Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[N:10][CH:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:26]([O:28][CH2:29][CH:30]([CH2:35][CH3:36])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:27]>O1CCCC1>[CH2:1]([O:5][C:6]([C:8]1[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:10]([C:26]([O:28][CH2:29][CH:30]([CH2:35][CH3:36])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:27])[C:11]([CH3:15])=[N:12][C:13]=1[CH3:14])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CC)COC(=O)Cl
Reactant: CCCCOC(=O)C1=C(C)NC(C)N=C1c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)C1=C(C)N=C(C)N(C(=O)OCC(CC)CCCC)C1c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.1 %

Procedure:
A solution of 1.4 g of 5-(n-butyloxycarbonyl)-4-(2-chlorophenyl)-2,6-dimethyl-dihydropyrimidine in 10 ml of tetrahydrofuran was added at room temperature to a suspension of 1 g of sodium hydride (as 50% suspension) in 5 ml of tetrahydrofuran. After 20 minutes, a solution of 1 g of 2-ethylhexyl chloroformate in 5 ml of tetrahydrofuran was added dropwise and after 30 minutes the reaction solution was diluted with ice water and extracted three times with ether. The organic layer was washed twice with water and dried over anhydrous magnesium sulfate and evaporated to remove the solvent to obtain 2 g of the residue. It was purified on 50 g of silica gel by column chromatography and eluted with 0.5% methanol/chloroform to obtain 1.47 g (71% yiled) of title compound.
Reaction SMILES: [Na].[NH:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:23])[C:12]4[C:17]([S:18](=[O:22])(=[O:21])[C:19]=3[CH:20]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:5][N:4]=[N:3]1.Cl.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29]Cl>C(O)C>[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][N:4]1[N:3]=[N:2][C:6]([C:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:23])[C:12]4[C:17]([S:18](=[O:21])(=[O:22])[C:19]=3[CH:20]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:5]1
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CN(C)CCCn1nnc(-c2ccc3c(c2)S(=O)(=O)c2ccccc2C3=O)n1

Procedure:
Sodium (0.69 g) was dissolved in ethanol (45 ml) and 3-(5-tetrazolyl)thioxanthone-10,10-dioxide (4.68 g) was added. 3-Dimethylaminopropyl chloride hydrochloride (2.37 g) was added to the mixture, which was then stirred and boiled under reflux for 2.5 hr. On cooling some solid separated, which was filtered off and discarded. Overnight yellow crystals of 3-(2-(3-dimethylaminopropyl)-5-tetrazolyl)thioxanthone-10,10-dioxide separated and were filtered off and recrystallised from ethanol, m.p. 141°-142° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][N:5]([S:14]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[CH:22]=O)(=[O:16])=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.C1CCN2C(=NCCC2)CC1>C(OCC)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]2[C:4]([C:3]([O:2][CH3:1])=[O:24])=[CH:22][C:21]3[CH:20]=[CH:19][S:18][C:17]=3[S:14]2(=[O:16])=[O:15])=[CH:7][CH:8]=1
