Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[O:8][N:7]=1>CO.CCOCC>[CH3:1][O:2][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[O:8][N:7]=1
Reactant: Cc1cc(CCl)no1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COCc1cc(C)on1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.3 %

Procedure:
Sodium methoxide (30% in methanol, 7.46 mmol) was added to 3-chloromethyl-5-methyisoxazole (491 mg, 3.73 mmol) in methanol (4 mL) at room temperature under nitrogen. The reaction mixture was stirred for 15 h at room temperature then heated to reflux for 3 h. After cooling to room temperature the reaction was diluted with ether (75 mL) and washed with saturated aqueous ammonium chloride (15 mL), water (15 mL), and brine (15 mL). The organic layer was dried over magnesium sulfate, filtered, and evaporated to provide 362 mg (76% yield) of 3-methoxymethyl-5-methyl isoxazole as a clear liquid which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ ppm 6.02 (s, 1H), 4.48 (s, 2H), 3.38 (s, 3H), 2.42 (d, J=0.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9](O)=[C:8]([Cl:14])[CH:7]=1.[O:16]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]O)=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:14][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH:3]=[C:2]([Cl:15])[Cl:1])[CH:11]=[C:10]([Cl:12])[C:9]=1[CH2:27][C:26]1[CH:29]=[CH:30][C:23]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:24][CH:25]=1
Reactant: OCc1ccc(Oc2ccccc2)cc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(Cc2ccc(Oc3ccccc3)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
To a solution of 0.46 g of 4-(3,3-dichloro-2-propenyloxy)-2,6-dichlorophenol, 0.32 g of p-phenoxybenzyl alcohol and 0.46 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.35 g of diisopropylazodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was concentrated, and then mixed with 20 ml of diethyl ether. The precipitate was filtered, and the filtrate was concentrated. The residue was subjected to silica gel chromatography, which afforded 0.51 g of 3,5-dichloro-4-(4-phenoxybenzyl)-1-(3,3-dichloro-2-propenyloxy)benzene (68% yield), nD25.5 1.6084.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:29]=[CH:28][O:27][CH:26]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:29]=[CH:28][O:27][CH:26]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: Brc1ccoc1
Product: OC1(c2ccoc2)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 71 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3-bromofuran, the title compound was formed in 71% yield as a white solid, mp 275°-276° C. (dec). free base: 1H NMR (CDCl3, 300 MHz) 7.36 (m, 2H), 7.23 (dd, J=2.5, 5.6 Hz, 2H), 7.17 (dd, J=2.0, 5.4 Hz, 2H), 6.93 (m, 4H), 6.40 (m, 1H), 4.27 (s, 1H), 3.44 (s, 2H), 2.80 (m, 2H), 2.70 (dt, J=2.8, 11.2 Hz, 2H), 2.60 (d, J=1.5 Hz, 2H), 1.99 (dt, J=4.2, 12.1 Hz, 2H), 1.80 (m, 2H), 1.55 (s, 1H) MS (CI, CH4) m/z 372 (M+1,100), 400 (M+29,21), 354 (57), 180 (16) hydrochloride salt:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:12]=[CH:11][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1.[Br:20]N1C(=O)CCC1=O>ClC1C=CC=CC=1.CO.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:20][CH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:12]=[CH:11][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1
Reactant: Cc1cc2c3ccccc3ccc2c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Solvent: CO
Product: BrCc1cc2c3ccccc3ccc2c2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
A solution of 6-methylchrysene (4,85 g, 20 mmol), N-bromosuccinimide (3.60 g, 20.2 mmol), and benzoyl peroxide (0.242 g, 1.0 mmol) in chlorobenzene (100 mL) was heated under nitrogen at 80° C. After 1 hour, NMR analysis indicated that the starting material had been consumed. The solution was cooled to 50° C. at which point a solid precipitate had formed. The mixture was diluted with methanol (100 mL) and further cooled to ambient temperature. The mixture was filtered and the solid washed with methanol to give 4.87 g (76% yield) of 6-bromomethylchrysene. 1H NMR (CDCl3) 5.17 (s, 2H), 7.25 (m, 4 H), 8.0 (t, J=8.7 Hz, 2 H), 8.31 (m, 1 H), 8.67 (d, J=9.0 Hz), 8.75 (d, J=9.0 Hz, 1 H), 8.81 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=4)=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
