Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([Si](C)(C)[O:6][CH:7]([C:9]#[C:10][CH2:11][CH:12]([O:61][Si:62]([C:75]([CH3:78])([CH3:77])[CH3:76])([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([O:43][Si:44]([C:57]([CH3:60])([CH3:59])[CH3:58])([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:30][C:31]#[C:32][CH:33]([O:35][Si](C(C)(C)C)(C)C)[CH3:34])=[CH:20][CH:19]=1)[CH3:8])(C)C.[NH+]1C=CC=CC=1>C(O)C>[CH3:58][C:57]([Si:44]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[O:43][CH:29]([CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([O:61][Si:62]([C:75]([CH3:76])([CH3:77])[CH3:78])([C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH2:11][C:10]#[C:9][CH:7]([OH:6])[CH3:8])=[CH:19][CH:20]=1)[CH2:30][C:31]#[C:32][CH:33]([OH:35])[CH3:34])([CH3:60])[CH3:59]
Reactant: CC(C#CCC(CCCCOc1ccc(OCCCCC(CC#CC(C)O[Si](C)(C)C(C)(C)C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(O)C#CCC(CCCCOc1ccc(OCCCCC(CC#CC(C)O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 55 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of the alkyne 12b (526 mg, 457 μmol) in absolute ethanol (6.0 mL) was added pyridinium p-toluenesulfanate (273 mg, 1.09 mmol) in one portion. The reaction mixture was stirred at 55° C. overnight (~14 h). The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by MPLC (3:1 hexane:ethyl acetate) to give the alcohol 14 (387 mg, 92%); IR (neat, thin layer): 3405, 3070, 3048, 2935, 2858, 1963, 1893, 1827, 1589, 1507, 1471, 1428, 1365, 1228, 1155, 1002, and 823 cm-1 ; Anal. Calcd for C58 H74O6Si2 : C, 75.44%; H, 8.08%. Found: C, 75.16%; H, 7.89%; tlc: Rf =0.14 in 3:1 hexane:ethyl acetate; [α]DRT =-7.9°, c=5.47 in ethyl acetate.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>CN(C=O)C.CCOC(C)=O>[C:9]1([C:6]2[C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)=[C:4]([NH:3][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[O:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1onc(-c2ccccc2)c1-c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1onc(-c2ccccc2)c1-c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (18 mg 0.45 mmol) is added to the solution of 2-[4-(5-Amino-3-phenyl-isoxazol4-yl)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol in DMF at 0° C. under argon atmosphere. The reaction mixture is stirred at room temperature under argon atmosphere for 30 minutes before adding isobutyryl chloride (23.8 ul, 0.23 mmol). The solution is allowed to stir for 8 hours and diluted with EtOAc. The organic layer is washed with H2O brine and dried over MgSO4. Concentration and purification by preparative TLC afford the title compound. 1HNMR 1.11 (s, 3H), 1.12 (s, 3H), 2.60 (m, 1H), 7.26 (d, 2H), 7.4 (m, 5H), 7.72 (d, 2H); ESIMS: m/z 471 (M−H).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]#[N:21])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1.P(Cl)(Cl)(Cl)=O>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:19][C:20]#[N:21])[C:13]=3[CH2:12][CH2:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CCc1ccccc1CCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Solvent: O=P(Cl)(Cl)Cl
Product: N#CCc1cccc2c1CCN=C2c1ccc([N+](=O)[O-])cc1
Temperature: 140 °C
Reaction time: 7 h
Yield: 75.2 %

Procedure:
1-(4-Nitrobenzoyl)amino-2-(2-cyanomethylphenyl)-ethane (12.7 g) was dissolved in 128 ml of xylene and 77 ml of phosphorus oxychloride. While the solution was heated with stirring over an oil bath at 140° C., 38 g of phosphorus pentoxide was added gradually. The reaction was performed for 7 hours. The upper layer of the reaction mixture was removed by decantation. Ice water was added to the residue, and an aqueous solution of sodium hydroxide was added to make it neutral. The crystals that precipitated were collected by filtration, and recrystallized from ethanol to afford 9 g of 1-(4-nitrophenyl)-3,4-dihydroisoquinoline-5-acetonitrile having a melting point of 137.7° to 138.7° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH:26]1([N:29]2[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27]1>>[CH:26]1([N:29]2[CH2:35][CH2:34][CH2:33][N:32]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:20])[CH2:31][CH2:30]2)[CH2:28][CH2:27]1
