Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[ClH:18].[CH2:19]([NH:26][C:27]1[C:36]([CH2:37][Cl:38])=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:39][CH3:40])[CH:33]=2)[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:38].[ClH:18].[CH2:19]([NH:26][C:27]1[C:36]([CH2:37][C:6]2[C:7]3[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=3)[C:3]([CH2:1][CH3:2])=[N:4][C:5]=2[OH:17])=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:39][CH3:40])[CH:33]=2)[N:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: COc1ccc2nc(NCc3ccccc3)c(CCl)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCc2ccccc2)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 9 %

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (70 mg, 0.30 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added N-benzyl-3-(chloromethyl)-6-methoxyquinolin-2-amine hydrochloride SLA 41008 (105 mg, 0.30 mmol) followed by a 2 N aq. LiOH (0.30 mL, 0.60 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided, after evaporation, 17.3 mg of 4-((2-(benzylamino)-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.28 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((2-(benzylamino)-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 44 as a yellow solid (16 mg, 9% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH2:24]([N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25].C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[CH2:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:3]=2)[CH2:28][CH2:27]1)[CH3:25]
Reactant: CCN1CCCNCC1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCN(CC)CC2)nc1-c1ccc(C)cc1
Temperature: 110 °C
Yield: 22.6 %

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.104 g; 0.312 mmol), 1-ethyl-1,4-diazepane (0.120 g; 0.937 mmol) and triethyl amine (0.220 mL; 1.56 mmol) in tetrahydrofuran (2 mL) was heated at 110° C. in a sealed tube for 5 h. The mixture was diluted with a saturated solution of sodium hydrogencarbonate, extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of methanol (1-30%) in dichloromethane furnished 0.030 g (21%) of the title compound as a brown oil.
Reaction SMILES: [CH:1]1(O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.C1C=CC=CC=1>O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:17])=[CH:13][CH:14]=1
Reactant: OC1CCCCC1
Reactant: O=C(O)Cc1ccc(O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(Cc1ccc(O)cc1)OC1CCCCC1
Yield: 104.6 %

Procedure:
Cyclohexyl alcohol (6 g), 4-hydroxyphenylacetic acid (7.6 g) p-toluenesulfonic acid (1 g) and benzene (300 mL) were refluxed with continuous water separation for 8 hours. The mixture was cooled and washed with a 10% Na2CO3 solution, then with water. Drying over MgSO4 and evaporation of the solvent in vacuo gave 12.24 g of cyclohexyl 4-hydroxyphenylacetate. That compound can be represented by the formula: ##STR24##
Reaction SMILES: [C:1]1([CH3:31])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[CH:12][CH:11]=[CH:10][C:9]=2[C:22]2[S:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[CH:23]=2)=[CH:3][CH:2]=1.[Br:32]C1C=CC2C(C3C=CC(C)=CC=3)=C(C3C=CC(C)=CC=3)SC=2C=1>>[Br:32][C:10]1[C:9]([C:22]2[S:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[CH:23]=2)=[C:8]([NH:7][C:4]2[CH:3]=[CH:2][C:1]([CH3:31])=[CH:6][CH:5]=2)[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(Nc2cccc(-c3cc4ccccc4s3)c2Nc2ccc(C)cc2)cc1
Reactant: Cc1ccc(-c2sc3cc(Br)ccc3c2-c2ccc(C)cc2)cc1
Product: Cc1ccc(Nc2ccc(Br)c(-c3cc4ccccc4s3)c2Nc2ccc(C)cc2)cc1

Procedure:
Intermediate C was synthesized in the same manner as in Synthesis Example 1, except that 2,3-di-p-tolylaminophenyl-benzo[b]thiophene was used instead of 2,3-di-p-tolyl-benzo[b]thiophene used to synthesize Intermediate B in Synthesis Example 1.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.C[Si](C)(C)O[CH2:43][C:44]([O:46][Si](C)(C)C)=[O:45].FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.C(Cl)Cl>C(OCC)(=O)C>[O:33]=[C:31]1[O:30][N:29]=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:15][C:12]3[C:13](=[O:14])[N:8]([CH:5]4[CH2:6][CH2:7][C:2]5([O:46][C:44](=[O:45])[CH2:43][O:1]5)[CH2:3][CH2:4]4)[C:9]4[N:10]([N:37]=[CH:38][N:39]=4)[C:11]=3[CH2:34][CH2:35][CH3:36])=[CH:21][CH:20]=2)[NH:32]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: C[Si](C)(C)OCC(=O)O[Si](C)(C)C
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCC(=O)O3)c2ncnn12
Temperature: -78 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), trimethylsilyl [(trimethylsilyl)oxy]acetate (0.16 mL), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.18 mL) and methylene chloride (5 mL) was stirred at −78° C. for 1 hr, and then at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.066 g, 26%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].CN(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:21][CH2:22][CH2:23][OH:24]>O>[OH:24][CH2:23][CH2:22][CH2:21][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: Oc1ccccc1S
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCSc1ccccc1O
Reaction time: 0.33 h

