Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][S:9][CH2:10][CH2:11][C@H:12]([NH2:16])[C:13]([OH:15])=[O:14])[CH2:2][C@H:3]([NH2:7])[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCOCC1.O.O1CCOCC1>[CH2:19]([O:26][C:27]([CH:1]([S:8][S:9][CH2:10][CH2:11][C@H:12]([NH2:16])[C:13]([OH:15])=[O:14])[CH2:2][C@H:3]([NH2:7])[C:4]([OH:6])=[O:5])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@@H](CCSSCC[C@H](N)C(=O)O)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N[C@@H](CCSSC(C[C@H](N)C(=O)O)C(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C

Procedure:
L-homocystine (5 g) was dissolved in a mixture (80 ml) of dioxane/H2O. At 0° C. and under stirring, 1.52 g (2.1 eq) of NaOH and a solution of 7.8 g (2.4 eq) of benzylchloroformate in 40 ml dioxane were added. The pH was maintained at 9 by addition of a solution of NaOH 1M. After stirring for 2.30 h at room temperature, 100 ml H2O were added and the white precipitate was extracted by Et20 (2×50 ml). The aqueous phase was acidified to pH 1 and the precipitate was extracted by EtOAc (4×80 ml). The organic phase was washed, dried over Na2SO4, filtered and evaporated in vacuo. White solid 10.2 g (100%).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([CH2:24]I)[CH:21]=[CH:20][C:19]=1[N:26]1[S:30](=[O:32])(=[O:31])[N:29]([CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:28](=[O:39])[CH2:27]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C2C=CC=CC=2)C=CC=CC=1.[CH2:52]([O:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62](Br)[N:61]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN(C)C(=O)C.[Zn].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]>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([CH2:24][C:62]2[CH:63]=[CH:64][CH:65]=[C:60]([O:59][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[N:61]=2)[CH:21]=[CH:20][C:19]=1[N:26]1[S:30](=[O:32])(=[O:31])[N:29]([CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:28](=[O:39])[CH2:27]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cccc(OCc2ccccc2)n1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CI)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: BrCCBr
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3cccc(OCc4ccccc4)n3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a pressure vessel, zinc powder (429 mg, 6.6 mmol) is dried by heating under vacuum, then cooled, placed under N2, and slurried in N,N-dimethylacetamide (0.75 mL). To the slurry is added 1,2-dibromoethane (0.044 mL, 0.51 mmol) and the mixture is heated until boiling. The mixture is allowed to cool, and TMSCl (65 mL, 0.51 mmol) is added, followed by stirring for 30 min to produce a green solution. To the activated zinc is added 5-(2-benzyloxy-4-iodomethylphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (600 mg, 1.1 mmol) in N,N-dimethylacetamide (1 mL) over 30 min. The organozinc solution is filtered and degassed with N2, then to it is added Pd2(dba)3 (50 mg, 0.055 mmol) and 2-di-t-butylphosphino)biphenyl (66 mg, 0.22 mmol), followed by degassed 2-benzyloxy-6-bromopyridine (350 mg, 1.3 mmol) in N,N-dimethylacetamide. The vessel is sealed and the reaction is stirred at 80° C. for 18 h. The reaction is allowed to cool to RT then is filtered through Celite. The resulting solution is diluted with EtOAc (10 mL) and washed with water and brine, then dried over MgSO4. The solvent is removed under reduced pressure and the crude residue is purified by silica gel chromatography using a gradient of 0-75% EtOAc/hexane to afford the title compound as a colorless oil: (M+H)+=616
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:47]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=2)[CH2:48][NH2:49])[CH:44]=[CH:45][CH:46]=1>>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2[NH:49][CH2:48][CH:47]([C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([Cl:40])[CH:42]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: NCC(c1cccc(Cl)c1)c1cccc(Cl)c1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4cccc(Cl)c4)c4cccc(Cl)c4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1

