Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH3:16])[CH2:11][CH2:10]1)=O)(C)(C)C.C(Cl)(=O)C>C(O)C>[CH3:16][O:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]1
Reactant: CO[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: CC(=O)Cl
Solvent: CCO
Product: CO[C@H]1CC[C@H](N)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
trans-(tert-Butoxy)-N-(4-methoxycyclohexyl)carboxamide (642 mg, 2.80 mmol) was dissolved in ethanol (5 mL) and cooled to 0° C. Acetyl chloride (1.5 mL) was added and the reaction was allowed to reach room temperature and stirred overnight. Solvent was removed in vacuo to give the desired product (458 mg, quantitative yield) as a hydrochloride salt. ES-MS: 130 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.S(=O)(=O)(O)[OH:29]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=[O:29]
Reactant: N#Cc1c(F)cccc1I
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1c(F)cccc1I
Reaction time: 0.42 h
Yield: 83 %

Procedure:
2-Fluoro-6-iodobenzonitrile (10.274 g) was dissolved in toluene (100 ml), followed by the dropwise addition of 1.5M diisobutyl aluminium hydride/toluene solution (31 ml) in nitrogen atmosphere at −70° C., and the mixture was stirred for 25 min. Subsequently, it was stirred at room temperature for further 45 min. To the mixture was added 5% sulfuric acid, and it was stirred for 1 hr. Sequentially, the resulting solution was extracted with ethyl acetate, and the resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow oil (8.683 g, yield; 83%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([F:16])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[N+](C1C=CC([O:24][C:25]([O:27][CH2:28][C:29]2[O:33][N:32]=[C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:30]=2)=O)=CC=1)([O-])=O>>[CH2:37]([O:36][C:34]([C:31]1[CH:30]=[C:29]([CH2:28][O:27][C:25]([NH:1][CH2:2][C:3]2([F:16])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:7][CH2:8]2)=[O:24])[O:33][N:32]=1)=[O:35])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CN)CC1
Reactant: CCOC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Product: CCOC(=O)c1cc(COC(=O)NCC2(F)CCN(C(=O)OC(C)(C)C)CC2)on1
Yield: 25.5 %

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.6.). Starting with 0.70 g (3.01 mmol) of tert-butyl 4-aminomethyl-4-fluoropiperidine-1-carboxylate (commercial) and 1.11 g (3.31 mmol) of ethyl 5-(4-nitrophenoxycarbonyloxymethyl)isoxazole-3-carboxylate, obtained in step 14.1., 0.33 g of pure product is obtained in the form of an orange-coloured oil.
Reaction SMILES: [C:1]([N:4]([CH2:22][CH3:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[N+:19]([O-])=O)(=O)[CH3:2]>C(O)(=O)C.C(O)C.[Fe]>[CH2:12]([O:11][C:7]1[C:6]2[N:19]=[C:1]([CH3:2])[N:4]([CH2:22][CH3:23])[C:5]=2[CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCN(C(C)=O)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCn1c(C)nc2c(OCc3ccccc3)cccc21
Yield: 34.2 %

Procedure:
To a solution of N-acetyl-3-benzyloxy-N-ethyl-2-nitroaniline (1.37 g) in acetic acid (11 ml) and ethanol (2.7 ml) was added iron (2.43 g), and the mixture was refluxed for 4 hours. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. To the residue was added saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel flash chromatography (hexane—ethyl acetate) to give 4-benzyloxy-1-ethyl-2-methyl-1H-benzimidazole (397 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O.[Na]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][Cl:12])[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(Cl)n1
Agent: [Na]
Solvent: ClCCl
Product: ClCc1cccc(Cl)n1

Procedure:
6-Chloro-2-pyridylmethanol, 0.982 g (6.84 mmole) in 10 ml methylene chloride was treated with 0.814 g thionyl chloride at room temperature for one hour. The mixture was neutralized with saturated sodium bicaronate solution, extracted with methylene chloride, the extracts dried and solvent evaporated to give 815 mg of product as colorless crystals. 1H--NMR(CDCl3)ppm (delta): 4.7 (s, 2H), 7.1-8.0 (m, 3H).
Reaction SMILES: [CH2:1]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[OH:17])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:12][C:11]=1[OH:17])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1O
Reactant: CC(C)CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)CCCCCCCOc1ccc(C(=O)Cc2ccccc2)c(O)c1

