Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[CH2:2]1.Cl[C:10]1[N:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=1>C(O)(C)C>[NH2:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[CH2:2]2)[N:15]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: O=C(O)C1CCNC1
Solvent: CC(C)O
Product: Nc1ccnc(N2CCC(C(=O)O)C2)n1
Temperature: 80 °C
Yield: 67.2 %

Procedure:
A 100 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with pyrrolidine-3-carboxylic acid (1.20 g, 10 mmol), 2-chloropyrimidin-4-amine (1.30 g, 10 mmol), isopropyl alcohol (IPA, 40 mL), and TEA (6 mL). The mixture was heated at 80° C. overnight (O/N). After this time the reaction was cooled to room temperature (r.t.). It was then filtered and the filter cake was washed with DCM to afford 102a (1.4 g, 67%) as a pale yellow solid. MS: [M+H]+ 209.1
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:38])=[C:4]([S:9]([N:12]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:39][C:40]1[CH:41]=[C:42]([S:47](Cl)(=[O:49])=[O:48])[CH:43]=[C:44]([Cl:46])[CH:45]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([OH:38])=[C:4]([S:9]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[S:47]([C:42]3[CH:41]=[C:40]([Cl:39])[CH:45]=[C:44]([Cl:46])[CH:43]=3)(=[O:49])=[O:48])=[CH:16][CH:15]=2)[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1ccc(CNCc2ccc(F)cc2)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1)N(Cc1ccc(F)cc1)Cc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.6 %

Procedure:
To a solution of 3,5-dichloro-N-(4-fluorobenzyl)-N-(4-((4-fluorobenzylamino)methyl)benzyl)-2-hydroxybenzenesulfonamide (47 mg, 0.10 mmol) in CH2Cl2 (1 mL) were added 3,5-dichlorobenzene-1-sulfonyl chloride (25 mg, 0.10 mmol) and diisopropylethylamine (0.042 mL, 0.30 mmol). The reaction mixture was stirred at rt for 2 h, and concentrated. The residue was dissolved in methanol and purified by prep HPLC to give the title compound (9.9 mg, 12%) as a white solid. 1H NMR (DMSO-d6) δ 11.17 (br s, 1H), 7.96 (t, 1H, J=5.1 Hz), 7.84 (d, 1H, J=2.1 Hz), 7.76 (d, 2H, J=2.5 Hz), 7.57 (d, 1H, J=2.1 Hz), 7.18-6.97 (m, 12H), 4.40 (s, 2H), 4.37 (s, 2H), 4.35 (s, 2H), 4.34 (s, 2H); MS (ESI) 786.8 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11]C)=[O:10])[C:3]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21](=O)([O-])[O-:22].[K+].[K+].CO.Cl>O>[Br:8][C:6]1[N:5]=[C:4]([C:9]([OH:11])=[O:10])[C:3]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:2]([O:22][CH3:21])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1nc(Br)cc(Br)c1OCc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(Br)nc(C(=O)O)c1OCc1ccccc1
Yield: 95.3 %

Procedure:
A vigorously stirred mixture of 15 (25.5 g), potassium carbonate (75 g) and methanol (300 mL) was heated at reflux for 30 hours. The mixture was cooled, poured into water (800 mL), and the pH adjusted to 2 by the addition of conc. HCl. The resulting mixture was extracted with CH2Cl2 (3×150 mL). The organic extracts were combined, dried (MgSO4) and the solvent was evaporated to give a nearly colorless oil (20.5 g) which slowly solidified upon standing. This was recrystallized from methanol (125 mL)/water (40 mL) to give the desired acid 16 (11.6 g), m.p. 134-135° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:21][CH2:22][Cl:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:23][CH2:22][CH2:21][O:19][C:15]1[CH:14]=[C:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: ClCCBr
Reactant: Cc1cc(Nc2cccc(O)c2)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(Nc2cccc(OCCCl)c2)c2ccccc2n1
Temperature: 70 °C
Yield: 44.5 %

