Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]2[C:10]([C:11]([C:21]([F:24])([F:23])[F:22])=[CH:12][C:13](=[O:20])[O:14]2)=[CH:9][CH:8]=1.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>O>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][O:6][C:7]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]2[C:10]([C:11]([C:21]([F:24])([F:22])[F:23])=[CH:12][C:13](=[O:20])[O:14]2)=[CH:9][CH:8]=1
Reactant: BrCCCCBr
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)cc(=O)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCCCCBr)ccc2c(C(F)(F)F)cc(=O)oc12
Yield: 105.4 %

Procedure:
An N,N-dimethylformamide (5 mL) solution of 7-hydroxy-8-propyl-4-(trifluoromethyl)-2H-chromen-2-one (500 mg, 1.84 mmol), 1,4-dibromobutane (2.19 mL, 18.36 mmol), and potassium carbonate (375 mg, 2.76 mmol) was stirred overnight at room temperature. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated under vacuum. The obtained residue was purified using silica-gel chromatography (hexane:ethyl acetate=10:1), and the title compound (0.79 g) was obtained as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[CH2:7][C:6]=2[N:5]=[N:4][CH:3]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl>C(O)C>[ClH:23].[NH:21]([N:22]=[C:10]1[CH2:9][CH:8]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH2:7][C:6]2[N:5]=[N:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:18]([NH2:20])=[NH:19]
Reactant: Cc1cnnc2c1C(=O)CC(c1ccsc1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1cnnc2c1C(=NNC(=N)N)CC(c1ccsc1)C2
Yield: 96.7 %

Procedure:
To a mixture of 4-methyl-7-(thiophen-3-yl)-5,6,7,8-tetrahydrocinnolin-5-one (0.195 g) and aminoguanidine hydrochloride (94 mg) were added ethanol (5 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was refluxed for 1.5 hours and cooled. Precipitated crystals were filtered, washed with ethanol and dried to give 5-guanidinoimino-4-methyl-7-(thiophen-3-yl)-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 130) (0.26 g) as colorless crystals.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[C:31]([NH:39][C:40]1[C:41]2[N:42]=[CH:43][N:44]([C:53]=2[N:54]=[CH:55][N:56]=1)[C@@H:45]1[O:52][C@H:49]([CH2:50]O)[C@@H:47]([OH:48])[CH2:46]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.ClCCl>[C:20]1(=[O:30])[N:24]([CH2:50][C@H:49]2[O:52][C@@H:45]([N:44]3[C:53]4[N:54]=[CH:55][N:56]=[C:40]([NH:39][C:31](=[O:38])[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:41]=4[N:42]=[CH:43]3)[CH2:46][C@@H:47]2[OH:48])[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CN2C(=O)c3ccccc3C2=O)O1)c1ccccc1
Reaction time: 2 h
Yield: 30.9 %

Procedure:
To a stirred solution of 13.11 g (50 mmol) Ph3P, 6.99 g (47.5 mmol) phthalimide and 17.77 g (50 mmol) N6-benzoyl-2′-deoxyadenosine in 400 mL dry THF was added 9.84 mL (50 mmol) of diisopropyl azodicarboxylate under a nitrogen atmosphere. The resulting mixture was stirred for 2 h in an ice water bath and then 4 h at room temperature. After most of the THF was evaporated under reduced pressure, the oily residue was added 100 ml of dichloromethane. The precipitate, which was formed after the addition of dichloromethane, was filtered and washed with small amounts of THF/dichloromethane mixture (1:1). The filtrate was concentrated and purified with a silica gel column chromatography (dichloromethane/THF=2:1 then dichloromethane/methanol=19:1) to give 7.1 g of compound 2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[O:10])[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
Using 4-nitro-benzoic acid (1 g) instead of 3-nitro-benzoic acid, and 1-methyl-piperazine (797 μl) instead of 1-ethyl-piperazine, in the same manner as Step A in Example 1-D-101, the desired compound was obtained as a crude product.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[CH2:3][CH:2]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)(=[O:20])[CH3:19]>N1CCCCC1.C(Cl)(Cl)Cl>[C:18]([NH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[C:3]1[C:4](=[O:5])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:1][CH:2]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Nc1cccc(C=O)c1
Reactant: O=C1CC(c2ccccc2)Oc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: CC(=O)Nc1cccc(C=C2C(=O)c3ccccc3OC2c2ccccc2)c1