Reactant: C1CNCCN(C2CC2)C1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCCN(C5CC5)CC4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-cyclopropyl-1,4-diazepane. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.66-1.06 (m, 4 H) 1.94-2.23 (m, 2 H) 2.33 (d, J=2.02 Hz, 3 H) 2.81-3.07 (m, 1 H) 3.41-4.30 (m, 8 H) 7.54-7.70 (m, 1 H) 7.75 (t, J=7.45 Hz, 1 H) 7.98-8.65 (m, 4 H). ESI-MS m/z [M+H]+ 461.3.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[C:7](=[O:14])[C:8]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[CH:2]12.CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][C:26]=1[S:35]([N:6]1[CH2:5][CH2:4][N:3]2[C:7](=[O:14])[C:8]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[CH:2]2[CH2:1]1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Reactant: O=C1c2cnccc2C2CNCCN12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1c2cnccc2C2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Br)CCN12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1,3,4,10b-tetrahydropyrido[4′,3′:3,4]pyrrolo[1,2-a]pyrazin-6(2H)-one (may be prepared as in Intermediate 22, 90 mg) in dichloromethane (15 mL) was added DIPEA (0.415 mL). This was cooled in an ice bath and to this was added 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (162 mg). The mixture was stirred at room temperature overnight. The reaction mixture was washed with aqueous saturated sodium bicarbonate solution in a hydrophobic frit and then re-extracted with DCM. The combined organic phases were evaporated to give the title compound as a yellow oil which was used in the next reaction (263 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: OB(O)c1cc(F)cc(F)c1
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cc(F)cc(F)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3,5-difluorophenylboronic acid according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 8.58 (s, 1H), 7.17 (dd, J=8.7, 2.5 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 6.95 (d, J=2.3 Hz, 1H), 6.51 (s, 1H), 6.49 (m, 2H), 3.28 (s, 3H), 1.99 (m, 4H), 0.81 (t, J=7.4 Hz, 6H). MS (ESI) m/z 347 ([M+H]+); MS (ESI) m/z 345 ([M−H]−); Anal. calcd for C19H20F2N2O2: C, 65.88; H, 5.82; N, 8.09. Found: C, 64.99; H, 5.63; N, 7.89.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[C:14]([C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=3[OH:24])[N:9]=[C:5]2[CH:4]=1.[CH2:29]([Sn:33](=[O:38])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH3:32]>>[CH2:29]([Sn:33]([CH2:34][CH2:35][CH2:36][CH3:37])([O:38][C:11]1[CH:12]=[CH:13][C:14]([C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17])=[CH:15][C:10]=1[N:8]1[N:7]=[C:6]2[CH:25]=[CH:26][C:3]([C:2]([F:1])([F:27])[F:28])=[CH:4][C:5]2=[N:9]1)[O:24][C:11]1[CH:12]=[CH:13][C:14]([C:16]([CH2:19][C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:17])[CH3:18])=[CH:15][C:10]=1[N:8]1[N:7]=[C:6]2[CH:25]=[CH:26][C:3]([C:2]([F:1])([F:27])[F:28])=[CH:4][C:5]2=[N:9]1)[CH2:30][CH2:31][CH3:32]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccc(C(F)(F)F)cc3n2)c1
Reactant: CCCC[Sn](=O)CCCC
Product: CCCC[Sn](CCCC)(Oc1ccc(C(C)(C)CC(C)(C)C)cc1-n1nc2ccc(C(F)(F)F)cc2n1)Oc1ccc(C(C)(C)CC(C)(C)C)cc1-n1nc2ccc(C(F)(F)F)cc2n1

Procedure:
Following the synthetic procedure of Example 25, the title compound is prepared by reaction of the corresponding equivalent amounts of 5-trifluoromethyl-2-(2-hydroxy-5-tert-octylphenyl)-2H-benzotriazole and dibutyltin oxide to give the title compound as a yellow resin (38 g, 99% yield) whose structure is consistent with 1Hnmr and 19Fnmr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[CH:11][C:10]=2[CH2:19][CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:6]=[CH:7][CH:8]=1.[Br:27]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[Br:27][C:11]1[C:10]([CH2:19][CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:17]2[C:12]=1[C:13]([NH2:18])=[N:14][CH:15]=[N:16]2
Reactant: COc1cccc(-c2c(CCCN3CCCC3)cc3c(N)ncnn23)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(CCCN3CCCC3)c(Br)c3c(N)ncnn23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 161 %

Procedure:
To a solution of the compound (98 mg, 0.28 mmol) prepared in Example 14 in DMF (4 mL) at −40° C. was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (40 mg, 0.14 mmol) portion wise over a period of 1 minute. The reaction was stirred for 30 minutes and was allowed to warm to room temperature, and stirred overnight. DMF was removed, and the crude solid was extracted with sodium hydroxide (1N) and DCM. The organic layer was dried, concentrated to obtain the title compound (97 mg) having the following physical data.
