Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.[Cl:16][C:17]1[C:27]2[CH:26]=[C:25]([C:28](O)=[O:29])[C:24]3[CH:31]=[CH:32][CH:33]=[CH:34][C:23]=3[O:22][C:21]=2[CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>C(COC)OC.O>[Cl:16][C:17]1[C:27]2[CH:26]=[C:25]([CH2:28][OH:29])[C:24]3[CH:31]=[CH:32][CH:33]=[CH:34][C:23]=3[O:22][C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C1=Cc2c(Cl)cccc2Oc2ccccc21
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: OCC1=Cc2c(Cl)cccc2Oc2ccccc21
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
2.0 ml (18.33 mmol) of N-methylmorpholine and 2.4 ml (18.33 mmol) of isobutyl chloroformate are added dropwise at -15° C. to a solution of 5.0 g (18.33 mmol) of 1-chloro-dibenz[b,f]oxepine-10-carboxylic acid in dimethoxyethane. After 5 minutes filtration is carried out and at -15° C. a solution of 1.39 g (36.67 mmol) of sodium borohydride in 15 ml of water is added dropwise to the filtrate. The mixture is stirred for 15 minutes at -15° C., then 35 ml of 1N hydrochloric acid are added and the mixture is allowed to warm to room temperature. The reaction mixture is rendered basic with sodium hydroxide and extracted 4× with ethyl acetate. The organic phase is washed 1× with water, dried over sodium sulfate and concentrated. 4.58 g (17.7 mmol)=96.6% of crude (1-chlorodibenz[b,f]oxepin-10-yl)-methanol are obtained in the form of a yellow oil; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =10.46; 1H-NMR (CDCl3, 200 MHz): 2.42 (sbr, 1H); 1H); 4.71 (s, 2H); 7.10-7.45 (m, 7H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCOC)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)ccc(OCCOC)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-7-(2-methoxy-ethoxy)-4-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH2:4]([O:11][C:12]([N:14]1[C:18]2[CH:19]=[N:20][CH:21]=[C:22]([O:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:17]=2[C:16]2[CH:30]=[C:31]([Br:34])[CH:32]=[N:33][C:15]1=2)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CO.ClCCl>[CH2:4]([O:11][C:12]([N:14]1[C:18]2[CH:19]=[N:20][CH:21]=[C:22]([O:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:1][CH3:2])[CH2:26][CH2:25]3)[C:17]=2[C:16]2[CH:30]=[C:31]([Br:34])[CH:32]=[N:33][C:15]1=2)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC=O
Reactant: O=C(OCc1ccccc1)n1c2cncc(OC3CCNCC3)c2c2cc(Br)cnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CCC(Oc2cncc3c2c2cc(Br)cnc2n3C(=O)OCc2ccccc2)CC1
Reaction time: 18 h
Yield: 61.3 %

Procedure:
Acetaldehyde (3M solution in dichloromethane, 0.16 mL, 0.48 mmol) was added to a mixture of 3-bromo-5-(piperidin-4-yloxy)-dipyrido[2,3-b;4′,3′-d]pyrrole-9-carboxylic acid benzyl ester (116 mg, 0.24 mmol), sodium triacetoxyborohydride (77 mg, 0.36 mmol) and acetic acid (17 OL, 0.29 mmol) in methanol (3 mL) and dichloromethane (1 mL) and the mixture stirred for 18 hours. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with dichloromethane (3×30 mL). The combined organic layer was dried (Na2SO4), filtered and evaporated to give a residue. The resultant residue was purified by flash chromatography (silica, 12 g cartridge, ISCO, 0-8% methanol in dichloromethane). The appropriate fractions were collected and evaporated to afford the title compound as a light yellow solid (75 mg, 61%). LCMS (Method B): RT=3.43 min, M+H+=509/511. 1H NMR (400 MHz, CDCl3): 9.23 (s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.62 (s, 1H), 8.31 (s, 1H), 7.60-7.60 (m, 2H), 7.40-7.40 (m, 3H), 5.63 (s, 2H), 4.85 (s, 1H), 2.91 (br s, 2H), 2.62 (br s, 2H), 2.33 (br s, 2H), 2.14 (br s, 2H), 1.59 (br s, 2H), 1.23 (br s, 3H).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH3:28])=[N:20][C:19]=2[CH:29]([NH2:31])[CH3:30])[CH:15]=[CH:16][CH:17]=1.C(N(CC)C(C)C)(C)C>C(O)C>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH3:28])=[N:20][C:19]=2[CH:29]([NH:31][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:30])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1nc(C(C)N)c(-c2cccc(F)c2)c2ccccc12
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c2ccccc12
Temperature: 100 °C

