Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([OH:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].[CH2:9](Cl)[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18]>C(Cl)Cl>[CH2:2]([OH:8])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: OCCOCCO
Reactant: COCCOCCOCCCl
Agent: [Na]
Solvent: ClCCl
Product: COCCOCCOCCOCCOCCO
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Under argon, 630 mg (27.4 mmol) of sodium are added to 10 ml of diethylene glycol and the mixture is heated for one hour at 100° C. At that temperature, 5 g (27.4 mmol) of 3,6,9-trioxadecyl chloride are added dropwise thereto using a syringe. The mixture is stirred overnight at 100° C. to complete the reaction. After cooling, the reaction solution is taken up in CH2Cl2, washed with water and brine and dried over Na2SO4. Removal of the solvent yields 3,6,9,12,15-pentaoxa-hexadecanol in the form of an oil (Liebigs Ann. Chem. 1980, 858); NMR(CDCl3): 3.8-3.5 (m,20H); 3.75 (s,3H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][C@H:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[C:5]([CH3:20])([CH3:19])[CH2:4][CH2:3]1.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:1][C@H:2]2[CH2:3][CH2:4][C:5]([CH3:20])([CH3:19])[C@H:6]([N:8]3[C:16](=[O:17])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]3=[O:18])[CH2:7]2)=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22]
Reactant: CC1(C)CC[C@H](O)C[C@@H]1N1C(=O)c2ccccc2C1=O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)CC[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C[C@H]1N1C(=O)c2ccccc2C1=O
Yield: 114.8 %

Procedure:
To a solution of the cis-2-(5-hydroxy-2,2-dimethylcyclohexyl)-1H-isoindole-1,3(2H)-dione (500 mg, 1.83 mmol) obtained in Example 590 in tetrahydrofuran (10 ml) were added 4-nitrobenzoic acid (321 mg, 1.05 mmol), triphenylphosphine (576 mg, 2.20 mmol) and a 40%-diethyl azodicarboxylate/toluene solution (1.00 ml, 2.20 mmol) at 3° C., and stirred overnight at room temperature. The reaction solution was concentrated and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain trans-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4-dimethylcyclohexyl 4-nitrobenzoate (509 mg, 66%).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[N:9]=[CH:8]1.C[Si](C)(C)CCOCN1C(NC(=O)C)=CN=C1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[N:9]=[CH:8]1
Reactant: CC(=O)Nc1cn(COCC[Si](C)(C)C)cn1
Agent: CC(=O)Nc1cncn1COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1c[nH]cn1

Procedure:
The mixture of regioisomers N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)acetamide and N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)acetamide (170 mg, 0.7 mmol) from Step 1 of this Example was stirred in 70% TFA in CH2Cl2 (10 mL) at rt for 4 h. The mixture was concentrated under reduced pressure to afford N-(1H-imidazol-4-yl)acetamide (147 mg) as a yellow film which was used in the next step without further purification. LCMS (ESI) m/z 126 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
15.26 g of 50% sodium hydride in oil is added, at 0° C., to a solution under inert gas of 50 g of parabromophenol in 320 ml of dimethylformamide, followed by agitation for 30 minutes at 0° C., then 37.7 ml of benzyl bromide is added. Agitation is carried out for 2 hours 30 minutes while allowing the temperature to return to 20° C., then the reaction mixture is poured into ice-cooled water, the precipitate is filtered and dried. 73.35 g of expected product is obtained. Rf: 0.85 (thin layer chromatography, support: silica, eluant: cyclohexane/ethyl acetate 7/3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[S-:10][C:11]#[N:12].[NH4+].N>CO>[Cl:1][C:2]1[CH:7]=[C:6]([S:10][C:11]#[N:12])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: N#C[S-]
Reactant: Oc1c(Cl)cccc1Cl
Agent: N
Agent: [NH4+]
Solvent: CO
Product: N#CSc1cc(Cl)c(O)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 14.8 %

