Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[N:7][CH:8]=1.FC(F)(F)C(O)=O>ClCCl>[NH:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:23])([F:1])[F:24])=[CH:8][N:7]=2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(NC2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.860 g (2.49 mmol) of tert-butyl 4-(5-(trifluoromethyl)(pyridin-2-ylamino)piperidine-1-carboxylate obtained in stage 6.1. is dissolved in 8.5 ml of dichloromethane. 1.91 ml of trifluoroacetic acid are added and the mixture is stirred at ambient temperature for 4 hours. The dichloromethane is evaporated and then the residue is coevaporated twice with 10 ml of 1,2-dichloroethane. The residue is taken up in a mixture of 50 ml of ethyl acetate, 10 ml of a 1N aqueous sodium hydroxide solution and 5 ml of a 33% aqueous ammonia solution. The organic phase is separated by settling. It is washed with 2 times 10 ml of water and then with 10 ml of a saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated to dryness to produce 0.572 g (2.33 mmol) of product in the form of an off-white solid.
Reaction SMILES: O=S(Cl)Cl.[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[Cl:17])[C:11]([OH:13])=[O:12])([O-:7])=[O:6].[CH3:21]O>>[Cl:17][C:16]1[C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]([C:11]([O:13][CH3:21])=[O:12])=[CH:9][C:8]=1[N+:5]([O-:7])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reaction time: 15 h

Procedure:
2.96 ml of SOCl2 is added at 0° C., under an inert atmosphere and dropwise to 10 g of 3,5-dinitro-4-chloro-benzoic acid (JANSSEN) in 150 ml of methanol and agitation is carried out under reflux of methanol for 2 hours then for 15 hours at ambient temperature. The reaction medium is poured into ice and precipitation of the product is observed. After drying, 10.3 g of expected product is obtained.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]3[CH:22]=[C:21]4[C:16]([CH:17]=[CH:18][CH:19]=[N:20]4)=[CH:15][C:14]=3[O:23][CH3:24])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>CO.[C].[Pd]>[O:4]1[C:5]2([CH2:6][CH2:7][N:8]([CH2:11][CH2:12][C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH2:19][NH:20]4)=[CH:15][C:14]=3[O:23][CH3:24])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: COc1cc2cccnc2cc1CCN1CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1CCN1CCC3(CC1)OCCO3)NCCC2
Reaction time: 10 h
Yield: 101.9 %

Procedure:
445 mg of 7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxyquinoline was dissolved in 10 ml of methanol. Thereafter, 100 mg of 10% palladium carbon was added to the reaction solution. The obtained mixture was stirred for 6 hours under a 4 kg/cm2 of hydrogen atmosphere. Palladium carbon was removed by filtration, followed by concentration under a reduced pressure. The reaction solution was stirred under the same conditions for 10 hours 3 times, followed by concentration under a reduced pressure. A saturated sodium bicarbonate aqueous solution was added to the residue, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure, so as to obtain 459 mg of 7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxy-1,2,3,4-tetrahydroquinoline. This compound was used in the following reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10]C)=[O:9])=[CH:4][N:3]=1.[CH:12]1([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13]1.[OH-].[Li+]>>[CH:12]1([O:17][C:2]2[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][N:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: OC1CCCC1
Reactant: COC(=O)c1cnc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cnc(OC2CCCC2)nc1
Temperature: 25 °C
