Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15]#[N:16]>>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:14][C:15]#[N:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#CCBr
Product: N#CCN1CCN(c2ccccc2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Phenyl-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a white solid; ES-MS: M+=202.2: AtRet=1.95.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][CH:28]=[C:27]([O:26][CH2:24][CH3:25])[CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCOc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOc1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (stage 56.1.1) to give the title compound as a white solid. (HPLC: tR 2.28 min (Method A); M+H=415 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.34-8.24 (m, 2H), 8.16-8.08 (m, 2H), 8.02-7.96 (m, 1H), 7.61-7.57 (m, 1H), 7.40-7.34 (m, 1H), 4.17 (q, 2H), 3.89 (s, 3H), 3.57 (s, 3H), 1.96 (s, 3H), 1.40 (t, 3H))
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:19][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)[CH3:21]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([C:25]4[CH:26]=[CH:27][C:22]([N:20]([CH3:21])[CH3:19])=[CH:23][CH:24]=4)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CN(C)c1ccccc1B(O)O
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CN(C)c1ccc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)cc1
Temperature: 150 °C

Procedure:
Following the same procedure described for Example 401(c), the mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401(b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), N,N-dimethylaminobenzeneboronic acid (Aldrich Chemical Company) (41 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150° C. for 10 min and purification on a Biotage 40S column (1.5:1 hexane:EtOAc), the title compound as a tan solid. MS (ESI, pos. ion) m/z: 348 (M+1). Mp: 154.0-155.5° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([N:15]=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:10]=2)[CH2:3]1.Cl>O1CCCC1.O>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)[CH2:3]1
Reactant: C[C@@H]1CN(c2ccnc(N=C(c3ccccc3)c3ccccc3)c2)C[C@H](C)N1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(c2ccnc(N)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-[cis-3,5-dimethyl-1-piperazinyl]-N-(diphenylmethylidene)-2-pyridinamine (D20) (650 mg, 1.76 mmol) in tetrahydrofuran (5 ml) was treated with 1.0M hydrochloric acid (5 ml) and the mixture stirred at room temperature for 1 hour. The mixture was diluted with water and washed with diethyl ether. The aqueous phase was basified with 50% aq. sodium hydroxide then saturated with sodium chloride. The mixture was extracted with ethyl acetate (×2). The combined extracts were dried and evaporated to give the title compound (D21). 1H NMR CDCl3 ppm δ (6H, d), 2.33-0.238 (2H, m), 2.91-2.96 (2H, m), 3.58-3.62 (2H, m), 5.85 (1H, s), 6.18-6.20 (1H, m), 7.78-8.00 (1H, d).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32].O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:34]([O:33][C:31]([N:24]1[C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][CH:13]=3)=[CH:29][C:19]=2[CH:20]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH2:22][CH2:23]1)=[O:32])[CH:35]=[CH2:36]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: C=CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: C=CCOC(=O)N1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In pyridine (4.3 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.43 g). To the solution was added allyl chloroformate (0.23 ml), and the mixture was stirred at room temperature for 14 hours. To the mixture was added 4-dimethylaminopyridine (40 mg), and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate→3/1) to give methyl 1-(allyloxycarbonyl)-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.30 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]([OH:14])=O)=[CH:8][N:7]=1.[Cl-].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([NH3+:26])[CH:21]=[C:20]2[CH3:27].C(N(C(C)C)CC)(C)C.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CN(C=O)C>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([NH:26][C:12]([C:9]1[CH:10]=[N:11][C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[N:7][CH:8]=1)=[O:14])[CH:21]=[C:20]2[CH3:27]
