-:37])=[O:36])[C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:24][CH2:23]2)=[CH:21][C:13]=1[Cl:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)O)cc2[N+](=O)[O-])CC1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(c3ccccc3C)CC2)cc1Cl
Yield: 92.8 %

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stir bar, the potassium carbonate (2.06 g, 14.91 mmol) was suspended in clean, dry N,N-dimethylformamide (50.00 ml, 645.74 mmol) and the mixture was stirred together under nitrogen at room temperature as the 2-chloro-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid 1d (2.54 g, 6.76 mmol) was added in one portion. The mixture was stirred until it appeared all the organic solids were in solution and then iodomethane (0.46 ml, 7.39 mmol) was added. The reaction was diluted with 100 ml of water and the product was extracted from the aqueous using ethyl acetate (3×100 ml). The layers were separated and the organic phases were combined, washed with brine (1×150 ml) and saturated aqueous lithium chloride solution (2×150 ml). The solution was then dried over Na2SO4; the solution was decanted and the solvent was removed under reduced pressure. The compound was purified using silica gel column chromatography, eluting a gradient of 100% heptanes to 75% ethyl acetate in heptane. 2-Chloro-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid methyl ester 10a (2.45 g, 6.27 mmol) was isolated as a yellowish-white solid and was carried on without further purification. LCMS (m/e)=390 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[O:12][CH:11]([CH2:13][OH:14])[CH:10]([O:15][C:16](=[O:29])[CH:17]([NH:21]C(OC(C)(C)C)=O)[CH:18]([CH3:20])[CH3:19])[C:9]2([OH:31])[CH3:30])[C:4](=[O:32])[N:3]=1.[ClH:33]>CCO>[ClH:33].[ClH:33].[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[O:12][CH:11]([CH2:13][OH:14])[CH:10]([O:15][C:16](=[O:29])[CH:17]([NH2:21])[CH:18]([CH3:20])[CH3:19])[C:9]2([OH:31])[CH3:30])[C:4](=[O:32])[N:3]=1
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC1C(CO)OC(n2ccc(N)nc2=O)C1(C)O
Agent: Cl
Solvent: CCO
Product: CC(C)C(N)C(=O)OC1C(CO)OC(n2ccc(N)nc2=O)C1(C)O

Procedure:
In another preferred embodiment of the present invention, compound (6) is reacted with Me2NCH(OMe)2 in DMF to form (7), N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethylformamidine, which is the amino-protected form of (i); reacting (2) with TBDPSCl and imidazole in DCM to provide the 5′-silyl-protected form of (6) as N′-{1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine (8), where the use of DCM provides the advantage of having greater control over disilyl by-product formation; reacting (8) with N—Boc-L-valine, EDC and DMAP in DCM at room temperature to form 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylamino-methyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (2); removing the silyl and amino-protecting groups by reacting (9) with NH4F in MeOH in the presence of approximately 10 mole equivalents of ethyl acetate to prevent cleavage of the 3′-O-valinyl ester by liberated ammonia, and refluxing the mixture to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester (10); and finally, reacting (10) with HCl in EtOH to provide 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester, dihydrochloride salt (11) as a final product.
Reaction SMILES: [OH-].[Na+].Cl.[NH:4]1[CH2:7][CH2:6][CH:5]1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH2:15][OH:16].[Cl:17][C:18]([Cl:25])([Cl:24])[CH2:19][O:20][C:21](Cl)=[O:22].Cl>O1CCOCC1.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH:5]2[CH2:6][CH2:7][N:4]2[C:21]([O:20][CH2:19][C:18]([Cl:25])([Cl:24])[Cl:17])=[O:22])=[C:9]([CH2:15][OH:16])[CH:10]=1
Reactant: OCc1cc(Cl)ccc1C1CCN1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC1c1ccc(Cl)cc1CO
Temperature: 25 °C

