Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH2:8]I)=[O:2].Cl.[CH3:23][NH:24][CH3:25].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:23][N:24]([CH2:8][CH2:7][CH2:6][C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][NH:3][CH:1]=[O:2])[CH3:25]
Reactant: CNC
Reactant: O=CNCC(CCCI)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C)CCCC(CNC=O)(c1ccccc1)c1ccccc1
Yield: 67.1 %

Procedure:
A mixture of 5-formylamino-1-iodo-4,4-diphenylpentane (8.5 g), dimethylamine hydrochloride (17.63 g), triethylamine (30.1 ml), and potassium carbonate (3 g) was heated in acetonitrile (250 ml) at 60° C. for 2 hours. This reaction mixture was concentrated to dryness and the group was extracted using ethyl acetate and water. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness. The group was crystallized from ethyl acetate-isopropyl ether to provide the title compound (4.5 g) as white powder.
Reaction SMILES: [OH:1][C:2]1[C:3]2[S:10][C:9]3[N:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[N:6][N:7]=1.[C:16]([O-])([O-])=O.[K+].[K+].CN(C=O)C.CI>O>[CH3:16][N:7]1[C:2](=[O:1])[C:3]2[S:10][C:9]3[N:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[N:6]1
Reactant: Cc1ccc2c(n1)sc1c(O)nnnc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)sc1c(=O)n(C)nnc12
Reaction time: 3 h

Procedure:
To a mixture of 6 g. (0.028 M) of 4-hydroxy-7-methylpyrido[3',2':4,5]thieno[3,2-d]-1,2,3-triazine, 12 g. of K2CO3 in 150 ml. DMF at 75° C. was added 6 ml. methyl iodide and stirring at this temperature was continued for 3 hours. The mixture was then diluted with water and the precipitated product was collected by filtration. Crystallization with chloroform gave m.p. 169°-171° C.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[CH2:21]([O:23][CH2:24][CH:25]=[O:26])[CH3:22]>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[CH:25]([OH:26])[CH2:24][O:23][CH2:21][CH3:22]
Reactant: CCOCC=O
Reactant: Fc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOCC(O)c1c(F)cncc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-BuLi (2.66 mL, 4.26 mmol) was added to a solution of diisopropylamine (0.607 mL, 4.26 mmol) in THF (10 mL) at −78° C. After 30 min, 3-bromo-5-fluoropyridine (0.500 g, 2.84 mmol) in THF (10 mL) is added dropwise. The mixture was stirred at −78° C. for 1 hr, and 2-ethoxyacetaldehyde (0.464 g, 4.26 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 2 hrs. The reaction is quenched with a saturated aqueous NaHCO3 solution and the cooling bath was removed. The mixture was shaken with ethyl acetate and the organic phase is washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography employing heptane-ethyl acetate (4:1) to give 1-(3-bromo-5-fluoro-pyridin-4-yl)-2-ethoxy-ethanol. MS (ESI) m/z 266.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:19][C:20]([Si:23]([CH3:33])([CH3:32])[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([CH3:22])[CH3:21].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:29][C:28]2[CH:27]=[CH:26][C:25]([O:24][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:32])[CH3:33])=[CH:31][CH:30]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2cc(Cl)ncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
The product from Example 1, Step 3 (20.0 g, 104 mmol) and triethylamine (17.4 mL, 125 mmol) were dissolved in THF (200 mL) and a solution of 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}aniline (25.0 g, 113 mmol) in THF (50 mL) was added and the mixture was allowed to stir at rt overnight. The reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated to give the title compound (37.5 g, 95%) as a yellow oil. MS (ES+) m/e 381 [M+H]+.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:15][C:16]1[C:17]([CH2:22]Br)=[CH:18][CH:19]=[CH:20][CH:21]=1.[CH3:24]N(C)C=O>>[C:7]1([CH3:24])[CH:2]=[CH:3][CH:4]=[C:5]([S:8]([N:11]2[CH2:22][C:17]3[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15]2)(=[O:9])=[O:10])[CH:6]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CN(C)C=O
Reactant: BrCc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(S(=O)(=O)N2Cc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 34.2 g (0.2 mol) of p-toluenesulfonamide in 100 ml of dry N,N-dimethylformamide was added dropwise to a suspension of 18.9 g (0.42 mol) of sodium hydride (50% oil dispersion) in 60 ml of N,N-dimethylformamide. The reaction was stirred at room temperature for one hour, followed by one hour at 60° C. A solution of 52.8 g (0.2 mol) of α,α'-dibromo-0-xylene in 300 ml of N,N-dimethylformamide was added at such a rate that the temperature of the reaction mixture remained between 60°-70° C. After further stirring for 48 hours at room temperature under nitrogen ice water was added to the reaction mixture. The precipitated solid was filtered and recrystallized from hot ethanol. Yield 33.58 g, m.p. 175°-177° C. NMR (CDCl3) δ 2.32 (3H, s), 4.5 (4H,s), 7.25 (8H, m).
Reaction SMILES: [CH3:1][C:2]1[C:7]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:17].N1C=CC=CC=1.[S:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]2[CH2:32][CH2:33][CH2:34][CH2:35][C:25]1=2>C(Cl)Cl>[CH3:1][C:2]1[C:7]([B:8]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:17][C:29]([C:28]1[S:24][C:25]2[CH2:35][CH2:34][CH2:33][CH2:32][C:26]=2[CH:27]=1)=[O:30]
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(Cl)c1cc2c(s1)CCCC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1.20 g, 5.16 mmol, 1.0 equiv) and pyridine (0.42 mL, 25.8 mmol) are dissolved in DCM (40 mL) at 0° C. under a nitrogen atmosphere. 4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carbonyl chloride (1) (1.03 g, 5.16 mmol) is then added in portions over 5 min and allowed to react warming to RT over 60 min. All solvent is then removed under reduced pressure, and the resultant oil is reduced from toluene (3×20 mL) to remove residual pyridine. The residue is then dissolved in ethyl acetate and washed with sodium hydroxide (1N, 1×100 mL), then washed with saturated sodium chloride (1×100 mL) and dried over sodium sulfate. The solution is then filtered and concentrated under reduced pressure to give 4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid [2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (2) as an off-white solid (1.87 g).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[C:18]3[CH:17]=[CH:16][C:15](=[O:19])[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].CN(C)C=O.C(O)C>[Fe].O>[O:19]=[C:15]1[NH:14][C:13]2[N:12]=[CH:11][CH:10]=[C:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:21][CH:20]=3)[C:18]=2[CH:17]=[CH:16]1
Reactant: O=c1ccc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2[nH]1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc3[nH]c(=O)ccc23)cc1

