Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[CH:4]=[C:3]1[C:17]([OH:19])=O.[NH:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[CH:4]=[C:3]1[C:17]([N:20]1[CH2:26][CH2:25][CH2:24][N:23]([C:17]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[C:8]([O:11][CH3:12])[CH:9]=3)=[O:19])[CH2:22][CH2:21]1)=[O:19]
Reactant: COc1cc2c(cc(C(=O)O)n2C)c(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc2c(cc(C(=O)N3CCCN(C(=O)c4cc5c(OC)c(OC)c(OC)cc5n4C)CC3)n2C)c(OC)c1OC

Procedure:
N-Methyl-4,5,6-trimethoxyindole-2-carboxylic acid (130 mg) and homopiperazine (24 mg) were reacted in the same manner as in Preparation Example 37 to obtain the title compound.
Reaction SMILES: [C:1]1([C:7]([O:9][C@H:10]2[CH2:20][O:19][C@H:12]3[C@H:13]([OH:18])[C@H:14]([O:17][C@@H:11]23)[O:15][CH3:16])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21]I>CN(C=O)C.C(OCC)(=O)C.[Ag-]=O>[CH3:21][O:18][C@H:13]1[C@@H:12]2[O:19][CH2:20][C@H:10]([O:9][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])[C@@H:11]2[O:17][C@@H:14]1[O:15][CH3:16]
Reactant: CO[C@H]1O[C@@H]2[C@@H](OC[C@@H]2OC(=O)c2ccccc2)[C@@H]1O
Reactant: CI
Agent: O=[Ag-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO[C@H]1O[C@@H]2[C@@H](OC[C@@H]2OC(=O)c2ccccc2)[C@@H]1OC
Temperature: 60 °C
Yield: 76 %

Procedure:
A mixture of methyl 3,6-anhydro-5-O-(phenylcarbonyl)-β-L-glucofuranoside (1.03 g, 3.7 mmol), silver (I) oxide (0.85 g, 3.7 mmol) and methyl iodide (0.34 mL, 5.5 mmol) in DMF (2 mL) was heated at 60° C. for 1 hour. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (50 mL), filtered over celite, adsorbed on silica gel (10 g) and purified by flash chromatography (silica gel, 5-30% ethyl acetate-hexane) to give methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-β-L-glucofuranoside as a colorless oil, 0.82 g, 76% yield. 1H NMR (400 MHz; CDCl3): 8.11-8.09 (d, 2H), 7.60-7.56 (m, 1H), 7.46-7.44 (m, 2H), 5.24-5.20 (m, 1H), 5.18-5.09 (tr, 1H), 4.99 (s, 1H), 4.61-4.60 (d, 1H), 4.21-4.17 (tr, 1H), 4.08-4.03 (tr, 1H), 3.81 (s, 1H), 3.40 (s, 3H), 3.57 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH:18]=O.[CH2:20]([NH:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][N:22]([CH2:20][CH3:21])[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCC=O
Reactant: CCNc1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCN(CC)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 531A (130 mg) and N-ethylnaphthalen-1-amine (82 mg) in dichloromethane (3 mL) was added sodium triacetoxyborohydride (2.35 g). The mixture was stirred at room temperature overnight. After this time the mixture was diluted with ethyl acetate (1500 mL) and washed with 1N NaOH, water, brine, and dried over Na2SO4. After filtration and concentration of the filtrate, the residue was purified by flash chromatography using silica gel and eluenting with 5% ethyl acetate in hexane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:20][OH:21])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])(=O)=O.[Na+].[Na+].[F:29][C:30]([F:38])(S(F)(=O)=O)C(O)=O>C(#N)C.C(OCC)C.[Cu]I>[CH2:13]([O:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:20][O:21][CH:30]([F:38])[F:29])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: CC(C)(C)OC(=O)NC(CO)C(=O)OCc1ccccc1
Agent: [Cu]I
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)OCc1ccccc1
Temperature: 60 °C
Yield: 39.2 %

