Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: COc1ccc(-c2cc(O)nc(N)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc(Cl)nc(N)n2)cc1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 75 %

Procedure:
A mixture of compound 2-amino-6-(4-methoxy-phenyl)-pyrimidin-4-ol (18 g, 83 mol) obtained in step (ii) and phosphorus oxychloride (POCl3) (150 mL) was stirred at 100° C. under anhydrous condition for 5 to 8 hours. The initial turbidity disappeared after completion of the reaction and excess phosphorus oxychloride was then removed by distillation under low vacuum. The residue was diluted with aqueous sodium bicarbonate solution to reach the pH˜7-8. The white solid separated was filtered, washed with water, and dried under vacuum to afford the desired product (15 g). Yield: 75%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(N(CCCC)CCCC)CCC.[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[CH:26]=[CH2:27]>CN(C=O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pd+2]>[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1/[CH:27]=[CH:26]/[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(Cl)cc1Br
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Cl)cc1/C=C/C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
To a degassed solution of 1-(2-bromo-4-chlorophenyl)ethanone (1.0 g, 4.28 mmol), tributylamine (2.041 mL, 8.57 mmol), and tert-butyl acrylate (1.255 mL, 8.57 mmol) in DMF (10 mL) was added palladium on carbon (0.456 g, 0.428 mmol) and Pd(OAc)2 (0.096 g, 0.428 mmol). The reaction mixture was warmed to 100° C. After 16 h, the reaction was cooled to rt. The reaction was filtered and the solid was rinsed with DMF. The filtrate was diluted with EtOAc, washed with H2O (2×), brine, dried over Na2SO4, filtered and concentrated. Purification by normal phase chromatography afforded Intermediate 4A (0.760 g, 63%), as a brown oil. MS (ESI) m/z: 225.0 (M-C4H8+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[C:22]=1[CH3:23].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=[O:37].[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:25][C:24]([F:27])([F:26])[C:11]([OH:15])=[O:37].[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([C:24]([F:26])([F:27])[F:25])[C:22]=4[CH3:23])[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1c(Br)cncc1C(F)(F)F
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Reactant: O=P([O-])([O-])[O-]
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c(N2CCN(c3ccc4ncsc4c3)C2=O)cncc1C(F)(F)F
Product: O=C(O)C(F)(F)F
Yield: 3.6 %

Procedure:
1-Benzothiazol-6-yl-imidazolidin-2-one (I-84b: 80 mg, 0.365 mmol) was reacted with 3-bromo-4-methyl-5-trifluoromethyl-pyridine (I-189a: 90 mg, 0.365 mmol), 1,4-dioxane (5 mL), copper iodide (6.95 mg, 0.0365 mmol), trans-1,2-diamino cyclohexane (12.5 mg, 0.1095 mmol) and potassium phosphate (232.4 mg, 1.095 mmol) to afford the crude product. Purification by preparative HPLC afforded Sing of the product (3.6% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=O)[C:13]([N:15]([CH3:30])[N:16]=[C:17]([CH3:29])[CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[O:14])[CH3:2].C1(C)C=CC=CC=1.O.[OH-].[Li+].S(=O)(=O)(O)O>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:14])[N:15]([CH3:30])[N:16]=[C:17]([CH3:29])[C:18]=1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(=O)(=O)c1ccc(C)cc1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCc1cc(C)cc(CC)c1-c1c(S(=O)(=O)c2ccc(C)cc2)c(C)nn(C)c1=O
