Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[N:18]O)[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.C(O)(C)C.[ClH:24]>[Pd]>[ClH:24].[NH2:18][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)=[O:10]
Reactant: O=C(C(=NO)c1ccnc(F)c1)c1ccc(F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: NC(C(=O)c1ccc(F)cc1)c1ccnc(F)c1
Temperature: 25 °C

Procedure:
With gentle heating, 22b (5.0 g; 19 mmol) was dissolved in HCl-containing isopropanol (IsOH/HCl-saturated IsOH 1+1, 60 ml). The yellowish solution was cooled to room temperature and transferred into a two-necked flask (100 ml). Pd—C 10% (1.5 g) was introduced into the initial charge. The reaction vessel was evacuated using an oil pump and H2 was then introduced via a gas inlet capillary (4×). At room temperature, the suspension was shaken in a closed three-necked flask under an atmosphere of H2 (240 strokes/min) until no more starting material could be detected by thin-layer chromatography (6.5 h). The catalyst was filtered off. The filtration residue was washed with plenty of methanol (about 800 ml). The combined filtrates were concentrated and the solid-amorphous residue was dried on an oil pump. The crude product was used without further purification for the next reaction step.
Reaction SMILES: C([NH:4][C:5]1[CH:17]=[CH:16][N:8]([C@@H:9]2[O:15][C@H:12]([CH2:13][OH:14])[CH:11]=[CH:10]2)[C:7](=[O:18])[N:6]=1)(=O)C.N>CO>[C@@H:9]1([N:8]2[CH:16]=[CH:17][C:5]([NH2:4])=[N:6][C:7]2=[O:18])[O:15][C@H:12]([CH2:13][OH:14])[CH:11]=[CH:10]1
Reactant: CC(=O)Nc1ccn([C@H]2C=C[C@@H](CO)O2)c(=O)n1
Agent: N
Solvent: CO
Product: Nc1ccn([C@H]2C=C[C@@H](CO)O2)c(=O)n1
Yield: 69.6 %

Procedure:
A solution of 33 (0.26 g, 1.03 mmol) in methanol saturated with ammonia (20 ml) was stirred at 45°-50° C. for 12 hours. The solvent was removed under reduced pressure. The residue was triturated with isopropanol, filtered, and then washed with isopropanol to yield 0.15 g (69%) of 3: mp 167°-169° C. (benzene-methanol) (Lit. mp 168°-169° C.); 1H NMR (DMSO-d6) δ 3.51 (2H, m, 5'-H), 4.75 (1H, m, 4'OH), 4.85 (1H, t, J=5.5 Hz, OH), 5.68 (1 H, d, J=7.3 Hz, 5-H), 5.85 (1H, br d, J=5.9 Hz, 2'-H), 6.35 (1H, br d, J=5.9 Hz, 3'-H), 6.89 (1H, m, 1'-H), 7.10 (2H, s, NH2), 7.67 (1H, d, J=7.3 Hz, 6-H).
Reaction SMILES: ClC1C=C[C:5]([CH:8](O)[C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4CCCC[O:25]4)[C:15](=[O:30])[N:14]([CH3:31])[C:13]=3[N:12]=[CH:11][C:10]=2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34](OC(F)(F)F)[CH:33]=2)=NC=1>C(O)=O.CC(=O)OCC.O.[Zn]>[CH2:8]([C:9]1[C:18]2[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][O:23][CH:24]=[O:25])[C:15](=[O:30])[N:14]([CH3:31])[C:13]=2[N:12]=[CH:11][C:10]=1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=1[CH:10]([CH3:32])[CH3:11])[CH2:5][CH:8]([CH3:9])[CH3:5]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cn3)c(-c3cccc(OC(F)(F)F)c3)cnc21
Agent: [Zn]
Solvent: O=CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CCc1c(-c2ccccc2C(C)C)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 80 °C
Yield: 276.8 %

Procedure:
To a solution of 5-((5-chloropyridin-2-yl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(3-(trifluoromethoxy)phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 0.048 mmol) in HCOOH (1 mL) was added Zn dust (30 mg, 0.48 mmol). The reaction was heated at 80° C. for 30 min, cooled to RT then diluted with EA (2 mL) and water (2 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(5-isopentyl-6-(2-isopropyl phenyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propylformate (30 mg, 90% yield) as a an oil. LCMS: MH+ 549 and TR=2.286 min. Used without further purification.
Reaction SMILES: C[O:2][C:3]([CH:5]1[O:9][CH:8]([C:10]([O:12]C)=[O:11])[CH2:7][O:6]1)=[O:4].[OH-].[Na+:15]>CO>[O:6]1[CH2:7][CH:8]([C:10]([O-:12])=[O:11])[O:9][CH:5]1[C:3]([O-:4])=[O:2].[Na+:15].[Na+:15]
Reactant: COC(=O)C1COC(C(=O)OC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C1COC(C(=O)[O-])O1
Reaction time: 8 h
Yield: 46.1 %