Procedure:
2,6-Dichlorophenol (100 g, 0.613 mole) and ammonium thiocyanate (102.73 g, 1.350 mole) were mixed in methanol and the solution cooled to 0° C. Chlorine gas was bubbled throught the reaction, maintaining the temperature below 10° C. The solution turned a pale yellow color. The reaction was stirred for a total of 3 hours until acidic, at which time ammonia gs was bubbled through and the solution stirred for an additional three hours at 0° to 10° C. The reaction was poured into iced distilled water, and filtered, yielding approximately 20 g of a yellow solid which was dried overnight in vacuo. The filtrate was extracted with ethyl acetate, the extracts dried over magnesium sulfate and solvent removed in vacuo to yield approximately 100 g of crude product. Following purification by silica chromatography, the material was taken up in 1 liter of toluene, charcoal added, filtered and recrystallized from hexane to yield 55.03 g of product as a yellow solid, m.p. about 94.5°-97° C. The structure was confirmed by NMR.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([F:26])[C:19]([CH3:25])=[C:20](B(O)O)[CH:21]=1)=[O:15])[CH3:12].C(=O)([O-])O.[Na+].O>C(O)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:11]([NH:13][C:14](=[O:15])[C:16]1[CH:21]=[C:20]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[CH:4][CH:3]=2)[C:19]([CH3:25])=[C:18]([F:26])[CH:17]=1)[CH3:12]
Reactant: CCNC(=O)c1cc(F)c(C)c(B(O)O)c1
Reactant: Ic1ccc2cn[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCNC(=O)c1cc(F)c(C)c(-c2ccc3cn[nH]c3c2)c1
Temperature: 150 °C

Procedure:
A stirred mixture of 6-iodo-1H-indazole (0.5 g, {5-[(ethylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (Intermediate 17, 0.56 g), tetrakis(triphenylphosphine)palladium(0) (0.05 g) and aqueous sodium hydrogen carbonate (1M, 1 ml) in isopropanol (10 ml) was heated at 150° C. for 30 min in a microwave oven. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (3×20 ml). The extracts were dried (Na2SO4) and concentrated under vacuum. The residual oil was purified by column chromatography on silica (50 g) eluting with ether/ethyl acetate (4:1). The resultant product was triturated with a small quantity of dichloromethane to give the title compound as a pale yellow solid (0.15 g).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[N:4]([CH3:10])[C:3]1=[O:11].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[C:12]([C:6]1[C:5](=[O:9])[N:4]([CH3:10])[C:3](=[O:11])[N:2]([CH3:1])[C:7]=1[CH3:8])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(=O)n(C)c(=O)n1C
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)c2ccccc2)c(=O)n(C)c(=O)n1C
Temperature: 0 °C
Yield: 28.1 %

Procedure:
A mixture of 1,3,6-trimethyl-compound 2 (12.3 g, 80 mmol), benzoyl chloride (11.5 g, 9.5 mL, 82 mmol) and anhydrous zinc chloride (10.8 g, 79 mmol) in toluene (100 mL) was heated to reflux for 6 h. The mixture was poured over ice (200 g), and the separated toluene layer was concentrated in vacuo. The crude residue was purified by flash chromatography to yield 3 (5.8 g, 28%): mp 132-134° C.; MS (ES+) (m/z): [M+1]+ calculated for C14H15N2O3, 259.28. found 259.09. This compound matched analytical data as reported (see, e.g., Tsupak et al., Khimiya Geterotsiklicheskikh Soedinenii. 7:1096-1102 (2003)).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[NH:8][C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH:23]=[O:24])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)=[N:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].CC(=CC)C.[O-:34]Cl=O.[Na+]>CC(O)(C)C>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[NH:8][C:7]([C:14]34[CH2:19][CH2:18][C:17]([CH2:22][C:23]([OH:34])=[O:24])([CH2:20][CH2:21]3)[CH2:16][CH2:15]4)=[N:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCn1c(=O)c2nc(C34CCC(CC=O)(CC3)CC4)[nH]c2n(CCC)c1=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCCn1c(=O)c2nc(C34CCC(CC(=O)O)(CC3)CC4)[nH]c2n(CCC)c1=O
Reaction time: 14 h

