Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH:9]=[O:10])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCCC(c1ccccc1)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=CCC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
4.69 mL (23.55 mmol, 1 eq.) of 3,3-diphenylpropanol are dissolved in 100 mL of CH2Cl2 under argon. 10.5 g (24.73 mmol, 1.05 eq.) of Dess Martin Periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one) are added to the mixture and the solution is stirred for 1 hour 30 min at 0° C. 100 mL of 2 M sodium hydroxide and 100 mL of CH2Cl2 are then added. The organic phase is washed with 2 M sodium hydroxide (twice), with water (twice), dried over MgSO4, filtered and concentrated. The crude reaction product is subjected to chromatography over silica gel (eluent: 5/1 heptane/AcOEt). An oil which crystallises in the form of a white product is recovered (4.76 g, yield=96%).
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[F:15]C1C=CC=CC=1CBr.COP(OC)OC>>[F:15][C:13]1[CH:14]=[CH:2][CH:3]=[CH:4][C:5]=1[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: Fc1ccccc1CBr
Reactant: COP(=O)(Cc1ccc(F)cc1)OC
Agent: COP(OC)OC
Product: COP(=O)(Cc1ccccc1F)OC

Procedure:
Following the procedure of Compound 11, 2-fluorobenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH:11]1/[CH:17]=[CH:18]/[CH:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:17][CH2:18][CH:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)CCCCCCN1C(=O)CCCC1/C=C/C(O)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCN1C(=O)CCCC1CCC(O)Cc1ccccc1
Reaction time: 22 h
Yield: 64.2 %

Procedure:
Palladium on carbon (10 wt. %, 5 mg) was added to a solution of 7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid methyl ester (20 mg, 0.052 mmol) in MeOH (2.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 22 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 13 mg (65%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2)=[O:23].Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]12[CH2:27][CH:28]3[CH2:29][CH:30]([CH2:31][CH:32]([CH2:34]3)[CH2:33]1)[CH2:35]2)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C=C2CCNCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 162.8 %

Procedure:
A solution of 4-[[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]methylene]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.10 g, Example 50b) in methanol (3 ml) was treated with a 4N solution of hydrochloric acid in dioxane (1 ml) and stirred for 14 h at room temperature. The reaction mixture was concentrated under vacuum and the residue recrystallised from iso-propanol/ether to give the title compound as a white solid (0.071 g).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:40]CC1.C(O)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 48 %

Procedure:
Treat a mixture of (R)-4-benzyl-3-[2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one (0.96 g, 1.8 mmol), THF (21 mL) and water (7 mL) with 2.5% osmium tetroxide in t-butanol (46 mg, 0.18 mmol). Add sodium periodate (1.17 g, 5.5 mmol) and stir the reaction 4 hr at room temperature. Quench the reaction with water and extract with ethyl acetate. Wash the organic phase with aqueous 1N sodium thiosulfate then brine. Dry the organic layer over magnesium sulfate, filter, and concentrate under vacuum. Purify the crude material by silica gel chromatography using hexanes:ethyl acetate to elute the pure product. Concentrate the fractions containing product under vacuum to afford 0.46 g (48%) of desired product. MS (m/z): 526 (M+).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:17](=[O:18])[C:16]2[C:15](=[O:19])[C:14]3[CH:13]=[CH:12][C:11]([Cl:20])=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]([OH:21])=[N:5]1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO.Cl>CN(C)C=O>[Cl:20][C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:19])[C:16]3[C:17](=[O:18])[N:4]([CH2:3][CH2:2][N:31]4[CH2:32][CH2:33][N:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)[N:5]=[C:6]([OH:21])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCBr)c(=O)c12
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCN3CCN(c4ccccc4)CC3)c(=O)c12
Temperature: 25 °C
Reaction time: 120 h
Yield: 70.2 %

Procedure:
2(2-Bromoethyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]-quinoline-1,10-dione (0.500 g, 1.35 mM) was stirred in dimethylformamide (10 mL), and N-phenylpiperazine (10 mL, 10.6 g, 65.5 mM) was added. The resulting yellow suspension was heated to ~110° C. to form a clear yellow solution. The solution was heated for 6 hours during which time a precipitate formed. The suspension was cooled to room temperature and stirred for five days. The resulting yellow suspension was dissolved into aqueous methanol (500 mL, 50%). The pH of this solution was carefullyadjusted to pH=6 with 1N hydrochloric acid (~20 mL) which gave a yellow precipitate. This suspension was stirred for 1 hour and filtered togive the title compound contaminated with N-phenylpiperazine (0.753 g). This material was recrystallized from hot ethanol (200 mL) to give the title compound (0.428 g, 70%) as a yellow powder, mp 361°-364° C.; MS(CI): 452 (M+H). Analysis for C23 H22ClN5O3 : Calculated: C,61.10; H,4.91; N,15.50; Found: C,60.72; H,5.06; N,15.30; NMR: 7.95 (d, J=8.67 Hz, 1H),7.64 (br s, 1H),7.26-7.18 (m, 3H), 6.95 (d, J=8.07 Hz, 2H), 6.78 (t, J=7.32 Hz, 1H), 4.15 (br s, 2H), 3.55-2.85 (br m, 10H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[Cl:13][C:14]1[CH:29]=[CH:28][C:17]([CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22](SC)=[N:23][CH:24]=2)=[CH:16][CH:15]=1>N1C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]3[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][N:7]=3)=[N:23][CH:24]=2)=[CH:28][CH:29]=1
Reactant: NCCCNc1ncccc1Cl
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Solvent: c1ccncc1
Product: O=c1[nH]c(NCCCNc2ncccc2Cl)ncc1Cc1ccc(Cl)cc1

