Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[C:8](C)[CH:7]=[CH:6][C:5]=1[O:11][S:12]([CH3:15])(=[O:14])=[O:13].[Li+].[BH4-].[CH3:19]O.Cl>C1COCC1.O.CCOC(C)=O>[OH:16][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:19])=[CH:6][C:5]=1[O:11][S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: COC(=O)c1cc(C)ccc1OS(C)(=O)=O
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(CO)c(OS(C)(=O)=O)c1
Reaction time: 0.25 h

Procedure:
To a solution of 2-methanesulfonyloxy-5-methylbenzoic acid methyl ester (15 g, 61.4 mmol) in THF (30 mL) at 0° C. is added portionwise LiBH4 (4.0 g, 184 mmol) and the mixture is stirred for 15 min. Then MeOH (8 mL, 196 mmol) is added dropwise over 30 min. The mixture is stirred under ice cooling for 30 min, then at RT for 18 h. EtOAc is added followed by ice and water. The mixture is acidified slowly with 1N HCl solution and organic phase is separated. The aqueous phase is extracted with EtOAc. The organic phases are combined, and washed with 1N HCl solution, and brine. It is then dried over Na2SO4 and MgSO4, and concentrated to give the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][C:6](=[CH:19][N:20]([CH3:22])[CH3:21])[C:5]2=[O:16]
Reactant: CCC(=O)N1CCC(=O)c2cc(Cl)ccc21
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC(=O)N1CC(=CN(C)C)C(=O)c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of 6-chloro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2 g), N,N-dimethylformamide dimethyl acetal (7.009 g), and triethylamine (0.87 g) in benzene (50 ml) was refluxed with stirring for 1 hour and then about three-fourths of the solvent was distilled slowly at atmospheric pressure over a period of approximately 1 hour. To the residue was added benzene (100 ml) and the solvent was distilled again. The resulting solid was collected by filtration, washed with diethyl ether, and dried to give 6-chloro-3-dimethylaminomethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.02 g).
Reaction SMILES: Br[CH:2]([C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].C([O-])=[O:19].[Na+]>CO>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([CH:2]([OH:19])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:17]
Reactant: O=C[O-]
Reactant: COC(=O)CCC(Br)C(=O)c1ccccc1Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCC(O)C(=O)c1ccccc1Cl
Yield: 100.2 %

Procedure:
A mixture of methyl 4-bromo-4-(chlorobenzoyl)butyrate (89.5 g), sodium formate (76.2 g) and methanol (400 ml) was stirred under reflux for 12 hours. The reaction mixture was concentrated, and water was added to the resulting residue and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried (MgSO4). The solvent was evaporated to give methyl 4-(chlorobenzoyl)-4-hydroxybutyrate (72.0 g, 100%) as an oily substance. This oily substance (72.0 g) was dissolved in tetrahydrofuran (400 ml), pyridine (22.2 g) was added thereto, and thereafter phenyl chlorocarbonate (43.8 g) was dropwise added thereto with cooling with ice. After the reaction mixture was stirred at room temperature for 1 hour, water was added to the reaction mixture and then extracted with ethyl acetate. The ethyl acetate layer was washed with 2 N hydrochloric acid and then with water, and dried (MgSO4). The solvent was evaporated, and the crystals thus precipitated were collected by filtration to obtain methyl 4-(4-chlorobenzoyl)-4-phenoxycarbonyloxybutyrate (61.2 g, 58%). This was recrystallized from methanol to give colorless prisms. mp 97-98° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:43][CH2:44][CH2:45][CH2:46][C:47](Cl)=[O:48]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:47](=[O:48])[CH2:46][CH2:45][CH2:44][Cl:43])=[CH:22][C:21]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:19])=[O:18])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(Cl)CCCCl
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(=O)CCCCl)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-(4-amino-2-benzyloxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester from Route J step 7 (0.958 g, 1.88 mmol), in anhydrous methylene chloride (20 mL) at 0° C. was added triethylamine (1.32 mL, 9.42 mmol) followed by 4-chlorobutyryl chloride (0.32 ml, 2.83 mmol) dropwise. The reaction was allowed to stir at 0° C. for 1 h and then allowed to slowly warm to room temperature overnight. The methylene chloride was evaporated and the reaction mixture was dissolved in ethyl acetate and water. The organic layer was collected and washed with 10% sulfuric acid, brine, dried over magnesium sulfate, and concentrated to yield (S)-3-[2-benzyloxy-4-(4-chloro-butanoylamino)-benzenesulfonylamino]-4,4-diethoxy-butyric acid tert-butyl ester (1.32 g) as a crude brown oil. MS (APCI) m/z 611.3 (M−1).
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=2)[C:6]2[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.C([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(OC(C)(C)C)=O.[ClH:36]>O1CCOCC1>[ClH:36].[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:3]2[N:4]=[C:5]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=3)[C:6]3[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[CH2:32][CH2:31]1
Reactant: CSc1nc(Nc2cccc(Br)c2)c2c(=O)[nH]ccc2n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(c2nc(Nc3cccc(Br)c3)c3c(=O)[nH]ccc3n2)CC1
Yield: 15 %