Procedure:
4-(4-Nitrophenoxy)-7-oxo-7,8-dihydro[1,8]naphthyridine (156 mg), iron powder (300 mg), ammonium chloride (600 mg), dimethylformamide (2 ml), ethanol (1 ml) and water (1 ml) were stirred at 100° C. for 20 minutes. The mixture was filtered with celite, and then water and ethyl acetate were added for extraction. The organic layer was washed 4 times with aqueous ammonium chloride solution and then dried over magnesium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 30 mg of the target substance as a light yellow solid.
Reaction SMILES: CC(C)(C)[C@@H](C(O)=O)N[C:5](OCCCC=C)=[O:6].[NH2:18][C@@H:19]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:20]([OH:22])=[O:21].[CH3:29][C:30]([CH3:37])([CH2:33][CH2:34][CH:35]=[CH2:36])[CH2:31][OH:32]>>[CH:23]1([C@H:19]([NH:18][C:5]([O:32][CH2:31][C:30]([CH3:37])([CH3:29])[CH2:33][CH2:34][CH:35]=[CH2:36])=[O:6])[C:20]([OH:22])=[O:21])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C=CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: N[C@H](C(=O)O)C1CCCCC1
Reactant: C=CCCC(C)(C)CO
Product: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)O)C1CCCCC1

