Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(O)C>[CH2:14]([O:5][C:4](=[O:6])[C:3]1[C:2]([OH:1])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1c(O)cccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(OCc1ccccc1)c1c(O)cccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,6-dihydroxybenzoic acid (500 mg, 3.24 mmol) in ethanol (8 mL) is added NaOH (130 mg, 3.24 mmol). After the mixture is stirred at RT for 3 h, the solvent is removed under reduced pressure. The resulting sodium salt is dissolved in DMF (10 mL) then benzyl bromide (0.39 mL, 3.24 mmol) is added and the mixture is stirred at RT for 18 h. Water is added and the mixture is extracted with EtOAc. The organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (10:1) as eluent to give the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([N:22]2[CH2:23][CH2:24][C:25]([F:29])([F:28])[CH2:26][CH2:27]2)[CH2:20][NH:21][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[CH3:1])=[CH:17][CH:18]=1
Reactant: NCC(c1ccc(Cl)cc1)N1CCC(F)(F)CC1
Reactant: Cc1cccc(C(=O)O)c1C
Product: Cc1cccc(C(=O)NCC(c2ccc(Cl)cc2)N2CCC(F)(F)CC2)c1C

Procedure:
From 2,3-dimethylbenzoic acid and 2-(4-chloro-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S([O-])(O)(=O)=O.[Na+].[CH3:15][C:16](=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O>[CH3:15][C:16]1[NH:7][C:1]2[C:6]([C:17]=1[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:5][CH:4]=[CH:3][CH:2]=2
Reactant: CCCCCC(C)=O
Reactant: NNc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCc1c(C)[nH]c2ccccc12
Temperature: 100 °C
Reaction time: 7 h
Yield: 62 %

Procedure:
27 g (0.25 mol) of phenylhydrazine were initially introduced at 90° C. in a solution of 1.12 mol of sodium hydrogen sulphate in 420 ml of water. 30 g (0.263 mol) of heptan-2-one were metered in in the course of 30 min. This mixture was stirred for 7 h at 100° C. After cooling, the batch was neutralised and the organic phase was separated off and distilled. 2-Methyl-3-butylindole was obtained in a yield of 62%.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C1N2CN3CN(C2)CN1C3.Cl.[OH2:23]>>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:3]([CH:2]=[O:23])[O:4][CH:5]=1
Reactant: FC(F)(F)c1coc(CBr)c1
Reactant: O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: O=Cc1cc(C(F)(F)F)co1
Temperature: -78 °C

Procedure:
A mixture of 2-bromomethyl-4-trifluoromethyl-furan (500 mg, 3.57 mmol), hexamethylenetetramine (HMTA) (637 mg, 4.54 mmol) and water (2.6 mL) were placed in a 50 mL pear-shaped flask equipped with a vigreaux column atop of which is attached to dry-ice condenser chilled at −78° C. The mixture was heated at reflux for 1 h, and then treated with concentrated HCl (1.7 mL). Reflux was maintained for an additional 1 h before the reaction was cooled to rt, diluted with water and extracted with DCM (4×50 mL). The combined organic extracts were washed with water, brine, dried (Na2SO4) and carefully concentrated to give 4-(trifluoromethyl)furan-2-carbaldehyde. 1H NMR (400 MHz, CDCl3) δ ppm 7.37 (m, 1H), 8.01 (m, 1H), 9.74 (d, J=0.54 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[NH:10][C:11]#[N:12].[NH:13]1[CH:17]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[N:14]1.Cl.O1CCOCC1>CCOCC>[CH2:21]([O:20][C:18]([C:16]1[CH:17]=[N:13][N:14]([C:11](=[NH:12])[NH:10][C:3]2[C:4]([Br:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Br:1])[CH:15]=1)=[O:19])[CH3:22]
Reactant: N#CNc1c(Br)cc(F)cc1Br
Reactant: CCOC(=O)c1cn[nH]c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)c1cnn(C(=N)Nc2c(Br)cc(F)cc2Br)c1
Temperature: 23 °C
Yield: 54.2 %