Reactant: COC(=O)CN(c1ccc(OC)cc1)S(=O)(=O)c1sccc1C=O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1=Cc2ccsc2S(=O)(=O)N1c1ccc(OC)cc1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A mixture of the product from Step B (3.67 g, 9.95 mmol), DBU (1.0 mL) and molecular sieves (1.5 g) in ethyl acetate (100 mL) was heated at reflux temperature for 4 h, cooled to room temperature, washed with 2N HCl (50 mL) and brine (50 mL), and dried (MgSO4). Evaporation of the solvent provided the desired ester (1.92 g) as an oil which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[N:14]=[C:13]([C:15]([NH2:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[BH4-].[Na+]>CO>[CH2:3]([NH:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[N:14]=[C:13]([C:15]([NH2:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[C:4]1[CH:19]=[CH:18][CH:7]=[CH:6][CH:5]=1
Reactant: NCCc1ccc(Oc2cccc(C(N)=O)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cccc(Oc2ccc(CCNCc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
Dissolve 6-[4-(2-aminoethyl)phenoxy]pyridine-2-carboxamide (0.0452 g, 0.176 mmol) in methanol (2.9 mL). Add benzaldehlyde (0.018 mL) and 3 Å molecular sieves. Stir at room temperature overnight. Add NaBH4 (0.0066 g, 0.176 mmol). Stir for additional 6.5 hours before filtering and concentrating. Purify by reverse phase chromatography, eluting with 0-99% 0.1% TFA/acetonitrile and 0.1% TFA/water to give the title compound (9.4 mg, 15.4%): MS ES+ 347.9 (M+H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min], tR=7.6 min, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][C@@H:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][C:3]=1[CH3:24].[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[NH:33][C:32](=[O:34])[N:31]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:30]=2[CH:41]=1>CCO.C(Cl)Cl>[C:17]([N:14]1[CH2:15][CH2:16][C:11]2[N:10]([CH2:20][C@@H:21]([OH:22])[CH2:23][N:38]3[CH2:37][CH2:36][CH:35]([N:31]4[C:30]5[CH:41]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=5[NH:33][C:32]4=[O:34])[CH2:40][CH2:39]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=3)[C:12]=2[CH2:13]1)(=[O:19])[CH3:18]
Reactant: O=c1[nH]c2ccc(Cl)cc2n1C1CCNCC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2C[C@@H]2CO2)C1
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2C[C@@H](O)CN2CCC(n3c(=O)[nH]c4ccc(Cl)cc43)CC2)C1
Temperature: 70 °C
Reaction time: 18 h
Yield: 11.7 %

Procedure:
(R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (31 mg, 0.10 mmol) and 6-chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (36 mg, 0.17 mmol) were combined in EtOH (0.3 mL) and heated to 70° C. After 18 h the mixture was allowed to cool, diluted with CH2Cl2 and purified by preparative TLC (silica, 8% MeOH/CH2Cl2) to give 7 mg (12%) of the title compound. HPLC (reverse phase conditions), tR=3.49 min. MS (electrospray): m/z calculated for C30H3535Cl2N6O3 [M++H] 597.22, found 597.20. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 9.16 (br d, J=10.1 Hz, 1H), 7.55 (br m, 1H), 7.40-7.28 (m, 2H), 7.18 (br s, 1H), 7.03 and 6.98 (A and B of ABX (with fine splittings), Jab=8.4 Hz, 2H), 4.85 and 4.74 (A and B of ABX (with fine splittings), Jab=15.7 Hz, 1H), 4.62 (s, 1H), 4.29-4.18 (m, 4H), 4.09-4.00 (m, 2H), 3.91-3.71 (m, 2H), 3.16-2.78 (m, 4H), 2.55-2.50 (m, 4H), 2.43 (s, 1.5H), 2.41 (s, 1.5H), 2.23 (m, 1H), 2.21 (s, 1.5H), 2.16 (s, 1.5H), 1.84 (br s, 2H).