Procedure:
A solid mixture of 9 g flavanone, 7.2 g 3-acetylaminobenzaldehyde and 5 drops piperidine is heated at 150°-160° C. for 3 hours. After allowing to cool, the crude brown glass is dissolved in chloroform and eluted from silicagel with chloroform. The pale yellow oil, obtained on evaporation of the solvent is crystallized from hexane and ethyl acetate to give 3(3-acetylaminobenzylidene)-flavanone as a cream coloured solid; m.p. 172°-173° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2n1
Reactant: CCCCCCCI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCCCCOc1ccc2cc(Br)ccc2n1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a mixture of 6-bromoquinolin-2-ol (352 mg1.57 mmol) and silver carbonate (863 mg, 3.14 mmol, 2.0 eq.) in toluene (20 mL) was added 1-iodoheptane (355 mg, 1.57 mmol, 1.0 eq.) and stirred for 3 h at 110° C. The reaction mixture was evaporated under reduced pressure to remove most of solvent, then filtered, and washed with ethyl acetate. The filtrate was concentrated to give crude the title compound. The crude product was purified by flash chromatography using PE/EA (20/1) as eluent to give product as a red oil (300 mg, 60%). ESI-MS: 323.8 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 7.84-7.83 (m, 2H), 7.70-7.68 (m, 2H), 6.89 (d, 1H), 4.43 (t, 2H), 1.81 (q, 2H), 1.51-1.28 (m, 8H), 0.90 (t, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1.[C:13]1([CH3:25])[CH:18]=[CH:17][C:16]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH3:25][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=2)=[O:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: OCCc1ccc(B(O)O)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(B(O)O)cc2)cc1
Temperature: 0 °C

Procedure:
4-(2-Hydroxyethyl)phenylboronic acid (step 1, 1.00 g, 6.02 mmol) was treated with pyridine (90 mL) and p-toluenesulfonylisocyanate (1.01 mL, 6.63 mmol) at room temperature for 2 h. The mixture was poured into ice-2 M HCl (200 mL) and extracted with ethyl acetate, (300 mL), and the organic fraction was dried (MgSO4). After removal of solvent, the residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (20:1) to give 2.20 g (quant.) of the title compound as white solids: MS (ESI) m/z 381 [M+NH4]+, 362 [M−H]−, 1H-NMR (DMSO-d6) δ 11.95 (1H, br.s), 7.97 (1H, s), 7.75-7.67 (2H, m), 7.40 (2H, d, J=8.6 Hz), 7.13 (2H, d, J=7.7 Hz), 4.18 (2H, t, J=6.6 Hz), 2.81 (2H, t, J=6.6 Hz), 2.40 (3H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:15][C:16]2[C:17]([NH2:22])=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1.O>ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([N:15]2[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][C:28]2=[O:29])([CH3:14])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(Nc2ccccc2N)CCN(Cc2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CC1(n2c(=O)[nH]c3ccccc32)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.4 %

Procedure:
A mixture of 121 mg N-(1-benzyl-4-methyl-piperidin-4-yl)-benzene-1,2-diamine and 79 mg CDI in 5 mL dichlormethane was stirred 24 h at RT. Water was added and the mixture was extracted with ethylacetate. The organic layer was concentrated to give 119 mg of the desired product. (M+H)+:322
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:28]([C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:40])=[O:39])=[CH:34][CH:33]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: CC(C)(C)c1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Yield: 72 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 4-tert-butylbenzenesulfonyl chloride under the conditions used in example 2 giving 72% of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1(C)C=CC=CC=1>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10]([C:13]([F:14])([F:16])[F:15])([OH:17])[CH2:11][NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Cc1ccc2c(N)cccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(C)ccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
300 mg (0.97 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 184 mg (1.16 mmol) of 5-amino-2-methylquinoline are heated in 10 ml of acetic acid over 6 hours to 125° C. After cooling to room temperature, it is mixed with 320 mg (1.51 mmol) of sodium triacetoxy borohydride, and it is allowed to stir for 16 hours. After the addition of another 320 mg (1.51 mmol) of sodium triacetoxy borohydride and 2 hours of stirring, toluene is added, and it is concentrated by evaporation in a vacuum. The residue is taken up in ethyl acetate, the organic phase is washed with saturated sodium bicarbonate and saturated sodium chloride solution, and it is dried on sodium sulfate. After chromatography on silica gel with hexane-ethyl acetate (0-60%), 221 mg of the product is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[OH:4].O=[C:16]([CH3:33])[CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[F:14][C:11]([F:12])([F:13])[C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][CH:16]([CH3:33])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:31][CH:32]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)c1cccc(C(F)(F)F)c1
Yield: 35.8 %