Procedure:
To a heterogeneous mixture of 20 (2.16 g, 6.90 mmol) in acetone (22 mL) were sequentially added 1-bromo-2-chloroethane (7.2 mL, 86.50 mmol) and potassium carbonate (3.00 g, 21.71 mmol). The reaction was stirred and heated at 70° C. for 17 hours before it was allowed to cool to room temperature and was filtered. The solids were rinsed with a 3:1 mixture of dichloromethane/methanol (25 mL×3), and the filtrate was isolated and evaporated to give the crude product. Column chromatography on silica (dichloromethane to 20/1 to 15/1 to 5/1dichloromethane/methanol) gave 21 as a pale yellow solid (0.96 g, 35.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.CC(O)=O.C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH2:8][CH2:9]2)[CH2:16][CH2:15]1
Reactant: CN1CCC(=O)CC1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCC(N2CCc3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Nitroindoline (5 g) was dissolved in 200 mL of dichloroethane. N-Methyl-4-piperidone (5 g) was added to the mixture, followed by NaHB(OAc)3 (12 g) and 1 mL of glacial AcOH. The mixture was stirred at RT overnight. A saturated NaHCO3 (200 mL) solution was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel. The organic layer was extracted once with saturated NaHCO3 solution and once with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 2:1 EtOAc:MeOH to afford orange oil. MS: 262 (M+1). Calc'd. for C14H19N3O2—261.3.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19]C)=[CH:17][CH:18]=2)=[CH:4][N:3]=1.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(Cc2cnc(Cl)c3ccccc23)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Cc2cnc(Cl)c3ccccc23)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Under exclusion of moisture, to 500 mg (1.76 mmol) of 1-chloro-4-[(6-methoxy-pyridin-3-yl)methyl]-isoquinoline (step 28.6) in 9 ml of chloroform, 488 μl (3.58 mmol) of Me3Sil are added. Then the mixture is stirred for 8 h at 60° C. Dilution of the mixture with EtOAc and NaHCO3-solution, stirring and filtration of the suspension yields 1-chloro-4-[(6-hydroxy-pyridin-3-yl)methyl]-isoquinoline, contaminated with 1-iodo-4-[(6-hydroxy-pyridin-3-yl)methyl]-isoquinoline; FAB-MS: (M+H)+=271chloride/363iodide; HPLC(gradient20-100) tRet=10.2chloride/10.8iodide. From the filtrate, more product can be obtained by extraction with EtOAc.
Reaction SMILES: [O-:1][C:2]#N.[K+].[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH:6]1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[NH2:30])[CH2:18][CH2:17]1.Cl>O>[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH:6]1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=3[NH:30][C:2]2=[O:1])[CH2:18][CH2:17]1
Reactant: N#C[O-]
Reactant: Nc1ccc(Cl)cc1NC1CCN(CC2COc3ccccc3O2)CC1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]c2ccc(Cl)cc2n1C1CCN(CC2COc3ccccc3O2)CC1

Procedure:
A solution of 4.8 g of potassium cyanate in 10 ml of water was added to 14.5 g of 1-[(benzo-1,4-dioxan-2-yl)-methyl]-4-(5-chloro-2-aminoanilino)-piperidine in 5 ml of 10% strength hydrochloric acid and 40 ml of water, whilst cooling and stirring. When the addition had ended, the mixture was stirred at room temperature for 1 hour and then under reflux for 24 hours. After the mixture had been cooled, it was extracted with chloroform. The extract was washed with 5% strength hydrochloric acid, dried and filtered and the filtrate was concentrated.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:8][CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: NCCCN
Reactant: Brc1ccccn1
Product: NCCCNc1ccccn1
Yield: 44.9 %

Procedure:
2-Bromopyridine (100 g; 0.633 mol) and 1,3-diaminopropane (234.5 g; 3.16 mol) was refluxed for 7 h. After the reaction was complete, the mixture was evaporated. Distillation of the remaining residue under oil pump vacuum afforded 43 g of the required product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:2]([N:27]2[CH2:28][CH2:29][O:25][C:26]2=[O:30])[CH:7]=1
Reactant: O=C1NCCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCOC3=O)CC2)c(C)c1
Yield: 56.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using (2-bromo-4-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.79 g) described in Preparation Example 119 and oxazolidin-2-one (0.381 g), the title compound (1.023 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([NH2:11])[CH:3]=1.[CH:12]([NH2:14])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[N:14][C:12](=[O:13])[NH:11]2)=[CH:9][CH:10]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: NC=O
Product: O=c1ncc2ccc(Cl)cc2[nH]1

