Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH2:21])[C:19]=3[N:20]=2)[CH2:6]1.[CH3:22][O:23][CH2:24][CH2:25][C:26](O)=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[NH2:21][C:18]1[C:19]2[N:20]=[C:11]([N:7]3[CH2:8][CH2:9][CH2:10][C@H:5]([NH:4][C:26](=[O:27])[CH2:25][CH2:24][O:23][CH3:22])[CH2:6]3)[CH:12]=[CH:13][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: COCCC(=O)O
Reactant: Nc1ncnc2ccc(N3CCC[C@H](N)C3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCC(=O)N[C@H]1CCCN(c2ccc3ncnc(N)c3n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To an 8 mL screw-cap vial was added (S)-6-(3-aminopiperidin-1-yl)pyrido[3,2-d]pyrimidin-4-amine trihydrochloride 44 (0.15 mmol, 53 mg) followed by 3-methoxypropanoic acid (1.2 equiv., 0.18 mmol, 19 mg), HATU (1.2 equiv., 0.18 mmol, 68 mg), dimethylformamide (1 mL), then triethylamine (6 equiv., 0.90 mmol, 0.13 mL). The reaction was capped and shaken at room temperature overnight. The reaction was diluted with 3 mL DCM, and washed with 2 mL water. Organic was concentrated via GeneVac, then purified by reverse phase HPLC, yielding 15 mg of desired product. 1H NMR (400 MHz, DMSO) δ 8.19-8.14 (s, 1H), 7.91-7.83 (d, J=7.0 Hz, 1H), 7.82-7.73 (d, J=9.3 Hz, 1H), 7.44-7.38 (d, J=9.3 Hz, 1H), 7.38-7.18 (m, 2H), 4.25-4.17 (d, J=12.7 Hz, 1H), 4.17-4.08 (d, J=13.8 Hz, 1H), 3.85-3.72 (m, 1H), 3.58-3.48 (m, 2H), 3.23-3.18 (s, 3H), 3.10-2.99 (m, 1H), 2.37-2.28 (m, 2H), 1.90-1.81 (m, 1H), 1.81-1.70 (m, J=8.7 Hz, 1H), 1.63-1.40 (m, 2H). LCMS M/Z (M+H)=331.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([CH3:27])=[CH:25][N:24]=[CH:23][C:22]=1[CH3:28].[CH3:31][NH:32][CH2:33][CH2:34][OH:35]>>[CH3:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH3:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]([CH2:33][CH2:34][OH:35])[CH3:31])[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: CNCCO
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCN(C)CCO

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 6) and and 2-(methylamino)ethanol following the procedure outlined in Example 18, Step 2 (modifications: 22° C., 60 h). 1H NMR (300 MHz, DMSO-d6):):δ: 9.67 (s, 1H), 8.42 (s, 3H), 7.91 (d, J=9 Hz, 1H), 7.04 (s, J=7 Hz, 1H), 4.55 (s, 1H), 4.31 (s, 1H), 3.98 (t, J=6.6 Hz, 5H), 3.46 (s, 2H), 2.40-2.28 (m, 4H), 2.15 (s, 9H), 1.75 (m, 2H), 1.35 (m, 6H). MS (ESI) 469.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Li+]>CCOCC.C1COCC1>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(CO)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 4-(4-formylphenyl)piperazine-1-carboxylate (1.0 g, 3.44 mmol) in ether (17 mL) and THF (3 mL) was added solid lithium borohydride (38 mg, 1.72 mmol) in one portion. The reaction mixture stirred for 1 h at 0° C. before being quenched with 1 N HCl to reach pH=7. The resulting organic layer was filtered through a pad of celite and concentrated to obtain tert-butyl 4-(4-(hydroxymethyl)phenyl)piperazine-1-carboxylate as an orange solid (1 g) 1H NMR (300 MHz, CDCl3): δ 7.30 (d, 2H, J=8.6 Hz), 6.93 (d, 2H, J=8.6 Hz), 4.61 (d, 2H, J=5.0 Hz), 3.59 (dd, 4H, J=5.3, 5.1 Hz), 3.14 (dd, 4H, J=5.2, 5.0 Hz), 1.49 (m, 9H); 13C NMR (150 MHz, CDCl3): δ 154.94, 151.11, 132.92, 128.59, 116.84, 80.14, 65.24, 49.66, 43.48, 28.64; Minor rotomeric populations are also visible; HRMS calcd for C16H24N2O3: 293.185969 found 293.18590.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[CH3:1])[CH2:6][OH:7]
Reactant: Cc1ccc(CO)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(CO)cc1N
Yield: 94.8 %

