Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[CH2:11][C:10]=2[CH:26]=1.C(=O)(O)[O-].[Na+].Br[C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1>C(O)C>[N:34]1[CH:35]=[CH:36][CH:37]=[N:38][C:33]=1[NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[CH2:11][C:10]=2[CH:26]=1
Reactant: Brc1ncccn1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCN)cc2Cc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1Cc2ccc(OCCCNc3ncccn3)cc2Cc2ccccc21
Yield: 39.4 %

Procedure:
A mixture of ethyl (±)-10,11-dihydro-3-(3-amino-1-propyloxy)-5H-dibenzo[a,d]cycloheptene-10-acetate (0.4 g, 1 mmole), sodium bicarbonate (0.5 g, 6 mmole), 2-bromopyrimidine (0.34 g, 2 mmole) and ethanol (10 mL) was heated at reflux under argon for 18 hr. The solution was then decanted and concentrated. The residue was purified by chromatography on silica gel (0.2-2% MeOH/CH2Cl2) to give the title compound (0.17 g, 34%) as a pale yellow oil: MS (ES) 432.3 (M+H)+.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.C(N(CC)CC)C.[CH3:20][NH:21][CH2:22][CH2:23][CH:24]1[O:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=2)=[O:31])[CH2:25]1>CCO>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[N:21]([CH3:20])[CH2:22][CH2:23][CH:24]1[O:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=2)=[O:31])[CH2:25]1)[CH3:10]
Reactant: CNCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1c(N(C)CCC2CN(C(=O)OCc3cc(Cl)cc(Cl)c3)CCO2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture comprising of 3,4-diethoxycyclobut-3-ene-1,2-dione (29.0 μl, 0.196 mmol) and triethylamine (1093 μl, 7.84 mmol) in EtOH (654 μl) was stirred at 40° C. for 20 minutes. The reaction was allowed to cool back to room temperature and 3,5-dichlorobenzyl 2-(2-(methylamino)ethyl)morpholine-4-carboxylate (Example 13, step 2) (68.1 mg, 0.196 mmol) was added. The reaction mixture was allowed to stir at room temperature for 16 hours. The resulting reaction mixture was concentrated under reduced pressure and purification was carried our using preparative LC-MS. The resulting product fractions were concentrated under reduced pressure to give an aqueous solution and then extracted with EtOAc. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH2:18][OH:19])[CH:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].CI.[CH3:38]COCC>CS(C)=O>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH2:18][O:19][CH3:38])[CH:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[CH2:23][CH2:22]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1cccc2ccccc12)N1CC(CO)C(CN2CCC(c3ccc(F)cc3)CC2)C1
Reactant: CCOCC
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CI
Product: COCC1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1

Procedure:
A solution of 0.0025 g (0.057 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxymethylpyrrolidine, 0.013 g (0.23 mmol) of KOH and 0.028 mL (0.46 mmol) of methyl iodide in 2 mL of DMSO was stirred at rt for 1.2 h. The reaction mixture was poured into ether and washed with sat'd NaHCO3 and NaCl solutions, dried over Na2O4 and filtered. The filtrate was concentrated and the residue was purified by chromatography (silica, acetone: hexanes, 1:2) to give the compound.
Reaction SMILES: [CH2:1]1[O:9][C@@H:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClCCCl.[C-:14]#[N:15].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[K+]>[C:3]1([C@@H:2]([OH:9])[CH2:1][C:14]#[N:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCCl
Product: N#CC[C@H](O)c1ccccc1
Yield: 33.6 %

Procedure:
To a 250 round bottom flask were sequentially added 10.0 g of (R)-styrene oxide, 40 ml of 1,2-dichloroethane, 40 ml of 1N potassium hydroxide, 5.96 g of potassium cyanide and 267 mg of tetrabutylammonium bromide. The resulting mixture was heated at reflux for 6 hours. The reaction mixture was cooled and diluted with 1N potassium hydroxide, and extracted with diethyl ether. The ether extracts were combined and washed twice with a saturated sodium chloride solution. The organics layer was dried over magnesium sulfate and concentrated in vacuo. The resulting yellow oil was vacuum distilled at 13 mm pressure and the distillate collected at 140°-180° C. providing 4.11 g of title intermediate.
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:26](O)=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4].[NH2:36][C@H:37]([C:41]([NH:43][C@H:44]([C:47]([NH:49][C@H:50]([C:60]([NH:62][C@H:63]([C:76]([O:78][CH3:79])=[O:77])[CH2:64][CH2:65][CH2:66][CH2:67][NH:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])=[O:61])[CH2:51][CH2:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:48])[CH2:45][OH:46])=[O:42])[C@@H:38]([CH3:40])[OH:39].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:26]([NH:36][C@H:37]([C:41]([NH:43][C@H:44]([C:47]([NH:49][C@H:50]([C:60]([NH:62][C@H:63]([C:76]([O:78][CH3:79])=[O:77])[CH2:64][CH2:65][CH2:66][CH2:67][NH:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])=[O:61])[CH2:51][CH2:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:56])[CH3:57])=[O:48])[CH2:45][OH:46])=[O:42])[C@@H:38]([CH3:40])[OH:39])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)[C@@H](C)O
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)[C@@H](C)O

