Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]([C:24]2[CH:29]=[C:28]([C:30]([NH:32][CH:33]4[CH2:35][CH2:34]4)=[O:31])[CH:27]=[CH:26][C:25]=2[CH3:36])[C:17]3=[O:37])[CH2:10][CH2:9]1)(C)(C)C.Cl.O>C(Cl)Cl.O1CCOCC1>[CH:33]1([NH:32][C:30]([C:28]2[CH:27]=[CH:26][C:25]([CH3:36])=[C:24]([N:18]3[C:17](=[O:37])[C:16]4[C:21](=[CH:22][CH:23]=[C:14]([N:11]5[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:38])=[O:5])[CH2:13][CH2:12]5)[CH:15]=4)[N:20]=[CH:19]3)[CH:29]=2)=[O:31])[CH2:34][CH2:35]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCN(CC(=O)OC(C)(C)C)CC3)cc2c1=O
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCN(CC(=O)O)CC3)cc2c1=O
Yield: 84.1 %

Procedure:
To a stirred solution of tert-butyl-[4-(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)piperazin-1-yl]acetate (0.28 g) in methylene chloride (10 ml) was added 4N HCl in dioxane (3 ml). After 72 hours water (15 ml) was added and the solution poured onto an ion exchange column (isolute SCX-2 column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK). The column was washed with water (2×50 ml), methanol (2×50 ml) and the product eluted with 2N ammonia in methanol. The fractions containing product were evaporated in vacuo, triuration with iso-hexane/ethyl acetate gave the title compound (0.21 g); NMR Spectrum: (DMSOd6) 0.61 (m, 4H), 2.12 (s, 3H), 2.70 (m, 4H), 2.84 (m, 1H), 3.09 (s, 2H), 3.28 (m, 4H), 7.49 (m, 2H), 7.62 (m, 2H), 7.81 (d, 1H), 7.89 (m, 1H), 8.07 (s, 1H), 8.44 (d, 1H); Mass Spectrum: M+H+ 462.
Reaction SMILES: [CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10][CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:36]=[C:37]1[O:41][C:39](=[O:40])[CH2:38]1>CO>[CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[N:10]([C:39](=[O:40])[CH2:38][C:37]([CH3:36])=[O:41])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C1CC(=O)O1
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)NCC2
Solvent: CO
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(=O)CC(C)=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To a mixture of the compound obtained in Example 3 (0.50 g) and methanol (10 ml) is added diketene (0.20 g), and the mixture is stirred at room temperature for two hours. The mixture is evaporated under reduced pressure to remove the solvent, and to the residue is added chloroform. The mixture is washed, dried and evaporated under reduced pressure. The resulting residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate/methanol=10:10:1) to give methyl 2-n-butyl-5-acetoacetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.29 g) as a foam.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17]C)=[O:16])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[Li+].[OH-].CO.Cl>O>[O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate (2.10 g; 8.23 mmol), 1N LiOH (15 mL), and methanol (50 mL) was stirred at 0° C. for 30 min and at room temperature overnight. The mixture was acidified to pH 1 with 1N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (87%) of snow-white solid which did not require further purification. 1H NMR (CDCl3) : d 0.87 (t, 3H) ; 1.22, 1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m, 1H); 3.53 (dd, 2H, J=10.4, 7.3); 4.55 (dd, 1H, J=8.6, 4.1).
