Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:32][CH:33](O)[CH2:34][CH3:35]>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH:34]([CH3:35])[CH2:33][NH2:32])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH:34]([CH3:35])[CH2:33][NH2:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(N)O
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Solvent: CCO
Product: CC(CN)OB(c1ccccc1)C(OC(B(OC(C)CN)c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
The entitled compound (40 mg) was obtained by allowing 41 mg of bis(4,4′-(phenylhydroxyboryl)benzyl) ether and 18 mg of 1-aminopropanol to act in 1 mL of ethanol.
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[OH:36].[Cl:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:43]=1[Cl:44]>>[Cl:37][C:38]1[CH:39]=[C:40]([C:26]2[C:27]([OH:36])=[CH:28][CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=2)[CH:41]=[CH:42][C:43]=1[Cl:44]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: Oc1ccc(C(F)(F)F)cc1-c1ccc(Cl)c(Cl)c1

Procedure:
3′,4′-Dichloro-5-(trifluoromethyl)-[1,1′-biphenyl]-2-ol was prepared as a yellow oil using the procedure described in Intermediate 5 from 2-bromo-4-(trifluoromethyl)phenol (Tetrahedron 2003, 59, 6545) and 3,4-dichlorophenylboronic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]([OH:14])=O)[N:9]=[CH:10][C:5]2=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[C:20]([C:27]1[NH:28][CH:29]=[CH:30][N:31]=1)([C:22]1NC=CN=1)=O.NC1C=CC=CN=1>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]([NH:28][C:27]3[CH:20]=[CH:22][CH:29]=[CH:30][N:31]=3)=[O:14])[N:9]=[CH:10][C:5]2=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1nc(-c2ccco2)c2cnn(CC(=O)O)c2n1
Agent: Nc1ccccn1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2cnn(CC(=O)Nc3ccccn3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
A solution of 6-amino-4-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidin-1-ylacetic acid (200 mg, 0.77 mmol) in DMF (3 mL) was treated with carbonyl diimidazole (125 mg, 0.77 mmol), stirred at room temperature for 2 h, treated with 2-aminopyridine (72 mg, 0.77 mmol), heated to 50° C. for 3 h, cooled and diluted with water. The resulting white solid was filtered, suspended in MeOH, treated with HCl in dioxan (4-M, 1 mL) diluted with diethyl ether and filtered to give the title compound (187 mg, 59%) as a yellow solid.
Reaction SMILES: [N:1]([CH2:4][C:5]12[CH2:12][CH2:11][C:8]([CH3:13])([CH2:9][CH2:10]1)[C:7](=[O:14])[O:6]2)=[N+]=[N-].[H][H]>C(O)C.[Pt](=O)=O>[NH2:1][CH2:4][C:5]12[CH2:12][CH2:11][C:8]([CH3:13])([CH2:9][CH2:10]1)[C:7](=[O:14])[O:6]2
Reactant: CC12CCC(CN=[N+]=[N-])(CC1)OC2=O
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CC12CCC(CN)(CC1)OC2=O
Yield: 84.6 %

Procedure:
0.025 g of platinum dioxide was added to a solution of 0.6 g of 1-azidomethyl-4-methyl-2-oxabicyclo[2.2.2]octan-3-one (Example 29) in 30 ml of ethanol. The resultant solution was reacted for 14 hours under 3.5 atom hydrogen gas. After reaction, the catalyst was filtered out, and the solvent was removed in vacuo from the filtrate. As a result, 0.44 g of 1-aminomethyl-4-methyl-2-oxabicyclo[2.2.2]-octan-3-one was obtained as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@H:10]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[F:19])[CH2:9][C:8](=[O:20])[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:6]1)=[O:4].