Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:13])[C:3]([NH2:5])=[O:4].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].CN1CCN(C)C1=O>>[Cl:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([Cl:12])[C:6]=1[CH:2]([NH:1][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])[C:3]([NH2:5])=[O:4]
Reactant: NC(=O)C(N)c1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CN1CCN(C)C1=O
Product: NC(=O)C(Nc1ccccc1[N+](=O)[O-])c1c(Cl)cccc1Cl
Temperature: 140 °C
Reaction time: 6 h

Procedure:
A mixture of 0.092 parts of α-amino-2,6-dichlorobenzeneacetamide, 0.032 parts of 2-fluoronitrobenzene and 1 part of 1,3-dimethyl-2-imidazolidinone was stirred for 6 hours at 140° C. The product was extracted and the extract was dried, filtered and evaporated at 100° C. and 133-266 Pa. The residue was purified by column chromatography (HPCL, silica gel; CH2Cl2CH3OH 99:1→90:10), yielding 0.12 parts of (-)-2,6-dichloro-α-[(2-nitrophenyl)amino]benzeneacetamide (e.e.=90%).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3OC=C[O:19]3)=[CH:14][CH:13]=2)[NH:7][C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([N:5]1[C:9](=[O:10])[C:8](=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]=[O:19])=[CH:16][CH:17]=2)[NH:7][C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)NC(=Cc2ccc(C3OC=CO3)cc2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCCCN1C(=O)NC(=Cc2ccc(C=O)cc2)C1=O

Procedure:
3-n-Butyl-5-[4-(1,3-dioxol-2-yl)benzylidene] hydantoin (2.7 g; 0.0085 mole) was dissolved in acetone (100 ml.) and stirred overnight at room temperature with p-toluene sulphonic acid (0.5 g.). The hazy solution was evaporated in vacuo and the resultant solid suspended in water (100 ml) and neutralised to pH 7 using dilute sodium bicarbonate solution. The residual solid was filtered off, washed with water and dried to give the title compound m.p. 180° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH2:10][N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[C:19]([CH2:27][CH3:28])[C:18]4=[O:29])[CH2:13][CH2:12]3)[C:7]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:6][C:5]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[F:41])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([C:4]2[CH:9]=[C:8]([CH2:10][N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[C:19]([CH2:27][CH3:28])[C:18]4=[O:29])[CH2:13][CH2:12]3)[C:7]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:6][C:5]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[F:41])[CH2:2][CH2:3]1
Reactant: CCc1c(C(=O)OC)ccn(C2CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4F)cc3OC(C)C)CC2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1c(C(=O)O)ccn(C2CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4F)cc3OC(C)C)CC2)c1=O
Yield: 76.9 %

Procedure:
A mixture of methyl 1-(1-((2-cyclopropyl-2′,4′-difluoro-5-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylate (208 mg), a 1 M aqueous sodium hydroxide solution (3 mL), and ethanol (6 mL) was stirred at 70 C for 1 hour. The reaction mixture was pH-adjusted to 3 using 1 M hydrochloric acid, followed by extraction with ethyl acetate twice. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized (2-propanol/hexane) to obtain the title compound (156 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.[C:7](Cl)([Cl:9])=[O:8].C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:9][C:7]([O:6][C@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: O[C@H]1CCOC1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Cl)O[C@H]1CCOC1
Temperature: 25 °C
Yield: 85 %