Procedure:
To a stirred solution of the compound of Formula XII(a), benzyl 2-(tert-butoxycarbonylamino)-3-hydroxypropanoate (1 g, 3.38 mmol) in acetonitrile (10 mL) was added copper(I) iodide (64.4 mg, 0.338 mmol) and sodium sulfate (48.1 mg, 0.338 mmol). The resulting mixture was stirred at 60° C. and treated with 2,2-difluoro-2-fluorosulfonylacetic acid (524 μL, 5.08 mmol), dropwise, as a solution in acetonitrile (2 mL) over a period of 1.5 h. Upon completion of the addition, the mixture was stirred for a further 30 min then cooled to room temperature. The mixture was diluted with diethyl ether and washed with brine (2×), water (3×) and brine (1×). The organic phase was dried, filtered and concentrated in vacuo then chromatographed in 0-30% ethyl acetate in hexanes, to provide the compound of Formula XIII(a), (S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionic acid benzyl ester (458 mg, 40%) as a colorless sticky oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 7.32-7.38 (m, 5H), 6.18 (wt, 1H), 5.28 (dd, 1H), 5.19 (dd, 2H), 4.55 (dt, 1H) 4.22 (td, 1H), 4.15 (m, 2H), 1.38 (s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[N:16]1([CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:6]=2[C:4]([OH:3])=[O:5])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CN1CCOCC1
Reactant: BrCc1cccc2ccccc12
Product: O=C(O)c1c(CN2CCOCC2)c2ccccc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 3-morpholin-4-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (Lit. 5) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 399.3 ([M−H]−).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C:24]2=[O:29])=[CH:19][CH:18]=1)[CH2:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].[CH2:30]([OH:32])C>C1(C)C=CC=CC=1>[O:32]=[C:30]1[N:16]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C:24]3=[O:29])=[CH:19][CH:18]=2)[CH2:15][C@H:2]([CH2:3][N:4]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:14])[O:1]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2=O)cc1
Reactant: CCO
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 27.5 °C

Procedure:
2641 g of 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione (V) are suspended in 22 l of toluene and, at 19° C., 1300 g of N,N-carbonyl-diimidazole are added. The reaction mixture is subsequently heated under reflux for one hour and then, at 60° C., 4.5 l of ethanol are added. After cooling to 25 to 30° C., the precipitated reaction product is filtered off with suction, washed with ethanol and then dried.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([NH2:17])=[CH:4][N:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:27][C@H:26]1[CH:38]=O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:29][C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:27][C@H:26]1[CH2:38][NH:17][C:5]1[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc(Oc2nc(Cl)ncc2N)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(Oc2nc(Cl)ncc2NC[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of Compound 1c (191 mg, 0.759 mmol) in 1,2-dichloroethane (4 mL) was added Compound 27d (250 mg; 0.759 mmol) and acetic acid (0.2 mL) at ambient temperature, and the mixture was stirred at room temperature for 1.5 h. The mixture was then treated with NaB(OAc)3H (240 mg; 1.14 mmol) and continually stirred at room temperature for 4 h. The resultant mixture was diluted with CH2Cl2, then washed with saturated NaHCO3 (aq) and water. The organic phase was washed sequentially with water and brine, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 27e. 1H-NMR (400 MHz, CDCl3): δ 7.70-7.75 (m, 1H), 7.10-7.13 (m, 2H), 6.94-7.01 (m, 2H), 5.79 (br. s, 0.6H), 4.73 (br. s, 0.4H), 4.30-4.39 (m, 2H), 3.84 (s, 3H), 3.12-3.69 (m, 4H), 2.06-2.16 (m, 1H), 1.80-1.87 (m, 1H), 1.45-1.48 (m, 9H), 0.88 (s, 9H), 0.08 (s, 6H); MS: m/z 565.2 (M+H)+.
Reaction SMILES: [CH2:1]([P:18](=[O:33])([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[P:2](=[O:17])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C=O.[CH2:36](NCC)C>CO>[C:1]([P:2](=[O:17])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])([P:18](=[O:33])([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH2:36]
Reactant: CCNCC
Reactant: CCCCCCOP(=O)(CP(=O)(OCCCCCC)OCCCCCC)OCCCCCC
Agent: C=O
Solvent: CO
Product: C=C(P(=O)(OCCCCCC)OCCCCCC)P(=O)(OCCCCCC)OCCCCCC
Yield: 73.6 %

Procedure:
22.2 g (44.0 mmol) of tetra-n-hexyl methylenebisphosphonate, 6.61 g (220.0 mmol) of paraformaldehyde and 3.22 g (64.0 mmol) of diethylamine are combined with the same reactants and the same conditions as described above in Example I. This mixture is then refluxed for 48 hours. After the methanol is eliminated as described above in Example I, about 17 g of tetra-n-hexyl ethenylidenebisphosphonate is produced as a clear liquid.
Reaction SMILES: O=[C:2]([C:8]1[S:9][C:10]2[CH2:16][CH2:15][CH2:14][CH2:13][C:11]=2[CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[Na+].Cl.[NH2:23][OH:24]>C(O)C>[OH:24][N:23]=[C:2]([C:8]1[S:9][C:10]2[CH2:16][CH2:15][CH2:14][CH2:13][C:11]=2[CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: NO
Reactant: CCOC(=O)C(=O)c1cc2c(s1)CCCC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=NO)c1cc2c(s1)CCCC2
Yield: 98.8 %

