Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[OH-].[Na+].[C:12](Cl)(=[O:17])[O:13][CH2:14][CH:15]=[CH2:16]>O.C(Cl)Cl>[CH2:14]([O:13][C:12]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])=[O:17])[CH:15]=[CH2:16]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of trans-4-hydroxy-L-proline (35.9 g) and sodium hydroxide (23.9 g) in water (330 ml) was added dropwise a solution of allyl chlorocarbonate (36.3 g) in methylene chloride (250 ml) under ice-cooling, and stirring was continued for 2 hours. Aqueous layer was separated from the reaction mixture, washed twice each with methylene chloride (100 ml), and then acidified by adding concentrated sulfuric acid (25 g) dropwise at a temperature below 30° C. After adding table salt (120 g), the mixture was extracted twice each with ethyl acetate (220 ml). Extract was dried over magnesium sulfate. Distillation of the solvent gave crude crystalline trans-1-allyloxycarbonyl-4-hydroxy-L-proline (62 g). Purification of the crude crystals by repulping with toluene gave trans-1-allyloxycarbonyl-4-hydroxyl-L-proline (56.1 g) having m.p. 93-°94° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.BrC1C=CC=CC=1CBr.[Br:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[CH2:40]Br>>[Br:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[CH2:40][N:3]1[C:2]([CH3:21])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4]1=[O:20]
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: COc1ccc(CBr)c(Br)c1
Agent: BrCc1ccccc1Br
Product: COc1ccc(CN2C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)c(Br)c1

Procedure:
Compound 110.2 was prepared as described for example 1.2, by reacting compound 1.1, instead of with 2-bromobenzyl bromide, with 2-bromo-1-bromomethyl-4-methoxybenzene (prepared by N-bromosuccinimide bromination from 2-bromo-4-methoxy-1-methylbenzene; 1H NMR: 7.56, d, 1H, 7.23, s, 1H, 7.0, d, 1H, 4.74, s, 2H; 3.8, s, 3H). 4-[3-(2-Bromo-4-methoxybenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile was obtained. (Molecular weight 495.04 (C21H17BrF3N3O3); 1H NMR: 8.38, d, 1H, 8.25, s, 1H, 8.1, d, 1H, 7.5, d, 1H, 7.22, s, 1H, 6.95, d, 1H, 4.6, s, 2H, 3.79, s, 3H, 1.4, s, 6H.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[C:32](Cl)(=O)[O:33]C1C=CC([N+]([O-])=O)=CC=1.[CH:45]1([CH2:48][NH2:49])[CH2:47][CH2:46]1>O1CCCC1>[CH:45]1([CH2:48][NH:49][C:32]([NH:1][C:2]2[CH:31]=[CH:30][CH:29]=[C:4]([CH2:5][CH:6]3[CH2:11][CH2:10][N:9]([CH2:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:28])([C:20]([F:21])([F:22])[F:23])[C:24]([F:27])([F:25])[F:26])=[CH:17][CH:18]=4)[CH2:8][CH2:7]3)[CH:3]=2)=[O:33])[CH2:47][CH2:46]1
Reactant: Nc1cccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCC1CC1
Solvent: C1CCOC1
Product: O=C(NCC1CC1)Nc1cccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A solution of 2-(4-((4-(3-aminobenzyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.224 mmol, 100 mg) and 4-nitrophenyl carbonochloridate (0.224 mmol, 45.1 mg) in tetrahydrofuran (5 mL) was stirred at room temperature for 30 minutes. Cyclopropylmethanamine (0.453 mmol, 46 μL, 32.2 mg) was added and the reaction was kept at room temperature overnight. The reaction mixture was concentrated under vacuum and residue purified by silica column chromatography (eluent: 2-10% methanol in dichloromethane) to afford the title compound (99 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4].Br[CH2:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:15][CH2:14][CH2:13][CH2:12][N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:3](=[O:4])[N:2]([CH3:10])[CH3:1]
Reactant: CN(C)C(=O)[C@@H]1CCCN1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)C(=O)[C@@H]1CCCN1CCCO
Yield: 48.3 %