Procedure:
4-chloro-2-amino-benzoic acid (10.0 g) was dissolved into 50 mL of formamide, the mixture was reacted under reflux for 5 h. A lot of solid was deposited, which was filtered and dried to obtain 1.5 g of 7-chloro-quinazolone.
Reaction SMILES: [NH:1]1[C:7](=[O:8])[C:6](=[N:9]O)[CH2:5][CH2:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.C(O)(=O)C.[H][H]>CO.[Pd]>[NH2:9][CH:6]1[C:7](=[O:8])[NH:1][C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: O=C1Nc2ccccc2CCC1=NO
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: NC1CCc2ccccc2NC1=O
Temperature: 50 °C
Yield: 67.3 %

Procedure:
5 g (26,3 mmol) of 4,5-dihydro-1H-benzo[b]azepine-2,3-dione 3-oxime is taken in 50 ml of methanol then 6,3 g (105 mmol) acetic acid is added. The reaction mixture is left to stir at 50° C. and 5 bar hydrogen pressure for 21 hours in the presence of 1,1 g Pd catalyst (5% on charcoal, containing 50% water). The reaction mixture is evaporated after filtration and the residue is dissolved in 16,5 ml water. 9,5 ml dichloromethane is added and the pH value is adjusted to pH 12–14 with NaOH (32%). After phase separation the aqueous layer is extracted two times with 5,5 ml dichloromethane each. The organic phases are dried over sodium sulfate and evaporated to give 3,12 g 3-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one, yield 67,4%, HPLC 94,5 area %, RT=2.45.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.[CH:15]12[O:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]2.[Cl-].[NH4+]>CCCCCC>[CH:1]1([C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[OH:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1=Cc2ccccc2C1
Reactant: C1CCC2OC2C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: O[C@@H]1CCCC[C@H]1C1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A solution of 29.4 g of indene (0.25 mol) in 500 mL of dry hexane was reacted with 100 mL of n-butyllithium (2.5M in hexanes, 0.25 mol) at room temperature. After 2 hrs. the slurry was chilled in ice water and a solution of 24.5 g of cyclohexene oxide (0.25 mol) in 200 mL of dry hexane added during 8 hrs. After warming to room temperature the slurry was stirred overnight. The resulting mixture was treated with aqueous ammonium chloride and the resulting organic layer was separated and washed with water and then with brine. After drying over sodium sulfate, the solution was evaporated to yield 47 g of crude title compound. Purification was achieved by chromatographing in two portions using 250 g of silica gel, eluting initially with 9:1 hexane:ethyl acetate and ultimately with 2:1 hexane:ethyl acetate. The total yield of purified trans-2-(1-indenyl)-cyclohexanol was 20.0 g (0.0935 mol, 37% yield based on indene). 1H NMR (500 MHz, apparent coupling constant in Hz, CDCl3) δ7.48 (1H, m), 7.46 (1H, m), 7.29 (1H, tm, J=7.6), 7.21 (1H, td, J=7.6, 1.2), 6.34 (1H, t, 0.8), 3.84 (1H, td, J=9.89, 4.4), 3.37 (2H, m), 2.63 (1H, m), 2.14 (1H, m), 1.98 (1H, dm, J=13.4), 1.92 (1H, br s), 1.86 (1H, m), 1.76 (1H, dm, J=12.0), 1.5-1.3 (4H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[F:25])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[F:25])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:3]=1
Reactant: NC1=NC(c2ccc(F)c(Br)c2)(c2ccncc2F)c2ccccc21
Reactant: COc1cccc(B(O)O)c1F
Product: COc1cccc(-c2cc(C3(c4ccncc4F)N=C(N)c4ccccc43)ccc2F)c1F
Yield: 25 %