Procedure:
Prepared from ((2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 47) and 2,2-bis(3-chlorophenyl)ethylamine by the same method as Preparation 48. The title compound was obtained as a yellow foam.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:5][C:4]2([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[O:3]1.Cl.[NH:28]1[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[OH:33][CH:30]1[CH2:31][CH2:32][N:28]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][N:6]4[CH2:5][C:4]5([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]5)[O:3][C:2]4=[O:1])=[CH:9][CH:10]=3)=[CH:19][CH:18]=2)[CH2:29]1
Reactant: O=Cc1ccc(-c2ccc(CN3CC4(CCCCC4)OC3=O)cc2)cc1
Reactant: O[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1OC2(CCCCC2)CN1Cc1ccc(-c2ccc(CN3CCC(O)C3)cc2)cc1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-4-carbaldehyde (50 mg, 0.143 mmol) was mixed with (R)-(−)-3-pyrrolidinol hydrochloride (20 mg, 0.157 mmol) in DCE (2.5 mL). Na(OAc)3BH was added as a solid at room temperature and the reaction was stirred overnight. The reaction was quenched with saturated aqueous NaHCO3 solution. The aqueous phase was extracted with DCM (3×5 mL), the combined organic phases were washed with brine (5 mL), dried over sodium sulfate and concentrated. The crude residue was purified on silica gel eluting with DCM containing 0.5˜2% 2M ammonia in methanol to give the product as off-white solid (34 mg, 56.5%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.59 (dd, 4H), 7.38 (d, 2H), 7.29 (d, 2H), 4.42 (s, 2H), 4.37 (m, 1H), 3.69 (s, 2H), 3.13 (s, 2H), 2.87 (m, 1H), 2.67 (d, 1H), 2.58 (dd, 1H), 2.37 (m, 2H), 2.2 (m, 1H), 1.76 (m, 4H), 1.51 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([C:22]#[N:23])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1.Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([C:22]([NH:25][OH:26])=[NH:23])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1
Reactant: NO
Reactant: N#Cc1nc2cnc3ccc(Cl)cc3c2n1-c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N=C(NO)c1nc2cnc3ccc(Cl)cc3c2n1-c1ccccc1Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 300 mg of (0.884 mmol) 8-chloro-1-(2-chloro-phenyl)-1H-imidazo[4,5-c]quinoline-2-carbonitrile (Example 84) and 245 mg (3.537 mmol) hydroxylamine hydrochloride in 7.5 ml DMF, a solution of 326 mg (3.08 mmol) sodium carbonate in 1.8 ml water is added by syringe within 2 min. The reaction mixture is heated at 70° C. for 4½ h. The cold solution is poured in ice-water and stirred for 1 h. The precipitate which is formed is filtered off and washed with water and ethanol. The compound is dried over night at 60° C. (high vacuum). mp: 265-267° C.; MS: 372 (M++1); HPLC: tret=80.43 min (Grad 1).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.C1C(CO)=CC=C(O)C=1.[Mn]([O-])(=O)(=O)=O.[K+].[CH2:29]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C:38]2[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)[CH2:30][CH3:31].C1CCC(N=C=NC2CCCCC2)CC1>>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C:41]2[CH:40]=[CH:39][C:38]([C@H:35]3[CH2:36][CH2:37][C@H:32]([CH2:29][CH2:30][CH3:31])[CH2:33][CH2:34]3)=[CH:43][CH:42]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)c1ccc(OC(F)F)cc1
Reactant: CCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: O=[Mn](=O)(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: OCc1ccc(O)cc1
Product: CCC[C@H]1CC[C@H](c2ccc(OC(=O)c3ccc(OC(F)F)cc3)cc2)CC1

Procedure:
4-Difluoromethoxybenzoic acid (available by etherification of the phenolic OH group of p-hydroxybenzyl alcohol analogously to Example 1, followed by oxidation with potassium permanganate) is esterified, as described in Example 5b), with 4-(trans-4-propylcyclohexyl)-phenol by the DCC method. m.p.: 104° C., c.p.: 193.5° C.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[OH:5][C:6]1[N:10]=[C:9]([S:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:8][N:7]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][NH:2][C:3]([N:7]1[C:6](=[O:5])[N:10]=[C:9]([S:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:8]1)=[O:4]
Reactant: CN=C=O
Reactant: CCOC(=O)CSc1nc(O)ns1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CSc1nc(=O)n(C(=O)NC)s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
10 ml of methyl isocyanate were added to a solution of 11 g of 3-hydroxy-5-(ethoxycarbonylmethylthio)-1,2,4-thiadiazole in 100 ml of tetrahydrofuran containing 0.5 ml of triethylamine and the mixture was stirred for 2 hours at 20° C. The mixture was evaporated to dryness under reduced pressure and the residue was empasted with ethyl acetate and vacuum filtered. The crystals were washed with water to obtain 10 g of 2-(N-methylcarbamoyl)-5-(ethoxycarbonylmethylthio)-1,2,4-thiadiazole-3-one which after crystallization from acetone melted at 163° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](O)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[CH:34]1([NH2:37])[CH2:36][CH2:35]1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:24])[NH:37][CH:34]4[CH2:36][CH2:35]4)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)NC1CC1
Yield: 76.7 %

Procedure:
The same operation as in Example (247a) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (50a) (300 mg, 0.60 mmol), cyclopropylamine (0.08 mL, 1.20 mmol), WSC hydrochloride (345 mg, 1.80 mmol) and 1-hydroxybenzotriazole (81 mg, 0.60 mmol), to obtain 248 mg of the title compound as a white solid (77%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](I)[CH:7]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(C1CCCCC1=O)(=O)C(C)C>CCOC(C)=O.O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[N:4][CH:3]=1
Reactant: Brc1cncc(I)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Agent: CC(C)C(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cncc(Br)c2)C1
Temperature: 55 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
A mixture of 3-bromo-5-iodopyridine (500 mg, 1.761 mmol, Aldrich), tert-butyl 3-aminopiperidine-1-carboxylate (388 mg, 1.937 mmol, Combi-blocks), Cut (33.5 mg, 0.176 mmol, Aldrich) and cesium carbonate (1148 mg, 3.52 mmol, Fluka) was capped, degassed and backfilled with argon (3×). Dioxane (2 mL) and 2-isobutyrylcyclohexanone (0.118 mL, 0.704 mmol) were added, and the reaction was heated to 55° C. After 16 h, the temperature was raised to 70° C. After 60 h at 70° C., the reaction mixture was cooled to 23° C., diluted with EtOAc (75 mL) and washed with brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 25-60% EtOAc/hexane), affording tert-butyl 3-(5-bromopyridin-3-ylamino)piperidine-1-carboxylate (375 mg, 60%). MS (ESI, pos. ion) m/z: 356.1 (M+1), 358.1 (M+3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][C:3]=1[CH3:22].[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:31][CH2:30][C:28]2[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=2)=[O:14])=[CH:4][C:3]=1[CH3:22]
Reactant: Cc1cc(-c2cc(C(=O)O)cnc2OC2CCC2)ccc1Cl
Reactant: NCc1nc(C(F)(F)F)no1
Product: Cc1cc(-c2cc(C(=O)NCc3nc(C(F)(F)F)no3)cnc2OC2CCC2)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-3-methylphenyl)-6-cyclobutoxy-nicotinic acid (example CC) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 93.8%, 467.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:14][CH2:15][C:16](Cl)=[O:17].Cl>CCOC(C)=O.O>[Cl:14][CH2:15][C:16]([C:5]1[CH:4]=[C:3]([CH3:9])[C:2]([F:1])=[CH:7][C:6]=1[F:8])=[O:17]
Reactant: Cc1ccc(F)cc1F