Procedure:
A mixture of 2,6-dibromo-4-fluoro-phenyl-cyanamide (0.167 g, 0.570 mmol), ethyl pyrazole-4-carboxylate (80.0 mg, 0.570 mmol), 4M HCl in dioxane (0.156 mL, 0.630 mmol), and 1,4 dioxane (2 mL) was heated to reflux for 2 h, during which time a precipitate formed. The mixture was allowed to cool to 23° C. Et2O (10 mL) was added to the mixture. The resulting precipitate was collected by filtration, washed with Et2O, and dried to yield the titled compound (0.134 g, 50%) as the HCl salt. MS (ESI/CI): mass calcd. for C13H11Br2FN4O2, 431.9; m/z found, 432.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.20 (s, 1H), 7.43 (s, 1H), 6.82 (d, J=7.9 Hz, 2H), 3.56 (q, J=7.1 Hz, 2H), 2.85 (s, 3H), 0.57 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Product: CC(=O)Oc1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 72 h
Yield: 87 %

Procedure:
A solution of 4-bromo-2-nitrophenol (297, 1.00 g, 4.59 mmol) (scheme 65) in acetic anhydride (10 mL) was heated in a pressure vessel at 130-140° C. for 16 h. Most of the solvent was evaporated in vacuo and the resulting oil was kept in the freezer for 3 days. Crystallization occurred while thawing. The white crystals were suspended in a mixture of EtOAc/hexanes (9:1) and collected by filtration affording the title compound 328 (1.03 g, 87% yield). 1H NMR: (400 MHz, DMSO-d6) δ (ppm): 8.33 (d, J=2.3 Hz, 1H), 8.02 (dd, J=8.6, 2.3 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 2.33 (s, 3H). LRMS: (m/z): 282.0/284.0 ((M+/M+2)+23).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:49]=[CH:48][C:40]([C:41]([NH:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:39][N:38]=1>>[C:44]([NH:43][C:41](=[O:42])[C:40]1[CH:48]=[CH:49][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[N:38][CH:39]=1)([CH3:47])([CH3:46])[CH3:45]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)(C)NC(=O)c1ccc(Br)nc1
Product: C[C@@H](c1ccc(-c2ccc(C(=O)NC(C)(C)C)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 6-bromo-N-tert-butylnicotinamide following procedures analogous to those described in Example 486 Step 4. LC-MS Method 2 tR=1.898 min, m/z=472.2; 1H NMR (CDCl3) 1.08 (s, 3H), 1.15 (s, 3H), 1.34 (s, 9H), 1.49 (d, 3H), 2.16 (m, 3H), 2.19 (m, 1H), 2.32 (m, 1H), 2.42 (m, 3H), 2.79 (m, 1H), 4.32 (m, 2H), 5.66 (m, 1H), 6.55 (s, 1H), 6.76 (s, 1H), 6.98 (m, 2H), 7.19-7.29 (m, 7H).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][CH:8]=1.[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH2:4][CH2:5][NH:6][S:2]4(=[O:1])=[O:18])=[CH:17][CH:16]=3)=[O:13])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CCOC(=O)c1ccc(N2CCNS2(=O)=O)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCNS4(=O)=O)cc3)CC2)c(C)c1
Yield: 72.9 %

Procedure:
Using ethyl 4-(1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)benzoate (198 mg) described in Preparation Example 46 and 1-(3,5-dimethylpyridin-2-yl)piperazine (141 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (222 mg) was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[C@@H:3]([C@H:5]1[CH2:10][O:9][C@@H:8]([O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C@H:7]([CH3:17])[NH:6]1)[OH:4].[C:27](OC(=O)C)(=[O:29])[CH3:28].[ClH:34]>C(OCC)C.C1C=CC=CC=1>[ClH:34].[F:26][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([F:25])[CH:22]=1)[CH2:18][C@H:2]([NH:1][C:27](=[O:29])[CH3:28])[C@@H:3]([C@H:5]1[CH2:10][O:9][C@@H:8]([O:11][CH2:12][C:13]([CH3:15])([CH3:16])[CH3:14])[C@H:7]([CH3:17])[NH:6]1)[OH:4]
Reactant: C[C@@H]1N[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO[C@H]1OCC(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1
Reaction time: 1 h
Yield: 45 %

Procedure:
Dissolve (1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-[(3R,5S,6R)-6-(2,2-dimethylpropoxy)-5-methylmorpholin-3-yl]-propan-1-ol (70 mg, 0.188 mmol) in dry dichloromnethane (1.8 mL) under nitrogen. Add dropwise acetic anhydride (22 μL, 0.233 mmol) and stir for 1 hour. Add 1 M hydrogen chloride in diethyl ether (1 mL) and dilute with benzene. Concentrate and purify (HPLC, eluting with 30% to 70% acetonitrile with 0.1% hydrochloric acid in water) to give the title compound as a white solid (38 mg, 45%)
Reaction SMILES: [I:1]I.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:27][O:28][C:29]1[N:34]=[C:33]([CH2:35]O)[CH:32]=[CH:31][CH:30]=1>ClCCl>[I:1][CH2:35][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([O:28][CH3:27])[N:34]=1
Reactant: II
Reactant: COc1cccc(CO)n1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(CI)n1
Reaction time: 0.33 h

Procedure:
To a 0° C. solution of iodine (1.094 g, 4.31 mmol) and imidazole (0.294 g, 4.31 mmol) in dichloromethane (10.27 ml) was added portionwise triphenylphosphine (1.131 g, 4.31 mmol). After 20 min of stirring, (6-methoxypyridin-2-yl)methanol (Adesis, New Castle, Del., 0.5 g, 3.59 mmol) was added to the solution. The reaction was allowed to stir for 1 h at 0° C., quenched with water (50 mL) and extracted with Et2O. The combined organics were dried over MgSO4, and concentrated in vacuo. Silica gel chromatography (gradient elution 1 to 5% Et2O in pentane) afforded 2-(iodomethyl)-6-methoxypyridine. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.49 (dd, J=7.3, 8.3 Hz, 1H), 6.96 (d, J=7.1 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 4.44 (s, 2H), 3.94 (s, 3H). Mass Spectrum (ESI) m/z=249.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:28]([F:31])([F:30])[F:29])[C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH2:32][CH2:33][CH3:34])[N:12]=1.CN(C=O)C.C(Cl)(C([Cl:44])=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:44])=[O:7])=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:28]([F:29])([F:30])[F:31])[C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH2:32][CH2:33][CH3:34])[N:12]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)O)ccc2Cl)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)Cl)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution was prepared using 4-chloro-3-(3-{[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}-1,2,4-oxadiazol-5-yl)benzoic acid (0.100 g, 0.204 mmol), DMF (0.100 mL), (COCl)2 (2.0 mL, 21.0 mmol) and anhydrous CH2Cl2 (25 mL). The mixture was stirred at rt and for a period of 16 h and concentrated to dryness. The resulting product was used without purification (0.113 g).
Reaction SMILES: C(OC([N:8]([CH2:20][CH:21]1[O:25][N:24]=[C:23]([Br:26])[CH2:22]1)[C:9](=[O:19])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:11])=O)(C)(C)C.[C:27]([C:31]([OH:33])=[O:32])([F:30])([F:29])[F:28].C(Cl)Cl>>[F:28][C:27]([F:30])([F:29])[C:31]([OH:33])=[O:32].[NH2:11][C@H:10]([C:9]([NH:8][CH2:20][CH:21]1[O:25][N:24]=[C:23]([Br:26])[CH2:22]1)=[O:19])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N(CC1CC(Br)=NO1)C(=O)[C@@H](N)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C(=O)NCC1CC(Br)=NO1

Procedure:
5-(N-tert-butoxycarbonyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole, 7 gm, was taken in 100 ml of 20% CF3CO2H/CH2Cl2 at 0° C. for 24 hrs. Concentration gave an oily foamy substance. 1H NMR [80 MHz, CDCl3 (H2O)]; delta 2.8-3.5 (m, 4H, CH2), 4.2-4.9 (m, 2H, CH), 4.7 (s, HOD), 7.3 ppm (s, 5H, pH).
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=O)[O:26]C4C=CC=CC=4)=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH:38][C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:6]2[N:7]=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])[C:9]3[CH2:10][N:2]([CH3:1])[CH2:3][C:4]=3[N:5]=2)=[CH:19][CH:20]=1)=[O:26]
Reactant: CN(C)CCN
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc2c1CN(C)C2
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCN(C)C)cc2)nc2c1CN(C)C2

Procedure:
Method as described for example 51 using intermediate 10 and N1,N1-dimethylethane-1,2-diamine as starting materials. Purified by prep. LCMS (high pH).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:40][CH3:41])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[O:21][C:20]2=[O:39])[CH:7]=1.N#N.[CH3:44][S:45]SC.N(OC(C)(C)C)=O>C(Cl)(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:27]1[CH:26]=[C:25]([C@H:22]2[O:21][C:20](=[O:39])[N:19]([CH2:18][C:9]3[CH:10]=[C:11]([C:14]([F:15])([F:17])[F:16])[CH:12]=[CH:13][C:8]=3[C:6]3[CH:7]=[C:2]([S:45][CH3:44])[CH:3]=[CH:4][C:5]=3[O:40][CH3:41])[C@H:23]2[CH3:24])[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=1
Reactant: CSSC
Reactant: COc1ccc(N)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: CC(C)(C)ON=O
Agent: N#N
Solvent: ClC(Cl)Cl
Product: COc1ccc(SC)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4S,5R)-3-{[5′-amino-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (Example 123) (40 mg, 0.0676 mmol) in CHCl3 (1 mL) that had been degassed with N2 was added methyl disulfide (10 μL, 0.101 mmol) and t-butyl nitrite (16 μL, 0.135 mmol). The reaction was stirred at room temperature for 30 minutes and then heated to reflux for 2 hours. The reaction was then cooled to room temperature and diluted with hexanes (3 mL). The solution was loaded directly onto a silica gel column and eluted with 25% EtOAc/hexanes. Fractions containing the desired product were combined and repurified by silica gel chromatography with 5 to 25% EtOAc/hexanes to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylthio)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.52 (40% EtOAc/hexanes). LCMS=624.1 (M+1)+. 1H NMR (CDCl3, 600 MHz, rotamers present) δ 6.94-7.85 (m, 9H), 5.58 (d, J=8.1 Hz) 5.25 (d, J=7.8 Hz), 4.94 (d, J=15.8 Hz), 4.85 (d, J=15.7 Hz), 3.65-4.12 (m, 5H), 2.47 (s), 2.44 (s), 0.54 (d, J=6.6 Hz), 0.40 (d, J=6.6 Hz).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=2)[CH2:4]1.[OH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[C:38]([O:40][CH3:41])=[O:39])[C:32](O)=[O:33].CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([NH:17][C:10]2[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=[C:8]([N:5]3[CH2:6][CH2:7][CH:3]([NH:2][C:32]([C:31]4[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[C:29]([OH:28])[CH:30]=4)=[O:33])[CH2:4]3)[N:9]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)cc1OC
Reactant: COC(=O)c1ccc(C(=O)O)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
A mixture of 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride (164 mg, 0.4 mmol), 3-hydroxy-4-(methoxycarbonyl)benzoic acid (78 mg, 0.4 mmol), EDCI (153 mg, 0.8 mmol) and N-methylimidazole (100 mg, 1.2 mmol) in 5 mL of DCM was stirred at room temperature for 16 hours. The mixture was washed with water (4 mL), The organic layer was dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography (silica gel, 100% DCM to DCM:MeOH=50:1) to give methyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)-2-hydroxybenzoate (100 mg, yield 45%). LC-MS: 551 [M+H]+, tR=1.61 min.
Reaction SMILES: [ClH:1].[NH2:2]N.C[N:5](/[CH:7]=[C:8]1/[CH:9]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=2[CH3:25])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]/1=O)C>C(O)C.C(O)(=O)C>[ClH:1].[CH3:15][C:12]1([CH3:16])[C:13]2[C:8](=[CH:7][NH:5][N:2]=2)[CH:9]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=2[CH3:25])[CH2:10][CH2:11]1
Reactant: Cc1cc(C#N)ccc1C1CCC(C)(C)C(=O)/C1=C\N(C)C
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C#N)ccc1C1CCC(C)(C)c2n[nH]cc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Hydrazine hydrochloride (0.14 g, 2 mmol) is added to 4-[(2Z)-2-(dimethylaminomethylene)-4,4-dimethyl-3-oxo-cyclohexyl]-3-methyl-benzonitrile (0.2 g, 0.67 mmol) in ethanol (30 mL), then acetic acid (two drops) is added to the mixture. After the addition is complete, the reaction mixture is stirred at 80° C. for 3 h. The mixture is cooled to room temperature and concentrated in vacuo. The residue is diluted with ethyl acetate (50 mL) and saturated sodium bicarbonate solution (50 mL). The organic phase is separated and the aqueous phase extracted with ethyl acetate (3×50 mL). The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (eluted with pet ether:EtOAc=2:1 to 1:1) to give the title compound. The product is added to HCl/ethyl acetate and concentrated in vacuo to give the HCl salt of the title compound (0.12 g, 67%). ES/MS 266 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]2[CH:25]=[CH:24][C:12]([C:13]([NH:15][C@H:16]([C:21]([OH:23])=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])=[C:11]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:10]=2)[CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:44](O)[CH2:45][CH:46]([CH3:48])[CH3:47].[O-]CC.[Na+]>C1COCC1>[CH2:44]([O:22][C:21](=[O:23])[C@H:16]([CH2:17][CH2:18][S:19][CH3:20])[NH:15][C:13](=[O:14])[C:12]1[CH:24]=[CH:25][C:9]([NH:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:10][C:11]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:45][CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)CCO
Reactant: CSCC[C@H](NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1)C(=O)O
Agent: CC[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1)C(=O)OCCC(C)C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
[4-(3-pyridylmethylamino)-2-phenylbenzoyl]methionine (200 mg, 0.46 mmol), prepared as in Example 192, carbonyldiimidazole (74 mg, 0.46 mmol), and isoamyl alcohol (40 mg, 0.46 mmol) were combined in 10 mL THF. After 2 hours at room temperature, sodium ethoxide (2.68 M in ethanol, 0.02 mmol) was added. After an additional 18 hours, the mixture was evaporated to dryness, partitioned between ethyl acetate and water, washed with water and brine, dried over Na2SO4, and chromatographed (Ethyl acetate) to give [4-(3-pyridylmethylamino)-2-phenylbenzoyl-L-methionine isoamyl ester (90 mg). MS m/e 506 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 0.90 (d, J=7 Hz, 6H), 1.48 (m, 2H), 1.64 (m, 4H), 1.88 (m, 1H), 2.01 (s, 3H), 2.11 (t, J=7 Hz, 2H), 4.08 (m, 2H), 4.42 (s, 2H), 4.60 (m, 1H), 5.87 (d, J=8 Hz, 1H), 6.51 (d, J=3 Hz, 1H), 6.63 (m, 1H), 7.28-7.44 (m, 5H), 7.68 (m, 2H), 8.55 (m, 1H), 8.63 (s, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[OH:18])[CH:14]([C:19]([OH:21])=[O:20])[CH2:13][CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:27](O)[CH3:28]>>[CH2:27]([O:20][C:19]([CH:14]1[C:15]2[C:11](=[CH:10][C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:17]([OH:18])[CH:16]=2)[CH2:12][CH2:13]1)=[O:21])[CH3:28]
Reactant: O=C(c1ccccc1)c1cc2c(cc1O)C(C(=O)O)CC2
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCc2cc(C(=O)c3ccccc3)c(O)cc21

Procedure:
Analogously to Example 3, 12 g of 5-benzoyl-6-hydroxyindane-1-carboxylic acid and ethanol containing sulphuric acid give 5-benzoyl-6-hydroxy-indane-1-carboxylic acid ethyl ester in the form of yellow platelets of melting point 83°-4° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:32])=[C:6]([NH:10][C:11]([C:13]2[C:14]([Cl:31])=[CH:15][C:16]3[O:20][CH:19]([CH2:21][CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18][C:17]=3[CH:30]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:33](OCC)(=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[Cl:31][C:14]1[C:13]([C:11]([NH:10][C:6]2[C:5]3[O:32][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:2][C:1](=[O:3])[C:4]=3[CH:9]=[CH:8][CH:7]=2)=[O:12])=[CH:30][C:17]2[CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:20][C:16]=2[CH:15]=1
Reactant: CC(=O)c1cccc(NC(=O)c2cc3c(cc2Cl)OC(CCCc2ccccc2)C3)c1O
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1cc(=O)c2cccc(NC(=O)c3cc4c(cc3Cl)OC(CCCc3ccccc3)C4)c2o1
Yield: 75 %

Procedure:
Following the process described in example 1 (point A), starting from N-(3-acetyl-2-hydroxyphenyl)-6-chloro-2-(3-phenylpropyl)-2,3-dihydrobenzofuran-5-carboxamide and diethyl oxalate, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with petroleum ether:chloroform, 4:6 (75% yield).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O>>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1ccccc1F
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Fc1ccccc1CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-fluorobenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-fluorophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.