Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]3[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[CH:11]3[O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[O:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][O:17][CH:13]2[CH:11]3[O:12][C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[O:9][CH:10]3[CH2:16][CH2:15][CH2:14]2)[CH2:23][CH2:24]1
Reactant: COc1cccc2c1OC1CCCC(O)C1O2
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: COc1cccc2c1OC1CCCC(OCCN3CCOCC3)C1O2
Yield: 55.7 %

Procedure:
In an analogous manner as described in Example 3, but starting with 10 g (0.042 mole) of the alcohol of Example 2 and 9 g (0.038 mole) of 4-(2-chloroethyl)morpholine hydrochloride, there were obtained 7.4 g of the title-compound of boiling point 192°-195° C. at a pressure of 65 Pa, having the elementary analysis:
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.NN.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH2:9])=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc([N+](=O)[O-])cc1
Yield: 82.9 %

Procedure:
2-(4-Nitrobenzyl)isoindoline-1,3-dione (1.6 g, 5.67 mmol) was dissolved in tetrahydrofuran (8 mL). To the solution hydrazine monohydrate (1.7 mL, 22.675 mmol) and p-toluenesulfonic acid monohydrate (108 mg, 0.57 mmol) was added. It was refluxed for 6 h. TLC showed complete consumption of starting material. The mixture was extracted with ethyl acetate and washed with water and brine. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography to give (4-nitrophenyl)methanamine (715 mg, 83%).
Reaction SMILES: O.[OH-].[Li+].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[O:15][C:14]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][C:32]([O:34]C)=[O:33])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[O:17])=[N:13][N:12]=1>O.C1COCC1>[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[O:15][C:14]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C@H:25]3[CH2:26][CH2:27][C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][CH2:30]3)=[CH:23][CH:24]=2)=[O:17])=[N:13][N:12]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccn4)o3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccn4)o3)cc2)CC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Lithium hydroxide monohydrate (60 mg) in water (2 mL) was added to a stirred suspension of methyl {trans-4-[4-({[5-(pyridin-2-ylamino)-1,3,4-oxadiazol-2-yl]carbonyl}amino)phenyl]cyclohexyl}acetate (Example 105, 309 mg) in THF (7 mL). After 16 hours the solution was heated to 40° C. and stirred for a further 5 hours then allowed to cool to ambient temperature. The THF was removed in vacuo and the residue was acidified with 2M HCl. The precipitate was filtered off, washed with ether, warm DCM and warm ether then dried overnight. The resultant solid was purified by HPLC using a gradient of 5-25% MeCN in water with 1% ammonia as the eluent to give the title compound (119 mg) as a solid; 1H NMR δ 10.80 (1H, bs), 10.91 (1H, s), 8.31 (1H, d), 7.86 (2H, m), 7.69 (2H, d), 7.23 (2H, d), 7.05 (1H, m), 2.45 (1H+DMSO, m), 2.14 (2H, d), 1.82 (5H, m), 1.47 (2H, m), 1.13 (2H, m); MS m/e MH+ 422.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9](=[O:15])[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[CH:6]=1.ClCC(O)COC1C2SC=CC=2C(=O)C2C=CC=CC=2C=1.CO.[CH3:44][C:45]1([CH3:52])[CH2:49][CH2:48][C:47]([CH3:51])([CH3:50])[NH:46]1>>[OH:1][CH:2]([CH2:20][N:46]1[C:47]([CH3:51])([CH3:50])[CH2:48][CH2:49][C:45]1([CH3:52])[CH3:44])[CH2:3][O:4][C:5]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9](=[O:15])[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[CH:6]=1
Reactant: O=c1c2ccccc2cc(OCC2CO2)c2sccc12
Reactant: CC1(C)CCC(C)(C)N1
Agent: O=c1c2ccccc2cc(OCC(O)CCl)c2sccc12
Solvent: CO
Product: CC1(C)CCC(C)(C)N1CC(O)COc1cc2ccccc2c(=O)c2ccsc12

Procedure:
20.0 g of a mixture of 10-(2,3-epoxypropoxy)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one and 10-(3-chloro-2-hydroxypropoxy)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one are boiled at reflux in 65 ml of 2,2,5,5-tetramethylpyrrolidine and 200 ml of methanol for 5 hours. The reaction mixture is evaporated to dryness and the residue is taken up in 600 ml of chloroform and 150 ml of 3N caustic soda solution. The organic solution is separated and is washed thrice with 3N caustic soda solution. After washing neutral with water, the solution is dried over sodium sulphate and concentrated by evaporation. The residue is chromatographed on 600 g of silica gel with a mixture of chloroform containing 5% methanol to give the title compound in free base form. (M.Pt. 104° - 107° from isopropanol).