Procedure:
2.4 g Boc-Gly-Gly-Phe-Met-OH, A(4), and 3.15 g H-Thr-Ser-Glu(OtBu)-Lys(Boc)-OMe, B(3), are coupled with the aid of 2 eq HOBt and 1 eq DCCI in the way described in B(1).
Reaction SMILES: [OH:1][C:2]([CH3:26])([CH3:25])[CH2:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[CH2:12][N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14](O)=[O:15])[C:10](=[O:21])[CH:9]=1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH:39][C:14](=[O:15])[C@@H:13]([N:11]3[CH2:12][C:8]([O:7][C:6]4[CH:22]=[CH:23][CH:24]=[C:4]([CH2:3][C:2]([OH:1])([CH3:25])[CH3:26])[CH:5]=4)=[CH:9][C:10]3=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:35]2)[CH2:30][O:29]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.1 %

Procedure:
To a solution of (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (prepared as in Example 235, 0.159 g, 0.44 mmol) in N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.129 g, 0.65 mmol), N,N-diisopropylethylamine (0.312 g, 2.41 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.778 g, 1.76 mmol) at 0° C. The mixture was allowed to slowly warm up to room temperature and stirred for 48 h. The solvents were then concentrated in vacuo. The residue was dissolved in ethyl acetate and the mixture formed was washed with aqueous saturated ammonium chloride and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was initially purified by flash column chromatography (silica gel 10% to 100% ethyl acetate/hexanes). Then followed by reverse phase HPLC (C18, 20×150 mm column and 45-100% water/acetonitrile gradient at a flow rate of 30 mL/min) to afford (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (0.181 g, 76%) as a white solid: HR-ES-MS m/z calculated for C29H40N4O6 [M+H]+ 541.3021, observed 541.3017; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.05 (s, 6H), 1.24 (s, 3H), 1.29 (s, 3H), 1.36-1.64 (m, 2H), 1.63-1.80 (m, 1H), 2.67 (s, 2H), 3.73 (dd, J=8.4, 5.9 Hz, 1H), 4.00 (dd, J=8.4, 6.3 Hz, 1H), 4.03-4.14 (m, 2H), 4.17 (d, J=18.4 Hz, 1H), 4.28-4.37 (m, 1H), 4.36 (s, 1H), 4.55 (d, J=18.4 Hz, 1H), 4.82 (s, 1H), 4.87 (dd, J=10.7, 4.7 Hz, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.03-7.17 (m, 3H), 7.24-7.41 (m, 1H), 7.59 (d, J=2.1 Hz, 1H), 10.77 (s, 1H).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([O:22][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:36][CH:37]=2)=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC(F)F
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCc2ccc(S(C)(=O)=O)cc2)c1OC(F)F
Temperature: 70 °C
Yield: 20.5 %

