Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=4)[N:13]=3)=[CH:10][C:5]=2[NH:4][C:3](=O)[CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29].Cl>N1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=4)[N:13]=3)=[CH:10][C:5]=2[NH:4][C:3](=[S:29])[CH2:2]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1COc2ccc(Nc3nc(Nc4cccc(O)c4)ncc3F)cc2N1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)NC(=S)CO4)n2)c1

Procedure:
N4-[2H-1,4-Benzoxazin-3(4H)-one-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (800 mg, 2.18 mmol) and phosphorus pentasulfide (800 mg, 1.80 mmol) were stirred in pyridine (5 mL) at 70° C. for 2 h. The reaction solution was treated with 1N HCl solution to pH 5. The precipitation was collected with filtration, washed with water, dried to give N4-[2H-1,4-benzoxazin-3(4H)-thione-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.[CH2:42]([N:44]([C:47]1[CH:52]=[CH:51][C:50]([CH2:53][N:54]([NH:67][C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:55][C@H:56]([OH:66])[C@@H:57]([NH2:65])[CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:49][CH:48]=1)[CH2:45][CH3:46])[CH3:43]>CN(C=O)C.C(Cl)Cl.CO>[CH2:42]([N:44]([C:47]1[CH:52]=[CH:51][C:50]([CH2:53][N:54]([NH:67][C:68]([O:70][C:71]([CH3:73])([CH3:72])[CH3:74])=[O:69])[CH2:55][C@H:56]([OH:66])[C@@H:57]([NH:65][C:19](=[O:21])[C@H:15]([CH:16]([CH3:17])[CH3:18])[NH:14][C:12]([O:11][CH3:10])=[O:13])[CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:49][CH:48]=1)[CH2:45][CH3:46])[CH3:43]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CCN(CC)c1ccc(CN(C[C@H](O)[C@@H](N)Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(CN(C[C@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](NC(=O)OC)C(C)C)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In analogy with Example 2e, 1.5 ml of Hünig's base are added to 0.77 g (4.3 mmol) of N-methoxycarbonyl-(L)-valine and 1.3 g (4.3 mmol) of TPTU in 20 ml of DMF and the whole is stirred at RT for 5 min. After that, 2.0 g (4.3 mmol) of 1-[p-(N,N-diethylamino)phenyl]-4(S)-hydroxy-2-(tert-butyloxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane (Example 2d), dissolved in DMF, are added and the mixture is stirred at RT for 2 h. After working up in the same manner as described for Example 2e, the residue is digested in DIPE and the title compound is filtered off. The suction filter residue is washed once again with DIPE and dried in a heated desiccator at 60° C., with the title compound thereby being obtained. TLC: Rf=0.80 (methylene chloride/methanol). HPLC20-100: tret=11.79.
Reaction SMILES: C[O:2][C:3](=[O:6])[CH2:4][NH2:5].[CH2:7]([O:14][C:15]1[C:16]([N+:25]([O-:27])=[O:26])=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([NH2:20])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Li+]>CO>[NH2:5][CH2:4][C:3]([OH:6])=[O:2].[N+:25]([C:16]1[C:15]([O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:23]([CH3:24])[CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19])([O-:27])=[O:26]
Reactant: COC(=O)CN
Agent: Cc1ccc(C(N)=O)c([N+](=O)[O-])c1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: NCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7.5 g (21 mmol) 4a in 250 ml methanol were added 100 ml of 1N lithium hydroxide and the mixture was allowed to stir at room temperature for 2 hours. The methanol was removed under reduced pressure followed by dilution with 150 ml water and slow acidification with 6N hydrochloric acid to pH 1. The product was removed by filtration and washed with 0.1N hydrochloric acid and ether followed by