Reaction SMILES: [CH:1]1[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=2[CH:4]=[N:3][CH:2]=1)=[O:8].[H-].[Na+].CI.[C:16](OCC)(=O)C>CN(C)C=O>[CH3:16][N:9]1[C:7](=[O:8])[C:6]2[CH:1]=[CH:2][N:3]=[CH:4][C:5]=2[C:10]1=[O:11]
Reactant: CCOC(C)=O
Reactant: O=C1NC(=O)c2cnccc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccncc2C1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3,4-pyridinedicarboximide (10.0 g, 67.5 mmol) in N,N-dimethylformamide was added sodium hydride (1.55 g, 60% dispersion in mineral oil, 67.5 mmol) at room temperature. The mixture was stirred for about 30 minutes, then methyl iodide (9.58 g, 67.5 mmol) was added, and the reaction was stirred overnight. Ethyl acetate was added to the reaction mixture, and the mixture was extracted once with water, twice with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo (azeotroping excess N,N-dimethylformamide with heptanes) to give crude product. Purification by silica gel chromatography using 0-5% methanol/dichloromethane as eluent afforded the title compound of part 11-A as an off-white solid (5 g, 46%): PB MS (M+1)+ 163; 1H NMR=250 MHz (CDCl3) δ: 9.11 (arom, s, 1H), 9.08 (arom, d, 1H), 7.75 (arom, d, 1H), 3.20 (Me, s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:35])=[C:31]([CH2:33]I)[N:32]=2)=[CH:24][CH:23]=1>>[CH3:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:10]([CH2:9][O:8][CH:4]2[CH2:5][CH2:6][CH2:7][CH:2]([O:1][CH2:33][C:31]3[N:32]=[C:28]([C:25]4[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=4)[O:29][C:30]=3[CH3:35])[CH2:3]2)[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: Cc1ccc(-c2nc(CI)c(C)o2)cc1
Product: Cc1ccc(-c2nc(COC3CCCC(OCc4cccc(C)c4C(=O)O)C3)c(C)o2)cc1

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(4-methylphenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 70 of molecular weight 449.55 (C27H31NO5), MS(ESI): 450.36 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=O.[C@@H:18]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1>>[C@@H:18]1([NH:28][CH2:1][C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: N#Cc1ccc(Oc2cccc(C=O)c2)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: N#Cc1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
The product from Example 50A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:8]([O:19][CH2:20][CH3:21])[CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.Cl>C1COCC1>[CH2:20]([O:19][C:8]1[CH:7]=[C:6]([CH2:4][OH:3])[CH:11]=[CH:10][C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(-c2ccc(F)cc2)c(OCC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: CCOc1cc(CO)ccc1-c1ccc(F)cc1
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a solution of 2-ethoxy-4′-fluoro-biphenyl-4-carboxylic acid ethyl ester (0.50 g, 1.73 mmol, 1.0 equiv) in anhydrous THF (10 mL) was added slowly over a time period of 15 min under cooling to −10° C. a solution of diisobutylaluminium hydride (5.2 mL, 5.20 mmol, 3.0 equiv; 1 M solution in hexane). After 1 h, the reaction mixture was poured on ice, the pH adjusted to 4 by addition of a 1 M solution of HCl, the solution extracted with ethyl acetate (2×100 mL) and the combined organic phases washed with water (2×100 mL) and a conc. solution of sodium chloride (100 mL). The organic phase was dried over MgSO4, concentrated by evaporation under reduced pressure to give 0.42 g (99%) of the title compound which was directly used in the consecutive step without further purification.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][C@H:14]([CH2:18][OH:19])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[C:23](O)[CH:24]=[N:25][CH:26]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([O:19][CH2:18][C@H:14]2[O:15][CH2:16][CH2:17][N:12]([CH2:11][CH2:10][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[CH2:13]2)[CH:24]=[N:25][CH:26]=1