Procedure:
(2S)-Cyclohexyl({[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}amino)acetic acid was prepared according to the procedure for 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine using (2S)-amino(cyclohexyl)acetic acid and 2,2-dimethylhex-5-en-1-ol. LRMS (ESI) m/z 312.3 [(M+H)+; calcd for C17H30NO4: 312.2].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[N:14]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:22][CH2:21][CH2:20][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: Nc1ccc(S(=O)(=O)NCCN2CCOCC2)cc1

Procedure:
Anilines with other sidechains will be readily prepared by a person having ordinary skill in the art having regard to that skill and this disclosure, and will be usable in the syntheses of Reaction Scheme 4. For example, diethyl (4-nitrobenzyl)phosphonate was reacted in a Wittig reaction with pyridin-3-carboxaldehyde and the resulting 3-(4-nitrostyryl)pyridine hydrogenated to give 4-[2-(pyridin-3-yl)ethyl]benzenamine, used to synthesize compound 99A, and the anilines used to synthesize compounds 97A and 98A were similarly prepared; 4-nitrobenzaldehyde was reacted with glyoxal and ammonia to give 2-(4-nitrophenyl)-1H-imidazole, which was N-methylated with methyl iodide and then reduced with stannous chloride to give 4-(1-methyl-1H-imidazol-2-yl)benzenamine, used to synthesize compound 106A; 2-fluoro-4-nitrobenzoic acid was converted to the corresponding benzoyl chloride with oxalyl chloride, then reacted with 3-(morpholin-4-yl)propan-1-amine and reduced to give 4-amino-2-fluoro-N-[3-(morpholin-4-yl)propyl]benzamide, used to synthesize compound 50A; and 4-nitrobenzenesulfonyl chloride was reacted with 2-(morpholin-4-yl)ethan-1-amine and then reduced with stannous chloride to give 4-amino-N[2-(morpholin-4-yl)ethyl]benzenesulfonamide, used to synthesize compound 128A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[C:33]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:34]2)=[CH:30][C:29]=1[O:42][CH3:43]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:27][C:28]3[CH:36]=[C:35]4[C:31]([CH:32]=[C:33]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:34]4)=[CH:30][C:29]=3[O:42][CH3:43])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CCOC(=O)c1cc2cc(OC)c(N)cc2[nH]1
Product: CCOC(=O)c1cc2cc(OC)c(NC(=O)C(CCOC)n3cc(OC)c(-c4cc(Cl)ccc4C#N)cc3=O)cc2[nH]1

Procedure:
150 mg (398 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 103 mg (438 μmol, 1.1 eq.) of ethyl 6-amino-5-methoxy-1H-indole-2-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (column: Chromatorex 125 mm×30 mm, 10 μm, mobile phase: water and acetonitrile, gradient 10% acetonitrile to 90% acetonitrile). Yield: 87 mg (36% of theory)
Reaction SMILES: F[C:2]1[C:7]2[N:8]=[CH:9][N:10]([C@H:11]3[C@H:18]4[C@H:14]([O:15][C:16]([CH3:20])([CH3:19])[O:17]4)[CH:13]=[C:12]3[F:21])[C:6]=2[C:5]([F:22])=[CH:4][N:3]=1.F[C:24]1[C:29]2[N:30]([C@H:33]3[C@H:40]4[C@H:36]([O:37][C:38]([CH3:42])([CH3:41])[O:39]4)[CH:35]=[C:34]3[F:43])[CH:31]=[N:32][C:28]=2[C:27]([F:44])=[CH:26][N:25]=1>N>[F:22][C:5]1[C:6]2[N:10]([C@H:11]3[C@H:18]4[C@H:14]([O:15][C:16]([CH3:19])([CH3:20])[O:17]4)[CH:13]=[C:12]3[F:21])[CH:9]=[N:8][C:7]=2[C:2]([NH2:25])=[N:3][CH:4]=1.[F:44][C:27]1[C:28]2[N:32]=[CH:31][N:30]([C@@H:33]3[C@H:40]4[C@H:36]([O:37][C:38]([CH3:42])([CH3:41])[O:39]4)[CH:35]=[C:34]3[F:43])[C:29]=2[C:24]([NH2:3])=[N:25][CH:26]=1
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(F)ncc(F)c43)C(F)=C[C@H]2O1
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(F)cnc(F)c43)C(F)=C[C@H]2O1
Agent: N
Product: CC1(C)O[C@@H]2[C@@H](C=C(F)[C@@H]2n2cnc3c(F)cnc(N)c32)O1
Product: CC1(C)O[C@H]2[C@H](n3cnc4c(N)ncc(F)c43)C(F)=C[C@H]2O1
Temperature: 100 °C