Reactant: Cc1cn([NH3+])c2ccc(F)cc12
Reactant: O=C(O)c1cnc(-c2nccs2)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(NC(=O)c2cnc(-c3nccs3)nc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58 %

Procedure:
A mixture of 2-thiazol-2-yl-pyrimidine-5-carboxylic acid (50 mg, 0.244 mmol), 5-fluoro-3-methyl-indol-1-yl-ammonium chloride (49 mg, 0.244 mmol), diisopropylethylamine (31.5 mg, 0.244 mmol) in DMF (1 mL) is stirred at rt for 5 min. 4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium chloride (37 mg, 0.244 mmol) is added. The reaction is heated to 50° C. for 1.5 h and then concentrated in vacuo. The residue is taken up in DMSO-d6 then purified via reverse phase C18 HPLC chromatography eluting with water and acetonitrile containing 0.1% TFA buffer to afford 2-thiazol-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)-amide (58%). MS: 354 (M+H); 1H NMR (300 MHz, CDCl3): δ=2.27 (s, 3H), 7.05 (dt, 1H), 7.32 (s, 1H), 7.32-7.44 (m, 2H), 8.11 (d, 1H), 8.19 (d, 1H), 9.42 (s, 2H), 12.12 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)=O.O.[NH2:19][NH2:20]>C(O)CCC>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:19][NH2:20])=[O:2])[CH2:6][CH2:7]2)[CH:13]=1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2cccnc2)CC1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: NNC(=O)[C@H]1CC[C@H](Oc2cccnc2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(pyridin-3-yloxy)-cyclohexanecarboxylic acid methyl ester (0.141 g, 0.599 mmol) and hydrazine hydrate (0.029 ml, 0.59 mmol) in n-butanol (0.5 ml) was heated at 120° C. for 22 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.061 g, 43%) as white solid, which was used in the next step without further purification. MS m/e: 236 (M+H+)
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].C1CCN2C(=NCCC2)CC1.[OH:20][CH:21]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH:22]1[CH2:24][CH2:23]1>C1COCC1>[O:20]([CH:21]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH:22]1[CH2:24][CH2:23]1)[Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC(c1nccs1)C1CC1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)OC(c1nccs1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
TBDMSCl (3.5 g, 23.2 mmol) and DBU (3.5 mL, 23.2 mmol) were added to a solution of 2-(1-hydroxy-1-cyclopropylmethyl)thiazole (3.0 g, 19.4 mmol) in dry THF (40 mL). The mixture was stirred at rt for 16 h, then quenched with water and the layers separated. The aqueous portion was extracted with EtOAc, the combined extracts dried (MgSO4) and concentrated. The material was purified by flash chromatography using 5% EtOAc/hexane to give 4.97 g (95%) of 2-(1-t-butyldimethylsiloxy-1-cyclopropylmethyl)thiazole as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:48]([O:52][C:53]([C@@H:55]1[CH2:59][CH2:58][CH2:57][N:56]1[CH2:60][CH2:61]O)=[O:54])([CH3:51])([CH3:50])[CH3:49]>O1CCCC1.CCCCCCC>[C:48]([O:52][C:53]([C@@H:55]1[CH2:59][CH2:58][CH2:57][N:56]1[CH2:60][CH2:61][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)=[O:54])([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CCO