Procedure:
4-Methyl-3-nitro benzylalcohol (9.7 g, 58 mmol) in ethanol (200 mL) was reduced under 4 atmospheres of hydrogen gas for 4 hours in the presence of 10% Pd/C (0.5 g) to yield after a standard workup 7.54 g (93%) of the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:13][C:12]2[C:7](=[C:8]([NH2:14])[CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:15].O.[C:17]([O:21][C:22]([NH:24][C@@H:25]([C:30](O)=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.O.C(OCC)(=O)C.C(N(CC)CC)C>[NH2:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:5](=[O:15])[CH:4]([NH:3][C:30](=[O:31])[C@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:13]2
Reactant: Nc1cccc2c1NC(=O)C(N)C2
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N)c2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
3,8-Diamino-3,4-dihydroquinolin-2(1H)-one dihydrochloride (9.0 g) was suspended in N,N-dimethylformaldehyde (90 mL), and triethylamine (15 mL) was added to the suspension under cooling on ice. Subsequently, N-tert-butoxycarbonyl-D-leucine monohydrate (9.87 g), 1-hydroxybenzotriazole (4.86 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.67 g) were sequentially added to the mixture, followed by stirring at room temperature for one hour. To the resultant mixture were added saturated aqueous sodium bicarbonate solution, ethyl acetate, and water, and the mixture was subjected to extraction. The organic layer was sequentially washed with water and saturated aqueous sodium chloride solution, and was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the precipitates were filtered by use of ethyl acetate, whereby tert-butyl (2R)-1-(8-amino-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylamino)-4-methyl-1-oxopentan-2-ylcarbamate (12.4 g) was yielded as a diastereomeric mixture. Subsequently, the thus-obtained tert-butyl (2R)-1-(8-amino-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylamino)-4-methyl-1-oxopentan-2-ylcarbamate (7.68 g) was dissolved in ethanol (77 mL), and concentrated hydrochloric acid (34 mL) was added thereto, followed by heating to 60° C. while being stirred for 30 minutes. The resultant mixture was neutralized with saturated aqueous sodium bicarbonate solution under cooling on ice and was then subjected to extraction with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the thus-recovered residue was purified through silica gel column chromatography (chloroform:methanol=15:1), whereby the title compound (diastereomer of lower polarity: 2.85 g, diastereomer of higher polarity: 2.73 g) was yielded.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]#[CH:20]>CN(C)C=O>[CH2:20]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]#[CH:18]
Reactant: C#CCBr
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCON=C(C(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.3 %