Procedure:
A solution of 14.0 g of ethyl α-oxo-α-(4,5,6,7-tetrahydro-2-benzothienyl)acetate in 300 ml of ethanol containing 5.31 g of sodium acetate and 6.50 g of hydroxylamine hydrochloride was heated at reflux for three hours. The reaction mixture was cooled and the solvent was removed by evaporation under reduced pressure to provide 14.7 g of ethyl α-hydroxyimino-α-(4,5,6,7-tetrahydro-2-benzothienyl)acetate.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2(CC(N)=O)[CH2:18][CH2:17]2)=[N:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].[CH2:24]([N+:28](CCCC)(CCCC)CCCC)[CH2:25]CC.[O:41]1CCCC1>>[OH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([NH:28][C:24](=[O:41])[CH3:25])[CH2:17][CH2:18]2)=[N:14][CH:15]=1
Reactant: C1CCOC1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C2(CC(N)=O)CC2)nc1
Agent: [F-]
Product: CC(=O)NC1(c2ccc(CO)cn2)CC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
1-[5-(tert-Butyldimethylsilanyloxymethyl)pyridin-2-yl]cyclopropylacetamide (156 mg) was dissolved in tetrahydrofuran (2 ml), and a solution (1 mol/1, 1.46 ml) of tetrabutylammonium fluoride in tetrahydrofuran was added thereto. The mixture was stirred at room temperature for 25 min. The solvent was evaporated and the obtained residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size L, elution solvent: ethyl acetate/methanol) to give the title compound (109 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:17][O:18][C:19](=[O:30])[C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([F:27])=[C:22]([CH2:28][NH2:29])[CH:21]=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>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:29][CH2:28][C:22]1[CH:21]=[C:20]([C:19]([O:18][CH3:17])=[O:30])[CH:25]=[C:24]([Cl:26])[C:23]=1[F:27])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Reactant: COC(=O)c1cc(Cl)c(F)c(CN)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(F)c(CNC(=O)[C@@H]2C[C@@H](F)CN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-boc-trans-4-fluoro-L-proline (143 mg, 0.61 mmol), 3-aminomethyl-5-chloro-4-fluoro-benzoic acid methyl ester (prepared as described in Part C, 275 mg, 0.61 mmol) and HATU (0.35 g, 0.92 mmol) in DMF (4 mL) was added DIPEA (430 μl, 2.45 mmol) and the resulting solution was stirred overnight at ambient temperature. The reaction mixture was splitted in two batches and the crude product was purified without aqueous workup by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 ml/min) to give the title compound. MS (LC-MS): 333.0 [M−100]+; tR (HPLC conditions c): 5.05 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][CH3:10]
Reactant: Oc1c(F)cccc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(F)cccc1F
Yield: 77.9 %

Procedure:
20 g (153.74 mmol) of 2,6-difluorophenol is dissolved in 200 ml of acetone and mixed under nitrogen with 42.5 g (307.48 mmol) of potassium carbonate. After 19.1 ml of methyl iodide (2 equivalents) is added, it is refluxed for three and one-half hours. After cooling, the reaction mixture is filtered, the filter residue is washed with acetone, and the filtrate is spun in until a dry state is reached. The residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 17.27 g (77.9%) of the desired product is obtained. It should be noted that the product is slightly volatile. The bath temperature should not exceed 30° C., and the vacuum of the rotary evaporator is to be adapted.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])C(=O)OC(C)(C)C)=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[CH2:38]([O:40][CH:41](O)[C:42]([F:45])([F:44])[F:43])[CH3:39]>CCO>[CH2:38]([O:40][CH:41]([NH:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([CH2:22][NH:23][CH2:31][CH2:32][O:33][CH3:34])=[CH:20][N:21]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1)[C:42]([F:45])([F:44])[F:43])[CH3:39]
Reactant: CCOC(O)C(F)(F)F
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: CCO
Product: CCOC(Nc1ccc(Oc2ccnc3cc(-c4ccc(CNCCOC)cn4)sc23)c(F)c1)C(F)(F)F
Yield: 76.2 %