Procedure:
A stirred solution of (S)-tetrahydrofuran-3-ol (7.9 g, 90 mmol) in anhydrous CH2Cl2 (50 mL) under an N2 atmosphere was cooled in an ice bath, and a 20% solution of phosgene in toluene (134 mL, 270 mmol) was slowly added. The reaction was allowed to warm to room temperature overnight, and the solvent was removed under vacuum to afford (S)-tetrahydrofuran-3-yl chloroformate (12.1 g, 85%) as a clear liquid. 1H NMR (400 MHz, CDCl3) δ 5.42-5.39 (m, 1H), 4.01-3.84 (m, 4H), 2.31-2.13 (m, 2H).
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(C(C)C)C(C)C.[OH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[O:26].[F:31][C:32]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:33]=1[O:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]2[N:46]=[C:45]3[CH2:47][NH:48][CH2:49][CH2:50][C:44]3=[N:43][C:42]=2[NH:51][CH:52]([CH3:54])[CH3:53])[CH2:37][CH2:36]1.C=O>CO>[F:31][C:32]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:33]=1[O:34][CH:35]1[CH2:36][CH2:37][N:38]([C:41]2[N:46]=[C:45]3[CH2:47][N:48]([CH3:1])[CH2:49][CH2:50][C:44]3=[N:43][C:42]=2[NH:51][CH:52]([CH3:54])[CH3:53])[CH2:39][CH2:40]1.[C:25]([OH:26])([C:27]([F:30])([F:29])[F:28])=[O:24]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCNC4)CC2)c(F)c1
Agent: C=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCN(C)C4)CC2)c(F)c1
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyborohydride (22.3 mg, 0.105 mmol) was added to a mixture of DIPEA (18 μL, 0.105 mmol), 3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (27.9 mg, 0.053 mmol) and formaldehyde (4 μL, 0.053 mmol) in MeOH (550 μL) at rt. After 30 min, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (27.9 mg, 97%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.25 (d, J=6.3 Hz, 6H), 1.88-1.98 (m, 2H), 2.04-2.14 (m, 2H), 2.93-3.05 (m, 3H), 3.07 (br s, 4H), 3.33-3.40 (m, 2H), 3.41-3.69 (m, 2H), 3.75 (s, 3H), 4.15-4.32 (m, 3H), 4.32-4.39 (m, 1H), 6.66 (ddd, J=8.9, 3.0, 1.5 Hz, 1H), 6.73 (dd, J=12.8, 2.9 Hz, 1H), 7.07 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 430.4.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.CC(C)([O-])C.[K+].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1(C)C=CC=CC=1>[Br:9][C:4]1[CH:3]=[C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: CN1CCNCC1
Reactant: Fc1cc(Br)cc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN1CCN(c2cc(F)cc(Br)c2)CC1
Temperature: 105 °C
Yield: 37.2 %

Procedure:
To a solution of 1,3-dibromo-5-fluorobenzene (LXI) (2.0 g, 7.88 mmol) in toluene (20 ml) was added potassium t-butoxide (2.65 g, 23.6 mmol) and 1-methylpiperazine (1.75 mL, 15.8 mmol). The reaction was heated at 105° C. overnight. The toluene was removed under vacuum and the residue was dissolved in water and extracted with EtOAc. The organic phase was separated, washed with brine, dried over MgSO4 and concentrated to dryness. The crude product was purified on a silica gel column (1:99 MeOH:CHCl3→7:93 MeOH:CHCl3) to produce 1-(3-bromo-5-fluorophenyl)-4-methylpiperazine (LXII) as an orange oil (800 mg, 2.93 mmol, 37.2% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.20 (s, 3H), 2.39 (t, J=5 Hz, 4H), 3.33 (t, J=5 Hz, 4H), 6.74-6.81 (m, 2H), 6.91 (s, 1H); ESIMS found for C11H14BrFN2 m/z 273 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:24]>>[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:24][C:17](=[O:19])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1

Procedure:
condensing the N-benzyloxycarbonyl-L-aspartic acid with the L-phenylalanine methyl ester through the action of the papain at a temperature of between 25° C. and 49° C to yield N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester; and
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].C([O:16][C:17](=[O:54])[CH2:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([C:36]3[CH:40]=[C:39]([C:41]([NH:43]C(OC(C)(C)C)=O)=[NH:42])[S:38][C:37]=3[S:51][CH3:52])(=[O:35])=[O:34])[CH:28]=2)=[C:22]([CH3:53])[CH:21]=1)(C)(C)C>>[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].[C:41]([C:39]1[S:38][C:37]([S:51][CH3:52])=[C:36]([S:33]([C:29]2[CH:28]=[C:27]([C:23]3[C:24]([CH3:26])=[CH:25][C:20]([O:19][CH2:18][C:17]([OH:54])=[O:16])=[CH:21][C:22]=3[CH3:53])[CH:32]=[CH:31][CH:30]=2)(=[O:35])=[O:34])[CH:40]=1)(=[NH:42])[NH2:43]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(OCC(=O)OC(C)(C)C)cc2C)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cc(OCC(=O)O)cc2C)c1
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of dichloromethane/trifluoroacetic acid (1/1) [2 mL] was added to {3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-2,6-dimethyl-biphenyl-4-yloxy}-acetic acid tert-butyl ester (0.020 g, 0.030 mmol) [example 215, step a] at room temperature and stirred for 1 hour. The reaction mixture was evaporated and purified via reverse-phase HPLC [acetonitrile/water (0.01% TFA)] to give the title compound (0.011 g, 75%) as a solid. 1H-NMR (MeOD): δ 8.36 (s, 1H), 8.01 (md, 1H, J=7.6 Hz), 7.81 (m, 1H), 7.72 (m, 1H), 7.51 (d, 1H, J=7.6 Hz), 7.26 (d, 1H, J=8.0 Hz), 6.74 (s, 2H), 4.67 (s, 2H), 2.73 (s, 3H), 1.96 (s, 6H). ESI-MS (m/z): Calcd. for C22H22N2O5S3: 490.07; found: 491.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][CH:10]=[N:9][CH:8]=1.[O:12]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28](O)=[O:29])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:12]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([C:10]2[O:11][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][N:9]=2)=[O:29])=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CCc1ccc(COc2ccccc2)cc1
Reactant: c1ccc(-c2cnco2)nc1
Product: O=C(CCc1ccc(COc2ccccc2)cc1)c1ncc(-c2ccccn2)o1
Yield: 32 %

Procedure:
The title compound (11e) was prepared from 5-(2-pyridyl)oxazole and 3-(4-(phenoxymethyl)phenyl)propanoic acid (S27) using General Procedure B. PTLC (SiO2, 50% EtOAc-hexanes) afforded 11e (40 mg, 0.10 mmol, 32%) as a pale yellow solid: 1H NMR (CDCl3, 400 MHz) 8.68-8.66 (m, 1H), 7.89 (s, 1H), 7.88-7.85 (m, 1H), 7.81 (td, 1H, J=7.9, 1.5 Hz), 7.38 (d, 2H, J=8.2 Hz), 7.34-7.27 (m, 5H), 6.99-6.94 (m, 3H), 5.03 (s, 2H), 3.48 (t, 2H, J=7.4 Hz), 3.13 (t, 2H, J=7.5 Hz); 13C NMR (CDCl3, 100 MHz) 187.2, 158.7, 157.1, 153.3, 150.1, 146.2, 140.1, 137.1, 137.0, 129.4, 128.6, 127.8, 126.9, 124.1, 120.8, 120.3, 114.7, 69.6, 40.5, 29.3; IR (film) νmax 2923, 1694, 1601, 1504, 1470, 1428, 1380, 1241, 1171, 1125, 1080, 1032, 1017, 989, 962, 911, 869, 815, 788, 760, 693 cm−1; ESI-TOF m/z 385.1550 (C24H20N2O3+H+ requires 385.1547).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]([N:16]3[C@@H:17]4[C@@H:22]([C:21]5[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=5[CH2:19][CH2:18]4)[CH2:13][CH2:14][CH2:15]3)=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2ncsc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2ncsc2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 24 %

Procedure:
The title compound is prepared from benzothiazole-6-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 24% of theory; LC (method 4): tR=1.97 min; Mass spectrum (ESI+): m/z=349 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:13]1([NH:16][CH:2]2[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCC(NC2CC2)CC1
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-oxocyclohexanecarboxylate (3.4 g) in dichloromethane (30 mL) was added cyclopropanamine (1.14 g) followed by sodium triacetoxyborohydride (4.24 g). The mixture was stirred overnight. The mixture was diluted with dichloromethane (300 mL) and washed with 2N NaOH, water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C@H:9]([C:16]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])[CH2:10][O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[CH:26]([C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([NH:38][O:39]C(OCC(C)C)C)=[O:37])=[CH:30][CH:29]=1)=O>ClCCCl>[C:12]([O:11][CH2:10][C@@H:9]([C:16]([O:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1)=[O:17])[NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH2:26][C:28]2[CH:29]=[CH:30][C:31](/[CH:34]=[CH:35]/[C:36]([NH:38][OH:39])=[O:37])=[CH:32][CH:33]=2)=[CH:25][CH:24]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)COC(C)ONC(=O)/C=C/c1ccc(C=O)cc1
Reactant: CC(C)(C)OC[C@H](NCc1ccc(CN)cc1)C(=O)OC1CCCC1
Solvent: ClCCCl
Product: CC(C)(C)OC[C@H](NCc1ccc(CNCc2ccc(/C=C/C(=O)NO)cc2)cc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 1.4 %

Procedure:
To a suspension of cyclopentyl N-[4-(aminomethyl)benzyl]-O-tert-butyl-L-serinate (prepared as described in Example 73—0.282 g, 0.67 mmol) and (2E)-3-(4-formylphenyl)-N-(1-isobutoxyethoxy)acrylamide (prepared as described in Example 12—0.230 g, 0.79 mmol) in DCE (25 mL) was added STAB (0.700 g, 3.3 mmol). The mixture was stirred at RT for 3 h, and then quenched with sat. NaHCO3 solution (75 mL). The product was then extracted with DCM (3×100 mL) and the combined organic extracts were dried (MgSO4), concentrated and purified by preparative HPLC to yield the desired product (5 mg, 2%). LCMS purity 98%, m/z=524.25 [M+H]+, 1H NMR (300 MHz, CD3OD) δ: 7.41 (2H, d, J=7.9 Hz), 7.24 (2H, d, J=7.7 Hz), 7.20 (3H, br s), 6.37 (1H, d, J=15.6 Hz), 5.09 (1H, t, J=5.7 Hz), 3.44-3.75 (8H, m), 3.25 (1H, t, J=3 Hz), 1.45-1.90 (8H, m), 1.04 (9H, s).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:44])([F:43])[C:31]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:32]=1[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[C:36]([C:39]([F:41])([F:42])[F:40])[CH:37]=[CH:38][C:31]=3[C:30]([F:29])([F:43])[F:44])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1ccc(C(F)(F)F)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,5-bistrifluoromethyl benzaldehyde. MS (ESI) m/z 605.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]2[C@@H:27]([C:28]([OH:30])=O)[CH2:26][O:25][CH2:24]2)=[O:22])=[CH:16][CH:15]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][C:39]2=[O:44])=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([N:23]2[C@@H:27]([C:28]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][C:39]4=[O:44])=[CH:36][CH:37]=3)=[O:30])[CH2:26][O:25][CH2:24]2)=[O:22])=[CH:18][CH:19]=1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C(O)[C@H]1COCN1C(=O)Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1COCN1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.1 1.49 ml (20.0 mmol) of 37% aqueous formaldehyde solution are added to a solution of 2.10 g (20.0 mmol) of D-serine in 10 ml of 1N aqueous sodium hydroxide solution. The resultant solution is left at 5° C. for 18 hours. The solution is heated to 80° C., 6.14 g (40 mmol) of 4-chlorophenyl isocyanate are added, and the mixture is stirred at this temperature for one hour. The mixture is allowed to cool, and the precipitate formed is filtered off. The filtrate is acidified using 1N HCl, and the precipitate formed is filtered off and dried, giving (R)-3-(4-chlorophenylcarbamoyl)oxazolidine-4-carboxylic acid as a colourless solid; ESI 271. 2.2 498 mg (2.60 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) are added to a solution of 541 mg (2.00 mmol) of (R)-3-(4-chlorophenylcarbamoyl)oxazolidine-4-carboxylic acid and 384 mg (2.00 mmol) of 4-(4-aminophenyl)morpholin-3-one in 4 ml of dimethylformamide (DMF), and the mixture is stirred at room temperature for 18 hours. The reaction mixture is added to saturated sodium hydrogencarbonate solution, and the precipitate formed is filtered off, giving 3-N-[(4-chlorophenyl)]-4-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(R)-oxazolidine-3,4-dicarboxamide (“A2”) as a colourless solid; ESI 461.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.B1([C:14]2[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=2)OCCCO1.C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1>[Br:7][C:5]1[CH:6]=[C:2]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[S:3][CH:4]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Brc1csc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1csc(-c2cccnc2)c1
Yield: 72.2 %

