Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)NC1C=CC=C(CN2C=CC(N[C:21](=[O:40])[C@@H:22]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=O)=O)=[C:31](Cl)[CH:30]=3)CC3CCCC3)=N2)C=1)(C)(C)C.[CH3:42][OH:43].[CH:44](Cl)(Cl)Cl>S(=O)(=O)(O)O>[CH3:42][O:43][C:21](=[O:40])[CH2:22][C:29]1[CH:34]=[CH:33][C:32]([S:35][CH3:38])=[C:31]([CH3:44])[CH:30]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Reactant: ClC(Cl)Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(SC)c(C)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 83 %

Procedure:
(3-Methyl-4-methylsulfanyl-phenyl)-acetic acid (prepared as in PCT WO 2004/052869 A1, Example 57, 1.50 g, 7.64 mmol) was placed in a pressure bottle with methanol (15 mL) and concentrated sulfuric acid (9 drops) and heated at 70° C. for 16 h and then stirred at 25° C. for 2 days. The reaction was then diluted with chloroform and concentrated with silica gel (4 g) in vacuo and purified on Biotage Flash chromatography system (40M column, silica gel, 20% ethyl acetate/hexanes) to afford (3-methyl-4-methylsulfanyl-phenyl)-acetic acid methyl ester (1.34 g, 83%) as an amber oil.
Reaction SMILES: C[CH2:2][N:3](C(C)C)C(C)C.[CH3:10][C@H:11]1[O:16][C@@H:15]([CH3:17])[CH2:14][N:13]([C:18]2[S:19][C:20]([C:25]3[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([CH3:32])[CH:26]=3)=[C:21](NC)[N:22]=2)[CH2:12]1.[CH3:33][C:34]1[CH:38]=[C:37]([C:39](Cl)=[O:40])[O:36][N:35]=1>C(Cl)Cl>[CH3:10][C@H:11]1[O:16][C@@H:15]([CH3:17])[CH2:14][N:13]([C:18]2[S:19][C:20]([C:25]3[CH:26]=[C:27]([CH3:32])[N:28]=[C:29]([CH3:31])[CH:30]=3)=[C:21]([CH2:2][NH:3][C:39]([C:37]3[O:36][N:35]=[C:34]([CH3:33])[CH:38]=3)=[O:40])[N:22]=2)[CH2:12]1
Reactant: Cc1cc(C(=O)Cl)on1
Reactant: CNc1nc(N2C[C@@H](C)O[C@@H](C)C2)sc1-c1cc(C)nc(C)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)NCc2nc(N3C[C@@H](C)O[C@@H](C)C3)sc2-c2cc(C)nc(C)c2)on1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
DIPEA (0.16 mL, 0.97 mmol) was added to a solution of Intermediate 5 (150 mg, 0.45 mmol) in DCM (6 mL). The reaction mixture was cooled to 0° C. under nitrogen atmosphere. 3-Methylisoxazole-5-carbonyl chloride (79 mg, 0.54 mmol) was then added dropwise and stirring was continued for 1 h at room temperature. The reaction was washed with sodium bicarbonate and then twice with water. The organic layer was dried over a magnesium sulphate plug and evaporated. The residue was purified by preparative HPLC (RP Shandon Hyperprep C18 BDS—8 μm, 250 g, 5 cm; mobile phase (0.25% NH4HCO3 solution in water, CH3CN)), yielding 127 mg (64%) of Compound 4.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][CH:15]([CH3:17])[CH3:16]>C1COCC1>[CH3:14][CH:15]([CH3:17])[CH2:16][CH:10]([C:7]1[CH:8]=[N:9][C:4]([CH3:3])=[CH:5][CH:6]=1)[C:11]#[N:12]
Reactant: Cc1ccc(CC#N)cn1
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C#N)CC(C)C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
To a cooled (0° C.) slurry of NaH (60% dispersion in oil, 2.74 g, 68.5 mmol) in THF (120 mL) was added a solution of (6-methylpyridin-3-yl)-acetonitrile (8.23 g, 62.3 mmol) in THF (60 mL). The mixture was stirred at room temperature for 3 h and then warmed to 40° C. for 1 h. The resulting reddish brown slurry was cooled to −20° C. and a solution of 1-bromo-2-methylpropane (8.53 g, 62.3 mmol) in THF (30 mL) was added dropwise and then stirred for 18 h at room temperature. The reaction was quenched with water and extracted with AcOEt. The organic extracts were combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (15% EtOAc in hexane) to give 7.52 g (64% yield) of 4-methyl-2-(6-methylpyridin-3-yl)-pentanenitrile as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.00 (dd, J=6.64, 4.30 Hz, 6 H), 1.53-1.70 (m, 1 El), 1.71-1.99 (m, 2 H), 2.57 (s, 3 H), 3.81 (dd, J=9.57, 6.45 Hz, 1 H), 7.19 (d, J=7.82 Hz, 1 H), 7.59 (dd, J=7.82, 2.34 Hz, 1 H), 8.43 (d, J=2.34 Hz, 1 H).
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]=1)=[O:5])C.[C:15]1([C@@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[Al](C)C.CCCCCC>ClCCl>[C:15]1([C@@H:21]([NH:23][C:4]([C:6]2[S:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[N:14]=2)=[O:5])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC(=O)c1nc2ccncc2s1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: C[C@H](NC(=O)c1nc2ccncc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of thiazolo [5,4-c]pyridine-2-carboxylic acid ethyl ester (16 mg, 0.08 mmol) and 1(S)-phenyl ethyl amine (0.03 mL, 0.23 mmol)in dichloromethane(0.3 mL) was added a solution of trimethylaluminum in hexane(0.115 mL, 2.0 M., 0.23 mmol). The solution was then stirred for 5 hours at room temperature. After usual work-up, the product was purified by flash chromatography (CH2Cl2/EtOAc 1:1)and triturated in hexane to give 12 mg of the thiazolo derivative.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C:22]1([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:24][CH2:23]1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:24][CH2:23]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)C1(N)CC1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C1(Nc2nc(Cl)nc3c2SCC3)CC1
Temperature: 160 °C

Procedure:
2.7 g (II) are placed in 30 ml dioxane, then 6.8 ml diisopropyl-ethylamine and 1.8 g 2-(1-aminocyclopropyl)-propan-2-ol (see Liebigs Ann. Chem. 1978.1194) are added. The reaction mixture is heated to 160° C., until there is no further reaction, and after cooling evaporated to dryness. The residue is combined with ice water. The product is extracted with dichloromethane and purified by chromatography. 125 mg (III-8) are obtained as a solid. Analytical HPLC-MS (method A): RT=1.08 min.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1O.C(=O)(OCC)OCC.Br.[CH3:21][CH:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH2:29][CH2:30][CH2:31][CH:32]([CH2:34][CH2:35][CH2:36][C:37]([OH:41])([CH:39]=[CH2:40])[CH3:38])[CH3:33])[CH3:28])[CH3:23]>[Br-].[Zn+2].[Br-]>[CH3:9][C:8]1[C:2]([CH3:1])=[C:3]2[C:5]([CH2:40][CH2:39][C:37]([CH2:36][CH2:35][CH2:34][CH:32]([CH2:31][CH2:30][CH2:29][CH:27]([CH2:26][CH2:25][CH2:24][CH:22]([CH3:21])[CH3:23])[CH3:28])[CH3:33])([CH3:38])[O:41]2)=[C:6]([CH3:11])[C:7]=1[OH:10]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: Br
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(=O)OCC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Temperature: 50 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To a mixture consisting of 23.3 g (0.153 mol) of 2,3,5-trimethylhydroquinone, 23.2 g (0.153 mol) of zinc bromide, 52.9 ml of diethyl carbonate and 4.3 g of 47% hydrobromic acid, was added dropwise, under stirring at 50±5° C. over one hour, 46.2 g (0.153 ml) of isophytol (purity: 98.1%). Further, the resulting mixture was stirred for one hour at the same temperature. The reaction liquid was washed several times with 50 ml of water, followed by concentrating under a reduced pressure, whereby 66.7 g of the title compound was obtained as a brown oil (yield: 99.1 %, GLC purity: 98.0%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@H:15]2[CH3:27])[C:3]=1[CH3:28].[O:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[N:39][CH:40]=2)[CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:41][C:37]1[CH:38]=[N:39][CH:40]=[C:35]([N:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)[CH:36]=1)=[C:3]([CH3:28])[C:4]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][C@H:15]1[CH3:27])=[N:5]2
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using (R)-tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-3-methylpiperazine-1-carboxylate (31.0 mg, 0.075 mmol) and 5-morpholinopyridin-3-amine in toluene to give (R)-tert-butyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-3-methylpiperazine-1-carboxylate. Mass Spectrum (ESI) m/e=555.5 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:12]([NH:20][NH2:21])(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[C:13]1([C:12]2[N:3]3[CH:4]=[CH:5][C:6]4[C:11]([C:2]3=[N:21][N:20]=2)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1nccc2ccccc12
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Product: c1ccc(-c2nnc3c4ccccc4ccn23)cc1
Yield: 3.3 %

Procedure:
To a solution of 1-chloro-isoquinoline (4 g, 24.45 mmol) in ethanol (50 ml) was added benzoic acid hydrazide (4 g, 29.34 mmol) and the mixture was stirred at reflux temperature for 16 hrs. The reaction mixture was cooled and the precipitate was filtered off and recrystallised from ethanol (50 ml) affording 1.9 g of impure (NMR) tile compound. The filtrate was purified by silicagel chromatography using a mixture of ethyl acetate/heptane (1:2) as eluent. Pure fractions were collected and the solvent evaporated in vacuo affording 0.2 g (3%) of the title compound as a solid.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[N:9]=[CH:8][C:7]=1[O:14][CH2:15][C:16]1[C:17]([C:22]([OH:24])=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1.O=S(Cl)Cl.[CH3:29]O>>[CH:2]([C:6]1[CH:11]=[C:10]([O:12][CH3:13])[N:9]=[CH:8][C:7]=1[O:14][CH2:15][C:16]1[C:17]([C:22]([O:24][CH3:29])=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:3]
Reactant: COc1cc(C2OCCO2)c(OCc2cccnc2C(=O)O)cn1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ncccc1COc1cnc(OC)cc1C=O

Procedure:
To 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinic acid (55 mg, 0.17 mmol, 1 equiv) in MeOH (15 mL) was added SOCl2 (5.0 mL). The mixture was heated to reflux O/N, concentrated, and neutralized to pH 8-9 with NaHCO3(sat.) solution. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give methyl 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinate (51.5 mg, quantitative yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.67 (dd, J=4.6, 1.5 Hz, 1H), 8.14 (dd, J=8.0, 1.5 Hz, 1H), 8.03 (s, 1H), 7.51 (dd, J=8.0, 4.6 Hz, 1H), 7.06 (s, 1H), 5.60 (s, 2H), 3.95 (s, 3H), 3.85 (s, 3H). LRMS (M+H+) m/z 303.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18].[C:23]([O:27][C:28]([NH:30][C:31]1([C@H:34]2[CH2:38][NH:37][CH2:36][C@H:35]2[F:39])[CH2:33][CH2:32]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CN1CCCCC1>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:37]2[CH2:38][C@H:34]([C:31]3([NH:30][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH2:32][CH2:33]3)[C@H:35]([F:39])[CH2:36]2)[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18]
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CC(C)(C)OC(=O)NC1([C@H]2CNC[C@H]2F)CC1
Solvent: CS(C)=O
Solvent: CN1CCCCC1
Product: Cc1c(N2C[C@@H](F)[C@@H](C3(NC(=O)OC(C)(C)C)CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture consisting of 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (45 mg, 0.144 mmol), (3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidine (52.8 mg, 0.216 mmol), 1-methylpiperidine (18.5 mg, 0.186 mmol) and dimethyl sulfoxide (1.8 ml) was stirred at an outer temperature of 80° C. for 7 hours. When analysis was carried out by a high performance liquid chromatography after completion of the reaction, formed ratio of the compound of interest 5-amino-7-[(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid was 4%. Also, residual ratio of the starting material was 90%.
Reaction SMILES: [C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@@:7]([C@H:17]2[CH2:21][C:20](=[O:22])[C@H:19]([OH:23])[CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)([CH3:4])([CH3:3])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1.C(OCC)(=O)C>[C:24]([O:23][C@@H:19]1[CH2:18][C@@H:17]([C@@:7]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8](=[O:10])[O:9][C@H:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:6]2)[CH2:21][C:20]1=[O:22])(=[O:26])[CH3:25]
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@H]2CC(=O)[C@H](O)C2)O1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1C[C@@H]([C@]2(c3ccccc3)O[C@@H](C(C)(C)C)OC2=O)CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 32 mg of (2R,5R)-2-(t-butyl)-5-((1R,3R)-3-hydroxy-4-oxocyclopentyl)-5-phenyl-1,3-dioxolan-4-one in 1 ml of pyridine, 0.5 ml of acetic anhydride was added, followed by 1 hour's stirring at room temperature. The reaction liquid was diluted with ethyl acetate, washed successively with water, 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue obtained was purified on preparative thin layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/acetone=20/1) to provide 27 mg of the title compound as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[CH:8][C:9]=2[CH3:11])[S:4][C:3]=1[C:22]([NH2:24])=[O:23].Cl[C:26]([O:29]C(Cl)=O)(Cl)Cl.N>O1CCOCC1.O>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([C:7]2[CH:8]=[C:9]([CH3:11])[C:10]3[C:2]4[NH:1][C:26](=[O:29])[NH:24][C:22](=[O:23])[C:3]=4[S:4][C:5]=3[N:6]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(-c2cc(C)c3c(N)c(C(N)=O)sc3n2)cc1OC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: N
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(C)c3c(n2)sc2c(=O)[nH]c(=O)[nH]c23)cc1OC
Yield: 95.8 %

Procedure:
3.0 g (8.7 mmol) 3-amino-6-(3,4-dimethoxyphenyl)-4-methyl-thieno[2,3-b]pyridine-2-carboxamide is suspended in 100 ml absolute dioxane. Then, 1.1 ml (8.7 mmol) chloroformic acid trichloromethylester (diphosgene) is added and refluxed for 3 h. Following cooling, the precipitate is sucked off and then suspended in 50 ml water. The suspension is adjusted to pH 8 using concentrated ammonia solution and the precipitate is sucked off, washed with some water, suck dried and in vacuo at 50° C. 3.08 g (96%) 7-(3,4-dimethoxyphenyl)-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-2,4-dione is obtained.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:12]=[C:13]([C:14]([OH:16])=O)[C:8]=2[C:7]([CH3:25])=[N:6]1)([CH3:4])[CH3:3].[NH2:26][CH2:27][C:28]1[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:4][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:12]=[C:13]([C:14]([NH:26][CH2:27][C:28]3[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=3[CH3:34])=[O:16])[C:8]=2[C:7]([CH3:25])=[N:6]1)([CH3:1])[CH3:3]
Reactant: COc1ccc(-c2cc(C(=O)O)c3c(C)nn(C(C)(C)C)c3n2)cc1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COc1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3c(C)nn(C(C)(C)C)c3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(1,1-dimethylethyl)-3-methyl-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (70 mg, 0.206 mmol) in DMSO (1 mL) were added 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (19.10 mg, 0.101 mmol), N-methylmorpholine (0.030 mL, 0.270 mmol), 1-hydroxy-7-azabenzotriazole (18.37 mg, 0.135 mmol) and EDC (25.9 mg, 0.135 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (10 mL), stirred for 10 min., and filtered. The contents were dried under high vacuum and collected as 71 mg (71%). LCMS E-S (M+H)=474.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79 (s, 9 H), 2.12 (s, 3 H), 2.25 (s, 3 H), 2.39 (s, 3 H), 3.33 (s, 1 H), 4.38 (d, J=4.80 Hz, 2 H), 5.88 (s, 1 H), 7.10 (d, J=8.84 Hz, 2 H), 7.61 (s, 1 H), 8.16 (d, J=8.84 Hz, 2 H), 8.70 (s, 1 H), 11.53 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][C:12]2([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:22])[CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:21][C:17]1[CH:16]=[C:15]2[C:20]([C:12]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)([NH:11][C:4]3[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=3[C:6]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:7])[C:13](=[O:22])[NH:14]2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc(Cl)cc1NC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1NC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
The mixture of 4-chloro-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid (23 mg, 0.05 mmol), morpholine (26 mg, 0.3 mmol) and EDCl (15 mg, 0.08 mmol) in dichloromethane (1 mL) was stirred at room temperature for overnight. The crude was then purified with chromatography to give 22 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-[5-chloro-2-(morpholine-4-carbonyl)-phenylamino]-1,3-dihydro-indol-2-one as a white solid. MS: [M+H]+=530.
Reaction SMILES: O=[C:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=O>CC(O)C.O.O.[Na+].Cl[Au-](Cl)(Cl)Cl>[F:27][C:24]1[CH:23]=[C:22]2[C:21](=[CH:26][CH:25]=1)[N:20]=[C:2]([CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4])[C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[C:28]2[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cc1ccccn1
Reactant: Nc1ccc(F)cc1C(=O)c1ccccn1
Agent: Cl[Au-](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2c(-c2ccccn2)c1-c1ccccn1
Temperature: 25 °C
Reaction time: 71 h
Yield: 58.9 %

Procedure:
A mixture of (S)-tert-butyl 3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate (0.427 g, 1.615 mmol), (2-amino-5-fluorophenyl)(pyridin-2-yl)methanone (0.384 g, 1.777 mmol), and sodium tetrachloroaurate(III) dihydrate (0.032 g, 0.081 mmol) in 2-propanol (9.50 mL) was heated under reflux. After 71 h, the mixture was cooled to rt and evaporated to dryness. The mixture was dissolved in DCM (50 mL) and washed with brine (1×50 mL), and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography eluting with a gradient of 0% to 50% EtOAc in hexane, to provide tert-butyl 1-(6-fluoro-3,4-di(pyridin-2-yl)quinolin-2-yl)ethylcarbamate (0.423 g, 0.952 mmol, 58.9% yield) as orange syrupy solid: LC-MS (ESI) m/z 445.1 [M+H]+. The orange syrupy solid was used without further purification. Epimerization occurred during the condensation.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][S:7](=[O:10])(=[O:9])[CH2:8][C:4]=2[CH:3]=1.[CH:13]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:14]=1.C([Si](C)(C)C)=C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:13]([C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][S:7](=[O:10])(=[O:9])[CH2:8][C:4]=2[CH:3]=1)=[CH2:14]
Reactant: O=S1(=O)Cc2ccc(Br)cc2C1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: C=C[Si](C)(C)C
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(c1)CS(=O)(=O)C2

Procedure:
Under classical Heck reaction conditions, 5-Bromo-1,3-dihydro-benzo(c)thiophene 2,2-dioxide was transformed with PPh3, Pd(OAc)2, TEA, and vinyltrimethylsilane at 90° C. in DMF. The crude product was extracted with CH2Cl2 and concentrated. Deprotection in CH2Cl2/TFA gave the pure product after purification with flash chromatography (CH2Cl2) in high yields.
Reaction SMILES: C(O)C.[NH2:4][OH:5].[CH3:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:33])[N:22]([CH:24]([C:29]([NH:31][CH3:32])=[O:30])[C:25](OC)=[O:26])[CH3:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>O1CCCC1>[OH:5][NH:4][C:25](=[O:26])[CH:24]([N:22]([C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH3:6])=[CH:14][CH:13]=2)=[CH:16][CH:17]=1)=[O:33])[CH3:23])[C:29]([NH:31][CH3:32])=[O:30]
Reactant: NO
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccc(COC)cc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)C(C(=O)NO)N(C)C(=O)c1ccc(-c2ccc(COC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
Ethanol (5.0 mL) and a 50% aqueous solution (5.0 mL) of hydroxylamine were added to a tetrahydrofuran (5.0 mL) solution of 4-(methoxymethyl)-4′-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (0.40 g) as obtained in Example 3-(4), and the mixture was stirred for 2 hours at room temperature. Then, the reaction mixture was concentrated under reduced pressure, and purified by preparative silica gel thin-layer chromatography (chloroform/methanol=85/15). IPE was added, and the precipitated solid was filtered off and dried to obtain N-hydroxy-2-[{[4′-(methoxymethyl)biphenyl-4-yl]carbonyl}(methyl)amino]-N′-methylpropanediamide (Compound 4, pink solid) (0.18 g, 46%).
Reaction SMILES: C(N(CC)[C:4]([C:6]1[CH:11]=[CH:10]C=C[C:7]=1[S:12]([C:14]1[C@H:15]([CH3:45])[C@@H:16]2[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=O)C.[N+:48]([C:51]1C=CC(CS)=C[CH:52]=1)([O-:50])=[O:49]>>[Si:37]([O:36][C@@H:34]([C@H:33]1[C:32](=[O:44])[N:17]2[C:18]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])=[C:14]([S:12][CH2:7][C:6]3[CH:4]=[CH:52][C:51]([N+:48]([O-:50])=[O:49])=[CH:10][CH:11]=3)[C@H:15]([CH3:45])[C@H:16]12)[CH3:35])([C:40]([CH3:42])([CH3:43])[CH3:41])([CH3:38])[CH3:39]
Reactant: O=[N+]([O-])c1ccc(CS)cc1
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12
Yield: 88 %

Procedure:
Following a procedure similar to that described in Example 21(b), but using 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 39) and 4-nitrobenzylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 88%.