Procedure:
The title compound was synthesized from 1-(3-bromo-4-fluorophenyl)-1-(3-fluoropyridin-4-yl)-1H-isoindol-3-amine (Example 70) as described in Example 67 Scheme #10, D in 25% yield using 2-fluoro-3-methoxyphenyl boronic acid. 1H NMR (DMSO-d6) δ 8.39 (d, J=3.03 Hz, 1 H), 8.26 (d, J=5.05 Hz, 1 H), 7.83-7.73 (m, 1 H), 7.71-7.64 (m, 1H), 7.48-7.39 (m, 2 H), 7.29-7.11 (m, 6 H), 6.92 (br s, 2 H), 6.81-6.73 (m, 1 H), 3.79 (s, 3 H); MS (ESI) m/z 446 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]1[N:26]=[N:27][N:28]=[C:21]1[C:20]([NH2:29])=[C:19]2[NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]1[N:26]=[N:27][N:28]=[C:21]1[C:20]1[N:29]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:30]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:19]2=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)CNc1c(N)c2nnnn2c2ccc(OCc3ccccc3)cc12
Reactant: CCOCC(=O)Cl
Solvent: c1ccncc1
Product: CCOCc1nc2c(c3cc(OCc4ccccc4)ccc3n3nnnc23)n1CC(C)C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Ethoxyacetyl chloride (2.7 g, 22 mmol) was added dropwise to a solution of 7-(benzyloxy)-N5-(2-methylpropyl)tetraazolo[1,5-a]quinoline-4,5-diamine (7.6 g, 21 mmol) in 200 mL of pyridine. The solution was stirred for 1 hour and additional ethoxyacetyl chloride was added. The solution was refluxed overnight, after which the solvent was removed. The solid material was dissolved in 300 mL of chloroform and stirred with 150 mL of 1% aqueous sodium carbonate. The pH was adjusted to 10 with 10% sodium hydroxide. The organic fraction was washed with 2 portions of 1% sodium carbonate and once with brine solution. The organic fraction was then dried over sodium sulfate and concentrated to give 8.8 g of 8-(benzyloxy)-5-(ethoxymethyl)-6-(2-methylpropyl)-6H-imidazo[4,5-c]tetraazolo[1,5-a]quinoline as a tan solid. A small portion was recrystallized from ethanol to provide an analytical sample, mp 183.5-184.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[F:17]>C(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:17]
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Br)c(F)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)c1ccc(Br)c(F)c1

Procedure:
(4-Bromo-3-fluoro-phenyl)-(4-chloro-phenyl)-methanol (2.26 g, 7.16 mmol) and MnO2 (6.22 g, 70.1 mmol) was stirred in CH2Cl2 (40 mL) for 40 hr. The solution was filtered through a celite pad and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.[CH2:9]=[C:10]1[CH2:15][CH2:14][CH:13]([C:16](OCC)=[O:17])[CH2:12][CH2:11]1>C1COCC1>[CH2:9]=[C:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:17])[CH2:1][C:2]#[N:3])[CH2:12][CH2:11]1
Reactant: CC#N
Reactant: C=C1CCC(C(=O)OCC)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C1CCC(C(=O)CC#N)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
CH3CN (2.55 mL, 48.8 mmol. 2.2 eq) was added dropwise to a solution of nBuLi (48.8 mmol) in 180 mL of THF at −78° C. After stirring for 1 h at −78° C., a solution of ethyl 4-methylenecyclohexanecarboxylate (3.73 g, 22.2 mmol) in 20 mL of THF was added dropwise and the resulting reaction mixture (turned into nearly clear solution after addition) was stirred at −78° C. for 1 h, then slowly warmed to 0° C. before being quenched with sat. NH4Cl. THF was removed and the residue was diluted with EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-30% EtOAc/Hexanes, Rf=0.2 in 20% EtOAc) to afford 3-(4-methylenecyclohexyl)-3-oxopropanenitrile as a colorless oil (3.25 g, 90%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=4)=[N:19][N:18]4[CH2:28][CH2:29][CH2:30][C:17]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Li+]>CO>[CH3:27][C:23]1[N:22]=[C:21]([C:20]2[C:16]([C:10]3[C:9]4[C:14](=[CH:15][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=4)[N:13]=[CH:12][CH:11]=3)=[C:17]3[CH2:30][CH2:29][CH2:28][N:18]3[N:19]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1ccc2c(-c3c(-c4cccc(C)n4)nn4c3CCC4)ccnc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(-c2nn3c(c2-c2ccnc4cc(C(=O)O)ccc24)CCC3)n1
Temperature: 60 °C

Procedure:
To a solution of 4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic acid ethyl ester (250 mg, 0.6 mmol) in methanol (4 mL) at room temperature is added 1 N lithium hydroxide (1.2 mL, 1.2 mmol). The mixture is heated at 60° C. for 4 h. The mixture is cooled to room temperature and concentrated in vacuo. The mixture is diluted with water and acidified to pH 6 with 1 N hydrochloric acid. The aqueous solution is extracted with dichloromethane 5 times. The combined organic extracts are dried (sodium sulfate), filtered, and concentrated in vacuo to yield the title compound, 150 mg (65%), as an off white solid.
Reaction SMILES: C(O)(=O)C.[C:5]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1)#[N:6].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:5]([C:7]1[CH:12]=[C:11]([CH2:13][Br:14])[CH:10]=[CH:9][N:8]=1)#[N:6]
Reactant: Cc1ccnc(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(CBr)ccn1
Temperature: 50 °C
Yield: 24.6 %