vacuum drying. The 6.8 g of crude product were digested in 250 ml boiling chloroform then allowed to stand at 5° C. overnight. Filtration followed by vacuum drying gave 6.5 g (90%) 4b as marble white crystals: NMR (DMSO-d6) δ 12.7 (s.1H), 9.12 (t, 1H, j=6 Hz), 7.59 (s, 2H), 7.41 (s,5H), 4.94 (s, 2H), 3.86 (d, 2H, j=6 Hz), 2.37 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23](O)=[O:24])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:32][C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.CN1C=CN=C1>ClCCl>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([NH:32][C:33]3[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[CH:35][CH:34]=3)=[O:24])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)c3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.8 %

Procedure:
A mixture of 3-(8-(6-(2-Methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (49 mg, 0.12 mmol), tert-butyl 4-aminobenzoate (23 mg, 0.12 mmol), EDCI (92 mg, 0.48 mmol), N-methyl-imidazole (40 mg, 0.48 mmol) and dichloromethane (3 mL) was stirred at room temperature for 16 h. The solution was concentrated in vacuo and the residue was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=40:1˜100:1) to give tert-butyl 4-(3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamido)benzoate (43 mg, 61%) as a yellow oil. [M+H]+, 590.2, tR=2.283 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(F)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(F)cc2)CC1
Yield: 84.3 %

Procedure:
1-tert-Butoxycarbonyl-4-(4-fluorobenzylidene)piperidine (47.0 g) was dissolved in methanol (450 ml). To the solution was added 10% palladium carbon (water content: 50%, 4.7 g), and the mixture was subjected to catalytic hydrogenation reaction for 5 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 1-tert-butoxycarbonyl-4-(4-fluorobenzyl)piperidine (39.9 g).
Reaction SMILES: [F:1][S:2]([F:14])([F:13])([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][S:2]([F:14])([F:13])([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:16][C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A mixture of 5.40 g (23.3 mmol) 4-pentafluorosulfanyl-benzaldehyde, 2.42 g (23.3 mmol) malonic acid, 0.20 g (2.3 mmol) piperidine and 10.0 ml pyridine was kept at reflux temperature until carbon dioxide development ceased (4 h). The reaction mixture was poured into a solution of 100 ml ice and 60 ml 6N HCl. The precipitate was isolated, washed with water, then with n-heptane and dried in vacuum at 40° C. Yield: 5.73 g (90%) 3-(4-pentafluorosulfanyl-phenyl)-acrylic acid.
Reaction SMILES: [CH:1]1([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:18][NH:19][C:20]([NH2:22])=[O:21].C([O-])(=O)C.[Na+]>C(O)C.O>[CH:1]1([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[N:18][NH:19][C:20]([NH2:22])=[O:21])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OC2CCCCCC2)cc1
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)NN=Cc1ccc(OC2CCCCCC2)cc1
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a solution of 4-cycloheptyloxybenzaldehyde (1.7 g) in ethanol (20 mL) was added a solution of semicarbazide hydrochloride (0.96 g) and sodium acetate (0.69 g) in water (10 mL) at room temperature. The mixture was stirred for 30 min, and the resulting solid was collected by filtration, washed with water (3×30 mL) and dried in vacuo to yield the title compound as a white solid (1.7 g; 79%), mp: 215-216° C. 1H NMR (DMSO-d6): δ 10.07 (s, 1H), 7.76 (s, 1H), 7.61 (d, J=8.4, 2H), 6.89 (d, J=8.4, 2H), 6.40 (s, 2H), 4.54 (m, 1H), 1.98-1.47 (m, 2H).