Yield: 32 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 32% yield starting from methyl 2-chloropyrimidine-5-carboxylate and cyclopentanol. The reduction was performed using 3 equiv of lithium hydroxide, the reaction mixture was stirred at ambient temperature over night; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.99 (s, 2 H), 5.38-5.48 (m, 1 H), 1.89-2.04 (m, 2 H), 1.67-1.83 (m, 4 H), 1.55-1.67 (m, 2 H); MS (ESI) m/z 207[M−H+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[CH2:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[CH2:10][CH3:11].C(N(CC)CC)C>C1COCC1>[CH2:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:8][CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:17])=[CH:19][CH:20]=1)[CH2:10][CH3:11]
Reactant: CCCc1ccc(C(=O)Cl)cc1
Reactant: NCCc1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1ccc(C(=O)NCCc2cccs2)cc1
Yield: 85.7 %

Procedure:
Reaction of 2-thiopheneethylamine (50 μL, 0.42 mmol) in THF (2.5 mL) with 4-propylbenzoyl chloride (92 μL, 0.55 mmol) in presence of triethylamine (78 μL, 0.55 mmol) according to method A gave 4-propyl-N-(2-thiophen-2-yl-ethyl)-benzamide (100 mg, 0.36 mmol, 85% yield) as a off-white powder after purification on silica gel (eluent: EtOAc/hexane 5/95 to 20/80).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]([OH:14])[CH3:13].[CH3:15][Si:16]([CH3:19])([CH3:18])Cl.C[Si](C)(C)N[Si](C)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]([O:14][Si:16]([CH3:19])([CH3:18])[CH3:15])[CH3:13]
Reactant: C[Si](C)(C)Cl
Reactant: CC(O)Cc1c[nH]c2ccc(F)cc12
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: C1CCOC1
Product: CC(Cc1c[nH]c2ccc(F)cc12)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The alcohol 49 (10 mmol) was dissolved in absolute THF (15 ml) with exclusion of moisture. Trimethylchlorosilane (2.1 ml, 15.3 mmol) and hexamethyldisilazane (4.9 ml, 23.3 mmol) were added, and the mixture was stirred at room temperature for 24 hours. The course of the reaction was monitored by thin layer chromatography. When the reaction had ended, the solvent was removed under vacuo. The remaining residue was a viscous oil which was taken up in diethyl ether (30 ml), and saturated NaHCO3 (30 ml) was added. The phases were separated, and the aqueous phase was extracted twice with 15 ml portions of Et2O. The combined organic phases were dried over Na2SO4 and concentrated under vacuo. The resulting product was initially in the form of an oil and crystallized spontaneously. The crude product was further purified by recrystallization from hexane.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:14][CH:13]=[CH:12][CH2:11][CH:10]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:14][CH:13]=[CH:12][CH2:11][CH:10]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[N:9]2[CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:37])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Cc1cccnc1C1CC=CCC(c2ncccc2C)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CC=CCC(c2ncccc2C)N1CCCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 25.6 %

Procedure:
A mixture of 2,7-bis-(3-methyl-pyridin-2-yl)-2,3,6,7-tetrahydro-1H-azepine (30.2 mg, 0.108 mmol), 2-(4-bromo-butyl)-isoindole-1,3-dione (33.5 mg, 0.119 mmol), DMF (3 mL), DIPEA (0.3 mL), and KI (4 mg) were heated to 110° C. for 4 h and overnight at 90° C. The solvent was removed and CH2Cl2 (20 mL) was added to the residue. It was washed with saturated NaHCO3 (10 mL). The aqueous layer was extracted two more times with CH2Cl2. The organic layer was dried (MgSO4), filtered and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 2:1 hexanes:EtOAc) provided 13.3 mg of 2-{4-[2,7-bis-(3-methyl-pyridin-2-yl)-2,3,6,7-tetrahydro-azepin-1-yl]-butyl}-isoindole-1,3-dione as a film. 1H NMR(CDCl3) δ 0.53-0.59 (m, 1H), 0.65-1.00 (m, 3H), 2.36 (s, 6H), 2.36-2.41 (m, 1H), 2.47-2.50 (m, 2H), 3.02-3.24 (m, 5H), 4.72 (dd, 2H, J=9.6, 1.8 Hz), 5.80-5.83 (m, 2H), 6.90 (dd, 2H, J=7.5, 4.2 Hz), 7.23 (d, 2H, J=7.5 Hz), 7.67-7.73 (m, 2H), 7.76-7.86 (m, 2H), 8.35 (d, 2H, J=4.2 Hz).