Reactant: Oc1ccc(Br)cc1Sc1cccc(F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1CCOc1ccc(Br)cc1Sc1cccc(F)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-Bromo-2-(3-fluoro-phenylsulfanyl)-phenol (2.898 g, 9.69 mmol) and triphenylphosphine (3.558 g, 13.6 mmol) was dissolved in tetrahydrofuran (70 mL) and cooled to 0° C. under an inert atmosphere. To the solution was added DEAD (2.81 mL, 14.27 mmol)dropwise. After 25 minutes was added 1-(2-hydroxy-ethyl)-pyrrolidine-2-(S)-carboxylic acid tertbutyl ester (2.504 g, 1.163 mmol) in THF (15 mL) via cannulation. The mixture was stirred at room temperature for 16 hours. Heptane (350 mL) and THF (100 mL) was added. The organic phase was then washed with water (4×50 mL) and then brine, dried (Na2SO4), filtered and the filtrate concentrated in the presence of silica gel. The crude products absorbed onto silica gel and eluted with a gradient of heptane-heptane ethyl acetate (85:15). The product was isolated after concentration of relevant fractions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.[Br:17]C1CC(=O)NC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:15][C:7]1[C:6]2[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][C:8]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1oc2ccc(Cl)cc2c1C
Reactant: O=C1CC(Br)C(=O)N1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1oc2ccc(Cl)cc2c1CBr
Yield: 75.6 %

Procedure:
A mixture of ethyl 5-chloro-3-methyl-2-benzofurancarboxylate (52.5 g, 0.22 mol), N bromosuccinimide (39.15 g, 0.22 mol) and benzoyl peroxide (0.4 g) in carbon tetrachloride (750 ml) was stirred and refluxed for 10 hours. The mixture was cooled, filtered and the filtrate was concentrated. The crude product was recrystallized from hexane to give 52.8 g (76%) of ethyl 3-bromomethyl-5-chloro-2-benzofurancarboxylate: mp 112°-114° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19][CH2:20][C:21](O)=[O:22])=[CH:14][CH:13]=3)[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:26][NH2:27]>>[C:1]1([C:7]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH2:19][CH2:20][C:21](=[O:22])[NH:26][N:27]=4)=[CH:14][CH:13]=3)[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCC(=O)c1ccc(-n2ccnc2-c2ccccc2)cc1
Reactant: NN
Solvent: O
Product: O=C1CCC(c2ccc(-n3ccnc3-c3ccccc3)cc2)=NN1

Procedure:
Similarly the reaction of 4-(2-phenyl-1H-imidazol-1-yl)-γ-oxobenzenebutanoic acid with hydrazine hydrate according to the procedure of this Example gives 4,5-dihydro-6-[4-(2-phenyl-1H-imidazol-1yl)phenyl]-3(2H)-pyridazinone (3c).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH2:16])[CH:11]=[CH:12][C:13]=1[Cl:14].[CH:17]([Br:20])(Br)[Br:18]>O>[Br:18][C:17]1([Br:20])[CH2:16][CH:15]1[C:10]1[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=1
Reactant: BrC(Br)Br
Reactant: C=Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: Clc1ccc(C2CC2(Br)Br)cc1Cl
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Potassium t-butoxide (5.1 g.) was added to a stirred mixture of 3,4-dichlorophenylethylene (6.1 g.), bromoform (8.9 g.) and petroleum ether (b.p. 60°-80° C.; 100 ml.) which was cooled to -30° C., and the mixture was stirred at that temperature for 30 minutes, then at laboratory temperature for 17 hours and then poured into water. The mixture was extracted with ethyl acetate and the extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column using petroleum ether (b.p. 40°-60° C.) as eluant, and there was thus obtained as an oil 1,1-dibromo-2-(3,4-dichlorophenyl)cyclopropane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1
Reactant: OCCC1CCNCC1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCC(CCO)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 95.7 %

Procedure:
To 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (Example 113, Step B) (21.5 g, 116 mmol) in DMSO (100 mL) was added 2-(4-piperidinyl)ethanol (15 g, 116 mmol) and K2CO3 (48.1 g, 348 mmol). The reaction was heated in a sealed tube at 80° C. overnight. The reaction mixture was cooled to rt and poured into H2O. The resultant solid was filtered, air dried, dissolved in DCM, dried (Na2SO4), filtered, and rotovapped down to give the title compound of Step F (32.6 g, 111 mmol, 95%). 1H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 6.63 (s, 1H), 4.33 (t, J=5.0 Hz, 1H), 3.85 (s, 3H), 3.39-3.49 (m, 2H), 3.23 (d, J=12.2 Hz, 2H), 2.65 (t, J=11.3 Hz, 2H), 2.14 (s, 3H), 1.72 (d, J=11.4 Hz, 2H), 1.46-1.61 (m, 1H), 1.39 (q, J=6.6 Hz, 2H), 1.25 (qd, J=12.0, 3.4 Hz, 2H).