Procedure:
Compound 84 was prepared as described in Example 1g starting from 2-(methylthio)-4-(3-bromophenylamino)pyrido[4,3-d]pyrimidin-5(6H)-one (80 mg, 0.23 mmol) and 4-(boc-amino)piperidine (70 mg, 0.35 mmol) and treating with 4 N HCl in dioxane to yield the title compound (15 mg, 15%). MS m/z: 405.2 (M+1)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.12 (s, 1H), 11.92 (s, 1H), 8.24 (s, 1H), 8.09 (s, 3H), 7.59-7.50 (m, 2H), 7.40-7.36 (m, 2H), 6.48 (s, 1H), 4.70 (s, 2H), 2.08-0.87 (m, 7H).
Reaction SMILES: CN(C)C=O.[CH2:6]([N:8]([CH2:22][CH3:23])[C:9]1[C:10]2S[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:11]=2[N:12]=[CH:13][N:14]=1)[CH3:7].O.[ClH:25]>[Ni].C(OCC)C>[ClH:25].[CH2:22]([N:8]([CH2:6][CH3:7])[C:9]1[CH:10]=[C:11]([C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:16]=2)[N:12]=[CH:13][N:14]=1)[CH3:23]
Reactant: CCN(CC)c1ncnc2c1sc1ccccc12
Agent: [Ni]
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCN(CC)c1cc(-c2ccccc2)ncn1
Reaction time: 48 h

