Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[O:17]1[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18]1>O>[O:17]1[CH:21]=[CH:20][C:19]([C:22]([NH:1][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:23])=[CH:18]1
Reactant: O=C(Cl)c1ccoc1
Reactant: Nc1nc2ccccc2[nH]1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccccc2[nH]1)c1ccoc1
Temperature: 25 °C

Procedure:
A solution of 20 g. of 2-aminobenzimidazole (II) in 150 ml. of pyridine is cooled to -20°C. and 20 g. of 3-furoyl chloride is added thereto. The thus-obtained reaction mixture is allowed to warm slowly to between 20°-30°C. (room temperature), and maintained at this temperature for 15 hours, diluted with water and filtered to give a residue which is recrystallized from acetic acid to yield 2-(3-furylcarbonylamino)-benzimidazole [(III), R = 3-furyl].
Reaction SMILES: C([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>Cl>[CH3:18][S:15]([C:13]1[CH:12]=[CH:11][C:8]2[CH2:9][CH2:10][NH:4][CH2:5][CH2:6][C:7]=2[CH:14]=1)(=[O:17])=[O:16]
Reactant: CC(=O)N1CCc2ccc(S(C)(=O)=O)cc2CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CS(=O)(=O)c1ccc2c(c1)CCNCC2
Temperature: 25 °C
Yield: 30.5 %

Procedure:
A solution of 3-acetyl-7-methylsulphonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.75 g, 6.55 mmol) in 5 M hydrochloric acid was heated at reflux for 18 h. The reaction mixture was then cooled to room temperature, basified to pH 12 with potassium carbonate and the solvent evaporated in vacuo. The solid residue was then extracted with ethyl acetate (5×60 ml) and the combined organics dried (Na2SO4). The solvent was then evaporated in vacuo to give the title compound (450 mg, 32%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[Br:5][C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([CH3:23])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:24])=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Br:5][C:6]1[C:11]([N:12]([CH2:3][O:2][CH3:1])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([CH3:23])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:24])=[CH:8][N:7]=1
Reactant: Cc1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C)c1
Reaction time: 5 h

Procedure:
Methoxymethyl chloride (1.2 g, 14.3 mmol) was added dropwise to a mixture of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-methyl-benzenesulfonamide (5.0 g, 12.7 mmol) and potassium carbonate (3.2 g, 23.2 mmol) in THF (30 mL) at room temperature. After 5 h, the potassium salts were removed by vacuum filtration and the filtrate was concentrated under reduced pressure. The residual light yellow solid was chromatographed on silica gel using ethyl acetate-hexane to provide the N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-methyl-benzenesulfonamide as white crystals. MS m/z 441.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)=[CH:9][C:8]=2[CH:26]([CH3:28])[CH3:27])[CH2:6][CH2:5]1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=3)=[CH:9][C:8]=2[CH:26]([CH3:27])[CH3:28])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2C(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
Using General Procedure I; A solution of ethyl 4-[4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-benzoate (Compound 99, 28.0 mg, 0.07 mmol) in ethanol (2 mL) and tetrahydrofuiran (2 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a, 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 24 mg (92%) the title compound as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][C:43]=1[CH3:51]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][C:43]=5[CH3:51])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1cc(C(=O)O)ccc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3C)cn2)cc1
Yield: 24.8 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 4-bromo-3-methylbenzoic acid (60 mg) instead of 4-bromobenzoic acid, in the same manner as Step A in Example 1-D-19, a crude product of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-benzoic acid (31 mg, 25%) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[CH:10]=[C:9]([NH:11][C:12]([CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[N:8]=[C:7]1CCCCCC)C.[OH-:34].[K+].CO.O>C(OCC)(=O)C>[CH2:21]([CH:5]([N:6]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2([OH:34])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:21]3[C:26]2=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:13])[N:8]=[CH:7]1)[C:4]([OH:3])=[O:33])[CH2:26][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: [OH-]
Reactant: CCCCCCc1nc(NC(=O)C2c3ccccc3-c3ccccc32)cn1CC(=O)OCC
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCC(C(=O)O)n1cnc(NC(=O)C2(O)c3ccccc3-c3ccccc32)c1