Procedure:
2-(3-Aminopropylamino)-3-chloropyridine (1 g) and 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (1.3 g) were heated together under reflux in pyridine (20 ml) for 48 hr. The mixture was stripped and recrystallised from dimethyl formamide/ethanol/water to give 5-(4-chlorobenzyl)-2-[3-(3-chloropyrid-2-ylamino)propylamino]-4-pyrimidone 0.7H2O, (1.55 g; 76%) m.p. 180°-81° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N+:26]([O-])=O)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:29])[CH:3]=1.[H][H]>C(O)C.[Pd]>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[CH:3][C:4]([CH3:29])=[C:5]3[N:10]=[C:9]2[CH2:11][CH3:12])=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2N)cc1
Reaction time: 1.5 h
Yield: 95.6 %

Procedure:
To a solution of 0.340 g (0.88 mmol) of the product of Step 1 in 15 mL of absolute ethanol was added 35 mg of 10% palladium on carbon catalyst and the mixture was hydrogenated at 40 psi of hydrogen on a Parr apparatus. Reduction was complete after 1.5 hours and the reaction mixture was filtered and evaporated in vacuo to afford a tan solid (0.300 g, 95%) which was used in the subsequent step without further purification.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:9]=1)=[O:7])(C)(C)C.O.[OH-].[Li+]>O1CCCC1.O>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Yield: 68.1 %

Procedure:
To a stirred solution of 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (6-01) (5 g, 10.68 mmol) in a mixture of tetrahydrofuran and water (2:1, 90 mL) was added lithium hydroxide, monohydrate (2.2 g, 53.4 mml). The mixture was refluxed for 18 h. After completion of the reaction, the volume was reduced by evaporation as much as possible, water was added and the mixture was washed with ethyl acetate to remove non-acidic impurities. The separated aqueous part was acidified with 1N HCl to bring the pH to about 5 to 6. The acidified aqueous part was extracted with dichloromethane to get 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (7-01) (3 g, 68%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CS(C)=O>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CNCCN1
Reactant: Clc1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Clc1cccnc1N1CCNCC1
Temperature: 80 °C

Procedure:
2,3-Dichloropyridine (15.0 g, 101.6 mmol), piperazine(9.78 g, 113.70 mmol), and triethylamine (14.36 g, 141.95 mmol) were dissolved in 300 mL of DMSO and the resulting mixture was heated at about 80° C. for about 24 h. The reaction mixture was then cooled to room temperature and extracted with a saturated aqueous sodium bicarbonate solution. The organic layer was dried, concentrated, and purified using a silica gel column eluted with a gradient elution from ethyl acetate to 2:1 ethyl acetate:methanol to provide N-(3-chloropyridin-2-yl)-piperazine (compound 1) as a yellow liquid.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[C:3](=[O:5])[CH3:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1>CC(=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:3](=[O:5])[CH3:4])=[CH:18][CH:17]=1
Reactant: CC(=O)C(Cl)=NNc1ccccc1Cl
Reactant: Sc1ccc(Cl)cc1
Solvent: CC(C)=O
Product: CC(=O)C(=NNc1ccccc1Cl)Sc1ccc(Cl)cc1