[OH-].[Li+]>O1CCCC1.CO>[CH2:21]([N:7]1[C:8](=[O:20])[CH2:9][C@@H:10]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[F:19])[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C(=O)C[C@H]1c1cc(F)c(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@@H]1CN(Cc2ccccc2)C(=O)C[C@H]1c1cc(F)c(F)cc1F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 8.4 g (22.2 mmol) of methyl-trans-1-benzyl-6-oxo-4-(2,4,5-trifluorophenyl)piperidine-3-carboxylate in 200 mL of 3:1 tetrahydrofuran/methanol was added 50 mL (50 mmol) of a 1N aqueous lithium hydroxide solution and the resulting mixture was stirred at 60° C. for 2 h. The solution was concentrated and acidified with 100 mL of 1N aqueous hydrochloric acid. The resulting mixture was then extracted with three 250-mL portions of ethyl acetate, and the organic phases combined and washed sequentially with 1N hydrochloric acid and saturated aqueous brine (200 mL each). The organic phase was dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the title acid as a colorless foamy solid that was used without further purification. LC/MS 364.3 (M+1).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][N:68]1[CH2:73][CH2:72][N:71]([CH2:74][C:75]2[CH:82]=[CH:81][C:78]([CH:79]=O)=[CH:77][CH:76]=2)[CH2:70][CH2:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:79]([C:78]3[CH:77]=[CH:76][C:75]([CH2:74][N:71]4[CH2:70][CH2:69][N:68]([CH3:67])[CH2:73][CH2:72]4)=[CH:82][CH:81]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CN1CCN(Cc2ccc(C=O)cc2)CC1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CN1CCN(Cc2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 20.5 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (50 mg, 0.13 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.38 mmol, 0.38 mL) and 4-[(4-methylpiperazin-1-yl)methyl]benzaldehyde (1.1 eq, 0.14 mmol, 31 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (15 mg, 21%) as a pale yellow solid; δH (500 MHz, DMSO-d6) 2.16 (s, 3H, CH3), 2.34-2.38 (m, 8H, 2× piperazine N(CH2)2), 2.62 (t, J=4.7 Hz, 4H, piperazine N(CH2)2), 3.52 (s, 2H, NCH2), 3.62 (s, 2H, NCH2), 3.70 (t, J=4.6 Hz, 4H, piperazine N(CH2)2), 7.39 (dd, J=7.6, 4.6 Hz, 1H, pyridine H-5), 7.45 (d, J=8.4 Hz, 2H, phenyl H-3 & H-5), 7.79 (dt, J=7.7, 1.8 Hz, 1H, pyridine H-4), 8.13 (d, J=8.3 Hz, 2H, phenyl H-2 & H-6), 8.23 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.8, 1.7 Hz, 1H, pyridine H-6), 8.56 (d, J=1.6 Hz, 1H, pyridine H-2), 13.47 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[N:10][C:11]([CH3:20])=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13](Cl)=[C:8]2[N:7]=[CH:6]1)CCC.ClC1[C:27]([C:28](OCC)=[O:29])=[C:26]([CH3:33])N=C2N(C)C=NC=12>>[CH2:28]([O:29][C:13]1[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([CH3:20])[N:10]=[C:9]2[N:5]([CH3:1])[CH:6]=[N:7][C:8]=12)[CH2:27][CH2:26][CH3:33]
Reactant: CCCCn1cnc2c(Cl)c(C(=O)OCC)c(C)nc21
Reactant: CCOC(=O)c1c(C)nc2c(ncn2C)c1Cl
Product: CCCCOc1c(C(=O)OCC)c(C)nc2c1ncn2C
Yield: 61 %

Procedure:
By replacing 3-butyl-7-chloro-5-methyl-3H-imidazo[4,5-b]-pyridine-6-carboxylic acid, ethyl ester in Example 5 with 7-chloro-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester of Example 2 c, 7-butoxy-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester is formed. Yield 61%, b.p. 180°-190°/0.01.
