Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=O.[CH2:20]([NH2:23])[CH2:21][NH2:22]>[Cl-].[Na+].O>[N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:6]([C:4]2[C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=3[NH:23][CH2:20][CH2:21][N:22]=2)[CH:7]=1
Reactant: O=C(c1cnc2ccccc2c1)c1ccccc1Br
Reactant: NCCN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: c1ccc2c(c1)NCCN=C2c1cnc2ccccc2c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 13 %

Procedure:
3-(2-Bromobenzoyl)quinoline (10.30 g, 33.0 mmol) was added to 100 mL of ethylene diamine, followed by stirring at 100° C. for 18 hours. Then the resulting reaction solution was cooled to room temperature, and poured into brine, followed by extracting with ethyl acetate. The organic layer was washed with brine twice, followed by drying with magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=9:1) to obtain the target compound (1.19 g, yield: 13%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1.Cl.CCOCC>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][N:10]([C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)=[O:33])[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: COc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(C(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.2 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) and DIEA (0.05 mL, 0.29 mmol) were dissolved in THF (2 mL). m-Anisoyl chloride (0.04 mL, 0.29 mmol) was added dropwise, and the reaction solution was stirred at room temperature for 1 h. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. The resulting precipitate was filtered and dried under vacuum to provide 25 (50 mg, 55% yield) as an off white solid. LC-MS (M+H=342, obsd.=342).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[Cl:7][CH2:8][C:9](OC)=[O:10]>CO>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:9](=[O:10])[CH2:8][Cl:7]
Reactant: NCC(O)CO
Reactant: COC(=O)CCl
Solvent: CO
Product: O=C(CCl)NCC(O)CO
Reaction time: 5 h
Yield: 95 %

Procedure:
A solution of 25 grams (g) (0.27 mole) of 3-amino-1,2-propanediol in 50 milliliter (ml) methyl alcohol is added slowly to a solution of methyl chloroacetate, 33.0 g (0.30 mole) in 50 ml methyl alcohol at 5°-10° C. The solution is stirred for five hours at 5°-10° C. and is then allowed to stand in the cold for four days. The solution is then evaporated in vacuum to leave 43 g of the desired product, a viscous oil, nD30 1.5148. (95% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13](=[O:24])[NH:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])[CH:12]=1)[C:7](O)=[O:8])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:58][O:59][C:60]1[CH:61]=[C:62]([CH:86]=[CH:87][CH:88]=1)[CH2:63][N:64]([CH2:72][C@@H:73]([OH:85])[C@@H:74]([NH2:84])[CH2:75][C:76]1[CH:81]=[C:80]([F:82])[CH:79]=[C:78]([F:83])[CH:77]=1)[C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68]>CN(C=O)C.C(OCC)(=O)C>[C:67]([O:66][C:65](=[O:71])[N:64]([CH2:72][C@@H:73]([OH:85])[C@@H:74]([NH:84][C:7](=[O:8])[C:6]1[CH:10]=[C:11]([C:13](=[O:24])[NH:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])[CH:12]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)[CH2:75][C:76]1[CH:77]=[C:78]([F:83])[CH:79]=[C:80]([F:82])[CH:81]=1)[CH2:63][C:62]1[CH:86]=[CH:87][CH:88]=[C:60]([O:59][CH3:58])[CH:61]=1)([CH3:70])([CH3:68])[CH3:69]
Reactant: COc1cccc(CN(C[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)C(=O)OC(C)(C)C)c1
Reactant: CC(=O)c1cc(C(=O)O)cc(C(=O)NC(C)c2ccc(F)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(C)=O)cc(C(=O)NC(C)c3ccc(F)cc3)c2)C(=O)OC(C)(C)C)c1
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
A mixture of 3-acetyl-5-((1-(4-fluorophenyl)ethyl)carbamoyl)benzoic acid (from step 3, 85.0 mg, 0.257 mmol), HATU (117 mg, 0.309 mmol) and Hunig's base (133 mg, 0.2 mL, 1.029 mmol) in DMF (2.0 mL) was stirred for 10 min and then tert-butyl 3-methoxybenzyl((2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl)-carbamate (112 mg, 0.257 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with H2O (3 times). The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase prep HPLC to give the title compound (150 mg): HPLC retention time: 2.265 min (method A). MS (ESI) (M+H)+ 748.47.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:19][CH2:20][N:21]=[C:22]=[O:23]>O1CCCC1>[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:19][CH2:20][NH:21][C:22]2=[O:23])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sc(N)nc1C
Reactant: O=C=NCCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1sc(N2CCNC2=O)nc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of 5-acetyl-2-amino-4-methylthiazole (5.50 g, 35.20 mmol) in tetrahydrofuran (200 mL) was added triethylamine (15.0 mL, 107.6 mmol) and 2-chloroethyl isocyanate (3.90 mL, 45.70 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, and then heated to reflux for 27 hours. The solvent was removed in vacuo, and the residue was washed with water (200 mL) and ethyl acetate/hexanes (1/1, 50 mL) to afford the title compound in 99% yield (7.9 g): MS (ES+) m/z 226.1 (M+1).
Reaction SMILES: CC(C)(C)C(OC[N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([O:32][CH3:33])=[CH:13][C:14]=2[O:18][CH2:19][C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[N:9]=[CH:8]1)=O.N>CO>[CH3:33][O:32][C:12]1[CH:11]=[C:10]2[C:15]([C:16](=[O:17])[NH:7][CH:8]=[N:9]2)=[C:14]([O:18][CH2:19][C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:13]=1
Reactant: COc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Agent: N
Solvent: CO
Product: COc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)c2c(=O)[nH]cnc2c1
Yield: 99.4 %

