Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](O)(=[O:19])=[O:18])[C:14]([F:21])=[CH:13][C:11]=2[N:12]=1.FC1C=CC2SC(C3C(C)=NNC=3N)=[N:28]C=2C=1.N>C(O)C>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17]([NH2:28])(=[O:19])=[O:18])[C:14]([F:21])=[CH:13][C:11]=2[N:12]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2cc(F)c(S(=O)(=O)O)cc2s1
Reactant: Cc1n[nH]c(N)c1-c1nc2cc(F)ccc2s1
Agent: N
Solvent: CCO
Product: Cc1n[nH]c(N)c1-c1nc2cc(F)c(S(N)(=O)=O)cc2s1
Yield: 25 %

Procedure:
The title compound (30 mg) was prepared in two steps from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-5-fluorobenzothiazole-6-sulfonic acid, which had been derived from the chlorosulfonation of 90 mg of 4-(5-fluorobenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine, and a solution of excess ammonia dissolved in ethanol. MS (m/z, ES+): 328.0 (M+1,100%). Yield=25%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:2]3[N:3]=[C:4]([O:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=4)[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[N:7]=3)=[N:32][CH:33]=2)[CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1cccc(Oc2nc(Cl)nc3ccsc23)c1
Reactant: CN1CCN(c2ccc(N)nc2)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)c4sccc4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70.1 %

Procedure:
0.6 g (1.94 mmol) of the compound obtained in Step 3 of Example 1 and 0.75 g (3.88 mmol) of 5-(4-methylpiperazin-1-yl)piridin-2-amine were dissolved in 8 ml of 1,4-dioxane, and 178 mg (0.2 mmol) of tris(dibenzylideneacetone)dipalladium(O) and 122 mg (0.2 mmol) of 2,2′-bis(diphenylphosphino)-1,1′-binaphthy were added thereto, and stirred for 5 minutes at room temperature. 1.27 g (3.88 mmol) of cesium carbonate was added thereto, and stirred for 3 hours at 100° C. Upon the completion of the reaction, the resulting mixture was cooled to room temperature and filtered over a short bed of Celite filter, and diluted with dichloromethane and washed with water. The organic layer was separated, dried over anhydrous Na2SO4, and filtered and distilled under a reduced pressure. The resulting residue was separated by column chromatography (dichloromethane:methanol (20:1, v/v)) to obtain 630 mg of the title compound (yield: 70%).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].C1(N2C3C(=CC(F)=C(N4CC(=NOC)C5(CNC5)C4)N=3)C(=O)C(C(O)=O)=C2)CC1>O>[NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: N[C@H](CC(=O)[O-])C(=O)[O-]
Agent: CON=C1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC12CNC2
Solvent: O
Product: N[C@H](CC(=O)O)C(=O)O

Procedure:
30 mg of D-aspartate of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid as prepared in Example 1 is dissolved in 100 ml of distilled water, and then subjected to stability test at room temperature. The results are shown in Table 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)/[C:7]([CH3:23])=[C:6]2[CH2:24][C:25]([OH:27])=O.C(Cl)(=O)C([Cl:31])=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)/[C:7]([CH3:23])=[C:6]2[CH2:24][C:25]([Cl:31])=[O:27]
Reactant: COc1ccc2c(c1)C(CC(=O)O)=C(C)/C2=C/c1ccc(S(C)(=O)=O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CC(=O)Cl)=C(C)/C2=C/c1ccc(S(C)(=O)=O)cc1

Procedure:
(Z)-5-methoxy-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid (70 mmol) in THF (500 ml) is allowed to react with oxalylchloride (2 M in CH2Cl2 ; 35 ml) under reflux conditions (24 hours). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: [CH:1]([O-])=[O:2].[NH4+].[O-2].[Zn+2:6].[C:7]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:9])[CH3:8].C=O>>[Zn:6].[C:7]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:8])[CH3:9].[CH2:1]=[O:2]
Reactant: [Zn+2]
Reactant: O=C[O-]
Agent: C=O
Agent: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Agent: [NH4+]
Product: [Zn]