Procedure:
To a solution of [4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acetaldehyde (170 mg, 0.440 mmol) in t-BuOH (10 ml) and 2-methyl-2-butene (10 eq, 4.4 mmol, 470 μL), cooled with the aid of an ice bath, was added NaClO2 (1.5 eq, 0.66 mmol). The resulting yellow solution as allowed to reach ambient temperature over a period of 14 h then concentrated in vacuo. The resulting oily residue was partitioned between water (10 ml) and CH2C (10 ml). The aqueous phase was acidified by the dropwise addition of concentrated HCl and the resulting precipitate was collected, washed with water and dried to afford 105 mg (59%) as a white powder. 1H NMR (400 MHz, CDCl3); d 0.91 (t, 3H), 0.93 (t, 3H), 1.63 (m, 2H), 1.77 (m, 2H; partially-obscured), 1.82 (m, 6H), 2.01 (m, 6H), 2.32 (s, 2H), 3.95 (m, 2H), 4.07 (m; 2H), 12.74 (s, 1H).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)[CH2:2][CH3:3].[C:13](OC(=O)C)(=[O:15])[CH3:14]>[Cl-].[Zn+2].[Cl-]>[CH2:1]([C:4]1[C:5]([C:13](=[O:15])[CH3:14])=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)[CH2:2][CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1ccc2c(c1)CCO2
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCc1cc2c(cc1C(C)=O)OCC2
Yield: 31.2 %

Procedure:
Following the same procedure as in Example 3a), 46.3 g (0.286 moles) of 5-propyl-2,3-dihydrobenzofuran were reacted with 29.2 g (0.286 moles) of acetic anhydride and 3.9 g (0.029 moles) of anhydrous zinc chloride. After washing and work up, 18.2 g of 5-propyl-6-acetyl-2,3-dihydrobenzofuran was obtained as an oil (129-131° C./0.5 mbar) (title 93%).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:14]([NH:15][NH2:16])=[CH:13][C:11](=[O:12])[N:10]([CH2:17][CH2:18][CH3:19])[C:8]2=[O:9])=[CH:4][CH:3]=1.[CH3:22][N:23]=[C:24]=S.CO>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:14]3[NH:15][N:16]=[C:22]([NH:23][CH3:24])[C:13]=3[C:11](=[O:12])[N:10]([CH2:17][CH2:18][CH3:19])[C:8]2=[O:9])=[CH:20][CH:21]=1
Reactant: CCCn1c(=O)cc(NN)n(Cc2ccc(Br)cc2)c1=O
Reactant: CN=C=S
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(Br)cc2)c1=O
Yield: 47 %

Procedure:
A solution of 1-(4-bromobenzyl)-6-hydrazino-3-propyluracil (4.15 g, 11.8 mM) and methyl isothiocyanate (2.7 ml, 40 mM) in DMF (50 ml) was heated at 120° C. for 24 hours. To the reaction solution was added 50% methanol (15 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol gave colorless needles (2.19 g, 47%), m.p. 308°-310° C.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:12][C@@H:11]([NH:13][C:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]=3[OH:26])=[O:15])[CH2:10][C@H:9]2[C:27](O)=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:30]1[CH2:33][CH2:32][CH2:31]1>>[N:30]1([C:27]([C@H:9]2[N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:12][C@@H:11]([NH:13][C:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]=3[OH:26])=[O:15])[CH2:10]2)=[O:28])[CH2:33][CH2:32][CH2:31]1
Reactant: O=C(N[C@H]1C[C@@H](C(=O)O)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O
Reactant: C1CNC1
Product: O=C(N[C@H]1C[C@@H](C(=O)N2CCC2)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O

Procedure:
Hydroxy-naphthalene-2-carboxylic acid [(3S,5S)-5-(azetidine-1-carbonyl)-1-cyclohexylmethyl-pyrrolidin-3-yl]-amide was prepared from (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid and azetidine in an analogous manner to example 1. MS calcd for C26H34N3O3 [(M+H)+] 436.0, obsd. 436.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])/[CH:5]=[CH:6]/[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:8][C:7](=[O:9])/[CH:6]=[CH:5]/[C:4]1[CH:10]=[CH:11][C:12]([F:13])=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)/C=C/c1ccc(F)c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)/C=C/c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of trans-3,4-difluorocinnamic acid (10 g, 54 mmol) in 300 mL methanol was added concentrated sulfuric acid (2 mL). The solution was stirred 48 h at ambient temperature and then concentrated in vacuo. The residue was taken up in ethyl acetate (500 mL) and washed with saturated sodium bicarbonate (2×100 mL), brine (1×100 mL), dried with magnesium sulfate, and concentrated in vacuo to provide trans-3,4-difluorocinnamic acid methyl ester (10.7 g, 54 mmol, 100%) as a white solid.
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[O:9][C:7](=[O:8])[C:6]2=[CH:12][CH:13]=1.[CH2:15]([N:17]([CH2:24][CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:16]>>[CH2:24]([N:17]([CH2:15][CH3:16])[C:18]1[CH:23]=[CH:22][C:21]([C:10]([C:5]2[CH:4]=[CH:3][CH:13]=[CH:12][C:6]=2[C:7]([OH:9])=[O:8])=[O:11])=[CH:20][CH:19]=1)[CH3:25]
Reactant: CCN(CC)c1ccccc1
Reactant: CN(C)c1ccc2c(c1)C(=O)OC2=O
Product: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)cc1