Reaction SMILES: C[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:17]=[O:18].[Li+].[BH4-]>C1COCC1>[F:15][C:13]([F:14])([F:16])[C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]([CH2:17][OH:18])=[CH:2][CH:6]=2)=[CH:12][CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-methyl-5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (0.140 g, 0.518 mmole) in THF (5 mL), is added to LiBH4 (0.056 g, 2.57 mmole) in one portion at 0° C. The reaction is kept at 0° C. for 15 minutes and warmed up to room temperature for 1 hour. The reaction is quenched using 1N HCl (10 mL) at 0° C. The THF is removed on rota vapor, the aqueous solution is then extracted with ethyl acetate (2×10 mL). The combined organic solution is washed with brine (3×20 mL), dried over Na2SO4 and concentrated. The crude product is purified on a silica gel column, eluting with 20% ethyl acetate in hexane and concentrated to provide the titled compound as white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1N(C)C)(C)(C)C>[O:27]([C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Reactant: Oc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Oc3ccccc3)cnc21
Temperature: 150 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
A mixture of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (3.29 g, 9.23 mmol), phenol (1.04 g, 11.08 mmol), K3PO4 (3.92 g, 18.46 mmol), [2′-(di-tert-butyl-phosphanyl)-biphenyl-2-yl]-dimethyl-amine (0.157 g, 0.46 mmol), Pd(OAc)2 (0.103 g, 0.46 mmol) and degassed toluene (50 mL) was stirred under nitrogen in a sealed tube at 150° C. overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by SiO2 column chromatography (0-30% EtOAc/hexanes) to afford 2.09 g (61%) of 2-phenoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a beige solid.
Reaction SMILES: [OH-].[K+:2].[C:3]([OH:12])(=[O:11])[CH:4]([CH:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5]>O>[C:8]([CH:6]([CH:4]([C:3]([O-:12])=[O:11])[OH:5])[OH:7])([O-:10])=[O:9].[K+:2].[K+:2]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C(O)C(O)C(=O)[O-]

Procedure:
A potassium tartrate buffer was prepared by mixing KOH with tartaric acid at a K:tartaric acid mole ratio of 2:1 and diluting the resulting compound with enough water to yield a buffer solution with a pH of 2.9. 73 g of the buffer was then added to a reconstituted (30% by weight) dried zirconyl chloride five-sixths basic aluminum chloride solution prepared at a mole ratio of Al:Zr of 4:1. This buffered solution was re-dried as in Example I, and analyzed: 12.9% Al, 11.2% Zr, 7.9% K, and 14.6% tartaric acid. The re-dried product was reconstituted to 20% by weight in water and exhibited a pH of 3.8.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([S:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])C.[OH-].[Li+].Cl>CO.O>[OH:21][C:18]1[CH:17]=[CH:16][C:15]([S:14][C:8]2[S:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=2[N+:11]([O-:13])=[O:12])=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)s1

Procedure:
The product from Example 351B (1 equiv) was dissolved in a methanol/water 3/1 mixture followed by the addition of lithium hydroxide (5 equiv). The resultant solution was stirred at room temperature for 24 hours followed by the addition of 1N aqueous hydrochloric acid until the solution was a pH of 2. The mixture was then extracted with ethyl acetate, the organic extracts dried and concentrated under vacuum to provide the title product.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[CH2:15]([O:17][C:18](=[O:28])[C:19]1[CH:24]=[C:23]([Br:25])[C:22](O)=[N:21][C:20]=1[CH3:27])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:28])[C:19]1[CH:24]=[C:23]([Br:25])[C:22]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:21][C:20]=1[CH3:27])[CH3:16]
Reactant: CCOC(=O)c1cc(Br)c(O)nc1C
Reactant: Cc1onc(-c2ccccc2)c1CO
Product: CCOC(=O)c1cc(Br)c(OCc2c(-c3ccccc3)noc2C)nc1C
Yield: 76 %

Procedure:
As described for example 4, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (402 mg, 2.12 mmol) was converted using 5-bromo-6-hydroxy-2-methyl-nicotinic acid ethyl ester instead of 2-hydroxy-5-trifluoromethylpyridine to the title compound (SiO2, heptane:ethyl acetate=100:0 to 50:50, 700 mg, 76%) which was obtained as a colourless oil. MS: m/e=431.1/433.2 [M+H]+.