Procedure:
tert-butyl (2R)-2-{[(3-{[(2,2-dimethylpropanoyl)oxy]methyl}-7-methoxy-4-oxo-3,4-dihydroquinazolin-5-yl)oxy]methyl}pyrrolidine-1-carboxylate (0.750 g, 1.5 mmol) was stirred in a 7N solution of ammonia in methanol (250 ml) at room temperature for 24 hours. The mixture was evaporated under reduced pressure to give tert-butyl (2R)-2-{[(7-methoxy-4-oxo-3,4-dihydroquinazolin-5-yl)oxy]methyl}pyrrolidine-1-carboxylate (0.560 g, 100% yield) which was used in the next stage without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)[CH:30]=1)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1Cl

Procedure:
The title compound was prepared from {2-amino-4-chloro-5-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-carbamic acid tert.-butyl ester (Example J4) (165 mg, 0.5 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example K1) (165 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (167 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: O=S(=O)(NC1CCCC1)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CN(C1CCCC1)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 80 °C
Yield: 94 %

Procedure:
A mixture of 2 g (7.67 mmol) of 6-chloro-N-cyclopentylpyridine-3-sulfonamide, 0.7 mL (7.67 mmol) of methyl bromoacetate and 1.2 g (8.4 mmol) of K2CO3 in 15 mL of CH3CN is heated for 12 hours at 80° C. After cooling to room temperature, the medium is filtered and the filtrate is concentrated. The residue is taken up in 100 mL of DCM, washed successively with 50 mL of saturated NaHCO3 solution and 50 mL of water, and the organic phase is then dried over Na2SO4, concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with an 8/2 heptane/EtOAc mixture. 2.4 g of methyl N-[(6-chloropyridin-3-yl)sulfonyl]-N-cyclopentylglycinate are obtained in the form of an oil.
Reaction SMILES: C([O:3][C:4](=[O:39])[C@H:5]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:21]([NH2:30])=[N:22][C:23]([NH2:29])=[N:24][C:25]=3[CH2:26][CH2:27][CH3:28])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)C.[OH-].[Na+]>CO.[OH-].[Na+]>[NH2:29][C:23]1[N:22]=[C:21]([NH2:30])[C:20]([N:17]2[CH2:16][CH2:15][N:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][C@H:5]([C:4]([OH:39])=[O:3])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])=[CH:13][CH:12]=3)[CH2:19][CH2:18]2)=[C:25]([CH2:26][CH2:27][CH3:28])[N:24]=1
Reactant: CCCc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A mixture of 1.3 g (2.47 mmole) of N-[4-[4-(2,4-diamino-6-propyl-5-pyrimidinyl)-1-piperazinyl]-benzoyl]-L-glutamic acid diethyl ester and 0.4 g (4.94 mmole) of a 50% aqueous sodium hydroxide solution in 300 ml of methanol was stirred at room temperature for four hours. One drop of 50% sodium hydroxide solution was added and the reaction mixture became a clear solution. Methanol was removed in vacuo below 23° C. The residue was dissolved in 200 ml of ice water and filtered. The filtrate was acidified with citric acid to pH 6. The precipitate was collected, washed with water, and triturated with boiling ethanol. After drying in vacuo at 78° C. for 16 hours, 0.9 g of the product was obtained as white powder, mp 280°-284° C.
