Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=2[O:40][CH3:41])[N:15]=1.Cl.[CH2:43]([O:45][P:46]([CH2:51][N:52]1[C:61]2[C:56](=[C:57]([NH2:62])[CH:58]=[CH:59][CH:60]=2)[C:55](=[O:63])[C:54]([CH3:64])=[CH:53]1)(=[O:50])[O:47][CH2:48][CH3:49])[CH3:44]>>[CH2:43]([O:45][P:46]([CH2:51][N:52]1[C:61]2[C:56](=[C:57]([NH:62][C:14]3[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][N:17]=[C:16]([NH:24][C:25]4[CH:39]=[CH:38][C:28]([CH2:29][P:30]([O:31][CH2:32][CH3:33])([O:34][CH2:35][CH3:36])=[O:37])=[CH:27][C:26]=4[O:40][CH3:41])[N:15]=3)[CH:58]=[CH:59][CH:60]=2)[C:55](=[O:63])[C:54]([CH3:64])=[CH:53]1)(=[O:50])[O:47][CH2:48][CH3:49])[CH3:44]
Reactant: CCOP(=O)(Cn1cc(C)c(=O)c2c(N)cccc21)OCC
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: CNC(=O)c1cc(F)ccc1N
Agent: Cl
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3c(=O)c(C)cn4CP(=O)(OCC)OCC)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to Compound 102A using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (45.4 mg, 0.100 mmol) and diethyl[(5-amino-3-methyl-4-oxoquinolin-1(4H)-yl)methyl]phosphonate hydrochloride (Compound 303A, 39.7 mg, 0.110 mmol). 1H NMR (CD3OD, 400 MHz): δ=1.24 (t, J=7.2 Hz, 6H), 1.28 (t, J=7.2 Hz, 6H), 2.12 (s, 3H), 3.28 (d, J=21.2 Hz, 2H), 3.91 (s, 3H), 4.06-4.11 (m, 8H), 4.86 (s, 2H), 6.91 (d, J=8.4 Hz, 1H), 7.04 (m, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.62 (m, 1H), 7.92 (s, 1H), 7.96 (dd, J=2.4, 8.4 Hz, 1H), 8.37 (s, 1H), 8.67 (d, J=8.0 Hz, 1H). MS (ES+): m/z 742.18 [MH+]. HPLC: tR=1.44 min (UPLC TOF, polar—3 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:26]([O:25][C:23]([N:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14])[CH2:9][CH2:10]1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
To a solution of 4.94 g piperidin-4-yl-carbamic acid tert-butyl ester, 300 mg DMAP and 5.2 ml triethylamine in 50 ml dichloromethane were added 6.3 ml benzyl chloroformate dropwise at 0° C. After 8 h the suspension was diluted with dichloromethane and washed with half-saturated NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was suspended in heptane, the supernatant solution being decanted yielding the product as colorless solid. Yield: 7.9 g.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:49])[C@@H:15]([O:47][CH3:48])[C@H:16](O)[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([O:27][CH2:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)[O:33][C:34]=2[CH3:35])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:49])[C@@H:15]([O:47][CH3:48])[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([O:27][CH2:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:37]=[CH:38][C:39]([C:42]([F:43])([F:44])[F:45])=[CH:40][CH:41]=3)[O:33][C:34]=2[CH3:35])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c2ccccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c2ccccc12)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 16 h

Procedure:
0.837 g of the above prepared (S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methoxy-3-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-propionyl]-oxazolidin-2-one (1.23 mmol) was dissolved in 3.2 ml of trifluoroacetic acid, treated at 0° with 0.977 ml of triethylsilane (5 eq.) and then kept for 16 h at ambient temperature, when TLC indicated the disappearance of starting material. The reaction mixture was then poured onto crashed ice/AcOEt/NaHCO3, the organic layer washed with water and brine (pH of aq. phase˜8), dried over magnesium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=7/3) delivered 0.702 g of the title compound as white foam.
