Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[O:11][C@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]1([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[CH2:34]Br)[CH2:30][CH2:29][CH2:28]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[O:14]=[C:12]1[C@H:13]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[C:31]([CH:27]3[CH2:28][CH2:29][CH2:30]3)[CH:32]=2)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:11]1
Reactant: BrCc1cccc(C2CCC2)c1
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2cccc(C3CCC3)c2)C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Yield: 54.1 %

Procedure:
According to example 81, 2.50 g of tert-butyl- (2R, 3S)-(-)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate (Aldrich) was alkylated with 1.59 g of 3-cyclobutylbenzyl bromide in 80 mL of anhydrous THF using 7.41 mL of 1M sodium bis(trimethylsilyl)amide in THF (Aldrich). The crude product was subjected to flash chromatography on 120 g of silica gel (8:2 hexane:EtOAc) and then recrystallization from EtOH-water to afford 1.90 g (54%) of tert-butyl (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-cyclobutylbenzyl)-4-morpholinecarboxylate as a white powder, m.p. 145-147° C.
Reaction SMILES: [OH:1][C:2]1([CH:14]([CH3:18])[C:15](O)=[O:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1.CCOCC>[OH:1][C:2]1([CH:14]([CH3:18])[CH2:15][OH:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C(=O)O)C1(O)CCCCC1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(CO)C1(O)CCCCC1c1ccccc1

Procedure:
A solution of 61 grams of 2-(1-hydroxy-2-phenylcyclohexyl)-propionic acid (I) in 200 ml tetrahydrofuran is added dropwise to 30 grams of lithium aluminum hydride in 700 ml ether. After refluxing for 21/2 hours, the mixture is cooled to -5° and treated successively with 140 ml ethyl acetate and 150 ml water. The slurry is filterd, the residue on the filter paper is washed well with ether which is combined wiht the filtrate and the solutin dried over magnesium sulfate. Evaporation of the solution left 57 grams of product (II) melting at 89°-93°C.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8](=O)[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[CH3:19][O:20][P:21]([CH2:25][NH2:26])(=[O:24])[O:22][CH3:23].C(N(CC)CC)C.C([BH3-])#N.[Na+]>C1COCC1.CCO.C1COCC1>[CH3:19][O:20][P:21]([CH2:25][NH:26][CH:8]([CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:2][CH:3]=1)[C:9]([OH:11])=[O:10])([O:22][CH3:23])=[O:24]
Reactant: O=C(O)C(=O)Cc1ccc(-c2ccccc2)cc1
Reactant: COP(=O)(CN)OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COP(=O)(CNC(Cc1ccc(-c2ccccc2)cc1)C(=O)O)OC
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 4-biphenylyl-pyruvic acid in anhydrous THF-EtOH (50 mL, 9:1) is added aminomethylphosphonic acid dimethyl ester (520 mg, 3.7 mmol) in THF-EtOH (5 mL, 9:1). The pH is then adjusted with triethylamine to 6.6. After 20 minutes, sodium cyanoborohydride (100 mg, 1.6 mmol) in THF (2.5 mL) is added over 30 minutes. The solution is stirred for 18 hours and then concentrated. Ether (20 mL) is added and the mixture is cooled and treated with 1N HCl (7 mL). After stirring at room temperature for 30 minutes, the solid is filtered off and washed with ether and water to yield 2-(dimethylphosphonomethylamino)-3-(4-biphenylyl)-propionic acid as a waxy solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[F:13][C:14]1[CH:15]=[C:16]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc(F)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-fluorobenzenesulfonyl chloride according to METHOD A, giving 0.55 g (80%) of a pink powder: MS (electrospray, [M−H]−) m/z 343.1
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH:15]=[C:16]([CH3:17])[C:10]=3[N:9]=2)=[C:6]([O:24][CH3:25])[N:5]=[C:4]([O:26][CH3:27])[N:3]=1.C(N(CC)CC)C.Cl.[NH2:36][CH2:37][C@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[CH:41]=1)[OH:39]>C(#N)C>[Cl:46][C:42]1[CH:41]=[C:40]([CH:38]([OH:39])[CH2:37][NH:36][C:2]2[C:7]([C:8]3[NH:12][C:11]4[CH:13]=[C:14]([N:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)[CH:15]=[C:16]([CH3:17])[C:10]=4[N:9]=3)=[C:6]([O:24][CH3:25])[N:5]=[C:4]([O:26][CH3:27])[N:3]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: COc1nc(Cl)c(-c2nc3c(C)cc(N4CCOCC4)cc3[nH]2)c(OC)n1
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1nc(NCC(O)c2cccc(Cl)c2)c(-c2nc3c(C)cc(N4CCOCC4)cc3[nH]2)c(OC)n1

