Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[CH2:7][NH2:8].[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH2:30][C:31](O)=[O:32])[CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH2:30][C:31]([NH:8][CH2:7][C:6]2[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:32])[CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:17]
Reactant: NCc1cc(Cl)ccc1N1CCCCC1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Product: CCOC(=O)c1ccc(CC(=O)NCc2cc(Cl)ccc2N2CCCCC2)cc1OCC

Procedure:
Prepared from 5-chloro-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1)=[O:9])([CH3:6])[CH3:5].O.O[Li].O>CO>[CH:28]([C:25]1[CH:24]=[CH:23][C:22](/[CH:21]=[CH:20]/[C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:31])=[O:2])=[O:9])=[CH:27][CH:26]=1)([CH3:30])[CH3:29]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1/C=C/c1ccc(C(C)C)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)c1ccc(/C=C/c2c(C(=O)NC(C)(C)C(=O)O)ccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52 %

Procedure:
207 mg 2-({1-[(E)-2-(4-isopropyl-phenyl)-vinyl]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid methyl ester were dissolved in 6 ml of MeOH and 2 ml of water was added. After addition of 114 mg of LiOH.H2O the reaction was stirred at room temperature for 14 h. Filtration of the crude mixture, RP-HPLC and freeze-drying gave 104 mg of 2-({1-[(E)-2-(4-isopropyl-phenyl)-vinyl]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid (42%).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH2:33][C@@H:34]([OH:36])[CH3:35]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][CH2:33][C@@H:34]([OH:36])[CH3:35])=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: C[C@H](O)CN
Product: C[C@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo -1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2S)-1-amino-2-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.28 (1H, t, J=5 Hz), 8.50 (1H, s), 7.75 (1H, s), 7.31 (2H, m), 7.12 (2H, m), 5.12 (2H, m), 4.94 (1H, d, J=5 Hz), 4.11 (2H, s), 3.78 (1H, m), 3.40 (1H, m), 3.18 (1H, m), 3.12 (3H, s), 2.82 (3H, s), 1.07 (3H, d, J=6 Hz); HRMS calcd for C23H25FN4O5+H+: 457.18817. Found: 457.18875.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[F:10].NC1C(O)=C(F)C(F)=CC=1.CC(C)([O-])C.[K+].Cl[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]([NH2:36])=[O:35])[CH:29]=1.[OH-].[Na+]>CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([C:34]([NH2:36])=[O:35])[CH:29]=2)=[C:4]([F:9])[C:3]=1[F:10]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: Nc1ccc(F)c(F)c1O
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(Oc2ccc(N)c(F)c2F)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The mixture of 4-amino-2,3-difluorophenol and 6-amino-2,3-difluorophenol (3.52 g) was dissolved in dimethyl sulfoxide (30 ml) under a nitrogen flow, and potassium tert-butoxide (1.49 g) was added at room temperature, followed by stirring for 30 min. 4-Chloropyridine-2-carboxamide (947 mg) was added thereto, followed by stirring at 80° C. for 6 hr. Then the reaction mixture was stirred at 100° C. for 14 hr. The reaction mixture was allowed to cool down to room temperature, and a 1N aqueous solution of sodium hydroxide (52.8 ml) was added, followed by stirring for 9 hr and 15 min. The reaction mixture was partitioned between ethyl acetate (300 ml) and water (300 ml). The aqueous layer was extracted with ethyl acetate (200 ml, twice), then the combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:3) and fractions containing the target compound were concentrated under reduced pressure. The residue was dried under reduced pressure to provide the titled compound as a pale brown solid (532 mg) which was a mixture of 4-(6-amino-2,3-difluorophenoxy)pyridine-2-carboxamide.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[Na].N[C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:12]=1[C:13]#[N:14]>CO>[N:7]1[C:11]2[C:12](=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[C:13]([NH2:14])=[N:5][C:6]=1[NH2:8]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: [Na]
Solvent: CO
Product: Nc1ccc2nc(N)nc(N)c2c1