To a mixture of (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 6, Step A; 30 mg, 0.1 mmol), nicotinic acid (25 mg, 0.2 mmol), and HATU (77 mg, 0.2 mmol) was added 0.7 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.053 mL, 0.3 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 3 hours. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 57% acetonitrile/water to yield the final product as a yellowish solid (30 mg, 74% yield). MS (apci) m/z=403.2 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Clc1ccc(Br)nc1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6′-methyl-[2,3′-bipyridin]-2′-yl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 436 (M+H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][O:17][C:18]2[C:19]([C:24](O)=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:10])[CH2:5][CH2:4]1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[N:42]1[N:43]=[C:44]([NH2:47])[NH:45][CH:46]=1>ClCCl.CN(C)C=O>[N:42]1[N:43]=[C:44]([NH:47][C:24](=[O:25])[C:19]2[C:18]([O:17][CH2:16][C@H:12]3[CH2:13][CH2:14][CH2:15][N:11]3[C:9]([C@H:6]3[CH2:5][CH2:4][C@H:3]([C:2]([F:27])([F:1])[F:28])[CH2:8][CH2:7]3)=[O:10])=[CH:23][CH:22]=[CH:21][N:20]=2)[NH:45][CH:46]=1
Reactant: O=C(O)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: Nc1nnc[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nnc[nH]1)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid (30 mg, 0.08 mmol, EXAMPLE 34 Step 3) in dichloromethane (1 mL) were added oxalyl chloride (33 microL, 0.38 mmol) and a catalytic amount of N,N-dimethylformamide at room temperature. After being stirred at room temperature for 30 min, the volatile was removed under reduced pressure. The resulting residue was dissolved in toluene (1 mL). Triethyl amine (10 microL, 0.08 mmol) and 4H-1,2,4-triazol-3-amine (8 mg, 0.09 mmol) were added to the mixture. After being refluxed for 15 h, the volatile was removed by evaporation. The residual material was dissolved in dichloromethane. The organic layer was washed with aq. sodium bicarbonate and concentrated in vacuo to afford the title compound as a brown oil. The crude product was purified by preparative HPLC.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([Cl:21])[N:9]=2)[CH3:5])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.C(Cl)Cl.CO>[Cl:21][C:10]1[N:9]=[C:8]2[C:13]([N:14]=[C:6]([CH:4]([NH2:1])[CH3:5])[N:7]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=1
Reactant: CC(N=[N+]=[N-])c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(N)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: 70 °C

Procedure:
To a solution of 8-(1-azido-ethyl)-2-chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purine (0.47 g, 1.20 mmol) in THF (13 mL) and water (4 mL) was added triphenylphosphine (0.33 g, 1.28 mmol). The reaction mixture was heated at 70° C. for 2 h, then cooled to RT. Ethyl acetate was added and the phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic fractions were dried (Na2 SO4), filtered and concentrated in vacuo. The resulting residue, together with crude product from a reaction performed similarly on a smaller scale (0.05 g, 0.14 mmol of 8-(1-azido-ethyl)-2-chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purine), was subjected to flash chromatography (SiO2) gradient 0-10% methanol in DCM). Eluted material containing title compound and triphenylphosphine oxide was subjected to flash chromatography (SiO2) gradient 0-20% methanol in TBME), and clean material from the two columns was combined to give 1-[2-Chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-ethylamine (0.41 g, 84%, mixture of two pairs of diastereomers). LCMS RT=2.15 min and 2.19 min, [M+H]+=367/369