Procedure:
Liquid ammonia (150 mL) was added to a mixture of 4,7-difluoro-1-((3aS,4S,6aR)-5-fluoro-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-1H-imidazo[4,5-c]pyridine (5-7) (140 mg, 0.45 mmol, 1 equiv) and 4,7-difluoro-3-((3aS,4S,6aR)-5-fluoro-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-3H-imidazo[4,5-c]pyridine (5-8) (160 mg, 0.51 mmol, 1 equiv). The resulting solution was heated in a high pressure vessel to 100° C. for 3 days. The mixture was then concentrated and purified via flash chromatography (40 g SiO2; 20-100% EtOAc in hexanes, holding at 100% EtOAc to elute 5-9) to yield 7-fluoro-1-((3aS,4S,6aR)-5-fluoro-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-1H-imidazo[4,5-c]pyridin-4-amine (5-9) as a white solid and 7-fluoro-3-((3aS,4R,6aR)-5-fluoro-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-3H-imidazo[4,5-c]pyridin-4-amine (5-10) as a white solid. 1H NMR (5-9) (500 MHz, CDCl3): δ 7.77 (d, J=3.5 Hz, 1H); 7.71 (s, 1H); 5.74 (s, 1H); 5.58 (s, 1H); 5.36 (m, 1H); 5.12 (s, 2H); 4.75 (t, J=5 Hz, 1H); 1.55 (s, 3H); 1.36 (s, 3H). LRMS m/z (M+H) 308.9 found, 309.1 required. LRMS m/z (5-10) (M+H) 308.9 found, 309.1 required.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:26][S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH2:36][NH2:37])=[N:34][CH:35]=1)(=[O:29])=[O:28].[CH3:38][C:39]1[N:44]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[C:43](=[O:55])[C:42]([C:56](O)=[O:57])=[CH:41][C:40]=1[C:59]1[N:60]([CH3:64])[N:61]=[CH:62][CH:63]=1.CC(N(C)C)=O>CN1C(=O)CCC1>[CH3:38][C:39]1[N:44]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:52])[F:53])[CH:46]=2)[C:43](=[O:55])[C:42]([C:56]([NH:37][CH2:36][C:33]2[CH:32]=[CH:31][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:35][N:34]=2)=[O:57])=[CH:41][C:40]=1[C:59]1[N:60]([CH3:64])[N:61]=[CH:62][CH:63]=1
Reactant: CS(=O)(=O)c1ccc(CN)nc1
Reactant: Cc1c(-c2ccnn2C)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccnn2C)cc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 20.4 %

Procedure:
HBTU (30 mg, 0.079 mmol) was added to {[5-(methylsulfonyl)pyridin-2-yl]methyl}amine hydrochloride (20 mg, 0.090 mmol), 6-methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid (Example 92 (a), 27 mg, 0.072 mmol) and DMA (23 μl, 0.31 mmol) in NMP (0.25 ml) and the mixture was stirred in a sealed vial overnight. The product was purified by preparative HPLC and freeze-dried to give the title compound as a white solid (8 mg, 20%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([NH2:17])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.[NH2:20][NH2:21]>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([NH2:17])=[C:7]([CH:16]=1)[C:8](=[N:20][NH2:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Reactant: NN
Product: NN=C(c1ccccc1)c1cc(C(F)(F)F)ccc1N

Procedure:
In the manner given in Preparation 1, 5-(trifluoromethyl)-2-aminobenzophenone is refluxed with hydrazine hydratein diethylene glycol to give 5-trifluoromethyl-2-aminobenzophenone hydrazone.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:7])C>CO>[C:8]1([C:6]([OH:7])=[O:5])[NH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12]2
Reactant: CCOC(=O)c1[nH]cc2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1[nH]cc2c1CCCC2