Procedure:
2-Hydroxythiophenol (1.00 g, 8.70 mmol) was added to a mixture of DMF (10 mL) and Cs2CO3 (2.90 g, 8.90 mmol). To this was added 3-bromopropanol (0.80 mL, 9.16 mmol) and the mixture was stirred for 20 min. The mixture was added to into water and extracted with EtOAc. The combined extracts were washed with water, dried over magnesium sulfate and concentrated to a clear oil (2.36 g, 100%). MS [M−H]− 183.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6]([OH:10])[CH2:7][CH2:8][CH3:9])[CH3:2].[C:12]([CH2:14][C:15](O)=[O:16])#[N:13].CN(C=O)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6]([O:10][C:15](=[O:16])[CH2:14][C:12]#[N:13])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: N#CCC(=O)O
Reactant: CCCC(O)CC(=O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)OC(=O)CC#N

Procedure:
A mixture of 100.14 g of ethyl-3-hydroxyhexanoate, 63.75 g of cyanoacetic acid, and 4.58 g of 4-dimethylaminopyridine (DMAP) in 625 ml of CH2Cl2 was stirred in a 2 L three-neck round bottom flask equipped with a mechanical stirrer. About 31 ml of N-N′-dimethylformide (DMF) was added to make a clear solution. The above clear solution was chilled in an ice water bath. A separately prepared dicyclohexylcarbodiimide (DCC) solution (154.75 g in 250 ml CH2Cl2) was added to the above chilled solution by using an addition funnel. White precipitate formed within five minutes after the start of the addition. The reaction mixture was left stirred overnight.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[CH2:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1.CN1C(=O)N(C)CC1>[CH2:19]([NH:26][C:27]([NH:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=C=NCc1ccccc1
Solvent: CN1CCN(C)C1=O
Solvent: C1COCCO1
Product: O=C(NCc1ccccc1)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With the exclusion of moisture, 261 mg (1.00 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) are dissolved in 2.5 ml of dioxane and 1 ml of DMEU; 138 μl (1.1 mmol) of benzyl isocyanate are added and the reaction mixture is stirred at RT overnight. The dioxane is evaporated off from the reaction mixture in a rotary evaporator. The resulting yellow solution is poured into 75 ml of water and the product that precipitates is filtered off. Stirring in boiling ethyl acetate yields 3-(benzylamino-carbonylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine; HPLC:tRet(grad20-100)=9.5; FAB-MS: (M+H)+=394.
Reaction SMILES: [C:1]([O:10][CH3:11])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[H-].[Na+].Cl[CH2:15][C:16]([C:18]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[CH:20]C=1F)=[O:17].O>CN(C=O)C>[CH3:27][O:26][C:21]1[CH:22]=[C:23]([O:24][CH3:25])[C:18]2[C:16](=[O:17])[C:15]3[S:4][C:3]4[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=4[C:1]=3[O:10][C:11]=2[CH:20]=1
Reactant: COC(=O)c1ccccc1S
Reactant: COc1cc(F)c(C(=O)CCl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c2c(=O)c3sc4ccccc4c3oc2c1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 40.8 %

Procedure:
A solution consisting of methyl thiosalicylate 28 (0.67 g, 4.0 mmol) in DMF was treated with NaH (0.19 g, 4.8 mmol as a 60% dispersion in mineral oil) and stirred at rt for approximately 5-10 minutes and then Example 27 (1 g, 4.3 mmol) was added followed by additional NaH (0.4 g, 10 mmol, as a 60% dispersion in mineral oil) and the reaction was heated at 100° C. for 30 minutes. The crude reaction mixture was poured into water, filtered, and the solid product washed with additional water, MeOH and hexanes. The product thus obtained was triturated with MeOH to yield 29 (0.51 g): 1H NMR (DMSO-d6) δ 8.16 (d, 2H, J=2.3 Hz), 7.71-7.61 (m, 2H), 6.91 (d, 1H, J=2.3 Hz), 6.63 (d, 1H, J=2.3 Hz), 3.95 (s, 3H), 3.89 (s, 3H); MS 335 (M+Na)+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([OH:12])=[CH:8][CH:9]=[C:10]([OH:11])[C:4]2=[CH:3][CH:2]=1.[CH:13]1(O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.S(=O)(=O)(O)O>C(OCC)(=O)C>[CH:13]1([O:12][C:7]2[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[C:10]([OH:11])=[CH:9][CH:8]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OC1CCCCC1
Reactant: Oc1ccc(O)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Oc1ccc(OC2CCCCC2)c2ccccc12
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 24.8 %

