Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[C:6]([C:9]1[C:10]([I:33])=[C:11]([NH:17][C:18](=[O:32])[CH2:19][N:20]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:12]([I:16])=[CH:13][C:14]=1[I:15])([OH:8])=[O:7].Cl>O.[OH-].[Na+]>[C:6]([C:9]1[C:10]([I:33])=[C:11]([NH:17][C:18](=[O:32])[CH2:19][N:20]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]([OH:5])=[O:4])[CH2:28][CH2:27][N:26]([CH2:2][C:3]([OH:5])=[O:4])[CH2:25][CH2:24][N:23]([CH2:2][C:3]([OH:5])=[O:4])[CH2:22][CH2:21]2)[C:12]([I:16])=[CH:13][C:14]=1[I:15])([OH:8])=[O:7]
Reactant: O=C(O)CBr
Reactant: O=C(CN1CCNCCNCCNCC1)Nc1c(I)cc(I)c(C(=O)O)c1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)Nc2c(I)cc(I)c(C(=O)O)c2I)CCN(CC(=O)O)CC1
Yield: 70.7 %

Procedure:
18.9 g of bromoacetic acid (product available on the market) (0.136 mol) are dissolved in 20 ml of H2O, and by keeping the temperature below 10° C., the solution pH is adjusted to 5 with 68 ml of 2N NaOH (0.136 mol). After adding a solution of 30 g of compound. (B) N-(3-carboxy-2,4,6-triiodophenyl)-1,4,7,10-tetraazacyclododecane-1-acetamide (0.041 mol) in 20.5 ml of 2N NaOH, the reaction mixture is heated at 50° C. for 15 h keeping the pH at 10 with 6.15 ml of 2N NaOH (0.123 mol). A solid precipitates which is then filtered and dissolved in 200 ml of H2O. After acidification of the solution with 82 ml of HCl 2N (0.164 mol) the precipitate is filtered. 28.2 g of 10-[2-[(3-carboxy-2,4,6-triiodophenyl)amino]-2-oxoethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (0.029 mol) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.C1(C)C=CC=CC=1.C([O-])(=O)C.[NH4+].[C:23]([CH2:25]C(O)=O)#[N:24]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH:25][C:23]#[N:24]
Reactant: N#CCC(=O)O
Reactant: COc1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cccc(C=CC#N)c1

Procedure:
3-Methoxybenzaldehyde (20.8 g, 0.15 mol) was treated with toluene (dry, 140 mL), pyridine (dry, 60 mL), ammonium acetate (0.59 g) and cyanoacetic acid (11.9 g, 0.14 mol) and then heated under reflux with a Dean-Stark trap for 71 h according to the procedure of Montgomery et. al (J. Med. Chem. 1993, 36, 55). The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with 10% aq. HCl, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel, eluting with 2-5% EtOAc in hexanes to give 3-methoxycinnamonitrile, 14.65 g (60%). This material was dissolved in EtOH (75 mL) and conc. HCl (15 mL) and hydrogenated with 10% Pd/C (2.0 g) at 70 psi on a Parr shaker for 67 h. The reaction mixture was filtered over Celite. The filtrate was extracted with EtOAc, and the EtOAc layer was concentrated under vacuum to give the hydrochloride salt of 3-(3-methoxyphenyl)propylamine as a waxy white solid, 17.3 g (93%). HPLC—(Method B)—tr=1.28 min. [M+H]+=166.30. 1H-NMR (300 MHz, CDCl3/CD3OD): δ=7.14-7.19 (m, 1H), 6.70-6.77 (m, 3H), 4.51-4.58 (m, 2H), 3.75 (s, 3H, OMe), 2.85-2.91 (m, 2H), 2.63-2.68 (m, 2H), 1.95-2.01 (m, 2H).
Reaction SMILES: C[Al](C)C.[NH2:5][CH2:6][CH:7]1[CH2:9][CH2:8]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:23][O:24][C:25]=2[CH2:26][OH:27])=[N:15][CH:14]=1.C1(C)C=CC=CC=1>O1CCOCC1>[CH:7]1([CH2:6][NH:5][C:12](=[O:11])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:22]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)=[N:23][O:24][C:25]=3[CH2:26][OH:27])=[N:15][CH:14]=2)[CH2:9][CH2:8]1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C(NCC1CC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
A trimethylaluminium solution (2 M in toluene, 418 μL, 0.84 mmol) was added to a solution of aminomethylcyclopropane (61.3 mg, 0.84 mmol) in dioxane (3.75 mL). 6-[3-(4-Fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (75.0 mg, 0.21 mmol) in dioxane (3.75 mL) was added after 1 h at 50° C. The reaction mixture was stirred at 85° C. overnight. Again trimethylaluminium solution in toluene (2 M in toluene, 418 μL, 0.84 mmol) was added and stirring was continued for 3 h at 85° C. The solvent was removed by distillation. The residue was purified by chromatography (silica, ethyl acetate:heptane=4:6 to 8:2) to yield the title compound (30 mg, 36%) as a light yellow solid. MS: m/e=398.2 [M+H]+.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[CH:21][CH:20]=2)[C:8]=1[C:9]([O:11]C)=[O:10])(=O)C.[OH-].[K+]>CCO>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:7]([CH2:6][CH2:5][SH:4])[C:8]=2[C:9]([OH:11])=[O:10])=[CH:24][CH:23]=1)([OH:27])=[O:26]
Reactant: COC(=O)c1ccc(COc2cccc(CCSC(C)=O)c2C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(COc2cccc(CCS)c2C(=O)O)cc1
Yield: 46.3 %