Procedure:
To a solution of 2-(4-chloro-2,6-dimethoxy-pyrimidin-5-yl)-4-methyl-6-morpholin-4-yl-1H-benzoimidazole (0.075 g, 0.192 mmol) in acetonitrile (5 mL) was added triethylamine (134 μl, 0.962 mmol) and (S)-2-Amino-1-(3-chloro-phenyl)-ethanol hydrochloride (42 mg, 0.202 mmol). The crude material was purified on silicagel dry colomn using AcOEt: Hex (8:2) to give the title compound as a beige solid. (0.055 g, 55%). HPLC 98%. LCMS 20 (+ESI, M+H+) m/z 525. IR (KBr, cm−1) 3446, 2955, 1595, 1472, 1367. 1H NMR (400 MHz, DMSO) δ 11.63 (s, 1H), 11.1 (m, 1H), 7.54 (s, 1H), 7.41-7.28 (m, 3H), 6.87 (d, J=2.0 Hz, 1H), 6.78 (s, 1H) 5.85 (s. 1H), 4.88 (m, 1H), 4.05 (s, 3H), 3.91-3.84 (m, 4H), 3.79-3.77 (m, 4H), 3.73-3.69 (m, 1H), 3.09-3.07 (m, 4H), 2.50 (3H, s). HRMS calcd for C26H29ClN6O4:525.2017; found 525.2008.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]2.[C:22](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.C(OCC)(=O)C>CN(C=O)C.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>[CH3:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Br)c(F)cc2OC1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1F)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 110 °C