Procedure:
A mixture of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 56.7 g), N,N-dimethylformamide (280 ml), potassium carbonate (72.3 g) and propargyl bromide (43 g) was stirred at room temperature for 4 hrs. The reaction mixture was treated in a conventional manner to give ethyl 2-propargyloxyimino-3-oxobutyrate (syn isomer, 71.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:33][C:34](=[O:36])[CH3:35])[C@H:11]([OH:32])[CH2:12][NH:13][C@@H:14]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=3)[O:17][C:16]3([CH2:31][CH2:30][CH2:29]3)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:37](OC)(OC)OC.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:33][C:34](=[O:36])[CH3:35])[C@H:11]([OH:32])[CH2:12][N:13]([C@@H:14]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]([CH3:27])([CH3:28])[CH3:26])[CH:22]=3)[O:17][C:16]3([CH2:31][CH2:30][CH2:29]3)[CH2:15]2)[CH3:37])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(OC)OC
Reactant: CC(=O)N[C@@H](Cc1ccc(F)c(Br)c1)[C@H](O)CN[C@H]1CC2(CCC2)Oc2ncc(CC(C)(C)C)cc21
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1ccc(F)c(Br)c1)[C@H](O)CN(C)[C@H]1CC2(CCC2)Oc2ncc(CC(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 15-mL RB flask, N-((1S,2R)-1-((3-bromo-4-fluorophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide (0.027 g, 0.048 mmol) was dissolved in DCM (1.5 mL). Trimethyl orthoformate (0.13 ml, 1.2 mmol) was added, followed by addition of Formaldehyde (37%, 0.0089 ml, 0.12 mmol) as an aqueous solution. The mixture was stirred at ambient temperature for 2 h. Then sodium triacetoxyborohydride (0.036 g, 0.17 mmol) was added, and the mixture was stirred at ambient temperature overnight. The reaction mixture was quenched with 10% aqueous sodium carbonate (5 mL), stirred vigorously for 2 h, and diluted with DCM (60 mL). The organic layer was separated and extracted with dilute brine (5 mL), dried over sodium sulfate and concentrated. The residue was purified by passing it through silica gel (20 g; deactivated with triethylamine (2.0 mL)), eluting with 95% EtOAc-hexane to provide the title compound. MS m/z 576/578 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[O:11][CH2:10][CH2:9][O:8]1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCCCCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCCCC2OCCO2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
To a stirred solution of 2-(5-bromopentyl)-1,3-dioxolane (4.38 g, 19.6 mmol) in dimethyl formamide (30 mL) was added 4-hydroxybenzaldehyde (3.00 g, 24.4 mmol) and potassium carbonate (4.52 g, 32.8 mmol). The reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to afford an oil. The crude material was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford the title compound (1.92 g, 36%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:33]=[CH:32][C:13]3[N:14]([C:17]4[N:22]=[C:21]([NH:23][C@H:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH3:25])[CH:20]=[N:19][CH:18]=4)[CH:15]=[N:16][C:12]=3[CH:11]=2)=O)[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:10]2[CH:33]=[CH:32][C:13]3[N:14]([C:17]4[N:22]=[C:21]([NH:23][C@H:24]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH3:25])[CH:20]=[N:19][CH:18]=4)[CH:15]=[N:16][C:12]=3[CH:11]=2)[CH2:4][CH2:3]1
Reactant: C[C@H](Nc1cncc(-n2cnc3cc(C(=O)N4CCN(C)CC4)ccc32)n1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Nc1cncc(-n2cnc3cc(CN4CCN(C)CC4)ccc32)n1)c1ccccc1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A solution of 6-{5-[(4-methylpiperazin-1-yl)carbonyl]-1H-benzimidazol-1-yl}-N-[(1S)-1-phenylethyl]pyrazin-2-amine (22 mg, 0.05 mmol) in dry THF (1 mL) was added to a suspension of LiAlH4 (4 mg, 0.1 mmol) in THF (1 mL) and the mixture heated at reflux for 4 h. Upon cooling to RT, the solution was treated consecutively with H2O (1 mL), aqueous NaOH (1 mL, 2M) and H2O (5 mL). The resulting mixture was extracted with CHCl3 (2×10 mL) and the combined organic layers dried (Na2SO4). The solvent was removed under reduced pressure and the product purified by flash chromatography using CH2Cl2-MeOH (10:1→1:1) as eluant to afford the product as a yellow solid (11 mg, 52%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:9][C:10]1[C:18]2[O:17][N:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:14]=2[CH:13]=[CH:12][C:11]=1[O:26][CH2:27][C:28]#[N:29].O>C1COCC1>[Cl:9][C:10]1[C:18]2[O:17][N:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:14]=2[CH:13]=[CH:12][C:11]=1[O:26][CH2:27][C:28]1[NH:29][N:3]=[N:2][N:1]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1ccc2c(-c3ccccc3F)noc2c1Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccccc1-c1noc2c(Cl)c(OCc3nnn[nH]3)ccc12