Procedure:
To a solution of 1.5 ml. of dimethylformamide containing 4-diethylaminobenzothieno[3,2-d]pyrimidine (2.0 g.) is added a large excess of Raney nickel and the resulting mixture heated to reflux. Water is allowed to distill from the reaction mixture until the temperature reaches 150° C. where refluxing is continued with rapid stirring for 48 hours. The solids are filtered and the filtrate concentrated in vacuo to an oil. The residual oil is partitioned between water and chloroform and the organic layer separated and dried over sodium sulfate. Removal of the solvent under reduced pressure provides an oil which when dissolved in ethyl ether and treated with gaseous hydrogen chloride provides 1.4 g. of the hydrochloride salt of the desired product, which is identical in every respect to that synthesized via Method A.
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([NH2:27])=[N:21][C:22]=3Cl)[O:12][C@@H:11]1[CH2:28][O:29]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.Cl.[NH:39]1[CH2:42][CH2:41][CH2:40]1.C(N(CC)CC)C.C[O-].[Na+].C(O)(=O)C>C(O)C>[NH2:27][C:20]1[N:19]=[C:18]2[C:23]([N:24]=[CH:25][N:17]2[C@@H:13]2[O:12][C@H:11]([CH2:28][OH:29])[C@@H:10]([OH:9])[C@:14]2([F:16])[CH3:15])=[C:22]([N:39]2[CH2:42][CH2:41][CH2:40]2)[N:21]=1
Reactant: C1CNC1
Reactant: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N3CCC3)nc(N)nc21
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
To a 350 mL of dry seal pressure flask (Chemglass) were added (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (12, 3.6 g, 6.85 mmol) and 150 mL of absolute ethanol. Azetidine hydrochloride (2.56 g, 27.4 mmol) was added and then followed by triethylamine (4.16 g, 41.1 mmol). The supension was stirred and heated to 70° C. while sealed for 5 hours. All the starting material was consumed but the benzoyl groups remained as shown by TLC. Sodium methoxide (7.8 mL, 34.3 mmol, 25% solution in methanol) was added to the mixture and heated at 50° C. The reaction was complete after 3.5 h. The reaction mixture was allowed to cool to room temperature and neutralized by addition of glacial acetic acid (0.41 g, 6.85 mmol). The mixture was concentrated under reduced pressure and then the residue was triturated with ethyl acetate. The resulting solid was removed by filtration and the solid was washed with EtOAc (2×15 mL). The filtrate was concentrated under reduced pressure and the residue was purified via column chromatography (Analogix, 120 g cartridge, gradient of 0 to 15% MeOH in DCM). The pure product containing fractions were combined, concentrated under reduced pressure and dried (50° C., 0.2 mmHg, 17 h) to a light pink colored foam solid (2.15 g, 6.35 mmol, 93%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:9][CH2:10][CH3:11])[NH:5][C:6]=1[CH2:7][OH:8]>C(Cl)Cl.O1CCOCC1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[N:3]=[C:4]([CH2:9][CH2:10][CH3:11])[NH:5][C:6]=1[CH:7]=[O:8]
Reactant: CCCc1nc(Cl)c(CO)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCc1nc(Cl)c(C=O)[nH]1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
A solution of (4-chloro-2-propyl-1H-imidazol-5-yl)methanol (0.927 g, 5.3 mmol) and manganese dioxide (2 g, 23.0 mmol) in CH2Cl2 (12 mL) and 1,4-dioxane (6 mL) was heated under reflux for 6 h. The reaction mixture was cooled to RT, then filtered through celite, washing thoroughly with CH2Cl2. The filtrate was concentrated and dried to provide the title compound (0.541 g, 59%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 11.61 (br. s., 1H), 9.63 (s, 1H), 2.80 (t, 2H), 1.83 (sex, 2 H), 0.99 (t, 3H). ES-LCMS: m/z 173.0 (M+1).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:35][C:36]([NH2:38])=[O:37].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([CH2:35][C:36](=[O:37])[NH2:38])[CH2:24][CH2:25]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)CBr
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CN1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.2 %

Procedure:
A mixture of the compound obtained in Example 66 (391 mg, 0.80 mmol), 2-bromoacetamide (132 mg, 0.96 mmol), potassium carbonate (265 mg, 1.92 mmol) and DMF (5 mL) was stirred at room temperature for 2 days. To the reaction mixture was added water (15 mL), and the mixture was extracted with ethyl acetate (15 mL×3). The organic layer was washed with water (5 mL×3), saturated sodium chloride solution (5 mL), successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (357 mg, 0.65 mmol, Yield 82%) as a colorless oily substance.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:7]=[C:6]([O:14][CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:5]=1.[OH-].[Na+]>O1CCOCC1>[NH:18]1[CH2:19][CH2:20][CH:15]([O:14][C:6]2[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[C:8]([C:10]([F:12])([F:11])[F:13])[N:7]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(CO)cc(C(F)(F)F)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: OCc1cc(OC2CCNCC2)nc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 75.4 %