Reaction SMILES: C([BH-](CC)CC)C.[Li+].[CH2:9]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[N:20][C:21]=1[CH3:22])[N:18]=[CH:17][C:16]([C:23](OCC)=[O:24])=[C:15]2[NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH3:10].Cl.O>C1COCC1>[CH2:9]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[N:20][C:21]=1[CH3:22])[N:18]=[CH:17][C:16]([CH2:23][OH:24])=[C:15]2[NH:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH3:10]
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Nc1ccc(OC)cc1
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc2c(Nc3ccc(OC)cc3)c(CO)cnc2nc1C
Temperature: 25 °C

Procedure:
Lithium triethylborohydride (a 1M solution in THF, 47 ml) was added to a solution of ethyl 6-ethoxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridine-3-carboxylate (4.5 g) in THF (150 ml) with stirring under nitrogen at 0°-10° C. The mixture was allowed to warm up to ambient temperature and stirred at this temperature for 18 hours. Further lithium triethylborohydride solution (15 ml) was added and the solution stirred at ambient temperature for 4 hours. The reaction mixture was cooled to 5° C. and then 5M hydrochloric acid (5 ml) was added carefully followed by water (50 ml). The organic layer was separated and the aqueous layer extracted with ether. The aqueous layer was basified with 5M sodium hydroxide solution and extracted into ethyl acetate. The residue, obtained from the ethyl acetate extracts, was purified by flash chromatography on silica, using dichloromethane/IMS (15/1) as the mobile phase, to give 6-ethoxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridin-3-ylmethanol, m.p. 193°-197° C.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:23])[O:11][CH:10]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]3[CH:18]=[CH:19][S:20][C:16]=3[CH:15]=2)[CH2:9][O:8]1.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.O>CCCCCC.O1CCCC1>[CH3:6][C:7]1([CH3:23])[O:11][CH:10]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]3[CH:18]=[C:19]([B:24]([OH:29])[OH:25])[S:20][C:16]=3[CH:15]=2)[CH2:9][O:8]1
Reactant: CC1(C)OCC(COc2ccc3ccsc3c2)O1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OCC(COc2ccc3cc(B(O)O)sc3c2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 M n-butyllithium (1.75 mL, 4.37 mmol) in hexane was slowly added to 6-[(R/S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyloxy]benzothiophene ((R/S)-25, 1.05 g, 3.97 mmol) obtained in step 1 dissolved in anhydrous tetrahydrofuran (150 mL) at −78° C. under nitrogen atmosphere. 15 Minutes later, the resulting mixture was agitated at room temperature for 1 hour. After cooling again to −78° C., triisopropyl borate ((i-PrO)3B; 1.10 mL, 4.77 mmol) was slowly added. After slowly heating to room temperature and agitating for 3 hours, water was added to quench the reaction. After extracting the organic compound with ethyl acetate and drying with sodium sulfate, column chromatography yielded the target compound 6-[(R/S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyloxy]benzothiophene-2-boronic acid ((R/S)-26, 880 mg, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([Cl:20])=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (4.2 g, 14.89 mmol) was dissolved in CH2Cl2 (42 mL) under N2 atmosphere. Oxalyl chloride (2.6 mL, 29.78 mmol) and DMF (5 drops) were added and the reaction stirred for 2.5 hours at room temperature. Then, additional oxalyl chloride (5 mL, 57.3 mmol) was added. After 30 minutes, the reaction mixture was concentrated and placed under high vacuum. The crude material was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:6][N:7]=[C:8]=[O:9].[N+:15](=[C:17]1[N:21]=[CH:20][N:19]=[C:18]1[C:22]([NH2:24])=[O:23])=[N-:16]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:6][N:7]1[C:8](=[O:9])[N:21]2[CH:20]=[N:19][C:18]([C:22]([NH2:24])=[O:23])=[C:17]2[N:15]=[N:16]1
Reactant: COc1ccc(CN=C=O)cc1OC