Procedure:
3.35 g NaN3 and 2.25 g of AlCl3 are stirred in 50 ml THF at reflux for 0.5 hour. A solution of 5 g {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}acetonitrile, of Example 50, in 50 ml THF is added and the reaction mixture is stirred at reflux for about 120 hours. To the reaction mixture is added water and the solvent is removed. The residue is treated with dilute HCl and extracted with CHCl3. Upon attempted extraction of the chloroform solution with 15% NaOH a precipitate forms which is filtered, dissolved in hot water and acidified to afford 7-chloro-3-(2-fluorophenyl)-6- {[5-tetrazolylmethyl]oxy}-1,2-benzisoxazole, mp 198°-200° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:18][NH:17][C:5]2=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].[NH2:27][CH2:28][C@@H:29]([OH:31])[CH3:30]>C(O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]1[C:4]2[C:5](=[N:6][C:7]([O:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[C:2]([NH:27][CH2:28][C@H:29]([OH:31])[CH3:30])[N:3]=2)[NH:17][N:18]=1
Reactant: C[C@H](O)CN
Reactant: Fc1ccc(Oc2nc3[nH]nc(-c4ccccc4Cl)c3nc2Cl)c(F)c1
Solvent: CCO
Product: C[C@@H](O)CNc1nc2c(-c3ccccc3Cl)n[nH]c2nc1Oc1ccc(F)cc1F
Reaction time: 16 h
Yield: 11.2 %

Procedure:
To a stirring ethanol (100 mL) suspension of 5-Chloro-3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-b]pyrazine (0.66 g, 1.7 mmol) under nitrogen at room temperature was added (S)-1-amino-2-propanol (0.63 g, 8.4 mmol). The reaction mixture was heated to reflux and stirred for 16 hours at reflux. The reaction mixture was cooled and concentrated under reduced pressure. The residue was chromatographed (2% MeOH in hexanes) to yield 82 mg of (R)-1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-b]pyrazin-5-ylamino]-propan-2-ol. Mass spec., M+1=433.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH:10]([OH:12])[CH3:11])[N:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH:10]([OH:12])[CH3:11])[N:5]=1
Reactant: CC(O)Cn1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(O)Cn1ccc(N)n1
Yield: 95.8 %

Procedure:
In a Parr shaker bottle was placed 1-(3-nitro-pyrazol-1-yl)-propan-2-ol (58 mg, 0.34 mmol), 10% palladium on activated carbon (12 mg) and ethanol (5 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 1 h. The reaction was then filtered through a pad of celite and washed with ethanol and concentration in vacuo afforded 1-(3-amino-pyrazol-1-yl)-propan-2-ol (46 mg, 96%) as a clear colorless oil and taken on to the next step without characterization.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:30][C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=[O:32])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.71 g) and N,N-dimethylformamide (30 mL) was added 60% sodium hydride (0.12 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (1.38 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[C:21](OCC)(OCC)(OCC)[CH3:22]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:21]([CH3:22])=[N:13][N:12]=[C:7]1[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: CCOC(C)(OCC)OCC
Reactant: NNc1cc(-c2ccccc2Cl)c2cc(F)ccc2n1
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3Cl)c3cc(F)ccc3n12

Procedure:
In the manner given in Example 2, 6-fluoro-4-(o-chlorophenyl)-2-hydrazinoquinoline and triethyl orthoacetate are refluxed in xylene to give 7-fluoro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].CO.[OH-].[Na+].S(=O)(=O)(O)O.[C:20](O)(=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]CCCC>O>[C:20]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)O