Procedure:
To 5.0 g of dimethyl-1,3-dioxolane-2,4-dicarboxylate (Example 5b)) in 100 ml methanol was added a solution of 4.6 g of 50% aqueous sodium hydroxide in 50 ml methanol. After stirring overnight the salt was isolated by filtration and washed with methanol and vacuum dried yielding 2.5 g (42%) of the title compound as a white hygroscopic solid. An additional 1.8 g (30%) could be isolated by addition of ether to the filtrate of the first sample.
Reaction SMILES: [OH:1][C@H:2]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([O:33][Si](C(C)(C)C)(C)C)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:18]([NH:30][CH:31]=[O:32])[CH:17]=2)=[CH:7][CH:6]=1.F.F.F.C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1.C(OC(C)C)(=O)C>[OH:1][C@H:2]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:33])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[C:18]([NH:30][CH:31]=[O:32])[CH:17]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(NC[C@H](O)c2ccccc2)cc1)c1ccc(OCc2ccccc2)c(NC=O)c1
Agent: F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)C
Solvent: CCN(CC)CC
Product: O=CNc1cc([C@@H](O)CNCCc2ccc(NC[C@H](O)c3ccccc3)cc2)ccc1OCc1ccccc1
Reaction time: 20 h
Yield: 98.8 %

Procedure:
Intermediate 5 (5.2 g, 8.1 mmol) was dissolved in tetrahydrofuran (26 mL) and triethylamine trihydrofluoride (1.4 mL, 8.6 mmol) was added. The solution was stirred for 20 h. The reaction was quenched by addition of water (7.6 mL) followed by 10.0 N sodium hydroxide (3.8 mL, 38 mmol). After 3 min, the reaction was diluted with isopropyl acetate (20 mL) and transferred to a separatory funnel. The mixture was shaken and the biphasic mixture was filtered through celite to remove undissolved solids. The filtrate was returned to a separatory funnel and the phases were separated. The organic layer was washed with a mixture of 9 mL water and 9 mL saturated aqueous sodium chloride followed by 15 mL of saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and concentrated to afford the product 6 as a brown gelatinous solid (4.2 g, 8.0 mmol, 99%). m/z: [M+H+] calcd for C32H35N3O4 526.3; found 526.4.
Reaction SMILES: [O:1]=[C:2]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[H][H]>O.[Pd]>[OH:1][CH:2]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: O=C1CCc2cc(C(=O)CCCN3CCN(c4ccccc4)CC3)ccc2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: O=C1CCc2cc(C(O)CCCN3CCN(c4ccccc4)CC3)ccc2N1