Procedure:
To a stirring solution of 4-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (105 mg, 0.75 mmol) and 1-bromomethyl-4-methanesulfonyl-benzene (93 mg, 0.375 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford the title compound as a solid (25 mg, 20%).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:18])[NH:10][N:11]([CH:16]=[O:17])[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:25]([O:31][C@@H:32]1[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:36]([O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C@@H:35]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[O:34][C@H:33]1Br)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C(#N)C>[CH2:1]([C:8]1[C:9]([O:18][C@@H:33]2[O:34][C@H:35]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:36]([O:45][C:46](=[O:51])[C:47]([CH3:48])([CH3:49])[CH3:50])[C@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@H:32]2[O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:27])[CH3:28])=[N:10][N:11]([CH:16]=[O:17])[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: CC(C)c1c(Cc2ccccc2)c(=O)[nH]n1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)c1c(Cc2ccccc2)c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)nn1C=O
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To solution of 4-benzyl-1,2-dihydro-1-formyl-5-isopropyl-3H-pyrazol-3-one (1.07 g) in acetonitrile (20 mL) were added potassium carbonate (0.905 g) and 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl bromide (2.65 g) under stirring at room temperature. In addition, the mixture was heated to 50° C. and stirred for 1 hour. After the reaction completed, the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 4-benzyl-1-formyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole (1.49 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:10][C:11]([F:41])([F:40])[CH2:12][CH2:13][CH:14]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)[NH:15][C:16]1[CH:17]=[N:18][C:19]([N:22]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[N:23]2)=[CH:20][CH:21]=1.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.O>[F:41][C:11]([F:10])([F:40])[CH2:12][CH2:13][CH:14]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:36])=[CH:38][CH:39]=1)[NH:15][C:16]1[CH:17]=[N:18][C:19]([N:22]2[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1ccc(C(CCC(F)(F)F)Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 3-aminopropionate hydrochloride (23 mg, 0.19 mmol), (+/−)-4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}amino)butyl]benzoic acid (44 mg, 0.096 mmol), hydroxybenzotriazole hydrate (15 mg, 0.096 mmol), and triethylamine (55 ul, 0.39 mmol) in dichloromethane (0.96 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21 mg, 0.11 mmol). The mixture was stirred for 2 hours at ambient temperature. The reaction was diluted with water and the organic layer was separated. The aq. layer was extracted with dichloromethane (2×) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:11][OH:12])[CH2:6][CH2:5]2.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14]>>[OH:12]/[N:11]=[C:7]1\[CH2:6][CH2:5][C:4]2[C:8]\1=[CH:9][CH:10]=[C:2]([C:18]1[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=1)[CH:3]=2
Reactant: ON=C1CCc2cc(Br)ccc21
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2ccc3c(c2)CC/C3=N\O)cc1

Procedure:
The title compound was prepared from 5-bromoindan-1-one oxime and 4-cyanophenyl boronic acid according to the procedure described in example 6. MS (ESI) m/z 249; HRMS: calcd for C16H12N2O+H+, 249.10224; found (ESI, [M+H]+), 249.1021.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)=[CH:5][N:4]=1
Reactant: Cc1cccc(Br)n1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ncc(-c2cccc(C)n2)c(OC)n1
Yield: 47.7 %

Procedure:
2,4-Di-methoxy-pyrimidine-5-boronic acid (500 mg, 2.72 mmol) was dissolved in degassed n-PrOH (40 mL) and then 2-bromo-6-methylpyridine (660 mg, 3.8 mmol), Na2CO3 (865 mg, 8.16 mmol), PPh3 (215 mg, 0.8 mmol) and Pd(OAc)2 (50 mg, 0.22 mmol) were added. The suspension was stirred at reflux for 4 hours. The solvent was evaporated and the crude was partitioned between water and Et2O. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (2-8) to give 300 mg of the title compound (47% yield).
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([CH:22]=1)[C:19](Cl)=[O:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH2:2]([N:6]1[C:10]([CH3:11])=[CH:9][S:8]/[C:7]/1=[CH:12]\[C:19]([C:18]1[CH:22]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=1[F:23])=[O:20])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Reactant: CCCC[n+]1c(C)csc1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCN1C(C)=CS/C1=C\C(=O)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 5-chloro-2-fluorobenzoyl chloride (30.9 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.95 (t, 3 H) 1.31-1.41 (m, 2 H) 1.57-1.77 (m, 2 H) 2.28-2.34 (m, 3 H) 3.95-4.02 (m, 2 H) 6.37-6.41 (m, 1 H) 6.55-6.68 (m, 1 H) 7.28-7.35 (m, 1 H) 7.48-7.54 (m, 1 H) 7.76-7.80 (m, 1 H); MS (ESI) positive ion 326 (M+H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Cl[C:39]1[N:44]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:42]=[C:41]([CH:49]2[CH2:51][CH2:50]2)[N:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:49]1([C:41]2[N:40]=[C:39]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:7]5[O:6][C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[N:9][N:8]=5)[CH:11]=4)[N:15]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:20])=[O:21])[CH:14]=3)[N:44]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:42]=2)[CH2:50][CH2:51]1
Reactant: COC(=O)c1cc(C2CC2)nc(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC(=O)c1cc(C2CC2)nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4nnc(NC(C)C)o4)cc23)n1
Temperature: 130 °C
Yield: 12.5 %