Procedure:
To a deoxygenated solution of 2-[2-(acetylthio)ethyl]-6-[4-(methoxycarbonyl)phenyl]methoxy-benzoic acid, methyl ester (0.20 g, 0.50 mmol) in 95% EtOH (3 mL) was added a deoxygenated solution of KOH (0.463 g, 8.3 mmol) in 95% EtOH (3 mL) under nitrogen. The solution was heated at reflux overnight and quenched by addition of 1 N HCl (20 mL). The mixture was extracted with EtOAc (3×20 mL) and the combined organic extracts were washed with water and brine, then dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (1:1 dichloromathane/hexanes with 1% acetic acid) provided 2-[(4-carboxyphenyl)methoxy]-6-(2-mercaptoethyl)-benzoic acid (0.077 g, 46%) as a white solid: 1H NMR (CD3OD) δ2.75 (m, 2H), 2.92 (m, 2H), 5.22 (s, 2H), 6.93 (d, J=7.5 Hz, 1H), 6.98 (d, J=8.2 Hz, 1H), 7.30 (t, J=8.3 Hz, 1H), 7.55 (d, J=7.9 Hz, 2H), 8.02 (d, J=8.0 Hz, 2H); 13C NMR (CD3OD) δ26.5, 39.8, 71.1, 112.4, 123.9, 126.9, 128.3, 131.3, 131.7, 131.8, 139.9, 144.2, 156.7, 170.0, 172.3. Anal. Calcd for C17H16O5S: C, 61.43; H, 4.85; S, 9.65. Found: C, 61.16; H, 4.95; S, 9.44.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[F:27][C:26]([F:29])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:21][CH:22]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(C(F)(F)F)cc4)c3c2s1
Yield: 61 %