Procedure:
2.0 Grams of 6-[1-oxo-4-(4-phenylpiperazinyl)-butyl]-3,4-dihydrocarbostyril and 0.5 g of palladium black were dispersed in 80 ml of water and stirred at a room temperature under 2 atmospheric pressure of hydrogen gas for 5 hours. The reaction mixture was filtered for removing the palladium black and the mother liquor was concentrated under a reduced pressure and the residue thus obtained was crystallized from acetone and a small amount of ethanol. The crude crystals thus obtained were collected by filtration and recrystallized from isopropanol to obtained 1.5 g of 6-[1-hydroxy-4-(4-phenyl-1-piperazinyl)butyl]-3,4-dihydrocarbostyril in colorless needle like crystals.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:46]=[S:47]1(=[O:71])[NH:60][C:59]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:53]2[C:48]1=[CH:49][CH:50]=[C:51]([CH2:61][CH2:62][O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH:52]=2.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17][N:60]3[C:59]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[C:53]4[C:48](=[CH:49][CH:50]=[C:51]([CH2:61][CH2:62][O:63][Si:64]([CH2:67][CH3:68])([CH2:69][CH3:70])[CH2:65][CH3:66])[CH:52]=4)[S:47]3(=[O:71])=[O:46])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: CC[Si](CC)(CC)OCCc1ccc2c(c1)-c1ccccc1NS2(=O)=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3c4ccccc4-c4cc(CCO[Si](CC)(CC)CC)ccc4S3(=O)=O)[C@H](C)[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-hydroxymethyl-1-methyl-carbapen-2-em-3-carboxylate (365 mg, 1.0 mmol), triphenylphosphine (315 mg, 1.2 mmol), and 9,9-dioxo-6-(2-triethylsilanyloxy-ethyl)-10H-9-thia-10-aza-phenanthrene (429 mg, 1.1 mmol) in anhydrous tetrahydrofuran (7.3 mL) is cooled in an ice-bath and stirred under a nitrogen atmosphere while diisopropyl azodicarboxylate (0.24 mL, 1.2 mmol) is added dropwise over a few minutes. The resulting solution is stirred in the cold for 30 minutes, then diluted with chloroform, washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated under vacuum. The residue is purified by silica gel flash chromatography , eluting with hexane-ethyl acetate, to afford allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-[9,9-dioxo-6-(2-triethylsilanyloxy-ethyl)-10H-9-thia-10-aza-phenanthren-10-ylmethyl)-1-methyl-carbapen-2-em-3-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O)([O-:3])=[O:2].NN>C(O)C.ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1CCCCOc1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: ClCCl
Solvent: CCO
Product: NCCCCOc1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of 17.0 g (50 mmol) of 2-[4-(3-nitro-phenoxy)-butyl]-isoindole-1,3-dione in 1000 ml of ethanol is mixed with 25 ml of hydrazine and stirred for 2 hours at 70° C. After cooling, the precipitate that is formed is suctioned off, and the filtrate is spun in. The residue is taken up in dichloromethane. It is filtered again, and the filtrate is fully concentrated by evaporation. 5.8 g (28 mmol, corresponding to 56% of theory) of the product is obtained.
Reaction SMILES: [OH-].[Na+].Cl[C:4]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[C:10]([Cl:24])[CH:9]=1)=[CH:5]C=O.ClCCl>O.O1CCOCC1>[Cl:24][C:10]1[CH:9]=[C:8]([C:4]#[CH:5])[CH:13]=[CH:12][C:11]=1[CH:14]1[CH2:19][C:18]([CH3:20])([CH3:21])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]1
Reactant: CC1(C)CC(c2ccc(C(Cl)=CC=O)cc2Cl)CC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: C#Cc1ccc(C2CC(C)(C)CC(C)(C)C2)c(Cl)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
5.3 g of sodium hydroxide are dissolved in 150 ml of water under an inert atmosphere and with vigorous stirring. 80 ml of 1,4-dioxane are added and the mixture is refluxed. 15 g of 3-chloro-3-[3-chloro-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]propenal (compound IV.1) dissolved in 130 ml of 1,4-dioxane are added rapidly, and the reaction mixture is maintained at reflux for 1 hour. After cooling to room temperature, the reaction mixture is poured into a large volume of dichloromethane. The phases are separated after settling has taken place, the organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. Purification is carried out by chromatography on a column of silica gel, eluting with cyclohexane; yield: 80%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>ClCCl>[CH2:11]([NH:10][C:8]([C:4]1[S:3][C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][Br:25])=[N:6][C:5]=1[CH3:7])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)CCCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(NC(=O)CCCCBr)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To a mixture 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (1.29 g, 5.20 mmol) and triethylamine (0.58 g, 5.72 mmol) in anhydrous dichloromethane (25.0 mL) was added dropwise 5-bromopentanoyl chloride (1.141 g, 5.72 mmol) in anhydrous dichloromethane (10 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 hours, then diluted with dichloromethane (40 mL) and washed with saturated aqueous sodium bicarbonate solution (2×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrate in vacuo to afford the title compound as a yellow oil (1.91 g, 92%): 1H NMR (300 MHz, CDCl3) δ 8.81 (br s, 1H), 7.33-7.23 (m, 5H), 5.91 (s, 1H), 4.14 (d, J=5.6 Hz, 2H), 3.51 (t, J=6.7 Hz, 2H), 2.46 (s, 3H), 2.35 (t, J=6.7 Hz, 2H), 1.82 (m, 2H), 1.53 (m, 2H); MS (ES+) m/z 410.1 (M+1), 412.1 (M+1).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=O)[C:7]3=[C:8]2[C:3](=[C:4]([Cl:16])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[Cl:16][C:4]1[CH:5]=[CH:6][C:7]2[C:14](=[O:13])[N:18]([OH:19])[C:11](=[O:12])[C:9]3[C:8]=2[C:3]=1[CH:2]=[CH:1][CH:10]=3
Reactant: NO
Reactant: O=C1OC(=O)c2ccc(Cl)c3cccc1c23
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3c(Cl)ccc(c23)C(=O)N1O
Yield: 80.8 %