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 10.3 mmol) was added to a stirring, room temperature solution of 171 (0.3966 g, 2.05 mmol) in MeOH (5.1 mL, 0.4 M) under N2. The reaction was then heated to reflux for 20 minutes. A small amount of starting material remained. A large amount of undesired product along with only a small amount of desired product was observed by HPLC. The reaction was concentrated, redissolved in H2O, and extracted with EtOAc (1 mL). 10% aq. HCl was added dropwise to the aqueous layer until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 0.0076 g (11.6%) of 172. 1H (CD3OD, 400 MHz): δ 5.62 (1H, s), 2.77 (2H, t, J=5.6 Hz), 2.52 (2H, t, J=5.4 Hz), 1.78-1.66 (4H, m) ppm. 13C (CD3OD, 100MHz): δ 164.87, 129.69, 122.48, 120.57, 118.42, 24.74, 24.69, 24.35, 22.94 ppm. DEPT (CD3OD, 100 MHz): CH2 carbons: 24.74, 24.69, 24.35, 22.94; CH carbons: 120.57 ppm. HPLC: 8.896 min.
Reaction SMILES: [C:1]([C:4]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])CCC1)(=[O:3])[CH3:2].II.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl.O1C[CH2:26][CH2:25][CH2:24]1>[Zn]>[CH2:20]([O:19][C:17]([C:16]1([CH:4]([CH:1]([OH:3])[CH3:2])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:26][CH2:25][CH2:24]1)=[O:18])[CH3:21]
Reactant: C1CCOC1
Reactant: CCOC(=O)C1(C(C)=O)CCC1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: II
Agent: [Zn]
Product: CCOC(=O)C(C(C)O)C1(C(=O)OCC)CCC1

Procedure:
Ethyl 1-acetylcyclobutanecarboxylate (13.79 g, 81 mmol) was dissolved in tetrahydrofuran (50 ml), and the solution was mixed with zinc powder (10.59 g) and a catalytic amount of iodine. While heating under reflux, a tetrahydrofuran solution (100 ml) of ethyl bromoacetate (13.48 ml, 121 mmol) was added dropwise thereto. The reaction solution was heated under reflux for an additional 1 hour, cooled and then mixed with 1 N hydrochloric acid (100 ml). After evaporating the solvent, the resulting residue was mixed with ethyl acetate (500 ml), washed, after removing insoluble material by filtration, with saturated brine (300 ml) and then dried over anhydrous sodium sulfate. By evaporating the solvent, the title compound was obtained quantitatively in an oily form.
Reaction SMILES: O([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][N:23]4[CH2:28][CH:27]5[CH:25]([CH:26]5[CH2:29][OH:30])[CH2:24]4)=[CH:20][CH:19]=3)[CH:16]=2)[N:11]=[CH:10][N:9]=1)C1C=CC=CC=1.[CH:33]1([CH2:36][N:37]2[C:45]3[C:40](=[CH:41][C:42]([NH2:46])=[CH:43][CH:44]=3)[CH:39]=[CH:38]2)[CH2:35][CH2:34]1.Cl.[NH+]1C=CC=CC=1.C1(O)C=CC=CC=1>C(Cl)(Cl)Cl>[CH:33]1([CH2:36][N:37]2[C:45]3[C:40](=[CH:41][C:42]([NH:46][C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([C:18]6[CH:19]=[CH:20][C:21]([CH2:22][N:23]7[CH2:28][CH:27]8[CH:25]([CH:26]8[CH2:29][OH:30])[CH2:24]7)=[CH:31][CH:32]=6)[CH:16]=5)[N:11]=[CH:10][N:9]=4)=[CH:43][CH:44]=3)[CH:39]=[CH:38]2)[CH2:34][CH2:35]1
Reactant: Nc1ccc2c(ccn2CC2CC2)c1
Reactant: OCC1C2CN(Cc3ccc(-c4ccc5ncnc(Oc6ccccc6)c5c4)cc3)CC12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: Oc1ccccc1
Solvent: ClC(Cl)Cl
Product: OCC1C2CN(Cc3ccc(-c4ccc5ncnc(Nc6ccc7c(ccn7CC7CC7)c6)c5c4)cc3)CC12
Temperature: 110 °C
Yield: 66.3 %