Reaction SMILES: Cl.Cl.[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[N:6]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:5]=1.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[OH-].[Na+]>ClC(Cl)C>[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[N:6]([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[N:5]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ncnc2c1c(I)nn2C1CCNCC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN1CCC(n2nc(I)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
To a mixture of 3-iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (0.5 g, 0.0012 mol) and sodium triacetoxyborohydride (0.36 g, 0.00168 mol) in dichloroethane (40 mL) was added formaldehyde solution (37% in water, 0.037 mL, 0.00132 mol) at room temperature. The mixture was stirred at room temperature under an atmosphere of nitrogen for 4 hours. A 5 N aqueous solution of sodium hydroxide (2 mL) was added to the mixture. The solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. 20 The aqueous layer was extracted with dichloromethane (3×150 mL). The combined organic extracts were washed with water, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave solid. The solid was resubjected to the same reaction and work-up conditions as above to yield 3-iodo-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.3 g, 0.00084 mol). TLC (methanol/dichloromethane=10:90) Rf 0.63 MS: MH+ 359.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]1)[C:5]2=[O:33].[CH2:34](I)[CH2:35][CH3:36]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:34][CH2:35][CH3:36])[C:7](=[O:12])[N:6]([CH:13]1[CH2:14][CH2:15][N:16]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)[CH2:17][CH2:18]1)[C:5]2=[O:33]
Reactant: CCCI
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc(Cl)cc5c4=O)CC3)c2cc1OC
Product: CCCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc(Cl)ccc21
Yield: 63 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.64 mmol) of Compound h was used in place of Compound 24 and propyl iodide was used in place of methyl iodide. As a result, 200.9 mg (yield: 63%) of Compound 42 was obtained as white crystals.
Reaction SMILES: [N+](C1C=CC([N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C@H:20]2[C:29]3[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=3)[CH2:23][N:22]([CH3:32])[CH2:21]2)[C:11](=O)[O-:12])=CC=1)([O-])=O.Cl.CO[C:36](=[O:40])[CH2:37][NH:38][CH3:39].C(N(CC)CC)C.Cl>C1COCC1.O>[ClH:30].[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[C:25]([Cl:31])[CH:26]=1)[CH2:23][N:22]([CH3:32])[CH2:21][C@H:20]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:10]1[C:36](=[O:40])[CH2:37][N:38]([CH3:39])[C:11]1=[O:12]
Reactant: CNCC(=O)OC
Reactant: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N(C(=O)[O-])c2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N2C(=O)CN(C)C2=O)C1
Reaction time: 8 h

