Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])=O)[CH3:12].[CH2:24]([O:26][C:27](=[O:32])/[CH:28]=[C:29](\[NH2:31])/[CH3:30])[CH3:25]>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:28]([C:27]([O:26][CH2:24][CH3:25])=[O:32])=[C:29]([CH3:30])[NH:31][C:16]=1[CH2:18][O:19][C:20](=[O:22])[CH3:21])=[O:23])[CH3:12]
Reactant: CCOC(=O)CC(=O)COC(C)=O
Reactant: COc1cccc(C=O)c1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(COC(C)=O)=C(C(=O)OCC)C1c1cccc(OC)c1

Procedure:
After heating a solution of 6.8 g of 3-methoxybenzaldehyde, 9.4 g of γ-acetoxyacetoacetic acid ethyl ester and 6.5 g of β-aminocrotonic acid ethyl ester in 40 ccs of ethanol for 20 hours, the mixture is cooled and the precipitate is filtered off.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:24]=[O:25].O>O1CCCC1.C(OCC)(=O)C>[CH3:14][C:10]1[N:9]=[C:8]([O:7][CH2:6][C:5]2[CH:15]=[CH:16][C:2]([CH:24]=[O:25])=[CH:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)C=O
Reactant: Cc1cccc(OCc2ccc(Br)cc2)n1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(OCc2ccc(C=O)cc2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a solution of 2-(4-bromo-benzyloxy)-6-methyl-pyridine (7.30 g, 26.2 mmol) described in Manufacturing Example 3-1-1 in anhydrous tetrahydrofuran (200 mL) was added dropwise n-butyl lithium (2.67 M n-hexane solution, 11.8 mL, 31.4 mmol) on a dry ice-ethanol bath (−78° C.), which was stirred for 30 minutes at −78° C. N,N-dimethylformamide (4.04 mL, 52.4 mmol) was added to this mixture at −78° C., and stirred for 5 minutes. Water and ethyl acetate were added to the reaction mixture, which was stirred for 10 minutes at room temperature, and the organic layer was then separated. This organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (4.19 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.C([O:28][C@@H:29]([CH3:33])[C:30](Cl)=O)(=O)C.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][N:9]2[C:10]3[N:11]=[C:12]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:13][C:14]=3[C:15](=[O:16])[N:17]=[C:30]2[C@@H:29]([OH:28])[CH3:33])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1Cn1c([C@H](C)O)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (200 mg, 0.545 mmol) in Tetrahydrofuran (THF) (20001) was added (1S)-2-chloro-1-methyl-2-oxoethyl acetate (164 mg, 1.090 mmol). The mixture was stirred at room temperature overnight, and then stirred at 60° C. for 3 h. To the mixture was added sodium hydroxide (454 μl, 2.73 mmol) and methanol (0.5 mL). After 30 min, the mixture was acidified (pH ˜5) with 6N HCl, and then concentrated. The residue was partitioned between dichloromethane and water. The organic layer was dried (sodium sulfate), filtered, and concentrated. The crude was purified by reversed-phase HPLC and subsequently converted to the HCl salt to provide 4-[(3-chloro-2-methylphenyl)methyl]-5-[(S)-1-hydroxyethyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (14 mg, 6%); LC/MS: MS (ES+) m/e 421 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (d, J=6.3 Hz, 3H), 2.44 (s, 3H), 3.53-3.62 (m, 4H), 3.67 (m, 4H), 4.57 (q, J=6.3 Hz, 1H), 5.67 (s, 2H), 6.51 (d, J=7.8 Hz, 1H), 7.14 (m, 1H), 7.37 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH2:16][CH2:17]CC)[CH2:12][C:13]([OH:15])=[O:14].[CH:20]([Mg]Br)(C)C>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH:16]([CH3:17])[CH3:20])[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CC(C)[Mg]Br
Reactant: CCCCC(CC(=O)O)c1ccc(OC)cc1OC
Product: COc1ccc(C(CC(=O)O)C(C)C)c(OC)c1

Procedure:
Following a similar procedure to that described in Preparation 42a, but using isopropylmagnesium bromide instead of butylmagnesium bromide, the title compound was obtained as an oily substance.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:24][N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:28]3[CH2:29][CH2:30][CH2:31][N:25]([CH3:24])[CH2:26][CH2:27]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CN1CCCNCC1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Product: CN1CCCN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cn2)CC1