Procedure:
To a 3 mL Wheaton vial was, added {3-[4-(4-phenoxy-quinazolin-6-yl)-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 16 (100 mg, 0.24 mmol), 1-cyclopropylmethyl-1H-indol-5-ylamine 19 (48 mg, 0.26 mmol), pyridinium hydrochloride (33 mg, 0.284 mmol), and phenol (155 mg, 1.652 mmol). The vial was capped and heated overnight at 110° C. The vial was cooled to room temperature and the residue taken up in CHCl3 and washed with 15% aqueous NaOH, water, brine, and dried (MgSO4). The solvent was removed and the residue purified by flash chromatography (silica gel, EtOAc:MeOH, 95:5) to provide compound 18 (88 mg, 0.159 mmol) as a light brown solid in 67% yield. For compound 18: MS (Cl) m/e 515 (M++1, 100); HPLC, rt=4.83 min.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:12][C:13]1[CH:29]=[C:28]([CH3:30])[C:16]2[NH:17][C:18]([S:20][C:21]3[O:25][C:24]([CH:26]=O)=[CH:23][CH:22]=3)=[N:19][C:15]=2[CH:14]=1.[C:31]1(=O)[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH2:32]1>C(O)CCC>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:26]([C:24]3[O:25][C:21]([S:20][C:18]4[NH:17][C:16]5[C:28]([CH3:30])=[CH:29][C:13]([Cl:12])=[CH:14][C:15]=5[N:19]=4)=[CH:22][CH:23]=3)[C:32]3[C:33](=[O:37])[CH2:34][CH2:35][CH2:36][C:31]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: O=C1CCCC(=O)C1
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: Cc1cc(Cl)cc2nc(Sc3ccc(C=O)o3)[nH]c12
Solvent: CCCCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3cc(Cl)cc(C)c3[nH]2)o1
Temperature: 25 °C

Procedure:
A mixture of 3-amino-2-ethoxycarbonyl-pyrrole (0.158 g, 1.02 mmol), 5-(5-chloro-7-methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (0.30 g, 1.02 mmol) and 1,3-cyclohexanedione (0.115 g, 1.02 mmol) in 5 ml of 1-butanol is heated at reflux temperature for 4 h. The reaction mixture is then concentrated under reduced pressure and the residue is purified on a silica gel column (34 g) eluted with a mixture of cyclohexane and ethylacetate (7/3, v/v). The fractions containing the expected product are concentrated under reduced pressure and the residue is triturated in diisopropylether and pentane. The obtained solid is then resuspended in 5 ml acetonitrile, heated at reflux temperature for 30 minutes and let to cool to room temperature. The insoluble material is collected by filtration and dried under vacuum to deliver 100 mg of 9-[5-(5-chloro-7-methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester. Yield=20%. Analytical LC/MS (method B): m/z=523 (positive ion mode [M+H]+, 1 Cl present), m/z=521 (negative ion mode [M−H]−, 1 Cl present).
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:12][C:13]1([OH:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.N>CN1C(=O)CCC1.CO.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:16]3[CH2:17][CH2:18][C:13]([CH3:12])([OH:19])[CH2:14][CH2:15]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: CC1(O)CCNCC1
Agent: N
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CO
Product: CC1(O)CCN(c2nnc3ccc(F)cn23)CC1
Temperature: 170 °C
Yield: 32.7 %

Procedure:
A mixture of Intermediate 24b (400 mg, 2.32 mmol) and Intermediate 79b (1.33 g, 11.6 mmol) in NMP (5 mL) was heated in the microwave at 170° C. for 3 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-8% [2M NH3 in MeOH] in DCM, gave the title compound (190 mg, 32%). LCMS (Method 1): Rt 2.01 min, m/z 251 [MH+].