Procedure:
A mixture of 6-bromo-9H-purine (0.31 g, 1.6 mmol), 1-[4-(3-fluorophenyl)-1-methylisoquinolin-3-yl]ethanamine (0.220 g, 0.785 mmol), and N,N-diisopropylethylamine (0.27 mL, 1.57 mmol) in ethanol (3 mL) was heated at 100° C. in a sealed tube overnight. The mixture was filtered and filtrate evaporated to dryness under reduced pressure. The resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product as the free base. LCMS calculated for C23H20FN6 (M+H)+: m/z=399.2; Found: 399.1.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1.[ClH:21]>>[ClH:21].[N+:17]([C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:9]2[C:5]([CH2:4][C:3]([OH:20])=[O:2])=[CH:6][N:7]=[CH:8]2)=[CH:16][CH:15]=1)([O-:19])=[O:18]
Reactant: COC(=O)Cc1cncn1Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C(O)Cc1cncn1Cc1ccc([N+](=O)[O-])cc1
Temperature: 55 °C

Procedure:
1-(4-Nitrophenylmethyl)-1H-imidazol-5-ylacetic acid methyl ester (0.115 g, 0.42 mmol) was dissolved in 1.0N hydrochloric acid (10 ml) and heated at 55° C. for 3 h. The solution was evaporated in vacuo to give 18 as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([NH:22][CH3:23])[N:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Cl:24][C:25]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[C:27]([Cl:35])[C:26]=1[N:36]=[C:37]=[O:38].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:28]=[C:27]([Cl:35])[C:26]=1[NH:36][C:37](=[O:38])[N:22]([C:20]1[CH:21]=[C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([N:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]3)=[CH:14][CH:13]=2)[N:17]=[CH:18][N:19]=1)[CH3:23]
Reactant: CCN1CCN(c2ccc(Nc3cc(NC)ncn3)cc2)CC1
Reactant: O=C=Nc1c(Cl)ccc(C(F)(F)F)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)ccc(C(F)(F)F)c4Cl)ncn3)cc2)CC1
Reaction time: 1.5 h

Procedure:
This oil is re-dissolved in 2 ml of toluene and added portion-wise to a boiling solution of N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine (156 mg, 0.50 mmol; Example 145A) in 6 ml of toluene during 10 min. After 1.5 h, another 2 eq of 2,6-dichloro-3-trifluoromethyl-phenylisocyanate are added and stirring is continued for totally 2 h. Then the reaction mixture is diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted twice with DCM. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2/MeOH/NH3aq, 95:5:0.5) gives the title compound: ESI-MS: 568/570 [MH]+; tR=4.1 min (gradient J); TLC: Rf=0.3 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: Cl.[C:2]([CH2:8][NH2:9])(=[O:7])[CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)(O)[O-].[Na+].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:9][CH2:8][C:2](=[O:7])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)CC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)CC(=O)CNC(=O)c1ccc(Cl)cc1
Yield: 97.5 %

Procedure:
3.8 g of isovalerylmethylamine hydrochloride, 5.04 g of sodium bicarbonate and 4.9 g of 4-chlorobenzoyl chloride are treated in the same manner as described in Preparation 1-(4). 6.2 g of N-(4-chlorobenzoyl)isovalerylmethylamine are thereby obtained. Yield: 98.0.
Reaction SMILES: [CH3:1][CH2:2][OH:3].[H-].[Na+].F[C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]>C1COCC1>[Br:13][C:11]1[CH:10]=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:3][CH2:2][CH3:1])[CH:12]=1
Reactant: CCO
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
To a cooled (0° C.) solution of EtOH (0.07 mL, 1.193 mmol) in THF (5 mL) was added NaH (60% suspension in mineral oil, 68 mg, 1.705 mmol). The reaction mixture was stirred under nitrogen at 0° C. for 15 minutes. 2-fluoro-4-bromo-nitrobenzene (250 mg, 1.136 mmol) was added and the reaction mixture stirred for a further 18 hours, whilst warming slowly to room temperature. The reaction mixture was concentrated in vacuo. Ether (20 mL) and HCl (0.5 M, 20 mL) were added. The aqueous layer was basified with aqueous saturated NaHCO3 solution and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo, to give the title compound (270 mg, 97%).
Reaction SMILES: [CH:1]([NH:3][NH2:4])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[C:21](=[NH:25])OCC)(=[O:14])=[O:13])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.O1CCOCC1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[C:21]2[N:25]=[CH:1][NH:3][N:4]=2)(=[O:13])=[O:14])=[CH:10][CH:11]=1
Reactant: NNC=O
Reactant: CCOC(=N)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC[C@H]1c1nc[nH]n1
Yield: 32.6 %