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16](O)=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2].S(Cl)(Cl)=O.[CH2:34]([NH2:36])[CH3:35]>C1(C)C=CC=CC=1>[CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16]([NH:36][CH2:34][CH3:35])=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc2cc(C(=O)O)c(=O)oc12
Reactant: CCN
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCNC(=O)c1cc2cc(/C=C/C(=O)c3ccc(C)cc3)cc(C(C)CC)c2oc1=O
Reaction time: 0.58 h

Procedure:
To a suspension of (E)-8-sec-butyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxylic acid of the formula (V) (0.5 g, 1.28 mmol) in toluene (15 mL), added thionyl chloride (1.0 mL), was refluxed for 3 h. The resulting solution was evaporated to dryness under reduced pressure, and the residue was dispersed in toluene (15 mL). The solvent was eliminated under reduced pressure. Dispersion in toluene and solvent elimination was repeated twice. The residue was dissolved toluene (10 mL) and added with stirring to a solution of the ethyl amine (0.06 g, 1.28 mmol). After 35 min at room temperature, the solvent was removed by evaporation under reduced pressure and extracted 3-fold with CHCl3 (20 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane, which upon concentration provides (E)-8-sec-butyl-N-ethyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxamide (General Formula VI). (0.34 g, 64% yield). White solid, m. p. 162-163° C.; 1H NMR (CDCl3 300 MHz): δ 8.93 (s, 1H), 7.96 (d, J=8.2 Hz, 2H), 7.83-7.76 (m, 3H), 7.54 (d, J=15.7 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 3.57-3.39 (m, 3H), 2.45 (s, 3H), 1.80-1.73 (m, 2H), 1.34 (d, J=6.9 Hz, 3H), 1.28 (t, J=7.3 Hz, 3H). 0.91 (t, J=7.3 Hz, 3H): 13C NMR (CDCl3, 75 MHz): δ 189.6, 161.2, 161.1, 153.1, 148.5, 144.1, 142.3, 136.5, 135.4, 132.2, 131.4, 128.8, 127.1, 123.2, 119.1, 119.0, 122.8, 34.9, 33.7, 29.8, 21.8, 20.6, 14.8, 12.1; ESI-MS (m/z): 418(M+H)+.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][C@H:14]([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Si:17]([O:16][CH2:15][C@@H:14]([CH3:24])[CH2:13][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1][CH2:2][C:3]1=[O:11])([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:18])[CH3:19]
Reactant: O=C1CSc2ccccc2N1
Reactant: C[C@@H](CBr)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)CSc2ccccc21
Yield: 70.4 %

Procedure:
4H-Benzo[1,4]thiazin-3-one (2.75 g, 16.7 mmol), (R)-(3-bromo-2-methylpropoxy)-tert-butyldimethylsilane (95MF94) (4.04 g, 15.1 mmol) and cesium carbonate (12.3 g, 37.9 mmol) in DMF (20 mL) were reacted according to GP2 to give the title compound (108LM25-22) (3.74 g, 70%). 1H NMR (CDCl3) δ 7.35 (d, J=7.6 Hz, 1H), 7.28-7.18 (m, 2H), 6.99 (t, J=7.6 Hz, 1H), 4.13 (dd, J=8.9 Hz, J=13.3 Hz, 1H), 3.95 (dd, J=5.9 Hz, J=13.3 Hz, 1H), 3.52-3.40 (m, 2H), 3.37 (s, CH2), 1.96-2.07 (m, 1H), 0.92-0.83 (m, 12H), 0.02 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH:19]([CH3:20])[CH2:18][O:17][CH2:16][CH:15]3[CH3:21])[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40](=O)[O:41]C2C=CC=CC=2)[CH:34]=1>>[CH3:21][CH:15]1[CH2:16][O:17][CH2:18][CH:19]([CH3:20])[N:14]1[C:12]1[N:11]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:31][CH3:32])=[CH:24][CH:23]=2)[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:40]([NH:39][C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)=[O:41])=[CH:7][CH:6]=2)[N:13]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3C(C)COCC3C)n2)cc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4cccnc4)cc3)nc(N3C(C)COCC3C)n2)cc1
Yield: 6 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-3-ylcarbamate. Yield 77 mg, 6% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[S:31][CH2:32][CH2:33][CH2:34][CH2:35]O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:35][CH2:34][CH2:33][CH2:32][S:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCCCSc1ccc2ccccc2c1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCCSc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 39.4 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate prepared from 4-(2-naphthylthio)butanol (1.55 g). The mixture was stirred and heated under argon at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 3:1) and crystallized from diethyl etherhexane to provide 0.625 g of 4-[[4-(2-naphthalenylthio)butyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 64°-65° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][N:14]([C@@H:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH3:17])[C:13](=[O:26])[CH2:12]2)[CH3:10])[C:5]2[N:27]([CH3:30])[CH:28]=[N:29][C:4]=2[CH:3]=1.