Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:3].[H-].[Na+].I[CH3:15]>CN(C=O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([N:4]([CH3:15])[C:2](=[O:3])[CH3:1])=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(=O)Nc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-bromoacetanilide (1.0 g, 4.67 mmol) in DMF (5 mL) is added dropwise to a suspension of sodium hydride (224 mg, 5.61 mmol, 60% dispersion in mineral oil) in DMF (5 mL) at 0° C. After stirring 1 h at 0° C., iodomethane (349 μl, 5.61 mmol) is added and the reaction mixture warmed to RT and stirred 16 h. The reaction is quenched with water (15 mL) and extracted into EtOAc (3×15 mL); the combined organic phases are then dried over Na2SO4 and reduced in vacuo. Purification by column chromatography (40% EtOAc in heptane) gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:21]([N:23]([CH2:35][CH3:36])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:22]>C(#N)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11]([N:32]3[CH2:33][CH2:34][CH:29]([CH2:28][CH2:27][O:26][CH2:25][CH2:24][N:23]([CH2:21][CH3:22])[CH2:35][CH3:36])[CH2:30][CH2:31]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Reactant: CCN(CC)CCOCCC1CCNCC1
Solvent: CC#N
Product: CCN(CC)CCOCCC1CCN(C(=O)N2c3cc(Cl)ccc3C(=O)Nc3cccnc32)CC1
Yield: 43 %

Procedure:
Prepared analogously to Example 4 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[2-[2-(diethylamino)ethoxy]ethyl]piperidine in a yield of 43% of theory. Colourless crystals, m.p. 145°-146° C. (acetonitrile), Rf 0.39 (conditions as in Example 54).
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:44](OC(Cl)(Cl)Cl)=[O:45]>O1CCOCC1>[C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]3[O:26][C:44](=[O:45])[NH:28][N:27]=3)=[CH:23][CH:22]=2)[CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C#N)cc2)Cc2ccc(C(=O)NN)cc2)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C#N)cc2)Cc2ccc(-c3n[nH]c(=O)o3)cc2)cc1
Yield: 96.6 %

Procedure:
A solution of 185 mg (0.29 mmol, 89% purity) of 4-{(3E)-4-{2-[(4-tert-butylbenzyl)oxy]phenyl}-2-[2-(4-cyanophenyl)ethyl]but-3-en-1-yl}benzohydrazide from Example 103A in 1 ml of dioxane is slowly added dropwise to a solution of 87.3 mg (0.44 mmol) of trichloromethyl chloroformate in 0.5 ml of dioxane. The reaction mixture is stirred under reflux for two hours. After cooling, the mixture is concentrated in vacuo, directly taken up on silica gel and purified by flash chromatography (mobile phase: dichloromethane/methanol/aq. ammonia 10:1:0.1). 166 mg (0.28 mmol, 96% yield) of an oil are isolated.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:44])=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:27](=[O:28])[C:26]([CH3:30])([CH3:29])[C:25]([C:31]4[CH:32]=[C:33]([O:42][CH3:43])[C:34]5[O:38][C:37]([CH3:40])([CH3:39])[CH2:36][C:35]=5[CH:41]=4)=[N:24]3)[CH2:19][CH2:18]2)=[O:16])[CH:14]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:44])=[C:13]([C:15]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[C:27](=[O:28])[C:26]([CH3:30])([CH3:29])[C:25]([C:31]4[CH:32]=[C:33]([O:42][CH3:43])[C:34]5[O:38][C:37]([CH3:39])([CH3:40])[CH2:36][C:35]=5[CH:41]=4)=[N:24]3)[CH2:21][CH2:22]2)=[O:16])[CH:14]=1
Reactant: COc1cc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4C)CC3)C(=O)C2(C)C)cc2c1OC(C)(C)C2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(C2=NN(C3CCN(C(=O)c4cc(O)ccc4C)CC3)C(=O)C2(C)C)cc2c1OC(C)(C)C2

Procedure:
Under a blanket of nitrogen 0.3 g of 2-(1-{[5-(benzyloxy)-2-methylphenyl]carbonyl}piperidin-4-yl)-5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 88) are dissolved in 20 ml of methanol and 0.04 g palladium on charcoal (10%) and 0.32 g ammonium formiate are added. The reaction mixture is heated to reflux or 4 h until the starting material is consumed according to TLC analysis. The mixture is filtered over a plug of celite, and the solvent is removed under reduced pressure resulting in the crude product, which is purified by column chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [OH-].[Na+:2].[NH2:3][C@H:4]([C:9]([OH:11])=[O:10])[CH2:5][C:6]([OH:8])=[O:7].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>O>[C:15]([NH:3][C@H:4]([C:9]([O-:11])=[O:10])[CH2:5][C:6]([O-:8])=[O:7])(=[O:16])[CH2:14][C:13]([CH3:12])=[O:17].[Na+:2].[Na+:2]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: C=C1CC(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)CC(=O)N[C@@H](CC(=O)[O-])C(=O)[O-]