Procedure:
Aqueous sodium hydroxide (1 M, 2.67 mL) was added to a stirred solution of (2-azetidin-2-yl-5-chlorophenyl)methanol hydrochloride (0.312 g, 1.33 mmol) and trichloroethoxycarbonyl chloride (0.184 mL, 1.33 mmol) in dioxane (8 mL) and water (0.4 mL) at 0° C. The reaction was warmed to ambient temperature and after 1 h was acidified with 1 M HCl solution, extracted into ether, dried (Na2SO4) and evaporated in vacuo to an oil. The crude product was purified by flash column chromatography on silica (eluting with 5% methylene chloride/10-50% ethyl acetate/hexanes gradient) to give 2,2,2-trichloroethyl 2-[4-chloro-2-(hydroxymethyl)phenyl]azetidine-1-carboxylate (283 mg a colorless gum: 1H NMR (CDCl3, 400 MHz) δ 2.24 (br m, 1H), 2.78 (m, 1H), 4.20 (br s, 2H), 4.61 (br m, 2H), 4.68 (br m, 2H), 5.66 (dd, J=8.6, 6.4 Hz, 1H), 7.34 (m, 2H), 7.56 (d, J=8.1 Hz, 1H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:16]1[C:22](=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH:17]1[CH3:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(P(N(C)C)(N(C)C)=O)C.C([C:38]([O:40][CH3:41])=[O:39])#N>C1COCC1>[CH2:9]([N:16]1[C:22](=[O:23])[CH:21]([C:38]([O:40][CH3:41])=[O:39])[CH2:20][O:19][CH2:18][CH:17]1[CH3:24])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC1COCCC(=O)N1Cc1ccccc1
Reactant: COC(=O)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1COCC(C)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of lithium diisopropylamide in THF (0.101 M, 100 mL, 10.1 mmol, 1.30 equiv) freshly prepared at −78° C. was added via cannula to a solution of 4-benzyl-3-methyl-1,4-oxazepan-5-one (4-3, 1.71 g, 7.80 mmol, 1 equiv) in THF (100 mL) at −78° C. and the resulting mixture was stirred for 20 min. HMPA (1.36 mL, 7.80 mmol, 1.00 equiv) was added followed by methyl cyanoformate (1.24 mL, 15.6 mmol, 2.00 equiv). The resulting mixture was warmed to 0° C., stirred for 20 min, and then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (20% EtOAc in hexanes initially, grading to 100% EtOAc) to give methyl 4-benzyl-3-methyl-5-oxo-1,4-oxazepane-6-carboxylate (4-4) as a mixture of diastereomers (colorless oil). LRMS m/z (M+H) 278.2 found, 278.1 required.
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:14]([O:16]C)=[O:15])[CH:11]=[N:12][CH:13]=2)=[CH:4]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[O:3]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[CH:11]=[N:12][CH:13]=2)=[CH:4]1
Reactant: COC(=O)c1cncc(-c2ccoc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cncc(-c2ccoc2)c1
Reaction time: 0.83 h
Yield: 65.6 %

Procedure:
A 4 mol/L aqueous solution of sodium hydroxide (2.0 mL) was added to a methanol (10 mL) solution of methyl 5-(furan-3-yl)pyridine-3-carboxylate (0.54 g) at room temperature, followed by stirring at the same temperature for 2 hours and 50 minutes. A 10% aqueous solution of citric acid (8 mL) was added to the reaction mixture at room temperature, and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.33 g of 5-(furan-3-yl)pyridine-3-carboxylic acid as a light yellow solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(OCC)=O)C.[CH3:16][C:17]([N:21]1[CH:25]=[C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[N:23]=[CH:22]1)([CH3:20])[CH:18]=O.O>C1COCC1>[CH3:15][O:14][C:12](=[O:13])[CH2:11][CH2:18][C:17]([CH3:20])([N:21]1[CH:25]=[C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[N:23]=[CH:22]1)[CH3:16]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: CC(C)(C=O)n1cnc(-c2cccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCC(C)(C)n1cnc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of sodium hydride (1.2 eq) in THF was added slowly methyl diethylphosphonoacetate (1.2 eq) at 0° C. under dry conditions and the mixture was stirred at room temperature for 30 minutes. A solution of 2-methyl-2-(4-pyridin-3-yl-imidazol-1-yl)-propionaldehyde (1 eq), in THF was added dropwise at room temperature and the mixture was stirred for 1 hour at the same temperature. The mixture was poured into H2O and the whole was extracted with ethyl acetate. The organic layer was washed with NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. To a solution of the residue in ethyl acetate, was added palladium, 10 wt. % on activated carbon and left stirring under 1 atm hydrogen overnight. After the catalyst was filtered off, the filtrate was purified by flash chromatography using a solvent gradient 97% DCM, 3% MeOH, and 0.1% TEA to yield 4-methyl-4-(4-pyridin-3-yl-imidazol-1-yl)pentanoic acid methyl ester (75%). MH+(274)
Reaction SMILES: [CH:1]12[CH2:10]C3CC(CC(C3)[CH:2]1OCC1C(Cl)=CC(C(NS(C)(=O)=O)=O)=C(F)C=1)C2.Cl[C:29]1[C:30]([O:45][CH2:46][CH:47]2[CH2:54][CH2:53][C:50]3([CH2:52][CH2:51]3)[CH2:49][CH2:48]2)=[CH:31][C:32]([F:44])=[C:33]([CH:43]=1)[C:34]([NH:36][S:37]([CH:40]1[CH2:42][CH2:41]1)(=[O:39])=[O:38])=[O:35]>>[CH:10]1([C:29]2[C:30]([O:45][CH2:46][CH:47]3[CH2:54][CH2:53][C:50]4([CH2:52][CH2:51]4)[CH2:49][CH2:48]3)=[CH:31][C:32]([F:44])=[C:33]([CH:43]=2)[C:34]([NH:36][S:37]([CH:40]2[CH2:41][CH2:42]2)(=[O:39])=[O:38])=[O:35])[CH2:1][CH2:2]1
Reactant: O=C(NS(=O)(=O)C1CC1)c1cc(Cl)c(OCC2CCC3(CC2)CC3)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 49 and making variations as required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro- N-(methylsulfonyl)benzamide with 5-chloro-N-(cyclopropylsulfonyl)-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide, the title compound was obtained as a colorless solid (0.024 g, 18%): 1H NMR (300 MHz, CDCl3) δ8.76-8.62 (m, 1H), 7.63-7.54 (m, 1H), 6.63-6.53 (m, 1H), 3.96-3.78 (m, 2H), 3.20-3.02 (m, 1H), 2.12-1.72 (m, 6H), 1.50-1.41 (m, 2H), 1.40-1.22 (m, 2H), 1.20-1.10 (m, 2H), 1.02-0.88 (m, 4H), 0.72-0.61 (m, 2H), 0.38-0.15 (m, 4H); MS (ES+) m/z 422.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[C:20]1([C:26]#[CH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:20]1([C:26]#[C:27][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([C:9]([F:12])([F:11])[F:10])[CH:4]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1ccc(C#Cc2ccccc2)cc1C(F)(F)F
Temperature: 70 °C
Yield: 66.7 %

