Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:9]=1[CH2:10][CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12](O)=[O:13].Cl>C1COCC1>[Cl:7][C:8]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:9]=1[CH2:10][CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][OH:13]
Reactant: CCCCC(Cc1ccc(Cl)cc1Cl)C(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCC(CO)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To 9.4 g (0.248 mole) of lithium aluminum hydride in 600 ml of THF is slowly added, at less than 10°; 46.0 g of the crude α-(2,4-dichlorobenzyl) hexanoic acid. The reaction is allowed to stir, and slowly warm up to ambient temperature. After 2 hours, the slurry is heated to reflux and held there for 16 hours. At the end of this period, the reaction is cooled and carefully poured into ice water to decompose the excess LiAlH4. The mixture is then made acidic by treatment with concentrated hydrochloric acid. The ether solution is separated, and the aqueous phase is extracted three times with 200 ml of ether. The extracts and the ether solution are combined and washed with 100 ml of dilute sodium bicarbonate solution and then with 100 ml of water. The solution is dried over anhydrous magnesium sulfate and the ether is stripped off to give 35.9 g of the crude alcohol product. Distillation (86.8°/.15 mm) provides 34.2 g (93%) of pure alcohol. The material is identified by ir and its purity as determined by glc.
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=2)[C:12]([NH:14][C:15]2[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=2)=[O:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:34](OC)[N:35]([CH3:37])[CH3:36]>>[CH3:34][N:35]([CH3:37])/[CH:36]=[CH:2]/[C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=2)[C:12]([NH:14][C:15]2[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=2)=[O:13])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(C)=O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)/C=C/N(C)C)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 100 °C
Yield: 83.3 %

Procedure:
A mixture of 3-(4-acetylphenoxy)-5-[(1S)-2-methoxy-1-methylethoxy]-N-(1′-methyl-1H-pyrazol-3-yl)benzamide (812 mg, 1.92 mmol) and N,N-dimethylformamide dimethyl acetal (10.2 mL, 77 mmol) was heated to 100° C. in a ‘Smith Creator’ microwave for 140 mins. The volatiles were removed under reduced pressure and the resulting oil purified by chromatography on silica, eluting with 0-20% methanol in DCM, to give the desired product (765 mg).
Reaction SMILES: [NH:1]([CH2:3][C:4]([O-:6])=[O:5])[CH3:2].[Na+].[N:8]#[C:9][NH2:10]>O>[OH2:5].[O:5]=[C:4]([CH2:3][N:1]([C:9](=[NH:8])[NH2:10])[CH3:2])[OH:6]
Reactant: N#CN
Reactant: CNCC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CN(CC(=O)O)C(=N)N
Temperature: 50 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
462.5 g (1.67 moles) of a technical 40% by weight aqueous sodium sarcosinate solution and 200 g of water were take. A pH value of 9.81 (at 20° C.) was adjusted with concentrated 98% by weight formic acid. The reaction mixture was heated to 50° C. 138.2 g (1.65 moles) of SKW cyanamide L 500 (technical aqueous cyanamide solution with a content of 50.2% by weight) were added uniformly with vigorous stirring at an internal temperature of 50° to 52° C. over the course of 3 hours. The reaction mixture was further stirred for 1 hour at an internal temperature of 50° C. Subsequently, the reaction product was filtered off with suction and, without washing, suspended in 330 g of water. The suspension was stirred for 2 hours at 20° C. It was then filtered off with suction and the residue washed twice with 100 ml of water. After drying in a vacuum at 30° C. and 20 mbar pressure, there were obtained 165.2 g (67.1% of theory) creatine monohydrate.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[CH3:19][S:20]([NH:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:21]>>[Cl:14][C:13]1[C:8]2[CH2:7][CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3](=[CH:2][C:26]3[CH:25]=[C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])[CH:29]=[CH:28][CH:27]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccc2c1CCc1ccccc1C2=CBr
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3c(Cl)cccc32)c1
Yield: 79.5 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 5-bromomethylene-1-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (100 mg, 0.313 mmol) and 3-methanesulfonylamino-phenylboronic acid (74 mg, 0.344 mmol), affords 102 mg (79%) of the title compound (Example 205(a)) as a mixture of geometric isomers. MS (ES) 408 (M−H); HPLC reveals a 57:43 mixture of geometric isomers—54% at 3.061 min, 40% at 3.197 min—overall 94% purity. Separate geometric isomers on a 1000 micron silica gel chromatatron rotor, (10% to 13% ethyl acetate/hexanes) to afford 22 mg (17%) of the Z-isomer of the title compound (Example 205(b), (MS (ES) 410 (M+H). HPLC shows 98% purity. Continue to elute to give 11 mg (9%) of the E-isomer of the title compound (Example 205(c)) (MS (ES) 410 (M+H), 408 (M−H); HPLC shows 94% purity).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8](=[O:18])[C:9]2[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:10]=2[F:17])=[CH:4][C:3]=1[O:21][CH3:22].CN(C)C=[O:26]>O.[Cu]Cl.[Pd](Cl)Cl>[C:15]([C:13]1[CH:12]=[CH:11][C:10]([F:17])=[C:9]([CH:14]=1)[C:8]([NH:7][CH2:6][C:5]1[CH:19]=[CH:20][C:2]([Cl:1])=[C:3]([O:21][CH3:22])[CH:4]=1)=[O:18])(=[O:26])[CH3:16]
Reactant: CN(C)C=O
Reactant: C=Cc1ccc(F)c(C(=O)NCc2ccc(Cl)c(OC)c2)c1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Solvent: O
Product: COc1cc(CNC(=O)c2cc(C(C)=O)ccc2F)ccc1Cl
Temperature: 25 °C