Procedure:
8.1 parts of sodium hydroxide were dissolved in 100 parts by volume of water and the solution cooled to 0°-5° C. 13.3 parts of L-aspartic acid were added and stirred until all dissolved, then 15.8 parts by volume of diketene were added dropwise over 90 minutes, stirred at 0°-10° C. for an additional 2.5 hours, and filtered. The homogeneous solution was evaporated to dryness under vacuum at 35°-40° C. Disodium N-acetoacetylaspartate was obtained as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[C:10]([F:11])=[CH:9][C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([F:25])[C:6]=1F)[CH3:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>CS(C)=O>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[C:10]([F:11])=[CH:9][C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([F:25])[C:6]=1[NH:31][CH:28]1[CH2:30][CH2:29]1)[CH3:2]
Reactant: CCOC(=O)c1c(F)cc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1F
Reactant: NC1CC1
Solvent: CS(C)=O
Product: CCOC(=O)c1c(F)cc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1NC1CC1
Yield: 81.2 %

Procedure:
A solution of 4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3,6-trifluorobenzoic acid ethyl ester (Example 2b, 5.4 g, 13.9 mmol), cyclopropylamine (40 mL, 577 mmol), and dimethyl sulfoxide (28 mL) in a sealed glass tube is heated at 100° C. for 27 hours. The excess amine is removed by blowing in compressed air before the solution is concentrated under high vacuum. The residue is then purified by column chromatography (1:1:8 ethyl acetate/chloroform/hexanes) to afford the title compound (4.80 g). 1H NMR (CDCl3): δ 7.42 (bs, 1H), 5.69 (ddd, 1H), 4.76–4.61 (m, 1H), 4.37–4.19 (m, 3H), 3.81–3.66 (m, 1H), 3.65–3.43 (m, 2H), 3.39–3.28 (m, 1H), 2.98–2.82 (m, 1H), 2.30–2.09 (m, 1H), 1.98–1.82 (m, 1H), 1.45 (s, 9H), 1.34 (t, 3H), 0.72–0.68 (m, 2H), 0.67–0.44 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH:14]1[O:18][CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:15]1[CH2:16][CH2:17][O:18][CH:14]1[CH2:13][NH:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: ClCC1OCCO1
Reactant: CCc1cccc(CC)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NCC1OCCO1
Reaction time: 18 h

Procedure:
2,6-Diethylaniline (75 grams; 0.5 mole), 2-chloromethyl-1,3-dioxolane (25 grams; 0.2 mole), potassium carbonate (22 grams; 0.2 mole) and dimethylformamide (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated, with stirring, for a period of about 18 hours. After this time the reaction mixture was filtered and then distilled to yield the desired product N-(1,3-dioxolan-2-ylmethyl)-2,6-diethylaniline.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])([O-:3])=[O:2].[I:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH:21]=O.[S]>>[I:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[C:14]=1[C:21]1[NH:11][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=2[N:10]=1
Reactant: COc1nccc(I)c1C=O
Reactant: Nc1cccc([N+](=O)[O-])c1N
Agent: [S]
Product: COc1nccc(I)c1-c1nc2cccc([N+](=O)[O-])c2[nH]1
Yield: 101 %

Procedure:
3-Nitro-benzene-1,2-diamine (0.153 g, 1.0 mmol), 4-Iodo-2-methoxy-pyridine-3-carbaldehyde (0.263 g, 1.0 mmol) and sulfur (0.032 g, 1.0 mmol) were heated at 160° for 60 min. The resulting slurry was purred on ice water (100 ml). Precipitates were collected by filtration and dried in vacuum to yield the desired product (0.40 g, quant.) which was used without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([NH:26][NH2:27])=[O:25])([CH3:22])([CH3:21])[CH3:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:19]([O:23][C:24]([NH:26][NH:27][C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=2)[CH2:9]1)=[O:16])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)C1CCCN(C(=O)c2ccc(F)cc2)C1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)C1CCCN(C(=O)c2ccc(F)cc2)C1
Reaction time: 72 h
Yield: 72.4 %

