Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:12][CH2:13][C:14]([CH3:16])=O.Cl.O1CCOCC1>CC(O)=O>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:14]([CH3:16])=[C:13]2[CH2:12][C:11]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCC(C)=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(C)[nH]c2ccc(Br)cc12
Yield: 70.9 %

Procedure:
A mixture of 4-bromophenylhydrazine hydrochloride (2.23 g, 10 mmol) and ethyl levulinate (1.58 g, 11 mmol) in 10 mL HOAc was heated to reflux for 20 h. The HOAc was removed under vaccum. The residue was dissolved in 10 mL EtOH. A solution of HCl in dioxane (12 mmol, 4M solution) was added. The mixture was heated to reflux for 4 h. The mixture was concentrated under vacuum and the residue was purified by flash chromatography on silica gel, eluting with 20% EtOAc in hexane to afford 2.1 g (78%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:26][N:27]1[C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]([CH3:35])=[N:28]1>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:2]([NH:1][C:32]([C:31]5[N:27]([CH3:26])[N:28]=[C:29]([CH3:35])[CH:30]=5)=[O:33])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: COc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CC(=O)N(C)C
Product: COc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cc(C)nn1C
Yield: 53.6 %

Procedure:
Using N-[6-(3-amino-4-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.59 mmol), N,N-dimethylacetamide (4.0 mL) and 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (113 mg, 0.71 mmol), and in the same manner as in Example 120, the title compound (146 mg, 54%) was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18]N)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7](=[O:20])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:21].Br[CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18][CH2:23][C:24]#[N:25])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7](=[O:20])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:21]
Reactant: Cc1ccc2c(c1C)N(CCCN)c1ccccc1S2=O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1C)N(CCCCC#N)c1ccccc1S2=O
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 27.6 %

Procedure:
2.25 g of 1,2-dimethyl-10-(3-aminopropyl)phenothiazine-5-oxide synthesized in Example 8, 990 mg of bromoacetonitrile and 1.2 g of potassium carbonate were dissolved in 50 ml of N,N-dimethylformamide followed by stirring at 80° C. for 10 min. Then the reaction mixture was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 670 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[CH:11]=1.[CH3:17][NH2:18]>O>[CH3:17][NH:18][C:2]1[C:3](=[O:16])[NH:4][C:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[CH:11]=1
Reactant: CN
Reactant: O=c1[nH]c2c(cc1Cl)-c1ccccc1CC2
Solvent: O
Product: CNc1cc2c([nH]c1=O)CCc1ccccc1-2

Procedure:
Add 23.1 gm of 2-chloro-5,6-dihydro-benzo[f]quinolin-3(4H)-one to 100 ml of 40% aqueous methylamine and 250 ml of water. Heat the system in a steel bomb at 140° C. for 5 days. Stop the reaction and isolate 2-(N-methylamino)-5,6-dihydro-benzo[f]quinolin-3(4H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([NH2:9])[C:6](=[NH:8])[NH2:7])[CH3:2].[CH:11]([C:13]([C:15]([F:18])([F:17])[F:16])=O)=O.C([O-])(=O)C.[Na+]>O>[CH2:1]([O:3][C:4]([C:5]1[C:6]([NH2:7])=[N:8][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:9]=1)=[O:10])[CH3:2]
Reactant: O=CC(=O)C(F)(F)F
Reactant: CCOC(=O)C(N)C(=N)N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ncc(C(F)(F)F)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of amino-carbamimidoyl-acetic acid ethyl ester (2 g, 9.22 mmol) and water (50 ml), a 20% aqueous solution of trifluoropyruvic aldehyde (2.32 g, 18.43 mmol) was added. To this mixture, sodium acetate (5.29 g, 64.52 mmol) was added (pH of the reaction mixture was pH5). The reaction mixture was left to stir at RT overnight. The resultant precipitate was filtered under vacuum purification by chromatography on silica eluting with iso-hexane: EtOAc (gradient of 0 to 10% EtOAc) afforded the title compound
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>O1CCCC1>[CH3:20][S:21]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
A mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (4.98 g, 28.7 mmol) and triethylamine (4.82 mL, 62.3 mmol) in tetrahydrofuran (75 mL) was cooled to 0° C. using an ice bath. Methanesulfonyl chloride (2.46 mL, 31.8 mmol) in tetrahydrofuran (12.5 mL) was added slowly to the reaction. Once the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 4 hours. Water (100 mL) was added to the reaction, and the mixture extracted with ethyl acetate (2×150 mL). The combined organic phase was washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a pale yellow oil (7.11 g, 98%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH:14]=[CH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCOCC1>[CH3:1][NH:2][CH2:3][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH:14]=[CH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: C=Cc1c(C(=O)NC)[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1c(CNC)[nH]c2ccccc12
Temperature: 0 °C
Yield: 62.4 %