Procedure:
When 2.1 g of -hexyl-4-[(9H-fluoren-9-yl-carbonyl)amino]-1H-imidazole-1-acetic acid ethyl ester was heated with 3.0 g of potassium hydroxide, 30 ml of methanol, and 15 ml of water at reflux for one hour, upon adjustment of pH to 3.8, a thick oil formed. The oil was dissolved in ethyl acetate and separated from the aqueous layer. The organic layer was dried and concentrated in vacuo. The oil was taken up in ethanol and saturated with hydrogen chloride gas. The resulting product was purified by high pressure liquid chromatography to provide 0.370 g of the titled product, m.p. 128° C.
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[N:7]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[N:15]=[CH:16][C:11]3=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1.CCN(C(C)C)C(C)C.Cl[CH2:46][CH2:47][S:48](Cl)(=[O:50])=[O:49].O>C(Cl)Cl>[F:35][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:22][CH2:21][N:20]([S:48]([CH:47]=[CH2:46])(=[O:50])=[O:49])[CH2:19][CH2:18]4)[N:15]=[CH:16][C:11]3=[C:10]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2cnn(C3CCNCC3)c2n1
Reactant: O=S(=O)(Cl)CCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCC(n2ncc3c(N4CCOCC4)nc(-n4c(C(F)F)nc5c(OC)cccc54)nc32)CC1
Temperature: -15 °C
Yield: 44.8 %

Procedure:
A mixture of 0.41 g (0.84 mmol) of 6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1-(4-piperidinyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 8) and 0.27 g (2 mmol) DIPEA in CH2Cl2 was cooled to −15° C., and 200 mg (1.2 mmol) of 2-chloroethanesulfonyl chloride was added. The mixture was allowed to warm to 0° C. over 1 hr, and water was added. The organic layer was dried and concentrated. Chromatography on silica, eluting with CH2Cl2/EtOAc (1:1), gave 216 mg (45% yield) of 6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1-[1-(vinyl-sulfonyl)-4-piperidinyl]-1H-pyrazolo[3,4-d]pyrimidine: mp (CH2Cl2-MeOH) 243-246° C.; 1H NMR (CDCl3) δ 8.00 (s, 1H), 7.81 (dd, J=8.4, 0.7 Hz, 1H), 7.44 (t, JHF=53.5 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 6.51 (dd, J=16.6, 9.9 Hz, 1H), 6.29 (d, J=16.6 Hz, 1H), 6.07 (d, J=9.9 Hz, 1H), 4.81 (tt, J=11.2, 4.1 Hz, 1H), 4.07 (s, 3H), 4.06 (m, 4H), 3.96 (m, 1H), 3.91 (m, 4H), 3.88 (m, 1H), 2.95 (dt J=12.4, 2.6 Hz, 2H), 2.43 (ddd, J=24.5, 11.8, 4.2 Hz, 2H), 2.14 (dd, J=11.8, 4.2 Hz, 2H); Anal. Calcd. for C25H28F2N8O4S: C, 52.3; H, 4.9; N, 19.5. Found: C, 52.3; H, 4.7; N, 19.8%.
Reaction SMILES: [C:1]([P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])Cl)([CH3:4])([CH3:3])[CH3:2].[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>C1COCC1>[CH2:11]([P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)P(Cc1ccccc1)C(C)(C)C
Temperature: 25 °C

Procedure:
Di-t-butylchlorophosphine (75.0 g (0.415 mole)) and 0.5 mole of 12M solution of benzylmagnesium chloride in THF (200 ml) were refluxed under argon for 2 days. The reaction mixture was allowed to cool off to RT and an aqueous solution of ammonium chloride was added slowly. The organic phase was separated, and dried with magnesium sulfate. After removal of the solvent, the product was purified by distillation in vacuum. The yield of benzyl-di-t-butylphosphine was 94.3 g (96%) with b.p. 56-59° C./0.1 mm. 31-P-NMR (CDCl3)+36.63 ppm. 1H NMR (CDCl3) 1.18 (s, 9H, Me3C), 1.20 (s, 9H, Me3C), 2.90 (d, 2JPH=2.92 Hz, P—CH2-Ph), 7.1-7:6 (m, 5H, aromatic protons).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[Li]CCCC.[C:15](Cl)(=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]C>C1COCC1>[O:5]=[C:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CCCCCCCCCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)CC(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 120.2 %