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a 10 ml volume two-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-1-methyl-2-oxoacetyl]-2-[1-(4-methylphenylsulfonyl)-2-propylidene]hydrazine ((4-36)-(1)-39) (809 mg), toluene (2.3 ml), and methanol (0.5 ml) were added. To the mixture, lithium hydroxide monohydrate (77 mg) was added at 0° C., stirred for 4 hours, and left to stand at 5° C. for 16 hours. The pH of the mixture was adjusted to 1 with 20 w/w % of sulfuric acid. The organic layer was removed, and then the aqueous layer was extracted with toluene 2 times. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane: ethyl acetate=3:1) to give 711 mg of 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-(4-methylphenylsulfonyl)-2,3-dihydro-3-pyridazinone ((2-36)-(1)-39).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[O:25]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:35]3[CH:36]=[CH:37][C:32]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:33][CH:34]=3)[C:3]=12
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2nc(I)c3c(N)ncnc32)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 90 °C
Reaction time: 24 h
Yield: 63.9 %

Procedure:
A mixture of tert-butyl 3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (1 g, 2.25 mmol, 1.00 equiv), (4-phenoxyphenyl)boronic acid (530 mg, 2.48 mmol, 1.10 equiv), sodium carbonate (480 mg, 4.53 mmol, 2.01 equiv) and tetrakis(triphenylphosphine)palladium (78 mg, 0.07 mmol, 0.03 equiv) in 1,4-dioxane (60 mL) and water (15 mL) was stirred under nitrogen at 90° C. for 24 h. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was dissolved in 500 mL of dichloromethane. The resulting solution was washed with 200 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 700 mg (64%) of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([N:25]=[N+:26]=[N-:27])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28]([O:30][C:31](=[O:38])[CH:32]=[C:33](NC)NC)[CH3:29]>O1CCOCC1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([N:25]5[CH:33]=[C:32]([C:31]([O:30][CH2:28][CH3:29])=[O:38])[N:27]=[N:26]5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N=[N+]=[N-])ccc32)n1)c1ccccc1
Reactant: CCOC(=O)C=C(NC)NC
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)ncn3-c2ccnc(N[C@@H](C)c3ccccc3)n2)nn1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A solution containing 12.5 mg of 2-[(S)-1-phenylethylamino]-4-[5-azidobenzimidazol-1-yl]pyrimidine and about 100 μL ethyl-3,3-dimethylaminoacrylate in 2 mL 1,4-dioxane was stirred at 90° C. for 48 hours. The solution was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with methanol in methylene chloride to give 6.0 mg of the title compound. RF: 0.4 (5% MeOH in CH2Cl2). 1H NMR (500 MHz, 1:1 CD3OD/CDCl3): δ 1.42 (t, J=7.1 Hz, 3H), 1.59 (d, J=7.1 Hz, 3H), 4.44 (q, J=7.1 Hz, 2H), 5.16 (m, 1H), 6.92 (d, J=5.5 Hz, 1H), 7.24 (br s, J=7.3 Hz, 1H), 7.36 (br s, J=7.3 Hz, 2H), 7.45 (d, J=7.3 Hz, 2H), 7.68-7.8 (m, 1H), 7.95 (m, 1H), 8.14 (br s, 1H), 8.38 (br s, J=5.3 Hz, 1H), 8.77 (m, 1H), 8.92 (s, 1H). Mass Spectrum (CH3CN-TFA-NH4HCO2-ESI): 455.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][N:11]=[N:10]1.[C:14]([Cu])#[N:15]>CN1C(=O)CCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[N:15])=[C:3]([N:9]2[CH:13]=[CH:12][N:11]=[N:10]2)[CH:4]=1
Reactant: Fc1ccc(Br)c(-n2ccnn2)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(F)cc1-n1ccnn1
Yield: 60.8 %

Procedure:
A mixture of 1-(2-bromo-5-fluorophenyl)-1H-1,2,3-triazole (0.603 g, 2.49 mmol), CuCN (0.245 g, 2.74 mmol), and 15 mL of NMP was subjected to microwave irradiation at 150° C. for 0.5 h. The brown mixture was filtered over celite and washed with DMF. This solution was treated with 10% aqueous NH4OH (28-30% solution) and extracted with EtOAc. The combined organic phase were successively washed with 10% aqueous NH4OH (28-30% solution), saturated aqueous NH4Cl, water, brine and dried over Na2SO4. The resulting mixture was concentrated in vacuo and the residue was purified with a Biotage system on silica gel with hexanes:ethyl acetate (7:3 to 6:4) gradient as the eluent to afford the title compound as a light yellow solid (0.285 g, 61% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 8.40 (1H, d, J=1.0 Hz), 7.96 (1H, s), 7.91 (1H, dd, J=8.6, 5.6 Hz), 7.77 (1H, dd, J=8.7, 2.4 Hz), 7.31-7.39 (1H, m).