Reaction SMILES: BrCC1N=C([C:8](OCC)=[O:9])SC=1.BrCCC1ON=C(C(OCC)=O)C=1.BrCC1N=C(C(OCC)=O)OC=1.[CH2:38]([N:40]([CH2:51][C:52]1[N:53]=[C:54]([CH2:57][OH:58])SC=1)[CH2:41]/[CH:42]=[CH:43]/[C:44]#[C:45][C:46]([O:49][CH3:50])([CH3:48])[CH3:47])[CH3:39].C(N(CC1ON=C(CO)C=1)C/C=C/C#CC(OC)(C)C)C>>[CH2:38]([N:40]([CH2:51][C:52]1[O:58][C:57]([CH2:8][OH:9])=[CH:54][N:53]=1)[CH2:41]/[CH:42]=[CH:43]/[C:44]#[C:45][C:46]([O:49][CH3:50])([CH3:48])[CH3:47])[CH3:39]
Reactant: CCN(C/C=C/C#CC(C)(C)OC)Cc1csc(CO)n1
Reactant: CCOC(=O)c1nc(CBr)cs1
Agent: CCN(C/C=C/C#CC(C)(C)OC)Cc1cc(CO)no1
Agent: CCOC(=O)c1cc(CCBr)on1
Agent: CCOC(=O)c1nc(CBr)co1
Product: CCN(C/C=C/C#CC(C)(C)OC)Cc1ncc(CO)o1

Procedure:
When the same reactions as in Referential Example 49 are carried out using ethyl 4-bromomethylthiazol-2-carboxylate [see Ann., 1981, 623] or ethyl 5-bromoethylisoxazol-3-carboxylate [synthesized by brominating ethyl 5-methylisoxazole-5-carboxylate [see J. Heterocyclic Chem., 19, 557(1982)] with N-bromosuccimide in carbon tetrachloride] insted of the starting ethyl 4-bromomethyloxazol-2-carboxylate, (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-2 -hydroxymethyl-4-thiazolylmethylamine and (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-hydroxymethyl-5-isoxazolylmethylamine are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:3]=1[NH2:15].[CH:16]1([CH2:22][CH2:23][C:24](Cl)=[O:25])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:3]=1[NH:15][C:24](=[O:25])[CH2:23][CH2:22][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1C(F)(F)F
Reactant: O=C(Cl)CCC1CCCCC1
Solvent: CC#N
Product: O=C(CCC1CCCCC1)Nc1c(Br)cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 150 °C
Yield: 33 %

Procedure:
2-Bromo-4-nitro-6-trifluoromethyl-phenylamine (2.0 g) and cyclohexylpropionyl chloride (1.30 mL) were mixed in acetonitrile (10 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction was cooled to 0° C., the product filtered off and washed with cold acetonitrile (50 mL) affording 0.97 g (33% yield) of the title compound as a yellow solid. The crude product was used without further purification. LC-MS (m/z) 424 (MH+); tR=3.53, (UV, ELSD) 95%, 99%. 1H NMR (500 MHz, DMSO-d6): 0.88 (m, 2H), 1.17 (m, 3H), 1.28 (m, 1H), 1.51 (m, 2H), 1.68 (m, 5H), 2.38 (t, 2H), 8.45 (d, 1H), 8.82 (d, 1H), 10.17 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([C:24](=[O:73])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([N:33]4[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]([CH2:44][C:45]5[C:54]6[C:49](=[CH:50][C:51]([Br:55])=[CH:52][CH:53]=6)[CH:48]=[CH:47][C:46]=5[O:56][CH3:57])[C:36](=[O:58])[C@@H:35]([NH:59][C:60](=[O:72])[C@@H:61]([N:63](C(OC(C)(C)C)=O)[CH3:64])[CH3:62])[CH2:34]4)=[O:32])[CH:26]=3)[CH2:16][C@H:15]([NH:74][C:75](=[O:87])[C@@H:76]([N:78](C)[C:79](=O)OC(C)(C)C)[CH3:77])[C:14]1=[O:88])=[C:7]([O:89][CH3:90])[CH:6]=[CH:5]2.[ClH:91]>O1CCOCC1>[ClH:91].[ClH:91].[Br:55][C:51]1[CH:50]=[C:49]2[C:54](=[CH:53][CH:52]=1)[C:45]([CH2:44][N:37]1[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[N:33]([C:31](=[O:32])[C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([N:17]4[C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[N:13]([CH2:12][C:8]5[C:9]6[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=6)[CH:5]=[CH:6][C:7]=5[O:89][CH3:90])[C:14](=[O:88])[C@@H:15]([NH:74][C:75](=[O:87])[C@@H:76]([NH:78][CH3:79])[CH3:77])[CH2:16]4)=[O:73])[CH:26]=3)[CH2:34][C@H:35]([NH:59][C:60](=[O:72])[C@@H:61]([NH:63][CH3:64])[CH3:62])[C:36]1=[O:58])=[C:46]([O:56][CH3:57])[CH:47]=[CH:48]2