Procedure:
A stirred solution of monoethyl malonate (1.26 g, 9.6 mmol) in 25 mL anhydrous THF was cooled to −78° C. under an argon atmosphere, and n-BuLi (2.5 M, 8 mL, 20 mmol) was added drop-wise via an air-tight syringe. After the addition, the temperature was raised to 0° C., and the stirring was continued for 1 hour. The mixture was then re-cooled to −78° C., and decanoyl chloride (1.044 mL, 5 mmol) was added drop-wise via an air-tight syringe. The mixture was stirred for one hour at −78° C., 30 minutes at 0° C. and 30 minutes at room temperature. The solvent was removed under reduced pressure, and the residue was re-dissolved in 50 mL ethyl acetate. The solution was washed with 1 M HCl (100 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried over MgSO4 and concentrated to give ethyl 3-oxododecanoate (1.456 g). The crude product was used for the next reaction. 1H NMR (500 MHz, CDCl3) δ 0.88 (t, J=7 Hz, 3H), 1.20-1.38 (m, 12H), 1.50-1.68 (m, 2H), 2.53 (t, J=7.5 Hz, 2H), 3.43 (s, 2H), 4.20 (q, J=7 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 13.975, 13.988, 22.5, 23.4, 28.91, 29.14, 29.26, 29.29, 31.8, 42.9, 49.2, 61.2, 167.2, 202.9.
Reaction SMILES: [CH2:1]([C:5]1[C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:18])=O.[OH-].[NH4+]>O>[CH2:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[Cl:18])=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1c[nH]c2ccccc2c1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCCCc1cnc2ccccc2c1Cl
Temperature: 120 °C

Procedure:
A mixture of 515 mg of the product of Step E and 0.6 ml of phosphorous oxychloride was heated for 2 hours at 120° C. and the mixture was cooled. 10 ml of water were added and the solution was alkalized to pH 9 with concentrated ammonium hydroxide. Extraction was carried out twice with methylene chloride and the extracts were washed with a saturated solution of sodium chloride, dried and evaporated to dryness. The residue was dissolved in 30 ml of ethanol and treated for 15 minutes at reflux in the presence of activated charcoal, followed by filtering on hyflosupercel to obtain 511 mg of the desired product.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]3[CH2:19][CH2:20][CH2:21]/[C:22](=[CH:23]\[C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]5)=[C:26]([O:36][CH3:37])[CH:25]=4)/[C:17]3=[N:16][C:15]=2[C:38](OC)=[O:39])=[CH:10][CH:9]=1.C(OCC)(=O)C.O>C1COCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]3[CH2:19][CH2:20][CH2:21]/[C:22](=[CH:23]\[C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]5)=[C:26]([O:36][CH3:37])[CH:25]=4)/[C:17]3=[N:16][C:15]=2[CH2:38][OH:39])=[CH:12][CH:13]=1
Reactant: COC(=O)c1nc2n(c1-c1ccc(F)cc1)CCC/C2=C\c1ccc(-n2cnc(C)c2)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CCCn3c2nc(CO)c3-c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
LAH (7 mg) was added to a solution of methyl 3-(4-fluorophenyl)-8-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate (86 mg) in THF (3 mL), and the reaction solution was stirred at 0° C. for one hour. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate→ethyl acetate:methanol=5:1) to obtain 25 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.[CH2:16](Br)[CH:17]=[CH2:18]>CC(C)=O>[CH2:18]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:8]=1[OH:7])[CH:12]=[O:13])[CH:17]=[CH2:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1cc(C=O)ccc1O
Temperature: 220 °C