Procedure:
Prepared from VII and 4-aminobenzotrifluoride. Flash chromatography eluent (DCM-EtOAc, 7:3). Yield: 61%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2851, 2229, 1649, 1604, 1582, 1512, 1457, 1382, 1318, 1272, 1252, 1221, 1165, 1117, 1101, 1062, 1011, 979, 863, 830; 19F NMR (282 MHz, DMSO-d6) δ −60.01; 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, 1H, J=9.0 Hz), 8.22 (s, 1H), 7.77 (d, 1H, J=9.0 Hz), 7.70 (d, 2H, J=8.4 Hz), 7.39 (d, 2H, J=8.4 Hz); HRMS calcd for C17H9N5SF3 (M+H+): 372.0529, found 372.0535.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[C:20]([C:26](O)=[O:27])=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:20]3[C:19]([Cl:18])=[CH:24][C:23]([Cl:25])=[CH:22][N:21]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)cc3Cl)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 3,5-dichloro-pyridine-2-carboxylic acid (CAS 81719-53-1) following procedure I yielded the title compound as a crystalline white solid. MS (ISP): m/z=415.1 [M+H]+ and 417.1 [M+2+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4](Cl)=[C:5]([F:21])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:8]2=[O:20])#[N:2].[C@@H:23]12[CH2:31][NH:30][CH2:29][C@@H:28]1[CH2:27][CH2:26][CH2:25][NH:24]2.N12CCN(CC1)CC2>C(#N)C>[C:1]([C:3]1[C:4]([N:30]2[CH2:31][C@@H:23]3[C@@H:28]([CH2:27][CH2:26][CH2:25][NH:24]3)[CH2:29]2)=[C:5]([F:21])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:8]2=[O:20])#[N:2]
Reactant: COC(=O)c1cn(C2CC2)c2c(C#N)c(Cl)c(F)cc2c1=O
Reactant: C1CN[C@@H]2CNC[C@@H]2C1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COC(=O)c1cn(C2CC2)c2c(C#N)c(N3C[C@@H]4CCCN[C@@H]4C3)c(F)cc2c1=O

Procedure:
200 mg (0.625 mmol) of methyl 8-cyano-1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 86 mg (0.683 mmol) of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane and 150 mg (1.34 mmol) of 1,4-diazabicyclo[2.2.2]octane are stirred in 6 ml of acetonitrile at room temperature for 48 hours. Thereafter, the mixture is evaporated and the residue is partitioned between 15 ml of chloroform and 20 ml of saturated sodium carbonate solution. The organic phase is separated off, the aqueous phase is extracted again with chloroform and, after drying with sodium sulfate, the combined extracts are evaporated. For purification, the residue is chromatographed over silica gel with ethyl acetate/ethanol/25% strength aqueous ammonia solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:17]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:7]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][C:8]1=[O:10])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: O=C1Oc2ccc(Cl)cc2C1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(c2ccccc2)C(=O)Oc2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 42.8 mmol of 5-chloro-2,3-dihydro-2-oxo-3-phenylbenzofuran in 50 ml of anhydrous dimethylformamide is added at room temperature to a suspension of 42.8 mmol of sodium hydride in 20 ml of anhydrous dimethylformamide. The mixture is stirred for one hour at 20° C. and 42.8 mmol of ethyl bromoacetate are added. The mixture is stirred for 12 hours at 20° C., the medium concentrated under vacuum, the residue taken up in 200 ml of 1% strength hydrochloric acid solution, the aqueous phase extracted with benzene, the organic phase dried over anhydrous sodium sulfate, the solvent evaporated off and the crystalline residue washed with a solution of ethyl ether and acetone (90:10). After filtration, 25.8 mmol of crystals are collected.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[NH:8][C:7](=O)[C:6]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:23]>>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([Cl:23])[C:6]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(I)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCc1nc(C)nc(Cl)c1Cc1ccc(I)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 485 mg (1.27 mmol) 6-butyl-2-methyl-5-[(4-iodophenyl)methyl]pyrimidine-4(3H)-one in 7 mL POCl3 was refluxed for 60 minutes. After cooling to room temperature, excess POCl3 was stripped off in vacuo. The crude product was partitioned between CH2Cl2 and a mixture of brine and NaHCO3. The organic layer was removed and the aqueous layer was extracted three more times with CH2Cl2. The combined organic material was dried over MgSO4, stripped of solvent in vacuo, then was medium pressure chromatographed on silica gel using 10% EtOAc/hexane to give 380 mg of 6-butyl-4-chloro-2-methyl-5-[(4-iodophenyl)methyl]pyrimidine, 75% yield.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C1COCC1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:2][CH2:3][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[C:6](=[O:23])[N:7]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:8]([CH3:14])=[N:9]3)=[O:40])=[CH:34][CH:33]=1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc2cccc(CNC(=O)Nc3ccc(Cl)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Yield: 66.1 %