Procedure:
A mixture of copper(I) chloride (464 mg) and palladium(II) chloride (83.2 mg) in a mixture of dimethylformamide (42 mL) and water (6 mL) was stirred for an hour under oxygen atmosphere (1 atm) at ambient temperature. To the mixture was added N-(4-chloro-3-methoxybenzyl)-2-fluoro-5-vinylbenzamide (1.50 g). After stirring for 6 hours at 60° C., the mixture was partitioned between ethyl acetate and 1N-hydrochoric, acid. The separated organic layer was washed with water, an aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (2:1 to 1:1) to give 5-acetyl-2-fluoro-N-(4-chloro-3-methoxybenzyl)benzamide as colorless powders (719 mg).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.C(N(CC)C(C)C)(C)C.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>C(Cl)Cl.CCOC(C)=O>[C:25]1([O:24][C:22](=[O:23])[NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N:7]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(F)(F)F)cn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
A solution of 5-(trifluoromethyl)pyridin-2-amine (100 mg, 0.617 mmol) and N,N-diisopropylethylamine (159.5 mg, 215 μL, 1.234 mmol) in 5 mL CH2Cl2 was treated with phenyl chloroformate (106 mg, 85 μL, 0.68 mmol) and left to stir for 3 h at rt. Solution was diluted with EtOAc and washed twice with 1 N HCl and 1 time with brine. The organic layer was dried (Na2SO4) and concentrated to provide a white solid. Tituration with 10% EtOAc in hexanes gave 120 mg (69%, 0.42 mmol) of the above compound as a white solid. 1H-NMR (DMSO-d6) δ 11.26 (s, 1H), 8.70 (s, 1H), 8.22 to 8.16 (m, 1H), 7.99 (d, J=8 Hz, 1H), 7.45 to 7.40 (m, 2H), 7.30 to 7.20 (m, 3H)
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8]1[C:9]([CH3:18])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)([O:5][CH3:6])=[O:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:37][CH2:18][C:9]1[C:8]([CH2:7][P:3]([O:5][CH3:6])([O:2][CH3:1])=[O:4])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COP(=O)(Cc1cc2ccccc2nc1C)OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COP(=O)(Cc1cc2ccccc2nc1CBr)OC
Yield: 61 %

Procedure:
A solution of the obtained 3-(dimethylphosphonomethyl)-2-methylquinoline (0.28 g, 1.0 mmol) in carbon tetrachloride (20 ml) was treated with benzoylperoxide (50 mg) followed by N-bromosuccinimide (0.20 g, 1.1 mmol). The reaction mixture was refluxed for 4 hours, filtered and concentrated in vacuo. The residue was flash chromatographed on silica gel with ethyl acetate as the eluent to give 0.21 g of 2-bromomethyl-3-(dimethylphosphonomethyl)quinoline.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(OCC)(=O)C.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14]>C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:12](=[O:15])[CH:13]=[CH2:14]
Reactant: COCCN
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CC(=O)NCCOC
Reaction time: 1 h