Reaction SMILES: Cl.Cl.Cl.Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[NH2:13])=[CH:7][CH:6]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[CH:37]=[C:36]([C:38](O)=[O:39])[S:35][C:34]=2[CH:41]=1>>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[CH:37]=[C:36]([C:38]([NH:13][C@@H:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH2:11][C:8]3[CH:7]=[CH:6][N:5]=[CH:10][CH:9]=3)=[O:39])[S:35][C:34]=2[CH:41]=1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)Cc3ccncc3)CC2)CC1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](Cc3ccncc3)NC(=O)c3cc4ccc(Cl)cc4s3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-[β-(4-pyridinyl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperazine tetrahydrochloride and 6-chlorobenzo[b]thiophene-2-carboxylic acid (49%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][CH2:34]Br>CN(C=O)C>[NH:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N:16]=[C:15]1[NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][N:1]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:6][CH2:7]1
Reactant: NCCCN1CCN(CCCNc2nc3ccccc3[nH]2)CC1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]c(NCCCN3CCN(CCCN4CCCC4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
[3-[4-(3-Amino-propyl)-piperazin-1-yl]-propyl]-(1H-benzimidazol-2-yl)-amine (intermediate) (65 mg, 0.021 mmol) was dissolved in anhydrous DMF (20 mL) in the presence of potassium carbonate (142 mg, 1.0 mmol). 1,4-dibromobutane (0.03 mL, 0.25 mmol) was added. The resulting mixture was stirred for 48 h at room temperature. The
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH:5]=[CH:4][C:3]=1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: CC(O)(c1ccc(S(=O)(=O)c2ccc(F)cc2Cl)cc1)C(F)(F)F
Reactant: c1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(O)(c1ccc(S(=O)(=O)c2ccc(-n3ccnc3)cc2Cl)cc1)C(F)(F)F
Reaction time: 12 h
Yield: 100 %

Procedure:
50 mg 2-[4-(2-Chloro-4-fluoro-benzenesulfonyl)phenyl]-1,1,1-trifluoropropan-2-ol (0.13 mmol) was combined in a pressure tube with 50 mg imidazole. The resulting mixture was then placed into a preheated 100° C. bath. After stirring for 12 h, the mixture was diluted with CH2Cl2 and sat. NaHCO3, then extracted (3×10% MeOH/CH2Cl2). The organics were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 3-5% MeOH/CH2Cl2) gave 60 mg of the product as a white solid (0.13 mmol, quant.). 1H NMR (DMSO-d6, 400 MHz) δ 8.49 (s, 1H), 8.39 (d, J=8.7 Hz, 1H), 8.1 (d, J=2.2 Hz, 1H), 8.02 (dd, J=2.2 Hz, 8.7 Hz, 1H), 7.99 (d, J=8.7 Hz, 2H), 7.94 (s, 1H), 7.86 (d, J=8.6 Hz, 2H), 7.16 (s, 1H), 6.91 (s, 1H), 1.71 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[I:22]N1C(=O)CCC1=O>CN(C=O)C>[OH:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([I:22])[CH:9]=2)[N:4]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=C(OCc1ccccc1)N1c2ccccc2CC1CO
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1c2ccc(I)cc2CC1CO
Temperature: 60 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution containing benzyl 2-(hydroxymethyl)-1-indolinecarboxylate (Preparation 6, 1.78 g), N-iodosuccinimide (2.83 g), and anhydrous DMF (12 mL) is stirred overnight at 60° C. in a foil-covered flask. This solution is cooled and concentrated to half volume with a stream of nitrogen. The resulting brown solution is partitioned between water (50 mL) and CH2Cl2 (150 mL). The organic phase is washed with brine, dried (Na2SO4), filtered, and concentrated to give a brown oil. The crude product is chromatographed eluting with 0-40% EtOAc in heptane (300 mL each 10%) to give 2.03 g (79%) of the title compound as a peach solid. Physical characteristics: M.p. 110-111° C.; HRMS (FAB) m/z 410.0270 (C17H16INO3+H). Anal. Found: C, 49.83; H, 3.95; N, 3.37.