Procedure:
To the mixture of ethyl 6-bromo-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (2.2g, 6 mmol), potassium carbonate(3.22g, 23.4mmol), and tetrakis(triphenylphosphine)palladium (0) (700 mg, 0.6 mmol) in 18 ml of anhydrous DMF was added trimethylboroxine(2.5 mL, 9 mmol). The resulting mixture was heated to 110° C. under nitrogen atmosphere for 15 hrs. After cooling to room temperature, to the reaction was added 200 mL of ethyl acetate, the resulting organic phase was washed with brine, and dried over anhydrous magnesium sulfate. After removing the solvents, the residue was purified on a short silica gel column with hexane/EtOAc mixture. The collected fraction was then evaporated to dryness. 300 mg of the purified intermediate was then dissolved in 9 mL of 1:1:1 THF/EtOH/Water, followed by addition of lithium hydroxide hydrate (102 mg). The resulting solution was heated to 80° C. for 1.5 hrs. The volatiles were then removed, the residue was diluted with water, and acidified at 0° C. with dilute hydrochloric acid. Plenty of precipitates were formed. The product was then extracted with ethyl acetate. After removing the solvents, the crude product was purified on reverse phase HPLC. Light yellow solid. 1H NMR (CDCl3/CD3OD/300 MHz) 7.76(s, 1H), 7.07(d, J=8.1 Hz, 1H), 6.68(d, J=9.9 Hz, 1H), 5.65(q, J=6.9 Hz, 1H), 2.20(s, 3H). 19F NMR(CDCl3/CD3OD/300 MHz) −78.93(d, J=6.9 Hz), −107.11(t, J=7.9 Hz). 13C NMR(CDCl3/CD3OD/300 MHz) 168.0, 165.8, 162.3, 153.2(d, J=12.8 Hz), 138.4, 132.2, 123.6(q, J=287.5 Hz), 119.8(d, J=18.5 Hz), 115.0(d, J=43.2 Hz), 104.1(d, J=27.1 hz), 70.7(q, J=33.3 Hz), 14.0(d, J=3.2 Hz). LC-MS(ES+): 277.2(M+1, 100). Hight resolution mass(ES−): m/z calc. For C12H8F4O3: 275.0337(M−H), found: 275.0341.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36])(=[O:31])=[O:30]>CN(C=O)C>[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][CH:10]=1)=[O:17])(=[O:30])=[O:31]
Reactant: Cc1nc(-c2ccc(F)cc2)ncc1C(=O)O
Reactant: CNS(=O)(=O)c1cccc(CN)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3ccc(F)cc3)nc2C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
A mixture of 2-(4-fluorophenyl)-4-methylpyrimidine-5-carboxylic acid (232 mg, 1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (380 mg 1 mmol) in dry DMF (12 mL) is treated with diisopropylethylamine (0.18 mL) and stirred at room temperature for 30 min. A solution of 3-methylsulfamoylbenzylamine (300 mg, 1.5 mmol) in dry DMF (1.5 mL) is added and the mixture is stirred at room temperature for 24 hours. The solvent is removed and the residue is partitioned between EtOAc and water. The organic phase is separated, washed with saturated NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 60% EtOAc in heptane to afford 2-(4-fluorophenyl)-4-methylpyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide (210 mg, 52%) as a solid. MS: 415 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.42 (s, 3H), 2.63 (s, 3H), 4.60 (d, 2H), 7.37-7.40 (t, 2H), 7.50 (s, 1H), 7.60-7.75 (m, 3H), 7.80 (s, 1H), 8.45-8.50 (dd, 2H), 8.88 (s, 1H), 9.30 (t, 1H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=O)[O:5]CC)[CH3:2].C(Cl)(=O)C([Cl:22])=O>C(OCC)C>[CH2:9]([P:4]([Cl:22])(=[O:5])[O:3][CH2:1][CH3:2])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCP(=O)(OCC)OCC
Solvent: CCOCC
Product: CCCCCCCCCCP(=O)(Cl)OCC
Temperature: -20 °C
Yield: 73 %

Procedure:
To a 500 mL round bottomed flask containing n-decylphosphonic acid diethyl ester, 22 g (79.0 mmol) was added to 100 mL of diethylether. This solution was stirred and cooled to −20° C. using an ice/salt water bath. Oxalyl Chloride (20.06 g, 158 mmol) was added in small portions over 45 minutes while maintaining the temperature at −20° C. The reaction mixture was then allowed to warm to room temperature and stirred for 24 hours. The solvent was removed by rotary evaporation to give a viscous liquid. The liquid was purified by vacuum distillation (boiling point: 126° C. at 0.4 mmHg) to give 15.5 g (73% yield) of the desired product. 1H NMR (400 MHz CDCl3): δ 4.2 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H), 1.2 (m, 17H), 0.75 (t, 3H).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([C@@H:10]([NH:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]1[C:36](O)=[O:37].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]1[C:36]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]([C@@H:10]([NH:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:37]
Reactant: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
To a solution of N-{(1S)-1-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-2,2-dimethylpropyl}-1H-indole-2-carboxamide (120 mg, 0.34 mmol) in CH2Cl2 (4 mL) was added 1H-indole-2-carboxylic acid (55 mg, 0.34 mmol), EDC (78 mg, 0.41 mmol), HOBt (9 mg, 0.07 mmol) and NMM (102 mg, 0.93 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was diluted with CH2Cl2 (5 mL) and washed with sat. NaHCO3 (10 mL), 1N HCl (10 mL), sat. NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to yield the crude product. The material was purified by HPLC (YMC C18 5.0 uM 250*20 mm) and then recrystallized from water, dried by lyophilization to afford 64 mg of the title compound: LCMS (m/z): 498.4 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 0.98-1.16 (9H, m), 1.83-2.07 (3H, m), 3.52-3.96 (4H, m), 4.65-5.20 (3H, m), 6.62-6.98 (3H, m), 7.06-7.18 (2H, m), 7.21-7.45 (3H, m), 7.53-7.68 (2H, m), 9.42-9.73 (2H, m).
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=3)[CH:10]=[C:9]([C:25]([F:28])([F:27])[F:26])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCOCC1.O.[OH-].[Li+].Cl>C(OCC)(=O)C.O>[CH:1]1([O:6][C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)[CH:10]=[C:9]([C:25]([F:27])([F:28])[F:26])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cc1ccc(Cc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 53.6 %