Procedure:
To a solution of 1-(4-Fluoro-benzoyl)-piperidine-3-carboxylicacid (1.13 g, 4.50 mmol) in DCM (6.5 ml) was successively added Hydrazinecarboxylic acid tert-butyl ester (0.59 g, 4.50 mmol), HOBT (0.69 g, 4.50 g) anf EDCI.HCl (1.29 g, 6.758 mmol). The mixture was stirred at R.T for 72 h. The solvent was removed under reduced pressure and the residue was diluted with DCM was added. The organic layer was washed twice with water, twice with HCl 1N and twice with water. The organic layer was dried over Na2SO4, filtered and evaporated to afford 1.19 g (73%) of N′-[1-(4-Fluoro-benzoyl)-piperidine-3-carbonyl]-hydrazinecarboxylic acid tert-butyl ester as a colorless semi-solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:15][O:14][C:11]1[N:10]=[CH:9][C:8]([C:5]2[C:4]([NH2:16])=[CH:3][C:2]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:7][N:6]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2ncc(Br)cc2N)cn1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ncc(N3CCOCC3)cc2N)cn1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5-bromo-6′-methoxy-2,3′-bipyridin-3-amine (711 mg, 2.54 mmol), morpholine (1.1 mL, 12.63 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropyl-biphenyl, (X-Phos) (97.7 mg, 0.21 mmol), and tris(dibenzylideneacetone)-dipalladium (0) (93.8 mg, 0.102 mmol) in dry THF (6.0 mL) was degassed by nitrogen. To this mixture was added lithium bis(trimethylsilyl)amide, 1.0M in THF (14.0 mL, 14.0 mmol) dropwise, and the resulting reaction was heated to 60° C. After 2.5 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic layers were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-60% of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM) to afford an orange tan solid as 6′-methoxy-5-morpholino-2,3′-bipyridin-3-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.46 (1H, dd, J=2.4, 0.7 Hz), 7.90 (2H, m), 6.83 (1H, dd, J=8.6, 0.8 Hz), 6.53 (1H, d, J=2.5 Hz), 3.97 (3H, s), 3.89 (4H, m), 3.78 (2H, s), 3.21 (4H, m). Mass Spectrum (pos.) m/e: 287.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14](I)=[CH:13][C:12]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.[C:49]([O-])([O-])=[O:50].[Cs+].[Cs+].CO>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([O:50][CH3:49])=[CH:13][C:12]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)cc(Cl)c1-c1nc2ccnc(Cl)c2s1
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Temperature: 70 °C
Yield: 49.4 %

Procedure:
A mixture of 4-chloro-2-(2,6-dichloro-4-iodophenyl)thiazolo[5,4-c]pyridine (0.300 g, 0.68 mmol), racemic-2-di-t-butylphosphino-1,1′-binaphthyl (0.035 g, 0.0884 mmol), Pd(OAc)2 (0.015 g, 0.068 mmol), Cs2CO3 (0.332 g, 1.02 mmol) and MeOH (0.275 mL, 6.8 mmol) in toluene (3 mL) was degassed with a stream of argon and the reaction mixture was heated at 70° C. for 18 hours. After cooling to room temperature, additional racemic-2-di-t-butylphosphino-1,1′-binaphthyl (0.035 g) and Pd(OAc)2 (0.015 g) were added. The resulting mixture was then degassed with a stream of argon and heated at 70° C. for 18 hours. The crude reaction mixture was filtered through Celite® and the filtrate was combined with two crude reaction mixtures obtained following the same method using 4-chloro-2-(2,6-dichloro-4-iodophenyl)thiazolo[5,4-c]pyridine (0.46 mmol). The volatiles were removed under reduced pressure and the resultant residue was purified by column chromatography on silica gel eluting with 0-10% diethyl ether in petroleum ether to afford the title compound as an off-white solid (116 mg, 30% yield). LCMS (Method D): RT=4.34 min, m/z: 345 [M+H+].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1C(=O)N([I:27])C(=O)C1>CC#N>[I:27][C:17]1[N:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=3)=[CH:12][C:13]2=[N:19][CH:18]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccn3ccnc3c2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2ccn3c(I)cnc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
Treat a solution of 7-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridine (101 g, 371.3 mmol, 1 eq) in 2000 mL of CH3CN at 0° C. with NIS (83.5 g, 371.3 mmol, 1 eq). Allow the mixture to stir at room temperature for 1 hour. Remove the solvent and the dissolve the residue in 5000 mL of CH2Cl2, wash with 10% NaOH solution, NaHSO3 sat., water and aqueous saturated sodium chloride. Dry over MgSO4 and evaporate. Triturate the solid obtained with hexanes, filter and dry in vacuo to afford 110 g of the title compound as a yellow solid. (Yield: 75%). MS (ES), m/z 399 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:23]C)[N:13]2[CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18]2)=[C:9]([NH2:25])[N:8]=1)[CH3:2].Cl.[OH-].[Na+]>CO.O1CCOCC1.O>[NH2:25][C:9]1[N:8]=[C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][O:19][CH2:18]1
Reactant: CCOCCOc1nc(N)c2nc(OC)n(CC3CCCOC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CCOCCOc1nc(N)c2[nH]c(=O)n(CC3CCCOC3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-ethoxyethoxy)-8-methoxy-9-(tetrahydro-2H-pyran-3-ylmethyl)-9H-purin-6-amine (245 mg) in dry methanol (10 ml) at room temperature and under nitrogen was added 4.0M hydrogen chloride in 1,4-dioxane (4.0 ml). The reaction was left to stir at room temperature for 1 hour. The reaction was concentrated in vacuo and the resulting residue purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (10-45%) to afford a white solid. This was taken up in water (15 ml) and neutralised by the addition of 2.0M sodium hydroxide solution. The solid was filtered and dried on the rotary evaporator (60° C.) for 30 minutes (90 mg).
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[CH:10][C:9]([N+:18]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CCO.O.[Pd]>[NH2:18][C:9]1[CH:10]=[C:11]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[C:2]([F:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(N2CCCC2=O)c1F
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(N)cc(N2CCCC2=O)c1F
Temperature: 25 °C
Yield: 62.7 %

