Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C@@H:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:9]=1)[C:6]#[CH:7].[CH3:23][C:24]1[N:28]=[C:27]([C:29]2[CH:30]=[C:31](I)[CH:32]=[CH:33][CH:34]=2)[O:26][N:25]=1>CCN(CC)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C@@H:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:9]=1)[C:6]#[C:7][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:27]2[O:26][N:25]=[C:24]([CH3:23])[N:28]=2)[CH:30]=1
Reactant: C#C[C@@H](CC(=O)OC)c1ccc(OC)c(OC2CCCC2)c1
Reactant: Cc1noc(-c2cccc(I)c2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](C#Cc1cccc(-c2nc(C)no2)c1)c1ccc(OC)c(OC2CCCC2)c1
Yield: 31.7 %

Procedure:
A solution of (R)-methyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-ethynylpropionate (150 mg, 0.5 mmol) and 3-(3-methyl[1,2,4]oxadiazol-5-yl) iodobenzene (144 mg, 0.5 mmol) in Et3N (4 ml) was treated with tetrakis(triphenylphosphine)palladium(0) (10 mg) and copper(I)iodide (10 mg). The reaction was heated to 55° for 30 min, and then the solvent was thoroughly evaporated. The residue was purified by flash chromatography (silica gel CH2Cl2 :hexane:Et2O/10:10:1) and gave the titled compound as an oil (73 mg, 17%) 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1 H), 8.02 (m, 1 H), 7.60 (m, 1 H), 7.60 (t, 1 H), 6.95 (m, 2 H), 6.86 (d, 1 H), 4.80 (m, 1 H), 4.33 (t, 1 H), 3.84 (s, 3 H), 3.72 (s, 3 H), 2.92 (d of d, 1 H), 2.82 (d of d, 1 H), 2.48 (s, 3 H), 1.78-2.02 (m, 6 H), 1.62 (m, 2 H).
Reaction SMILES: C([N:8]1[C@@H:16]2[C@@H:11]([CH2:12][C:13]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:14]=3[CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:22][O:21][C:17]1[C:14]2[CH2:15][C@H:16]3[C@H:11]([CH2:10][CH2:9][NH:8]3)[CH2:12][C:13]=2[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc2c1C[C@H]1[C@H](CCN1Cc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cccc2c1C[C@@H]1NCC[C@@H]1C2
Yield: 101.8 %

Procedure:
1.7 g (5.8 mmol) of cis-(±)-1-benzyl-8-methoxy-2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole (9b) are dissolved in 35 mL of methanol and hydrogenated at 20° C. and 5 bars of hydrogen pressure on 0.2 g of Pd/C (10%). After 5 h the mixture is filtered over silica gel and the solvent is eliminated in vacuo. 1.2 g (100%) 10b are obtained as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([F:26])([F:25])[F:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:27]1([C:33]#[CH:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([C:34]#[C:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([F:26])([F:25])[F:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cc1
Reactant: C#Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(C#Cc3ccccc3)cc2)cc1
Temperature: 80 °C
Yield: 85.7 %