Procedure:
A multinecked flask as described in Example 1 was charged with 10.0 g (0.042 mol) of 2-amino-5-bromobenzotrifluoride, 100 ml of dried, degassed triethylamine, 5.32 g (0.052 mol) of phenylacetylene, 0.48 g (0.41 mmol) of tetrakis(triphenylphosphine)palladium(O), 0.1 g (0.38 mmol) of triphenylphosphine, and 0.05 g (0.26 mmol) of cuprous iodide. The reaction mixture was heated at 70° C. for 48 hours at which point thin layer chromatography showed the reaction to be complete. The product mixture was cooled to room temperature and diluted with 50 ml of toluene. Filtration of the triethylamine hydrobromide salt by-product followed by concentration of the filtrate under reduced pressure gave the crude product as a yellow oil. Fractionation under reduced pressure (bp 146°-150° C./1.2 mm Hg) gave 7.22 g (0.028 mol, 66% yield) of the product as a viscous yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH:20]([F:22])[F:21])[CH:17]=2)[C:12]([CH2:23][C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[CH:26][C:25]=2[Cl:31])=[N:11][N:10]=1>CN(C=O)C>[Cl:31][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:30])[C:24]=1[CH2:23][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:19][CH:20]([F:21])[F:22])=[CH:15][CH:14]=2)[C:9]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[N:10][N:11]=1
Reactant: FC(F)Oc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-n3cncn3)c2c1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
A solution under N2 of 1,2,4-triazole (2.4 g, 34.8 mmoles) in DMF (100 ml) was added with NaH (1.05 g, 26.1 mmoles). The mixture was stirred at room temperature up to clarity, then added with 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-difluoromethoxy-phthalazine (6.8 g, 17.4 mmoles), prepared as described in example 99. The mixture was heated at 100° C. for 5 hours, extracted three times with CH2Cl2. The organic phase was anhydrified and dried to give a solid which was flash chromatographed (eluent: ethyl acetate/petrolatum 7:3 to 100% of ethyl acetate) to give 4.14 g of the title compound (yield: 28%). m.p.: 220-224° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1.CCN(C(C)C)C(C)C.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:34][CH2:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)ccn2n1
Reactant: NCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)ccn2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 35.1 %

Procedure:
2,4-Dichloro-5-phenylpyrrolo[2,1-f][1,2,4]triazine (0.560 g, 2.12 mmol) was dissolved in THF (15 mL) and then DIPEA (1.85 mL, 10.6 mmol) was added followed by the addition of pyridin-2-ylmethanamine (0.688 g, 6.36 mmol). Then the reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure to remove THF and to this residue water (10 mL) added. The aqueous solution was extracted with CH2Cl2 (25×3 mL) and the organic layer was separated, dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 20% EtOAc/hexanes) to afford 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.250 g, 35.1%). LCMS Condition B-39: retention time 2.10 min, [M+1]=336.0.