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Solvent: CS(C)=O
Product: COc1ccc(Cn2nnc3c(C(N)=O)ncn3c2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude 3,4-dimethoxybenzyl isocyanate (4 mmol) was added to a suspension of 5-diazoimidazole-4-carboxamide (0.274 g, 2 mmol) in dry dimethylsulfoxide (2.5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product was removed by filtration and purified by column chromatography to give the title compound as a white solid. Yield: 0.068 g, 10%. IR vmax/cm−1 1734, 1686, 1616. 1H NMR δH (DMSO-d6) 3.73 (3H, s, OMe), 3.74 (3H, s, OMe), 5.42 (2H, s, CH2Ar), 6.91-6.98 (2H, m, ArH), 7.03 (1H, d, J=1.9, ArH), 7.70 (1H, br s, NH), 7.82 (1H, br s, NH), 8.83 (1H, s, 6-H). δC (DMSO-d6) 52.2, 56.0, 56.0, 112.1, 112.4, 121.1, 128.3, 129.4, 131.3, 134.9, 139.6, 149.1, 149.2, 162.0.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:11]2[C:16]([Cl:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:11]3[C:16]([Cl:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1Cl
Product: Cc1sc2nc(-n3ccnc3C)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2,5-dichloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-chloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]2[CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[C:12](=[O:13])[C:3]=12.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]3[CH2:10][N:11]([CH2:14][CH2:15][C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=4)[C:12](=[O:13])[C:3]=23)=[CH:30][CH:29]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Product: COc1ccc(-c2c3c(cn(C)c2=O)CN(CCc2ccc4ccccc4n2)C3=O)cc1

Procedure:
The title compound was prepared in analogy to the process of Example 13 starting from 7-chloro-5-methyl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (see Example c4)) and 4-methoxyphenylboronic acid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([C:12]12[CH2:19][CH2:18]C(C(O)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)[CH2:8][CH2:9][CH2:10][CH3:11]>C(Cl)Cl>[CH2:7]([C:12]12[CH2:19][CH2:18][C:1]([C:2]([Cl:4])=[O:3])([CH2:14][CH2:13]1)[CH2:16][CH2:17]2)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC12CCC(C(=O)O)(CC1)CC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCCC12CCC(C(=O)Cl)(CC1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (505 μL, 5.79 mmol) was added dropwise to a mixture of 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid (3-A) in methylene chloride (10 mL). The solution was stirred at room temperature for 3 h and then concentrated in vacuo to give 4-pentylbicyclo[2.2.2]octane-1-carbonyl chloride (3-B). 1H NMR (500 MHz, CDCl3): δ 0.90 (t, 3H); 1.21 (m, 8H); 1.45 (m, 6H); 1.88 (m, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([CH:11]=CC3C=CC=CC=3)[S:8][C:6]=2[N:7]=1.I(O)(=O)(=O)=[O:26]>C1COCC1.C(#N)C.O.[Ru](Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([CH:11]=[O:26])[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(C=Cc3ccccc3)sc2n1
Reactant: [O-][I+3]([O-])([O-])O
Agent: Cl[Ru](Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
To a suspension of 2-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-yl)-1-phenyl-ethanol (1.1 g, 2.9 mmol) in toluene (25 mL) was added p-toluenesulfonic acid (0.11 g, 0.58 mmol) and the resulting solution stirred at 120° C. for 24 h. The reaction mixture was concentrated in vacuo to give 5-chloro-7-morpholin-4-yl-2-styryl-thiazolo[5,4-d]pyrimidine as a crude yellow solid which was used without purification. To a suspension of 5-chloro-7-morpholin-4-yl-2-styryl-thiazolo[5,4-d]pyrimidine (2.9 mmol) in THF (9 mL), acetonitrile (9 mL) and H2O (3 mL) were added ruthenium(III) chloride (18 mg, 0.081 mmol) and periodic acid (1.3 g, 5.80 mmol). The resulting solution was stirred at RT for 2 h, then partitioned between EtOAc and an aqueous solution of sodium thiosulfate. The aqueous layer was isolated and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a yellow solid (0.34 g, 42%).