Reaction SMILES: [NH:1]1[C:5]2[NH:6][CH:7]=[CH:8][C:9](=O)[C:4]=2[CH:3]=[N:2]1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][N:2]=[CH:3][C:4]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc[nH]c2[nH]ncc12
Product: Clc1ccnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
1,7-Dihydro-pyrazolo[3,4-b]pyridin4-one (1.2 g, 8.8 mmol) (Dorn, H. et al., Prakt. Chem., 324, 557-62 (1982)) in POCl3 (15 ml) at 0° C. was treated with PCd5 (2.5 mg, 0.01 mmol). The solution was allowed to warm to rt over 1 h, then heated to 90° C. and held 3h. The solution was concentrated under reduced pressure, then treated with ice and water (50 ml). The resulting mixture was extracted with ethyl acetate (100 ml), and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate (30 ml). The organic layer was dried over MgSO4, then evaporated under reduced pressure to give 4-chloro-1H-pyrazolo[3,4-b]pyridine as a yellow solid (820 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 8.57 (d, 1H, J=5.2 Hz), 8.25 (s, 1H), 7.28 (d, 1H, J=5.2 Hz).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:47])([F:46])[C:13]1[CH:14]=[C:15]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29])[CH2:20][C@H:19]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:17].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[F:47][C:12]([F:11])([F:46])[C:13]1[CH:14]=[C:15]([CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=1)[C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][O:26][CH2:27][CH:28]=[O:29])[CH2:20][C@H:19]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:17]
Reactant: Cc1ccc(C[C@@H]2CN(CCOCCO)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H]2CN(CCOCC=O)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
To a stirred solution of oxalyl chloride (151 mg) in dichloromethane (3 ml) was added dropwise a solution of dimethylsulfoxide (123 mg) in dichloromethane (0.25 ml) at −78° C. under nitrogen atmosphere. After 15 minutes, (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(2-hydroxyethoxy)ethyl]piperazine (317 mg) was added at the same temperature. After 15 minutes, the resulting mixture was stirred at −45° C. for 1 hour. Triethylamine (446 mg) was added at −45° C., and the whole was stirred at 0° C. for 20 minutes and then treated with aqueous solution of ammonium chloride (2 ml). The organic layer was separated and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by column chromatography on silica gel using ethyl acetate as eluent to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(formylmethoxy)ethyl]piperazine (171 mg).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45])=[CH:37][CH:36]=1>FC(F)(F)C(O)=O>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][CH2:42][CH2:43][S:44]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][C@:2]3([CH3:1])[O:6][C:5]4=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]4[CH2:3]3)[CH2:15][CH2:16]2)(=[O:46])=[O:45])=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=S(=O)(Cl)CCCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(CN2CCN(S(=O)(=O)CCCc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A mixture of tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylate prepared in Example 393 (300 mg, 0.82 mmol) and trifluoroacetic acid (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (10 ml). To the solution, triethylamine (3 ml, 21.52 mmol) was added followed by stirring at room temperature for 10 minutes, and then 3-(4-chlorophenyl)propane-1-sulfonyl chloride (300 mg, 1.19 mmol) was added followed by stirring at room temperature for 3 days. The reaction mixture was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-2-{4-[3-(4-chlorophenyl)propane-1-sulfonyl]piperazin-1-ylmethyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (330 mg, yield 84%) as a white powder.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:18])[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]2=[C:5]([C:19]([F:22])([F:21])[F:20])[CH:4]=1.C[Si](I)(C)C>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl>[CH3:18][N:9]1[C:7]2[NH:8][C:3](=[O:2])[CH:4]=[C:5]([C:19]([F:21])([F:20])[F:22])[C:6]=2[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10]1