Procedure:
2-Methoxyethylamine (44.6 g), ethyl acetate (100 mL) and triethylamine (50.6 g) were introduced into a 300 mL flask equipped with a dropping funnel and a magnetic stirrer. The flask was immersed in an ice bath and the contents of the flask were stirred as nitrogen gas was being introduced. Acryloyl chloride (45.3 g) was introduced into the dropping funnel and was added dropwise over a period of approximately one hour. After the dropwise addition was completed, stirring was continued for 1 hour at room temperature. The salt, which was separated out by suction filtration using celite, was separated by filtration, after which low boiling point components were removed with a rotary vacuum evaporator. Purification was performed by distillation under reduced pressure and N-(2-methoxyethyl)acrylamide was obtained as a colorless transparent liquid.
Reaction SMILES: [CH3:1][N:2]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C@@H:35]([OH:72])[C@@H:36]([OH:71])[C@@H:37]([NH:45][C:46](=[O:70])[C@H:47]([CH:67]([CH3:69])[CH3:68])[NH:48][C:49]([N:51]([CH2:53][C:54]1[N:55]=[C:56]([NH:59]C(OC(C)(C)C)=O)[S:57][CH:58]=1)[CH3:52])=[O:50])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:3][C:4]1[N:5]=[C:6]([NH:9]C(OC(C)(C)C)=O)[S:7][CH:8]=1.CO.C(N)(C)C>C(Cl)(Cl)Cl>[CH3:52][N:51]([C:49]([NH:48][C@H:47]([C:46]([NH:45][C@H:37]([C@@H:36]([OH:71])[C@@H:35]([OH:72])[C@@H:27]([NH:26][C:24](=[O:25])[C@H:20]([CH:21]([CH3:22])[CH3:23])[NH:19][C:17]([N:2]([CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)[CH3:1])=[O:18])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:70])[CH:67]([CH3:69])[CH3:68])=[O:50])[CH2:53][C:54]1[N:55]=[C:56]([NH2:59])[S:57][CH:58]=1
Reactant: CC(C)[C@H](NC(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1)C(C)C
Solvent: CO
Solvent: CC(C)N
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)N(C)Cc1csc(N)n1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(N)n1)C(C)C

Procedure:
Using the procedure of Example 58B but replacing the resultant compound of Example 58A with the resultant compound of Example 93 provided, after silica gel chromatography using first 5% then 10% methanol in chloroform followed by 2% isopropylamine/10% methanol in chloroform, 53 mg (38%) of the desired compound (Rf 0.15, 10% methanol in chloroform) as a white solid, m.p. 130°-134° C. Mass spectrum: (M+1)+ =837.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3].[OH:10]O.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:10])[CH2:2][CH3:3]
Reactant: OO
Reactant: CCCc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCc1cccc[n+]1[O-]
Temperature: 65 °C
Reaction time: 3 h

Procedure:
20 ml of 2-n-propylpyridine were dissolved in 60 ml of glacial acetic acid, mixed with 40 ml of H2O2 (30%) and stirred for 16 hours at room temperature and 3 hours at 65° C. The acetic acid was then partly rotated out, the residue was adjusted to pH 8 with NaOH (20%), extracted with dichloromethane and the organic phase rotated in to dryness. 20 g of crude 2-propylpyridine-N-oxide were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[C:11]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)(=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: Cc1ccccc1C
Product: COc1ccc(C(=O)Nc2nc(C(Cl)(Cl)Cl)ns2)cc1

Procedure:
A solution of 11.0 g (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 12.8 g (0.08 mole) 4-anisoyl chloride in 200 ml xylene was heated at reflux for 20 hours. Cooling of the reaction mixture resulted in precipitation of the crude product, which was then isolated by filtration. Purification was achieved by washing the crude product with hot hexane. Yield was 12.0 g (82%); m.p. 172° C.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[S:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)s1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)s1
Yield: 81.2 %