Procedure:
A mixture of 22.8 parts of 2,4-dihydroxyphenyl benzyl ketone, 22.1 parts of isodecyl bromide, 27.6 g. anhydrous potassium carbonate and 250 parts of dry acetone was stirred under reflux for 3 days. After cooling and filtering the filtrates were evaporated to dryness, the residue dissolved in petrol ether and the solution filtered. The filtrates well washed with 4 × 50 parts of N sodium hydroxide solution followed by 5 × 100 parts of water. The dried petrol solution was evaporated to give 26.2 parts of 2-hydroxy-4-isodecyloxyphenyl benzyl ketone as a dark, viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([NH:16][C@H:17]([C:25]([O:27]CC)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH:8]=[CH:7]2)([O-])=O.[C:30]([C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:1][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH2:13][C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH:8]=[CH:7]3)(=[O:42])=[O:41])=[CH:36][CH:35]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3c(ccn3CC(=O)N[C@@H](Cc3ccccc3)C(=O)O)c2)cc1

Procedure:
The title compound was prepared from ethyl N-[(5-nitro-1H-indol-1-yl)acetyl]-L-phenylalaninate and 4-tert-butylphenylsulfonyl chloride following the procedures of Example 10 Step 4 & Step 5: MS (ESI) m/z 534; MS (ESI) m/z 532.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]=[CH:11][CH:12]=2)=[N:6][CH:7]=1.[Br:20]N1C(=O)CCC1=O.O>O1CCCC1>[Br:20][C:10]1[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:8]([C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(-c2cccn2C(=O)OC(C)(C)C)cn1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(-c2ccc(Br)n2C(=O)OC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 14 h
Yield: 87.3 %

Procedure:
t-Butyl 2-(5-methylpyrazin-2-yl)-1H-pyrrole-1-carboxylate (373 mg, 1.44 mmol) synthesized in Example (10a) was dissolved in tetrahydrofuran (20 mL), and cooled to 0° C. N-Bromosuccinimide (256 mg, 1.44 mmol) was added, and stirring was carried out at room temperature for 14 hours under nitrogen atmosphere. Water (20 mL) was added, and extraction was carried out with diethyl ether (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-30%) to afford the desired compound (425 mg, yield 87%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[OH:10].Cl.[CH2:12]([O:14]CC)C>CO>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[N:9][O:14][CH3:12])[CH:5]=[CH:4][C:3]=1[OH:10]
Reactant: CCOCC
Reactant: N#Cc1ccc(O)c(Cl)c1
Agent: Cl
Solvent: CO
Product: CON=Cc1ccc(O)c(Cl)c1
Reaction time: 8 h

Procedure:
While being cooled in ice, a solution of 4.5 g of 2-chloro-4-cyanophenol in 50 ml of methanol was saturated with dried gaseous hydrogen chloride (HCl). The solution was left standing overnight at room temperature and mixed with 100 ml of ethyl ether to precipitate crystals which were collected by filtration to obtain 4.0 g of 2-chloro-4-methoxyiminomethylphenol hydrochloride.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[NH2:44][C@H:45]([CH3:48])[CH2:46][OH:47]>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:23]=[C:20]([CH2:21][NH:44][C@H:45]([CH3:48])[CH2:46][OH:47])[CH:19]=[N:18][C:17]=2[NH:24][C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: C[C@@H](N)CO
Product: COc1ccc(Nc2ncc(CN[C@H](C)CO)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.230 g, 0.398 mmol) and (R)-2-aminopropanol (Aldrich, St. Louis, Mo.) (0.047 mL, 0.597 mmol). 1H NMR (400 MHz, d6-DMSO) δ 11.82 (s, 1H); 8.93 (d, J=2.35 Hz, 1H); 8.60-8.80 (m, 2H); 8.56 (d, J=2.54 Hz, 1H); 8.38 (d, J=2.54 Hz, 1H); 8.13 (dd, J=8.90, 2.84 Hz, 1H); 7.76-7.95 (m, 2H); 6.85 (d, J=8.80 Hz, 1H); 4.17 (t, J=5.67 Hz, 2H); 3.85 (s, 3H); 3.50-3.56 (m, 2H); 3.22-3.32 (m, 1H); 2.44 (s, 3H); 1.26 (d, J=6.65 Hz, 3H). m/z (ESI, +ve ion) 397.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][CH:13]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1B(O)O
Reactant: O=C(O)c1cccc(Br)n1
Product: Nc1ccccc1-c1cccc(C(=O)O)n1