Procedure:
A mixture of (S)-2-(N, N-dimethylcarbamoyl)pyrrolidine (426 mg, 3 mmol), (Chem. pharm. Bull. 1973, 21, 2112-2116), 3-bromo-1-propanol (0.41 ml, 4.5 mmol) and potassium carbonate (829 mg, 6 mmol) in acetonitrile (6 ml) was heated at reflux for 8 hours. The mixture was allowed to cool and was partitioned between methylene chloride and water. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography, eluting with methylene chloride/methanol (a gradient from 90/10 to 60/40) to give (S)-1-(3-hydroxypropyl)-2-(N, N-dimethylcarbamoyl)pyrrolidine (290 mg, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:31][C:32]1[C:40]2[C:35](=[CH:36][C:37]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:39]=2)[N:34]([CH3:45])[CH:33]=1>C1COCC1.CC(C)=O>[Br:31][C:32]1[C:40]2[C:35](=[CH:36][C:37]([S:41]([N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=3[O:2][CH3:1])[C:7]3[S:11][N:10]=[CH:9][N:8]=3)(=[O:42])=[O:43])=[CH:38][CH:39]=2)[N:34]([CH3:45])[CH:33]=1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: Cn1cc(Br)c2ccc(S(=O)(=O)Cl)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reaction time: 0.08 h

Procedure:
A 1 L round bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (10.36 g, 41.2 mmol) and THF (190 ml) to give a clear, pale-yellow solution. The flask was cooled to −78° C. in a dry ice and acetone bath, then lithium bis(trimethylsilyl)amide (1M in THF) (43.1 ml, 43.1 mmol) was added dropwise. The cooling bath was removed for 10 min, which led to the formation of a clear, orange-colored solution. The flask was placed back in the cooling bath for 5 min, then a solution of 3-bromo-1-methyl-1H-indole-6-sulfonyl chloride (11.56 g, 37.5 mmol) in minimal THF was added dropwise via cannula. Following the addition, the cooling bath was removed and the reaction was stirred for two hours. The reaction mixture was diluted with a saturated aq. ammonium chloride solution and water, and extracted with EtOAc (2×). The aq. layer was filtered to give some desired product as a pink solid. The filtrate was again extracted with EtOAc, and the organic extracts were combined. The combined solution was dried over sodium sulfate, filtered, and concentrated. The residue was triturated with EtOAc, and the resulting solid was collected via filtration to give a second crop of desired product. The filtrate was absorbed onto silica gel, and the impregnated silica gel was eluted onto a silica gel column (0 to 100% EtOAc/Heptane). The material thus obtained was still impure, so it was further purified by chromatography on silica gel (0 to 10% EtOAc/DCM) to give a third crop of desired product. The three crops were combined to afford 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (16.47 g, 31.5 mmol, 84% yield) as a light pink solid. 1H NMR (400 MHz, DMSO-d6) δ=8.34 (s, 1 H), 8.05 (dd, J=0.6, 1.6 Hz, 1 H), 7.95 (s, 1 H), 7.66-7.52 (m, 2 H), 6.95 (d, J=8.4 Hz, 1 H), 6.47-6.26 (m, 2 H), 5.12 (s, 2 H), 3.88 (s, 3 H), 3.69 (s, 3 H), 3.66 (s, 3 H). m/z (ESI) 545.0 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:21])[C:14]([C:22]3[CH:26]=[CH:25][O:24][C:23]=3[CH:27]=[CH2:28])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.O.C(OCC)(=[O:34])C>C1COCC1>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:21])[C:14]([C:22]3[CH:26]=[CH:25][O:24][C:23]=3[CH2:27][CH2:28][OH:34])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1occc1-c1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1O
Reactant: CCOC(C)=O
Agent: OO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2CCO)c1O
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A solution of 9-borobicyclononane (0.5M in THF, 12.6 mL) was added to methyl 6-(benzenesulfonylmethyl)-2-hydroxy-3-(2-vinylfuran-3-yl)-benzoate (Intermediate 24, 1.0 g) in THF (20 mL) at 50° C. and the resultant mixture was stirred and heated at 50° C. for 75 minutes. After cooling to room temperature, 35% hydrogen peroxide (2 mL) was added and the mixture was stirred for 1.5 hours. Water and ethyl acetate were added to the mixture and the organic layer was separated, washed with water, sodium metabisulfite and brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 30-70%. The product was triturated with diethyl ether and the solid was collected by filtration and dried in vacuo to give methyl 6-(benzenesulfonylmethyl)-2-hydroxy-3-[2-(2-hydroxyethyl)-furan-3-yl]-benzoate (0.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[H-].[Na+]>CN(C)C=O.O>[C:10]([CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:11]
Reactant: COc1cccc(CC#N)c1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCC(C#N)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Two grams of (3-methoxyphenyl)acetonitrile and 1.5 ml of ethyl 4-bromobutyrate are dissolved in 50 ml of dimethylformamide at 0° C. Six hundred milligrams of 60% sodium hydride (600 mg; 15 mmol) are progressively added to the solution. The reaction mixture is stirred at ambient temperature for 4 hours, taken up in 100 ml of acidic water and extracted with ether. The organic phase is then dried over magnesium sulphate, filtered and evaporated under reduced pressure. The oil obtained is purified on a column (eluant:ether/cyclohexane 4/6) to yield the title product in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](O)=[O:21])[CH:15]=1)[C:7]2=[O:23].CC1C=CC=C2C=1NC(=O)NC2=O.BrCC1C=C(C=CC=1)C(OC)=O.[N:49]1([C:55]2[N:60]=[CH:59][CH:58]=[CH:57][N:56]=2)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([N:52]3[CH2:53][CH2:54][N:49]([C:55]4[N:56]=[CH:57][CH:58]=[CH:59][N:60]=4)[CH2:50][CH2:51]3)=[O:21])[CH:15]=1)[C:7]2=[O:23]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Cc1cccc2c(=O)n(Cc3cccc(C(=O)O)c3)c(=O)[nH]c12
Agent: COC(=O)c1cccc(CBr)c1
Agent: Cc1cccc2c(=O)[nH]c(=O)[nH]c12
Product: Cc1cccc2c(=O)n(Cc3cccc(C(=O)N4CCN(c5ncccn5)CC4)c3)c(=O)[nH]c12