Procedure:
To a solution of guanidine carbonate (0.9 g, 5.0 mmol) in 30 mL methanol was added sodium (0.24 g, 10.4 mmol) and the mixture was heated under reflux for 30 minutes. The precipitated sodium carbonate was filtered off and washed with methanol. 2-Amino-5-nitrobenzonitrile (0.88 g, 5.4 mmol) was added to the methanolic solution which was then heated under reflux for additional 24 hours. The solvent was evaporated and the crude 6-nitro-2,4-quinazolinediamine subjected to catalytic hydrogenation as described in EXAMPLE 41.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][C:13]([CH3:16])(C)C)=[O:11])=[C:5]([O:17][CH3:18])[CH:4]=1)#[N:2].Cl.O1CCOCC1.C(C1C=CC(CC(OCC)=O)=C(OC)C=1)#N.C(O[CH:45](OCC)[N:46]([CH3:48])[CH3:47])C>C(O)C.CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:45][N:46]([CH3:48])[CH3:47])[C:10]([O:12][CH2:13][CH3:16])=[O:11])=[C:5]([O:17][CH3:18])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1CC(=O)OC(C)(C)C
Reactant: CCOC(OCC)N(C)C
Agent: CCOC(=O)Cc1ccc(C#N)cc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1OC
Temperature: 100 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
Combined tert-butyl 2-(4-cyano-2-methoxyphenyl)acetate (549 mg, 2.218 mmol) and 4N HCl in dioxane (0.277 mL, 1.109 mmol) in ethanol (7.4 mL) and stirred for 16 hours at 60° C. The reaction was concentrated by rotary evaporation and then combined with ethyl 2-(4-cyano-2-methoxyphenyl)acetate (0.486 g, 2.217 mmol) and 1,1-diethoxy-N,N-dimethylmethanamine (1.9 mL, 11.08 mmol) in DMF (4.43 mL) and stirred for 16 hours at 100° C. The reaction mixture was diluted with 200 mL EtOAc and washed twice with 200 mL water. Organic layer was dried with sodium sulfate and concentrated to give a residue which was purified on a 60 g NH silica gel column eluting with hexanes and EtOAc to give the title compound (405 mg, 74%).
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[C:12]([NH2:13])=[N:11][C:10]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:30]=[C:29]([NH2:31])[C:28]4[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:32][CH3:33])[CH:27]=4)[N:22]=3)[CH2:17][CH2:16]2)=[C:9]([Cl:36])[N:8]=1)=[O:6]>C(O)C>[NH2:13][C:12]1[C:7]([C:5]([OH:6])=[O:4])=[N:8][C:9]([Cl:36])=[C:10]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:30]=[C:29]([NH2:31])[C:28]4[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:32][CH3:33])[CH:27]=4)[N:22]=3)[CH2:17][CH2:16]2)[N:11]=1
Reactant: COC(=O)c1nc(Cl)c(NC2CCN(c3nc(N)c4cc(OC)c(OC)cc4n3)CC2)nc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2nc(N3CCC(Nc4nc(N)c(C(=O)O)nc4Cl)CC3)nc(N)c2cc1OC
Temperature: 85 °C
Yield: 85.6 %

Procedure:
Potassium hydroxide (0.26 g, 4.7 mmol) was added to a solution of (1) (0.06 g, 0.123 mmol) in ethanol (2 mL) at 25° C. The reaction mixture was heated at 85° C. for 12 h then cooled to room temperature. The mixture was concentrated, acidified with HCl (aq) (2 mL, 3M) and the desired product was filtered and rinsed with cold H2O to give 0.05 g (89%) of the title compound: 1H NMR (DMSO) δ 12.20 (br s, 1H), 8.50 (br s, 1H), 7.69 (s, 1H), 7.40 & 7.31 (br s, 2H), 7.16 (d, 1H, J=7.2), 4.70 (d, 2H, J=11.5), 4.24 (m, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.10 (m, 2H), 1.92 (m, 2H), 1.66 (m, 2H); 13C NMR (DMSO) δ 167.4, 161.3, 155.7, 155.1, 150.6, 146.5, 119.0, 109.2, 104.8, 101.7, 56.2, 55.9, 47.7, 43.9, 30.4; HRMS (FAB) m/z 475.1589 (M+H)+ (C20H23N8O4Cl requires 475.1604); Anal. (C20H23N8O4Cl·2HCl·1/2H2O) C, H, N.
Reaction SMILES: [S:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[CH:8]=[N:9][CH:10]=[CH:11][C:2]1=2.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:18][CH2:19][CH2:20][CH2:21]I>>[Cl:18][CH2:19][CH2:20][CH2:21][N:4]1[C:5](=[O:7])[CH2:6][S:1][C:2]2[CH:11]=[CH:10][N:9]=[CH:8][C:3]1=2
Reactant: ClCCCI
Reactant: O=C1CSc2ccncc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1CSc2ccncc2N1CCCCl
Yield: 110.1 %

Procedure:
4H-pyrido[4,3-b][1,4]thiazin-3-one (81MF939a) (0.087 g, 0.52 mmol), Cs2CO3 (0.256 g, 0.78 mmol) and 3-chloro-1-iodopropane (0.116 g, 0.57 mmol) were mixed according to GP5 giving the crude title compound (0.139 g). 1H NMR (CDCl3) δ 8.43 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.25 (d, J=5.2 Hz, 1H), 4.20-4.15 (m, 2H), 3.55 (t, J=6.2 Hz, 2H), 3.41 (s, 2H), 2.17-2.10 (m, 2H).
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:42]1[C:43]2[CH:73]=[C:72]([Cl:74])[CH:71]=[CH:70][C:44]=2[N:45]([CH2:61][C:62]2[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=2)[C:46](=[O:60])[CH:47]([CH2:49][C:50]2[CH:59]=[CH:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]=2)[N:48]=1.[O:75]1[C:79]2([CH2:84][CH2:83][NH:82][CH2:81][CH2:80]2)[O:78][CH2:77][CH2:76]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:74][C:72]1[CH:71]=[CH:70][C:44]2[N:45]([CH2:61][C:62]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=3)[C:46](=[O:60])[CH:47]([CH2:49][C:50]3[CH:59]=[CH:58][C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[CH:51]=3)[N:48]=[C:42]([N:82]3[CH2:83][CH2:84][C:79]4([O:78][CH2:77][CH2:76][O:75]4)[CH2:80][CH2:81]3)[C:43]=2[CH:73]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccc4ccccc4c3)N=C(Cl)c3cc(Cl)ccc32)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(CN2C(=O)C(Cc3ccc4ccccc4c3)N=C(N3CCC4(CC3)OCCO4)c3cc(Cl)ccc32)cc1
Temperature: 120 °C
Yield: 77 %

Procedure:
Palladium acetate (8 mg, 0.038 mmol), X-Phos (18 mg, 0.038 mmol), and cesium carbonate (270 mg, 0.83 mmol) were combined in anhydrous toluene (2 mL), and nitrogen bubbled through the solution for 5 minutes. A solution of 5,7-dichloro-1-(4-methoxybenzyl)-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (370 mg, 0.76 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (0.12 mL, 0.91 mmol) in toluene (2 mL) was added and then heated to 120° C. under a nitrogen blanket for 14 hours. The solution was cooled, diluted with ethyl acetate, washed with water, brine, dried with sodium sulfate, decanted, then concentrated in the presence of silica. Column chromatography eluting with a gradient of 10-70% ethyl acetate in hexanes provided 7-chloro-1-(4-methoxybenzyl)-3-(naphthalen-2-ylmethyl)-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one. (345 mg, 77% yield). ESI m/z measured 596.2321 [M+H]+. calculated 596.2316.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[NH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])=[O:8].[CH3:20][C@H:21]1[CH2:23][C@@H:22]1[CH2:24]Br.O>O1CCCC1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].C[C@H]1C[C@@H]1CBr>[CH:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]([CH2:20][C@H:21]2[CH2:23][C@@H:22]2[CH3:24])[C:10]=1[C:16]([O:18][CH3:19])=[O:17])=[O:8]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: C[C@H]1C[C@@H]1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(C=O)c(C)c(C)n1C[C@H]1C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
Potassium tert-butoxide (3.94 g, 35.1 mmol) was added to a solution of methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate (5.79 g, 31.9 mmol) and 18-crown-6 (0.41 g, 1.55 mmol) in tetrahydrofuran (130 ml) and the mixture was stirred at room temperature for 1 hour. After dropwise addition over 30 minutes of (1S,2S)-2-methylcyclopropylmethyl bromide (5.71 g, 38.3 mmol) to the reaction mixture at 50° C., the mixture was heated under reflux for 3 hours. Potassium tert-butoxide (0.36 g, 3.22 mmol) and (1S,2S)-2-methylcyclopropylmethyl bromide (0.48 g, 3.21 mmol) was further added to the mixture and this mixture was heated for 1 hour. The reaction mixture was poured into iced water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to afford the desired compound (8.26 g, 100%) as a pale brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][C:15]=2[CH2:26][NH:27][CH2:28][CH3:29])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][C:15]=2[CH2:26][N:27]([CH2:28][CH3:29])[C:39]([NH:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:40])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(-c2cnn(C)c2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3cnn(C)c3)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 95, Step 2, using the following starting materials: [2′-ethylaminomethyl-6-methoxy-4′-(1-methyl-1H-pyrazol-4-yl)-biphenyl-3-yl]-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [CH2:1]([O:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[C:16](=[O:17])[N:15]2[CH:18]=[N:19][C:20]([C:21](Cl)=[O:22])=[C:14]2[N:13]=[N:12]1>C1COCC1.O>[CH2:1]([O:8][NH:9][C:21]([C:20]1[N:19]=[CH:18][N:15]2[C:16](=[O:17])[N:11]([CH3:10])[N:12]=[N:13][C:14]=12)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nnc2c(C(=O)Cl)ncn2c1=O
Reactant: NOCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnc2c(C(=O)NOCc3ccccc3)ncn2c1=O
Reaction time: 0.5 h
Yield: 63 %

Procedure:
O-benzylhydroxylamine (195 μL, 1.68 mmol, 2 eq.) was added to a solution of crude 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl chloride (200 mg, 0.84 mmol; see Arrowsmith et al., J. Med. Chem., 2002, Vol. 45, No. 25, p. 5458) in THF (6 mL) and a precipitate formed instantly. The resulting suspension was stirred for 1 hour and 30 minutes and was then poured into ice. The suspension was diluted with water and the precipitate was filtered and washed successively with water, ethyl acetate and diethyl ether to give 158 mg of the pure title compound as an off-white solid (63% yield). δH (DMSO-d6): 11.9 (1H, s), 8.85 (1H, s), 7.42-7.50 (2H, m), 7.36-7.42 (3H, m), 4.96 (2H, s), 3.88 (3H, s).
Reaction SMILES: CC([O-])(C)C.[K+].[NH:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18]>C1COCC1.CCOC(C)=O.O>[CH3:16][Si:17]([CH3:19])([CH3:18])[CH2:20][CH2:21][O:22][CH2:23][N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1cnc2cn[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc2ncccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
KOtBu (2.38 g, 21.24 mmol) was added to a solution of 1H-pyrazolo[4,3-b]pyridine (2.3 g, 19.3 mmol) in THF (60 mL) at 0° C. After stirring at 0° C. for 1 hr, trimethylsilylethoxymethyl chloride (3.54 g, 21.24 mmol) was added. The reaction mixture was kept at 0° C. for 1 hr with stirring, then 1.5 hr at rt. The mixture was diluted with EtOAc and water and extracted with EtOAc. The combined organic phases were washed with brine, dried with Na2SO4, and concentrated. The crude product was purified by flash chromatography to afford 1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridine in (2.32 g, 48%) and the regio-isomer.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.[CH3:20][O:21]C1C(OC)=CC=CC=1C=O>>[C:11]1([C:10]#[C:9][CH:8]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([O:21][CH3:20])[C:5]=2[O:18][CH3:19])[OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1cccc(C=O)c1OC
Product: COc1cccc(C(O)C#Cc2ccccc2)c1OC
Yield: 66 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,3-dimethoxybenzaldehyde was reacted to give the title compound as a colourless oil (352 mg, 66%). LCMS (Method B): RT=4.09 min, [M+Na]+=291.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[N:13][CH:14]=1.Cl.CN(C)CCCN=C=NCC.Cl>C(OCC)(=O)C.C(Cl)(Cl)Cl.ClCCl>[Cl:15][C:12]1[N:13]=[CH:14][C:9]([CH2:8][NH:7][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:10][CH:11]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: N#CCC(=O)NCc1ccc(Cl)nc1
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Cyanoacetic acid (2.6 g, 0.030 mmol), 5-aminomethyl-2-chloropyridine (4.3 g, 0.030 mmol) and 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloric acid salt (5.8 g, 0.030 mol) were added to dichloromethane (50 ml), and stirred overnight. Chloroform and 1N hydrochloric acid were added thereto, and crystals were separated out. The crystals were filtered off, dissolved in ethyl acetate, and water was added thereto and subjected to extraction. The organic phase was washed with a saturated sodium bicarbonate and a saturated brine, and then dried anhydrous sodium sulfate. The residue obtained by filtrating and concentrating was washed with hexane and a little amount of ethyl acetate to obtain N-(6-chloro-3-pyridylmethyl)-2-cyanoacetic acid amide (6.1 g, 0.029 mmol, 97%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:14]1[C:19]([OH:20])=[CH:18][CH:17]=[C:16]([CH2:21][O:22][Si](C(C)(C)C)(C)C)[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:30][O:31][CH2:32]Cl.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O.CN(C)C=O>[CH2:7]([C:14]1[C:19]([O:20][CH2:30][O:31][CH3:32])=[CH:18][CH:17]=[C:16]([CH2:21][OH:22])[N:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(O)c(Cc2ccccc2)n1
Reactant: COCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(CO)nc1Cc1ccccc1

Procedure:
63 g of potassium carbonate and 300 ml of N,N-dimethylformamide were added to 100 g of 2-benzyl-6-(tert-butyldimethylsilyl)oxymethyl-3-hydroxypyridine and 23 ml of chloromethyl methyl ether was added dropwise into the mixture at room temperature under stirring using a mechanical stirrer. After heating under stirring at 50° C. for 2 hours in an oil bath, water was added thereto and the mixture was extracted with ethyl acetate. Further, the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The resulting residue was dissolved by adding 400 ml of tetrahydrofuran and 300 ml of a tetrahydrofuran solution containing 1 mol of tetra-n-butylammonium fluoride was added thereto under ice-cooling. After stirring under ice-cooling, water was added thereto and the mixture was extracted with ethyl acetate. Further, the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was dissolved in 50% ethyl acetate/hexane and filtered through silica gel. The filtrate was evaporated and dried, to give 73 g of the target compound.
Reaction SMILES: [F:1][C:2]1[N:3]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[C:5](C=O)[N:6]=1.Cl.[CH3:29][O:30][NH2:31].N1C=CC=CC=1>CCO>[F:1][C:2]1[N:3]([C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:4][C:5](=[N:31][O:30][CH3:29])[N:6]=1
Reactant: CON
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C(F)=N1

Procedure:
2-Fluoro-4-formyl-1-triphenylmethylimidazole was reacted in EtOH with O-methylhydroxylamine hydrochloride and pyridine, to give 2-fluoro-4-methoxyimino-1-triphenylmethylimidazole, as a 3:1 mixture of geometrical isomers, having the following n.m.r. in CDCl3 : 3.87 (s, 0.75H); 3.93 (s, 0.25H); 7.05-7.5 (m, 17H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH2:25]([S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:26]>>[CH2:25]([S:27]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:11]\[OH:12])=[CH:4][CH:3]=2)=[CH:32][CH:31]=1)(=[O:28])=[O:29])[CH3:26]
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O/N=C(\CC(c1ccccc1)c1ccc(Br)cc1)c1ccncc1
Product: CCS(=O)(=O)c1ccc(-c2ccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)cc2)cc1

Procedure:
In analogy to example 22, from (E)-3-(4-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 5) and 4-(ethanesulfonyl)benzeneboronic acid was prepared the title compound as a white foam, MS (ESI+): m/z=471.1 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]([OH:17])=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[C:19](OC(=O)C)(=O)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[OH:18])[O:17][C:19]([CH3:20])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]2=[O:16]
Reactant: O=C(Cc1ccccc1)c1cc(Cl)c(O)cc1O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccccc1

Procedure:
This compounds was synthesised in the same manner as described above. 1-(5-Chloro-2,4-dihydroxy-phenyl)-2-phenyl-ethanone (1.5 g, 5.7 mmol), acetic anhydride (2.0 ml), Potassium carbonate (2.1 g 15.2 mmol). 6-Chloro-7-hydroxy-2-methyl-3-phenyl-chromen-4-one was obtained as white solid (1.4 g, 85.8%).