Procedure:
Following a procedure similar to that described in Example 2, but using 5.88 g of 2-amino-1-(3-trifluoromethylphenyl)ethanol (prepared as described in Preparation 42), 8 g of 5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Preparation 2), 200 ml of benzene, 150 ml of absolute methanol and 5.4 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 4.8 g of the title compound were obtained as crystals, melting at 100°-105° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30]([O:32][CH3:33])=[O:31])=[O:24])[O:20][N:19]=2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30]([O:32][CH3:33])=[O:31])=[O:24])[O:20][N:19]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)c1cc(-c2ccc(N)cc2)no1
Reactant: O=C=Nc1ccccc1F
Product: COC(=O)[C@@H]1CCCN1C(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Yield: 53 %

Procedure:
The title compound was prepared according to the procedure as set forth in example 151, except that 1-fluoro-2-isocyanatobenzene was used in place of 1-fluoro-3-isocyanatobenzene and (S)-methyl 1-(3-(4-aminophenyl)isoxazole-5-carbonyl)pyrrolidine-2-carboxylate was used in place of methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate to yield 53% of the title compound. MS (ES+): m/z 453 (M+1); 1H NMR (DMSO-d6, 300 MHz) δ: 9.35 (s, 1H), 8.65 (s, 1H), 8.15 (m, 1H), 7.92 (d, 2H), 7.66 (s, 1H), 7.6 (d, 2H), 7.26 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 3.92 (t, 1H), 3.67 (s, 3H), 3.65 (m, 1H), 2.29 (m, 1H), 1.97 (m, 2H), 1.24 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:9]=2[C:8]1=[O:27].[N:37]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:45]3[CH2:46][CH2:47][CH:42]([N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:43][CH2:44]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:9]=2[C:8]1=[O:27]
Reactant: O=C1c2c(-c3ccccc3F)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CCN(C2CCNCC2)C1
Product: O=C1c2c(-c3ccccc3F)cc(N3CCC(N4CCCC4)CC3)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 51.9 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (100 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (70.2 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-fluorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (63.4 mg, 52%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]#[N:7].[C:8](OC)(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[SH:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8](=[O:16])[N:7]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1nccs1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2nccs2)sc2ccccc12
Yield: 71.4 %