Procedure:
The compound was prepared from 8-methyl-3-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared from 8-methylquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)benzoate using a procedure similar to those used for Examples 222 and 223), and 2-(piperazin-1-yl)pyrimidine using a procedure similar to those described for the synthesis of compound of Example 3. 1H NMR (DMSO-d6): 10.81 (s, 1H), 8.36 (d, J=4.5 Hz, 2H), 7.83 (d, J=7.5 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.45-7.30 (m, 4H), 7.13 (t, J=7.7 Hz, 1H), 6.67 (t, J=4.7 Hz, 1H), 5.15 (s, 2H), 3.92-3.46 (m, 8H), 2.36 (s, 3H). MS: m/z 457.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([N+:22]([O-])=O)([CH3:21])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(O)C>[Ni].O1CCCC1>[CH3:21][C:2]([NH2:22])([CH3:1])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(Cc1c[nH]c2c(OCc3ccccc3)cccc12)[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(N)Cc1c[nH]c2c(OCc3ccccc3)cccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(2-methyl-2-nitropropyl)-7-(benzyloxy)indole (25.0 g, 77.1 mmol), Raney Nickel® (9.5 g wet lump), and 3A ethanol (250 mL) is pressurized to 50 psig with H2 and is heated to 60° C. After 1 hour, the mixture is cooled to ambient temperature. The mixture is diluted with tetrahydrofuran (100 mL) and is warmed to 50° C. The catalyst is removed by filtration and the cake is rinsed with 50° C. tetrahydrofuran (4×50 mL). The filtrate is concentrated to a solid which is dried in a 50° C. vacuum oven to provide 22.41 (99%) of 2-methyl-1-[7-(benzyloxy)indol-3-yl]prop-2-ylamine. MS (ES+) m/z 295 (100%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[N:34]1[CH:38]=[C:37]([NH2:39])[C:36]([C:40]([F:43])([F:42])[F:41])=[N:35]1.C1C=CC2N(O)N=NC=2C=1.[C:54]12([CH2:64][C:65](O)=[O:66])[CH2:63][CH:58]3[CH2:59][CH:60]([CH2:62][CH:56]([CH2:57]3)[CH2:55]1)[CH2:61]2.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:54]12([CH2:64][C:65]([NH:39][C:37]3[C:36]([C:40]([F:43])([F:41])[F:42])=[N:35][N:34]([C:29]4[N:28]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:38]=3)=[O:66])[CH2:61][CH:60]3[CH2:59][CH:58]([CH2:57][CH:56]([CH2:62]3)[CH2:55]1)[CH2:63]2
Reactant: Nc1cn(-c2ncccn2)nc1C(F)(F)F
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cn(-c2ncccn2)nc1C(F)(F)F
Reaction time: 6 h