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.O=[C:28]([CH2:34][C:35](=O)[CH3:36])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[N:26]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:34]=[C:35]([CH3:36])[N:25]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: CCOC(=O)c1cc(C)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 170 °C
Yield: 62.3 %

Procedure:
A mixture of N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (371 mg, 1.0 mmol), ethyl 2,4-dioxo-pentanoate (158 mg, 1.0 mmol) and potassium carbonate (69 mg, 0.5 mmol) in ethanol (2 mL) was heated in a sealed tube in a microwave oven to 170° C. for 0.5 h. The mixture was cooled, diluted with ethyl acetate (50 mL), and then washed with water (20 mL) and with brine (20 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using dichloromethane/0-10% methanol as eluent to give the title compound (229 mg, 62%) as a yellow solid. MS ISP (m/e): 368.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.04 (d, 1H), 7.64 (s, 1H), 7.40 (s, 1H), 7.34 (s, 1H), 7.17 (d, 1H), 6.98 (dd, 1H), 6.87 (s, 1H), 4.46 (q, 2H), 3.91 (s, 3H), 2.54 (s, 3H), 2.30 (s, 3H), 1.43 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][CH2:27][C:28]1[C:29]([NH2:43])=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)[CH3:25]>>[NH2:43][C:29]1[N:30]=[CH:31][C:32]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:33][C:28]=1[CH2:27][O:26][CH2:24][CH3:25]
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCOCc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Product: CCOCc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1N

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-ethoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (Stage 166.1.1) to give the title compound as a white solid. (HPLC: tR 2.17 min (Method A); M+H=444 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.13 (s, 1H), 8.08-8.06 (m, 1H), 8.05-8.01 (m, 1H), 7.86-7.82 (m, 1H), 7.49-7.47 (m, 1H), 7.44-7.42 (m, 1H), 6.02 (s, br, 2H), 4.37 (s, 2H), 3.92 (s, 3H), 3.57 (s, 3H), 3.51 (q, 2H), 1.95 (s, 3H), 1.18 (t, 3H))
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:30]=[C:29]([C:31]([NH:33][CH2:34][CH2:35][OH:36])=[O:32])[NH:28][C:27]=1[C:37]([OH:39])=O.[NH2:40][CH2:41][C:42]1[C:43]([F:59])=[C:44]([O:49][C:50]2[CH:51]=[C:52]([CH:55]=[C:56]([Cl:58])[CH:57]=2)[C:53]#[N:54])[C:45]([Cl:48])=[CH:46][CH:47]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:25][C:26]1[CH:30]=[C:29]([C:31]([NH:33][CH2:34][CH2:35][OH:36])=[O:32])[NH:28][C:27]=1[C:37]([NH:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([O:49][C:50]2[CH:51]=[C:52]([C:53]#[N:54])[CH:55]=[C:56]([Cl:58])[CH:57]=2)[C:43]=1[F:59])=[O:39]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(NCCO)c1cc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C(=O)NCCO)cc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added to a DMF (2 mL) solution of 3-chloro-5-{[(2-hydroxyethyl)amino]carbonyl}-1H-pyrrole-2-carboxylic acid (0.037 g, 0.161 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), and DIPEA (0.028 mL, 0.161 mmol). This solution was stirred overnight at RT. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with a 15% solution of Na2CO3, dried over MgSO4, filtered and evaporated. The residue was subjected to silica gel column chromatography (EtOAc/hexanes) to afford an impure solid. A second purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.014 g, 15%) as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 11.00 (br. s., 1H), 7.86 (d, 1H), 7.63 (s, 1H), 7.33-7.52 (m, 3H), 6.86 (d, 1H), 4.71 (d, 1H), 3.65 (t, 1H), 3.39-3.57 (m, 5H). LCMS: m/z 525.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH:16]=[CH2:17])[O:13][C:5]2=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.[OH2:18].C[N+]1([O-])CC[O:23]CC1>C(O)(C)(C)C.CC(C)=O.O.[Os](=O)(=O)(=O)=O>[OH:18][CH:16]([CH:14]1[O:13][C:5]2=[C:6]3[C:11](=[C:2]([CH3:1])[CH:3]=[C:4]2[CH2:15]1)[NH:10][C:9](=[O:12])[CH:8]=[CH:7]3)[CH2:17][OH:23]