Procedure:
Preparation analogous to Ex. 10, A, using 110 mmol of 2-aminophenylboronic acid [5570-18-3] instead of 110 mmol of 3-carboxybenzeneboronic acid, and using 100 mmol of 6-bromopyridine-2-carboxylic acid [21190-87-4] instead of 100 mmol of 1-bromo-2-aminonaphthalene. Yield: 17.5 g (82 mmol), 81.7%; purity according to 1H-NMR about 99%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][SH:15].[Na]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:14]([S:15][CH:14](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[NH2:11])[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[NH2:11]
Reactant: C#Cc1ccc(F)cc1F
Reactant: Nc1ccccc1CS
Agent: [Na]
Product: Nc1ccccc1C(/C=C\c1ccc(F)cc1F)SC(/C=C\c1ccc(F)cc1F)c1ccccc1N

Procedure:
A solution of 2,4-difluorophenylacetylene (0.02 mol), 2-aminobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-difluorostyryl-2-aminobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:13])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[OH:14][C@:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=2)[CH2:20][CH2:19][O:18][C@@H:17]([CH3:21])[CH2:16]1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:13][C:26]2[CH:27]=[C:22]([C@@:15]3([OH:14])[CH2:20][CH2:19][O:18][C@@H:17]([CH3:21])[CH2:16]3)[CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: C[C@H]1C[C@@](O)(c2cccc(I)c2)CCO1
Reactant: O=C1CCc2cc(S)cc(Cl)c2N1
Product: C[C@H]1C[C@@](O)(c2cccc(Sc3cc(Cl)c4c(c3)CCC(=O)N4)c2)CCO1
Yield: 69 %

Procedure:
Using an analogous procedure to that described in Example 6, 8-chloro-6-mercapto-1,2,3,4-tetrahydroquinolin-2-one was reacted with (2S,4R)-4-hydroxy-4-(3-iodophenyl)-2-methyltetrahydropyran to give (2S,4R)-4-[3-(8-chloro-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-4-hydroxy-2-methyltetrahydropyran in 69% yield as a gum;
Reaction SMILES: N[C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[OH:19]S(O)(=O)=O.N([O-])=O.[Na+]>O>[F:13][C:12]([F:15])([F:14])[C:11]([N:8]1[CH2:9][CH2:10][C:4]2[CH:3]=[C:2]([OH:19])[CH:18]=[CH:17][C:5]=2[CH2:6][CH2:7]1)=[O:16]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(N1CCc2ccc(O)cc2CC1)C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Into a 250 ml flask, the product of step (c) (2 g, 7.75 mmol) dissolved in water (8.5 ml) and concentrated H2SO4 (1.5 ml) was added. The stirred mixture was heated to 70° C., followed by the addition of a solution NaNO2 (615 mg, 8.91 mmol) in water (20 ml). The reaction mixture was stirred at 70° C. for 1 hour. The mixture was then allowed to cool to room temperature and diluted with water (50 ml). The aqueous mixture was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the sub-title compound as a brown solid (1.8 g) that was used without further purification. MS: ESI (positive): 260 (M+H).
Reaction SMILES: [NH:1]([CH2:3][C:4]([O-:6])=[O:5])[CH3:2].[Na+].C(O)(=O)C.[N:12]#[C:13][NH2:14]>CO>[O:5]=[C:4]([CH2:3][N:1]([C:13](=[NH:12])[NH2:14])[CH3:2])[OH:6]
Reactant: CNCC(=O)[O-]
Reactant: N#CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CC(=O)O)C(=N)N
Temperature: 15 °C