Procedure:
BOP (35 mg, 0.08 mmol) is added to a solution of 1-pyrimidin-2-yl-3-trifluoromethyl-1H-pyrazol-4-ylamine (15 mg, 0.065 mmol), HOBt (5 mg), 1-adamantaneacetic acid (16 mg, 0.08 mmol) and DIEA (17 μL, 0.1 mmol) in DMF (0.5 mL) at RT. The mixture is stirred for 6 h. H2O is added to the mixture and is extracted with EtOAc (3×10 mL). The organic phase is dried. The crude material is purified by PTLC using 4% MeOH in CH2Cl2 to afford the title compound. 1H NMR (CDCl3): 9.38 (s, 1H), 8.6-81 (m, 2H), 7.30 (m, 1H), 2.16 (s, 2H), 2.01-1.97 (m, 3H), 1.80-1.50 (m, 12H). MS (M+1)=406.11; RT=1.4 min. *IC50.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C-:5]#[N:6].[Na+].[F:8][C:9]1[N:10]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[C:12]([CH:14]=O)[N:13]=1>C1COCC1>[CH3:2][N:3]([CH3:4])[CH:14]([C:5]#[N:6])[C:12]1[N:13]=[C:9]([F:8])[N:10]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: [C-]#N
Reactant: CNC
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(C#N)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 3 h

Procedure:
An aqueous solution of dimethylamine hydrochloride and NaCN was added to a solution of 2-fluoro-4-formyl-1-triphenylmethylimidazole in THF. After stirring 3 hours at 20°, work-up gave 4-(1-dimethylaminocyanomethyl)-2-fluoro-1-triphenylmethylimidazole having the following n.m.r. in CDCl3 : 2.31 (s, 6H); 4.64 (s, 1H); 6.68 (s, 1H); 7.04-7.45 (m, 15H).
Reaction SMILES: C([O-])(=O)C.[NH4+].C([BH3-])#[N:7].[Na+].[CH3:10][C:11]([CH3:26])=[CH:12][CH2:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21](=O)[CH3:22])=[CH:17][CH:16]=1>CO>[CH3:10][C:11]([CH3:26])=[CH:12][CH2:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH:21]([NH2:7])[CH3:22])=[CH:17][CH:16]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)COc1ccc(OCC=C(C)C)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)=CCOc1ccc(OCC(C)N)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Ammonium acetate (3.29 g, 42.7 mmol), sodium cyanoborohydride (0.20 g, 3.0 mmol) and 3A molecular sieves are added to the above phenoxyacetone (1.0 g, 4.3 mmol) in 20 ml of anhydrous methanol under N2 and at RT. The reaction is stirred at RT for 4 days. The methanol is removed by rotoevaporation, and ether and water are added to the residue, followed by 10% NaOH. The mixture is extracted with ether (3X), and the combined organic layers are washed with water until neutral, dried and filtered and the solvent evaporated off to give 2-[4-(3-methyl-2-butenoxy)phenoxy]-1-methylethylamine.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([N:15]1[C:21](=[O:22])[C:20]2[CH:23]=[C:24]([I:27])[CH:25]=[CH:26][C:19]=2[NH:18][C:17](=[O:28])[CH:16]1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[CH3:14].C(N(CC)CC)C>O1CCCC1.C(Cl)(Cl)Cl>[C:1]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([N:15]1[C:21](=[O:22])[C:20]2[CH:23]=[C:24]([I:27])[CH:25]=[CH:26][C:19]=2[NH:18][C:17](=[O:28])[CH:16]1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(c1ccc(Cl)cc1N)N1C(=O)c2cc(I)ccc2NC(=O)C1c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(Cl)ccc1C(C)N1C(=O)c2cc(I)ccc2NC(=O)C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
Acetyl chloride (15 μL, 0.212 mmol) was added at 0° C. under argon to a solution of 1,3-dihydro-4-[1-(2-amino-4-chlorophenyl)ethyl]-3-(4-chloropenyl)-7-iodo-1,4-benzodiazepine-2,5-dione (100 mg, 0.177 mmol), in tetrahydrofuran (5 mL) and chloroform (5 mL). Then, triethylamine (30 μL, 0.21 mmol) was added drop wise and the reaction mixture was allowed warm up to room temperature. After 30 minutes, the solution was concentrated under reduced pressure and the residue was petitioned between ethylacetate and 1N sodium bicarbonate. Organic layer was dried (Na2SO4), evaporated, and the residue was purified by column chromatography to give the title compound (49 mg, 45%) as a colorless powder: 1H NMR (400 MHz, CDCl3) δ 1.81 (d, J=6.8 Hz, 3H), 2.44 (s, 3H), 5.33 (s, 1H), 6.37 (q, J=6.8 Hz, 1H), 6.47 (d, J=8.4 Hz, 2H), 6.55 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 2H), 7.03 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.59 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 8.28 (br s, 1H), 8.54 (d, J=2.0 Hz, 1H), 9.94 (s, 1H). Mass spectrum (LCMS, ESI pos.): Calcd for C25H20Cl2IN3O3: 607; found: 608 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][N:14]1[C:22]2[C:21]([Br:23])=[CH:20][N:19]=[C:18]([NH2:24])[C:17]=2[N:16]=[C:15]1[CH2:25][CH2:26][CH3:27].[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>ClCCl>[NH2:24][C:18]1[C:17]2[N:16]=[C:15]([CH2:25][CH2:26][CH3:27])[N:14]([CH2:13][CH2:12][O:11][CH2:10][CH2:9][NH:8][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=3)[C:22]=2[C:21]([Br:23])=[CH:20][N:19]=1
Reactant: CCCc1nc2c(N)ncc(Br)c2n1CCOCCN
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc2c(N)ncc(Br)c2n1CCOCCNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.6 %