Procedure:
4-Nitrophenyl[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]carbamate (125 mg) was dissolved in absolute THF (5 ml), and sarcosine methyl ester hydrochloride and triethylamine were added dropwise with stirring. After stirring for 5 h, the reaction mixture was freed of the solvent, and the residue was admixed with water and 2 N hydrochloric acid and refluxed for 2 h. After standing overnight, the reaction mixture was concentrated and admixed with ethyl acetate, water and saturated potassium carbonate solution. After separation of the phases, the organic phase was washed five times with saturated potassium carbonate solution and twice with saturated sodium chloride solution. Drying over magnesium sulfate and filtration were followed by concentration. The residue was purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated potassium carbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. The residue was taken up with water/hydrochloric acid and freeze-dried. 60 mg of the title compound were obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[N:9][C:10]=1[CH3:11])=O)C.CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:11][C:10]1[N:9]=[C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[NH:7][C:6]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1[nH]c(-c2cccc3ccccc23)nc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc3ccccc23)[nH]c1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-methyl-2-naphthalen-1-yl-3H-imidazole-4-carboxylic acid ethyl ester (280 mg) in THF (8 ml) is added DIBAL-H (3.3 ml, 1.5 M in toluene) at 0° C. The resulting solution is stirred at rt for 2 hr, and quenched with brine. The THF layer is separated and then evaporated. The residue is dissolved in EtOAc, washed with water and brine, dried and solvent evaporated to afford (5-methyl-2-naphthalen-1-yl-3H-imidazol-4-yl)-methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=O)[CH:8]3[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[CH2:13][CH2:12][N:9]32)=[CH:4][CH:3]=1.B.C1COCC1.CO>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][CH2:7][CH:8]3[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[CH2:13][CH2:12][N:9]32)=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(Cl)cc2N2CCN(C(=O)OCc3ccccc3)CC12
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCN2c3cc(Cl)ccc3NCC2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.4 %

Procedure:
To a solution of 9-chloro-3-carbobenzyloxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a ]-quinoxalin-5(6H)-one (1.45 g, 3.9 mmol) in 50 ml THF was added a solution of borane-THF complex (1M in THF, 12.2 ml, 12.2 mmol). After 15 min, the reaction was heated to reflux. After MS showed the absence of starting material, the reaction mixture was cooled to rt. Methanol was added and the solution concentrated to a yellow residue. This was repeated and the crude material was purified by column chromatography using a Biotage© Flash 40i (4.0×15.0 cm column, load with methylene chloride, elute with 25-30% ethyl acetate/hexanes) to give 9-Chloro-3-carbobenzyloxy-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline as an off-white solid (898.3 mg, 65%). 1H NMR (CDCl3, 300 MHz) δ7.32-7.38 (m, 5H), 6.56-6.66 (m, 2H), 6.37-6.40 (m, 1H), 5.16 (s, 2H), 4.19 (m, 2H), 3.61-3.71 (m, 2H), 3.33-3.36 (m, 1H), 3.05-3.23 (m, 2H), 2.72-2.79 (m, 2H) ppm. MS (ESI) m/z=358 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]3[C:13]([C:14]#[N:15])=[CH:12][N:11](S(C4C=CC(C)=CC=4)(=O)=O)[C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1.C1C(=O)N([Br:33])C(=O)C1.CN(C=O)C>O>[Br:33][C:12]1[NH:11][C:8]2=[N:9][CH:10]=[C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:6]3=[C:7]2[C:13]=1[C:14]#[N:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c2ncc2cnn(C)c23)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2cnc3[nH]c(Br)c(C#N)c3c21
Temperature: 150 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
A 10 mL microwave reaction vial was charged with 1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine-8-carbonitrile (0.011 g, 0.30 mmol, prepared using General Procedure AK from Preparation #1, Step D with NBS, General Procedure AE), NBS (0.012 g, 0.66 mmol) and DMF (2 mL). The suspension was heated in a microwave at about 150° C. for about 30 min (250 psi maximum pressure, 2 min ramp, 300 max watts). Additional NBS (134 mg, 0.754 mmol) was added and mixture was stirred at rt for about 2 h. To the reaction mixture was added water (4 mL) and the solid was collected by filtration and washed with water (5 mL). The solid was dried in a vacuum oven at about 70° C. for about 40 min to give 7-bromo-1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine-8-carbonitrile (0.036 g, 43%): LC/MS (Table 2, Method c) Rt=1.25 min; MS m/z: 276 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[N:5]=[C:4]([NH:18][C@H:19]2[C@@H:23]3[O:24][C:25]([CH3:28])([CH3:27])[O:26][C@@H:22]3[C@@H:21]([CH2:29][OH:30])[CH2:20]2)[N:3]=1>CCO.[Pd]>[C@@H:9]1([NH:8][C:6]2[N:7]=[CH:2][N:3]=[C:4]([NH:18][C@H:19]3[C@@H:23]4[O:24][C:25]([CH3:27])([CH3:28])[O:26][C@@H:22]4[C@@H:21]([CH2:29][OH:30])[CH2:20]3)[N:5]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3nc(Cl)nc(N[C@H]4CCc5ccccc54)n3)[C@@H]2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3ncnc(N[C@H]4CCc5ccccc54)n3)[C@@H]2O1
Reaction time: 48 h
Yield: 47.8 %