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CN(C(=O)c2cccc(C(=O)N3C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc4c(OC)ccc5cc(Br)ccc45)c4ccccc43)c2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@H]1CN(C(=O)c2cccc(C(=O)N3C[C@H](NC(=O)[C@H](C)NC)C(=O)N(Cc4c(OC)ccc5cc(Br)ccc45)c4ccccc43)c2)c2ccccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
To a stirred solution of tert-butyl N-[(1S)-2-[[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-1-[3-[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-3-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-4-oxo-2,3-dihydro-1,5-benzodiazepine-1-carbonyl]benzoyl]-4-oxo-2,3-dihydro-1,5-benzodiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (15 mg, 0.01 mmol) in dioxane (0.2 mL) at 0° C. was added 4 N HCl in dioxane (0.2 mL), the cooling bath was removed and the mixture was stirred at RT. After 2 h, the mixture was evaporated to provide the title compound (8 mg, 58.9%) as an off white solid. LC-MS: 1153.6 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].O>CN(C)C=O>[C:28]([O:27][C:25](=[O:26])[CH2:24][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)c1cccc(CCN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNCCc1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl 3-(2-aminoethyl)benzoate (900 mg) in N,N-dimethylformamide (20.0 mL) were added potassium carbonate (600 mg) and tert-butyl bromoacetate (0.600 mL) under ice-cooling, followed by stirring at room temperature for 5 hours. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-{2-[(2-tert-butoxy-2-oxoethyl)amino]ethyl}benzoate (738 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](OB(O)O)[CH:5]=[CH:6][CH:7]=1.Cl[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][C:17]([CH3:23])=[CH:18][CH:19]=2)[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>[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.C1(C)C=CC=CC=1.C1COCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][C:17]([CH3:23])=[CH:18][CH:19]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2ccc(Cl)nc2c1
Reactant: Cc1cccc(OB(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2ccc3ccc(C)cc3n2)c1
Reaction time: 24 h

Procedure:
3-methyl-phenyl-boric acid (1.3 mmol), 2-chloro-7-methyl-quinoline (1 mmol), tetrakis (triphenyl phosphine) palladium(0) (0.05 mmol), and potassium carbonate (3 mmol) are dissolved in a two-neck round bottom flask containing THF (30 ml) and H2O (10 ml). The mixture is then stirred for 24 hours in a bath of 100 degrees Celsius (° C.). Subsequently, when reaction no longer occurs, the THF and toluene are discarded. The mixture is extracted by using dichloromethane and water, which is then treated with vacuum distillation. Then, after filtering the mixture with a silica gel column, a solvent is treated with vacuum distillation. Thereafter, by using dichloromethane and petroleum ether, the mixture is re-crystallized and filtered, thereby yielding solid 2-(3-methylphenyl)-7-methyl-quinoline.