Reaction SMILES: N(C1N(CC(C)C)C(=O)N(C)C(=O)C=1)N.ClC1C=C2C(=CC=1)NC=C2C=O.C(C1C=C(C=O)N(C)C=1)(=O)C.[C:39]([C:42]1[CH:43]=[C:44]([C:48]2[N:49]([CH2:64][C:65]3[C:73]4[C:68](=[CH:69][CH:70]=[C:71]([Cl:74])[CH:72]=4)[NH:67][CH:66]=3)[N:50]=[C:51]3[C:56]=2[C:55](=[O:57])[N:54]([CH3:58])[C:53](=[O:59])[N:52]3[CH2:60][CH:61]([CH3:63])[CH3:62])[N:45]([CH3:47])[CH:46]=1)(=O)[CH3:40].Cl.[CH3:76][O:77][NH2:78]>>[Cl:74][C:71]1[CH:72]=[C:73]2[C:68](=[CH:69][CH:70]=1)[NH:67][CH:66]=[C:65]2[CH2:64][N:49]1[C:48]([C:44]2[N:45]([CH3:47])[CH:46]=[C:42](/[C:39](=[N:78]/[O:77][CH3:76])/[CH3:40])[CH:43]=2)=[C:56]2[C:51]([N:52]([CH2:60][CH:61]([CH3:62])[CH3:63])[C:53](=[O:59])[N:54]([CH3:58])[C:55]2=[O:57])=[N:50]1
Reactant: CC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1
Reactant: CON
Agent: CC(=O)c1cc(C=O)n(C)c1
Agent: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Agent: Cl
Product: CO/N=C(\C)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first 5-chloro-1H-indole-3-carbaldehyde, followed by 4-acetyl-1-methyl-1H-pyrrole-2-carbaldehyde. To the isolated 3-(4-acetyl-1-methyl-1H-pyrrol-2-yl)-2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione was added 4 equivalents of methoxyamine hydrochloride, triethylamie and heated at 80° C. in N,N′dimethylacetamide for 4 h. The mixture was stirred at room temperature for 4 h. The crude reaction product was purified by semi-prep RPHPLC eluting with water/acetonitrile/trfluoroacetic acid mixtures. 536.2 (M+H).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH:15]=[CH:14][C:13]2[CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].O>C(O)C.O1CCOCC1.[Fe]>[CH2:1]([NH:8][CH:9]1[CH:15]=[CH:14][C:13]2[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C=CC(NCc1ccccc1)CC2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc2c(c1)C=CC(NCc1ccccc1)CC2
Yield: 92.6 %

Procedure:
A solution of N-benzyl-6,7-dihydro-2-nitro-5H-benzocyclohepten-7-amine (3.03 g) in ethanol (19 ml) and dioxane (19 ml) was added dropwise to a stirred mixture of iron powder (3.03 g) and ammonium chloride (0.36 g), in ethanol (15 ml), dioxane (15 ml), and water (15 ml) under reflux over 20 minutes. The resulting mixture was stirred under reflux for 20 minutes and the hot reaction mixture was filtered. The filtrate was evaporated in vacuo and the residue was partitioned between ethyl acetate and sodium bicarbonate aqueous solution. The organic layer was washed with brine, dried over magnesium sulfate, evaporated in vacuo, and chromatographed over silica gel using dichloromethane and methanol to afford N7 -benzyl-6,7-dihydro-5H-benzocyclohepten-2,7-diamine (2.52 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH:18]=[C:19]([CH3:21])[O:20][C:16]=3[C:15]([C:22](O)=[O:23])=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C1COCC1.[F:53][C:54]1[CH:61]=[CH:60][C:57]([CH2:58][NH2:59])=[CH:56][CH:55]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH:18]=[C:19]([CH3:21])[O:20][C:16]=3[C:15]([C:22]([NH:59][CH2:58][C:57]3[CH:60]=[CH:61][C:54]([F:53])=[CH:55][CH:56]=3)=[O:23])=[CH:14][C:12]=2[N:13]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1cc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cncc3Cl)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc2c(o1)c(C(=O)NCc1ccc(F)cc1)cc1nc(Nc3c(Cl)cncc3Cl)[nH]c12
Yield: 19.5 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7-methyl-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-8, 0.060 g, 0.159 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.102 g, 0.318 mmol), TEA (0.032 g, 0.318 mmol), THF (5.0 mL), DMF (1.0 mL), 4-fluoro benzyl amine (0.035 g, 0.318 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 2.49 (s, 3H), 4.55 (d, J=5.4 Hz, 2H), 6.22 (s, 1H), 7.13-7.16 (m, 2H), 7.41 (m, 3H), 8.44 (s, 2H), 8.61 (s, 1H), 11.22 (s, 1H), 11.76 (s, 1H); MS [M+H]+: 484.24.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][N:16]([CH2:24][CH:25]([CH3:27])[CH3:26])C(=O)OC(C)(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][NH:16][CH2:24][CH:25]([CH3:27])[CH3:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)CN(OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CNOCc1ccccc1