Reactant: COc1cc(C(F)(F)F)c2c(-c3ccccc3)cn(C)c2n1
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: Cn1cc(-c2ccccc2)c2c(C(F)(F)F)cc(=O)[nH]c21
Yield: 64 %

Procedure:
A mixture of 6-Methoxy-1-methyl-3-phenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (70 mg, 0.23 mmol), trimethylsilyl iodide (686 mg, 3.43 mmol) and DMAP (3 mg, 0.01 mmol) in chloroform (3 ml) was heated at reflux for 3 days. The reaction mixture was concentrated under reduced pressure. To the mixture water was added and the solution was extracted with EtOAc. The organic layer was washed with water, saturated aqueous sodium bisulfite solution and brine, filtered and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The crude product was purified by flash column chromatography (20% EtOAc in hexane) to yield the title compound (43 mg, 64%). [LCMS RtC=0.45 min; [M+H]+=292.8]
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[CH3:14])(=O)[CH3:2].[CH:17]([NH2:20])([CH3:19])[CH3:18].[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:17]([NH:20][CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:2])([CH3:19])[CH3:18]
Reactant: CC(=O)c1ccccc1NC(=O)C=C(C)C
Reactant: CC(C)N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Product: CC(C)=CC(=O)Nc1ccccc1C(C)NC(C)C
Reaction time: 16 h
Yield: 83 %

Procedure:
The product of Example 10 (217 mg, 1.0 mmol) was placed in a flame dried 25 mL round bottom flask, and flushed with Ar(g). The flask was charged with 8 mL of absolute ethanol, followed by isopropylamine (85.2 μL, 1.0 mmol), followed by the addition of titanium(IV) isopropoxide (0.59 mL, 2.0 mmol). The reaction was allowed to proceed at room temperature for 16 hours. After this time sodium borohydride (60 mg, 1.5 mmol) was added slowly over 10 minutes, and the mixture was allowed to stir for an additional 2 hours. The white precipitate was then filtered off, and washed with dichloromethane (20 mL). The washings were then collected, transferred to a separatory funnel, and washed successively with 1N NaOH (2×15 mL), and brine (1×15 mL). The organic layer was then dried over magnesium sulfate, filtered and evaporated to yield a crude oil, which was purified by column chromatography in ethyl acetate-hexane (3:7), to yield 216 mg of a yellow oil (83% yield). 1H NMR (360 MHz, CDCl3) δ 8.46-8.36 (m, 1H), 7.26-7.17 (m, 1H), 7.07-7.00 (m, 1H), 6.99-6.90 (m, 1H), 5.70-5.66 (m, 1H), 4.08 (q, J=6.5 Hz, 1H), 2.71 (sep., J=6.5 Hz, 1H), 2.25 (d, J=0.8 Hz, 3H), 1.90 (d, J=1.2 Hz, 3H), 1.38 (d, J=6.5 Hz, 3H), 1.09 (d, J=6.5 Hz, 3H), 1.05 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.S(Cl)(C1C=CC(C)=CC=1)(=O)=[O:16]>CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>[Br:1][C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2cc(Br)c[n+]([O-])c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc2cc(Br)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-bromo-7-methoxyquinoline 1-oxide (2.04 g, 8.03 mmol) in EtOAc (50 mL) and 15% aqueous K2CO3 (15 mL) at RT, TsCl (1.68 g, 8.83 mmol) was added. The reaction mixture was stirred vigorously at RT for 18 hours, at which time the product was collected by filtration and washed with EtOAc. The solid was dried under vacuum and used with no further purification. LRMS (M+H)+=254.1.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[CH3:13][C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:16]=2[N:15]=1.N>>[ClH:1].[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:23]([C:21]3[CH:20]=[CH:19][C:17]4[NH:18][C:14]([CH3:13])=[N:15][C:16]=4[CH:22]=3)=[O:24])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: Cc1nc2cc(C(=O)O)ccc2[nH]1
Agent: Cl
Agent: N