Procedure:
A mixture of the title compound of Example 2 (200 mg, 1.37 mmol), thionyl chloride (500 μl, 6.85 mmol) and DMF (20 μl) in dry methylene chloride was refluxed for 2 hours. The solvents were evaporated and the residue dried in vacuo to give 183 mg (81%) of the title product as a brown solid, mp 123-5 C. 1H-NMR (CDCl3): δ 7.74 (m, 1H), 6.64 (m, 1H),). GC-MS (m/e, %) 166/164 (M+, 11), 129(100).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:13])[CH:6]([NH2:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3].C(N(CC)CC)C.[CH3:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].O>ClCCl>[CH2:10]([O:9][C:7](=[O:8])[CH:6]([NH:12][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([CH3:21])[CH:23]=1)[C:5]([O:4][CH2:2][CH3:3])=[O:13])[CH3:11]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(NC(=O)c1cccc(C)c1)C(=O)OCC
Reaction time: 2 h
Yield: 94.9 %

Procedure:
41.1 g of aminomalonic acid diethyl ester hydrochloride were dissolved in 200 ml of dichloromethane, and 80.7 ml of triethylamine were added with cooling in an ice bath. A solution of 30 g of 3-methyl-benzoyl chloride in 200 ml of dichloromethane was slowly added dropwise. After 2 h at 0° C., 100 ml of water were added dropwise. The phases were separated, and the aqueous phase was extracted with 100 ml of dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and evaporated to give 54 g of the crude title compound.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:40][CH2:39][N:38]4[C@H:33]([CH2:34][O:35][CH2:36][CH2:37]4)[CH2:32]3)[N:27]=[C:26]([CH3:41])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12]CC2C=CC=CC=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:40][CH2:39][N:38]4[C@H:33]([CH2:34][O:35][CH2:36][CH2:37]4)[CH2:32]3)[N:27]=[C:26]([CH3:41])[N:25]=2)=[O:21])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCN3CCOC[C@@H]3C2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CCN3CCOC[C@@H]3C2)n1
Reaction time: 4 h
Yield: 78.1 %

Procedure:
To a solution of [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (assumed 38.74 g, 68.0 mmol) in methanol (225 mL) was added 10% Pd/C (5.81 g). The mixture was hydrogenated under balloon pressure for 4 h, and was then filtered through a glass fiber filter with MeOH washes. The resulting solution was concentrated in vacuo to approximately 10% volume, diluted with EtOAc (400 mL), and concentrated in vacuo to approximately 30% volume. The resulting solid was collected by vacuum filtration and washed with EtOAc. The mother liquor and EtOAc washings were concentrated in vacuo to approximately 10% volume, and the resulting solid was collected by vacuum filtration and washed with EtOAc. The two crops of solid were combined and dried at 50° C. for 16 h under high vacuum to afford [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide (25.48 g, 78% yield for 2 steps) as a white solid. LCMS: (M+H)+: 480.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[OH:10]O.O>C(O)(=O)C.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N+:7]([O-:10])[CH:8]=1
Reactant: OO
Reactant: COc1ccc(C)nc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C)[n+]([O-])c1
Reaction time: 8 h

Procedure:
A solution consisting of 5-methoxy-2-methylpyridine (12.3 g.) and 30% hydrogen peroxide (12 ml.) dissolved in glacial acetic acid (50 ml) was heated in a steam bath for a period of 12 hours and then allowed to stand overnight (~16 hours) at room temperature (~25° C.). Water (5 ml.) was next added to the mixture, followed by manganese dioxide until effervescence ceased. The resulting mixture was then filtered and the recovered filtrate was subsequently evaporated under reduced pressure to afford crude 5-methoxy-2-methylpyridine-N-oxide (yield, 13.5 g.) as the residual oil.
Reaction SMILES: C[Si]([CH2:5][C:6]([NH2:8])=[O:7])(C)C.Cl[Si:10]1(Cl)[CH2:13][CH2:12][CH2:11]1>C(Cl)Cl>[C:6]([NH:8][Si:10]1([NH:8][C:6](=[O:7])[CH3:5])[CH2:13][CH2:12][CH2:11]1)(=[O:7])[CH3:5]
Reactant: Cl[Si]1(Cl)CCC1
Reactant: C[Si](C)(C)CC(N)=O
Solvent: ClCCl
Product: CC(=O)N[Si]1(NC(C)=O)CCC1