Procedure:
4.0 M Hydrogen chloride in dioxane (12 mL, 47 mmol) was added to a solution of tert-butyl 4-{[4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.89 g, 2.4 mmol, from Step 3) in 1,4-dioxane (12 mL) and the reaction was stirred for 3 hours. The reaction was made basic by the addition of 1N NaOH to achieve a pH between 12 and 13. The product was extracted with DCM (6×) and the combined extracts were dried over sodium sulfate, filtered and concentrated to afford product as a light yellow solid (0.50 g, 75%). 1H NMR (300 MHz, CDCl3) δ 7.22 (s, 1H), 6.91 (s, 1H), 5.23 (tt, J=7.9, 3.8 Hz, 1H), 4.74 (s, 2H), 3.26-3.06 (m, 2H), 2.88 (ddd, J=12.3, 8.6, 3.4 Hz, 2H), 2.11 (ddt, J=12.9, 6.7, 3.2 Hz, 2H), 1.92-1.56 (m, 2H). 19F NMR (282 MHz, CDCl3) δ −68.89 (s). LCMS (M+H)+: 277.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].C(Cl)CCl.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:40][C:41]1[CH:49]=[CH:48][C:47]([I:50])=[CH:46][C:42]=1[C:43](O)=[O:44]>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:43](=[O:44])[C:42]2[CH:46]=[C:47]([I:50])[CH:48]=[CH:49][C:41]=2[NH2:40])=[CH:21][CH:22]=1)[NH:5][C:6](=[O:15])[C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(I)cc1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2cc(I)ccc2N)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
The mixture of N-(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine methylester(2.22 g), EDC/HCl (960 mg), HOBT (675 mg), triethylamine (834 μL), 2-amino-5-iodobenzoic acid (1.3 g) and dichloromethane (100 mL) was stirred overnight. The mixture was extracted with ethyl acetate and treated in accordance with the ordinary method to obtain a crude material of the intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.Cl.[CH3:26][O:27][C:28](=[O:32])[C@@H:29]([CH3:31])[NH2:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:26][O:27][C:28](=[O:32])[C@H:29]([NH:30][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22])[CH3:31]
Reactant: COC(=O)[C@@H](C)N
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](C)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C
Yield: 82.1 %

Procedure:
(R)-2-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid methyl ester (508 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (500 mg), D-alanine methyl ester hydrochloride (214 mg), HBTU (634 mg), and DIEA (364 uL).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C@H:11]([NH2:13])[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: Cc1cccc2c1nc([C@@H](C)N)n2-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cccc2c1nc([C@@H](C)Nc1ncnc3[nH]cnc13)n2-c1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of (R)-1-(4-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 2 (100 mg, 0.398 mmol), 6-chloro-9H-purine (68 mg, 0.438 mmol) and DIPEA (83 μL, 0.478 mmol) in n-butanol (1 mL) was stirred in a sealed vial at 100° C. for 20 h. After cooling to RT, the mixture was partitioned between DCM and water. The organic layer was then separated, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then sonicated in cyclohexane affording 109 as a brown solid (62 mg, 42%) LCMS: RT 3.17 min [M+H]+ 370.1. 1H NMR (DMSO, 400 MHz): δ 8.18-8.06 (2H, m), 7.95-7.86 (1H, m), 7.66-7.45 (5H, m), 7.11-7.00 (2H, m), 6.86 (1H, d, J=7.81 Hz), 5.49 (1H, br), 2.56 (3H, s), 1.57 (3H, d, J=6.84 Hz)
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](O)=[O:4].O.[NH2:16][NH2:17]>C(O)C>[CH3:1][CH:2]1[CH2:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:17][NH:16][C:3]1=[O:4]
Reactant: NN
Reactant: CC(CC(=O)c1ccccc1)C(=O)O
Solvent: CCO
Solvent: O
Product: CC1CC(c2ccccc2)=NNC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
7.7 g (40 mmole) of 2-methyl-4-oxo-4-phenylbutanoic acid was added to a 100 ml single-necked round bottom flask followed by 3.0 ml (60 mmole) of hydrazine monohydrate and then 20 ml of reagent grade ethanol (100%, 95% of ethanol should be fine also). The flask was fitted with a reflux condenser and the reaction mixture was heated to reflux in an oil bath at 110 C (temperature of oil bath) and stirred for 2 h. The flask was then removed from the oil bath and the reaction mixture cooled to ambient temperature. The stir bar was removed and the solvent was evaporated in vacuo in a water bath at 45° C. The residue was then treated with 50 ml of Milli-Q water and stirred for 10 minutes to give a suspension. The precipitate was collected by filtering, washed with 100 ml of 2N NaHCO3, then washed with 60 ml Milli-Q water three times, and dried over a medium frit sintered glass funnel in vacuo to give 7.15 g of white crystals (Syn. ID, WH-8-004). Yield, 95%, confirmed by ESI-MS. ESI-MS: m/z 189.2 (M+H+).
Reaction SMILES: C([Si](C)(C)[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]2[CH:8]=[CH:7]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl-].[Na+].O>[CH3:15][C:13]1[CH:14]=[C:9]2[CH:8]=[CH:7][NH:6][C:10]2=[N:11][CH:12]=1
Reactant: Cc1cnc2c(ccn2[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc2[nH]ccc2c1
Yield: 82.2 %