Procedure:
A solution of 11 (2 g, 3.62 mmol), PTSA monohydrate (0.76 g, 3.98 mmol) and trifluoroacetaldehyde ethyl hemiacetal (2.38 mL, 18.11 mmol) in EtOH (50 mL) was heated to reflux overnight. More trifluoroacetaldehyde ethyl hemiacetal (1.2 mL, 9.13 mmol) was added and the reaction mixture was heated to reflux overnight. Once again, more trifluoroacetaldehyde ethyl hemiacetal (2 mL, 15.22 mmol) were added and the reaction mixture was heated to reflux overnight. Finally, another portion of trifluoroacetaldehyde ethyl hemiacetal (2 mL, 15.22 mmol) and PTSA monohydrate (0.76 g, 3.98 mmol) were added and the reaction mixture was heated to reflux for 5 days. The reaction mixture was concentrated and partitioned between AcOEt and water. The organic layer was successively washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 100 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV), to afford the title compound 14 (1.519 g, 2.76 mmol, 76% yield) as a pale orange sticky solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.56 (d, J=1.4 Hz, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.30 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.89 (dd, J=8.0, 2.2 Hz, 1H), 7.31 (t, J=9.1 Hz, 1H), 7.11-7.02 (m, 2H), 6.87 (dd, J=9.0, 1.8 Hz, 1H), 6.62 (dd, J=5.3, 0.8 Hz, 1H), 5.73-5.64 (m, 1H), 3.78 (s, 2H), 3.77-3.59 (m, 2H), 3.41 (t, J=5.7 Hz, 2H), 3.24 (s, 3H), 2.65 (t, J=5.7 Hz, 2H), 1.15 (t, J=7.0 Hz, 31-1), one NH proton is missing. MS (m/z): 551.6 (M+H).
Reaction SMILES: [H][H].[CH2:3]([CH:5]1[CH:31]=[C:30]([CH3:32])[CH2:29][CH:28]([CH3:33])[CH2:27][CH:26]([O:34][CH3:35])[CH:25]2[O:36][C:21]([OH:40])([CH:22]([CH3:39])[CH2:23][CH:24]2[O:37][CH3:38])[C:20](=[O:41])[C:19](=[O:42])[N:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[C:12](=[O:43])[O:11][CH:10]([C:44]([CH3:60])=[CH:45][CH:46]2[CH2:51][CH2:50][CH:49]([O:52][CH2:53][CH:54]=[CH2:55])[CH:48]([O:56][CH2:57][CH:58]=[CH2:59])[CH2:47]2)[CH:9]([CH3:61])[CH2:8][CH2:7][C:6]1=[O:62])[CH3:4]>[Rh]>[CH2:3]([CH:5]1[CH:31]=[C:30]([CH3:32])[CH2:29][CH:28]([CH3:33])[CH2:27][CH:26]([O:34][CH3:35])[CH:25]2[O:36][C:21]([OH:40])([CH:22]([CH3:39])[CH2:23][CH:24]2[O:37][CH3:38])[C:20](=[O:41])[C:19](=[O:42])[N:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[C:12](=[O:43])[O:11][CH:10]([C:44]([CH3:60])=[CH:45][CH:46]2[CH2:51][CH2:50][CH:49]([O:52][CH2:53][CH2:54][CH3:55])[CH:48]([O:56][CH2:57][CH2:58][CH3:59])[CH2:47]2)[CH:9]([CH3:61])[CH2:8][CH2:7][C:6]1=[O:62])[CH3:4]
Reactant: [H][H]
Reactant: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CC1OCC=C
Agent: [Rh]
Product: CCCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CC1OCCC
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 65.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-diallyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (6.8 mg in 600 μl ethyl acetate) was added 4 mg of 5% rhodium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 25 minutes, the mixture was filtered over Celite, concentrated and purified by flash chromatography on silica gel (ethyl acetate: hexane (1:3)+1% methanol) to give the title compound (4.5 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].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.[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:56]=[C:57]([NH2:64])[C:58]4[CH:59]=[N:60][NH:61][C:62]=4[CH:63]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:64][C:57]1[CH:56]=[C:55]([C:50]2[CH:51]=[CH:52][CH:53]=[C:54]3[C:49]=2[CH:48]=[CH:47][NH:46]3)[CH:63]=[C:62]2[C:58]=1[CH:59]=[N:60][NH:61]2)=[O:8])[CH3:2]
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: CCOc1ccccc1C(=O)O
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: CCOc1ccccc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 8 h