Procedure:
To a stirred suspension of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.44 g, 1.3 mmol) and triethylamine (0.25 mL, 1.8 mmol) in THF (8 mL) at 5˜10° C., was added 4-chlorophenyl isocyanate (0.21 mL, 1.7 mmol) and stirred for ten minutes. Then the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(4-chloro-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-urea as a yellow solid (390 mg, 66% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.34 min (98.7%); mp, 255-257° C.; 1HNMR (DMSO-d6) 2.17-2.23 (m, 1H, CHH), 2.59-2.94 (m, 6H, CHCH2, CH3), 4.72 (d, J=6 Hz, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 6.65 (t, J=5 Hz, 1H, CH2NH), 7.21-7.78 (m, 7H, Ar), 8.92 (s, 1H, NH), 11.04 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.70, 23.31, 30.62, 42.30, 56.51, 117.81, 119.02, 124.42, 125.77, 126.21, 128.42, 133.99, 139.47, 141.32, 148.50, 154.76, 154.88, 161.02, 169.49, 172.65. LCMS MH=454, 456; Anal Calcd For C22H20N5O4Cl: C, 58.22; H, 4.44; N, 15.43; Cl, 7.81. Found: C, 58.11; H, 4.24; N, 15.16; Cl, 7.80.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19](O)=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.FC1C=CC([N:30]2C3C(=CC=C(C4C=CN=CC=4)C=3)C(=O)C(C(N)=O)=C2)=CC=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([NH2:30])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(Cl)ccc2c1=O
Product: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(Cl)ccc2c1=O

Procedure:
1,4-Dihydro-7-chloro-1-(4-fluorophenyl)-4-oxo-3-quinolinecarboxamide [IV; R=H, R1 =4-FC6H4, R2 =H, R6 =H, X=Cl]was prepared from 2.65 g 1,4-dihydro-7-chloro1-(4-fluorophenyl)-4-oxo-3-quinolinecarboxylic acid by the procedure of Example 1, part (h), and was obtained (1.26 g) in the form of a colorless solid, m.p. 253-255° C when recrystallized from acetonitrile.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH:1]1([CH2:6][C@H:7]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:14][N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SC#N)s2)cc1
Reactant: ClCCN1CCOCC1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SCCN3CCOCC3)s2)cc1

Procedure:
The title compound was prepared from (R)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-thiocyanato-thiazol-2-yl)-propionamide and 4-(2-chloroethyl)morpholine as described in Example 10. 1H-NMR (CD3OD): δ 7.92 (d, 2H), 7.67 (d, 2H), 7.55 (1H), 3.96 (t, 1H), 4.00-3.37 (broad m, 8H), 3.34 (m, 2H), 3.10 (s, 3H), 3.09-3.05 (m, 2H), 2.26-2.29 (m, 1H), 1.89-1.47 (m, 8H), 1.18 (m, 2H); HPLC-MS: m/z: 524 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[F:15][C:16]([F:30])([F:29])[CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:15][C:16]([F:30])([F:29])[CH2:17][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: NC(=O)c1ccnc(-c2c[nH]cn2)c1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Product: NC(=O)c1ccnc(-c2cn(CC(F)(F)F)cn2)c1
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield from 2-(1H-imidazol-4-yl)pyridine-4-carboxamide (PREPARATION 7) and toluene-4-sulfonic acid 2,2,2-trifluoro-ethyl ester according to the procedure for the preparation Example 128, part A. [M+H] Calc'd for C11H9F3N4O, 271. Found, 271.
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].CC(C)([O-])C.[K+].C(OC(N[C@@H:41]1[C@H:46]([CH2:47][CH:48]=O)[CH2:45][C@H:44]2[CH2:50][C@H:42]1[C:43]2([CH3:52])[CH3:51])=O)(C)(C)C.O>O1CCCC1>[C:2]([CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:48]\[CH2:47][CH:46]1[CH2:41][CH:42]2[CH2:50][CH:44]([C:43]2([CH3:51])[CH3:52])[CH2:45]1)#[N:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1[C@H](CC=O)C[C@H]2C[C@H]1C2(C)C
Reactant: N#CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C2CC(C/C=C\CCCC#N)CC1C2
Yield: 41.8 %