Procedure:
674.5 g (2.43 moles) of 40% by weight aqueous sodium sarcosinate solution were taken and a pH value of 8.5 adjusted at 70° C. with 99% by weight acetic acid. After the addition of 500 ml methanol, 491.1 g (2.92 moles) of a 25% by weight aqueous cyanamide solution were added thereto with vigorous stirring at reflux temperature in the course of 2 hours. After ending of the addition of the cyanamide solution, the reaction mixture was further stirred for 2 hours under reflux while stirring. After cooling to 15° C., the crystalline precipitate was filtered off with suction, washed twice with, in each case, 250 ml of water and subsequently recrystallised from water. After drying in a vacuum drying cabinet at 80° C. and 15 mbar pressure, there were obtained 176.7 g (48.8% by weight) of anhydrous creatine.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[N:12][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=[CH:4]1)[CH3:2].[BH4-].[Na+]>C(O)(C)C.C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[N:12][C:7]=2[S:6](=[O:14])(=[O:15])[NH:5][CH2:4]1)[CH3:2]
Reactant: CCN1C=NS(=O)(=O)c2ncc(C)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CCN1CNS(=O)(=O)c2ncc(C)cc21
Reaction time: 0.5 h

Procedure:
A solution of 0.6 g of 4-ethyl-6-methyl-4H- pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide (Example 78}in 30 cm3 of a 1/1 isopropanol/chloroform mixture is treated, in small portions, with 0.45 g of sodium borohydride with good stirring and under an inert atmosphere. After 30 minutes at ambient temperature, the excess borohydride is destroyed by addition of a few drops of acetic acid and the solvent is removed under reduced pressure. The residue is taken up in 10 cm3 of water and the pH of the mixture is brought to neutrality. The precipitate obtained is collected on a filter, washed with water and dried.
Reaction SMILES: C([O:8][C:9](=[O:39])[C@H:10]([CH:36]([CH3:38])[CH3:37])[N:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[CH:21][CH:20]=1)[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:9]([C@@H:10]([N:11]([C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:32][N:33]=[N:34][N:35]=2)=[CH:23][CH:24]=1)[CH:36]([CH3:37])[CH3:38])([OH:39])=[O:8]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C

Procedure:
A solution of 21.1 g (40 mmol) of N-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester in 210 ml of methanol is hydrogenated at room temperature with the addition of 4 g of Pd/C (10% ) until the calculated amount of hydrogen has been absorbed (24 hours). The crude acid is obtained by filtration and evaporation of the solution. It is partitioned between 80 ml of 2N potassium hydroxide solution and 50 ml of ether. The aqueous phase is separated off and rendered acidic, and the title compound is isolated by extraction with ethyl acetate. It is obtained from ethyl acetate in crystalline form and has a melting interval of 105°-1150° and an optical rotation [α]D20 of -69.95°±0.05° (c=1% in methanol).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([O:24][CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:38].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCl.O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([O:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:38])[C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(OC)CCCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(OC)CCCC1
Reaction time: 1.5 h

Procedure:
To a solution of 2-(ethoxymethyl)-1-[(1-methoxycyclopentyl)methyl]-1H-imidazo[4,5-c]quinoline (0.30 g, 0.88 mmol) in dichloromethane at rt was added m-CPBA (278 mg, 0.88 mmol). The solution was stirred for 1.5 h and concentrated ammonium hydroxide (5.73 mL) was added and the mixture was cooled in an ice bath. To the mixture was added TsCl (176 mg, 0.924 mmol). The mixture was stirred 3 h at rt. Water (10 mL) was added and the mixture was extracted with dichloromethane (3×20 mL). The combined organics were washed twice with brine, dried over Na2SO4, filtered, and concentrated to a yellow oil. The crude product was purified by flash chromatography (silica gel, gradient elution with 1-10% CMA/CHCl3). The purified product was crystallized from acetonitrile to provide 2-(ethoxymethyl)-1-[(1-methoxycyclopentyl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine as off white crystals (0.122 g, 39%) after vacuum drying at 80° C., mp 148.0-150.0° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][NH:9][C:10]=1[CH3:11])C.[NH:14]1C=C(CC(O)=O)C=[N:15]1.O.NN>C(O)CCC>[CH3:12][C:7]1[C:6]([CH2:5][C:4]([NH:14][NH2:15])=[O:3])=[C:10]([CH3:11])[NH:9][N:8]=1
Reactant: O=C(O)Cc1cn[nH]c1
Reactant: CCOC(=O)Cc1c(C)n[nH]c1C
Agent: NN
Solvent: CCCCO
Solvent: O
Product: Cc1n[nH]c(C)c1CC(=O)NN
Yield: 68 %