Reaction SMILES: [Br:1][C:2](=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:3][NH:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32].C(N(CC)CC)C.C(O)(C(F)(F)F)=O>C(#N)C>[Br:1][C:2](=[CH:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH2:3][N:4]([CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:31](=[O:32])[C:30]1[CH:29]=[C:28]([O:27][CH3:26])[C:36]([O:37][CH3:38])=[C:35]([O:39][CH3:40])[CH:34]=1
Reactant: Fc1ccc(C=C(Br)CNCC2CCCN2CC2CCCCC2)cc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(C(=O)N(CC(Br)=Cc2ccc(F)cc2)CC2CCCN2CC2CCCCC2)cc(OC)c1OC

Procedure:
Experimental condition analogous to Example 12 were used with [2-bromo-3-(4-fluoro-phenyl)-allyl]-(1-cyclohexylmethyl-pyrrolidin-2-ylmethyl)-amine 0.15 g (0.36 mmol), 3,4,5-trimethoxy-benzoylchloride 0.1 g (0.47 mmol), and triethylamine 0.08 ml. Reverse phase high pressure liquid chromatography with a gradient of 20-80% acetonitrile phase lead to 120 mg of white powder as a TFA salt.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([O:17][CH2:18][C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([C@H:31]3[CH2:33][C@H:32]3[CH2:34][CH2:35][OH:36])[CH2:27][CH2:26]2)=[N:23][CH:24]=1)[CH3:16].[F:37][C:38]1[CH:43]=[C:42](O)[CH:41]=[CH:40][C:39]=1[CH2:45][C:46]([O:48][CH3:49])=[O:47].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:15]([O:17][CH2:18][C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([C@H:31]3[CH2:33][C@H:32]3[CH2:34][CH2:35][O:36][C:42]3[CH:41]=[CH:40][C:39]([CH2:45][C:46]([O:48][CH3:49])=[O:47])=[C:38]([F:37])[CH:43]=3)[CH2:27][CH2:26]2)=[N:23][CH:24]=1)[CH3:16]
Reactant: COC(=O)Cc1ccc(O)cc1F
Reactant: CCOCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
DIAD (0.955 ml, 4.91 mmol) was added to a stirred mixture of 2-[(1S,2R)-2-{1-[5-(ethoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl]ethanol (1 g, 3.27 mmol), methyl (2-fluoro-4-hydroxyphenyl)acetate (0.724 g, 3.93 mmol) and triphenylphosphine (1.288 g, 4.91 mmol) in toluene (10 ml). The mixture was stirred at RT for 5 hrs. The mixture was diluted with ethyl acetate (20 mL), washed with brine, dried over MgSO4, filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel, Biotage 100M, using a gradient eluant of 0-100% EtOAc/hexanes to afford the title compound. LC/MS (m/z): 472 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Cl:10][SiH:11]([Cl:13])[Cl:12]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Si:11]([Cl:13])([Cl:12])[Cl:10])=[CH:4][CH:3]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: ClCc1ccc(Cl)cc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Clc1ccc(C[Si](Cl)(Cl)Cl)cc1
Yield: 70.2 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.22 g (0.75 mmol) of tetrabutylphosphonium chloride, 1.21 g (7.51 mmol) of 4-chlorobenzyl chloride, and 3.05 g (22.5 mmol) of trichlorosilane were reacted at 130° C. for 4 hrs. The resulting mixture was distilled to give 1.37 g of (4-chlorobenzyl)trichlorosilane (yield; 81%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11](=[O:14])([O-])[O-].[K+].[K+].[CH3:17]N(C)C=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][O:14][CH3:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: CN(C)C=O
Reactant: COc1cc(O)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COCOc1ccc(Br)c(OC)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of 4-bromo-3-methoxyphenol (500 mg, 2.46 mmol), chlorodimethylether (281 μL, 3.70 mmol), and potassium carbonate (850 mg, 6.15 mmol) was suspended in anhydrous N,N-dimethylformamide (8 mL) and stirred at 50° C. for 1 hour. After cooling down, the reaction mixture was diluted with ethyl acetate (150 mL). The mixture was washed with water (150 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (421 mg) as a colorless oil. (Yield 69%)
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[NH:14][C:13](=[O:15])[CH:12]=[CH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:21][O+](C)C>C(Cl)Cl>[CH3:21][O:15][C:13]1[CH:12]=[CH:11][CH2:10][CH2:9][CH:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:14]=1