Procedure:
An 100-mL round bottom flask was charged with methyl 2-(4-((2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate (0.100 g, 0.25 mmol), dioxane (6 ml) and water (3 ml). To this solution was then added lithium hydroxide monohydrate (0.053 g, 1.26 mmol). The resulting mixture was stirred at 50° C. for 1.5 h. The cooled reaction mixture was treated with 2N aqueous HCl until pH˜5, then diluted with ethyl acetate (75 mL). The organic layer was washed with saturated sodium chloride (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexane/ethyl acetate (10:0 to 0:10) as the eluent, followed by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.051 g, 53%) as an off-white solid. MW=380.36. M.p. 97-99° C. 1H NMR (DMSO-d6, 500 MHz) δ 12.28 (br s, 1H), 7.52 (s, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 5.35 (septet, J=3.0 Hz, 1H), 4.11 (s, 2H), 3.52 (s, 2H), 2.00-1.89 (m, 2H), 1.77-1.65 (m, 4H), 1.65-1.55 (m, 2H); APCI MS m/z 381 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J27) (328 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (330 mg, 50%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([S:6][C:7]([CH3:27])([CH3:26])[C:8]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)([OH:15])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[CH2:4][OH:5].FC(F)(F)[C:30]1[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[CH:38]=[CH:39]/[CH:40]=O)=[CH:32][CH:31]=1>>[CH3:26][C:7]([S:6][C@@H:3]1[CH2:4][O:5][C@@H:40](/[CH:39]=[CH:38]/[CH:37]=[CH:36]/[C:33]2[CH:32]=[CH:31][CH:30]=[CH:35][C:34]=2[C:22]([F:25])([F:24])[F:23])[O:1][CH2:2]1)([CH3:27])[C:8]([C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=1)([OH:15])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: CC(C)(SC(CO)CO)C(O)(Cn1cncn1)c1ccc(C(F)(F)F)cc1
Reactant: O=C/C=C/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(C)(S[C@H]1CO[C@H](/C=C/C=C/c2ccccc2C(F)(F)F)OC1)C(O)(Cn1cncn1)c1ccc(C(F)(F)F)cc1