Procedure:
To a 5 mL glass microwave tube containing N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (120 mg, 0.230 mmol) was added methyl 2-chloro-6-cyclopropylpyrimidine-4-carboxylate (58.6 mg, 0.276 mmol), potassium phosphate (146 mg, 0.689 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (6.6 mg, 0.014 mmol), and Pd2(dba)3 (6.3 mg, 6.89 μmol). The tube was purged with argon, the solids were treated with dioxane (5 mL) and water (0.5 mL), the tube was sealed, and the contents were heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 130° C. for 25 min. The mixture was treated with H2O and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (eluting with 20-100% EtOAc in Hex) affording methyl 6-cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrimidine-4-carboxylate (16.4 mg, 13%) as a light yellow amorphous solid. MS (ESI, pos. ion) m/z: 397.1 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:33])[C:20]([OH:32])([C:25]3[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=3)[C:21]([F:24])([F:23])[F:22])=[C:15]([Cl:34])[CH:14]=2)=[CH:7][CH:6]=1)C.[Li+].[OH-].Cl>O1CCCC1.CO>[Cl:34][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[CH:19]([CH3:33])[C:20]([OH:32])([C:25]1[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=1)[C:21]([F:24])([F:22])[F:23])[O:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:35])=[O:3])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(COc2ccc(C(C)C(O)(c3cnc(C)cn3)C(F)(F)F)c(Cl)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cnc(C(O)(C(C)c2ccc(OCc3ccc(C(=O)O)cc3)cc2Cl)C(F)(F)F)cn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a solution of 4-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenoxymethyl}-benzoic acid ethyl ester (Example 1, 130 mg, 0.26 mmol) in tetrahydrofuran (2.5 ml) and methanol (0.5 ml) was added a 1 M aqueous LiOH solution (0.31 ml). The mixture was stirred for 4 h at 60° C. (bath temperature). The cooled mixture was acidified with 1 M aqueous HCl. Tetrahydrofuran and methanol were evaporated in vacuo. To the suspension water was added. The precipitation was filtered, washed with water and dried to give the title compound as a white solid (105 mg). MS (m/e, ISP neg. ion)=479.4 [M−H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11](O)[CH:10]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:25])CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:25])[C@H:10]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(O)C(N2CCCC2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](N2CCCC2)[C@@H](F)C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
Dissolve 4′-hydroxy[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester (573 mg, 2.24 mmol) in dichloromethane (15 mL) and cool the mixture to −78° C. Add diethylaminosulfur trifluoride (504 mg, 3.13 mmol) dropwise and then allow the mixture to warm to room temperature. Stir the mixture overnight. Evaporate the solution and purify by silica gel chromatography, eluting with 0-3% methanol (2N NH3)/CH2Cl2 to give 520 mg (89%) of the title compound as a yellow oil. 1H NMR(DMSO-d6): δ 1.37 (s, 9H), 1.61-1.67 (m, 4H), 2.43-2.54 (m, 4H), 2.86 (bs, 1H), 3.30-3.41 (m, 1H), 3.45-3.60 (m, 1H), 5.09-5.25 (m, 1H).
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[CH3:16][C:17]1([CH3:24])[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>C1COCC1>[CH3:16][C:17]1([CH3:24])[CH2:22][CH2:21][C:20](=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)[CH2:19][CH2:18]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(=C2SCCCS2)CC1
Temperature: -78 °C

Procedure:
To a solution of 2-trimethylsily-1,3-dithiane (42.3 g, 0.22 mol) in THF (400 mL) at 0° C. under an argon atmosphere was added a solution of n-butyl lithium (2.5 M in hexanes, 88 mL, 0.22 mol) and the mixture was cooled to −78° C. A solution of 4,4-dimethyl cyclohexanone (13.9 g, 0.11 mol) in THF (50 mL) was added over 10 min. After 2 h the reaction mixture was quenched with saturated aqueous NH4Cl solution (200 mL). The aqueous phase was extracted with EtOAc (200 mL×2) and the combined organic layers were dried (MgSO4) and were evaporated. The reaction by-products were removed by vacuum distillation to yield the desired product as a white wax (21 g, 85%). MH+229