Procedure:
To a solution of methyl 2-fluoro-5-nitro-3-(2-oxo-1-pyrrolidinyl)benzoate (D140) (3.3 g, 11.7 mmol, 1 equiv) in EtOH (100 ml) and H2O (10 ml) were added NH4COOH (7.4 g, 117 mmol, 10 equiv) and 10% palladium on charcoal (50% wet, 660 mg, 10% w/w) and the resulting mixture was refluxed for 2 h then cooled to room temperature. The catalyst was removed by filtration through a pad of celite and most of the solvent removed in vacuo. The residue was partitioned between AcOEt and H2O and the two layers were separated. The organic phase was dried over MgSO4 and concentrated in vacuo to give methyl 5-amino-2-fluoro-3-(2-oxo-1-pyrrolidinyl)benzoate (D150) (1.85 g, 63%) as a pale yellow solid which was used in the next step without further purification. [M+H]+=253.0, RT=2.12 min.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:45])[CH2:11][NH:12][C:13]2[N:18]=[C:17]([N:19]3[CH:24]=[C:23]([CH:25]4[C:31]5[CH:32]=[CH:33][C:34]([CH2:36][CH3:37])=[CH:35][C:30]=5[CH:29]=[CH:28][C:27]5[CH:38]=[C:39]([CH3:42])[CH:40]=[CH:41][C:26]4=5)[C:22](=[O:43])[NH:21][C:20]3=[O:44])[CH:16]=[CH:15][N:14]=2)[S:7][CH:8]=1)#[N:2].C[Sn]([N:50]=[N+:51]=[N-:52])(C)C.CO>C1(C)C=CC=CC=1>[CH2:36]([C:34]1[CH:33]=[CH:32][C:31]2[CH:25]([C:23]3[C:22](=[O:43])[NH:21][C:20](=[O:44])[N:19]([C:17]4[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH2:11][C:10]([NH:9][C:6]5[S:7][CH:8]=[C:4]([CH2:3][C:1]6[NH:52][N:51]=[N:50][N:2]=6)[N:5]=5)=[O:45])[N:18]=4)[CH:24]=3)[C:26]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:27]=3[CH:28]=[CH:29][C:30]=2[CH:35]=1)[CH3:37]
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(CC#N)cs3)n2)c(=O)[nH]c1=O
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(Cc4nnn[nH]4)cs3)n2)c(=O)[nH]c1=O

Procedure:
A mixture of the product of step (iv) (0.35 g) and trimethyltin azide (0.5 g) in toluene (10 ml) was heated at reflux for 48 hours. Methanol was added and the resultant precipitate filtered off. The solution was evaporated to dryness and the residue purified by reverse phase chromatography. The fraction containing product was concentrated under reduced pressure, acidified with 2N HCl and extracted with ethyl acetate. The extract was evaporated to dryness and the residue triturated with diethyl ether. The product was collected by filtration. Yield 0.16 g.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)[NH2:2].[CH3:10][C:11](=O)[CH2:12][CH2:13][CH:14]=[CH2:15]>>[CH3:15][C:14](=[N:2][NH:1][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)[CH2:13][CH2:12][CH:11]=[CH2:10]
Reactant: C=CCCC(C)=O
Reactant: NNc1cc[nH]c(=O)c1
Product: C=CCCC(C)=NNc1cc[nH]c(=O)c1
Yield: 71.3 %