Procedure:
4-Chloro-1,8-naphthalic anhydride (1.4 g, 6.0 mmol) and hydroxylamine hydrochloride (0.8 g, 11.5 mmol) were reacted in pyridine (50 mL) following the procedure of Example 1 to give 1.2 g of the title compound, mp 234-236° C.;
Reaction SMILES: ClC1C=C(C=CC=1F)C1C(C2C=CC3C(=CC=C(C4N(C5CCCCC5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5N=4)C=3)N=2)=CC(OC)=CC=1.C[O:46][C:47]([C:49]1[CH:82]=[CH:81][C:52]2[N:53]([CH:75]3[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]3)[C:54]([C:56]3[CH:57]=[C:58]4[C:63](=[CH:64][CH:65]=3)[N:62]=[C:61]([C:66]3[CH:71]=[C:70]([O:72][CH3:73])[CH:69]=[CH:68][C:67]=3Br)[CH:60]=[CH:59]4)=[N:55][C:51]=2[CH:50]=1)=[O:48]>>[C:36]([C:34]1[CH:33]=[C:32]([CH:24]=[CH:23][CH:35]=1)[C:67]1[C:66]([C:61]2[CH:60]=[CH:59][C:58]3[C:63](=[CH:64][CH:65]=[C:56]([C:54]4[N:53]([CH:75]5[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80]5)[C:52]5[CH:81]=[CH:82][C:49]([C:47]([OH:46])=[O:48])=[CH:50][C:51]=5[N:55]=4)[CH:57]=3)[N:62]=2)=[CH:71][C:70]([O:72][CH3:73])=[CH:69][CH:68]=1)([OH:38])=[O:37]
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2cccc(C(=O)O)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 23 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with ethyl 3-boronic acid benzoate (51 mg, 0.2625 mmol) to produce the title compound (26 mg, 23% yield).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[O:16][CH2:17][O:18][C:10]=12)C1C=CC=CC=1>O1CCCC1.[Pd]>[CH2:17]1[O:16][C:11]2[C:12](=[O:15])[CH:13]=[CH:14][C:9](=[O:8])[C:10]=2[O:18]1
Reactant: Oc1ccc(OCc2ccccc2)c2c1OCO2
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1C=CC(=O)C2=C1OCO2
Yield: 102.2 %

Procedure:
A solution of 4-benzyloxy-2,3-methylenedioxyphenol (7.7 g) in tetrahydrofuran (50 ml) was hydrogenated at atmospheric pressure over palladium-on-carbon overnight. The catalyst was removed by filtration, and the resulting hydroquinone intermediate was oxidized in actonitrile solution with ceric ammonium nitrate (25 g). After 5 minutes the reaction was quenched with water and extracted with ethyl acetate. Evaporation of the organic extract and chromatography afforded 4.9 g of 2,3-methylenedioxy-1,4-benzoquinone, mp 106°-7° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][OH:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:16]1[CH2:30][CH:17]1[CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>>[OH:16][CH:17]([CH2:30][O:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)[CH2:18][N:19]1[C:20](=[O:29])[C:21]2[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:24]
Reactant: OCc1cccc(CN2CCCCC2)c1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Product: O=C1c2ccccc2C(=O)N1CC(O)COCc1cccc(CN2CCCCC2)c1
Temperature: 130 °C
Reaction time: 1.33 h
Yield: 42.1 %