Procedure:
In this example a mol-for-mol combination of phthalic anhydride (I) and N,N-diethylaniline (T) are reacted, as disclosed previously, to yield the keto acid (II). The keto acid is similarly reacted with N-vinyl carbazole to yield the title compound. The title compound imparts a blue-yellow color to paper coated with a phenolic resin or silton clay or a combination of the two. A reflectance spectrum of the blue-yellow color has an absorption peak at 630 nanometers.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:18])=[CH:7][CH:8]=2)[N:3]=1.CCN(CC)CC.Cl[C:27]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17][C:27](=[O:28])[O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:18])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(Cl)nc2c1
Reactant: CC(C)(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCC(C)(C)C)C3)nc(Cl)nc2c1
Reaction time: 0.08 h
Yield: 69.8 %

Procedure:
A solution of (R)-1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-amine (100 mg, 0.38 mmol) in 2 mL of THF was cooled to −30° C. To it was added Et3N followed by the addition of neopentyl chloroformate (53 μL, 0.38 mmol) dropwise. The reaction was complete after 5 minutes. The reaction was quenched with water, the layers separated, and the aqueous layer was twice extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography using 0%-10% EtOAc in DCM gave (R)-neopentyl 1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (100 mg, 70% yield). LC/MS: m/z 377.5 (M+H)+ at 2.90 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=N1.[C:28]([O:32][C:33]([NH:35][CH:36]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=1)[C:37]([OH:39])=O)=[O:34])([CH3:31])([CH3:30])[CH3:29].N1CCCC1.C(N1CCOCC1)C>CN(C=O)C>[C:28]([O:32][C:33]([NH:35][CH:36]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=1)[C:37]([N:10]1[CH2:11][CH2:16][CH2:15][CH2:14]1)=[O:39])=[O:34])([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(C#N)cc1)C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CCN1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(C#N)cc1)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
7.5 g of BOP are added to a mixture of 4.06 g of 2-(tert-butoxycarbonylamino)-3-(4-cyanophenyl)propionic acid and 1.15 ml of pyrrolidine in 20 ml of DMF, and the mixture is stirred for 2 hours at RT, while maintaining the pH at 7 by adding N-ethylmorpholine. The reaction mixture is concentrated under vacuum and the residue is chromatographed on silica gel, eluting with a chloroform/MeOH mixture (95/5; v/v). 3.8 g of the expected product are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([C:18](=O)[C:19]#[CH:20])=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(O)(O)(=O)=O.[CH:27]1([NH:30][C:31]([NH2:33])=[NH:32])[CH2:29][CH2:28]1.[O-]CC.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([C:18]3[CH:19]=[CH:20][N:33]=[C:31]([NH:30][CH:27]4[CH2:29][CH2:28]4)[N:32]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N=C(N)NC1CC1
Reactant: C#CC(=O)c1c(-c2cccc(Br)c2)nn2c(Cl)cccc12
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Clc1cccc2c(-c3ccnc(NC4CC4)n3)c(-c3cccc(Br)c3)nn12
Yield: 39 %