Reaction SMILES: Cl.Cl.[CH:3]1([NH:8][C:9]2[N:14]=[C:13]([C:15]3[C:16]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[N:17][N:18]4[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:19]=34)[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:32]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:32]1([NH:24][C:22]2[CH:21]=[CH:20][C:19]3[N:18]([N:17]=[C:16]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[C:15]=3[C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:3]4[CH2:7][CH2:6][CH2:5][CH2:4]4)[N:14]=3)[CH:23]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Nc1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1ccc(-c2nn3cc(NC4CCCC4)ccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
To a suspension of 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine dihydrochloride (90 mg, 0.20 mmol) in 1,2-dichloroethane was added cyclopentanone (26 μL, 0.29 mmol), acetic acid (56 μL, 0.98), and sodium triacetoxyborohydride (82 mg, 0.39 mmol). The reaction mixture was stirred at room temperature 16 hours then quenched with water. The resultant mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated and washed with water and brine. The organic layer was dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 hexanes:ethyl acetate to 7:3 hexanes:ethyl acetate) provided N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine (40 mg, 45%) as a green oil. Rf 0.25 (2:1 hexanes:ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.25 (d, 1H), 8.00 (d, 1H), 7.79 (s, 1H), 7.61 (m, 2H), 7.13 (t, 2H), 6.86 (d, 1H), 6.32 (d, 1H), 5.23 (br, 1H), 4.36 (m, 1H), 3.72 (m, 1H), 3.54 (d, 1H), 2.14–2.02 (m, 4H), 1.81–1.51 (m, 12H); MS m/z 457 (M+1). To a solution of the product in ether was added 1 M HCl in ether. The precipitated solid was isolated to give the corresponding HCl salt.
Reaction SMILES: [I:1][C:2]1[NH:3][C:4]([I:8])=[C:5]([I:7])[N:6]=1.[H-].[Na+].[C:11]([NH:18][CH2:19][CH2:20]Br)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O>CN(C=O)C>[C:14]([O:13][C:11](=[O:12])[NH:18][CH2:19][CH2:20][N:3]1[C:4]([I:8])=[C:5]([I:7])[N:6]=[C:2]1[I:1])([CH3:17])([CH3:16])[CH3:15]
Reactant: Ic1nc(I)c(I)[nH]1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCn1c(I)nc(I)c1I
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a yellow solution of 2,4,5-triiodo-1H-imidazole (15.295 g; 34.313 mmol) in anhydrous DMF (200 ml) was added portionwise, at rt, 55-65% sodium hydride moistened with oil (2.058 g; 51.469 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 20 min. The mixture was then heated to 100° C., and a colorless homogeneous solution of 2-(Boc-amino)-ethylbromide (11.534 g; 51.469 mmol) in anhydrous DMF (100 ml) was added dropwise, over 1 h, with an addition funnel. After completion of the addition, the resulting mixture was further heated at 100° C. for 1 h. The reaction mixture was cooled to 0° C., and water (200 ml) was added slowly. This mixture was extracted with ether (5×200 ml). The combined organic layers were washed with brine (100 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give a yellow oil. The crude was purified by FC (heptane/EA=3/2) to give the pure product [2-(2,4,5-triiodo-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester as a colorless solid which was further dried under HV (8.540 g; 42%). LC-MS: tR=0.93 min.; [M+H]+=589.89 g/mol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13]C)=[CH:4][C:5]2[C:9]([CH3:10])=[CH:8][S:7][C:6]=2[C:11]=1[Cl:12].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]2[C:9]([CH3:10])=[CH:8][S:7][C:6]=2[C:11]=1[Cl:12]
Reactant: COc1cc2c(C)csc2c(Cl)c1Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1csc2c(Cl)c(Cl)c(O)cc12
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A mixture of 5.6 g of 6,7-dichloro-5-methoxy-3-methylbenzo[b]thiophene and 50 g of pyridine hydrochloride is stirred at 190°-195° for 2 hours. The cooled reaction mixture is diluted with water and extracted with three 300 ml-portions of ether. The combined ether extracts are washed, dried and concentrated to give a tan-colored solid, mp 137°-139°. Recrystallization from hexane gives 3.8 g of 6,7-dichloro-5-hydroxy-3-methylbenzo[b]thiophene as silky needles.