Procedure:
50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide was reacted with 1-methyl-1,4-diazepane via Procedure F. The reaction was evaporated to dryness and purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-methyl-1,4-diazepan-1-yl)nicotinamide. MS (Q1) 422 (M)+.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[C:24](=[O:36])([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[O:25][CH:26](Cl)[CH3:27]>>[CH:30]1([O:29][C:24]([O:25][CH:26]([O:14][C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=2[C:15]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=2)=[O:16])[CH3:27])=[O:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Product: CC(OC(=O)OC1CCCCC1)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the procedure of Example 6, piroxicam (3.00 g, 9.1 mmol) and alpha-chloroethyl cyclohexyl carbonate (5.37 g, 26.1 mmol) were converted to chromatographed title product, 3.85 g pale yellow foam (7.7 mmol, 84.7%) which gave 2.45 g white crystals from toluene/hexane: mp 142°-144° C.; IR (KBr) 1749, 1682 cm-1 ; 1H NMR (CDCl3) delta 0.99-1.93 (br m, 10 H), 1.76 (d, J=6 Hz, 3H), 3.11 (s, 3H), 4.40-4.58 (br m, 1H), 6.36 (q, J=6 Hz, 1H), 7.06-7.18 (m, 1H), 7.62-7.97 (m, 5H), 8.32-8.43 (m, 2H), 9.40 (br s, 1H); precise mass calcd for C24H27N3O7S m/e 501.1576, found 501.1613.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1.[NH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]>C(O)(C)C>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=[C:2]([NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=1
Reactant: CC(C)(C)Nc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)CN
Solvent: CC(C)O
Product: CC(C)(C)CNc1cc(Cl)nc(NC(C)(C)C)n1

Procedure:
After dissolving 5.0 g of 4,6-dichloro-2-(1,1-dimethylethylamino)pyrimidine in 25 ml of isopropanol and adding 5 ml of 1-amino-2,2-dimethylpropane the reaction mixture is boiled under reflux for 20 hours. Then, the reaction mixture is evaporated and the residue is distributed between 80 ml of chloroform and 15 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 20 ml of water each, then dried and evaporated. After recrystallizing the evaporation residue from hexane the title product is obtained in a yield of 4.49 g (73%), m.p.: 109.5°-111° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH:19]=O)=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]=2)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:19][C:18]1[C:13]([C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=2)=[N:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:16][C:17]=1[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=C(Br)Br
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
A solution of carbon tetrabromide (2.866 gm, 8.64 mmol) in CH2Cl2 (8 ml) was added over a 10 minute period to a cold (-10° C.) solution of 2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde (1.840 gm, 5.76 mmol) (the preparation of which is described in Example 3) and triphenylphosphine (4.590 gm, 17.5 mmol) in CH2Cl2 (30 ml). After the addition was complete, the cooling bath was removed and the mixture was stirred for 20 minutes. The solution was quenched with saturated NaHCO3 and extracted 2× with CH2Cl2. The combined organic layers were washed with saturated NaHCO3, dried (Na2SO4), filtered and concentrated. The concentrate was chromatographed (flash, Merck, SiO2, 1:1 CH2Cl2 : hexane) to give 3-(2,2-Dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine as a white solid (2.701 gm, 99%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH3:18]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([O:8][CH2:17][CH3:18])=[CH:6][N:7]=1
Reactant: CCI
Reactant: Oc1cnc(Cl)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cnc(Cl)cc1I
Temperature: 25 °C

Procedure:
6-Chloro-4-iodo-pyridin-3-ol (0.41 g, 1.62 mmol) was dissolved in anhydrous DMF (4 mL) and stirred at room temperature. Potassium carbonate (0.67 g, 4.9 mmol) and iodoethane (0.40 mL, 4.9 mmol) were added sequentially. The mixture was heated to 60° C. and maintained for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was diluted with diethyl ether (25 mL) and washed with 20% aqueous citric acid (25 mL). The aqueous was extracted with diethyl ether (2×20 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was triturated with hexane resulting in a tan solid (0.42 g, 91%). 1H NMR (400 MHz, CDCl3): δ7.80 (s, 1H), 7.74 (s, 1H) 4.18 (q, J=7.1 Hz, 2H), 1.51 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][C@H:13]([OH:15])[C@@H:12]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:29]([O:15][C@H:13]1[CH2:14][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[CH2:10][CH2:11][C@@H:12]1[C:16]1[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cn1nccc1[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1OC(=O)c1ccccc1
Yield: 71.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 107a by using the (1S*,2R*,5R*)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (774 mg, 2.49 mmol) prepared in Example 160a, triethylamine (2.08 mL, 14.9 mmol), benzoyl chloride (1.45 mL, 12.6 mmol) and dichloromethane (8.0 mL), to yield the title compound (739 mg, 72%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:17]=1[C:18]([NH:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:19]
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)c(Br)c1
Temperature: 25 °C