Procedure:
To a solution of [(3aR,4R,6R,6aS)-6-({4-Chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1,3,5-triazin-2-yl}amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol (182 mg, 0.421 mmol) in EtOH (2.91 mL) was added 10% palladium on carbon (44.8 mg) and the mixture was placed under an atmosphere of hydrogen for 2 d. Filtration of the mixture through a pad of celite, followed by silica gel chromatography eluting with 5% MeOH in DCM afforded the title compound as a white solid (80.0 mg, 48%). LC/MS: Rt=1.24 min, ES+ 398 (FA standard).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:37]=[CH:36][N:14]3[C:15](=[O:35])[C:16]([C:21]4[N:22]=[N:23][N:24](CC5C=CC(OC)=CC=5)[N:25]=4)=[C:17]([O:19][CH3:20])[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:37]=[CH:36][N:14]3[C:15](=[O:35])[C:16]([C:21]4[NH:25][N:24]=[N:23][N:22]=4)=[C:17]([O:19][CH3:20])[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(Cn2nnc(-c3c(OC)nc4cc(CCc5nc(C(C)C)cs5)ccn4c3=O)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1nc2cc(CCc3nc(C(C)C)cs3)ccn2c(=O)c1-c1nnn[nH]1
Reaction time: 48 h
Yield: 31.3 %

Procedure:
The 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-methoxy-3-[2-(4-methoxy-benzyl)-2H-1,2,3,4-tetrazol-5-yl]-4H-pyrido[1,2-a]pyrimidin-4-one (5 mg) obtained in (A) was added with trifluoroacetic acid (0.3 ml) and anisole (0.1 ml) and stirred for 2 days. The solvent was evaporated under reduced pressure, and the residue was added with hexane and ethyl acetate. Insoluble solids were collected by filtration and dried to obtain the title compound (1.2 mg).
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][C:14](=[O:18])[C:15]([OH:17])=[O:16])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Na].C([O-])=O.[Na+]>C(O)C(N)(CO)CO>[C:1]([NH:11][CH2:12][CH2:13][C@@H:14]([OH:18])[C:15]([OH:17])=[O:16])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(NCCC(=O)C(=O)O)OCc1ccccc1
Agent: NC(CO)(CO)CO
Agent: O=C[O-]
Agent: [Na+]
Product: O=C(NCC[C@@H](O)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.9 %

Procedure:
Sodium N-carbobenzoxy4-amino-2-oxobutyric acid 5 (67 mg, 0.25 mmol) and sodium formate (17 mg, 0.25 mmol) in aqueous Tris buffer (20 cm3) were deoxygenated by bubbling a stream of nitrogen through the solution for 30 minutes. RLB2HADH in Tris buffer (0.5 cm3, 2 mg dry mass of enzyme), β-nicotinamide adenine dinucleotide (2 mg), formate dehydrogenase (2 mg) and dithiothreitol (1M, 1 μl) were added and the mixture was stirred at room temperature under nitrogen, the reaction was complete in 1 day. The pH was maintained at from 6.5-7.0 by the addition of dilute aqeuous hydrochloric acid (0.1 M). When no further change in pH was observed, the mixture was concentrated in vacuo. Saturated brine (5 cm3) and concentrated hydrochloric acid (0.5 cm3) were added and the mixture was extracted with ethyl acetate (3×20 cm3). The combined organic phases were dried over anhydrous sodium sulphate and concentrated in vacuo to give (R)-N-carbobenzoxy-4-amino-2-hydroxybutyric acid 6 as an off-white solid (55 mg, 89% yield).