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: C=CC1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(C(O)CO)C2
Temperature: 25 °C
Reaction time: 10 h
Yield: 152.7 %

Procedure:
5-Methyl-2-vinyl-2,3,6,7-tetrahydrofuro-[2,3-f]-quinoline-7-one (1.5 g, 6.61 mmol) was dissolved in a solvent mixture of t-butanol (200 ml), acetone (200 ml) and water (100 ml). A solution (14 ml) of 0.16 N osmium tetraoxide and t-butanol, and N-methyl morpholine N-oxide hydrate (3.57 g, 3.46 mmol) were added to the mixture, and stirred at room temperature for 10 hours. The reaction mixture was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent=chloroform: methanol m 4:1) to obtain crude crystals. The obtained crude crystals were recrystallized from chloroform--methanol--ether to obtain 1.38 g of the title compound as colorless powdery crystals (80.0%).
Reaction SMILES: C([O:4][C:5](=[O:35])[C@@H:6]([C:25]([S:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])([CH3:27])[CH3:26])[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9])C=C.CNC1C=CC=CC=1>C(OCC)(=O)C.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>[F:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([S:8]([NH:7][C@@H:6]([C:5]([OH:35])=[O:4])[C:25]([S:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])([CH3:26])[CH3:27])(=[O:10])=[O:9])=[CH:16][CH:15]=2)=[CH:23][CH:22]=1
Reactant: C=CCOC(=O)[C@H](NS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1)C(C)(C)SCCC(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CNc1ccccc1
Product: COC(=O)CCSC(C)(C)[C@@H](NS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1)C(=O)O
Reaction time: 3 h
Yield: 89 %

Procedure:
To a 0° C. solution of N-[4-(4-fluorophenoxy)benzenesulfonyl]--S--[2-(methoxycarbonyl)ethyl]-D-penicillamine allyl ester (0.36 g, 0.687 mmol) in 5 mL of ethyl acetate was added N-methylaniline followed by Pd(PPh3)4 (16 mg, 0.014 mmol). After 3 hours, the solution was concentrated, and the residue was purified by chromatography on silica gel, eluting first with 1:1 ethyl acetate:hexane and then with 10% methanol in dichloromethane to give N-[4-(4-fluorophenoxy)benzenesulfonyl]--S--[2-(methoxycarbonyl)ethyl]-D-penicillamine as a white solid in 89% yield: mp 123-124° C.; 1H--NMR(CDCl3) δ 1.27 (s, 3H), 1.35 (s, 3H), 2.40-2.82 (m, 4H), 3.71 (s, 3H), 3.94 (d, 1H, J=11 Hz), 5.60 (d, 1H, J=11 Hz), 6.93-7.82 (m, 8H); FAB HRMS: expected (M+Cs)=618.0033. Found (M+Cs)=618.0038
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12]O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>ClCCl>[C:1]([O:5][C:6](=[O:14])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][Br:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)COCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a solution of 17.02 g of 2-(4-hydroxybutyloxy)acetic acid tert-butyl ester in 400 ml of dichloromethane, 24.04 g of triphenylphosphine and 31.78 g of carbon tetrabromide were added. After stirring at room temperature for one hour, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 16.95 g of the desired compound as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:5][C@H:6]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C@H:7]([OH:21])[CH2:8][NH:9][C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[CH:14]=2)[CH2:12][CH2:11]1.