Procedure:
4′-chloro-[1,1′-biphenyl]-4-amine (159 mg, 0.78 mmol), 2-bromo-4-methylbenzoic acid (140 mg, 0.65 mmol), EDC (125 mg, 0.65 mmol), HOBt (100 mg, 0.65 mmol), and diisopropylethyl amine (0.22 mL, 1.30 mmol) were dissolved in THF (2.6 mL) and stirred at room temperature. After 3 h the resulting mixture directly purified via column chromatography to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[Cl:24][C:25]1[C:33]([CH:34]2[CH2:36][CH2:35]2)=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=O.F[P-](F)(F)(F)(F)F.[N:44]1(OC(N(C)C)=[N+](C)C)[C:48]2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[Cl:24][C:25]1[C:33]([C:34]2([C:48]#[N:44])[CH2:36][CH2:35]2)=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)[CH:3]=1)=[O:29]
Reactant: O=C(O)c1cccc(C2CC2)c1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)sc5n4)c3)c2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8664.9 %

Procedure:
A solution of N-[5-(3-aminophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (120 mg, 3.68 μmol) produced in Example C111(v), 2-chloro-3-(1-cyclopropyl)benzoic acid (90 mg, 405 μmol) produced in Example C62(ii) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (154 mg, 405 μmol) in pyridine (3 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/70→10/90), and fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran and ethanol to give the title compound (169 mg, 87%) as colorless crystals.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:42][C:43]1[C:44]([NH:61][CH:62]2[CH2:67][CH2:66][N:65]([CH2:68][CH2:69][C:70]#[N:71])[CH2:64][CH2:63]2)=[C:45]2[CH:51]=[CH:50][N:49]([S:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)(=[O:54])=[O:53])[C:46]2=[N:47][CH:48]=1>CN(C=O)C>[C:55]1([S:52]([N:49]2[C:46]3=[N:47][CH:48]=[C:43]([NH:42][C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][CH3:8])[C:44]([NH:61][CH:62]4[CH2:63][CH2:64][N:65]([CH2:68][CH2:69][C:70]#[N:71])[CH2:66][CH2:67]4)=[C:45]3[CH:51]=[CH:50]2)(=[O:53])=[O:54])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CCC(C)CC(=O)O
Reactant: N#CCCN1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)CC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
Racemic 3-methylpentanoic acid (0.180 ml, 1.4 mmol), HATU (0.53 g, 1.4 mmol), and diisopropylethylamine (0.46 ml, 2.7 mmol), were added sequentially to a solution of 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile (0.54 g, 1.3 mmol, prepared as described in Example 118) in DMF (20 ml) at 25° C. The reaction mixture was stirred for 4 h at 25° C., then was concentrated under reduced pressure. The residue was partitioned between half-saturated NaHCO3 (100 ml) and EtOAc (2×200 ml). The organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 8% CH3OH in CH2Cl2) afforded 3-methyl-pentanoic acid {1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-amide (0.706 g, 110%) as an off-white solid. LCMS (Method G, ESI): RT=0.73 min, m+H=523.4. This material was used in the next step below without further characterization.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=O.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[NH:21])=[CH:18][CH:17]=1>C(#N)C>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[NH:22][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N+:11]([O-:13])=[O:12])[N:21]=2)=[CH:18][CH:17]=1
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reactant: COc1ccc(C(=N)N)cc1
Solvent: CC#N
Product: COc1ccc(-c2nc(-c3ccccc3[N+](=O)[O-])c[nH]2)cc1
Temperature: 40 °C
Yield: 78.1 %