Procedure:
A mixture of 6.5 g of ammonium formate and 3.65 g of zinc oxide (JIS No. 1) was added over the course of 10 minutes to 100 g of the p-tert-octylphenol/formaldehyde condensate kept at 160° C., and the mixture was maintained at 160° to 170° C. for 1 hour to give a brown transparent zinc salt of the p-tert-octylphenol/formaldehyde condensate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([C:19](O)=[O:20])=[CH:18][C:12]=2[N:11]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26]>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[F:22][C:23]([F:31])([F:32])[C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH:26][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[NH:14][C:10]([NH:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:11][C:12]=2[CH:18]=1)=[O:20]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1C(F)(F)F)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Reaction time: 0.75 h

Procedure:
A mixture of 2-(2,6-dichloro-phenylamino)-1H-benzimidazole-5-carboxylic acid (600 mg, 1.86 mmol) and 1-chloro-N,N-2-trimethyl-1-propenylamin (420 μL, 3.2 mmol) in 8 mL dichloromethane was stirred for 45 min. 2-Trifluoromethyl-aniline (2.3 mL, 18.6 mmol) in pyridine was added. After stirring overnight, the mixture was diluted with ethyl acetate, washed with water and brine, dried and concentrated i.vac.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[CH3:26][O:27][CH2:28][CH2:29][O:30][C:31]1[CH:32]=[C:33]([NH:41][C:42](=O)[O:43]C2C=CC=CC=2)[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([NH:22][C:42]([NH:41][C:33]2[CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:36]=[C:31]([O:30][CH2:29][CH2:28][O:27][CH3:26])[CH:32]=2)=[O:43])[CH:23]=[CH:24][CH:25]=1
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: ClCCl
Solvent: CO
Product: COCCOc1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OCCOC)c(OC)cc34)c2)cc(C(F)(F)F)c1
Yield: 76 %

Procedure:
3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from the previous step (102 mg, 0.3 mmol) was reacted with phenyl 3-(2-methoxyethoxy)-5-(trifluoromethyl)phenylcarbamate from Example 117A (160 mg, 0.45 mmol) in the manner described in Example 115C. The final product was purified by column chromatography (25-100% EtOAc/hexanes then 5-10% MeOH/DCM) to give 1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)urea (137 mg, 0.23 mmol, 76%). 1H NMR (300 MHz, DMSO-d6) δ 9.10 (s, 1H), 9.04 (s, 1H), 8.56 (s, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.49 (s, 1H), 7.45-7.38 (m, 2H), 7.32-7.26 (m, 2H), 6.96 (d, 1H), 6.87 (s, 1H), 4.37-4.31 (m, 2H), 4.19-4.12 (m, 2H), 4.00 (s, 3H), 3.80-3.73 (m, 2H), 3.70-3.63 (m, 2H), 3.36 (s, 3H), 3.31 (s, 3H); LC-MS (ESI) m/z 603 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[C:7]([CH3:16])=[C:8]([C:11]([O:14]C)=[CH:12][CH:13]=1)[CH:9]=[O:10].O.C(OCC)(=O)C.CCCCCC>ClCCl>[Br:5][C:6]1[C:7]([CH3:16])=[C:8]([C:11]([OH:14])=[CH:12][CH:13]=1)[CH:9]=[O:10]
Reactant: COc1ccc(Br)c(C)c1C=O
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1c(Br)ccc(O)c1C=O
Reaction time: 1.5 h
Yield: 73.9 %

Procedure:
A solution of boron tribromide (12.62 ml, 0.087 mol) in dichloromethane (50 ml) was added to a stirred solution of 3-Bromo-6-methoxy-2-methyl-benzaldehyde (20.0 g, 0.087 mol) in dichloromethane (350 ml) under nitrogen at 0° C. The reaction mixture was stirred for 1.5 hours. Water (400 ml) was added cautiously and the mixture was stirred for 15 min. The organic layer was washed with sodium bicarbonate solution (200 ml), water (200 ml) and brine (200 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product as orange brown solid. Column chromatography using 3/97 ethyl acetate/hexane yielded 3-Bromo-6-hydroxy-2-methyl-benzaldehyde (13.82 g, 73.6%).
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:33][CH2:32]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 92 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[CH:10][C:9]([C:23]3[CH:24]=[C:25]([C:29]4([NH2:33])[CH2:32][O:31][CH2:30]4)[CH:26]=[CH:27][CH:28]=3)=[N:8]2)[N:3]=[CH:2]1.[F:34][C:35]([F:42])([F:41])[CH2:36][S:37](Cl)(=[O:39])=[O:38].O>C(Cl)Cl>[F:22][C:19]([F:20])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([O:12][C:11]2[N:7]([CH2:6][C:4]3[N:3]=[CH:2][O:1][CH:5]=3)[N:8]=[C:9]([C:23]3[CH:24]=[C:25]([C:29]4([NH:33][S:37]([CH2:36][C:35]([F:42])([F:41])[F:34])(=[O:39])=[O:38])[CH2:32][O:31][CH2:30]4)[CH:26]=[CH:27][CH:28]=3)[CH:10]=2)=[CH:14][CH:15]=1
Reactant: NC1(c2cccc(-c3cc(Oc4ccc(C(F)(F)F)cc4)n(Cc4cocn4)n3)c2)COC1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(CC(F)(F)F)NC1(c2cccc(-c3cc(Oc4ccc(C(F)(F)F)cc4)n(Cc4cocn4)n3)c2)COC1
Reaction time: 0.5 h