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C(=O)CCl)c(F)cc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 2,4-difluorotoluene was added 6.3 g (47.3 mmol) of AlCl3, and 3.4 mL (42.6 mmol) of chloroacetyl chloride at 0° C. After the mixture was stirred for 10 min. at 0° C. and then at 45° C. for 30 min. The mixture was allowed to cool to r.t., about 16 mL of conc. HCl, 25 mL of water, and 100 mL of EtOAc were added. The organic layer was separated and washed with brine and sat. NaHCO3 (2×), and dried over Na2SO4. The solution was filtered and concentrated to give 9.0 g of 2-chloro-1-(2,4-difluoro-5-methylphenyl)ethanone as a colorless solid that was used without further purification.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:4]1=[O:16].[C:17]([C:19]1[CH:32]=[CH:31][C:22]([CH2:23][N:24]2[C:28]([CH:29]=O)=[CH:27][N:26]=[CH:25]2)=[CH:21][C:20]=1[F:33])#[N:18].C(N(CC)C(C)C)(C)C.[BH3-]C#N.[Na+]>CO>[F:33][C:20]1[CH:21]=[C:22]([CH2:23][N:24]2[C:28]([CH2:29][NH:2][C@@H:3]3[CH2:7][CH2:6][N:5]([CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=4)[C:4]3=[O:16])=[CH:27][N:26]=[CH:25]2)[CH:31]=[CH:32][C:19]=1[C:17]#[N:18]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: N[C@@H]1CCN(Cc2cccc(O)c2)C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2CN[C@@H]2CCN(Cc3cccc(O)c3)C2=O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3-Amino-1-(3-hydroxybenzyl)-2-oxopyrrolidine hydrochloride, as described above in Step N, (200 mg, 0.82 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, as described above in Step G, (197 mg, 0.86 mmol), were stirred in MeOH (7 mL) and N,N-diisopropylethylamine was added dropwise to adjust the mixture to ca. pH 5, as judged by wetted pH paper. The mixture was stirred for 1 hour at ambient temperature, then NaCNBH3 (54 mg, 0.86 mmol) was added and stirring was continued for 18 hours. The reaction was quenched with saturated aqueous NaHCO3 (2 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous NaHCO3 (3 mL) and CH2Cl2 (10 mL). The aqueous layer was extracted further with CH2Cl2 (3×10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with two column volumes of EtOAc—10% MeOH, then two column volumes of CHCl3—4% MeOH, then CHCl3—4% MeOH—0.4% NH4OH to yield the titled product as a colorless oil.
Reaction SMILES: [C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:34]=[CH:33][C:15]([O:16][C:17]2[CH:26]=[C:25]3[C:20]([CH:21]([C:27]([O:29]CC)=[O:28])[CH2:22][CH2:23][O:24]3)=[CH:19][C:18]=2[Cl:32])=[CH:14][CH:13]=1)=[O:11].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[C:1]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[CH:26]=[C:25]3[C:20]([CH:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][O:24]3)=[CH:19][C:18]=2[Cl:32])=[CH:33][CH:34]=1)=[O:11]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccccc4-c4ccccc4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NCCc1ccccc1-c1ccccc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Ethyl 7-(4-(2-(biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (29 mg, 0.052 mmol) was diluted with THF (1 mL) followed by the addition of NaOH (261 μL, 0.26 mmol) and ethanol (500 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 7-(4-(2-(biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid (26 mg, 0.049 mmol, 94% yield).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]([C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[N:5]1>O>[Br:1][C:7]1[C:6]([C:12]([F:23])([F:24])[C:13]([F:21])([F:22])[C:14]([F:19])([F:20])[C:15]([F:18])([F:17])[F:16])=[N:5][N:4]([CH3:3])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: Cn1nc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1C(=O)O
Reactant: BrBr
Solvent: O
Product: Cn1nc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(Br)c1C(=O)O
Reaction time: 1 h

Procedure:
At 40° C., 255 mg (1.60 mmol) of bromine are added dropwise to a solution of 0.50 g (1.45 mmol) of 1-methyl-3-nonafluorobutyl-1H-pyrazole-5-carboxylic acid in 3.5 ml of water and the reaction mixture is afterstirred firstly for one hour at 60° C. and then for three days at room temperature. The aqueous phase is extracted three times with dichloromethane and the organic phase is dried over sodium sulphate. The dichloromethane is distilled off at reduced pressure on a rotary evaporator. This gives 0.54 g of 4-bromo-1-methyl-3-nonafluorobutyl-1H-pyrazole-5-carboxylic acid (80%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[C:11]([OH:13])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:14]1COCC1.C(=O)([O-])[O-].[Cs+].[Cs+].CI>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[N:12]=[C:11]([O:13][CH3:14])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: Oc1cnn(-c2ccc(Br)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Product: COc1cnn(-c2ccc(Br)cc2)n1
Temperature: 60 °C

Procedure:
2-(4-bromophenyl)-2H-1,2,3-triazol-4-ol (200 mg, 0.833 mmol) was weighed into a 20 ml vial equipped with a septa cap. THF (10.0 ml) was added. To this was added cesium carbonate (814 mg, 2.5 mmol), followed by the addition of methyl iodide (65.8 uL, 1.04 mmol) via syringe. The reaction was heated at 60° C. for 16 hours. Water (20 ml) was added and the product was extracted with ethyl acetate (2×75 ml). Organic phases were combined, dried over potassium carbonate, filtered and concentrated to furnish a light tan solid (190 mg, 89% TY). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.04 (s, 3H) 7.30 (s, 1H) 7.56 (d, J=8.98 Hz, 2H) 7.84 (d, J=8.98 Hz, 2H)
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:9]2[C:4](=[C:5]([NH2:23])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:23][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([CH3:1])[N:11]=[C:10]3[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: Cc1nc(Nc2cccc(C(F)(F)F)c2)c2cccc(N)c2n1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Nc2cccc(C(F)(F)F)c2)c2cccc(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)c2n1
Yield: 9.2 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 2-methyl-N4-(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-27, 100 mg, 0.314 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 181 mg, 0.629 mmol), oxalyl chloride (119 mg, 0.94 mmol), DMF (1 drop) and DIPEA (122 mg, 0.94 mmol) in CH2Cl2 (4 mL) to afford 17 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.42 (s, 1H), 10.04 (s, 1H), 8.77 (d, 1H), 8.43 (s, 1H), 8.31 (m 2H), 8.16 (m, 1H), 7.64 (m, 2H), 7.48-7.36 (m, 3H), 4.31 (d, 2H), 2.58 (s, 3H), 1.14 (s, 9H); MS (m/z): 588.31 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:34]=[CH:33][C:14](/[CH:15]=[CH:16]/[C:17]([O:19][CH:20]2[CH2:25][CH2:24][C:23]([CH3:32])([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[CH2:22][CH2:21]2)=[O:18])=[CH:13][C:12]=1[O:35][CH3:36])(=O)C.Cl>CO>[OH:10][C:11]1[CH:34]=[CH:33][C:14](/[CH:15]=[CH:16]/[C:17]([O:19][CH:20]2[CH2:25][CH2:24][C:23]([CH3:32])([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[CH2:22][CH2:21]2)=[O:18])=[CH:13][C:12]=1[O:35][CH3:36]
Reactant: C=CCOC(=O)C1(C)CCC(OC(=O)/C=C/c2ccc(OC(C)=O)c(OC)c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCOC(=O)C1(C)CCC(OC(=O)/C=C/c2ccc(O)c(OC)c2)CC1
Yield: 86.6 %

Procedure:
5 g of potassium carbonate was added to a solution of 1.4 g of allyl trans-4-(4-acetoxy-3-methoxycinnamoyloxy)-1-methyl-1-cyclohexanecarboxylate (Example 12) in 70 ml of methanol. The resultant solution was stirred for 2 hours at room temperature. After reaction, 2N hydrochloric acid was added to the solution, acidifying the solution. The solution was extracted three times with 50 ml of ethyl acetate. The organic layer obtained was washed once with an aqueous sodium hydrogencarbonate solution and once with an aqueous sodium chloride solution, and was then dried over magnesium sulfate. The solvent was removed in vacuo, yielding 1.09 g of allyl trans-4-(4-hydroxy-3-methoxycinnamoyloxy)-1-methyl-1-cyclohexanecarboxylate (a compound of the present invention) as white crystal, which had the following physiochemical properties: