Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH:33]2[CH2:35][CH2:34]2)[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH:33]2[CH2:35][CH2:34]2)[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: COc1c(C#N)cc(C(=O)Cl)cc1C1CC1
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(C#N)cc(C(=O)N2CSc3ccccc32)cc1C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (346 mg) and 37% formalin (0.23 mL) in the same manner as in Example 1 was dissolved in chloroform (3 mL), and triethylamine (0.38 mL) and 3-cyano-5-cyclopropyl-4-methoxybenzoyl chloride were added to the solution, and then stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (e).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:4]=[N:3][CH:2]=1>C(O)C.[Pd]>[N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:4]=[N:3][CH:2]=1
Reactant: OCCCCC#Cc1cncnc1
Agent: [Pd]
Solvent: CCO
Product: OCCCCCCc1cncnc1
Yield: 93.9 %

Procedure:
A solution of 6-(5-pyrimidinyl)-5-hexynol (3.52 g) in ethanol (20 ml) was added to a pre-hydrogenated suspension of 10% palladium on carbon (1 g) in ethanol (130 ml) and hydrogenated at room temperature and pressure. The mixture was filtered through hyflo and the filtrate evaporated in vacuo to give the title compound as a pale yellow oil (3.38 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1.C(OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1)C1C=CC=CC=1>>[CH2:11]([O:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][S:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)(=[O:27])=[O:26])[O:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1cc(=O)c(OCc2ccccc2)co1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1OCc1ccccc1
Product: O=c1cc(CNS(=O)(=O)c2cccc(Cl)c2)occ1OCc1ccccc1
Yield: 56.9 %

Procedure:
N-(5-Benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-3-chloro-benzenesulfonamide (7-05) (25.0 g, 56.92%) was synthesized as a brown solid from 2-aminomethyl-5-benzyloxy-pyran-4-one (5) (25 g, 108.22 mmol) and 3-chloro-benzenesulfonyl chloride (6-05) (22.98 mL, 162.33 mmol) following the procedure described for N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (7-01).
Reaction SMILES: [ClH:1].[N:2]1([NH2:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1>CC(O)=O.O>[ClH:1].[N:2]1([N:12]=[C:13]2[CH2:18][CH2:17][CH2:16][C:15]([OH:19])=[CH:14]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCCC(=O)C1
Reactant: NN1CCCc2ccccc21
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: OC1=CC(=NN2CCCc3ccccc32)CCC1
Temperature: 40 °C
Yield: 69.1 %

Procedure:
3,4-Dihydro-1(2H)-quinolinamine hydrochloride (5.0 g, 27 mmol) and 1,3-cyclohexanedione (3.1 g, 27 mmol) was mixed in AcOH (4.3 mL) and H2O (4.3 mL). The mixture was heated at 40° C. for 10 min until dissolved completely. The mixture was then concentrated to dryness. The residue was washed with acetonitrile then filtered to yield 3-(3,4-dihydro-1(2H)-quinolinylimino)-1-cyclohexen-1-ol hydrochloride (5.2 g, 69%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=O)[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[CH:21][CH:20]=1)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:26]([C:25]([C:22]1[CH:21]=[CH:20][C:19]([CH:17]([NH:16][C:12](=[O:14])[CH2:11][N:8]2[C:7]3[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=3[N:10]=[CH:9]2)[CH3:18])=[CH:24][CH:23]=1)([CH3:29])[CH3:28])#[N:27]
Reactant: O=C(O)Cn1cnc2cccc(F)c21
Reactant: CC(N)c1ccc(C(C)(C)C#N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(NC(=O)Cn1cnc2cccc(F)c21)c1ccc(C(C)(C)C#N)cc1
Reaction time: 0.17 h