Reactant: C[O+](C)C
Reactant: O=C1C=CCCC(Cc2ccccc2)N1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(Cc2ccccc2)CCC=C1

Procedure:
The product of Example 187 is reacted with one equivalent of trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10](O)=[O:11])[C:6](=[O:13])[N:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.CN([C:34]([O:38]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:55][C:56]1[CH:57]=[C:58]([NH2:75])[CH:59]=[CH:60][C:61]=1[O:62][C:63]1[C:72]2[C:67](=[CH:68][C:69]([O:73][CH3:74])=[CH:70][CH:71]=2)[N:66]=[CH:65][CH:64]=1>CN(C=O)C.ClCCl>[CH3:34][O:38][C:70]1[CH:71]=[C:72]2[C:67](=[CH:68][C:69]=1[O:73][CH3:74])[N:66]=[CH:65][CH:64]=[C:63]2[O:62][C:61]1[CH:60]=[CH:59][C:58]([NH:75][C:10]([C:7]2[C:6](=[O:13])[N:5]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:4]([CH2:3][C:2]([OH:1])([CH3:21])[CH3:20])[C:8]=2[CH3:9])=[O:11])=[CH:57][C:56]=1[F:55]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Reactant: COc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(CC(C)(C)O)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Temperature: 37 °C
Reaction time: 0.25 h
Yield: 73.8 %

Procedure:
To a stirring solution of 1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (104 mg, 358 μmol) and diisopropylethylamine (62 μl, 358 μmol) in DMF (1 mL) was added HATU (136 mg, 358 μmol) and stirred at 37° C. under nitrogen for 15 min. To this was added 3-fluoro-4-(7-methoxyquinolin-4-yloxy)benzenamine (98 mg, 344 mmol) and stirred overnight at 37° C. The reaction mixture was diluted with dichloromethane (10 mL) and washed with 1M NaOH (20 mL), and extracted with dichloromethane (3×5 mL). Combined organics layer was washed with brine and then dried with MgSO4. Residual DMF was removed with repeated azeotroping with toluene (4×5 mL) under reduced pressure. The residue was purified on 12 g silica (10>30% of 6% 2 M NH3 in MeOH/DCM). Final material was lyophilized from 50% ACN/water to give the title compound (155 mg, 74% yield) as a white fluffy solid. MS (ESI pos. ion) m/z: 587 (MH+). Calc'd exact mass for C32H31FN4O6 587. 1H NMR (400 MHz, CHLOROFORM-d) 10.88 (1H, s), 8.47 (1H, d, J=5.3 Hz), 7.92 (1H, dd, J=12.5, 2.0 Hz), 7.59 (1H, s), 7.54 (2H, t, J=7.7 Hz), 7.40-7.49 (2H, m), 7.30 (3H, d, J=7.8 Hz), 7.17 (1H, t, J=8.7 Hz), 6.45 (1H, d, J=5.3 Hz), 4.06 (3H, s), 4.05 (3H, s), 3.88 (2H, s), 2.89 (3H, s), 2.01 (1H, s), 1.15 (6H, s)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[F:11])[C:5](F)=[O:6].[Cl:14][C:15]1[C:16]([F:35])=[C:17]([CH:30]=[C:31]([Cl:34])[C:32]=1[F:33])[C:18]([C:20](=COCC)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:19].ClC1C=C2C(=C(Cl)C=1F)[N:43]([CH:49]1[CH2:51][CH2:50]1)[CH:42]=[C:41]([C:52]([O:54][CH2:55][CH3:56])=[O:53])C2=O>>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][C:18](=[O:19])[C:17]1[CH:30]=[C:31]([Cl:34])[C:32]([F:33])=[C:15]([Cl:14])[C:16]=1[F:35])[CH3:25].[Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[F:11])[C:5]([C:41](=[CH:42][NH:43][CH:49]1[CH2:50][CH2:51]1)[C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:6]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c(Cl)cc2c1=O
Reactant: O=C(F)c1cc(Cl)c(F)c(Cl)c1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(Cl)c(F)c(Cl)c1F
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(Cl)c(F)c(Cl)c1F
Product: CCOC(=O)CC(=O)c1cc(Cl)c(F)c(Cl)c1F
Yield: 43 %
Yield: 96 %

Procedure:
3,5-Dichloro-2,4-difluoro-benzoyl fluoride is reacted analogously to Example A, the reaction passing through the following stages: ethyl(3,5-dichloro-2,4-difluoro-benzoyl)-acetate (yield: 43%, boiling point 133° C./2.5 mm Hg), ethyl 2-(3,5-dichloro-2,4-difluoro-benzoyl)-3-ethoxy-acrylate (crude yield: 91%, oil), ethyl 2-(3,5-dichloro-2,4-difluoro-benzoyl)-3-cyclopropylamino-acrylate (yield: 96%, melting point 71°-74° C.), ethyl 6,8-dichloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (yield: 97%, melting point 215°-217° C., with decomposition) and 6,8-dichloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (yield: 93%; melting point 204°-206° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([CH3:29])([C:25](=[O:28])[NH:26][CH3:27])[CH3:24])[CH:17]=1)[C:10]([CH3:31])([CH3:30])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:30][C:10]1([CH3:31])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([CH3:29])([C:25](=[O:28])[NH:26][CH3:27])[CH3:24])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)NC)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CNC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 34.6 %