Product: Cc1nc2cc(C(=O)NC3C4CC5CC3CN(C5)C4)ccc2[nH]1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 2-methyl-1H-benzimidazole-5-carboxylic acid (Acros) according to methods A and C; yield 83 mg, 0.21 mmol (58%): 1H NMR (300 MHz, methanol-d4) δ 2.02-2.31 (m, 5H), 2.50 (s, 2H), 2.89 (s, 3H), 3.50 (d, J=13 Hz, 2H), 3.57 (s, 2H), 3.92 (d, J=13 Hz, 2H), 4.32 (s, 1H), 7.82 (d, J=9 Hz, 1H), 8.11 (dd, J=9, 2 Hz, 1H), 8.33 (s, 1H), 8.57 (d, J=5 Hz, 1H); MS (DCI/NH3) m/z 311 (M+H)+; Anal. C18H22N4O2HCl1.0H2O: C, H, N.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:19][CH2:20][CH2:21][S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C=O.[BH3-][C:45]#N.[Na+]>CC#N.O>[C:1]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:19][CH2:20][CH2:21][S:22][C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:18])[CH3:45])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)NCCNCCCCCC(=O)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN(CCCCCC(=O)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Boc-NH—(CH2)2—NH—(CH2)5—CONH—(CH2)2-STrt (189 mg, 0.27 mmol) and HCHO (35% aqueous, 113 μl) were dissolved in MeCN (1.5 ml) and NaCNBH3 (34 mg, 0.54 mmol) was added. The reaction mixture was stirred for 5 h at RT. After completion of the reaction (MS) the solution was diluted with H2O (5 ml) and extracted with CH2Cl2 (3×5 ml). The combined organic layers were dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by RP-HPLC to get Boc-NH—(CH2)2—N(CH3)—(CH2)5—CONH—(CH2)2-STrt.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][CH3:14])=[CH:8][C:3]=1[C:4](OC)=[O:5].[BH4-].[Li+]>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][CH3:14])=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1cc(OC)c(Cl)cc1Br
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)c(Br)cc1Cl
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of methyl 2-bromo-4-chloro-5-methoxybenzoate (1.88 g, 6.7 mmol, Powers, J. J.; Favor, D. A.; Jeganathan, A.; Rankin, T.; Sharma, R.; Pandit, C.; Maiti, S, N. Tetrahedron Lett. 2009, 50(12), 1267-1269) in anhydrous THF (20 mL) was added lithium borohydride (0.644 g, 30 mmol). The resulting mixture was heated under reflux for about 72 h. After cooling to rt the mixture was concentrated in vacuo. The residue was partitioned between water (50 mL) and ethyl acetate (90 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with water (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 1:1) to give (2-bromo-4-chloro-5-methoxy-phenyl)methanol (1.57 g, 6.3 mmol, 93%) as a white solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.01 (1 H, t, J=6 Hz), 3.92 (3 H, s), 4.71 (2 H, d, J=6 Hz), 7.12 (1 H, s), 7.53 (1 H, s).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[O:14][CH:13]=[C:12]([C:15]#[N:16])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:17][OH:18].O>C(O)C.CCOCC>[Si:1]([O:8][CH2:9][C:10]1[O:14][CH:13]=[C:12]([C:15](=[N:17][OH:18])[NH2:16])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C#N)co1
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(C(N)=NO)co1
Yield: 97 %

Procedure:
To a solution of 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-furonitrile (1.8 g, 7.6 mmol) that was obtained in Example 1 (1c) in ethanol (10 ml) was added a 40% aqueous solution of hydroxylamine (1.0 ml) with stirring, and the resulting mixture was stirred at 60° C. for 1 hour. After evaporating the reaction mixture in vacuo, the residue obtained was diluted with ether, poured into water (40 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1) as the eluent to afford the title compound (2.0 g) in a yield of 97% as a white crystalline solid.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:27]([CH2:28][NH2:29])=[CH:26][C:25]3[C:20](=[C:21]([O:30][CH3:31])[CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:15]=[CH:16][CH:17]=1.C(N(CC)C(C)C)(C)C.C(O)CCC>CCOC(C)=O>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:27]([CH2:28][NH:29][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)=[CH:26][C:25]3[C:20](=[C:21]([O:30][CH3:31])[CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc2cc(CN)c(-c3cccc(F)c3)nc12