Procedure:
1-chloro-1-[(2-chlorophen yl)hydrazono]-2-propanone is reacted with 4-chlorothiophenol as Example 11 to yield 1-[(4-chlorophenyl)thio]-1-[3-chlorophenyl)hydrazono]-2-propanone.
Reaction SMILES: [OH-].[Na+].[C:3]1([C:11]([O:13]CC)=[O:12])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1>O.C(O)C>[CH2:9]([O:8][C:6]([C:3]1([C:11]([OH:13])=[O:12])[CH2:4][CH2:5]1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of sodium hydroxide (2.15 g, 54 mmol) in water (15 ml) was added dropwise to a stirred solution of diethyl 1,1-cyclopropanedicarboxylate (10 g, 54 mmol) in ethanol (30 ml) while the temperature was maintained below 25° C. After the completion of the addition, the resulting mixture was stirred at room temperature for 60 hours. Most of ethanol was removed by evaporation in vacuo and the residue was diluted with brine, acidified with 6N hydrochloric acid and extracted with diethyl ether. The extract was dried over magnesium sulfate, filtered and concentrated. The residue was purified by distillation to give the title compound (bp 66°-9° C./0.15 mm) as a viscous oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:32]=[CH:31][C:9]2[O:10][CH2:11][CH2:12][N:13]([C:17](=O)[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=3)[CH2:14][CH2:15][O:16][C:8]=2[CH:7]=1)(=[O:4])=[O:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:29][S:26]([NH:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][N:13]2[CH2:12][CH2:11][O:10][C:9]3[CH:31]=[CH:32][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=3[O:16][CH2:15][CH2:14]2)=[CH:24][CH:23]=1)(=[O:27])=[O:28]
Reactant: CS(=O)(=O)Nc1ccc(CC(=O)N2CCOc3ccc(NS(C)(=O)=O)cc3OCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CS(=O)(=O)Nc1ccc(CCN2CCOc3ccc(NS(C)(=O)=O)cc3OCC2)cc1

Procedure:
In a manner similar to example 8, react 9-[(methylsulfonyl)amino]-4-[2-[4-[(methylsulfonyl)amino]phenyl]acetyl]-3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonine with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][C@H:22]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][C@H:22]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (51.7 mg, 0.187 mmol) in dry dichloromethane (2 mL) was added a solution of tert-butyl (4S)-4-aminoazepane-1-carboxylate (69 mg, 0.275 mmol), triethylamine (0.090 mL, 0.646 mmol), HOBT (42.5 mg, 0.278 mmol), and EDC (54.7 mg, 0.285 mmol) sequentially at room temperature under nitrogen. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue was purified by HPLC on a 30×100 mm Waters Sunfire column eluted with 15% to 100% CH3CN+0.05% TFA/water+0.05% TFA over 15 minutes to afford the title compound as a white solid after lyophilization.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([N+:17]([O-])=O)=[CH:4][N:3]=1>C1COCC1.[Ni]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([NH2:17])=[CH:4][N:3]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2[N+](=O)[O-])cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(Cl)ncc2N)cc1

Procedure:
A solution of 1.86 g (6.64 mmol) (2-chloro-5-nitro-pyrimidin-4-yl)-(4-methoxy-phenyl)-amine (from example 1) in 20 ml THF is hydrogenated with 1.0 g sponge-nickel as catalyst at room temperature and under atmospheric pressure. The catalyst is filtered off; the filtrate is evaporated and dried under vacuum giving 2-chloro-N4-(4-methoxy-phenyl)-pyrimidine-4,5-diamine as grey solid; HPLC/MS (A): 1.63 min, [M+H] 251;
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17]([OH:19])=[S:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)O[CH2:29][CH:30]([CH3:32])[CH3:31].Cl.CNO>ClCCl>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][C:17]([O:19][CH2:29][CH:30]([CH3:32])[CH3:31])=[S:18])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=1[OH:11])([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)c1cc(CC(O)=S)cc(C(C)(C)C)c1O
Agent: CNO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)COC(=S)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 53 %

Procedure:
To 20 ml of a solution of 1.48 g (5 mmol) of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)thioacetic acid (II1) in dichloromethane was added 555 mg (5.5 mmol) of triethylamine and 5 ml of a solution of 750 mg (5.5 mmol) of isobutyl chlorocarbonate in dichloromethane was added dropwise to the resulting mixture over an about 5 minutes period under cooling at -45° C.±5° C. and stirring. The mixture was stirred for 1 hour at the same temperature. To the reaction mixture was added 450 mg (5.5 mmol) of N-methyl hydroxylamine hydrochloride and then added dropwise 5 ml of a solution of 1.21 g (12 mmol) of triethylamine in dichloromethane. The mixture was stirred at the same temperature for 30 minutes and then additional 2 hours after removal of the cooling bath. The reaction mixture was poured into 50 ml of a cold 5% aqueous solution of hydrochloric acid and extracted with 50 ml of dichloromethane. The extract was washed twice with 50 ml of water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel. The fractions eluted with a mixture of ethyl acetate-n-hexane (2:1) were collected. From the first fraction, 892 mg of isobutyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)thioacetate was obtained as colorless oil in 55% yield and the aimed compound (I1) obtained from the second fraction was recrystallized from a mixture of ether-n-hexane (1:1) to give 350 mg of colorless prismatic crystals in 21.5% yield. Mp. 84°-85° C.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:23]1[S:24][C:25]([CH2:28][N:29]2[N:33]=[N:32][CH:31]=[N:30]2)=[CH:26][CH:27]=1)[NH:6][C:7](=[O:22])[CH:8]([CH2:17][S:18]C(=O)C)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.CO.C(Cl)(Cl)Cl>ClCCl>[N:30]1[N:29]([CH2:28][C:25]2[S:24][C:23]([CH:5]([C:4]([OH:34])=[O:3])[NH:6][C:7](=[O:22])[CH:8]([CH2:17][SH:18])[CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:27][CH:26]=2)[N:33]=[N:32][CH:31]=1
Reactant: CCOC(=O)C(NC(=O)C(CCc1ccccc1)CSC(C)=O)c1ccc(Cn2ncnn2)s1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(NC(C(=O)O)c1ccc(Cn2ncnn2)s1)C(CS)CCc1ccccc1