Reaction SMILES: [C:1]([N:3]=[CH:4]OCC)#[N:2].[NH2:8][C:9]1[N:13]2[CH:14]=[CH:15][C:16]3[C:21]([C:12]2=[N:11][C:10]=1[CH2:23]C)=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22]>C(O)C>[C:1]([NH:3][CH:4]=[N:8][C:9]1[N:13]2[CH:14]=[CH:15][C:16]3[C:21]([C:12]2=[N:11][C:10]=1[CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])#[N:2]
Reactant: CCc1nc2c3cccc(Cl)c3ccn2c1N
Reactant: CCOC=NC#N
Solvent: CCO
Product: Cc1nc2c3cccc(Cl)c3ccn2c1N=CNC#N
Temperature: 25 °C
Reaction time: 45 h
Yield: 37.7 %

Procedure:
Ethyl N-cyanoformimidate (3.2 g) was added to a suspension of 3-amino-7-chloro-2-ethylimidazo[2,1-a]isoquinoline (2.3 g) in ethanol (60 ml) and the mixture was stirred at room temperature for 45 hours. The mixture was evaporated in vacuo and the residual solid was washed successively with diethyl ether and ethyl acetate to give N-cyano-N'-(7-chloro-2-methylimidazo[2,1-a]isoquinolin-3-yl)formamidine (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([OH:10])[CH:5]=[CH:4][C:3]=1[O:11][C:12](=[O:14])[CH3:13].Cl[CH2:16][C:17](=[O:19])[CH3:18].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:17]([C:18]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:11][C:12]([CH3:13])=[O:14])=[C:2]([Cl:1])[C:7]=2[C:8]=1[NH2:9])(=[O:19])[CH3:16]
Reactant: CC(=O)Oc1ccc(O)c(C#N)c1Cl
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)Oc1ccc2oc(C(C)=O)c(N)c2c1Cl
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 107.8 %

Procedure:
To a solution of 7D (2.2 g, 10.4 mmol) in MeCN (20 mL) was added 1-chloro-propan-2-one (1.25 g, 13.52 mmol, 1.3 eq), followed by K2CO3 (1.868 g, 13.52 mmol, 1.3 eq). The mixture was stirred at 90° C. for 40 min. TLC monitored the reaction. After the reaction completed, the mixture was quenched with water (100 mL) The white solids were precipitated out and collected by filtration and dried to give product 7E (3 g, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:25]([F:28])([F:27])[F:26])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:29]([NH2:32])([CH3:31])[CH3:30].C(OCC)C>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:14][C:15]3[C:16]([C:17]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:19])=[CH:20][CH:21]=[CH:22][C:23]=3[CH3:24])=[O:18])=[CH:11][C:10]([C:25]([F:27])([F:26])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CC(C)N
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cccc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a suspension of the benzoxazinone product of Step D (124 g, 300 mmol) in dichloromethane (500 mL) was added dropwise isopropylamine (76 mL, 900 mmol) at room temperature. The temperature of the reaction mixture rose and the suspension thinned during the addition. The reaction mixture was then warmed to reflux for 1.5 h. A new suspension formed. The reaction mixture was cooled to room temperature and diethyl ether (1.3 L) was added and the mixture stirred at room temperature overnight. The solids were collected and washed with ether. The solids were air-dried and then dried in vacuo at 90° C. for 5 h to yield 122 g of the title compound, a compound of the present invention, as a fluffy white solid, melting at 194-196° C.
Reaction SMILES: I[C:2]1[N:3]([I:19])[C:4]([OH:18])=[C:5]2[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]=[C:6]2[N:7]=1>C(O)(=O)C.O.[Zn]>[I:19][N:3]1[C:4]([OH:18])=[C:5]2[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13]([CH3:15])([CH3:14])[CH3:16])[N:8]=[C:6]2[N:7]=[CH:2]1
Reactant: CC(C)(C)C(=O)Nc1cc2c(O)n(I)c(I)nc-2n1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)C(=O)Nc1cc2c(O)n(I)cnc-2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 4.86 g of 2,3-diiodo-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine in 100 mL of glacial acetic acid and 25 mL of water are added 1.3 g (20 mmol) of zinc powder. The mixture is stirred at ambient temperature for 18 hours, diluted with 500 mL of water, and cooled. The solid is collected through filtration and dried under vacuum over phosphorus pentoxide to yield 3-iodo-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine which can be purified further by chromatography over silica eluting with 2.5% methanol in methylene chloride.