Procedure:
1,3-Thiazole-2-carbonitrile (0.32 g, 2.9 mmol) and methyl thiosalicylate (0.98 g, 5.8 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The reaction mixture was refluxed for 2 hrs. After cooling, the precipitates were collected by filtration and recrystallized from diisopropyl ether-ethanol to give the titled compound (0.51 g, 70%) as yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5][CH2:4][O:3]1.[CH:18]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[O:1]=[C:2]1[N:6]([CH:7]([CH3:18])[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5][CH2:4][O:3]1
Reactant: O=C(CN1CCOC1=O)OCc1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C(=O)OCc1ccccc1)N1CCOC1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a stirred solution of 0.50 g (2.1 mmol) of benzyl (2-oxo-1,3-oxazolidin-3-yl)acetate from step A above in 15 mL of anhydrous THF at −78° C. under an atmosphere of nitrogen was added 1.2 mL (2.4 mmol) of a 2.0 M solution of lithium diisopropylamide in anhydrous THF. The resulting yellow solution was stirred for 15 min at −78° C. and then 0.0360 g (2.55 mmol) of iodomethane was added. The resulting mixture was stirred for 2 h with gradual warming to ambient temperature then quenched with a saturated aqueous ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (3×20 mL) and the combined organics were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was purified by silica gel chromatography eluting with 40% ethyl acetate in hexanes to afford the title compound as a clear gum 0.37 g (70%). LC-MS: m/z (ES) 250 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[C:33](Cl)[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[CH3:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][OH:42].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[C:33]([O:42][CH2:41][CH2:40][CH2:39][CH2:38][O:37][CH3:36])[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(c2cc(Cl)ncn2)CC1
Reactant: COCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COCCCCOc1cc(N2CCN(C(=O)Cn3nc(-c4ccc(F)cc4)nc3-c3ccc(F)cc3)CC2)ncn1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
50 mg 2-(3,5-Bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-1-(4-(6-chloro-pyrimidin-4-yl)-piperazin-1-yl)-ethanone and 53 mg 4-methoxy-1-butanol were added to 14 mg potassiumcarbonate in 2 mL n-methyl-2-pyrrolidinone. The reaction was sonicated for a few minutes and stirred 30 min at 200° C. The reaction was purified by HPLC to give 29 mg desired product. Rt: 1.82 min (method N), (M+H)+: 564
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:6]([OH:8])=[O:7])[CH3:5].[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11].Cl>O.C1COCC1>[C:9]([NH:3][C@H:4]([C:6]([OH:8])=[O:7])[CH3:5])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C[C@H](N)C(=O)O
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C(=O)N[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydroxide (1.24 g) and L-alanine (2.76 g) were dissolved in pure water and, under cooling with ice, a solution where methacryloyl chloride (3 ml) was dissolved in THF (15 ml) and an aqueous solution (17 ml) containing sodium hydroxide (1.21 g) were simultaneously dropped thereinto. After that, the mixture was stirred at room temperature for 4 hours, acidified with 2M hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, concentrated in vacuo, washed with ether and dried in vacuo to give the aimed product. Yield: 1.76 g (36%).
Reaction SMILES: [CH3:1][C@H:2]([NH2:12])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[C:13](O)(=[O:22])[C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CO>[OH:15][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:22]
Reactant: C[C@H](N)CCCc1cccnc1
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: CC(CCCc1cccnc1)NC(=O)C(O)c1ccccc1

Procedure:
Under the conditions outlined in Example 14a, 76.2 g of the amine was reacted with 74.2 g of (S)-mandelic acid in the presence of 105.2 g of 1,3-dicyclohexylcarbodiimide and 78.4 g of 1-hydroxybenzotriazole in 1 L of dimethylformamide. A similar workup furnished 109 g of [S-(S*,S*)]-alpha-hydroxy-N-[1-methyl-4-(3-pyridinyl)butyl]benzeneacetamide, mp 143°-145° C, [α]D25 +27.8° (c, 1.0, MeOH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:16])([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[F:20][C:21]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH2:16])([CH2:14][NH:15][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:21]=2[F:20])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(CN)CC1
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N)(CNC(=O)c2ccc(F)cc2F)CC1

Procedure:
To a solution of 4-Amino-4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (250 mg; 1.1 mmol; 1.0 eq.) in pyridine (12 ml) at room temperature, a 0.1 M DCM solution of 2,4-difluoro-benzoyl chloride (182.8 mg; 1.04 mmol; 0.95 eq.) was added slowly. The reaction mixture was quenched by adding 0.5 mL of methanol when LC-MS showing no starting material remaining. The reaction mixture and concentrated to dryness to afford 4-Amino-4-[(2,4-difluoro-benzoylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12]>N1C=CC=CC=1>[F:1][C:2]1[N:7]=[C:6]([NH:8][C:11](=[O:12])[C:10]([CH3:15])([CH3:14])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(F)n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cccc(F)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
6-fluoropyridin-2-amine (13.1 g, 117 mmol) was dissolved in anhydrous pyridine (100 mL), and cooled to 0° C. followed by fast dropwise addition of trimethylacetyl chloride (15.9 mL, 129 mmol) over 2 min. 5 min later, the resulting slurry was stirred over night at room temperature. Partial of the solvent was removed on rotary vacuum. The residue was partitioned between saturated ammonium chloride (200 mL) and EtOAc (200 mL). After separation, the organic layer was washed with brine (50 mL), dried over MgSO4, concentrated on rotary vacuum, and purified on flash chromatography eluting with 25˜75% EtOAc/Hexanes (1400 mL) to afford the expected product as a white solid (21.4 g, 93% yield); 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 9 H), 6.63 (dd, J=8.06, 2.01 Hz, 1 H), 7.76 (q, J=8.14 Hz, 1 H), 7.85 (s, 1 H), 8.09 (dd, J=8.06, 1.76 Hz, 1 H); Mass spec. 197.15 (MH+), Calc. for C10H13FN2O196.1.