Procedure:
Triethylamine (0.07 g, 0.66 mmol) was added to a solution of 1-[2-(2-aminoethoxy)ethyl]-7-bromo-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine (0.15 g, 0.44 mmol) in dichloromethane ( 2 mL). 4-Chlorobenzoyl chloride (0.09 g, 0.53 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at ambient temperature for 10 minutes at which time analysis by thin layer chromatography indicated that the reaction was complete. The reaction mixture was partitioned between dichloromethane (30 mL) and saturated aqueous sodium bicarbonate (20 mL). The layers were separated. The organic layer was washed sequentially with saturated aqueous ammonium chloride (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide 0.23 g of a clear, glassy solid. The crude material was purified by chromatography (silica gel eluting with 95:5 dichloromethane:methanol) to provide 0.05 g of N-{2-[2-(4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethyl}-4-chlorobenzamide as a white amorphous solid.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:25])[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[CH2:18]([O:17][C:15]1[C:14]([Br:25])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(OCc3ccccc3)c(Br)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CNCCc2cc(OCc3ccccc3)c(Br)cc21
Reaction time: 8 h
Yield: 65 %

Procedure:
A solution of N-trifluoroacetyl-7-benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.81 g, 1.83 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (20 mL), and stirred overnight at 20 C. The product mixture was diluted with water (200 mL), extracted twice with EtOAc (200 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.412 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.38 (d, J=8 Hz, 2 H), 7.30 (dd, J=7, 8 Hz, 2 H), 7.23 (m, 2 H), 6.61 (s, 1 H), 5.03 (s, 2 H), 2.94 (m, 3 H), 2.81 (m, 3 H), 2.62 (m, 1 H), 2.30 (bs, 1 H), 1.24 (d, J=7 Hz, 3 H). MS calculated for C18H20BrNO+H: 346, observed: 346.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>CN(C)C=O>[C:24]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])(=[O:26])[CH3:25]
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ncn(Cc2ccccc2)c1C(N)=O
Reaction time: 8 h
Yield: 33.3 %

Procedure:
2.2 g (10 mmol) of 4-amino-1-benzyl-5-imidazole carboxamide prepared in Reference Example 2 was dissolved in 200 ml of N,N-dimethylformamide. 2.1 ml (15 mmol) of triethylamine and 1.06 ml (15 mmol) of acetyl chloride were added to the mixture while cooling with ice, followed by stirring overnight. The reaction product was concentrated under vacuum to obtain a crude product, which was recrystallized from hot methanol to obtain 0.86 g of 4-acetylamino-1-benzyl-5-imidazolecarboxamide (yield 33%).