Reaction SMILES: Cl.[OH:2][C@@H:3]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:8]([O:9][C@@H:10]2[O:18][C@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]2[OH:12])[C@H:6]([OH:7])[C@H:4]1[OH:5].P([O-])([O-])([O-])=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[OH:2][CH:3]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:8]([O:9][C@@H:10]2[O:18][C@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]2[OH:12])[C@H:6]([OH:7])[C@H:4]1[OH:5]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
A solution of 0.2 mg of bovine pancreatic insulin (Wako Pure Chemical Industries, Itd.) in 1 mL of a 2 mmol/L aqueous solution of hydrochloric acid, a solution of 320 mg of anhydrous β-lactose (Nacalai Tesque, Inc.) in 2 mL of distilled water, and 1 mL of a 200 mmol/L phosphate buffer (pH 8.4) were mixed in a test tube. The mixture was subjected to reaction at 40° C. for 24 hours. To 3 mL of the resulting solution was added 0.5 mL of a 150 mmol/L aqueous solution of citric acid to adjust the pH to 5.0, and the mixture was subjected to reaction at 40° C. The reaction mixture was intermittently sampled and analyzed for products obtained by the reaction of insulin with lactose by HPLC in a manner similar to that in Example 1. The results are shown in Table 5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.N1C=CC=CC=1.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Cu+2].C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:38]3[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(N(CC)CC)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(N(CC)CC)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-(4-diethylaminophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (200 mg, 0.46 mmol, see step (b) above), Cu(OAc)2 (83 mg, 0.46 mmol), 4-trifluoromethylbenzeneboronic acid (129 mg, 0.68 mmol), pyridine (55 μL, 0.68 mmol), Et3N (94 μL, 0.68 mmol), molecular sieves 4 Å and anhydrous CH2Cl2 (10 mL) was stirred at rt for 2 d, filtered, concentrated and purified by chromatography to give the sub-title compound. Yield 150 mg, 56%.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].CN(C)C1C=CC=CC=1.Cl[C:22]([O:24][CH3:25])=[O:23]>O1CCCC1>[CH3:25][O:24][C:22]([O:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:11])=[O:10])=[O:23]
Reactant: COC(=O)Cl
Reactant: O=C(O)C(O)c1ccccc1
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)OC(C(=O)O)c1ccccc1
Reaction time: 0.5 h

Procedure:
60 gms. (0.4 moles) of DL-mandelic acid are dissolved in 50 ml. of tetrahydrofuran. 50 gms. (0.4 moles) of dimethylaniline are added and the mixture is cooled to -20°. 45 gms. (0.5 moles) of methyl chloroformate are added with vigorous stirring. After 30 minutes, the reaction mixture is poured into 500 ml. of ice-water and extracted with ethyl acetate. The organic phase is washed with 100 ml. of 2N HCl solution and concentrated after drying over sodium sulfate. A light oil is obtained which crystallizes on standing overnight. The product, DL-α-[(methoxycarbonyl)oxy]-phenylacetic acid is recrystallized from cyclohexane to obtain white crystals, m.p. 103°-105°.
Reaction SMILES: [F:1][C:2]1([F:15])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][CH2:13]O)=[CH:10][C:4]=2[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O>C(Cl)Cl>[Br:35][CH2:13][CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([F:15])([F:1])[O:3][C:4]=2[CH:10]=1
Reactant: OCCCc1ccc2c(c1)OC(F)(F)O2
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC1(F)Oc2ccc(CCCBr)cc2O1
Yield: 89.7 %

Procedure:
Compound 87-2 (3.54 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (4.73 g) and N-bromosuccinimide (3.21 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2.5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (4.10 g) as a colorless oil.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([NH:10][C:11](=[O:32])[NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]=4)=[CH:15][CH:14]=3)[CH:7]=[CH:6][C:5]=12.FC(F)(F)C(O)=O>ClCCl>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([NH:10][C:11]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH:20]=4)=[CH:17][CH:18]=3)=[O:32])[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(NC(=O)Nc3ccc4nccn4c3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C2=CCNCC2)cc1)Nc1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 4-(4-(3-imidazo[1,2-a]pyridin-6-ylureido)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.57 g, 1.315 mmol) in dichloromethane (5 ml) was treated with trifluoroacetic acid (0.608 ml, 7.88 mmol) and the reaction mixture was stirred at room temperature for 4 hours. Concentration provided the title compound.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[C:6]([C:11]3[O:15][C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])=[N:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.C(NCC)(C)C.[CH2:38]([CH2:40][NH2:41])[OH:39]>C(Cl)Cl>[OH:39][CH2:38][CH2:40][NH:41][CH:2]1[C:10]2[C:5](=[C:6]([C:11]3[O:15][C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])=[N:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CCC4O)o2)cc1C#N
Reactant: NCCO
Agent: CCNC(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CCC4NCCO)o2)cc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
Prepared using General Procedure 14. To a stirring solution of 5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxazol-2-yl)-2-isopropoxybenzonitrile 56 (50 mg, 0.1 mmol) in DCM (3 mL) was added thionyl chloride (25 mg, 0.21 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated and the crude chloride re-dissolved in dimethyl acetamide (3 mL). Isopropyl ethylamine (40.8 mg, 0.316 mmol) and ethanolamine (19.3 mg, 0.31 mmol) were added and the reaction mixture heated at 70° C. overnight. The reaction mixture was quenched with NaHCO3 and extracted with EA. The combined organic extracts were washed with brine and then dried over MgSO4. The product was purified by chromatography (10% MeOH/DCM) to afford 25 mg (60%) of 5-(5-(1-(2-hydroxyethylamino)-2,3-dihydro-1H-inden-4-yl)oxazol-2-yl)-2-isopropoxybenzonitrile 57. LCMS-ESI (m/z) calculated for C24H25N3O3: 403.5; found 404.1 [M+H]+, tR=2.41 min. 1H NMR (400 MHz, DMSO) δ 8.18 (t, J=2.3 Hz, 1H), 8.08 (dd, J=9.0, 2.3 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.44 (d, J=17.4 Hz, 1H), 7.42-7.32 (m, 1H), 7.30-7.11 (m, 2H), 4.70 (dt, J=12.2, 6.1 Hz, 2H), 4.39 (s, 1H), 3.40 (t, J=5.0 Hz, 2H), 3.18-2.95 (m, 2H), 2.93-2.75 (m, 1H), 2.73-2.54 (m, 2H), 2.38-2.16 (m, 1H), 1.98-1.78 (m, 1H), 1.15 (d, J=6.0 Hz, 61-1). 13C NMR (101 MHz, CDCl3) δ 161.35, 159.17, 151.04, 146.60, 139.78, 132.16, 127.43, 125.59, 125.07, 123.99, 120.49, 116.10, 113.90, 103.77, 72.60, 62.95, 61.51, 48.70, 33.27, 31.29, 29.91, 22.02.
Reaction SMILES: [OH-].[Li+].[CH:3]1([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([N:16]3[C:20]([C:21]([F:24])([F:23])[F:22])=[N:19][N:18]=[C:17]3[S:25][C:26]([CH3:33])([CH3:32])[C:27]([O:29]CC)=[O:28])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1>C1COCC1>[CH:3]1([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([N:16]3[C:20]([C:21]([F:22])([F:24])[F:23])=[N:19][N:18]=[C:17]3[S:25][C:26]([CH3:33])([CH3:32])[C:27]([OH:29])=[O:28])=[CH:8][CH:7]=2)[CH2:4][CH2:5]1
Reactant: CCOC(=O)C(C)(C)Sc1nnc(C(F)(F)F)n1-c1ccc(C2CC2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(Sc1nnc(C(F)(F)F)n1-c1ccc(C2CC2)c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
Lithium hydroxide solution (1M aqueous, 0.67 mL, 0.67 mmol) was added to a solution of ethyl 2-(4-(4-cyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate (0.1 g, 0.22 mmol) in THF (0.88 mL) and the mixture stirred at room temperature for 18 h. The crude reaction mixture was concentrated; water (100 mL) added and then washed with ethyl acetate (2×40 mL). The aqueous layer was acidified with HCl (1N aqueous, 10 mL) and extracted with ethyl acetate (30 mL). The combined organic extracts were dried over sodium sulfate and concentrated to afford 2-(4-(4-cyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoic acid as an off-white solid (49 mg, 53%).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])/[CH:9]=[C:10](\[CH3:14])/[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C(N(CC)CC)C.[H][H]>C(OC(C)C)(=O)C.[Pd]>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C/C(=C\[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: [Pd]
Solvent: CC(=O)OC(C)C
Solvent: CCN(CC)CC
Product: C[C@@H](C[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
To a suspension of (E)-(S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid 3(ii-b) (10 g, 26.2 mmol) and triethylamine (3.6 ml, 26.2 mmol) in isopropyl acetate is added palladium on carbon (1 g, 10% loading). Hydrogen atmosphere is then applied for 5 h. Upon filtering off the catalyst, the solvent is removed in vacuo to give the title compound {3(i-d): 3(i-c) 80:20 ratio; 3(i-d): 3(i-c) 99.9:0.1 ratio upon recrystallization; as determined by HPLC analysis}.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[C:16]1([C:22]2[N:23]=[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:23]=[C:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(-c2csc(C3CCNCC3)n2)cc1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCC(c2nc(-c3ccccc3)cs2)CC1
Yield: 33.1 %

Procedure:
A solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (187 mg, 0.696 mmol), 4-(4-phenyl-1,3-thiazol-2-yl)piperidine (170 mg, 0.696 mmol), diisopropylethylamine (0.121 ml, 0.696 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain the desired product (84.0 mg, 33.1%) as a solid.
Reaction SMILES: C[C:2]([S:7]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)(=[O:9])=[O:8])([CH3:6])[C:3]([OH:5])=O.O=S(Cl)Cl.[NH2:20][C:21]1[O:25][N:24]=[C:23]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])[CH:22]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.N1C=CC=CC=1.O>[C:27]([C:26]([CH3:30])([CH3:29])[C:23]1[CH:22]=[C:21]([NH:20][C:3](=[O:5])[CH:2]([S:7]([CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)(=[O:8])=[O:9])[CH3:6])[O:25][N:24]=1)#[N:28]
Reactant: CC(C)(C#N)c1cc(N)on1
Reactant: CC(C)(C(=O)O)S(=O)(=O)C1CCOCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CC(C(=O)Nc1cc(C(C)(C)C#N)no1)S(=O)(=O)C1CCOCC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To 3.43 g (14.6 mmol) 2-Methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid (intermediate 1) in 38 mL toluene and 17 μL pyridine at 90° C. is added 2.60 g (21.8 mmol) SOCl2 dropwise within 20 min and stirring is continued for 2 h at 90° C. The solvent is evaporated under reduced pressure and the residue is coevaporated twice with toluene (16 mL each) to afford the crude acid cloride. To 2.00 g 2-(5-Amino-isoxazol-3-yl)-2-methyl-propionitrile (13.2 mmol, intermediate 7) in 14 mL toluene is added 3.80 mL (21.8 mmol) DIPEA. To this mixture at 60° C. is added dropwise a mixture of the acid chloride in 16 mL toluene within 10 min and stirring is continued overnight at 50° C. After addition of water (24 mL) the mixture is heated to 70° C. for 2 h and then allowed to cool to RT. The precipitate is filtered, washed with water (2×8 mL) and dried at 50° C. to afford 3.43 g of N-[3-(Cyano-dimethyl-methyl)-isoxazol-5-yl]-2-(tetrahydro-pyran-4-sulfonyl)-propionamide.