Procedure:
A mixture of 1-(tert-butyl-dimethyl-silanyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine (7.92 g, 32.2 mmol) and a solution tetrabutylammonium fluoride in tetrahydrofuran (1 M, 161 mL, 161 mmol) was stirred for 2 h at room temperature. The mixture was poured into brine (50 mL), extracted with ethyl acetate (2×200 mL), washed with a saturated aqueous ammonium chloride solution (3×60 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by a flash column chromatography (Qingdao silica gel, 300 mesh, 20% ethyl acetate/hexanes) afforded 5-methyl-1H-pyrrolo[2,3-b]pyridine (3.5 g, 82%) as a white solid: LC/MS m/e calcd for C8H8N2 [M+H]+ 133.17, observed 133.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>C(OCCO)C.O>[CH3:15][C:4]1[CH:3]=[C:2]([N:24]2[CH2:25][CH2:26][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23]2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: Cc1cc(Cl)c2cc([N+](=O)[O-])ccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCCO
Solvent: O
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc([N+](=O)[O-])ccc2n1

Procedure:
4-Chloro-2-methyl-6-nitroquinoline (0.2 g), 3-phenylpyrrolidine (0.14 g) and diisopropyl-ethylamine (0.27 mL) in 2-ethoxyethanol (4 mL) was heated in a microwave to 200° C. for 15 minutes. The reaction mixture was diluted with water and extracted with dichloromethane, washed with water, dried (Na2SO4), filtered and evaporated to give a yellow oil. The residue was purified by chromatography on silica, eluting with a mixture of dichloromethane, ethanol and ammonia (200:8:1). The desired fractions were concentrated to give the title compound as an orange oil.
Reaction SMILES: CN1CCCCC1.[O:8]([C:15]([NH:17][C@H:18]([C:22]([OH:24])=O)[CH:19]([CH3:21])[CH3:20])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[C:33]([C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][CH:41]([NH2:43])[CH3:42])=[CH:37][CH:36]=1)#[N:34]>C(Cl)Cl.O>[C:33]([C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][CH:41]([NH:43][C:22](=[O:24])[C@H:18]([CH:19]([CH3:20])[CH3:21])[NH:17][C:15]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:16])[CH3:42])=[CH:37][CH:36]=1)#[N:34]
Reactant: CC(N)COc1ccc(C#N)cc1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Solvent: O
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
1.3 g of N-methylpiperidine was added to a solution containing 3 g of N-phenoxycarbonyl-L-valine dissolved in 50 mL of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 1.7 g of isobutyl chloroformate was added to the mixture at -40° C., and stirred for 1 hour at -20° C. 2.2 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature, with stirring, and stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue, which was a crude crystal, was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of a white powder (yield: 22%).