Procedure:
Reaction was carried out in the same manner as in Example 4 using (RS)-3-[(1,3-dihydroxy-2-propyl)thio]-3-methyl-2-[4-(trifluoromethyl)phenyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Reference example 55 and (2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienal as described in Reference example 25 to obtain the title compound, a major product as a colorless foam.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)[N:4]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[N:24]=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[N:4]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:29][C:25]3[N:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:19][CH2:18]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: Cc1cccc(Oc2cccc(C=C3CCNCC3)c2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnn4)CC3)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
2-Methyl-6-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (500 mg, 1.42 mmol, from Example 40, Step 5), phenyl pyridazin-3-ylcarbamate (335 mg, 1.56 mmol) and triethylamine (0.79 mL, 5.66 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 h, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-5%, (8:1 EtOH:conc. NH4OH):CH2Cl2) to afford the title compound (336 mg) as a foamy white solid. MS (APCI 10V) AP+ 402.0, 281.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.42 (s, 3H) 2.46 (td, J=5.84, 0.80 Hz, 2H) 2.58 (td, J=5.78, 1.13 Hz, 2H) 3.52-3.63 (m, 2H) 3.63-3.72 (m, 2H) 6.45 (s, 1H) 6.65 (dt, J=8.21, 0.69 Hz, 1H) 6.90-6.97 (m, 2H) 6.99 (dt, J=7.16, 0.48 Hz, 1H) 7.04-7.11 (m, J=8.10, 1.21, 0.84, 0.63 Hz, 1H) 7.36 (dd, J=8.86, 7.71 Hz, 1H) 7.59 (dd, J=9.11, 4.65 Hz, 1H) 7.68 (dd, J=8.08, 7.52 Hz, 1H) 8.12 (d, J=8.87 Hz, 1H) 8.79 (d, J=3.90 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH2:8][C:9]#[N:10].C(N(CC)CC)C.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)([O-:21])=[O:20]>C1(C)C=CC=CC=1.CS(C)=O>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH:8]([C:29](=[O:30])[NH:28][C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][CH:26]=1)[C:9]#[N:10]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: Cn1cccc1C(=O)CC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
The solution of 4.9 g of the 1-methyl-β-oxo-2-pyrrolpropionitrile in 50 ml of toluene, 5 ml of dimethylsulfoxide and 4 g of triethylamine is treated with the solution of 5.7 g of p-nitrophenylisocyanate in the minimum amount of toluene while stirring. After standing overnight it is evaporated and the residue taken up in methanol. The solution is filtered, diluted with water and 6 ml of triethylamine, washed with ethyl acetate, and the washings extracted once with 5% aqueous sodium hydroxide. The combined aqueous solutions are acidified with 5 N hydrochloric acid and the precipitate collected. It is washed with water, triturated with methanol-ethanol and recrystallized from dimethylformamide, to yield the 1-methyl-β-oxo-α-(p-nitrophenylcarbamoyl)-2-pyrrolpropionitrile melting at 245°-250° with decomposition.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:23])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[C:12]=2[C:13]=1[CH3:14])(=O)=O.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)(C)C.CC(OC)(C)C>[CH3:22][O:21][C:15]1[C:12]2[C:13]([CH3:14])=[C:8]([CH2:7][CH2:6][N:33]3[CH2:34][CH2:35][N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:31][CH2:32]3)[C:9](=[O:23])[O:10][C:11]=2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: COc1cc(OC)c2c(C)c(CCOS(C)(=O)=O)c(=O)oc2c1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: COc1cc(OC)c2c(C)c(CCN3CCN(c4ccccc4)CC3)c(=O)oc2c1
Yield: 50 %

Procedure:
Process B; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 35) and 1-phenylpiperazine; yield 50%; m.p. 112°-114° C. (from isopropanol/TBME).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@H:4]([O:7][C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=2)[C:11]([O:13]C)=[O:12])[C:3]1=[O:26].CO.[OH-].[Li+].O>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][C@H:4]([O:7][C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=2)[C:11]([OH:13])=[O:12])[C:3]1=[O:26]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@H]2CCN(C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN1CC[C@H](Oc2cc(OCc3ccccc3)cc(C(=O)O)c2)C1=O
Yield: 90.7 %

Procedure:
Methyl 3-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-5-phenylmethoxy-benzoate (Intermediate 9) (2.4 g, 6.8 mmol) was dissolved in THF (45 mL), methanol (15 mL) and 1 N lithiumhydroxide (8.1 mL). Water (60 mL) was added dropwise until the solution went cloudy and the resultant solution was stirred for 3 hours at room temperature. The organics were removed by evaporation under reduced pressure, the aqueous solution was filtered, acidified with 2N hydrochloric acid, extracted with ethyl acetate (3×20 mL), washed with water (10 mL), brine (10 mL) and evaporated to dryness under reduced pressure to give product (2.106 g, 92%). 1H NMR 6 (300 MHz, CDCl3) 2.07-2.21 (m, 1H), 2.51-2.65 (m, 1H), 2.96 (s, 3H), 3.32-3.55 (m, 2H), 4.92 (t, 1H), 5.06 (s, 2H), 6.88 (s, 1H), 7.28-7.46 (m, 7H); m/z 340 (M−H)−.