Procedure:
To a solution of 2-(ethyloxy)benzoic acid (67 mg, 0.40 mmol) in DMF (1 ml), HATU (248 mg, 0.40 mmol) and DIPEA (0.211 mL, 1.21 mmol) were added. The reaction was stirred for 30 mins under nitrogen before addition of 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.20 mmol). The reaction was stirred overnight then it was loaded onto a PS-aminopropyl cartridge (5 g) and left for 3 h. The cartridge was washed with 10% MeOH in DCM. Appropriate fractions were combined and the solvent was evaporated. The residue was dissolved in MeOH:DMSO (1 ml; 1:1, v/v) and purified by Mass Directed Automated Preparative HPLC using method B. Appropriate fractions were dried under a stream of nitrogen to give title compound, 27 mg.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:2]1=2.S(Cl)(Cl)=O.[C:17]([NH2:26])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:20].N1C=CC=CC=1>C(Cl)(Cl)Cl>[NH2:26][C:17]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:10]([C:7]1[CH:8]=[CH:9][C:2]2[O:1][CH2:5][CH2:4][C:3]=2[CH:6]=1)=[O:12])=[O:25]
Reactant: O=C(O)c1ccc2c(c1)CCO2
Reactant: NC(=O)c1ccccc1N
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccccc1NC(=O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
A mixture of 2,3-dihydrobenzo[b]furan-5-carboxylic acid (1.0 g, 6.1 mmol) in thionyl chloride (2.2 mL, 30.5 mmol) is stirred at room temperature for 4 h. The volatiles were removed by evaporation. To a solution of the residue and anthranilamide (750 mg, 5.5 mmol) in CHCl3 (30 mL) is added pyridine (670 □L, 8.3 mmol) and the mixture stirred at room temperature for 18 h. The volatiles were removed by evaporation and the residue is partitioned between EtOAc and 1 N sodium carbonate. The resulting precipitate that formed between the aqueous and organic phases is collected by filtration and dried under vacuum to afford the desired intermediate (1.5 g, 5.3 mmol; 87% yield); ); Rf=0.31 (EtOAc/hexanes, 95/5); mp=230-235° C.; ES MS(M+H)+=283.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][Si](C)(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CO.C(Cl)Cl.C(Cl)Cl>[C:14]([C:10]1[CH:9]=[C:8]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=1)#[CH:15]
Reactant: C[Si](C)(C)C#Cc1cccc(-c2cccnc2F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1cccc(-c2cccnc2F)c1
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of 2-fluoro-3-{3-[(trimethylsilyl)ethynyl]phenyl}pyridine (2.20 g, 8.1 mmol) in MeOH/CH2Cl2 (1/1, 60 mL) is added Cs2CO3 (3.17 g, 9.7 mmol) at room temperature. After stirring for 1 h, the reaction mixture is diluted with CH2Cl2 and passed through a thin layer of silica gel. The solution is concentrated and the crude material is purified by chromatography (silica gel, EtOAc/hexane: 20/80) to give the title compound (1.23 g, 77%) as a solid. mp: 45-47° C. MS (+) EI: 198 M+.
Reaction SMILES: BrC1C=CC(OC)=C([N+]([O-])=O)C=1.C[Sn](C)(C)[C:15]1[CH:19]=[CH:18][S:17][CH:16]=1.[CH3:22][O:23][C:24]1[C:29]2[N:30]=[C:31]([NH:33][C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:35])[S:32][C:28]=2[C:27](C2C=CC=CC=2)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[C:29]2[N:30]=[C:31]([NH:33][C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:35])[S:32][C:28]=2[C:27]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[CH:26][CH:25]=1
Reactant: C[Sn](C)(C)c1ccsc1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)N3CCOCC3)nc12
Agent: COc1ccc(Br)cc1[N+](=O)[O-]
Product: COc1ccc(-c2ccsc2)c2sc(NC(=O)N3CCOCC3)nc12

Procedure:
The title compound was prepared strarting from 4-bromo-1-methoxy-2-nitro-benzene and trimethyl-thiophen-3-yl-stannane as described for morpholine-4-carboxylic acid (4-methoxy-7-phenyl-benzothiazol-2-yl)-amide (Example 157) and obtained as a light yellow solid in about 10% overall yield, MS: m/e=376 (M+H+).