Procedure:
A mixture of 10.25 g (0.05 mol) of 3-(1-piperidylmethyl)-benzyl alcohol and 10.15 g (0.05 mol) of N-(2,3-epoxypropyl)-phthalimide is stirred under nitrogen for 80 minutes at 130° C. The viscous resin obtained is chromatographed on silica gel, using methylene chloride/methanol 9:1. The main fraction yields 8.60 g (42%) of the title compound in the form of a light brown oil after concentration by evaporation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][C@@H:13]([CH3:15])[C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:23][C:9]2=3)=[N:6][CH:7]=1.Br[C:34]1[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][C@@H:13]([CH3:15])[C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][C:22]([C:34]4[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=4)=[CH:23][C:9]2=3)=[N:6][CH:7]=1
Reactant: Cc1nnc2n1-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1N(c1ccc(Cl)cn1)C[C@H]2C
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1-c1ccc(-c3cnc(N)cn3)cc1N(c1ccc(Cl)cn1)C[C@H]2C
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
To a solution of (R)-6-(5-chloropyridin-2-yl)-1,4-dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine in 1,4-dioxane/H2O (10:1, 5 mL) were added 5-bromopyrazin-2-amine (69.33 mg, 0.40 mmol), Cs2CO3 (197.3 mg, 0.61 mmol) and Tetrakis(triphenylphosphine)palladium(0) (24.1 mg, 0.033 mmol). The mixture was purged with N2 and stirred in the microwave at 130° C. for 20 min. The reaction solution was concentrated and purified by prep-TLC (elute: DCM:CH3OH=15:1) to give (R)-5-(6-(5-chloropyridin-2-yl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyrazin-2-amine (110 mg, 59%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]1[C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=[CH:12]1)[CH3:2].S(Cl)(Cl)=O.C[N:24](C)C=O>>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[N:11]1[C:15]([C:16]([NH2:24])=[O:18])=[CH:14][N:13]=[CH:12]1)[CH3:10]
Reactant: CN(C)C=O
Reactant: CCc1cccc(CC)c1-n1cncc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCc1cccc(CC)c1-n1cncc1C(N)=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
24.4 g (0.1 mol) of 1-(2,6-diethylphenyl)-imidazole-5carboxylic acid were added in portions to 36 g (0.3 mol) of thionyl chloride and 1 ml of dimethylformamide. After the addition, the mixture was heated at 80° C. until the evolution of gas had ended, and the solid residue was dried in vacuo and introduced in portions into 150 ml of ice-cold concentrated aqueous ammonia solution with thorough stirring. The mixture was stirred at room temperature for 1 hour; the precipitate was filtered off and dried. 20.2 g of 1-(2,6-diethylphenyl)-imidazole-5-carboxamide were obtained as a colorless solid of melting point 171°-171.5° C. (ethyl acetate/hexane); yield: 83% of theory.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19]([CH3:24])[C:18]=3[CH:17]=[C:16]([C:25]([OH:27])=O)[CH:15]=1)[CH2:5][CH2:6][O:7]2.Cl.[CH3:29][NH2:30]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19]([CH3:24])[C:18]=3[CH:17]=[C:16]([C:25]([NH:30][CH3:29])=[O:27])[CH:15]=1)[CH2:5][CH2:6][O:7]2
Reactant: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2n1C
Reactant: CN
Agent: Cl
Product: CNC(=O)c1cc(OC2CCOc3cc(F)cc(F)c32)c2nc(C)n(C)c2c1
Yield: 96 %

Procedure:
The title compound was prepared as a colorless amorphous in 96% yield (0.99 g) from 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (1.0 g, 2.7 mmol, STEP 2) and methanamine hydrochloride (0.54 g, 8.0 mmol) by the same manner in STEP 3 of Example 11.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C@H:12]([CH2:21][OH:22])[CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[C:4](Cl)[N:3]=1.[OH-].[K+].C(O)(=[O:28])C>O>[CH2:16]([O:15][CH:14]([O:18][CH2:19][CH3:20])[CH2:13][C@@H:12]([CH2:21][OH:22])[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:28])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2)[CH3:17]
Reactant: CCOC(C[C@@H](CO)Cn1cnc2c(Cl)nc(N)nc21)OCC
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(C[C@@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21)OCC
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To the product of Example 30, step a) (22.5 kg, 65.4 moles) was added an aqueous solution of KOH (prepared by dissolving 12.9 kg of KOH in 225 kg of water). This mixture was refluxed for 16 hours. The reaction was cooled to about room temperature and filtered into a larger reactor equipped with a pH electrode standardized to pH 7–10. The filtered solution was cooled to 5° C. and the product precipitated by slow addition of dilute acetic acid solution (prepared by mixing glacial acetic acid (12.6 kg, 210 moles) with 75 kg of water and cooling the mixture to 5° C.) until the pH is between 7.5 and 9.0 (target 8.5). The resulting slurry was immediately filtered and the filter cake was recharged back to the reactor. The reactor was charged with 225 kg of distilled water. The mixture was heated to not more than 50° C. for 30 minutes, then cooled to 15±10° C. and stirred for 30 minutes. The resulting precipitate was filtered by vacuum filtration, rinsed with 50 kg of distilled water and dried in a vacuum oven at not more than 45° C. for not less than 8 hours to provide the desired product as a tan solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([NH2:10])[N:7]=[C:6]([NH2:11])[CH:5]=1.[NH3:13]>CO>[NH2:11][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([NH2:10])[N:7]=1)[C:3]([NH2:13])=[O:2]
Reactant: COC(=O)c1cc(N)nc(N)c1
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(N)nc(N)c1
Temperature: 62 °C

Procedure:
A solution of 3.9 g (20 mmol) 2,6-diamino-isonicotinic acid methyl ester in 200 ml methanol was treated for 1 at 0° C. with gaseous ammonia. The mixture was heated for 36 h at 62° C. in an autoclave (4 bar) and afterwards filtered through decalite and evaporated to dryness. 3.5 g (quant.) of the title compound was obtained as a yellow solid.