Procedure:
A mixture of 2-bromo-2'-nitroacetophenone (18 g), 4-methoxybenzamidine (20 g), and silica gel (20 g) in acetonitrile (500 ml) is heated at 40° C. for 24 hours. The reaction is evaporated and the residue put on a layer of silica gel and eluted with 50% ethyl acetate/hexane (1500 ml). The solution is evaporated under reduced pressure to approximately 250 ml and extracted with 5% HCl (3×250 ml) . The combined aqueous solution is basified with K2CO3 and extracted with ethyl acetate (3×400 ml) to afford 2-(4-methoxyphenyl)-4-(2-nitrophenyl)-imidazole (17 g) as a dark yellow oil which is used in the next step without further purification.
Reaction SMILES: [C:1]([NH:5][OH:6])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C(NO)(C)(C)C.C(=O)(O)[O-].[Na+].[H-].[Na+].[C:24]([C:28]1[S:32]/[C:31](=[N:33]\[C:34](=[O:46])[C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=2F)/[N:30]([CH2:47][CH2:48][CH2:49][C:50]#[N:51])[N:29]=1)([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:1]([NH:5][O:6][C:36]1[CH:37]=[CH:38][C:39]([C:41]([F:42])([F:43])[F:44])=[CH:40][C:35]=1[C:34](/[N:33]=[C:31]1\[S:32][C:28]([C:24]([CH3:25])([CH3:27])[CH3:26])=[N:29][N:30]\1[CH2:47][CH2:48][CH2:49][C:50]#[N:51])=[O:46])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nn(CCCC#N)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Reactant: CC(C)(C)NO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)NOc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)nn1CCCC#N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-tert-butylhydroxylamine (133 mg, 1.50 mmol) (prepared from commercially available N-tert-butylhydroxylamine acetate (Aldrich) by adding saturated sodium bicarbonate solution and extracting the free base with ethyl ether) in anhydrous THF (10 mL) was added sodium hydride (53.9 mg, 1.35 mmol). The mixture was stirred at 0° C. for 20 min. A solution of Example 151A (310 mg, 0.75 mmol) in THF (4 mL) was added and the mixture was stirred at 22° C. for 5 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried with MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 using an Analogix® Intelliflash280™ (Hexanes-EtOAc: 0-50% gradient) to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.22 (s, 9H), 1.42 (s, 9H), 2.23-2.37 (m, 2H), 2.48 (t, J=7.1 Hz, 2H), 4.54 (t, J=6.5 Hz, 2H), 5.75 (s, 1H), 7.61 (dd, J=8.7, 2.4 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H); MS (ESI) m/z 484 (M+H)+.
Reaction SMILES: N[C:2]12[CH:17]([OH:18])[CH2:16][CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=31)[C:8]1[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+]>C(O)(=O)C.O>[CH:17]([C:2]12[CH2:16][CH:9]([C:8]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=31)[C:10]1[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: NC12c3ccccc3C(CC1O)c1ccccc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=CC12CC(c3ccccc31)c1ccccc12
Reaction time: 5 h
Yield: 100.5 %

Procedure:
To a solution of 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene (3.0 g) in acetic acid (240 ml) was added a solution of sodium nitrite (6.7 g) in water (120 ml) at 2°-5° C., and the resulting mixture was stirred at the same temperature for 1 hour and at 95°-105° C. for 5 hours. The reaction mixture was diluted with water and extracted with benzene. The benzene layer was washed with water, dried over sodium sulfate and evaporated to dryness to give crude crystals of 9-formyl-9,10-dihydro-9,10-methanoanthracene (2.8 g), which were recrystallized to give colorless crystals (2.45 g). M.P. 99°-100° C. Further, purification by recrystallization gave analytically pure 9-formyl-9,10-dihyfro-9,10-methanoanthracene, M.P. 102.5° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:12]=1.C1COCC1.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>C1(C)C=CC=CC=1>[CH:14]([O:13][C:11]1[CH:12]=[C:7]([B:26]([OH:27])[OH:25])[CH:8]=[N:9][CH:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)Oc1cncc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)Oc1cncc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred, −78° C. solution of 2.5 M n-butyllithium (44.0 mL, 110 mmol) in toluene (120 mL) was slowly added a solution of 3-bromo-5-isopropoxypyridine (21.6 g, 100 mmol) in toluene (40 mL) while maintaining the temperature below −50° C. After the addition was complete, the reaction was stirred at −78° C. for 30 min. Distilled THF (40 mL) was added, and the reaction stirred for 15 min at −78° C., followed by the addition of triisopropylborate (27.7 mL, 120 mmol) in one portion. After warming to −15° C., the reaction was quenched with 1M HCl (260 mL), and stirred for one hour. The mixture was then neutralized (to pH 7) with 5 M NaOH and extracted with THF (4×100 mL). The combined extracts were dried (Na2SO4), filtered and concentrated. The residue was dissolved in 1:1 THF/MeOH, filtered, concentrated, and dissolved in warm acetonitrile. Upon cooling, the acetonitrile solution deposited a light brown powder, which was collected by filtration and vacuum dried (8.94 g, 49%).