Procedure:
160 g of naphthohydroquinone and 416 g of cyclohexanol were placed in a 1 l three-necked flask, and 80 ml of concentrated sulfuric acid was dropwisely added thereto for 10 minutes under nitrogen gas stream while stirring. Thereafter, the reaction mixture was heated at 60° C. for 40 minutes and then cooled to room temperature. The reaction mixture was extracted with 500 ml of ethyl acetate. The ethyl acetate layer was washed with water until the washing reached neutral and, then, dried with MgSO4 overnight. The dried ethyl acetate solution was concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain 140 g of oily substance. The oily substance was dissolved in ethyl acetate and treated with about 20 g of active carbon followed by concentration under reduced pressure. The residue was recrystallized from benzene two times to obtain 60 g of white crystals having a melting point of 120° to 121° C.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15].[CH3:17]OS(OC)(=O)=O>O1CCCC1>[F:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:17])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: COS(=O)(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Lithium hydroxide monohydrate (4.5 g, 1 eq) is added in small portions to a solution of 4-fluoro-3-nitrobenzoic acid (20 g, 1 eq) in tetrahydrofuran (100 ml). After stirring for 1 hour at approximately 20° C., dimethylsulphate (10.2 ml) is added dropwise to the yellow precipitate. The reaction mixture is then heated under reflux for 8 hours then concentrated under reduced pressure at 40° C. The residue is diluted in dichloromethane and Na2C0-3 saturated water. After decanting and extracting, the combined organic phases are washed with salt water, dried over sodium sulphate and concentrated under reduced pressure at 40° C. The yellow solid obtained is recrystallized from a diethyl ether/petroleum ether mixture in order to produce the expected compound in the form of a light yellow powder (16.7 g, 78% yield). Melting point=59° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13]OS(C)(=O)=O)[C:9]2=[O:19])=[CH:4][CH:3]=1.[CH2:20]([O:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:21]#[CH:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:29]3[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][O:23][CH2:20][C:21]#[CH:22])[CH2:27][CH2:28]3)[C:9]2=[O:19])=[CH:4][CH:3]=1
Reactant: C#CCOCCN1CCNCC1
Reactant: CS(=O)(=O)OCC1CCN(c2ccc(Cl)cc2)C1=O
Product: C#CCOCCN1CCN(CC2CCN(c3ccc(Cl)cc3)C2=O)CC1

Procedure:
The title compound was prepared from 1-(4-chlorophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 1-(2-(2-propynyloxy)ethyl)piperazine, in the same manner as in Preparation Example 1(8).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[CH:11]=[CH:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1.CN(C=O)C>C(Cl)Cl>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:9]3[CH:10]=[CH:11][N:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[N:8]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: Cn1cc(-n2ccc(C(=O)O)n2)cn1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccn(-c2cnn(C)c2)n1
Yield: 66 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 1′-methyl-1′H-[1,4′-bipyrazole]-3-carboxylic acid (0.921 mmol, 177 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.767 mmol, 200 mg) using DMF (2 ml) as the solvent. DCM was added and evaporated. The residue was purified by flash chromatography. The product was further purified by dissolving it in DCM and washing three times with 1 M NaHCO3 and evaporating the separated DCM phase. 220 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.14 (d, 3H), 3.89 (s, 3H), 4.27-4.42 (m, 2H), 4.42-4.53 (m, 1H), 6.76 (d, 1H), 6.95 (d, 1H), 7.83-7.87 (m, 3H), 7.94 (dd, 1H), 8.06 (d, 1H), 8.16 (d, 1H), 8.18 (s, 1H), 8.21 (d, 1H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C:8]([NH:16][CH:17]([CH2:21][C:22]#[CH:23])C(O)=O)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1.O>[C:8]([NH:16][CH:17]([C:5](=[O:7])[CH3:6])[CH2:21][C:22]#[CH:23])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: C#CCC(NC(=O)c1ccccc1)C(=O)O
Solvent: O
Solvent: c1ccncc1
Product: C#CCC(NC(=O)c1ccccc1)C(C)=O
Temperature: 90 °C