Procedure:
L-Glutamic acid 2.9 g was dissolved in 30 ml water and 30 ml methanol and 1.6 g of sodium hydroxide. To this solution was added 8.8 g of the crystal of palmitic acid sulfuric acid mixed anhydride and 10 N sodium hydroxide to keep pH 12 to 13, with stirring at 21° - 22°C. The reaction mixture was stirred for an additional 1 hour, and then treated by the same manner as in Example 1. N-Lauroyl-L-glutamic acid was obtained. Yield 6.4 g (96.9%). M.P. 101° - 104.5°C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:29])=[C:18]([CH2:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[CH3:28])=O)[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]([CH3:29])=[C:18]([CH2:20][CH2:21][N:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[CH3:28])[N:19]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CC(=O)N1CCC[C@H]1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CCN1CCC[C@H]1C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2-[2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-1-(2-(R)-methyl-pyrrolidin-1-yl)-ethanone (See Intermediate 18) (0.62 g, 1.6 mmol) in THF (5 mL) at 0° C. is added a solution of lithium aluminum hydride in THF (1 M, 1.6 mL, 1.6 mmol). The cooling bath is removed, and the reaction mixture is allowed to warm to room temperature and stirred for 3.5 h. The reaction is quenched by the sequential addition of water (0.06 mL), 5 N NaOH (0.06 mL), and water (0.18 mL). The mixture is stirred at room temperature overnight and filtered. The solvent is removed in vacuo, and the crude product is obtained (0.49 g, 81%) and used without purification. MS (m/e): 377.2 (M+1)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12]>C(O)C.[Pd]>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:12][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: O=Cc1ccsc1
Reactant: COC(CN)OC
Agent: [Pd]
Solvent: CCO
Product: COC(CNCc1ccsc1)OC
Temperature: 25 °C
Reaction time: 60 h
Yield: 94 %

Procedure:
To 3-thiophenecarboxaldehyde (8.75 mL) cooled to 0° C. was added aminoacetaldehyde dimethylacetal (14.2 mL). The clear solution was stirred at room temperature for 60 h. The solution was diluted with ethanol and hydrogenated at 56 psi in the presence of 10% Pd/C (5 g) overnight. The catalyst was filtered off and washed with MeOH. The solvent was removed by rotary evaporation and co-evaporated with toluene to afford an oil (19 g, 94% yield).
Reaction SMILES: [B].[C:2]1([C:8]2[O:14][C@H:13]3[C@H:10]([C:11](=[O:15])[NH:12]3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][CH2:17][C:18]#[C:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21].C([O-])(O)=O.[Na+]>O1CCCC1>[C:8]([NH:9][C@@H:10]1[C@@H:13]([O:16][CH2:17][C:18]#[C:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[NH:12][C:11]1=[O:15])(=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@H]2OC(c3ccccc3)=N[C@@H]12
Reactant: O=C(C#CCO)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [B]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C#CCO[C@H]1NC(=O)[C@@H]1NC(=O)c1ccccc1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
10 μl of boron trifuloride etherate were sprayed into a stirred suspension of 376 mg (2mmols) of (1R, 5S)-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one and 941 mg (4 mmols) of 4-nitrobenzyl 4-hydroxy-2-butinoate in 8 ml of anhydrous tetrahydrofuran at room temperature. After a short time, a clear, light yellow solution formed, and was stirred at room temperature for 0.5 hour. Thereafter, the solution was poured into dilute NaHCO3 solution, the mixture was extracted with methylene chloride and the extract was washed with water and dried over MgSO4. After the solvent had been evaporated off in vacuo and the residue had been chromatographed on 60 g of silica gel (toluene:ethyl acetate 35:65), 557 mg (66%) of 4-nitrobenzyl 4-[3(R)-benzoylamino-2-azetidinon-4(R)-yloxy]-2-butinoate were obtained as a colorless rigid foam.