Procedure:
N-{1-[4-(1-Cyano-1-methylethyl)phenyl]ethyl}-2-(7-fluoro-1H-benzimidazol-1-yl)acetamide is synthesized according to example 1 by mixing (7-fluoro-1H-benzimidazol-1-yl)acetic acid (200 mg, 1.03 mmol) prepared according to scheme 5, 2-[4-(1-aminoethyl)phenyl]-2-methylpropanenitrile hydrochloride (231 mg, 1.03 mmol) prepared according to scheme 6, DMAP (249 mg, 2.06 mmol) and HATU (391 mg, 1.03 mmol) in DMF (4.0 mL). The product is purified on HPLCMS: Waters prep LCMS, 27 ml/min, Column: SynerSi (4μ) Polar RP, 21.2×50 mm, Mobile phase: A=water (0.05% TFA) B=MeCN, Gradient used 30% to 50% B in A, in 10 min. The fractions are combined, NaOH 1 N is added and the desired compound is extracted with ethyl acetate. The combined organic fractions are concentrated under reduced pressure to yield the product (226 mg, 0.621 mmol, 60%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.48 (d, J=7.03 Hz, 3H) 1.69 (s, 6H) 5.03 (q, J=6.90 Hz, 4H) 5.09 (d, J=16.99 Hz, 1 H) 5.14 (d, J=16.99 Hz, 1H) 7.00 (dd, J=11.43, 8.11 Hz, 1H) 7.20 (td, J=8.11, 4.88 Hz, 1H) 7.37 (d, J=8.20 Hz, 2H) 7.43-7.50 (m, 3H) 8.10 (s, 1H); MS [M+H], calcd: 365.2. found: 365.3.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:12][C:11]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:10]2)=[N:6][CH:7]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:29]2[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3B(O)O)=[N:32][N:31]=[N:30]2)C=CC=CC=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:18]([C:11]1[N:12]=[C:13]([CH2:14][CH2:15][CH2:16][CH3:17])[N:9]([CH2:8][C:5]2[N:6]=[CH:7][C:2]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[C:33]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:3][CH:4]=2)[N:10]=1)[CH2:19][CH2:20][CH3:21]
Reactant: OB(O)c1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCc1nc(CCCC)n(Cc2ccc(Br)cn2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCc1nc(CCCC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cn2)n1
Yield: 29.4 %

Procedure:
Under nitrogen, 2.04 g (5.8 mmol) of 5-bromo-2-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]pyridine from step 4 and 2.83 g (6.6 mmol) of 2-(N-triphenylmethyltetrazol-5-yl)phenylboronic acid from step 5 were treated with 1.0 g (0.86 mmol) of tetrakis(triphenylphosphine)palladium zero, 18 mL of toluene, 14 mL of ethanol, and 7.5 mL of 2M aqueous sodium carbonate. The reaction mixture was heated to reflux and vigorously stirred overnight. The product was purified by reverse phase chromatography (Waters Deltaprep-3000) using acetonitrile/water (20-40:80-60) (0.05% TFA). The pure fractions (by analytical HPLC) were combined, the acetonitrile removed in vacuo, the pH adjusted to four with dilute sodium hydroxide, and the resulting suspension extracted 4 times with ether. The extracts were combined, dried (MgSO4), and concentrated in vacuo to give 710 mg (30%) of 5-[2-[6-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-3 -pyridinyl]phenyl]-1H-tetrazole as a colorless solid: mp 136°-138° C.; NMR (CD3OD) δ0.88-0.98 (m, 6H), 1.27-1.45 (m, 4H), 1.60-1.75 (m, 4H), 2.66 (t, J=7 Hz, 2H), 2.84 (t, J=7 Hz, 2H), 5.45 (s, 2H), 7.21 (d, J=8 Hz, 1H), 7.56-7.68 (m, 3H), 7.70-7.78 (m, 2H), 8.29 (d, J=2 Hz, 1H); MS (FAB) m/e (rel intensity) 417 (100), 389 (10), 374 (10), 360 (10), 208 (35), 182 (25); HRMS. Calc'd for M+H: 417.2515. Found: 417.2486.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:35])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)=[O:20])[CH2:15]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([NH:22][CH2:21][C:19](=[O:20])[NH:18][CH:16]2[CH2:15][N:14]([CH:10]3[CH2:11][CH2:12][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8][CH2:9]3)[CH2:17]2)=[O:35])=[CH:25][C:26]=1[C:31]([F:34])([F:32])[F:33]
Reactant: O=C(CNC(=O)c1ccc(F)c(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2ccccc2)CC1
Product: O=C(CNC(=O)c1ccc(F)c(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-phenyl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-4-fluoro-3-trifluoromethyl-benzamide using the procedure described in Step C of Example 4.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][C@@H:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[OH:24])=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.I[CH2:26][C:27]1([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.C(OCC)(=O)C.O>[OH:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[O:18][C:14]1[C:13]2[C:9]([O:8][CH2:7][CH:4]3[CH2:5][CH2:6][N:1]([CH2:26][C:27]4([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:2][CH2:3]3)=[N:10][O:11][C:12]=2[CH:17]=[CH:16][CH:15]=1
Reactant: O[C@@H]1CCC[C@H]1Oc1cccc2onc(OCC3CCNCC3)c12
Reactant: COC(=O)C1(CI)CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(O[C@@H]5CCC[C@H]5O)c34)CC2)CCCC1
Temperature: 120 °C
Yield: 11 %

Procedure:
A mixture of trans-2-{[3-(piperidin-4-ylmethoxy)-1,2-benzisoxazol-4-yl]oxy}cyclopentanol (77 mg, 0.23 mmol, EXAMPLE 33, Step 2), methyl 1-(iodomethyl)cyclopentanecarboxylate (75 mg, 0.28 mmol, EXAMPLE 33, Step 1), and N,N-diisopropylethylamine (0.12 mL, 0.70 mmol) in N-methylpyrrolidone (3.0 mL) was heated at 120° C. for 14 h. The mixture was cooled to room temperature and the mixture was diluted with ethyl acetate and water. The mixture was extracted with ethyl acetate (30 mL×2) and washed with brine. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to give a brown solid. The residual solid was purified by silica gel column chromatography (hexane/ethyl acetate 3:2) to give 12 mg (11%) of the title compound as a colorless viscous oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]([CH3:34])[CH2:14][CH2:15][CH2:16][N:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:12])=[CH:5][CH:4]=1)#[N:2].[S].[CH2:36](N)[CH2:37][NH2:38]>>[NH:2]1[CH2:36][CH2:37][N:38]=[C:1]1[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([N:13]([CH3:34])[CH2:14][CH2:15][CH2:16][N:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])=[O:12])=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCN(C)C(=O)CCc2ccc(C#N)cc2)c2ccccc2)cc1
Reactant: NCCN
Agent: [S]
Product: Cc1ccc(S(=O)(=O)N(CCCN(C)C(=O)CCc2ccc(C3=NCCN3)cc2)c2ccccc2)cc1

Procedure:
Analogously to 13b), 3-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methyl-N-{3-[phenyl(toluene-4-sulphonyl)amino]propyl}propionamide was prepared from 1.82 g (3.83 mmol) of 3-(4-cyanophenyl)-N-methyl-N-{3-[phenyl(toluene-4-sulphonyl)amino]propyl}propionamide, 122 mg (3.83 mmol) of sulphur and 7 ml of ethylenediamine.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]([C:5]1[CH:22]=[C:21]([O:23]CC2C=CC=CC=2)[C:8]2[N:9]=[C:10]([CH3:20])[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=2[CH:6]=1)=[O:4]>C(O)C.[Pd]>[CH3:31][N:2]([CH3:1])[C:3]([C:5]1[CH:22]=[C:21]([OH:23])[C:8]2[N:9]=[C:10]([CH3:20])[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])[C:7]=2[CH:6]=1)=[O:4]
Reactant: Cc1nc2c(OCc3ccccc3)cc(C(=O)N(C)C)cc2n1COCC[Si](C)(C)C
Agent: [Pd]
Solvent: CCO
Product: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1COCC[Si](C)(C)C
Yield: 89.6 %

Procedure:
A solution of 3.6 g (8.3 mmol) 7-benzyloxy-2-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzo-imidazole-5-carboxylic acid dimethylamide in 400 ml ethanol was hydrogenated over 365 mg 10% Pd/C at room temperature for 1 h. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was crystallized from diisopropyl ether to afford 2.6 g (89%) of the title compound as a while solid. m.p. 150°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH2:34])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>ClCCl.CO>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:34][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1cc(N)ccc1OCCN1CCOCC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN1CCOCC1

Procedure:
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl)propynoic acid and 3-methoxy-4-(2-morpholin-4-ylethoxy)phenylamine. Yield: 20 mg (6.9% of theory); melting point: 209° C.-211° C.; C23H22ClF3N2O4 (M=482.89); calc.: molecular ion peak (M+H)+: 483/485; found: molecular ion peak (M+H)+: 483/485; Rf value: 0.5 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH:12]([CH3:36])[C:13]([NH:15][CH:16]1[C:22](=[O:23])[N:21]([CH3:24])[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=2[C:18]([C:29]2[CH:34]=[CH:33][C:32](F)=[CH:31][CH:30]=2)=[N:17]1)=[O:14])(=[O:10])=[O:9].[F:37][C:38]([F:50])([F:49])C1C=CC=CC=1S(Cl)(=O)=O>>[CH3:24][N:21]1[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=2[C:18]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[N:17][CH:16]([NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:38]([F:50])([F:49])[F:37])(=[O:10])=[O:9])[CH3:36])[C:22]1=[O:23]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CC(NS(=O)(=O)c1ccccc1F)C(=O)NC1N=C(c2ccc(F)cc2)c2ccccc2N(C)C1=O
Product: CC(NS(=O)(=O)c1ccccc1C(F)(F)F)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Yield: 68 %

Procedure:
The compound of Example 53 was synthesized in a procedure analogous to the synthesis of the compound of Example 52 using 2-trifluoromethyl benzene sulfonyl chloride in 68% yield. MS (ESI) M+H=545.2
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24](Br)[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[C:16]([F:32])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[CH3:38][CH2:39]OC(C)=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24]([CH:38]=[CH2:39])[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[C:16]([F:32])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Temperature: 90 °C

Procedure:
Intermediate (16a) (9.5 g, 18.9 mmol), tetrakis(triphenylphosphine) palladium(0) (1.0 g, 0.9 mmol), (2-ethenyl)tri-n-butyltin (11.0 mL, 37.8 mmol) were dissolved in DMF (70 mL, 900 mmol), and heated at 90° C. for 1.5 hours. The mixture was cooled to room temperature and 300 mL of EtOAc was added. The organic layer was washed using a 20% potassium fluoride solution (2×100 mL) and saturated aqueous NaCl. The resulting material was purified by silica gel chromatography (0-60% EtOAc:hexanes) to yield intermediate (16b) (7.7 g). MS m/z: [M+H+] calcd for C26H27FN2O4, 451.2. found 451.0. 1H-NMR (CDCl3): 8.17 (1H, s), 7.79 (1H, d), 7.48 (1H, t), 7.40 (1H, t), 7.28 (1H, s), 7.01 (2H, m), 6.86 (1H, t), 6.67 (1H, m), 5.95 (1H, d), 5.41 (2H, s), 5.27 (1H, d), 4.48 (2H, q), 1.38 (3H, t), 1.25 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[C:26](=[O:34])[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[C:26](=[O:34])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCC(=O)c1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C(=O)CCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of ethyl 4-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]-4-oxobutanoate (D52) (20 mg) in THF (2 mL) was added aqueous NaOH (2 M, 1 mL), the reaction was stirred at room temperature overnight. The mixture was acidified with aqueous HCl (2M) to pH 4-5, and then partitioned with ethyl acetate (10 mL) and water (10 mL). The organic phase was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford 4-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]-4-oxobutanoic acid (E33) (12 mg). δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 2.59 (2H, t), 3.20 (2H, t), 4.91 (1H, m), 7.41 (1H, t), 7.47 (1H, d), 8.04 (1H, dd), 8.22 (1H, dd), 8.36 (1H, d), 8.41 (1H, d), 8.44 (1H, dd), 11.81 (1H, br s). MS (ES): C23H20ClN3O5 requires 453; found 454.2 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].CC(C)([O-])C.[K+].C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C1(C)C=CC=CC=1>[CH2:26]([O:25][C:23](=[O:24])/[C:22](/[O:21][CH2:20][CH2:19][O:18][CH3:17])=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COCCOCC(=O)OCc1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCCO/C(=C\c1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: -20 °C
Yield: 31.2 %

Procedure:
4-(Benzyloxy)benzaldehyde (3.00 g; 14.0 mmole) and benzyl 2-(2-methoxyethoxy)acetate (4.23 g; 17.0 mmole) were dissolved in dry tetrahydrofuran (100 ml) and cooled to −20° C. Potassium tert-butoxide (1.91 g; 17.0 mmole) dissolved in dry tetrahydrofuran (10 ml) was slowly added and the reaction was stirred over night at −20° C. The reaction was quenched with acetic acid (0.85 g; 14.0 mmole). The crued product was isolated, redissolved in toluene and refluxed over night with p-toluenesulfonic acid (0.24 g; 1.4 mmole) in a Dean-Stark apparatus to separate the water. The solution was cooled, washed with sodium hydrogene carbonate, dried with magnesium sulfate and evaporated. Purification of the crude product with preparativ HPLC (Kromasil C8, 10 μm, 50×500 mm) using acetronitrile (50-70%) in ammonium acetate buffer (pH 7) as mobil phase gave 1.83 g (29% yield) of (Z)-3-[4-(benzyloxy)phenyl]-2-(2-methoxyethoxy)-2-propenoic acid benzyl ester.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([O:18]C(C)(C)C)=[O:17])[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[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]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([OH:18])=[O:17])[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[CH:26]=[C:27]([C:35]([F:37])([F:38])[F:36])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 24; 3.37 g, 5.43 mmol), trifluoroacetic acid (4 ml) and dichloromethane (6 ml) was stirred at reflux for 4.5 hour then concentrated in vacuo to give crude title compound which crystallised from dichloromethane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][C:18]([S:21]([NH2:23])=[O:22])([CH3:20])[CH3:19].O>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N:23][S:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22]
Reactant: CC(C)(C)S(N)=O
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(=O)N=C(c1ccccc1)c1cc(Br)ccc1N

Procedure:
A solution of (2-Amino-5-bromo-phenyl)-phenyl-methanone (67 g, 244 mmol), 2-Methyl-propane-2-sulfinic acid amide (35.38 g, 292 mmol) and Ti(OEt)4 (111.15 g, 487 mmol) in THF (800 mL) is heated to reflux overnight. Then H2O is added and filtered and concentrated. The residue is purified by chromatography on silica gel to give desired product.