Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[CH:17][S:18][C:11]=12)[NH2:5].C(N(C(C)C)CC)(C)C.[CH2:28]([O:35][CH2:36][C:37](Cl)=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:28]([O:35][CH2:36][C:37]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[CH:17][S:18][C:11]=23)=[C:2]([F:1])[CH:3]=1)=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COCc1ccccc1)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)aniline (Example 1-B; 67 mg, 0.258 mmol) in 1 mL CH2Cl2 at room temperature under nitrogen was added diisopropylethylamine (68 μL, 0.387 mmol) followed by 2-(benzyloxy)acetyl chloride (41 μL, 0.258 mmol). After 1 hour, the reaction was diluted to 30 mL with CH2Cl2 and washed 2×30 mL with 10% citric acid and 2×30 mL with saturated NaHCO3. The organics were isolated, dried (MgSO4), filtered and concentrated. The crude product was loaded onto a Biotage 12S column with 2/3 EtOAc/hexanes and eluted. The fractions containing the product were pooled and concentrated to a yellow oil (68 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 8.51 (d, 1H), 8.44 (br s, 1H), 7.74 (d, 1H), 7.57 (d, 1H), 7.39 (m, 5H), 7.24 (m, 3H), 6.50 (d, 1H), 4.68 (s, 2H), 4.13 (s, 2H). LRMS (ESI pos) m/e 409.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH2:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N+:14]([O-])=O)[CH3:2].[Cl-].[NH4+]>C1COCC1.C(O)C.[Fe]>[CH2:1]([O:3][C:4]([C:5]1[NH:14][C:8]2[C:7](=[N:12][C:11]([Cl:13])=[CH:10][CH:9]=2)[CH:6]=1)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc2nc(Cl)ccc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of 3-(2-chloro-5-nitropyridin-6-yl)-2-oxopropionic acid ethyl ester (Preparation 4, 1.53 g, 5.6 mmol) in THF (65 mL) and ethanol (30 mL) was added saturated aqueous ammonium chloride solution (30 mL) and the suspension was vigorously stirred at rt. Iron powder (1.95 g, 34.8 mmol) was added portionwise and the mixture was heated under reflux for 2 h then allowed to cool prior to filtration through a celite plug, and washed through with warm THF. The mixture was concentrated under reduced pressure to give an aqueous suspension, which was filtered through a sinter, washing with water. The wet solid was washed with methanol and dried. The residue was adsorbed onto silica gel and purified via flash chromatography eluting with ethyl acetate/hexane (1:19) to give the title compound as a white solid. δH (CD3OD): 1.42 (3H, t, 7.03 Hz), 4.42 (2H, q, 7.32 Hz), 7.15 (1H, s), 7.30 (1H, d, 8.79 Hz), 7.89 (1H, d, 8.35 Hz); m/z (ES+)=225.03 [M+H]+; RT=3.32 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20](S(C)(=O)=O)[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]=3[N:24]=2)=[CH:11][C:10]=1[CH3:33])([CH3:4])([CH3:3])[CH3:2].[CH:35]1([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36]1.C(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)(C)C>>[C:1]([O:5][C:6](=[O:34])[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20]([O:40][CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]=3[N:24]=2)=[CH:11][C:10]=1[CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Reactant: OC1CCCC1
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Product: CCCOc1nc(OC2CCCC2)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Temperature: 100 °C
Yield: 27.2 %

Procedure:
A solution of 98 mg of [4-(5-methanesulfonyl-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-acetic acid tert-butyl ester, 19 mg of cyclopentanol and 69 mg of (tert-butylimino)tris(pyrrolidino)phosphorane was reacted at room temperature for 16 h and subsequently heated in a microwave reactor to 100° C. for 10 min. The mixture was poured onto water and extracted twice with ethyl acetate. The combined organic layers were washed with a 10% aqueous solution of citric acid and brine, dried and evaporated. After purification by preparative HPLC, 27 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)[CH3:35]>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6](/[CH:33]=[C:34](/[C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)\[CH3:35])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC(=CBr)c1cccnc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (600 mg, 3 mmol) was dissolved in DMF (12 mL). Copper (I) iodide (114 mg, 0.6 mmol), L-proline (100 mg, 0.87 mmol) and potassium phosphate (1.2 g, 6 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 3-(1-Bromoprop-1-en-2-yl)pyridine (0.772 g, 3.9 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85° C. for 2 h and 140° C. for h (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 85 mg. 1H NMR (CD3OD, TFA salt) δ (ppm): 9.05 (d, 1H), 8.78 (d, 1H), 8.60 (d, 1H), 7.90 (m, 1H), 7.30 (d, 2H), 7.18 (d, 1H), 7.10 (d, 1H), 4.75 (m, 1H), 4.40 (m, 1H), 3.82 (m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 3.10 (s, 3H), 2.42 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: CS(O[C@H:6]1[CH2:9][C@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.O>[C:14]([O:13][C:11](=[O:12])[NH:10][C@H:8]1[CH2:9][C@@H:6]([N:18]=[N+:19]=[N-:20])[CH2:7]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N=[N+]=[N-])C1
Temperature: 85 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
To a solution of trans-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (29 g, 109 mmol) in DMF (100 mL) was added sodium azide (5.68 mL, 162 mmol, Sigma-Aldrich Chemical Company, Inc.) portionwise and the mixture stirred at 85° C. for 18 h. The reaction was diluted with water (200 mL) after cooling and extracted with EtOAc (3×100 mL). The combined organic was washed with water (2×100 mL) and brine, dried over Na2SO4 and evaporated in vacuo to give the title compound (22 g, 104 mmol, 95% yield) that was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[O:31]1[C:35]2[CH:36]=[CH:37][C:38](B(O)O)=[CH:39][C:34]=2[CH2:33][CH2:32]1>>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:38]2[CH:37]=[CH:36][C:35]3[O:31][CH2:32][CH2:33][C:34]=3[CH:39]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc3c(c2)CCO3)sc1C(=O)OCC

Procedure:
Prepared from 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethy ester, example 81(b), and 2,3-dihydro-1-benzofuran-5-yl-boronic acid under conditions analogous to experimental example 81(c). MS: (+) m/z 541.4 (M+1).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([F:20])[CH:13]=2)[CH:9]=[N:8][CH:7]=1)(=O)C.O.[OH-].[Li+].Cl>C1COCC1.O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:6]([CH2:5][OH:4])=[CH:7][N:8]=[CH:9]2)=[CH:13][C:14]=1[F:20])#[N:19]
Reactant: CC(=O)OCc1cncn1Cc1ccc(C#N)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(Cn2cncc2CO)cc1F
Reaction time: 4 h

Procedure:
To a solution of 5-(acetoxymethyl)-1-(4-cyano-3-fluorobenzyl) imidazole, as described above in Step E, (19.8 g, 72.5 mmol) in 5:1 THF/water (430 mL) at ambient temperature was added lithium hydroxide monohydrate (3.33 g, 79.4 mmol). After 4 hours, the solution was adjusted to pH 7 with 1.0 N hydrochloric acid and concentrated in vacuo. The residue was concentrated from toluene in vacuo (3×100 mL) to give the titled product as a pale solid.
Reaction SMILES: [C:1]([N:5]1[CH2:11][CH:10]([N:12]2[C:16]3[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([N:5]1[CH2:11][CH:10]([N:12]2[C:16]3[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)[CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)N1CCN(C(=O)OC(C)(C)C)CC(n2c(NC(=O)c3ccnc(C)c3)nc3cccc(Cl)c32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)N1CCNCC(n2c(NC(=O)c3ccnc(C)c3)nc3cccc(Cl)c32)C1
Reaction time: 1.5 h

Procedure:
A solution of Example 12 (150 mg, 0.278 mmol) in CH2Cl2 (2 mL) was treated with a 1:1 solution of 2,2,2-trifluoroacetic acid in CH2Cl2 (4 mL) and stirred for 90 min. The volatiles were removed under reduced pressure, the residue partitioned between CH2Cl2 and saturated aqueous Na2CO3, the layers separated, and the aqueous phase extracted with CH2Cl2 (2×). The combined organics were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (Example 13). 1H NMR (400 MHz, MeOD) δ 8.58 (d, J=5.2 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.88 (s, 1H), 7.60-7.47 (m, 1H), 7.31 (s, 1H), 7.30-7.21 (m, 1H), 6.83 (dd, J=10.6, 16.8 Hz, 1H), 6.31 (d, J=16.7 Hz, 1H), 6.17-5.85 (m, 1H), 5.78 (dd, J=10.5, 34.2 Hz, 1H), 4.79-4.39 (m, 1H), 4.37-4.12 (m, 1H), 4.12-3.56 (m, 1H), 3.55-3.34 (m, 1H), 3.25-2.97 (m, 3H), 2.96-2.82 (m, 1H), 2.65 (s, 3H); MS calculated for C22H24ClN6O2 (M+H+) 439.16. found 439.2.
Reaction SMILES: C(C(CCCC)C([O-])=O)C.[Na+:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:31]1[CH:36]=[CH:35][C:34]([S:37][C:38]2[CH2:39][C@@H:40]3[C@@H:50]([C@H:51]([OH:53])[CH3:52])[C:49](=[O:54])[N:41]3[C:42]=2[C:43]([O:45]CC=C)=[O:44])=[CH:33][CH:32]=1>C(OCC)(=O)C.ClCCl.CC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:31]1[CH:36]=[CH:35][C:34]([S:37][C:38]2[CH2:39][C@@H:40]3[C@@H:50]([C@H:51]([OH:53])[CH3:52])[C:49](=[O:54])[N:41]3[C:42]=2[C:43]([O-:45])=[O:44])=[CH:33][CH:32]=1.[Na+:11]
Reactant: C=CCOC(=O)C1=C(Sc2ccncc2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd]
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Sc3ccncc3)C[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
2.8 ml (1.4 mmol - 1.05 equivalents) of 0.5 M sodium 2-ethylhexanoate in ethyl acetate, 35 mg (0.13 mmol - 0.1 equivalent) of triphenylphosphine and 35 mg (0.03 mmol) of tetrakis-(triphenylphosphine)-palladium (0) were successively added to a solution of 462 mg (1.33 mmol) of allyl (5R,6S)-2-(4-pyridylthio)-6-[(1R)-1-hydroxyethyl]-carbapen-2-em-3-carboxylate in 3.4 ml of anhydrous dichloromethane, and the mixture was stirred at room temperature for 1 h. It was then diluted with 20 ml of anhydrous acetone. The precipitate was filtered off with suction and vigorously stirred with 50 ml of ether for 0.5 h, again filtered off with suction and dried over P4O10 under high vacuum. 361 mg (83%) of the title compound were obtained as a colorless hygroscopic powder.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O[NH:38][C:39](=[NH:48])[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=1>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]2[O:11][N:48]=[C:39]([C:40]3[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=3)[N:38]=2)=[CH:12][CH:13]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Reactant: N=C(NO)c1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
A solution of 4-iso-propoxybenzoic acid (2.0 g, 11.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.13 g, 11 mmol), 1-hydroxybenzotriazole hydrate (1.50 g, 11.1 mmol) and DMF (14 mL) was stirred at room temperature for 30 minutes. N-hydroxyl-4-(hydroxylmethyl)benzamidine (1.84 g, 11.1 mmol) was added to the reaction mixture and stirred at 140° C. for 2 hours. The reaction mixture was cooled to room temperature, quenched with water (20 mL) and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with 1N HCl and sat. NaHCO3, dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound (2.0 g, 58% yield) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[F:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][NH2:27])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[F:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][NH:27][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:22][CH:21]=1
Reactant: NCCOc1ccc(F)cc1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3ccc(F)cc3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 4.3 %

Procedure:
Compound A (200 mg, 813 mmol), 2-(4-fluorophenoxy)ethylamine hydrochloride (466 mg) and sodium hydrogencarbonate (683 mg) were added to DMSO (6 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-(4-fluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile (38 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:29][CH2:28][CH2:27][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:14][C:15]3[C:16]([CH3:25])=[N:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (200 mg) was dissolved in N,N-dimethylformamide (10 ml) to prepare a solution. 1-Bromo-2-chloroethane (432 mg) and potassium carbonate (416 mg) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (186 mg, yield 78%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].C[N+](C)(C)C.COP(C)(=O)O>CC(C)P([O-])(=O)[O-].O.[Zn]>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]([Cl:11])=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: CC(C)P(=O)([O-])[O-]
Agent: COP(C)(=O)O
Agent: C[N+](C)(C)C
Solvent: O
Product: Clc1cc(Cl)c(Cl)nc1Cl
Temperature: 80 °C
Yield: 91.8 %

Procedure:
A suspension of 12.8 g (0.05 mol) of pentachloropyridine and 4.1 g (0.062 gram atom) of zinc dust in 120 ml of dimethylmethanephosphonate is heated with stirring to 80° C. There is then added dropwise within 15 minutes a solution of 13.76 g (0.075 mol) of the tetramethylammonium salt of methanephosphonic acid monomethyl ester in 30 ml of water. The mixture is subsequently filtered hot, the filter residue is washed with 30 ml of dimethylmethanephosphonate, and the filtrate is poured into 600 ml of ice water containing 12.5 ml of concentrated hydrochloric acid. The resulting white crystal suspension is stirred for 30 minutes; it is then filtered, and the filter residue is washed with water and dried to yield 9.95 g (90% of theory) of crude 2,3,5,6-tetrachloropyridine, m.p. 87.5° to 89° C., which contains, according to gas-chromatographical analysis, 96.9% of 2,3,5,6-tetrachloropyridine, 1.6% of 2,3,5-trichloropyridine, 0.9% of 2,3,6 -trichloropyridine and 0.6% of pentachloropyridine.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([CH3:24])([CH3:23])[CH3:22])=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:25]([F:28])([F:27])[F:26].[CH:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)=[O:30]>>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:9]1[C:8]([NH:7][C:5]2[S:6][C:2]([C:35]3[CH:36]=[C:31]([CH:32]=[CH:33][CH:34]=3)[CH:29]=[O:30])=[C:3]([C:25]([F:28])([F:27])[F:26])[N:4]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(C(F)(F)F)c(Br)s1
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(C(F)(F)F)c(-c2cccc(C=O)c2)s1

Procedure:
Example 374a was synthesized from N-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine (Example 323a) and 3-formylphenyl boronic acid according to a similar procedure described for Example 107. Example 374a was obtained as a white foam. (M+H)+=498.3.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([C:17]3[CH:18]=[N:19][N:20]([CH2:23][CH3:24])[C:21]=3[OH:22])=[O:16])[C:12]=2[CH3:14])[S:7](=[O:26])(=[O:25])[CH2:6][CH2:5]1.[CH2:27](Br)[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([C:17]3[CH:18]=[N:19][N:20]([CH2:23][CH3:24])[C:21]=3[O:22][CH2:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:29])=[O:16])[C:12]=2[CH3:14])[S:7](=[O:25])(=[O:26])[CH2:6][CH2:5]1
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(=NOC)CCS3(=O)=O)c1O
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(=NOC)CCS3(=O)=O)c1OCC(=O)c1ccccc1

Procedure:
0.4 Gram (1.1 mmol) of 4-methoxyimino-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4- yl) carbonylthiochroman-1,1-dioxide, 0.23 g (1.2 mmol) of phenacyl bromide and 0.15 g of potassium carbonate were added to 10 ml of acetone, and the mixture was stirred under heat for 8 hours. Insolubles were removed by filtration, and then the acetone was distilled off. The remainder was dissolved in ethyl acetate, and the resultant solution was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the remainder was subjected to column chromatography (hexane/ethyl acetate) to give intended 4-methoxyimino -5-methyl-6-(1- ethyl -5-phenacyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound 26) at a yield of 52%.
Reaction SMILES: [CH:1]([C:3]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:2].CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[CH:5]1[C:4]2[C:3]3([C:1]([OH:20])=[O:2])[CH2:17][CH:10]([C:11]4[C:16]3=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=CC12CC(c3ccccc31)c1ccccc12
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C12CC(c3ccccc31)c1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 9-formyl-9,10-dihydro-9,10-methanoanthracene (3.5 g) in acetone (17 ml) was dropwise added Jones' reagent (5.0 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9,10-dihydro-9,10-methanoanthracene-9-carboxylic acid. M.P. 199.5°-200.5° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[H-].[Na+].[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18].O>C1COCC1>[CH3:16][Si:17]([CH3:19])([CH3:18])[CH2:20][CH2:21][O:22][CH2:23][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1cc2cccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc2cccnc2n1COCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate (H-1) (528 mg, 3 mmol) in dried THF (5 mL) at 0° C. was added NaH (240 mg, 6 mmol). The reaction was stirred for 0.5 h under N2, and then SEMCl (526 mg, 3 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. H2O was added to quench the reaction. The resulting mixture was extracted with EtOAc. The oragnic layer was dried over Na2SO4, and concentrated to afford the title compound (750 mg), which was used for the next step without purification. MS (m/z): 307 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=O)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:24]1([CH:30]([NH2:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][NH:37][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)cc1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(CNC(c3ccccc3)c3ccccc3)cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
A suspension (12 mL) of 1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (1.2 g), diphenylmethylamine (1.35 g) and powder molecular sieves 4A (5.0 g) in dichloromethane was stirred at room temperature for 6 hr, sodium triacetoxyborohydride (1.56 g) was added, and the mixture was further stirred at room temperature for 3 hr. The reaction mixture was filtered through celite, and the filtrate was partitioned using an ethyl acetate-saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1). The obtained oil was left standing in a freezer (temperature: −20° C.) to give the title compound as a colorless solid (yield 1.61 g, 89%).