Procedure:
A solution of N-methyl-3-vinyl-1H-indole-2-carboxamide (740 mg, 3.7 mmol) in dioxane was added slowly to an ice-cooled solution of lithium aluminium hydride (2.1 g, 55.5 mmol) in dioxane (100 mL). The mixture was stirred at reflux overnight. Excess lithium aluminium hydride was quenched with 15% NaOH (10 mL) and the mixture separated. The aqueous phase was washed twice with ethyl acetate and the combined organic phases dried to afford the title compound (430 mg 61%). 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.75 (d, J=8 Hz, 1H), 7.49 (d, J=6.4 Hz, 1H), 7.09-7.05 (m, 2H), 7.04-6.90 (m, 1H), 5.54 (d, J=16 Hz, 1H), 5.06 (d, J=10.0 Hz, 1H), 3.84 (s, 2H), 2.27 (s, 3H).
Reaction SMILES: [ClH:1].NC(C1N=C(NC(=O)C)C=CC=1Br)CC1C=C(F)C=C(F)C=1.[Br:24][C:25]1[C:26]([C@@H:33]([NH:43][S@](C(C)(C)C)=O)[CH2:34][C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=2)=[N:27][C:28]([S:31][CH3:32])=[N:29][CH:30]=1>>[ClH:1].[Br:24][C:25]1[C:26]([C@@H:33]([NH2:43])[CH2:34][C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=2)=[N:27][C:28]([S:31][CH3:32])=[N:29][CH:30]=1
Reactant: CSc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)N[S@@](=O)C(C)(C)C)n1
Agent: CC(=O)Nc1ccc(Br)c(C(N)Cc2cc(F)cc(F)c2)n1
Agent: Cl
Product: CSc1ncc(Br)c([C@@H](N)Cc2cc(F)cc(F)c2)n1

Procedure:
The title compound (12A) was prepared according to the method presented for the synthesis of compound 1F of Example 1 utilizing 11D. MS (m/z) 362.13 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([OH:16])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:17][CH3:18])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:19])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.I[CH2:32][C:33]([OH:35])=[O:34]>O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:32][C:33]([OH:35])=[O:34])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:17][CH3:18])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:19])[CH:5]=1
Reactant: O=C(O)CI
Reactant: CCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Temperature: 50 °C

Procedure:
5,6-Dichloro-9a-ethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one, (Example 1, Step C) (15 gm., 0.048 mole), potassium carbonate (13.3 gm., 0.096 mole), dimethylformamide (100 ml.) and iodoacetic acid (10.6 gm., 0.057 mole) is stirred at room temperature for 24 hours. The reaction mixture is poured into water (150 ml.), stirred, warmed to 50° C., filtered and the filtrate acidified with 6 N hydrochloric acid to obtain [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid, which after recrystallization from acetic acid, melts at 237° C.-238° C.
Reaction SMILES: O[CH:2]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16]C)[CH:12]=2)[C:7]1=O)[C:3](O)=[O:4].[CH3:19][NH:20][NH2:21].B(Br)(Br)Br>CC(O)C>[OH:16][C:11]1[CH:10]=[CH:9][C:8]2[C:7]3[C:6](=[CH:2][C:3](=[O:4])[N:20]([CH3:19])[N:21]=3)[CH2:15][CH2:14][C:13]=2[CH:12]=1
Reactant: COc1ccc2c(c1)CCC(C(O)C(=O)O)C2=O
Reactant: CNN
Agent: BrB(Br)Br
Solvent: CC(C)O
Product: Cn1nc2c(cc1=O)CCc1cc(O)ccc1-2
Reaction time: 3 h
Yield: 27 %