Procedure:
Two equivalents of potassium carbonate are added slowly with stirring to a solution of 4-hydroxybenzaldehyde in acetone. A solution of allyl bromide (1.1 equivalent) in acetone is added and the mixture is refluxed for two hours, filtered to remove inorganic salts and volatiles stripped under reduced pressure. The resulting 4-allyloxybenzaldehyde is then heated for six hours at 220° C. to yield the rearrangement product, 3-allyl-4-hydroxybenzaldehyde. One equivalent of 3-allyl-4-hydroxybenzaldehyde is dissolved in acetone and two equivalents of potassium carbonate are added slowly with stirring followed by a solution of 1.1 equivalents of methyl iodide in acetone. This mixture is refluxed for several hours, filtered and stripped to yield 3-allyl-4-methoxybenzaldehyde.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:6][C@H:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([N+:18]([O-])=O)=[C:14]([F:17])[CH:15]=3)[CH:10]=[C:9]2[C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][OH:24])[CH2:4][O:3]1.FC1C=C2C(C=C(C(C)(C)CCO)N2)=CC=1[N+]([O-])=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:18][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[F:17])[N:8]([CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:27])[O:6]1)[C:9]([C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][OH:24])=[CH:10]2
Reactant: CC1(C)OC[C@@H](Cn2c(C(C)(C)CCO)cc3cc([N+](=O)[O-])c(F)cc32)O1
Agent: [Pd]
Agent: CC(C)(CCO)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Agent: O=C[O-]
Solvent: CCO
Product: CC1(C)OC[C@@H](Cn2c(C(C)(C)CCO)cc3cc(N)c(F)cc32)O1

Procedure:
To a solution of (R)-3-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-3-methylbutan-1-ol containing some 3-(6-fluoro-5-nitro-1H-indol-2-yl)-3-methylbutan-1-ol (500 mg, 1.3 mmol) in ethanol (10 mL) was added ammonium formate (500 mg, 7.9 mmol) and Pd/C (10%, 139 mg, 0.13 mmol). The mixture was refluxed for 5 min. The Pd catalyst was removed via filtration through Celite and washed with ethanol. The filtrate was evaporated to dryness and purified by column chromatography (30-50% ethyl acetate-hexanes) to provide (R)-3-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-3-methylbutan-1-ol (220 mg, 48%, contains some 3-(5-amino-6-fluoro-1H-indol-2-yl)-3-methylbutan-1-ol). ESI-MS m/z calc. 350.2 found 351.4 (M+1)+. Retention time 0.94 minutes.
Reaction SMILES: [C:1]([C:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:48][CH3:49])=[C:30]([CH:47]=1)[O:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[N:40]=2)[N:37]=1>CN(C)C=O.CN(C)C(=O)C>[C:1]([C:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([O:48][CH3:49])=[C:30]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]5[CH2:46][CH2:45]5)=[O:43])[N:40]=4)[N:37]=3)[CH:47]=2)=[O:13])[N:10]=1)([CH3:4])[CH3:5])#[N:2]
Reactant: CC(C)(C#N)c1nc(C(=O)O)cs1
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2csc(C(C)(C)C#N)n2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 78.6 %