[O:31]1[CH2:34][CH:33]([N:35]2[CH2:40][CH2:39][N:38]([C:41]3[CH:42]=[N:43][C:44]([Sn](CCCC)(CCCC)CCCC)=[CH:45][CH:46]=3)[CH2:37][CH2:36]2)[CH2:32]1.[F-].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C@H:16]([N:14]2[CH2:15][C@H:11]([C@H:9]([O:8][C:6]3[C:5]4[N:27]([CH3:30])[CH:28]=[N:29][C:4]=4[CH:3]=[C:2]([C:44]4[CH:45]=[CH:46][C:41]([N:38]5[CH2:37][CH2:36][N:35]([CH:33]6[CH2:32][O:31][CH2:34]6)[CH2:40][CH2:39]5)=[CH:42][N:43]=4)[N:7]=3)[CH3:10])[CH2:12][C:13]2=[O:26])[CH3:17])=[CH:19][CH:20]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cc4ncn(C)c34)CC2=O)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(N2CCN(C3COC3)CC2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(N5CCN(C6COC6)CC5)cn4)cc4ncn(C)c34)CC2=O)cc1
Temperature: 140 °C
Yield: 100.4 %

Procedure:
Into the mixture of (R)-4-((R)-1-((6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.05 (60 mg, 0.14 mmol) and 1-(oxetan-3-yl)-4-(6-(tributylstannyl)pyridin-3-yl)piperazine 7.16 (78 mg, 0.154 mmol) in dioxane (3 mL) was added tetrakis(triphenylphosphine)palladium (16 mg) and KF (24 mg). Then the mixture was flushed with Argon, and heated by microwave at 140° C. for 20 min. The reaction was diluted with 50 mL of ethyl acetate and filtered to remove the solid. After removal of solvent, the residue was purified by silica gel column chromatography to provide 86 mg of (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-((R)-1-((3-methyl-6-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one. LCMS [M+H]+: 612.27.
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([O:12][CH2:13][C:14]1[CH2:15][S:16][C@@H:17]2[C@H:37]([NH:38][C:39](=[O:49])[C:40]([C:44]3[O:45][CH:46]=[CH:47][CH:48]=3)=[N:41][O:42][CH3:43])[C:36](=[O:50])[N:18]2[C:19]=1[C:20]([O:22]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21])(=[O:11])[NH2:10]>FC(F)(F)C(O)=O>[C:9]([O:12][CH2:13][C:14]1[CH2:15][S:16][C@@H:17]2[C@H:37]([NH:38][C:39](=[O:49])[C:40]([C:44]3[O:45][CH:46]=[CH:47][CH:48]=3)=[N:41][O:42][CH3:43])[C:36](=[O:50])[N:18]2[C:19]=1[C:20]([OH:22])=[O:21])(=[O:11])[NH2:10]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(N)=O)CS[C@H]12)c1ccco1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
Trifluoroacetic acid (20 ml) was added slowly to a mixture of anisole (5 ml) and diphenylmethyl (6R,7R)-3-carbamoyloxymethyl-7-[2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate (syn isomer) (4.7 g, 8 mmole) which had been cooled in an ice-bath. The flask was shaken occasionally during the next 10 minutes to ensure complete solution of the solid. It was then removed from the icebath and excess trifluoroacetic acid was removed on a rotary evaporator. Trituration of the residue with ethyl acetate (5 ml) gave (6R,7R)-3-carbamoyloxymethyl-7-[2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (syn isomer) (3.3 g, 94%) as a solid which was filtered off and washed with diethyl ether.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[C:4]([NH2:16])[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][C:7]=1[CH3:8].[CH2:29]([O:31][CH2:32][C:33](Cl)=O)[CH3:30]>N1C=CC=CC=1.Cl.N1C=CC=CC=1>[CH2:29]([O:31][CH2:32][C:33]1[N:17]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[C:3]2[C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=[C:5]([O:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]=2[N:16]=1)[CH3:30]
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCOCCCc2nccs2)c1C
Reactant: CCOCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCOCCCc1nccs1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 5,6-dimethyl-2-phenoxy-N4-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}pyridine-3,4-diamine (4.12 g, 10.3 mmol) and pyridine hydrochloride (0.024 g, 0.21 mmol) in pyridine (30 mL) was cooled to 7° C. Ethoxyacetyl chloride (1.33 g, 10.9 mmol) was added, and the reaction was stirred for 30 minutes. The cloudy solution was then heated at 100° C. for 20 hours and then allowed to cool to room temperature. The volatiles were removed under reduced pressure, and the residue was partitioned between water and dichloromethane. The organic layer was washed with potassium carbonate (2×50 mL) and brine (2×50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was triturated with heptane to provide a solid that was isolated by filtration. 2-(Ethoxymethyl)-6,7-dimethyl-4-phenoxy-1-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}-1H-imidazo[4,5-c]pyridine (3.68 g) was obtained as a tan solid.