Procedure:
In a similar manner as described in Example 46 from 1-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (0.45 g, 1.25 mmol), N-cyclopropylguanidine sulfate and sodium ethoxide (0.61 mL, 21 wt % in ethanol, 1.6 mmol) at room temperature was obtained 4-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine (0.21 g, 39%) as a pale yellow solid. 1H NMR (CDCl3): δ 8.57 (d, 1 H), 8.12 (d, 1 H), 7.86 (t, 1 H), 7.57 (m, 2 H), 7.28 (m, 2 H), 7.06 (d, 1 H), 6.37 (d, 1 H), 5.38 (bs, 1 H), 2.84 (m, 1 H), 0.88 (m, 2 H), 0.63 (m, 2 H); MS m/z 440 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl.[C:18]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=O)[CH3:19]>C(O)C>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:18]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[CH:19]2
Reactant: CC(=O)C1CCNCC1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Clc1ccc2[nH]c(C3CCNCC3)cc2c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
A mixture of 0.60 gm (3.4 mMol) 4-chlorophenylhydrazine hydrochloride and 0.54 mL (6.7 mMol) pyridine in 20 mL ethanol were stirred at 60° C. for 15 minutes. To this mixture was then added 4-acetylpiperidine hydrochloride and the reaction mixture was stirred for 2 hours at 70° C. The reaction mixture was concentrated under reduced pressure and the residue was treated with polyphosphoric acid. This mixture was heated at 90-100° C. for 48 hours. The reaction mixture was quenched with a slurry of ice in 5N sodium hydroxide. The aqueous mixture was extracted well with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a dichloromethane gradient containing 4-20% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.26 gm (36%) of the title compound as a tan solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[CH:5][C:4]=1[F:25])[CH3:2].[C:26](#N)C.O>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24][CH3:26])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[CH:5][C:4]=1[F:25])[CH3:2]
Reactant: CCc1ccc(COc2ccnn2-c2cc(C(=O)O)ccn2)cc1F
Reactant: CC#N
Solvent: O
Product: CCc1ccc(COc2ccnn2-c2cc(C(=O)OC)ccn2)cc1F

Procedure:
The title compound was prepared from 2-[5-[(4-ethyl-3-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid (EXAMPLE 96) according to the procedure for the preparation of Example 62. 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=7.6 Hz), 2.67 (2H, q, J=7.6 Hz), 3.97 (3H, s), 5.20 (2H, s), 5.75 (1H, d, J=1.6 Hz), 7.12-7.23 (3H, m), 7.58 (1H, d, J=2.0 Hz), 7.78 (1H, dd, J=1.6, 5.2 Hz), 8.34 (1H, s), 8.71 (1H, d, J=5.2 Hz). LCMS (mobile phase: 30%-95% Acetonitrile-Water-0.02% NH4Ac): purity is >95%, Rt=3.783 min. [M+H] Calc'd for C19H18FN3O3, 356; Found, 356.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.[H-].[Na+].Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:9]=1
Reactant: CC1C(=O)NN=C2COc3ccc(Br)cc3N21
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(Br)cc3N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
A solution of 6-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (4.0 g, 13.5 mmol) in anhydrous DMF (20 mL) was stirred at 0° C. Sodium hydride (60% in mineral oil, 0.8 g, 20.3 mmol) was added portion-wise and the reaction mixture was stirred at 0° C. for 0.5 h. (2-(Chloromethoxy)ethyl)trimethylsilane (3.4 g, 20.3 mmol) was added to the solution dropwise and the reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was concentrated in vacuo, washed with brine (3×30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by chromatography on silica gel (eluting with 1% EtOAc in petroleum ether) to give 6-bromo-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (4 g, 70%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.08 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 5.08 (d, J=10.0 Hz, 2H), 4.67 (m, 1H), 4.6 (d, J=12.8 Hz, 2H), 3.65 (t, J=8.4 Hz, 2H), 1.47 (d, J=6.8 Hz, 3H), 0.95 (t, J=8.4 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][N:17]3[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH3:24]>O1CCCC1>[CH3:24][N:14]1[CH2:13][CH2:12][C:11]2([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]3[CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[O:10]2)[CH2:16][CH2:15]1
Reactant: c1ccc(C2OC3(CCNCC3)N3CCCCC23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC2(CC1)OC(c1ccccc1)C1CCCCN12
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.2 g of a 50% dispersion in a mineral oil) is added in portions to a stirred solution of 5.4 g of hexahydro-1-phenylspiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine] in 100 ml of tetrahydrofuran at 25° C. The mixture is stirred 0.5 hours under nitrogen and 5 g iodomethane in 10 ml of tetrahydrofuran is added dropwise. The mixture is stirred at 45° C. for 3 hours, filtered and the filtrate is evaporated in vacuo. The residue is dissolved in methylene dichloride, washed with water, dried over magnesium sulfate and the solvent is evaporated. The residue is crystallized from ethyl acetate to obtain the desired hexahydro-1'-methyl-1-phenylspiro[3H-oxazolo-[3,4-a]pyridine-3,4'-piperidine]; mp 157°-159° C.