Procedure:
Using 2-(1-cyano-1-methylethyl)-1,3-thiazole-4-carboxylic acid (104 mg, 0.53 mmol), oxalyl chloride (57 μL, 0.66 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (5.0 mL), N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.44 mmol) and N,N-dimethylacetamide (4.0 mL) as starting materials and in the same manner as in Example 335, the title compound (179 mg, 78%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.CCN(C(C)C)C(C)C.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2([CH2:37][NH2:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[Cl:1][C:2]1[C:6]([C:7]([NH:38][CH2:37][C:31]2([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[O:9])=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cn(-c2ncccn2)nc1Cl
Reactant: NCC1(c2cccnc2)CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(c2cccnc2)CCCCC1)c1cn(-c2ncccn2)nc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (75 mg, 0.33 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.11 mL, 0.66 mmol), 1-(1-pyridin-3-ylcyclohexyl)-methanamine (63 mg, 0.33 mmol), and BOP (177 mg, 0.40 mmol). The resulting mixture is stirred at RT for 20 h. Water (3 mL) is added, and the mixture is extracted with EtOAc (5 mL). The EtOAc layer is dried (Na2SO4), filtered, and evaporated in vacuo. The residue is purified by preparative chromatography (5% MeOH/CH2Cl2) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (1H, s), 8.90 (2H, d, J 4.8), 8.58 (1H, s), 8.37 (1H, d, J 3.6), 8.05 (1H, s), 7.76 (1H, d, J 8.4), 7.56 (1H, t, J 4.8), 7.31 (1H, m), 2.16 (2H, m), 1.60 (4H, m), 1.43 (1H, m), 1.21 (5H, m). MS (M+1)=397.16; RT=1.07 min. *IC50.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[O:7][C:8]1[CH:30]=[N:29][C:11]2[N:12]([CH3:28])[C:13](=[O:27])[N:14]([CH2:17][CH2:18][CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:15](=[O:16])[C:10]=2[CH:9]=1)([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[CH:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1>[OH:49][CH:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:9]1[C:10]2[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:13](=[O:27])[N:12]([CH3:28])[C:11]=2[N:29]=[CH:30][C:8]=1[O:7][C:6]1[CH:31]=[CH:32][CH:33]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)c1cccc(Oc2cnc3c(c2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1cccc(Oc2cnc3c(c2C(O)c2ccccc2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a solution of 6-(3-isopropylphenoxy)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (220 mg, 0.50 mmol) in THF (10 mL) at −78° C. was added LDA (2.0 M in THF, 1.25 mL, 2.50 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then a solution of benzaldehyde (106 mg, 1.00 mmol) in THF (2 mL) was added dropwise. The reaction was stirred at −78° C. for 1 h, quenched with aq. NH4Cl (10 mL) then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to give a residue which was purified by chromatography PE/EA (7:1) to give 5-(hydroxy(phenyl)methyl)-6-(3-isopropylphenoxy)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (120 mg, 45% yield) as a solid. LCMS: MH+ 560 and TR=1.869 min.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.Br[C:16]1[C:17]([CH:38]([CH3:40])[CH3:39])=[N:18][N:19]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1>CN(C=O)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[N:19]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)[N:18]=[C:17]([CH:38]([CH3:40])[CH3:39])[C:16]=2/[CH:3]=[CH:2]/[C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:23]=1
Reactant: CC(C)c1nn(-c2ccc3ccccc3n2)c(-c2ccc(F)cc2)c1Br
Reactant: C=CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1c(C(C)C)nn(-c2ccc3ccccc3n2)c1-c1ccc(F)cc1
Yield: 86.9 %

Procedure:
Ethyl acrylate (4.9 mL, 45 mmoles) and bis-triphenyl phosphine palladium (II) chloride (0.25 g, 0.36 mmoles) were suspended in a 1:1 mixture of triethyl amine and DMF. This mixture was heated to reflux under an atmosphere of N2. When the suspension had completely dissolved, 2-[4-bromo-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]quinoline (3.70 g, 9.0 mmoles) was carefully added. The resulting yellow solution was refluxed for 16 hours, then cooled and partitioned between H2O and Et2O. The ether layer was dried over MgSO4, filtered, and evaporated to give a yellow solid which was recrystallized from hexanes to give 3.36 g (87%) of the title compound as a tan solid, mp 140°-143° C.
Reaction SMILES: [C:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-])=O)[CH2:5][CH2:4][CH2:3][CH:2]=1>C(OCC)(=O)C.[Pd]>[CH:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ccccc1C1=CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccccc1C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a solution of 1-(cyclopent-1-en-1-yl)-2-nitrobenzene (0.58 g, 3.0 mmol) in ethyl acetate (30 mL) in a 200 mL roundbottom flask equipped with a magnetic stir bar and nitrogen inlet was added palladium on carbon (0.63 g, 0.30 mmol, 5%). The flask was evacuated and purged with nitrogen (3×), and then evacuated and placed under hydrogen (1 atmosphere (atm)). The mixture was stirred at room temperature overnight, filtered through a pad of Celite®, and the filter cake washed with ethyl acetate. The filtrate was concentrated to provide the title compound (0.46 g, 2.9 mmol, 98% yield) as a clear and slightly red oil: 1H NMR (400 MHz, CDCl3) δ 7.14 (dd, J=7.7, 1.3 Hz, 1H), 7.02 (td, J=7.6, 1.5 Hz, 1H), 6.76 (td, J=7.4, 1.1 Hz, 1H), 6.68 (dd, J=7.8, 1.2 Hz, 1H), 3.66 (bs, 2H), 3.04-2.92 (m, 1H), 2.13-1.98 (m, 2H), 1.88-1.58 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 144.12, 130.34, 126.51, 125.95, 118.78, 115.70, 39.89, 32.17, 25.21; ESIMS m/z 162 ([M+H]+).