Procedure:
Formylhydrazine (120 mg) was added to a solution of ethyl (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboximidate (295 mg) [see Preparation 41] in toluene (5 ml) and 1,4-dioxane (5 ml). The reaction mixture was stirred at reflux for 26 hours after which time the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 0:100 (in 10% increments), by volume, hexane:ethyl acetate to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2-(1H-1,2,4-triazol-3-yl)piperidine (95 mg) as an off-white foam.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:15])[N:6]=1)=O.[NH3:16]>>[NH2:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[CH:14][C:5]([C:3]([NH2:16])=[O:2])=[N:6]2
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Reactant: N
Product: NC(=O)c1ccc2c(N)cccc2n1
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
840 mg (4.16 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester is dissolved in 70 ml of a 7N methanolic ammonia solution. It is stirred for 3.5 hours at 40° C., then for 20 hours at room temperature. After the solvent is removed in a vacuum, the purification is carried out on silica gel with hexane-ethyl acetate (0-100%) as well as with ethyl acetate-methanol (0-10%). 690 mg (88% of theory) of the product is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:4][CH:3]=1.[NH2:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43](O)=[O:44])[N:41]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH:7]3[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:8]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:34][CH:35]=2)=[O:44])[N:41]=1
Reactant: Nc1nc(CC(=O)O)cs1
Reactant: CC(C)(C)OC(=O)N1C(Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1C(Cc2ccc(NC(=O)Cc3csc(N)n3)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
To a solution of 10 mg (5:1 mixture cis/trans, 0.02 mmol) of tert-butyl(5R)-2-(4-aminobenzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidine-1-carboxylate (i-3) and (2-amino-1,3-thiazol-4-yl)acetic acid (3.18 mg, 0.02 mmol) in 0.5 mL anhydrous DMF was added a 0.5 M solution of HOAt in DMF (0.04 mL, 0.02 mmol) followed by EDC (5.8 mg, 0.03 mmol) and DIEA (3.5 μL, 0.02 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. The mixture was washed with water and extracted with dichloromethane (2×2 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by preparative TLC plate (500 uM) eluting with 5% MeOH in dichloromethane to afforded the product (10.3 mg, 81%). m/z (ES) 637 (MH)+, 659 (MNa)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[C:17](Cl)=[O:18].[N:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[S:22][C:21]=1[C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].CCN(C(C)C)C(C)C>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[C:17]([NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=1[C:21]1[S:22][C:23]2[C:28]([N:20]=1)=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:18]
Reactant: COCCCc1sc(-c2ccccc2)nc1C(=O)Cl
Reactant: Nc1ccccc1-c1nc2cccnc2s1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCCc1sc(-c2ccccc2)nc1C(=O)Nc1ccccc1-c1nc2cccnc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
5-(3-methoxypropyl)-2-phenylthiazole-4-carbonyl chloride (229 mg, 0.774 mmol) was added to a suspension of 2-(thiazolo[5,4-b]pyridin-2-yl)aniline (141 mg, 0.619 mmol) in acetonitrile (15 mL). DIPEA (162 μL, 0.929 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The resulting ppt was collected by filtration, and rinsed with acetonitrile to give the title compound as a white solid (260 mg, 86% yield). MS Calcd for C26H22N4O2S2: 486.12. Found (M+H)+ m/z=487.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([F:13])[CH:4](F)[C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7].C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]([F:14])([F:15])[CH:3]([F:13])[CH2:4][C:5]([F:11])([F:10])[C:6]([F:7])([F:9])[F:8]
Reactant: FC(C(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(CC(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 30 °C
Reaction time: 10 h