Procedure:
0.146 ml of acetic acid is added to a solution of 0.236 g of 2-cyano-4-methylpyridine in 5 ml of carbon tetrachloride, under an inert atmosphere of argon at a temperature in the region of 20° C. The mixture is brought, with stirring, to a temperature of 50° C. 0.712 g of N-bromosuccinimide and 0.096 g of benzoyl peroxide are successively added at this temperature. The mixture is maintained at 80° C. for about 18 hours. After cooling, the reaction medium is placed on a cartridge 27 mm in diameter packed with 25 g of 20-40 μm silica not conditioned beforehand, and then eluted with dichloromethane at a flow rate of 10 ml/minute. The fractions between 140 and 175 ml are concentrated to dryness under reduced pressure. 0.097 g of 2-cyano-4(bromomethyl)pyridine is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)#[CH:20].[I-]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[C:19][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#Cc1ccccn1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CC1CCCC1)c1ccc(C#Cc2ccccn2)cc1
Temperature: 70 °C
Yield: 96.7 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.0 g, 2.79 mmol) and triethylamine (4 mL, 0.02 mmol) in N,N-dimethylformamide (4 mL) was treated with 2-ethynylpyridine (345 mg, 3.34 mmol). The resulting reaction mixture was degassed with argon for 10 min and then treated with cooper iodide (168 mg, 0.88 mmol) and bis(triphenylphosphine)palladium (II) chloride (305 mg, 0.44 mmol). The reaction was then heated at 70° C. for 1.5 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-pyridin-2-ylethynyl-phenyl)-propionic acid methyl ester (900 mg, 97%) as a yellow oil: EI-HRMS m/e calcd for C22H23NO2 (M+) 333.1728, found 333.1724.
Reaction SMILES: [NH:1]([C:3](=[S:5])[NH2:4])[NH2:2].[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[C:9]([F:16])[CH:8]=1>C1COCC1>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:2][NH:1][C:3](=[S:5])[NH2:4])=[O:12])=[C:9]([F:16])[CH:8]=1
Reactant: NNC(N)=S
Reactant: O=C(Cl)c1ccc(Br)cc1F
Solvent: C1CCOC1
Product: NC(=S)NNC(=O)c1ccc(Br)cc1F
Reaction time: 1 h

Procedure:
Hydrazinecarbothioamide (6.8 g, 75 mmol) was added to a solution of 4-bromo-2-fluorobenzoyl chloride (11.8 g, 50.0 mmol) in THF (50 mL) at rt and stirred for 1 hour. The reaction mixture was concentrated to give 2-(4-bromo-2-fluorobenzoyl)-hydrazinecarbothioamide as a white solid, which was used directly in the next step without purification. MS (ESI): mass calcd. for C8H7BFN3OS, 290.95, m/z found, 292.1 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11](/[CH:19]=[CH:20]/[CH:21]2[CH2:26][CH2:25][N:24](C(OCC3C=CC=CC=3)=O)[CH2:23][CH2:22]2)[C:10]=1[CH3:37])C1C=CC=CC=1.C1COCC1>[Pd].C(O)C>[CH3:37][C:10]1[C:9](=[O:8])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: Cc1c(/C=C/C2CCN(C(=O)OCc3ccccc3)CC2)nc2ccccc2c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(CCC2CCNCC2)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
To a mixture of benzyl 4-{(E)-2-[4-(benzyloxy)-3-methylquinolin-2-yl]vinyl}piperidine-1-carboxylate (978 mg), THF (6 mL) and ethanol (6 mL) was added 10% palladium-activated carbon (200 mg) under nitrogen atmosphere. The mixture was stirred at room temperature under hydrogen atmosphere of 3 atms, for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Fuji Silysia Chemical Ltd., NH, eluent: chloroform/methanol=97/3˜92/8), and the solvent was evaporated. The residue was washed with ether, and collected by filtration to obtain 3-methyl-2-(2-piperidin-4-ylethyl)quinolin-4(1H)-one (490 mg).