Procedure:
To a stirred solution of 1-[4-(methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole (445 mg; 1 mmol) and phenylacetylene (102 mg; 1 mmol) in pyrrolidine (2 mL) was added tetrakis(triphenylphosphine)palladium (35 mg) under a nitrogen atmosphere, and the mixture was heated at 80° C. for 1 hour. After cooling, the volatiles were removed by evaporation. The residue was purified by flash chromatography (SiO2) eluting with ethyl acetate/hexane (1:3) to give the title compound (0.4 g, 86% yield).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.[ClH:20]>O1CCOCC1.CO>[ClH:20].[ClH:20].[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:10]1[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccccn2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@H]1CCN(c2ccccn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ((S)-1-pyridin-2-yl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (0.221 g, 0.84 mmol) in dioxane (4 ml) and methanol (1 ml) is added 4M HCl (in dioxane) (0.525 ml, 2.1 mmol) and the reaction mixture is stirred at room temperature overnight. The resulting suspension is filtered and washed with dioxane (3×1 ml) to yield the titled compound.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].CCN(C(C)C)C(C)C.Br[CH:15]1[CH2:19][CH2:18][O:17][C:16]1=[O:20]>C1COCC1>[OH:4][CH2:3][CH2:2][S:1][CH:15]1[CH2:19][CH2:18][O:17][C:16]1=[O:20]
Reactant: O=C1OCCC1Br
Reactant: OCCS
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1OCCC1SCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-mercapto-ethanol (2560 μmol) in THF (4 ml) were added DIEA (1.1 eq) and 3-bromo-dihydro-furan-2-one (1 eq). The reaction mixture was stirred at RT for 4 hours. The precipitate was filtered and the solvent was removed under reduced pressure.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[N:7]=[CH:8][N:9]([CH:11]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12](OCC)=[O:13])[CH:10]=1)(=[O:5])[NH2:4].O>CO>[OH:13][CH2:12][CH:11]([N:9]1[CH:10]=[C:6]([C:3]([NH2:4])=[O:5])[N:7]=[CH:8]1)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(CCc1ccccc1)n1cnc(C(N)=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)c1cn(C(CO)CCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
NaBH4 (491 mg) was added portionwise to an ice cooled solution of ethyl 2-(4-carbamoyl-1-imidazolyl)-4-phenylbutyrate (obtained in Preparation 2) (391 mg) in methanol (20 ml) under an nitrogen atmosphere. After the addition was completed, the reaction mixture was stirred at room temperature for 30 minutes. Water was added, and the resulting mixture was stirred for several minutes and then evaporated under reduced pressure. The residue was partitioned between chloroform and water. The organic layer was washed with brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave 1-(1-hydroxy-4-phenyl-2-butyl)imidazole-4-carboxamide (347 mg) as a white solid.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C@H:11]2[CH2:13][C@H:12]2[CH2:14][CH2:15][OH:16])[CH2:7][CH2:6]1)=[NH:4].[C:17](Cl)(=O)[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.CCOC(C)=O>[CH:18]([C:20]1[O:1][N:2]=[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([C@H:11]3[CH2:13][C@H:12]3[CH2:14][CH2:15][OH:16])[CH2:7][CH2:6]2)[N:4]=1)([CH3:19])[CH3:17]
Reactant: N=C(NO)N1CCC([C@H]2C[C@H]2CCO)CC1
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)c1nc(N2CCC([C@H]3C[C@H]3CCO)CC2)no1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
N-hydroxy-4-((1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboximidamide (4.8 g, 21.10 mmol) was dissolved in Pyridine (60 ml) and isobutyryl chloride (18.44 ml, 176 mmol) was added. The mixture was stirred at 80° C. for 3 h and the solvent was evaporated to dryness. The residue was dissolved in MeOH (100 ml) and potassium carbonate (24.32 g, 176 mmol) was added. The mixture was stirred at 50° C. for 2 h. Another potassium carbonate (24.32 g, 176 mmol) was added and the mixture was stirred at 50° C. for another 2 h. The mixture was cooled down and diluted with EtOAc (100 mL), washed with water, sat. NH4Cl, dried over MgSO4, evaporated. The crude material was purified by silica gel column eluting with 20-70% EtOAc in hexane to afford the desired product. LC/MS (m/z): 280 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[CH3:24])[CH2:19][NH2:20].C1CCN2C(=NCCC2)CC1>CN1CCCC1=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:16]([Cl:15])[CH:17]=2)=[N:4][N:3]=1
Reactant: Cc1ccc(CN)cc1Cl
Reactant: N#Cc1ccc2c(Cl)nnc(Cl)c2c1
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl

Procedure:
1,4-Dichlorophthalazine-6-carbonitrile and 3-chloro-4-methylbenzylamine were stirred at room temperature in 1-methyl-2-pyrrolidinone in the presence of DBU, whereby the title compound was obtained as a less polar compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:14][N+:15]([O-:17])=[O:16].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]([F:12])([F:11])[F:10])=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])C=C(c1ccc(Br)cc1)C(F)(F)F

Procedure:
A stirred solution of 4′-bromo-2,2,2-trifluoroacetophenone (0.392 g, 2.00 mmol). and CH3NO2 (0.488 g, 8.0 mmol) in dry toluene (70 mL) containing N,N-diethylenediamine (30 mmol) is heated at reflux with a Dean and Stark trap until complete removal of H2O. The cooled solution is washed with 5% aqueous HCl, dried over MgSO4, filtered, evaporated in vacuo and the resulting residue when purified by chromatography gives the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl>ClCCl.CN(C1C=CC=CN=1)C>[C:18]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.2 %

Procedure:
13.8 Grams (0.1 mol) of 4-hydroxybenzoic acid was dissolved in 140 ml of dichloromethane. To this mixture were consecutively added 16 ml of triethylamine, 20.1 g (0.11 mol) of n-decanoic acid chloride and 0.97 g (0.0079 mol) dimethylaminopyridine, and the mixture was stirred at room temperature over 1 day and night. To this reaction mixture was added 50 ml of 10% hydrochloric acid, and the mixture was extracted with 100 ml of ether three times. An organic layer was washed with 100 ml of sodium chloride aqueous solution three times, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was washed with 400 ml of hexane to give 25.5 g (yield 82%) of 4-decanoyloxybenzoic acid as an end product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[NH:19][CH:20]=[N:21]2>C(O)(=O)C>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[NH:19][CH:20]=[N:21]4)[CH:3]=2)[NH:7][CH:6]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Solvent: CC(=O)O
Product: CN(C)CCc1c[nH]c2ccc(Nc3ncnc4nc[nH]c34)cc12
Temperature: 116 °C
Yield: 66 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 6-chloropurine were used. No base was used, acetic acid was used as solvent, and the reaction was heated at reflux (116° C.) for 15 hours. Chromatography afforded the title compound (66%) as a white foam: mp, decomposes 175° C.; 13C NMR (CD3OD) δ153.7, 153.4, 141.5, 136.0, 131.5, 128.3, 125.6, 119.2, 113.3, 113.0, 109.9, 59.1, 43.6, 21.9. Anal. calcd for C17H19N7.HCl.2H2O: C, 51.84; H, 6.14; N, 24.89. Found: C, 52.14; H, 6.22; N, 25.03.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[F:27][C:28]([F:40])([F:39])[C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:26][C:24]1[CH:23]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][N:20]([S:35]([C:32]2[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:39])[F:40])=[CH:34][CH:33]=2)(=[O:37])=[O:36])[CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Reaction time: 18 h
Yield: 42.2 %

Procedure:
To a solution of compound 24 (0.099 g, 0.27 mmol) in CH2Cl2 (3 mL) was added 4-(trifluoromethyl)benzenesulfonyl chloride (0.093 g, 0.38 mmol) and triethylamine (0.039 g, 0.38 mmol). The reaction mixture was stirred for 18 hrs, whereupon the starting material was consumed (TLC, 1% MeOH in CH2Cl2). The reaction mixture was then concentrated in vacuo, redissolved in a minimal amount of CH2Cl2, and chromatographed over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white solid. The solid was triturated with diisopropyl ether/hexanes and vacuum filtered to afford compound 60 as a white powder. (0.065 g, 42.2% yield, 95.7% HPLC purity). 1H NMR (500 MHz, CDCl3): 8.23 (d, J=2 Hz, 1H), 7.86 (m, 4H), 7.67 (dd, J1=9 Hz, J2=2 Hz, 1H), 6.95 (s, 1H), 6.89 (d, J=9 Hz, 1H), 6.68 (s, 2H), 3.48 (m, 4H), 3.15 (m, 4H), 2.35 (s, 6H); MS (ESI, EI+): m/z=580 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33]OS(C5C=CC(C)=CC=5)(=O)=O)=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:45]([O:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[O:46])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1.[CH3:55][NH:56][CH3:57]>C(N(CC)CC)C>[CH3:55][N:56]([CH3:57])[CH2:33][CH2:32][CH2:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH:23]2[CH2:22][CH2:21][N:20]([C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:46])[CH2:19][CH:18]2[O:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]3[O:9][CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]=3[CH:12]=2)=[CH:29][CH:28]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOS(=O)(=O)c4ccc(C)cc4)cc3)cc21
Reactant: CNC
Solvent: CCN(CC)CC
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCN(C)C)cc3)cc21