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([OH:8])[C@@H:6]([OH:9])[CH:5]([OH:10])[O:4][C@@H:3]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[O:21]=[S:22]1(=[O:69])[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30][C@:31]23[CH2:65][CH2:64][C@@H:63]([C:66]([CH3:68])=[CH2:67])[C@@H:32]2[C@@H:33]2[C@@:46]([CH3:49])([CH2:47][CH2:48]3)[C@@:45]3([CH3:50])[C@@H:36]([C@:37]4([CH3:62])[C@@H:42]([CH2:43][CH2:44]3)[C:41]([CH3:52])([CH3:51])[C:40]([C:53]3[CH:61]=[CH:60][C:56]([C:57](O)=[O:58])=[CH:55][CH:54]=3)=[CH:39][CH2:38]4)[CH2:35][CH2:34]2)[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>O1CCOCC1>[O:69]=[S:22]1(=[O:21])[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30][C@:31]23[CH2:65][CH2:64][C@@H:63]([C:66]([CH3:68])=[CH2:67])[C@@H:32]2[C@@H:33]2[C@@:46]([CH3:49])([CH2:47][CH2:48]3)[C@@:45]3([CH3:50])[C@@H:36]([C@:37]4([CH3:62])[C@@H:42]([CH2:43][CH2:44]3)[C:41]([CH3:52])([CH3:51])[C:40]([C:53]3[CH:54]=[CH:55][C:56]([C:57]([O:10][C@H:5]5[O:4][C@H:3]([C:11]([O:13][CH2:14][C:15]6[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=6)=[O:12])[C@@H:2]([OH:1])[C@H:7]([OH:8])[C@H:6]5[OH:9])=[O:58])=[CH:60][CH:61]=3)=[CH:39][CH2:38]4)[CH2:35][CH2:34]2)[CH2:24][CH2:23]1
Reactant: O=C(OCc1ccccc1)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O[C@H]7O[C@H](C(=O)OCc8ccccc8)[C@@H](O)[C@H](O)[C@H]7O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
A mixture of (2S,3S,4S,5R)-benzyl 3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate (61.7 mg, 0.217 mmol), 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (100 mg, 0.145 mmol), HATU (88 mg, 0.232 mmol) and N-methylmorpholine (0.048 mL, 0.434 mmol) in dioxane (3 mL) was stirred overnight at room temperature. The reaction mixture was filtered, the clear solution was purified by prep HPLC with acetonitrile/water/ammonium acetate to provide the desired product as white solid (20 mg, 14%). LCMS: m/e 957.7 (M+H)+, 2.36 min (method 6). 1H NMR (500 MHz, Acetic) δ 8.05 (d, J=8.2 Hz, 2H), 7.58-7.14 (m, 7H), 5.95 (d, J=7.6 Hz, 1H), 5.38 (d, J=4.6 Hz, 1H), 5.26 (s, 2H), 4.84 (s, 1H), 4.74 (s, 1H), 4.30 (d, J=9.5 Hz, 1H), 4.05-3.78 (m, 3H), 3.46 (d, J=11.9 Hz, 1H), 3.38-3.22 (m, 6H), 3.20-3.11 (m, 3H), 3.07 (br. s., 2H), 2.95 (dt, J=10.8, 5.5 Hz, 1H), 2.42-1.01 (m, 22H), 1.77 (s, 3H), 1.30 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([CH3:40])(=[O:39])=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.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>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([CH3:40])(=[O:39])=[O:38]
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3S(C)(=O)=O)c2)OC1(C)C
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
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: C1CCOC1
Product: CS(=O)(=O)c1ccccc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F
Temperature: 65 °C
Yield: 79.2 %

Procedure:
A stirred mixture of 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.1073 g, 0.403 mmol) and 2-(2-fluoro-2′-(methanesulfonyl)biphenyl-5-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (228 mg, 0.607 mmol) in tetrahydrofuran (5 ml) and 2M aqueous sodium carbonate (containing 1 ml/l of 40 wt % tetrabutylammonium hydroxide in water) (0.605 ml, 1.21 mmol) was degassed by bubbling nitrogen through the mixture for 15 min. Tetrakis(triphenylphosphine)palladium(0) (24.6 mg, 0.0213 mmol) was then added and the mixture was heated at 65° C. under nitrogen for 6 h. After cooling, the mixture was partitioned between ethyl acetate (25 ml) and water (15 ml). The aqueous layer was extracted further with ethyl acetate (2×25 ml) and the combined organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with isohexane on