Reactant: Brc1ncnc2nc[nH]c12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1cccc2cc(CNc3ncnc4[nH]cnc34)c(-c3cccc(F)c3)nc12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 6-bromopurine (0.1418 g, 0.7125 mmol), (2-(3-fluorophenyl)-8-methoxyquinolin-3-yl)methanamine (0.2213 g, 0.7838 mmol), and N,N-diiso-propylethylamine (0.2482 mL, 1.425 mmol) in 1-butanol (7.125 mL, 0.7125 mmol) was stirred at 100° C. After 24 h, the mixture was removed from the heat and concentrated under reduced pressure. The residue was purified by flash column chromatography on a silica gel column using 50% of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 as eluent to give an off-white solid. The off-white solid was suspended in EtOAc and filtered to give N-((2-(3-fluoro-phenyl)-8-methoxyquinolin-3-yl)methyl)-9H-purin-6-amine as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.95 (1 H, s), 8.18-8.30 (2 H, m), 8.11 (2 H, s), 7.42-7.61 (5 H, m), 7.28-7.36 (1 H, m), 7.16 (1 H, dd, J=7.1, 1.7 Hz), 4.71-4.95 (2 H, m), 3.95 (3 H, s); LC-MS (ESI) m/z 401.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][N:18]3[CH:26]=[CH:27][CH:28]=[C:17]3[CH2:16]2)=[O:14])=[CH:9][CH:8]=1)=[O:5].[Cl:33]N1C(=O)CCC1=O>O1CCCC1>[Cl:33][C:26]1[N:18]2[C:17]([CH2:16][N:15]([C:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:29]=[CH:30][CH:31]=[CH:32][C:2]=4[CH3:1])=[CH:12][CH:11]=3)=[O:14])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19]2)=[CH:28][CH:27]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccc(Cl)n3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
To an ice-water cooled suspension of 211 mg of 2-methyl-N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-ylcarbonyl)-phenyl]benzamide in 5 ml of tetrahydrofuran is added 67 mg of N-chlorosuccinimide followed by continued stirring in the cold for 10 minutes. The bath is removed and stirring continued for 2.25 hours. The reaction mixture is added to ice-water and extracted with ether. The organic layer is dried and concentrated in vacuo to give a foam which is crystallized from ethyl acetate-hexane to give 157 mg of the desired product as an orange-pink solid, m.p. 185°-187° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:42])[CH2:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])=[O:32])=[CH:24][C:23]=3[F:43])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1.[N:44]1([C:49](N)=[NH:50])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C.ClCCl.CO>[F:43][C:23]1[CH:24]=[C:25]([NH:28][C:29](=[O:42])[CH2:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])=[O:32])[CH:26]=[CH:27][C:22]=1[O:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:49]([NH2:50])=[NH:44])[CH:7]=3)[S:20][C:19]=12
Reactant: N=C(N)n1cccn1
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cccc(OCCCN)c4)sc23)c(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cccc(OCCCNC(=N)N)c4)sc23)c(F)c1
Yield: 87.5 %

Procedure:
Amine 367 (0.095 g, 0.16 mmol), pyrazole-1-carboxamidine (60 mg, 0.41 mmol), and Hunigs base (0.07 g, 0.5 mmol) were stirred in dry DMF (10 mL) for 48 h at r.t. The mixture was then partitioned between ethyl acetate and water. The aqueous phase was collected and treated with brine; a precipitate was formed which was isolated by suction filtration. The resulting solid was re-dissolved in 1:1 dichloromethane/methanol, filtered, and the filtrate was concentrated to afford 361 as a solid (90 mg, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.71 (br s, 1H); 9.63 (br s, 1H); 8.49 (d, J=5.5, 1H); 8.10 (s, 1H); 8.05 (d, J=8.4, 1H); 7.93-7.70 (m, 2H); 7.51-7.40 (m, 5H); 7.08-7.02 (m, 3H); 6.92-6.88 (m, 1H); 6.63 (d, J=5.5, 1H); 4.13 (t, J=5.9, 2H); 3.84 (s, 3H); 3.64 (s, 2H); 1.95 (quint, J=6.3, 2H). [A triplet corresponding to 3H is hidden by the residial DMSO peak]. LRMS (M+H): 643.0.