Procedure:
A solution of 0.21 g of benzyl 3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[3-(toluene-4-sulphonyloxy)propoxy]phenyl}piperidine-1-carboxylate, 0.140 g of triethylamine and 1.892 g of dimethylamine (33% in ethanol) is stirred at room temperature for 3 days and then concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.21 (200:10:1 dichloromethane-methanol-conc. ammonia); Rt=4.49.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH2:19].CCN(C(C)C)C(C)C>CC#N>[Cl:11][C:9]1[C:8]([F:12])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:19][CH2:18][CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([F:13])[CH:15]=2)[N:10]=1
Reactant: NCCc1cccc(F)c1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(O)c1cc(F)c(Cl)nc1NCCc1cccc(F)c1
Yield: 49 %

Procedure:
A mixture of 2,6-dichloro-5-fluoronicotinic acid (1.26 g, 6.0 mmol), 3-fluorophenethyl amine (1.25 mL, 9.0 mmol), DIEA (3.14 mL, 18 mmol) and MeCN (6 mL) was refluxed for 48 hrs and concentrated. The residue was dissolved in EtOAc (120 mL) and washed with saturated citric acid, water, brine, dried and concentrated. The organic layers were combined, dried (MgSO4) and concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 6-chloro-5-fluoro-2-(3-fluorophenethylamino)nicotinic acid as a solid (920 mg, 49%). LRMS (M+H+) m/z 313.0.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[NH:9]C(=O)C(C)(C)C)=[O:2]>Cl>[NH2:9][C:8]1[C:3]([CH:1]=[O:2])=[CH:4][N:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1ccncc1C=O
Agent: Cl
Product: Nc1ccncc1C=O
Yield: 87.7 %

Procedure:
A solution of Example 25B (870 mg, 4.2 mmol) in 3N HCl (aq.) (10 mL) was heated to reflux overnight, and extracted three times with diethyl ether. The aqueous layer was adjusted to pH >7 with solid K2CO3 and extracted six times with 20% isopropanol/chloroform. The combined extracts were dried (Na2SO4), filtered, and concentrated to provide the desired product (450 mg; 87%).
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[C:11]([CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:10][CH:9]=[C:8]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[N:7]=1.[OH-].[Na+]>CO>[CH3:4][O:5][C:6]1[C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=[C:8]([O:24][CH2:25][C:26]([F:29])([F:27])[F:28])[N:7]=1
Reactant: COc1nc(OCC(F)(F)F)ccc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1nc(OCC(F)(F)F)ccc1CN
Temperature: 50 °C
Reaction time: 20 h
Yield: 94.9 %

Procedure:
Hydrazine monohydrate (0.13 mL, 2.74 mmol) is added to a solution of 2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (0.67 g, 1.83 mmol, Step-3) in methanol (20 mL) and stirred at 50° C. for 20 hours. The reaction mixture is poured into 2 M aqueous sodium hydroxide solution (10 mL) and extracted with DCM (30 mL×3). The organic layer is dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo to give 0.41 g (95% yield) of the title compound as white solid. This material is used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH2:23][CH2:24][CH3:25])[N:14]([CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[CH:27]([B-](F)(F)F)=[CH2:28].[K+]>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH2:23][CH2:24][CH3:25])[N:14]([CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH:27]=[CH2:28])=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCNS(C)(=O)=O
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Product: C=Cc1ccc2c(c1)nc(N)c1nc(CCCC)n(CCNS(C)(=O)=O)c12