a gradient of ethyl acetate (40-50%), to afford 3-[2-fluoro-2′-(methanesulfonyl)biphenyl-5-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid (139 mg, 79%): mp 211-213° C. (ethyl acetate/isohexane); δH (360 MHz, CDCl3) 2.89 (3H, s), 7.27 (1H, d, J 6.9), 7.40 (1H, td, J 1.2, 9.0), 7.46 (1H, dd, J 1.2, 7.4), 7.62-7.66 (2H, m), 7.68 (1H, td, J 1.6, 7.4), 7.74 (1H, td, J 1.6, 7.4), 8.10 (1H, s), 8.29 (1H, dd, J 1.4, 8.0), 9.22 (1H, d, J 7.0); MS (ES+) m/z 436 [M+H]+. Anal. Found: C, 55.02; H, 3.02; N, 9.23%. Required for C20H13F4N3O2S.0.1H2O: C, 54.94; H, 3.04; N, 9.61%.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:33])[C:14]=2[NH:18][C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([F:31])[CH:22]=2)[C:9]1=[O:34])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[Cl:33][C:13]1[C:14]([NH:18][C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[C:23]([F:31])[CH:22]=2)=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:34])[N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[CH:17]=[CH:16]2
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(Cl)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@H](CO)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with (R)-2-(6-chloro-5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-1-oxoisoquinolin-2(1H)-yl)propyl acetate (1.200 g, 0.002406 mol), potassium carbonate (0.997 g, 0.00722 mol) and methanol (20 mL, 0.5 mol) and 2 drops of water. The reaction was stirred at room temperature for 1 hour and was filtered over sodium sulfate and washed with methanol. the solvent was removed under reduced pressureunder reduced pressure and the residue purified by flash chromatography to afford the product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([CH3:16])[C:3]=1[C:17]#[N:18].[N:19]1(C(N2C=CN=C2)=N)C=CN=[CH:20]1>O1CCCC1>[NH2:19][C:20]1[O:8][C:7]2[C:2](=[C:3]([C:17]#[N:18])[C:4]([CH3:16])=[C:5]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[F:9])[N:1]=1
Reactant: N=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Solvent: C1CCOC1
Product: Cc1c(-c2ccccc2)c(F)c2oc(N)nc2c1C#N
Temperature: 25 °C
Yield: 87.3 %

Procedure:
4-Amino-6-fluoro-5-hydroxy-2-methylbiphenyl-3-carbonitrile (I-41) (1.66 g, 6.86 mmol) and di(imidazol-1-yl)methanimine (2.821 g) were suspended in tetrahydrofuran (33 ml), and stirred under reflux under nitrogen atmosphere for 120 hours. After cooling to room temperature, the solvent was evaporated away under reduced pressure. The residue was fractionated with 10% methanol-containing chloroform and water. The organic layer was separated, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, and the solvent was evaporated away under reduced pressure. The residue was recrystallized form methanol to obtain the entitled compound (1.60 g, 87%) as a pale brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11](N(OC)C)=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[Mg][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH3:10])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: COc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1cccc(C(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of N2-(tert-butoxycarbonyl)-N-methoxy-N-methyl-L-alaninamide (777 mg, 3.3 mmol) in dry THF (50 ml) was added a solution of bromo(3-methoxyphenyl)magnesium (1M in THF, 10 ml, 10 mmol). The mixture was stirred at r.t. for 5 h, then quenched with saturated aqueous NH4Cl (50 ml). After stirring for 30 min, the layers were separated, the aqueous layer extracted with ethyl acetate (50 ml). The combined organic layers were dried with Na2SO4, and the solvent was removed in vacuo. The subtitle compound was isolated by flash chromatography on silica gel (n-heptane/ethyl acetate, gradient from 20 to 50% ethyl acetate). Yield 471 mg (94%).