Procedure:
Acetic anhydride (150 ml) was added to a solution of 2-benzoylamino-4-pentynoic acid (J. Org. Chem. 1983, 48, 3318) (73 g, 0.34 mol) in pyridine (200 ml) and the solution was heated to 90° C. for 1 hour, then allowed to cool to 60° C. and water (150 ml) was added. The mixture was heated to 85°-90° C. for 20 minutes, then cooled, diluted with water (300 ml) and extracted with chloroform (2×400 ml). The combined extracts were washed with water, 1N hydrochloric acid (3×500 ml), sodium bicarbonate and brine, and dried over magnesium sulfate. The chloroform solution was decolorized with charcoal, filtered and concentrated. The residue was recrystallized from butyl chloride to yield a tan solid (51 g, mp 101°-103° C.).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:31][CH3:32])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C)C=O>[CH2:31]([C:20]1[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:8][C:34](=[O:35])[O:36][CH2:37][CH3:38])[C:18]=2[N:19]=1)[CH3:32]
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1nc2ccccc2c2c1nc(CC)n2CCCCNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Triethylamine (3.86 mL, 10 eq) was added to a chilled (ice/water bath) suspension of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide (1.0 g, 1 eq) in N,N-dimethylformamide (DMF) (10 mL). Ethyl chloroformate (1.5 g, 5 eq) was added dropwise to give a clear solution. The reaction mixture was allowed to come to ambient temperature with stirring for 2 hours. Additional triethylamine (3.86 mL, 10 eq) and ethyl chloroformate (3.86 mL, 10 eq) were added and the reaction mixture was stirred overnight. The reaction mixture was poured onto crushed ice and then extracted with dichloromethane (50 mL). The organic layer was washed sequentially with water (2×50 mL), 4% sodium carbonate (50 mL), water (50 mL), and brine (50 mL) and then concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel eluted with a linear gradient of 0-25% CMA in chloroform, 2500 mL) followed by recrystallization from acetonitrile to provide 0.815 g of ethyl 2-ethyl-1-{4-[(methylsulfonyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-4-ylcarbamate as a white crystalline solid, mp 185-187° C. Anal calcd for C20H27N5O4S: C, 55.41; H, 6.28; N, 16.15. Found: C, 55.30; H, 6.29; N, 16.24.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10].Cl[CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)=[O:30]>>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:21]2[CH2:22][CH2:23][CH:18]([C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH:8]([CH3:24])[CH3:7])[CH:17]=[CH:16][CH:15]=3)[CH2:19][CH2:20]2)=[CH:32][CH:33]=1
Reactant: COc1ccc(C(=O)CCCCl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Prepared by Procedure K (KI) and Scheme E (K2CO3) using 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide and 4-chloro-1-(4-methoxyphenyl)-1-butanone: ESMS m/e:423.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.N1C=CC=CC=1.[Br:19]Br>C(Cl)(Cl)(Cl)Cl>[Br:19][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: BrBr
Reactant: COc1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2ncccc2c1Br
Temperature: 25 °C
Yield: 35.9 %

Procedure:
To a mixture of 6-methoxy-quinoline (13.0 g, 0.082 mol) and pyridine (13.2 mL, 0.164 mol) in CCl4 (130 mL) was added bromine (8.4 mL, 0.164 mol) dropwise. The mixture was heated to reflux for 2 hrs and cooled to room temperature. The liquid in the flask was decanted and washed with saturated aqueous NaHCO3 and water. The dark solid on the bottom of the flask was treated with NaHCO3 and dichloromethane. The combined organic layers were washed with water again and dried before being evaporated to dryness. The crude product was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (10/1˜1/1) to give 7 g of 5-bromo-6-methoxy-quinoline as a red solid (36% yield).
Reaction SMILES: Br[C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[C:21]1([C:27]2[NH:36][C:30]3[N:31]=[CH:32][N:33]=[C:34]([SH:35])[C:29]=3[CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[N+:7]([C:4]1[S:3][C:2]([S:35][C:34]2[C:29]3[CH:28]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[NH:36][C:30]=3[N:31]=[CH:32][N:33]=2)=[CH:6][CH:5]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(Br)s1
Reactant: Sc1ncnc2[nH]c(-c3ccccc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2ncnc3[nH]c(-c4ccccc4)cc23)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 1.05 g of 2-bromo-5-nitrothiophene, 0.95 g of potassium carbonate and 15 ml of dimethylformamide to the 6-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-thiol synthesized in Production Example 161-1 and stirring the mixture overnight at room temperature, water was added and the precipitated crystals were filtered out, blow-dried and dried under reduced pressure to obtain 1.30 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:12]=[C:11]([O:13]C)[C:10]([N+:15]([O-:17])=[O:16])=[C:9]([O:18]C)[N:8]=2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:8]=[C:9]([OH:18])[C:10]([N+:15]([O-:17])=[O:16])=[C:11]([OH:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COc1nc(Cc2ccc(F)cc2)nc(OC)c1[N+](=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1c(O)nc(Cc2ccc(F)cc2)nc1O
Temperature: 25 °C
Yield: 62 %

Procedure:
(27) A mixture of compound (26) (1.0 g, 3.4 mmol) and pyridine hydrochloride (3.9 g, 34 mmol) was heated to 140 C for 1 hour. After it cooled to room temperature, the resultant was diluted with water. The product was collected on a filter and dried in vacuo. 2-(4-Fluoro-benzyl)-5-nitro-pyrimidine-4,6-diol (27) was obtained in a yield of 62% (1.1 g). 1H NMR (DMSO-d6)