Procedure:
A mixture of 2,4-dibromothiophene (3 g, 12.4 mmol) and pyridine-3-boronic acid-1,3-propanediol cyclic ester (2.22 g, 13.6 mmol) in EtOH (30 ml) and toluene (30 ml) together with 2N Na2CO3 solution (12.4 ml) was degassed with a stream of N2 for 10 min. Tetrakis-(triphenylphosphine)palladium(0) (0.25 g, 0.22 mmol) was added and the reaction heated at reflux for 4 h. The mixture was concentrated under reduced pressure to remove the organic solvents and H2O (100 ml) was added. The organics were extracted with EtOAc (200 ml) and then washed with brine (75 ml), dried (MgSO4), and concentrated under vacuum. The resulting crude residue was purified by column chromatography on silica using 70% diethyl ether in hexane as the eluent to yield 3-(4-bromothien-2-yl)pyridine (2.15 g, 75%): δH (360 MHz, CDCl3) 7.26 (1H, s), 7.32 (1H, dd, J 8.6 and 4.9), 7.81 (1H, dt, J 8.6 and 1.7), 8.56 (1H, s), 8.86 (1H, s); m/z (ES+) 240, 242 (1:1) (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:27](O)=[O:28]>>[CH:27]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:28]
Reactant: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1cccc(N)c1
Reactant: O=CO
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1cccc(NC=O)c1

Procedure:
2,6 g of cis-6-(3-aminophenyl)-8,9-dimethoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridine are heated to 100° for 21/2 hours in 50 ml of 90% formic acid. The reaction solution is evaporated to dryness in a vacuum, the resulting residue is made alkaline with a dilute potash solution and this aqueous phase is extracted with methylene chloride. After drying and concentrating the organic phase by evaporation, the title compound is obtained as yellowish foam and crystallizes after the addition of acetone in the form of yellowish prisms having a melting point of 209°-210°.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH2:10][C:11]([OH:13])=[O:12])=[CH:8][N:7]=[C:6]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:5]=2)[CH2:3][CH2:2]1.[CH3:24]O>>[CH3:24][O:12][C:11](=[O:13])[CH2:10][C:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)=[N:7][CH:8]=1
Reactant: CO
Reactant: O=C(O)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Product: COC(=O)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1

Procedure:
In analogy to the procedure described in example 8 d], [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid was esterified with methanol to give the title compound as yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:6][CH:5]=1)=O.[C:19]([O-:22])(=[O:21])[CH3:20].[Na+].C(OC(=O)C)(=O)C>CCOC(C)=O>[C:19]([O:22][CH2:1][S:2][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:6][CH:5]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1nc(-c2ccc(S(C)=O)cc2)cs1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(-c2ccc(SCOC(C)=O)cc2)cs1
Temperature: 25 °C
Yield: 47 %

Procedure:
N-{4-[4-(Methylsulfinyl)phenyl]-1,3-thiazol-2-yl}acetamide (1.5 g), sodium acetate (1.54 g), and acetic anhydride (30 ml) were combined under N2 atmosphere. The reaction mixture was refluxed for 2 hours. After cooled to r.t., the mixture was diluted in AcOEt. The organic solution was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residual solid was washed with ethyl ether/n-hexane to give ({4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}thio)methyl acetate (811.2 mg) as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](Cl)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:20]1([CH2:26][N:27]2[CH2:32][CH:31]=[C:30]([C:33]3[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=3)[CH2:29][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(Cl)Cl.C(N(CC)CC)C>[C:20]1([CH2:26][N:27]2[CH2:28][CH:29]=[C:30]([C:33]3[CH:34]=[CH:35][C:36]([NH:39][C:15]([C:10]4[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=5)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[O:16])=[CH:37][CH:38]=3)[CH2:31][CH2:32]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 88.3 %

Procedure:
4′-(Trifluoromethyl)-[1,1′-biphenyl]-2-carbonyl chloride (0.12 mol) was added dropwise to a stirring mixture of 4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]benzenamine (0.095 mol) in DCM (300 ml) and triethylamine (50 ml). The mixture was stirred overnight, poured out into water and then stirred for 30 minutes. The organic layer Was separated, washed, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 43 g of N-[4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 20).