Reactant: OC[C@@H]1CN(CCN2CCc3ccccc32)CCO1
Reactant: Oc1cncc(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1cncc(OC[C@@H]2CN(CCN3CCc4ccccc43)CCO2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Compound 27s was synthesised by essentially the same procedure as compound 18s (Example 16). Compound 51 (Example 10; 80 mg, 0.30 mmol), was reacted with 5-chloro-3-hydroxypyridine (59 mg, 0.46 mmol), PPh3 (120 mg, 0.46 mmol), DIAD (90 μl, 0.46 mmol) and THF (1.5 ml). The reaction mixture was stirred at RT for 48 hrs. After this time, the solvent was removed and the crude mixture purified twice by flash column chromatography (silica, DCM/MeOH 1:0 to 94:6, then Hex/EtOAc 1:0 to 0:1) to afford compound 27s (71 mg, 91%). Analyses were performed on the free base. The compound was re-purified (36.7 mg, purity 100%), and converted to the HCl salt for assaying.
Reaction SMILES: [NH2:1][CH:2]([C:6]#[N:7])[C:3]([NH2:5])=[O:4].[N:8]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=[C:9]=[S:10]>CCOC(C)=O>[NH2:7][C:6]1[S:10][C:9]([NH:8][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[N:1][C:2]=1[C:3]([NH2:5])=[O:4]
Reactant: S=C=Nc1ccc2ccccc2c1
Reactant: N#CC(N)C(N)=O
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Yield: 78.2 %

Procedure:
To a suspension of 2-amino-2-cyanoacetamide (0.486 g, 2.70 mmol) in EtOAc (15 mL), was added 2-isothiocyanatonaphthalene (0.5 g, 2.70 mmol), and the mixture was refluxed for 30 min. The solvent was evaporated under reduced pressure, and the resulting crude residue was purified by silica gel column chromatography eluted with 2% MeOH in DCM to give 0.6 g (78% yield) of the titled compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:37])[C@@H:3]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[N:9]=[CH:8]2.[F:38][C:39]([F:44])([CH3:43])[C:40](O)=[O:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:38][C:39]([F:44])([CH3:43])[C:40]([NH:1][C@@H:2]([CH3:37])[C@@H:3]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][CH2:20][CH:21]([CH3:22])[CH3:23])=[O:18])[N:9]=[CH:8]2)=[O:41]
Reactant: CC(F)(F)C(=O)O
Reactant: CC(C)COC(=O)c1cccc(-n2ncc3cc(O[C@H](c4ccc5c(c4)OCCO5)[C@H](C)N)ccc32)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)COC(=O)c1cccc(-n2ncc3cc(O[C@H](c4ccc5c(c4)OCCO5)[C@H](C)NC(=O)C(C)(F)F)ccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isobutyl 3-(5-((1R,2S)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)benzoate (I4b) (0.5 g, 1.00 mmol), 2,2-difluoropropanoic acid (0.16 g, 1.45 mmol) and HBTU (0.567 g, 1.50 mmol) in DCM (4 mL) was treated with DIEA (0.696 mL, 3.99 mmol), the mixture was stirred at ambient temperature for 1 hour. The reaction was quenched by addition 10% NaHSO4 (aq), brine was added to help phase separation. The lower red DCM phase was separated, the waterphase was extracted with one portion of EtOAc, the combined organic solutions were dried over MgSO4 and filtered, solvents was removed by evaporation. Obtained a crude product as red oil. The crude material was further purified by flashchromatography using an 70 g prepacked silica column, an gradient of 0% to 50% EtOAc in Heptane was applied. Fractions with product was combined and solvents was removed by evaporation. An slightly yellow sticky oil was obtained after final evaporation from DCM. Yield 540 mg (91%).