Yield: 101.2 %

Procedure:
Trifluoroacetic acid (21 mL, 270 mmol) was added in a single portion to a solution of tert-butyl N-benzyloxy-N-(2-methylpropyl)carbamate (7.6 g, 27 mmol) in methylene chloride (21 mL). A spontaneous reflux occurred. The reaction mixture was stirred without external heating for 20 minutes and then concentrated under vacuum at 45° C. Saturated aqueous sodium bicarbonate was added to the residue followed by a quantity of solid sodium bicarbonate sufficient to bring the pH of the reaction mixture up to a value of 9. The mixture was extracted twice with methylene chloride. The extracts were combined, dried over magnesium sulfate then concentrated under vacuum to provide 4.9 g of N-benzyloxy-N-(2-methylpropyl)amine as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[N:2]1.CC([O-])(C)C.[K+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][CH:21]=1>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=3)[CH:3]=[N:2]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=Cc1ccc2cn[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3ccc(C=O)cc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
To a solution of 1H-indazole-6-carbaldehyde (1.5 g, 10.3 mmol) in DMF (10 mL) at 0° C. was added KOtBu (1.4 g, 12.4 mmol) and let stir for 10 min. PMBCl (1.7 mL, 12.4 mmol) was then added and let slowly warm to room temperature. After 1.5 h the reaction was quenched with NH4Cl. The product was extracted with Et2O and the organic layers was washed brine and then dried over MgSO4. The solvent was removed and the crude material (mixture of N1 and N2 isomers) was dried under high vacuum. To the resulting residue was added PMBCl (0.70 mL, 5.15 mmol) and the mixture heated to 170° C. for 2.5 h. Cooled to room temperature and purified residue using Biotage Isolera (silica gel, 20-50% EtOAc in hexane) which gave the title compound (1.97 g, 72%). 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 5.62 (s, 2H), 3.77 (s, 3H); MS ESI 266.9 [M+H]+, calcd for [C16H14N2O2+H]+ 267.1.
Reaction SMILES: C([O:8][C@@H:9]([CH2:38][O:39]CC1C=CC=CC=1)[CH2:10][C:11]1([S:14]([NH:17][C:18]2[C:26]3[O:25][CH:24]=[CH:23][C:22]=3[C:21]([F:27])=[C:20]([F:28])[C:19]=2[NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])(=[O:16])=[O:15])[CH2:13][CH2:12]1)C1C=CC=CC=1.B(Cl)(Cl)Cl.Cl.CCCCCCC>C(Cl)Cl.C(OCC(C)C)(=O)C>[F:27][C:21]1[C:22]2[CH:23]=[CH:24][O:25][C:26]=2[C:18]([NH:17][S:14]([C:11]2([CH2:10][C@@H:9]([OH:8])[CH2:38][OH:39])[CH2:12][CH2:13]2)(=[O:15])=[O:16])=[C:19]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])[C:20]=1[F:28]
Reactant: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12)C1(C[C@H](COCc2ccccc2)OCc2ccccc2)CC1
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: CCCCCCC
Solvent: CC(=O)OCC(C)C
Solvent: ClCCl
Product: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12)C1(C[C@@H](O)CO)CC1
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To a solution of (R)-1-(2,3-bis(benzyloxy)propyl)-N-(4,5-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-7-yl)cyclopropane-1-sulfonamide (140 g, 183.6 mmol) in DCM (700 mL) was added 1M BCl3 solution in DCM (1.8 L, 1.84 mol) at −65-70° C. The mixture was stirred at −65˜−70° C. for 30 minutes until HPLC analysis showed the reaction had gone to completion. The cold solution was added to 1N HCl solution (1.8 L) at below 15° C., stirred for 15 mins and separated. The DCM layer was washed with water (2 L), the brine (1.5 L). DCM layer was concentrated to ˜250 mL and filtered to give white solid. The solid was dissolved in isobutyl acetate (240 mL) and heptane (500 mL) was added. The suspension was stirred overnight, filtered and dried to give 70 g of (R)—N-(4,5-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-7-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide with 98.4% purity (65.5% yield, ee>99%).