Reaction SMILES: [CH:1]1([C@H:4]([O:6][C:7](=[O:30])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([OH:26])[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1.O>CN(C=O)C>[CH:1]1([C@H:4]([O:6][C:7](=[O:30])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:27]4[CH2:28][CH2:29]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: C[C@@H](OC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CC2)cc1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](OC(=O)Nc1ccc(-c2c(C#N)c3ccc(Oc4ncccn4)cc3n2C2CC2)cc1)C1CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A mixture of (R)-[4-(3-cyano-1-cyclopropyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (0.060 g, 0.15 mmol), Cs2CO3 (0.122 g, 0.375 mmol), 2-chloropyrimidine (0.034 g, 0.3 mmol) in DMF (1.5 mL) was stirred at 70° C. for 2 h. After cooling to room temperature the mixture was poured into water (15 mL) and the precipitate was collected via filtration, washed with water, and purified on silica gel (CH2Cl2/EtOAc, 9.5:0.5) to provide (R)-{4-[3-cyano-1-cyclopropyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}carbamic acid 1-cyclopropyl-ethyl ester as a solid (72 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=[N:14][OH:15])[CH3:13].C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35].Cl>O1CCCC1>[C:34]([O:15][N:14]=[C:12]([CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:19][C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:17][C:16]=1[Cl:26])[CH3:13])(=[O:36])[CH3:35]
Reactant: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NO
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)ON=C(C)COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Yield: 42.6 %

Procedure:
First, 0.45 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone oxime, 0.12 g of triethylamine, and 10 ml of tetrahydrofuran were placed in a reaction vessel, to which 0.12 g of acetic anhydride was slowly added dropwise with stirring at room temperature. After completion of the addition, the reaction mixture was further stirred at room temperature for 30 minutes, poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with saturated aqueous sodium hydrogencarbonate solution and water in this order, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.21 g (yield, 43%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone O-acetyloxime, nD25.6 1.5318.
Reaction SMILES: Cl[S:2]([C:5]1[N:9]=[CH:8][N:7]([C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[N:6]=1)(=[O:4])=[O:3].C(OCC)(=O)C.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[N:21]1([S:2]([C:5]2[N:9]=[CH:8][N:7]([C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[N:6]=2)(=[O:4])=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: c1ccncc1
Reactant: CN(C)C(=O)n1cnc(S(=O)(=O)Cl)n1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)n1cnc(S(=O)(=O)N2CCCCC2)n1
Reaction time: 1 h

Procedure:
To a mixture of 3-chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole (240 mg) and ethyl acetate (2 ml) was added pyridine (0.2 ml) on a water bath at room temperature. At this temperature the mixture was stirred for 1 hour. The reaction solution was washed with water, followed by saturated aqueous sodium chloride solution, and concentrated. The residue was subjected to a silica-gel column chromatography with 20 to 30% (20% 2-propanol/ethyl acetate)/hexane to yield the title compound (29 mg).