Procedure:
The title compound was prepared from 2-[5-(2-tetrazolylmethyl)thien-2-yl]-N-[2-(acetylthiomethyl)-4-phenylbutyryl]glycine ethyl ester (Description 54) using the procedure described in Example 24 except that the eluent used was 10% methanol in dichloromethane. vmax (CHCl3) 3294 and 1646 cm-1. δ (CD3SOCD3) 1.68-1.81 (2H, m), 2.42-2.73 (5H, m), 5.74-5.83 (1H, m), 6.09 (2H, s), 6.88-6.96 (1H, m), 7.05-7.31 (6H, m), 8.20-8.31 (1H, m), 8.94 and 8.98 (1H, two s's). m/z 530 (M-H)-.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][N:2]([CH3:21])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([CH2:18][OH:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][N:4]=1
Reactant: CN(C)c1ncc(-c2nc3cccc(C(=O)O)c3o2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN(C)c1ncc(-c2nc3cccc(CO)c3o2)cn1
Yield: 53.8 %

Procedure:
Methyl ester of 2-(2-dimethylaminopyrimidin-5-yl)benzoxazole-7-carboxylic acid (480 mg, 1.61 mmol) was reduced by using lithium aluminium hydride as in Preparation 2-3) to give 2-(2-dimethylamino-pyrimidin-5-yl)benzoxazole-7-methanol (234 mg, 54%) as yellow crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[N:4][N:3]=1.[OH:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1.C(N(CC)CC)C>C(O)CC(C)C>[CH3:15][O:14][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][CH3:13])[C:2]([N:20]1[CH2:21][CH2:22][CH2:23][CH:18]([CH2:17][OH:16])[CH2:19]1)=[N:3][N:4]=[CH:5]2
Reactant: COc1cc2cnnc(Cl)c2cc1OC
Reactant: OCC1CCCNC1
Solvent: CCN(CC)CC
Solvent: CC(C)CCO
Product: COc1cc2cnnc(N3CCCC(CO)C3)c2cc1OC
Yield: 60.2 %

Procedure:
1-Chloro-6,7-dimethoxy phthalazine (2.25 g.), 3-hydroxymethylpiperidine (1.72 g.) and triethylamine (1.3 ml.) in iso-amyl alcohol (60 ml.) were heated at 95° C. for 42 hours. The cooled reaction mixture was then filtered and the filtrate was taken to dryness in vacuo. The residue was dissolved in water (100 ml.), 5 N sodium hydroxide solution was added to give a pH of 11 and the basic mixture was then extracted with chloroform (2×100 ml.). The chloroform extracts were combined, dried (MgSO4) and concentrated in vacuo to give a brown oil, which was triturated with ether (50 ml.) and filtered. The resultant solid was crystallized twice from acetonitrile, yielding 6,7-dimethoxy-1-(3-hydroxymethylpiperidino)phthalazine (1.83 g.), m.p. 162°-165° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11]1)([O-])=O.CC(O)=O.O>CCO.[Fe]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2[N+](=O)[O-])C1
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a solution of tert-butyl [(3S)-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate (2.69 g, 8.34 mmol) in EtOH (30.0 mL), iron powder (2.335 g, 41.81 mmol) was added, followed by AcOH (7.04 g, 117 mmol) and water (7.00 mL, 388 mmol). The reaction mixture was stirred at room temperature for 3 h then concentrated under reduced pressure. EtOAc (100 mL) was added to the residue and the resulting mixture was filtered through a pad of diatomaceous earth. The diatomaceous earth pad was washed with 10 wt % aq. K3PO4 (150 mL) and EtOAc (100 mL). The organic layer was separated and was then washed with brine (150 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-30% MeOH in DCM) to give the sub-title compound as an off-white solid (2.13 g, 87%). LCMS calc. for C15H25N4O2 (M+H)+: m/z=293.2. found 293.2.