Reaction SMILES: [OH:1][CH:2]([CH2:8][NH:9][OH:10])[CH2:3][P:4](=[O:7])([OH:6])[OH:5].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][C:17](Cl)=[O:18].C(=O)(O)[O-].[Na+].[OH-].[Na+].Cl>O.CO>[OH:1][CH:2]([CH2:8][N:9]([OH:10])[C:17](=[O:18])[CH2:16][C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)[CH2:3][P:4](=[O:6])([OH:5])[OH:7]
Reactant: O=C(Cl)Cc1cccs1
Reactant: O=P(O)(O)CC(O)CNO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(Cc1cccs1)N(O)CC(O)CP(=O)(O)O
Temperature: 25 °C
Yield: 100 %

Procedure:
2-Hydroxy-3-(N-hydroxyamino)propylphosphonic acid (342 mg) was dissolved in a mixture of water (7 ml) and methanol (3 ml). To the solution was added dropwise thienyl acetyl chloride (385 mg) with stirring under ice-cooling, while maintaining the solution at pH 7.2-7.4 with 5% aqueous sodium bicarbonate solution. After the reaction mixture was stirred under ice-cooling for 1.5 hours, the mixture was adjusted to pH 10 with 1 N aqueous sodium hydroxide solution, and stirred under ice-cooling for 2 hours and at ambient temperature for 3 hours. Subsequently, the resultant mixture was adjusted to pH 4.0 with 1N hydrochloric acid, washed with diethyl ether (40 ml) and concentrated under reduced pressure. To the residue was added methanol to give insoluble materials, which was removed by filtration. The filtrate was concentrated under reduced pressure. To the residue was added ethanol (20 ml) and the mixture was stirred at ambient temperature for an hour to give precipitates, which were separated by filtration and dried to give powdery 2-hydroxy-3-(N-hydroxy-N-thienylacetylamino)propylphosphonic acid (0.59 g).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH3:32])[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][CH:34]1[C:41](=[O:42])[N:40]2[CH:35]1[S:36][CH2:37][C:38]([CH3:59])=[C:39]2[C:43]([O:45][CH:46]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>C(Cl)Cl>[CH:46]([O:45][C:43]([C:39]1[N:40]2[CH:35]([S:36][CH2:37][C:38]=1[CH3:59])[CH:34]([NH:33][C:27](=[O:29])[C:26](=[N:30][O:31][CH3:32])[C:24]1[N:25]=[C:21]([NH:20][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:22][CH:23]=1)[C:41]2=[O:42])=[O:44])([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)C2SC1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.25 h

Procedure:
A solution of 2-(2-tritylamino-thiazol-4-yl)-2-methoxyimino-acetic acid (syn isomer) (7.2 g) in methylene chloride (22.4 cc) is added, in a single shot, to a solution of 7-amino-2-benzhydryloxycarbonyl-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (3.15 g) in methylene chloride (31.5 cc). The temperature rises from 8° to 14° C. The mixture is kept stirred for one hour 15 minutes, during which the temperature rises to 20° C., and is then washed with 0.5 N hydrochloric acid (10 cc), distilled water (10 cc) and a saturated sodium bicarbonate solution (20 cc). The insoluble matter formed is filtered off, and the organic phase is washed again with distilled water (2×20 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg) at 40° C. The residue is chromatographed on a column (diameter: 3 cm, height: 33 cm) containing silica gel (125 g), elution being carried out with a 20:80 (by volume) mixture of ethyl acetate and cyclohexane (1.2 liters) and then with a 40:60 (by volume) mixture (1 liter), and 50 cc fractions of eluate being collected. Fractions 31 to 44 are evaporated and 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylamino-thiazol-4yl)-acetamido]-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene, syn isomer (2.8 g) is obtained in the form of a pale yellow solid.