Procedure:
As described for example 112a, (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (Rainer, Georg. 4-Pyrazoleacetic acid derivatives. U.S. (1979), U.S. Pat. No. 4,146,721) in butanol was reacted with hydrazine hydrate (3 equivalents) and the resulting mixture was heated under reflux for 6 h. Evaporation of all volatiles afforded the title compound as a colourless oil (yield: 68%). MS: m/e=183.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]1([C:21]2[CH:22]=[CH:23][C:24]([CH3:29])=[C:25]([CH:28]=2)[CH2:26]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(#N)C>[CH3:1][O:2][C:3]1[N:4]([CH2:26][C:25]2[CH:28]=[C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:22]=[CH:23][C:24]=2[CH3:29])[C:5](=[O:8])[NH:6][N:7]=1
Reactant: COc1n[nH]c(=O)[nH]1
Reactant: Cc1ccc(-c2ccccc2)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1n[nH]c(=O)n1Cc1cc(-c2ccccc2)ccc1C
Reaction time: 5 h
Yield: 44.9 %

Procedure:
To a solution of 626 mg (5.44 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one (said compound is a known compound described in J. Chem. Soc. Perkin I, 2645 (1973) and this was produced according to the method described in this literature. In this literature, said compound is named as 3-methoxy-1,2,4-triazol-5(4H)-one) in 7 ml of dry acetonitrile was added 0.79 g (5.71 mmol) of potassium carbonate. To the mixture was added dropwise a solution of 1.42 g (5.44 mmol) of 5-phenyl-2-methylbenzylbromide in 20 ml of dry acetonitrile at 55° C. After the mixture was stirred at the same temperature for additional 5 hours, water was added to the reaction mixture and it was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated. To the resultant solid residue (1.51 g) was added tert-butyl methyl ether and the solid was washed and ice-cooled. The solid was collected by filtration and dried to obtain 0.72 g (2.44 mmol) of 5-methoxy-4-(2-methyl-5-phenylbenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:31][CH:32]=[O:33])[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[NH2:34][C@H:35]([CH2:40]O)[C:36]([CH3:39])([CH3:38])[CH3:37].C(O)(=O)C>ClCCl>[CH3:37][C:36]([C@@H:35]1[N:34]2[C:3](=[O:4])[C:5]3[N:6]([CH:7]=[C:8]([C:20]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[O:30])[C:9](=[O:19])[C:10]=3[O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:31][C@H:32]2[O:33][CH2:40]1)([CH3:39])[CH3:38]
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: CC(C)(C)[C@H](N)CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N21
Yield: 85.5 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (41 mg, 0.09 mmol) and freebased L-tert-leucinol (59 mg, 0.50 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (3S,11aR)-3-(1,1-dimethylethyl)-N-[(4-fluorophenyl)methyl]-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (40 mg, 85%). This material was hydrogenated in a second step as described in example Z-2 to give (3S,11aR)-3-(1,1-Dimethylethyl)-N-[(4-fluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (32 mg, 97%) as a tinted white solid. 1H NMR (CDCl3) δ 11.15 (br, 1H), 10.32 (s, 1H), 8.38 (s, 1H), 7.29 (m, 2H), 6.98 (m, 2H), 5.43 (m, 1H), 4.58 (m, 2H), 4.36 (m, 2H), 4.21 (m, 1H), 3.99 (m, 1H), 3.79 (m, 1H), 1.02 (s, 9H); ES+ MS: 430 (M+1).