Reaction SMILES: N1(CCN2C=C(C3C=NC=C(C(F)(F)F)C=3)N=C2C2CCN([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])CC2)CCC1.[N:37]1([CH2:41][CH2:42][N:43]2[CH:47]=[C:46]([C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([O:54][C:55]([F:58])([F:57])[F:56])[CH:49]=3)[N:45]=[C:44]2[CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH2:40][CH2:39][CH2:38]1>>[N:37]1([CH2:41][CH2:42][N:43]2[CH:47]=[C:46]([C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([O:54][C:55]([F:58])([F:56])[F:57])[CH:49]=3)[N:45]=[C:44]2[CH:59]2[CH2:60][CH2:61][N:62]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:63][CH2:64]2)[CH2:40][CH2:39][CH2:38]1
Reactant: FC(F)(F)Oc1cccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)c1
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3cccc(OC(F)(F)F)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine of using 4-(1-(2-(azetidin-1-yl)ethyl)-4-(3-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)piperidine instead of 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride salt. LC-MS: (M+1=516, obsd.=516).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([I:9])[CH:3]=1.C(O)(C(F)(F)F)=O.[CH3:17][O:18][CH2:19][CH2:20]Cl.[OH-].[K+].[F-].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:20][CH2:19][O:18][CH3:17])=[C:4]([I:9])[CH:3]=1
Reactant: COCCCl
Reactant: Nc1cnc(F)cc1I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [I-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COCCNc1cnc(F)cc1I
Temperature: 100 °C
Yield: 20 %

Procedure:
Mix 6-fluoro-4-iodopyridin-3-amine in TFA salt (0.36 g, 1.50 mmol), 2-chloroethyl methyl ether (0.31 g, 3.30 mmol), potassium hydroxide (0.19 g, 3.30 mmol), potassium fluoride (0.19 g, 3.30 mmol), and tetrabutylammonium iodide (0.11 g, 0.30 mmol) in 1,4-dioxane (1.5 mL) in a seal reactor. Heat the reaction mixture at 100° C. overnight. Cool the reaction mixture to RT. Quench with water. Extract with ethyl acetate, wash the organic layer with water and saturated aqueous sodium chloride. Dry over MgSO4. After the filtration, remove the reaction solvent under reduced pressure. Purify by FCC (0.1% to 1% 2 M NH3 methanol solution/CH2Cl2) to give the title compound (0.09 g, 20%) with 80% HPLC purity. MS (ES) m/z 279 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([C:26]([OH:28])=O)[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]([NH2:33])([CH3:32])[CH3:31].CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH:30]([NH:33][C:26]([C:24]1[CH:25]=[C:20]2[CH:19]=[C:18]([CH:7]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=3)[CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[NH:29][C:21]2=[N:22][CH:23]=1)=[O:28])([CH3:32])[CH3:31]
Reactant: CC(C)N
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)NC(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 36.7 %

Procedure:
To a solution of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (200 mg, 0.48 mmol) and isopropylamine (50 μL, 0.62 mmol) in dichloromethane (1 mL), N,N-dimethylformamide (500 μL) and N-methylmorpholine (150 μL, 1.45 mmol) was added 1-hydroxybenzotriazole hydrate (132 mg, 0.97 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (186 mg, 0.97 mmol) in one portion. The mixture was then stirred at 25° C. for 14 h. The mixture was diluted with ethyl acetate (100 mL), washed with a 1 N aqueous sodium bicarbonate solution, 1 N aqueous hydrochloric acid solution, brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid isopropylamide (80 mg, 36%) as a white solid: LC/MS m/e calcd for C25H31N3O3S [M+H]+ 454.61, observed 454.4; 1H NMR (400 MHz, CDCl3) δ ppm 1.12 (m, 2H), 1.24 (d, J=6.7 Hz, 6H), 1.43 (m, 2H), 1.52-1.81 (m, 5H, H), 2.04 (m, 1H), 2.17 (m, 1H), 2.99 (s, 3H), 4.18 (t, J=7.9 Hz, 1H), 4.25 (m, 1H), 6.34 (s, 1H), 6.60 (d, J=7.6 Hz, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.78 (d, J=8.1 Hz, 2H), 8.23 (d, J=1.8 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H), 10.72 (br, 1H).
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6])#[N:2].[CH3:15]S(O)(=O)=O>CO>[C:1]([CH:3]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[CH2:4][C:5]([O:7][CH3:15])=[O:6])#[N:2]
Reactant: CS(=O)(=O)O
Reactant: N#CC(CC(=O)O)c1ccc(O)cc1
Solvent: CO
Product: COC(=O)CC(C#N)c1ccc(O)cc1
Yield: 93.3 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged with methanol (15 mL). To the stirred solvent was added 3-cyano-3-(4-hydroxyphenyl)propanoic acid (0.6 g, 3.1 mmol), followed by the addition of methanesulfonic acid (1 mL). The reaction mixture was refluxed for 1 h. After completion of the reaction, the reaction mixture was concentrated to distill off the solvent. Water (10 mL) was added and extracted with ethyl acetate (25 mL). The organic layer was washed with water (5 mL) and saturated brine solution (5 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as pale yellow liquid (0.6 g, yield: 93.3%). 1H NMR (300 MHz, CDCl3): δ 7.13-7.15 (d, 2H), 6.75-6.78 (d, 2H), 4.14-4.19 (t, 1H), 3.65 (s, 3H), 2.89-2.97 (m, 1H), 2.71-2.79 (m, 1H).