Procedure:
N-[2-(4-Amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide was coupled with potassium vinyltrifluoroborate according to the procedure described in Part D of Examples 440–455 and recrystallized from acetonitrile to provide N-[2-(4-amino-2-butyl-7-vinyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide as an off-white solid.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:6]([C:7]1[N:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cnc2cccnn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cnc2cccnn12
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
To a solution of 3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine (28.46 g, 0.132 mol) in 200 mL of THF was added 145 mL (0.145 mol) of tetrabutylammonium fluoride (1.0M in THF) at ambient temperature. The solution was stirred for 15 min, concentrated, and the crude product purified by silica gel flash chromatography (eluted with 0-5% MeOH/DCM) to provide 17.84 g of product.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][CH:15]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[N:25]=[C:24]([NH2:26])[NH:23][N:22]=1.[BH4-].[Na+]>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:26][C:24]2[NH:23][N:22]=[C:21]([NH2:20])[N:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1n[nH]c(N)n1
Reactant: O=CCCCOc1cccc(CN2CCCCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Nc1n[nH]c(NCCCCOc2cccc(CN3CCCCC3)c2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.3 %

Procedure:
A solution of 4-[3-(1-piperidinylmethyl)phenoxy]butanal (522 mg) and 3,5-diamino-1,2,4-triazole (200 mg) in absolute ethanol (20 ml) was heated under reflux for 2 h. The cooled solution was treated with sodium borohydride (200 mg) and stirred at room temperature for 18 hr. The mixture was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The combined organic extracts were evaporated in vacuo and the residue was chromatographed on silica with methanol as eluant to give the title compound as an oil (250 mg), TLC silica (ethyl acetate:isopropanol:water:ammonia 25:15:8:2) 0.4, NMR (CDCl3) 2.8 t (1H); 3.0-3.3 m (3H); 5.3 m (2H); 6.2 m (2H); 6.6-6.8 m (4H); 7.7 m (4H); 8.0-8.8 m (10H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[CH:10]=[C:11]([S:16]([NH:19][C:20]2[S:24][N:23]=[CH:22][N:21]=2)(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1F)#[N:8].[I:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[OH:36]>CS(C)=O.C(OCC)(=O)C>[C:7]([C:9]1[CH:10]=[C:11]([S:16]([NH:19][C:20]2[S:24][N:23]=[CH:22][N:21]=2)(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1[O:36][C:27]1[CH:28]=[CH:29][C:30]([C:32]([F:33])([F:34])[F:35])=[CH:31][C:26]=1[I:25])#[N:8]
Reactant: Oc1ccc(C(F)(F)F)cc1I
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(C(F)(F)F)cc1I
Temperature: 80 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a suspension of potassium carbonate (0.850 g, 0.006150 mol) and 3-cyano-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 65, 0.500 g, 0.001759 mol) in dimethyl sulfoxide (5.0 mL) was added 2-iodo-4-(trifluoromethyl)phenol (Preparation 224, 0.595 g, 0.002066 mol) and stirred at 80° C. under nitrogen for 16 hours. The reaction mixture was diluted with ethyl acetate (10.0 mL) and the organic phase was washed with saturated aqueous sodium chloride solution (2×10.0 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was triturated in ethyl acetate (5.0 mL) to yield title compound as a white solid, 560 mg, 58% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][CH:28]=[CH:27]5)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Product: CCN1c2ncc(COc3ccc4[nH]ccc4c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 22 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 176°-178° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 5-hydroxyindole. The yield was 22% of theory.