Reaction SMILES: [Cl:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]2[N:6]([C@H:9]3[O:21][C@@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:10]3[O:11][C:12](=[O:14])[CH3:13])[CH:7]=[N:8][C:4]=2[CH:3]=1.[Br:30]N1C(=O)CCC1=O>O1CCOCC1.C(OCC)(=O)C>[Br:30][C:7]1[N:6]([C@H:9]2[O:21][C@@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:10]2[O:11][C:12](=[O:14])[CH3:13])[C:5]2[CH:27]=[C:28]([Cl:29])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: CC(=O)OC[C@@H]1O[C@H](n2cnc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 80 °C

Procedure:
5,6-Dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (1.0 g, 2.25 mmol) was combined with N-bromosuccinimide (0.88 g 4.94 mmol) in anhydrous 1,4-dioxane (50 mL). This solution was heated in an 80° C. oil bath for 15 min. The solution was cooled, diluted with ethyl acetate and extracted with 10% sodium bicarbonate (2×50 mL). The organics were dried with anhydrous Na2SO4, decanted and concentrated. The residue was purified on a silica gel column (5×11 cm, 230-400 mesh) with (1:50) methanol:dichloromethane to give a white solid which was identified as product by comparing it's 1H NMR to that of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(NC(C)C)(C)C.[Li]CCCC.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:24]([CH3:26])([CH3:25])[CH3:23])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1ccccc1Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cccc(Br)c1C(=O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
2-Bromobenzoic acid (30.15 g, 150 mmol), THF (400 mL), and diisopropyl amine (33.4 g, 330 mmol) were stirred under nitrogen and cooled to -78° C. 10M n-BuLi in hexanes (31 mL, 0.31 mol) was then added dropwise, followed by the dropwise addition of TMSCl (17.4 g, 160 mmol). The mixture was allowed to slowly warm to -30° C., stirred for 1 h, then was poured into 25% citric acid (100 mL) and stirred for 15 min. The mixture was extracted with two 100 mL portions of ether, which were combined and washed three times with sat aq NaHCO3 solution. The bicarbonate solution was acidified with 25% citric acid and extracted with three 100 mL portions of ether. These extracts were combined, dried (MgSO4), and concentrated. The crude product was purified by recrystallization from ether/hexanes, and the desired product was recovered as a white solid in 35% yield. m.p. 139°-141° C.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([NH:5][C:6]1[NH:7][C:8](=O)[C:9]2[NH:14][C:13]([CH3:15])=[CH:12][C:10]=2[N:11]=1)=[O:4].[OH-].[NH4+].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:8]1[C:9]2[NH:14][C:13]([CH3:15])=[CH:12][C:10]=2[N:11]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:18])([CH3:17])[CH3:1])[N:7]=1
Reactant: Cc1cc2nc(NC(=O)C(C)(C)C)[nH]c(=O)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc2nc(NC(=O)C(C)(C)C)nc(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a 100-mL round-bottomed flask was added 9 (1.16 g, 4.67 mmol) suspended in 30 mL phosphorus oxychloride. The reaction mixture was heated at reflux with stirring in an anhydrous atmosphere for 3 h. The dark orange solution was allowed to cool to room temperature and concentrated in vacuo. Water (20 mL) was then added to the residue at 0° C. with vigorous stirring to give an exothermic reaction. Concentrated aqueous ammonium hydroxide was added to pH 5 to give a precipitate, which was collected by filtration, washed with water (3×5 mL), and dried in vacuo. The crude product was purified by silica gel column chromatography with 2% MeOH/CHCl3. Recrystallization from MeOH afforded 1.07 g (86%) of 10 as a white solid: TLC Rf0.35 (MeOH/CHCl3, 1:10); mp 162-163° C.; 1H NMR (DMSO-d6) δ 1.19 (s, 9 H), 2.47 (s, 3 H), 6.33 (s, 1 H), 9.85 (s, 1 H), 12.07 (s, 1 H) Anal. (C12H15ClN4O) C, H, N, Cl.