Reaction SMILES: [CH:1]1([NH:7][N:8]2[C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N+:13]([O-])=[CH:12][C:11]=3[N:10]=[C:9]2[CH2:22][O:23][CH2:24][CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[NH4+:27].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.CO>ClCCl.O.C(Cl)(Cl)Cl>[CH:1]1([NH:7][N:8]2[C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:13]=[C:12]([NH2:27])[C:11]=3[N:10]=[C:9]2[CH2:22][O:23][CH2:24][CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1NC1CCCCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NC1CCCCC1
Temperature: 25 °C

Procedure:
N-Cyclohexyl-2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-amine (0.425 g, 1.25 mmol) was placed in a 100 mL round bottom flask and dissolved in dichloromethane (20 mL). Ammonium hydroxide solution (10 mL) was added and the mixture was stirred vigorously. The stirred mixture was chilled in an ice water bath. Para-toluenesulfonyl chloride (0.250 g, 1.31 mmol) was added over 5 min. After 30 min of stirring at 0° C. TLC (SiO2, 95:5 chloroform:methanol) showed complete conversion. The mixture was warmed to room temperature and then diluted with dichloromethane (25 mL) and water (10 mL). The mixture was transferred to a separatory funnel and the phases separated. The organic portion was washed sequentially with 2% sodium carbonate solution (15 mL), water (15 mL) and brine (15 mL), dried over Na2SO4, filtered and then concentrated to yield an orange/tan foamy solid. The material was purified by column chromatography (40 g SiO2, 95:5 chloroform:methanol) to yield the product as an off white solid. The off-white solid was dissolved in 3 mL of a 9:1 chloroform:methanol mixture. A small spatula tip full of activated carbon (DARCO G 60–100 mesh) was added and the mixture was stirred at room temperature for 3 h. The mixture was filtered through a short column of SiO2 (5 g) eluting with 9:1 chloroform:methanol. The filtrate was concentrated to yield a glassy solid. The glassy solid was triturated in 15 mL diethyl ether for 2 h to provide a white solid. The solid was collected by vacuum filtration and rinsed with diethyl ether. The solid was dried in a vacuum oven (70° C.) to yield 0.062 g of N1-cyclohexyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline-1,4-diamine. mp 143–145° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.61 (dd, J=8.1, 1.1 Hz, 1H), 7.58 (dd, J=8.3, 0.9 Hz, 1H), 7.46–7.38 (m, 1H), 7.28–7.21 (m, 1H), 6.99 (d, J=1.9 Hz, 1H), 6.69 (s, 2H), 4.77 (s, 2H), 3.63 (q, J=7.0 Hz, 2H), 3.32–3.23 (m, 1H), 1.71–1.52 (m, 5H), 1.30–1.05 (m, 8H); 13C NMR (75 MHz, DMSO-d6) δ; MS m/z 152.1, 150.3, 145.0, 133.4, 127.4, 125.8, 123.9, 121.6, 121.1, 115.0, 65.8, 63.1, 59.8, 30.9, 25.8, 24.3, 15.4; MS m/z 340 (M+H)+; Anal. Calcd for C19H25N5O: C, 67.23; H, 7.42; N, 20.63; Found: C, 67.32; H, 7.37; N, 20.55.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20]>>[C:18]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)(=[O:21])[CH:19]=[CH2:20]
Reactant: O=[N+]([O-])c1ccc(NCc2ccccc2)cc1
Reactant: C=CC(=O)Cl
Product: C=CC(=O)N(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-benzylamino-nitrobenzene and acrylic acid chloride