[CH2:35](Cl)[CH2:36]Cl.[CH:39]1[CH:40]=C[C:42]2[N:47](O)N=[N:45][C:43]=2[CH:44]=1>CN(C=O)C>[N:47]12[CH2:36][CH2:35][CH:44]([CH2:39][CH2:40]1)[C@H:43]([NH:45][C:27](=[O:29])[CH2:26][CH2:25][CH2:24][C:23]([NH:22][C@@H:6]([CH2:5][C:4]1[CH:31]=[C:32]([F:34])[CH:33]=[C:2]([F:1])[CH:3]=1)[C@H:7]([OH:21])[CH2:8][NH:9][C:10]1([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[CH:14]=3)[CH2:11][CH2:12]1)=[O:30])[CH2:42]2.[CH:27]([OH:29])=[O:28]
Reactant: ClCCCl
Reactant: CCc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)CCCC(=O)O)CC2)c1
Reactant: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)CCCC(=O)N[C@@H]3CN4CCC3CC4)CC2)c1
Product: O=CO
Temperature: 45 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of R-aminoquinuclidine (0.084 g, 0.421 mmol) TEA (0.294 ml, 2.11 mmol), and anhydrous DMF (2.5 ml) was added 5-[((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)amino]-5-oxopentanoic acid (0.200 g, 0.421 mmol), EDC (0.121 g, 0.632 mmol), HOBT (0.085 g, 0.632 mmol) under nitrogen, with stirring at 45° C. overnight. Reaction mixture was quenched with 10% sodium bicarbonate (aq.) then extracted with ethyl acetate then concentrated in vacuo, yielding product (0.122 g). Prep-HPLC yielded the product as its formate salt. (ES+: 583.3)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24]([OH:26])=O)=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]2[C:74]([CH2:77][CH3:78])([CH2:75][CH3:76])[O:73][B:72]([OH:79])[C:71]=2[CH:80]=1>CN(C=O)C>[CH2:77]([C:74]1([CH2:75][CH3:76])[O:73][B:72]([OH:79])[C:71]2[CH:80]=[C:67]([CH2:66][NH:65][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:26])[CH:68]=[CH:69][C:70]1=2)[CH3:78]
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: CCC1(CC)OB(O)c2cc(CN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC1(CC)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(Cl)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.22 mmol) and DIPEA (114 mg, 0.88 mmol) in DMF (5.0 mL) can be stirred at rt for 5 min and then HATU (169 mg, 0.44 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-diethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (113 mg, 0.44 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified on column chromatography and prep-HPLC to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[N:13]=[C:12]([NH2:15])[NH:11][C:10]=2[CH:9]=[C:8](SCC)[CH:7]=1)=[O:5])[CH3:2].[CH:19]1C=C(Cl)C=C(C(OO)=O)[CH:20]=1.C([O-])(O)=O.[Na+].[O-:35][S:36]([O-:39])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[N:13]=[C:12]([NH2:15])[NH:11][C:10]=2[CH:9]=[C:8]([S:36]([CH2:19][CH3:20])(=[O:39])=[O:35])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(SCC)cc2[nH]c(N)nc12
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cc(S(=O)(=O)CC)cc2[nH]c(N)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
0.26 g (1.0 mmol) of 2-amino-6-ethylsulfanyl-1H-benzoimidazole-4-carboxylic acid ethyl ester (See Example 489) in DCM was stirred with 0.35 g (2.0 mmol) of MCPBA and 0.34 g (4.0 mmol) of NaHCO3 at room temperature for 3 h. The reaction mixture was treated with Na2S2O3 solution and stirred for 0.5 h at room temperature. EtOAc extraction, followed by washing with dilute NaOH solution and brine, and evaporation of the solvent produced 0.28 g (0.94 mmol, 94%) of 2-amino-6-ethylsulfonyl-1H-benzoimidazole-4-carboxylic acid ethyl ester. LCMS: 298 (M+1)+.