Procedure:
To a suspension of 30.3 g of (4-cyanobutyl)triphenylphosphonium bromide in 140 ml of tetrahydrofuran is added 8.07 g of potassium-tert-butoxide under stirring in an nitrogen atmosphere and the mixture is stirred at room temperature for 1.5 hours. A solution of the above prepared crude aldehyde 3c in 50 ml of tetrahydrofuran is dropwise added at 0° C. and the resulting mixture is stirred at the same temperature for 1 hour. Water is added to the reaction mixture, then which is extracted with ether. The organic layer is washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue is purified by flash chromatography on 200 g of silica gel (hexane:ethyl acetate=6:1) to give 6.9 g of the titled compound 7a in 41.8% yield.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([O:27]C)=[O:26])=[CH:18][C:17]=4[CH:29]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=4[CH:29]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(N4CCCCC4)cc3)ccc2S(=O)(=O)CC1
Agent: Cl
Product: O=C(O)C1=Cc2cc(-c3ccc(N4CCCCC4)cc3)ccc2S(=O)(=O)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 94.8 %

Procedure:
To methyl 7-(4-piperidinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (600 mg) was added 6N hydrochloric acid (60 ml), and the mixture was stirred at 70° C. for 5 hours and concentrated under reduced pressure. To the residue was added ethanol, and to the mixture were added 8N sodium hydroxide solution and 1N sodium hydroxide solution to make the solution pH 6-7. The mixture was concentrated under reduced pressure to give solid, which was collected by filtration and washed with water, 2-propanol, acetone and diisopropylether to give yellow powder of 7-(4-piperidinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (549.5 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:20])[N:3]=1.B([C:24]1[CH:35]=[CH:34][C:27]([CH2:28][C@@H:29]([C:31]([OH:33])=[O:32])[NH2:30])=[CH:26][CH:25]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:30][CH:29]([CH2:28][C:27]1[CH:34]=[CH:35][C:24]([C:2]2[N:3]=[C:4]([NH2:20])[N:5]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:7]=2)=[CH:25][CH:26]=1)[C:31]([OH:33])=[O:32]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: Nc1nc(Cl)nc(OC(c2ccccc2)C(F)(F)F)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Nc1nc(OC(c2ccccc2)C(F)(F)F)nc(-c2ccc(CC(N)C(=O)O)cc2)n1
Temperature: 150 °C
Yield: 7.4 %

Procedure:
A microwave vial was charged with 4-chloro-6-[2,2,2-trifluoro-1-phenyl-ethoxy]-[1,3,5]triazine-2-ylamine (33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol), 1 ml of actonitrile, and 0.7 ml of water. Aqueous sodium carbonate (0.3 ml, 1M) was added to above solution followed by 5 mol percent dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, was then purified with Prep-LC to give 3.2 mg 2-amino-3-{4-[4-amino-6-(1-phenyl-2,2,2-trifluoro-ethoxy]-[1,3,5]triazin-2-yl]-phenyl)-propionic acid. 1H NMR (300 MHz, CD3OD) δ 8.22 (d, J=8.20 Hz, 2H), 7.52 (m, 2 H), 7.33 (m, 5H) 6.62 (m, 1H), 4.19 (t, 1 H), 3.1-3.33 (m, 2 H).
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:8]>CC(C)=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7](=[O:8])[CH2:6][CH2:5][CH2:4][I:1])=[CH:10][CH:11]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CCCI)c1ccc(F)cc1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
Sodium iodide (7.47 g, 49.84 mmol, 2 equiv) was added to a solution of 4-chloro-1-(4-fluorophenyl)butan-1-one (5 g, 24.92 mmol, 1 equiv) in acetone. The reaction mixture was refluxed for 16 h. After cooling to ambient temperature, it was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and sodium bisulfite, followed by a wash with brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.5, gradient—1%-10% ethyl acetate in hexanes) to afford the title compound as a clear oil (5.62 g, 77%). The bottle containing the compound was wrapped in aluminium foil and stored in the freezer to avoid further darkening of the mixture; MS for C10H10FIO m/z 291.98 (M+H)+.