Reaction SMILES: [Na].[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH:5](P(OCC)(=O)OCC)[NH:4]1.[CH:17]1([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[C:33]([CH:40]=O)[CH:32]=2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>CCO>[CH:17]1([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[C:33]([CH:40]=[C:5]3[NH:4][C:3](=[O:2])[NH:7][C:6]3=[O:8])[CH:32]=2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Reactant: O=Cc1cc(OCCCNC(=O)NC2CCCCC2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cc(OCCCNC(=O)NC3CCCCC3)ccc2[N+](=O)[O-])N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
Sodium (0.50 g, 20 mg atom) was dissolved in absolute EtOH (100 mL), diethyl 2,4-dioxoimidazolidine-5-phosphonate (4.70 g, 20 mmol) added and the mixture stirred at room temperature for about 15 minutes. N-Cyclohexyl-N'-[3-(3-formyl-4-nitrophenoxy)propyl]urea (5.33 g, 15 mmol) in EtOH (75 mL) was added and the mixture stirred for about 1 hour. The solution was acidifed with 2N HCl solution, concentrated to ca. 75 mL and diluted with water. After stirring overnight, a pale yellow solid was filtered off and dried in air to give N-cyclohexyl-N'-[3-[4-nitro-3-[(2,4-dioxoimidazolidin-5-ylidene)-methyl]phenoxy] propyl]urea (6.50 g, 99 %). A 1.00 g sample was recrystallized from aqueous acetonitrile to give 0.79 g as a 5:1 (Z) to (E) mixture, mp 132°-138° C. IR (KBr) 1760, 1725, 1650, 1570, 1500, 1375, 1340, 1290, 1250 cm-1 ; 1 H NMR (DMSO-d6) δ 1.00 to 2.00 (10H, m, CH2 of cyclohexyl ring), 3.30 (2H, quintet, J=6 Hz, CO.NH.CH2), 3.35 (1H, m, N-CH), 4.11 (0.32H, t, J=6Hz, OCH2 of (Z) isomer), 4.20 (1.67H, t, J=6 Hz, OCH2 of (E) isomer), 6.62 (0.16H, s, olefinic H of (Z) isomer), 6.74 (0.84H, s, olefinic H of (E) isomer), 7.05 to 7.20 (2H, m, aryl H), 8.15 (1H, 2×d, aryl H ortho to NO2); MS m/Z 432 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]12[O:11][C:8]([CH2:12][O:13][CH3:14])([CH:9]=[CH:10]1)[CH2:7][C:6](OS(C(F)(F)F)(=O)=O)=[CH:5]2.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)O1>CCOC(C)=O.C(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]12[O:11][C:8]([CH2:12][O:13][CH3:14])([CH:9]=[CH:10]1)[CH2:7][C:6]([C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1)=[CH:5]2
Reactant: COCC12C=CC(COC)(CC(OS(=O)(=O)C(F)(F)F)=C1)O2
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCC12C=CC(COC)(CC(c3ccc(N)cc3)=C1)O2
Yield: 81 %

Procedure:
The title compound was prepared by the procedure of Example 4, step (b) using trifluoromethanesulfonic acid 1,5-bis-methoxymethyl-8-oxa-bicyclo[3.2.1]octa-2,6-dien-3-yl ester (as prepared in the previous step, 3.25 g, 9.45 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (2.28 g, 10.4 mmol). Silica gel chromatography (5-10% EtOAc/DCM) afforded the title compound (2.19 g, 81%) as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C17H21NO3, 288.2 (M+H), found 288.2.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:22][NH:23][O:24][CH3:25].C(N(CC)CC)C>ClCCl>[CH3:25][O:24][N:23]([CH3:22])[C:6]([CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)C1CCOC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of tetrahydrofuran-3-carboxylic acid (10 g, 86.1 mmol) in dichloromethane (200 mL). EDC.HCl (18.2 g, 94.9 mmol), N,O-dimethylhydroxylamine hydrochloride (10 g, 103 mmol) and triethylamine (24.0 mL, 172 mmol) were added and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with DCM (50 mL) and washed with aqueous HCl (1 M, 3×10 mL), sodium bicarbonate (sat., 2×30 mL) and brine (3×20 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the title compound as light yellow oil (6.71 g, 49%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[CH2:20][N:19]([C@H:29]([CH2:33][CH:34]4[CH2:37][CH2:36][CH2:35]4)[C:30]([OH:32])=[O:31])[CH2:18]3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]1([CH2:44]CCC2CCNCC2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl>>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[CH2:20][N:19]([C@H:29]([CH2:33][CH:34]4[CH2:35][CH2:36][CH2:37]4)[C:30]([O:32][CH2:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:31])[CH2:18]3)[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: O=C(O)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2cccc(F)c2)C1
Agent: Cl
Product: O=C(OCc1ccccc1)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2cccc(F)c2)C1
Yield: 102.1 %

Procedure:
The title compound was prepared from 23.2 mg (0.052 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, benzyl ester (from EXAMPLE 26, Step A) and 12.8 mg (0.052 mmol) of 4-(3-phenylpropyl)piperidine.HCl using a procedure analogous to that described in EXAMPLE 1, Step J to provide 31.7 mg (96%) of the title compound: RF: 0.57 (1:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 1.13-3.27 (m, 33H), 5.14 (s, 2H), 6.86-6.99 (m, 3H), 7.14-7.38 (m, 11H).