Procedure:
A solution of the product from step 1 (700 mg, 2.8 mmol) and N-methylhydrazine (0.3 mL) in 2-propanol (10 mL) was heated to reflux 18 h. The solvent was removed under vacuum and the solid was triturated with methanol (2 mL), collected and then suspended in methylene chloride (2 mL) at 0° C. BBr3 (10 mL of 1M solution in DCM, 10 mmol) was slowly added dropwise and the ice bath removed. After 3 h at ambient temperature, saturated NH4Cl solution (10 mL) was added. The DCM was removed under vacuum and the resulting slurry was carefully neutralized with saturated NaHCO3 solution and washed with water. The solids were collected to afford 8-hydroxy-2-methyl-5,6-dihydro-2H-benzo[h]cinnolin-3-one (175 mg, 27%) as a white solid; mp>300° C. MS m/z 229 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16]C(C)(C)C(C)(C)[O:13]2)=[CH:8][C:7]=1[O:21][CH3:22].I([O-])(=O)(=O)=O.[Na+].C([O-])(=O)C.[NH4+].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]([OH:13])[OH:16])=[CH:8][C:7]=1[O:21][CH3:22]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1Oc1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(B(O)O)ccc1Oc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
To a solution of the compound (179.0 mg, 0.50 mmol) prepared in Example 9 in 10 mL acetone were added sodium periodate (318.0 mg, 1.49 mmol), ammonium acetate (84.0 mg, 1.09 mmol), and water (10 mL). The suspension was allowed to stir at room temperature for 18 hours. The acetone was removed under reduced pressure and the resulting aqueous layer was acidified with concentrated hydrochloric acid to pH 3. The resulting solid was collected and washed several times with water then dried under vacuum to obtain the title compound (106 mg) having the following physical data.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH:20]1[CH2:22][O:21]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[O:32])=[C:26]([F:41])[CH:25]=1)#[N:7]>O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH:20]([OH:21])[CH2:22][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)=[O:32])=[C:26]([F:41])[CH:25]=1)#[N:7]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCC1CO1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)CC(O)COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)c2cc1C#N
Temperature: 50 °C

Procedure:
After adding tetrahydrofuran (1 ml) and diethylamine (0.1 ml) to N-[4-(6-cyano-7-oxiranylmethoxyquinolin-4-yloxy)-2-fluorophenyl]-N′-(4-fluorophenyl)urea (100 mg), the mixture was heated at 50° C. for 30 minutes. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (32 mg) as light yellow crystals.
Reaction SMILES: [CH2:1]([N:5]([C:8]1[C:13]([CH2:14][CH3:15])=[C:12](Cl)[N:11]=[C:10]([CH3:17])[N:9]=1)[CH2:6][CH3:7])[CH2:2][CH2:3][CH3:4].[CH3:18][C:19]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:20]=1[NH2:21]>>[CH2:1]([N:5]([CH2:6][CH3:7])[C:8]1[C:13]([CH2:14][CH3:15])=[C:12]([NH:21][C:20]2[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:19]=2[CH3:18])[N:11]=[C:10]([CH3:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CCCCN(CC)c1nc(C)nc(Cl)c1CC
Product: CCCCN(CC)c1nc(C)nc(Nc2c(C)cc(C)cc2C)c1CC
Yield: 209.4 %

Procedure:
A mixture of butyl-(6-chloro-2-methyl-5-ethyl-pyrimidin-4-yl)-ethylamine (200 mg, 0.78 mmol) and 2,4,6-trimethylaniline (0.963 g, 7.1 mmol) was heated at reflux for 4 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated potassium carbonate and brine, dried and concentrated to give a dark oil. The oil was distilled to give 579 mg of the dark oil which was then purified through silica gel column chromatography using chloroform as eluent to give the title compound as a brown oil. 1H NMR (CDCl3) δ 0.93 (t, 3H), 1.14 (t, 3H), 1.1-1.4 (m, 4H), 1.45-1.60 (m, 2H), 2.17 (s, 6H), 2.30 (s, 3H), 2.33 (s, 3H), 3.2-3.4 (m, 4H), 6.90 (s, 2H) ppm.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([I:11])=[CH:7][N:6]2[C:12]=1[CH3:13])=[CH2:2].[N+](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-]>C1(C)C(C)=CC=CC=1>[I:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:12]([CH3:13])=[C:3]([CH:1]3[CH2:2][CH:16]3[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:4]=2)[CH:7]=1
Reactant: C=Cc1nc2ccc(I)cn2c1C
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1CC1c1nc2ccc(I)cn2c1C
Temperature: 25 °C

Procedure:
To a stirred solution of 2-ethenyl-6-iodo-3-methylimidazo[1,2-a]pyridine (680 mg) in xylene (20 ml) was added ethyl diazoacetate (1.5 ml) at room temperature. The reaction mixture was heated at reflux for 5 h. The resulting reaction mixture was then cooled to room temperature, concentrated in vacuo, and purified by preparative HPLC to afford the title compound (200 mg) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]([CH3:40])[CH3:39])[C:6]2[O:10][C:9]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][C:19]4([CH3:34])[O:23][C:22](=[O:24])[N:21]([C:25]5[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][N:26]=5)[CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:37]=1)#[N:2].[H][H]>CO.O1CCCC1.[Pd]>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([N:21]2[CH2:20][C:19]([CH2:18][NH:17][C:15](=[O:16])[C:14]3[CH:13]=[CH:12][C:11]([C:9]4[O:10][C:6]5[C:5]([CH:38]([CH3:40])[CH3:39])=[CH:4][C:3]([C:1]#[N:2])=[CH:37][C:7]=5[N:8]=4)=[CH:36][CH:35]=3)([CH3:34])[O:23][C:22]2=[O:24])=[N:26][CH:27]=1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C)CN(c5ccc([N+](=O)[O-])cn5)C(=O)O4)cc3)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C)CN(c5ccc(N)cn5)C(=O)O4)cc3)oc12
Temperature: 25 °C
Yield: 83.9 %

Procedure:
To a mixture of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[5-methyl-3-(5-nitropyridin-2-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}benzamide (154 mg, EXAMPLE 57) in 10 ml of methanol and 10 ml of tetrahydrofuran was added 50 mg of palladium on carbon (10% wet). The mixture was stirred at 40° C. under a balloon of hydrogen for 15 h. The sample was cooled to room temperature, and was filtered through a small plug of Celite, eluting with methanol. The eluent was concentrated and purified via column chromatography on a Biotage Horizon 40M column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 100% ethyl acetate in hexanes (over 10 column volumes), and held at 100% ethyl acetate for 6 column volumes to provide the title compound (122 mg, 84%). Mass spectrum (ESI) 511.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12](OS(C)(=O)=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N:24]=[N+:25]=[N-:26])(C)C.[F-].[Cs+].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:24]=[N+:25]=[N-:26])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N=[N+]=[N-])CC1
Temperature: 25 °C

Procedure:
A solution of Intermediate 36 (196 g) and trimethylsilyl azide (283 ml, Tokyo Kasei Kogyo) in dimethylformamide (667 ml) was added with cesium fluoride (305 g, Wako Pure Chemical Industries) with stirring and stirred at 70° C. for 4 days. The reaction mixture was cooled to room temperature and then added twice with water in a volume of 2.75 l in total. This reaction mixture was stirred with ice cooling for 2 hours, and the deposited precipitates were collected by filtration. Then, the precipitates were washed with water to obtain a roughly purified product of the title compound (142 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)([O-])=O.[H][H]>CO.ClCCl.[Pd]>[O:11]1[C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:12][C:8]=2[CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCO2
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc2c(c1)CCO2
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a suspension of 10.3 g (62.37 mmol) of 5-nitro-2,3-dihydrobenzofuran in 50 mL of MeOH and 10 mL of dichloromethane was added 350 mg of 10% palladium on carbon and the mixture was placed under 55 psi of hydrogen gas. Hydrogen gas uptake was evident during the first 30 minutes. After 18 hours, the mixture was then filtered through diatomaceous earth and concentrated to afford 8.2 g of 2,3-dihydrobenzofuran-5-ylamine as a gray solid which was used without further purification.
Reaction SMILES: [C:1]([C:6]1[CH:17]=[CH:16][C:9]2[N:10]([CH3:15])[C:11]([CH2:13][OH:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Mn]([O-])(=O)(=O)=[O:19].[K+]>>[C:1]([C:6]1[CH:17]=[CH:16][C:9]2[N:10]([CH3:15])[C:11]([C:13]([OH:19])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCC(=O)c1ccc2c(c1)nc(CO)n2C
Agent: [K+]
Product: CCCC(=O)c1ccc2c(c1)nc(C(=O)O)n2C

Procedure:
In a manner analogous to that described in Example 12, 18.5 g of 5-butyryl-1-methyl-benzimidazole-2-methanol can be oxidised with 18.5 g of potassium permanganate to give 5-butyryl-1-methyl-benzimidazole-2-carboxylic acid with a melting point above 90° (decomposition).
Reaction SMILES: [OH-].[K+].[CH2:3]([C:6]1([CH2:22][CH2:23][CH3:24])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[C:17][Si](C)(C)C)[CH:14]=2)[S:9][CH2:8][CH2:7]1)[CH2:4][CH3:5]>O.C(O)C>[CH2:22]([C:6]1([CH2:3][CH2:4][CH3:5])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[CH:17])[CH:14]=2)[S:9][CH2:8][CH2:7]1)[CH2:23][CH3:24]
Reactant: CCCC1(CCC)CCSc2ccc(C#C[Si](C)(C)C)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#Cc1ccc2c(c1)C(CCC)(CCC)CCS2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1.82 g (32.4 mmol) of potassium hydroxide in 1.8 mL of water and 10.0 mL of ethanol was added to 1.22 g (3.70 mmol) of (4,4-dipropylthiochroman-6-yl)(trimethylsilyl)acetylene (Compound 30) and the resulting mixture stirred at room temperature for 5 hours during which time it became homogeneous. The solvent was removed in-vacuo and the residue was acidified with 5% aq H2SO4 and the product was extracted with 2×50 mL of ether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:14][OH:15])[NH:5][C:6](=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:17][C:18]1C=CC(S(O)(=O)=O)=C[CH:23]=1.C([O-])([O-])=O.[K+].[K+].CCCCCC.CCOC(C)=O>CC(C)=O.COC(OC)(C)C>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:14][O:15][C:18]([CH3:23])([CH3:17])[N:5]1[C:6](=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:16]
Reactant: CCCCCCC(=O)N[C@@H](CO)C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCC(=O)N1[C@H](C(=O)OC)COC1(C)C

Procedure:
Compound 2j (320 mg, 1.38 mmol) and p-TSA (40 mg) are dissolved in dry acetone (2 ml) and 2,2-dimethoxypropane (2 ml). The resulting solution is heated overnight at reflux. Solid K2CO3 is added and the volatiles removed in vacuo to give a residue. Flash chromatography (2×21 cm column, 6:1 hexane/EtOAc) of the residue provides 8a as an oil: NMR δ0.88 (m, 3H), 1.29 (m, 6H), 1.57 (s, 3H), 1.62 (m, 2H), 1.70 (s, 3H), 2.15 (m, 2H), 3.81 (s, 3H), 4.20 (m, 2H), 4.46 (m, 1H); [α]D26 =-47±1 (CHCl3).
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([CH2:11][CH2:12][C:13]([NH:15][CH3:16])=[O:14])=[O:10])=[CH:7][CH:6]=1.[CH:20]([NH2:23])([CH3:22])[CH3:21]>CO>[OH:1][CH:2]([CH2:19][NH:23][CH:20]([CH3:22])[CH3:21])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([CH2:11][CH2:12][C:13]([NH:15][CH3:16])=[O:14])=[O:10])=[CH:7][CH:6]=1
Reactant: CC(C)N
Reactant: CNC(=O)CCC(=O)c1ccc(OCC2CO2)cc1
Solvent: CO
Product: CNC(=O)CCC(=O)c1ccc(OCC(O)CNC(C)C)cc1
Yield: 97.9 %

Procedure:
A mixture of 3-[4-(2,3-epoxypropoxy)benzoyl]-N-methylpropionamide (20 g, 0.076 mole), methanol (200 ml) and isopropylamine (36 ml, 0.42 mole) was heated under reflux for 1 hour. Evaporation under reduced pressure gave 3-[4-(2-hydroxy-3-isopropylaminopropoxy)benzoyl]-N-methylpropionamide (24 g, 97%, m.p. 139°-142°C). Crystallisation from water gave the pure amide, m.p. 140°-142°C.
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)O[C:7]1([N:30]=[N+]=[N-])[CH2:10][CH:9]([CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C1)(C)C.[CH:45]([O-:47])=O.[NH4+]>CO.[Pd]>[CH3:27][C:26]([Si:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[O:12][CH:11]1[CH:9]([CH2:45][O:47][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH:7]1[NH2:30])([CH3:28])[CH3:29]
Reactant: O=C[O-]
Reactant: CC(C)(C)[Si](OCC1CC(N=[N+]=[N-])(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)[Si](OCC1CC(N)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 184.5 %

Procedure:
2-(((1,1-dimethylethyl)diphenylsilyloxy)-3-(((1,1-dimethylethyl)diphenyl-silyl)oxymethyl)-1-azidocyclobutane (800 mg, 1.29 mmol), the product of Step M, was dissolved in 20 mL of methanol. To this solution was added 200 mg of 5% palladium on carbon, followed by 420 mg of ammonium formate. The flask was stoppered and the reaction mixture was stirred at ambient temperature for 23 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in 200 mL of diethyl ether and the ether solution was washed with 100 mL of 5% aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 707 mg (92% yield) of the title compound; MS DCI-NH3M/Z: 594 (M+H)+ ; 1H NMR (CDCl3) δ 0.88-1.08 (m, 18H), 1.95-2.15 (m, 3H), 3.01 (q, 1H), 3.5 (m, 2H), 3.68 (t, 1H).