Procedure:
In accordance with the same procedures as in Step 2 of Preparation 1, except for using 4-hydrazino-1H-pyridin-2-one (5.39 g, 43.1 mmol) prepared in Step 1 of Preparation 1 and 5-hexen-2-one (7.41 ml, 64.6 mmol), the titled compound was obtained as a white solid. (Yield: 71.3%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3[CH:14]=[C:15]([O:20][CH3:21])[C:16]([NH2:19])=[N:17][CH:18]=3)[N:12]=2)=[CH:4][CH:3]=1.[Br:22]Br>C(Cl)(Cl)Cl>[Br:22][C:10]1[O:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:12][C:11]=1[C:13]1[CH:14]=[C:15]([O:20][CH3:21])[C:16]([NH2:19])=[N:17][CH:18]=1
Reactant: COc1cc(-c2coc(-c3ccc(F)cc3)n2)cnc1N
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2nc(-c3ccc(F)cc3)oc2Br)cnc1N
Yield: 74.1 %

Procedure:
To a solution of 5-(2-(4-fluorophenyl)oxazol-4-yl)-3-methoxypyridin-2-amine (145 mg, 0.5 mmol) in chloroform (20 mL) at 0° C. was added a pre-cooled solution of bromine (40 μL, 0.7 mmol) in CHCl3 (5 mL). The reaction mixture was stirred for <5 min, concentrated in vacuo, and the resulting residue was azeotroped with CHCl3 (2×). Purification by flash chromatography (SiO2, 100:0-95:5 DCM-MeOH) provided 135 mg of 5-(5-bromo-2-(4-fluorophenyl)oxazol-4-yl)-3-methoxypyridin-2-amine as a yellow solid: LCMS (m/z): 365.8 (MH+), tR=0.83 min.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1>>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)=[N:14][CH:15]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc(Br)nc1
Product: O=Cc1ccc(-c2ccc(Br)cn2)cc1

Procedure:
Scheme 40, Example 1, illustrates the coupling reaction of 4-formylphenylboronic acid 40.1 with 2,5-dibromopyridine 40.11, using the procedure described above, to afford 4-(5-bromo-2-pyridyl)benzaldehyde 40.12. This compound is then coupled, as described above, with a dialkyl phosphite 40.4, to afford the pyridyl phosphonate 40.13.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]1)[CH:6]=[CH:5]2.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(Cl)Cl>C(N(CC)CC)C>[CH3:18][C:15]1([CH3:19])[O:16][CH2:17][C:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:35]=4)[CH:3]=3)[CH:8]=2)[CH2:13][O:14]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc(O)ccc3c2)COC(C)(C)OC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(c2ccc3cc(Oc4cccc(C(F)(F)F)c4)ccc3c2)COC(C)(C)OC1
Reaction time: 10 h
Yield: 62 %

Procedure:
[5-(6-Hydroxy-naphthalen-2-yl)-2,2-dimethyl-1,3-dioxinan-5-yl]-carbamic acid tert-butyl ester (Example 13, 50.0 mg, 0.000134 mol), 3-(trifluoromethyl)phenylboronic acid (50.8 mg, 0.000268 mol), cupric acetate (24.3 mg, 0.000134 mol) were placed in a vial, purged with N2, following by methylene chloride (2 mL, 0.03 mol) and triethylamine to (0.0933 mL, 0.000669 mol) at 23° C. The reaction was allowed to stir for about for 10 hours, and filtrated. The crude material was then purified via chromatography (SiO2, 4 g, 0-35%) to give a pure product (43 mg, 62%). 1H NMR (CHLOROFORM-d) δ: 7.84 (d, J=8.8 Hz, 1H), 7.79 (s, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.55 (dd, J=8.7, 1.6 Hz, 1H), 7.41-7.49 (m, 1H), 7.31-7.40 (m, 2H), 7.16-7.30 (m, 3H), 5.57 (br. s., 1H), 4.22-4.29 (m, 2H), 4.14 (d, J=11.3 Hz, 2H), 1.49-1.58 (m, 6H), 1.36 (br. s., 9H). MS (M-113): 404.20.