Procedure:
A mixture of 3,3-dimethyl-2-[3-(1-methyl-1-methylcarbamoyl-ethylamino)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.4 g, 0.95 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (5 mL) was stirred at 50° C. for 16 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-[3-(1-methyl-1-methylcarbamoyl-ethylamino)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (130 mg, 34%) as a white solid: LC/MS m/e calcd for C, 23H; 29N, 3; O, 3; (M+H)+: 396.51, observed: 396.2.
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C@@:2]21[CH:14]1[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]1)[CH2:10]2.[N+:17]([O-])([OH:19])=[O:18].O.C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[N+:17]([C:8]1[CH:9]=[C:4]2[CH2:3][C@:2]3([CH:14]4[CH2:13][CH2:12][N:11]([CH2:16][CH2:15]4)[CH2:10]3)[O:1][C:5]2=[N:6][CH:7]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Temperature: 67.5 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
(R)-(−)-Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (3.03 g, 14 mmol) was dissolved in concentrated sulfuric acid (7 mL) at 0-5 ° C., fuming nitric acid (3.3 mL, 70.2 mmol) was added over 10 minutes, the mixture was stirred for 1 hour, and heated at 65-70° C. for 24 hours. Cooled, poured onto ice (200 gm), added 300 mL of water, basified to pH 10 with solid potassium carbonate, stirred for 1 hour, filtered off and dried the solid title compound (3.6 g, 13.8 mmol, 98%): electrospray MS (m/z, relative intensity) 262 ([MH]+, 100).
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:12]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:51]([C:53]1[N:54]=[C:55]([C:66]([O-])=[O:67])[N:56]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[CH:57]=1)#[N:52].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([NH:5][S:6]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:66]([C:55]2[N:56]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[CH:57]=[C:53]([C:51]#[N:52])[N:54]=2)=[O:67])=[C:13]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:12]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(CCS(=O)(=O)NC(C)(C)C)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(CCS(=O)(=O)NC(C)(C)C)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
A solution of 267 mg (0.732 mmol) of 2-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-ethanesulfonic acid tert-butyl amide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 512 mg (1.10 mmol) of PyBroP, 246 mg (0.806 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)) and 383 μL (2.20 mmol) of DIEA. The mixture was stirred at RT for 3 h, diluted with CH2Cl2 (20 mL), and washed with saturated aqueous NaHCO3 (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 25% EtOAc-hexane afforded 311 mg (69%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 9.73 (br s, 1H), 8.32 (d, 1H, J=8.4 Hz), 7.76 (s, 1H), 7.13 (dd, 1H, J=8.4, 2.0 Hz), 7.02 (d, 1H, J=2.0 Hz), 5.94 (s, 2H), 5.77-5.72 (m, 1H), 4.07 (br s, 1H), 3.69-3.62 (m, 2H), 3.35-3.27 (m, 2H), 3.14-3.06 (m, 2H), 2.31-2.23 (m, 2H), 2.12-2.07 (m, 2H), 1.58 (t, 2H, J=6.4 Hz), 1.34 (s, 9H), 1.10 (s, 6H), 1.00-0.94 (m, 2H).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:17]([NH2:18])=[C:16]([O:24][CH3:25])[CH:15]=1.Cl[C:27]1[N:32]=[C:31]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH:30]=[CH:29][N:28]=1>CC(O)CCC>[F:13][C:14]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:17]([NH:18][C:27]2[N:32]=[C:31]([C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][CH:34]=3)[CH:30]=[CH:29][N:28]=2)=[C:16]([O:24][CH3:25])[CH:15]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Reactant: Clc1nccc(-c2c[nH]c3ccccc23)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)O
Solvent: O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 120 °C
Reaction time: 18 h
Yield: 55.2 %

Procedure:
p-Toluenesulfonic acid hydrate (225 mg, 1.18 mmol) was added in one portion to a mixture of 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 200 mg, 1.07 mmol) and 3-(2-chloropyrimidin-4-yl)-1H-indole (247 mg, 1.07 mmol) in 2-pentanol (10 mL). The resulting mixture was then stirred at 120° C. for 18 h. The resulting precipitate was collected by filtration, washed with 2-pentanol (5 mL) and dried in vacuo to give a yellow solid. The solid was triturated with CH3CN to give a solid which was collected by filtration and dried in vacuo to give the title compound (224 mg, 55%) as a yellow solid; m/z: ES+ MH+ 380.21.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH:11]([CH3:16])[CH2:12][C:13](O)=[O:14])[N:10]=[C:6]2[C:5]([CH3:17])=[N:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH:11]([CH3:16])[CH2:12][C:13]([Cl:21])=[O:14])[N:10]=[C:6]2[C:5]([CH3:17])=[N:4][CH:3]=1
Reactant: Cc1ncc(C)n2nc(C(C)CC(=O)O)nc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ncc(C)n2nc(C(C)CC(=O)Cl)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 3-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)butanoic acid (200 mg, 0.086 mmol) in DCM (15 mL) was added oxalyl chloride (3 mL) and DMF (0.1 mL). The mixture was stirred at room temperature for 2 h. The mixture was then evaporated under reduced pressure to give the product as a brown solid (208 mg, 96% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[Br:70][C:71]1[CH:72]=[CH:73][C:74]([NH2:77])=[N:75][CH:76]=1>C(Cl)Cl>[Br:70][C:71]1[CH:72]=[CH:73][C:74]2[N:75]([C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:77]=2)[CH:76]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: Nc1ccc(Br)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(F)cc2)nc2ccc(Br)cn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
Ethyl 3-(4-fluorophenyl)-3-oxopropanoate (2.6 g, 12 mmol) was dissolved into DCM (32 mL), cooled to 0° C. and treated with tetra-n-butylammonium tribromide (6.75 g, 14.0 mmol). The reaction mixture was stirred at 0° C. for 1 h, rt for 1 h and then washed with sat NaHCO3 (aq) (2×50 mL), dried (MgSO4), filtered and concentrated. The crude material was dissolved into EtOH (60 mL) and then 5-bromopyridin-2-amine (6.22 g, 36.0 mmol) was added and the reaction was stirred at 70° C. under nitrogen overnight (complete by LCMS). The reaction mixture was diluted with DCM (˜120 mL), washed with sat. NaHCO3 (aq) (2×100 mL) and the organic layer was dried (MgSO4), filtered and concentrated. The resulting solid was dissolved into DCM (˜30 mL), diluted with hexanes (˜70 mL) and stirred. The solids were filtered away (contained some desired product) and the mother liquor was concentrated, dissolved into DCM and purified by Biotage Horizon (40M, 10% EtOAc/hex, SiO2) (the compound crashed out in the instrument resulting in an unknown quantity being shunted to waste). The collected fractions had solid material precipitating out which was collected by filtration to yield ethyl 6-bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxylate (594 mg, 1.636 mmol, 13% yield) as a white fluffy solid. 1H NMR (500 MHz, CDCl3) δ ppm 9.60 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.62 (d, J=9.2 Hz, 1H), 7.52 (dd, J=9.2, 1.5 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H). LCMS: m/e=743 (M+H)+, retention time=2.24 min, (Column=(2)phenomenex 4.6×50 mmC18 10 um, Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA Start % B=0, Final % B=100, Gradient Time=2 min, Hold time=1 min, Flow Rate=5 mL/min) LC-MS retention time 2.04 min; m/z 362, 364 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.