Procedure:
When 1.72g of trimethylsilylacetamide was mixed with 0.92 g of 1,1-dichlorosilacyclobutane in 5 g of methylene chloride, a white precipitate formed. The precipitate dissolved upon shaking and slowly recrystallized as .white needles. There was no trimethylchlorosilane detected in the residual fluid, indicating that the expected reaction to form 1,1-diacetamidosilacyclobutane did not occur.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>>[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:24])[CH2:22][CH3:23]
Reactant: CCCCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CCC(=O)Cl
Product: CCCCN1CCC(c2c[nH]c3ccc(NC(=O)CC)nc23)CC1
Yield: 281.7 %

Procedure:
Beginning with 0.15 gm (0.55 mMol) 5-amino-3-(1-butylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.058 mL (0.067 mMol) propionyl chloride, 0.062 gm (35%) of the title compound were prepared as an ivory foam essentially by the procedure described in Example 4. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[OH-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: ClCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc2ccccc2n1CCCCl
Temperature: 60 °C
Yield: 61.8 %

Procedure:
2-methyl-1H-benzimidazole (13.2 g, 0.10 mol) was dissolved into 200 ml of 20% wt. sodium hydroxide, 3-chlorobromopropane (31.4 g, 0.20 mol) and tetrabutyl ammonium bromide (1.0 g) were added, and mixed for 5 min. The mixture was heated to 60° C., stirred to react for 2 hours. Then the reaction solution was cooled down to ambient temperature, 100 ml of dichloromethane was added for extraction and liquid separation. To the aqueous phase, 100 of dichloromethane was added for extraction. Organic phases were mixed, washed with 100 ml of saturated saline. Liquid was separated, and organic phase was evaporated to dryness to produce oily product. Oily products were separated and purified by chromatography with neutral Al2O3 to produce 12.9 g of 1-(3-chloropropyl)-2-methyl-1H-benzimidazole, with a yield of 62.1%.
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][NH2:27])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][NH:27][S:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:14])=[O:13])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(C)(CN)CNC(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)(CNC(=O)OC(C)(C)C)CNS(=O)(=O)c1cccc2cnccc12
Yield: 97.8 %

Procedure:
According to Reference Example 5, Step B, a reaction was performed by using isoquinoline-5-sulfonyl chloride hydrochloride (7.8 g) and Intermediate 56 (5.97 g) to obtain the title compound (11.36 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])[CH:5]=[C:4]([CH3:27])[N:3]=1.Cl.CN.C[CH2:32][N:33](C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:32][NH:33][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])[CH:5]=[C:4]([CH3:27])[N:3]=1
Reactant: Cc1cc(NCc2cc3cccc(C)c3nc2-c2ccccc2)nc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CN1CCCC1=O
Product: CNc1nc(C)cc(NCc2cc3cccc(C)c3nc2-c2ccccc2)n1
Temperature: 220 °C
Yield: 44 %

Procedure:
To a solution of Example 75 (50 mg, 0.13 mmol) in NMP (2 mL) was added methylamine hydrochloride (18 mg, 0.26 mmol) and DIPEA (0.5 mL). The mixture was heated in a microwave at 220° C. for 2 h. Purification by preparative HPLC (Method 1) gave the title compound as an off-white solid (23 mg, 44%). δH (CDCl3) 8.17 (s, 1H), 7.63-7.70 (m, 3H), 7.38-7.57 (m, 5H), 5.47 (s, 1H), 4.80-4.95 (m, 2H), 4.69 (d, J 5.8 Hz, 2H), 2.91 (d, J 5.1 Hz, 3H), 2.81 (s, 3H), 2.14 (s, 3H). LCMS (ES+) 370.2 (M+H)+, RT 2.34 minutes (Method 3).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[Br-].[Cl-].[NH4+].[CH2:19]1COC[CH2:20]1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]([OH:13])[C:19]#[CH:20])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Reactant: C1CCOC1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Product: C#CC(O)c1ccc(N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.2 %

Procedure:
To a solution of 4-(4-methyl-piperazin-1-yl)-benzaldehyde (28.9 mmol) in THF (100 ml), ethnylmagnesium bromide (0.5M solution in THF) (43.4 mmol) is added at 78° C. The solution is then stirred at room temperature for 18 h. The reaction mixture is treated with saturated ammonium chloride and extracted with ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate and evaporated down. CH2Cl2 is added to the residue to afford a precipitate, which is collected by filtration. yield 84.2%, Rf=0.23 (CH2Cl2:MeOH=9:1).