Procedure:
To 1,1,1,2,3,4,4,5,5,5-decafluoropentane (at a purity of 99.9%, 20 g, 79.4 mmol) was added 100 ml of an aqueous 4M potassium carbonate solution; and the resulting mixture was agitated at 30° C. for 10 hours. The reaction solution was separated into two layers; and the organic layer was again charged, together with 5% palladium carbon (0.55 g) and 0.33 g of tridecane, in a 70-ml autoclave, for hydrogenation at 50 ° C. under a hydrogen pressure of 6 kg/cm2. When hydrogen absorption was ceased 15 hours later, the reaction was terminated; then, the resulting solution was neutralized with saturated sodium bicarbonate solution, followed by distillation, to recover nonafluoropentane (1,1,1,2,4,4,5,5,5- and 1,1,1,3,4,4,5,5,5-nonafluoropentane mixture)(at a total purity of 99.7%; 10.4 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:9]([NH2:11])[N:10]=1)=[O:5])[CH3:2].[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:12][CH:13]2[CH2:14][CH2:15]2)[CH:8]=[C:9]([NH:11][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][C:17]([F:16])([F:28])[F:29])=[CH:20][CH:21]=2)=[O:27])[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(N)cn1CC1CC1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cn1CC1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7.49 g (35.8 mmol) of 4-amino-1-(cyclopropylmethyl)-1H-imidazole-2-carboxylic acid ethyl ester is mixed in 18 ml of THF under argon with 6 g (35.8 mmol) of 4-(trifluoromethoxy)phenylisocyanate and stirred for 4 hours at room temperature. The reaction mixture is concentrated by evaporation in a vacuum, and the product that crystallizes out in this case is stirred in 40 ml of ethyl acetate and suctioned off.
Reaction SMILES: C([O:3][C:4](=O)[C@@H:5]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH:8]([CH3:10])[CH3:9])C.CO.Cl>C1(C)C=CC=CC=1>[C:26]([O:25][C:23]([NH:22][C@@H:5]([CH2:6][C@H:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:16][CH:17]=1)[CH:8]([CH3:10])[CH3:9])[CH:4]=[O:3])=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: CCOC(=O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)[C@@H](Cc1ccc(C(C)(C)C)cc1)C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A 1.2M diisobutylal hydridesolution in toluene (4.2 ml) is slowly added dropwise at -75° C. to a solution of 2(S)-(tert-butoxycarbonyl)amino-4(S)-(p-tert-butyl-benzyl)-5-methyl-hexanoic acid ethyl ester (1 g) in toluene (20 ml). The reaction mixture is stirred for 30 minutes at -70° C., then 10 ml of methanol are added and the mixture is poured onto a mixture of ice and 1N hydrochloric acid (10 ml) and extracted with ethyl acetate. The title compound is obtained: Rf (dichloromethane)=0.35.
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6]([N:11]1[CH2:16][CH:15]([CH3:17])[C:14](=O)[CH:13]([CH3:19])[CH2:12]1)([O:8][CH2:9][CH3:10])=[O:7].C([BH3-])#[N:21].[Na+]>CO>[NH2:21][CH:14]1[CH:15]([CH3:17])[CH2:16][N:11]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:12][CH:13]1[CH3:19]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)N1CC(C)C(=O)C(C)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CC(C)C(N)C(C)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (20 g) was added to the stirred solution of 1-carbethoxy-3,5-dimethyl-4-piperidinone (4.5 g, 22.5 mmol) in methanol (200 ml) and stirred for 3 hr. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (1.4 g, 22.5 mmol) was added to it. Cooling was removed and stirring was for 3 hr at 35° C. The reaction mixture was concentrated, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to give 4-amino-1-carbethoxy-3,5-dimethylpiperidine. The obtained 4-amino-1-carbethoxy-3,5-dimethylpiperidine was subjected to silica gel column chromatography. Elution with 5% methanol in chloroform furnished a solid, which was a mixture of stereoisomers, conformational analysis of which was not obtained.
Reaction SMILES: [Cl:1][CH:2]([C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(=O)C.[BH4-].[Na+]>C(O)C>[Cl:1][CH:2]([CH:8]([OH:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(Cl)C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl 2-chloro-3-oxo-3-phenylpropionate (CI, 100 g, 0.44 mol) and glacial acetic acid (25 ml, 0.44 mol) in ethanol (1 l) is cooled to −5° and stirred for 10 min. Sodium borohydride pellets (12.54 g, 0.33 mol, diam. 11 mm) are added in portions (4.2 g×3) with vigorous stirring. The reaction temperature is maintained at −5 to 0°. After the addition, the reaction mixture is stirred continuously at 0° for 5 hr and is then poured slowly into ice-water with stirring. The mixture is extracted with ethyl acetate (1 l). The organic phase is washed three times with water (100 ml) and saline (100 ml), dried over magnesium sulfate, and the solvent is removed under reduced pressure to give the title compound as a 1:4 mixture of the anti and syn isomers as determined by NMR, MS (m/z, CI+NH3) 246 (M++17), 228 (M+), 210, 194; “Anti” NMR (500 MHz, CDCl3) 7.60-7.50, 5.33, 4.64, 4.33, 1.33 δ; CMR (300 MHz, CDCl3) 167.9, 138.2, 128.7, 128.5, 126.7, 74.6, 62.9, 62.2 and 13.7 δ; “Syn” NMR (500 MHz, CDCl3) 7.60-7.50, 5.24, 4.58, 4.44 and 1.46 δ; CMR (300 MHz, CDCl3) 168.9, 138.8, 126.7, 126.5, 126.9, 75.2, 62.3, 59.2 and 13.8 δ.
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:12]([C:8]3[N:9]=[CH:10][O:11][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:14])[CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)cc1)C1CCN(C(=O)c2ncoc2-c2ccccc2)CC1
Temperature: 25 °C

Procedure:
5-Phenyl-1,3-oxazole-4-carboxylic acid (40 mg, 0.211 mmol), 4-(4-Fluorobenzoyl)piperidine hydrochloride (56.2 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.0 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C22H19FN2O3: 378.1380, found 378.1384.