Procedure:
A stirred solution of 3-{3-[1-(1,3-oxazol-4-ylmethyl)-5-(4-trifluoromethylphenoxy)-1H-pyrazol-3-yl]phenyl}oxetan-3-amine (35 mg, 0.077 mmol) in 1 mL of CH2Cl2 was cooled in an ice bath. To the solution was added TEA (21 uL, 0.15 mmol) and 2,2,2-trifluoroethylsulfonyl chloride (12 uL, 0.12 mmol) and the solution was stirred for 30 min. Water was added and the organic phase was washed with brine, died over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed on a 12 g silica gel column using 0-5% MeOH:CHCl3 over 16 min at 30 mL/min. Product containing fractions were combined and the solvent was removed under reduced pressure to give N-(3-{3-[5-(4-trifluoromethylphenoxy)-1-(1,3-oxazol-4-ylmethyl)-1H-pyrazol-3-yl]phenyl}oxetan-3-yl)-2,2,2-trifluoroethanesulfonamide as a foam. Calcd (M+1)+: 603.1131. found 603.1153. 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.78 (d, J=7, 1H), 7.65 (d, J=7, 2H), 7.61 (s, 1H), 7.49 (1, J=7, 1H), 7.37 (d, J=7, 2H), 7.28 (d, J=7, 2H), 7.09 (s, 1H), 6.08 (s, 1H), 6.05 (s, 1H), 5.44 (s, 2H), 5.23 (d, J=7, 2H), 5.05 (d, J=7, 2H), 3.03 (q, J=9, 2H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1([C:29]([OH:31])=O)[CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C.[N:41]1([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:46][CH2:45][CH:44]([N:47]2[C@H:51]3[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:50]3[NH:49][C:48]2=[O:56])[CH2:43][CH2:42]1>CC(N(C)C)=O>[CH3:25][C:26]1([C:29]([N:60]2[CH2:61][CH2:62][CH:57]([N:41]3[CH2:42][CH2:43][CH:44]([N:47]4[C@H:51]5[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:50]5[NH:49][C:48]4=[O:56])[CH2:45][CH2:46]3)[CH2:58][CH2:59]2)=[O:31])[CH2:28][CH2:27]1
Reactant: CC1(C(=O)O)CC1
Reactant: O=C1N[C@H]2CCCC[C@@H]2N1C1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C(=O)N2CCC(N3CCC(N4C(=O)N[C@H]5CCCC[C@@H]54)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
HBTU (284 mg, 0.75 mmol) was added to a solution of 1-methylcyclopropanecarboxylic acid (75 mg, 0.75 mmol), N,N-diisopropylethyl amine (194 mg, 1.50 mmol) and (3aS,7aS)-1-(1,4′-bipiperidin-4-yl)hexahydro-1H-benzo[d]imidazol-2(3H)-one (153.22 mg, 0.50 mmol) in DMA (10 mL) and stirred at room temperature for overnight. Concentrated in vacuo, diluted in dichloromethane (50 ml) and washed with sat. NaHCO3 (10 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by high pH Prep LCMS to give the titled compound (40 mg, 20.6%). 1H NMR (400 MHz, CHLOROFORM-D): δ ppm 0.51-0.59 (m, 2H) 0.86-0.94 (m, 2H) 1.30 (s, 3H) 1.33-1.45 (m, 6H) 1.68 (s, 1H) 1.74-1.84 (m, 7H) 1.96 (d, J=10.16 Hz, 1H) 2.21-2.32 (m, 3H) 2.48 (t, J=11.13 Hz, 1H) 2.76 (s, 1H) 2.92-3.03 (m, 4H) 3.71-3.81 (m, 1H) 4.49 (s, 3H). MS (M+1): 389.2
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.Br[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[F:16]>C1COCC1.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:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccs1
Reactant: Cc1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccs2)c(F)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a mixture of magnesium (0.25 g, 10.58 mmol) in anhydrous THF (5.3 mL) was added 2-bromothiophene (1.73 g, 10.58 mmol) dropwise. The mixture was heated at reflux under argon for 0.5 h. An additional 0.35 g of 2-bromothiophene was added to consume the remaining magnesium. The reaction mixture was heated for additional 1.5 h to afford a solution which was transferred to a mixture of 1-bromo-2-fluoro-4-methylbenzene (2.0 g, 10.58 mmol), Pd(PPh3)4 (0.61 g, 0.53 mmol), and THF (23.5 mL). The resulting mixture was heated under argon for 3 h. The reaction was allowed to cool to rt and quenched with water. The mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated down under reduced pressure. The crude product was purified by flash column chromatography eluting with hexane to afford a colorless liquid (1.46 g, 72%): 1H NMR (CDCl3), δ 7.48-7.02 (m, 6H), 2.36 (s, 3H), GC/MS m/z 192 (M+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([O:17]C)[CH:16]=[C:11]2[C:10]([CH3:20])([CH3:19])[C:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([CH3:26])=[CH2:25].Cl>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]([CH2:25][C:24]([CH3:26])=[CH2:23])[C:15](=[O:17])[CH:16]=[C:11]2[C:10]([CH3:20])([CH3:19])[C:9]1=[O:21])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc2c(cn1)N(C(=O)OC(C)(C)C)C(=O)C2(C)C
Reactant: C=C(C)CBr
Agent: Cl
Solvent: CCOC(C)=O
Product: C=C(C)Cn1cc2c(cc1=O)C(C)(C)C(=O)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Methoxy-3,3-dimethyl-2-oxo-2,3-dihydro-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester was heated with 3-bromo-2-methylpropene (4 eq.) at 100° C. for 4 h in a reactivial and then allowed to cool. Saturated HCl in EtOAc ˜10 vol) was added and the reaction was stirred for 30 minutes at room temperature. The reaction was then concentrated in vacuo to give the title compound, used without further purification. MS: [M+H]+=333.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:41][OH:42]>[Cl-].[Na+].O.CN(C=O)C>[CH:10]1[C:11]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:41][OH:42])=[O:27])=[O:16])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CCCCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Reactant: NO
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C=C1c2ccccc2-c2ccccc21)NCCCCCCCC(=O)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
8-(2-(9H-fluoren-9-ylidene)acetamido)octanoic acid (363 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (166 mg, 44%) as a yellow solid. LC-MS (m/z) 379 (M+1).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:14][C:15]([N:17]1[CH2:29][C@@H:28]([CH3:30])[N:27]2[C@H:19]([CH2:20][C:21]3[C:26]2=[N:25][C:24]([CH2:31]OCCO)=[CH:23][CH:22]=3)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>ClCCl>[C:10]([O:14][C:15]([N:17]1[CH2:29][C@@H:28]([CH3:30])[N:27]2[C@H:19]([CH2:20][C:21]3[C:26]2=[N:25][C:24]([CH2:31][F:7])=[CH:23][CH:22]=3)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CF)nc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
A solution of 82.0 μl (0.11 g, 0.63 mmol) diethylaminosulphur trifluoride in 2 ml dichloromethane was cooled to −78 deg C. and treated with a solution of 0.20 g (0.63 mmol) (4R,9aR)-6-(2-hydroxy-ethoxymethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 15, intermediate b) in 2 ml dichloromethane. The cooling bath was removed and the reaction stirred for 1 h at room temperature. The solution was extracted with 10% aqueous sodium bicarbonate solution, washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:2) as eluant to afford the desired compound as a colorless oil (51.7%).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[F:13].C([O-])([O-])=O.[K+].[K+]>CO>[C:4]([C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[F:13])#[CH:3]
Reactant: C[Si](C)(C)C#Cc1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 20.9 %

Procedure:
A mixture of trimethyl((2,4,5-trifluorophenyl)ethynyl)silane (10 g, 46 mmol, prepared using General Procedure J from 1-bromo-2,4,5-trifluorobenzene and ethynyltrimethylsilane), K2CO3 (0.64 g, 4.6 mmol) and MeOH (25 mL) was stirred at ambient temperature for about 3.5 h. The reaction was quenched with water and extracted with Et2O. The organic layer was concentrated under reduced pressure. The crude material was purified by silica gel chromatography using pentane as eluent to give the title compound as oil (1.5 g, 21% yield): LC/MS (Table 1, Method a) Rt=3.58 min; 1H NMR (CDCl3) 3.38 (s, 1 H), 7.00-7.06 (m, 1 H), 7.35-7.40 (m, 1 H). Additional product (5.6 g, ˜40% purity, ˜33%) was recovered from rotary evaporator condenser.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH3:18])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:38][C:39](O)=[O:40])[CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])=[O:29].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH:16]([NH:17][CH3:18])[C:39](=[O:40])[CH2:38][C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])=[O:29])=[C:21]([O:20][CH3:19])[CH:22]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(OCCNC)c(OC)c1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC(NC)C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Reaction time: 48 h
Yield: 85.6 %

Procedure:
To a stirred solution of ethyl 3-methoxy-4-(2-methylaminoethoxy)benzoate (510 mg, 2.01 mmol) in DMF (13 mL) was added pentafluorophenyl ester of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (900 mg, 1.87 mmol) and Et3N (0.420 mL, 3.01 mmol), and the resulting mixture was stirred for 2 days. The mixture was diluted with EtOAc, washed with 1 N HCl, sat. NaHCO3, brine, and dried over Na2SO4. After being evaporated, the residue was purified by column chromatography on silica-gel with CHCl3:MeOH (50:1, v/v) to give 880 mg (85%) ethyl 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-N-methylaminoethoxy]benzoate as a colorless amorphous solid. 1H-NMR (CDCl3) d 1.37-1.41 (m, 3 H), 2.28 (s, 3 H), 3.03 and 3.18 (s, 3 H), 3.56 (s, 2 H), 3.65 (s, 2 H), 3.75-3.87 (m, 6 H), 4.06-4.24 (2 H, m), 4.33-4.39 (m, 2 H), 6.68-8.08 (series of m, 12 H).
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:33])([CH3:32])[C@H:10]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[NH2:31])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[Cl:35][CH2:36][C:37](=N)OCC>ClCCCl>[Si:1]([O:8][C:9]([CH3:33])([CH3:32])[C@H:10]([N:20]1[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:31]=[C:37]1[CH2:36][Cl:35])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOC(=N)CCl
Reactant: CC(C)(O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2ccccc12
Agent: Cl
Solvent: ClCCCl
Product: CC(C)(O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 70 °C
Yield: 25.4 %

Procedure:
N4-[(1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylpropyl]quinoline-3,4-diamine (6.12 g, 12.5 mmol) was dissolved in 100 mL of dry 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (2.77 g, 17.5 mmol) was then added and the reaction mixture was heated to 70° C. After stirring for 3 days, the reaction mixture was treated with an additional 1.00 g of ethyl 2-chloroethanimidoate hydrochloride and the reaction temperature was increased to 85° C. After stirring for 2 days, the reaction was cooled and the 1,2-dichloroethane was removed under reduced pressure. The resulting material was partitioned between 200 mL of saturated NaHCO3 solution and 200 mL of ethyl acetate. The layers were separated and the organic portion was washed with H2O and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 25%-50% ethyl acetate/hexanes) gave 1-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylpropyl]-2-(chloromethyl)-1H-imidazo[4,5-c]quinoline (1.74 g) as a golden syrup.