Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=13)[N:8]=[CH:7][N:6]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]1[OH:29])[C:5]2=[O:30].[Cl-].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][Zn+])=[CH:35][N:34]=1>ClCCl.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>[Cl:32][C:33]1[N:34]=[CH:35][C:36]([CH2:39][C:2]2[CH:3]=[C:4]3[C:9](=[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=24)[N:8]=[CH:7][N:6]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][CH:17]2[OH:29])[C:5]3=[O:30])=[CH:37][CH:38]=1
Reactant: Clc1ccc(C[Zn+])cn1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc3c(cc(Br)c4ccccc43)c2=O)C(O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2cnc3c(cc(Cc4ccc(Cl)nc4)c4ccccc43)c2=O)C(O)C1
Temperature: 90 °C

Procedure:
To a dry 25 mL round bottom flask containing tert-butyl rac-(3R,4R)-4-(6-bromo-4-oxobenzo[h]quinazolin-3(4H)-yl)-3-hydroxypiperidine-1-carboxylate (0.163 g, 0.344 mmol) under N2(g) was added (2-chloro-5-pyridyl)methylzinc chloride (0.5 M in THF, 2.06 mL, 1.03 mmol) and tetrakis(triphenylphosphine)palladium (0) (10 mol %). The reaction was heated to reflux at 90° C. for 20 h, cooled to room temperature, and diluted with dichloromethane. Hexanes were added to the solution and the resultant beige precipitate was collected via filtration, washed with dichloromethane and hexanes, and dried on high vac to provide crude tert-butyl rac-(3R,4R)-4-[6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl]-3-hydroxypiperidine-1-carboxylate that gave a mass ion (ES+) of 520.9 for M+H+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:13]C3)[CH:10]=[C:6]2[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN1C(=O)CCC1>[CH2:11]([C:9]1[CH:10]=[C:6]2[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:25])([CH3:23])[CH3:24])=[CH:20][CH:21]=3)[CH:3]=[C:2]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:7]2[N:8]=1)[CH3:13]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nc(C4CC4)cc3n2)cc1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Product: CCc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCOCC3)n2n1
Temperature: 25 °C
Yield: 50 %

Procedure:
In a 2 mL microwave vial was placed N-(7-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2H, 75 mg, 0.21 mmol) and morpholine (36 mg, 0.42 mmol). To the sealed vial was then added NMP (2 ml) and the mixture was then heated in the microwave at 120° C. for 30 minutes. After cooling to room temperature, the reaction mixture was partitioned between brine and EtOAc. The aqueous layer was extracted once more with EtOAc, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by recrystallization from ether and EtOAC to give the titled compound (43 mg, 50% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=10.87 (s, 2H), 8.05-7.92 (m, 2H), 7.59 (d, J=8.6 Hz, 2H), 7.36 (s, 1H), 6.19 (s, 1H), 5.18 (s, 1H), 3.91-3.79 (m, 4H), 3.77-3.69 (m, 4H), 2.74 (q, J=7.6 Hz, 2H), 1.45 (s, 6H), 1.35-1.23 (m, 3H); ESI-MS: m/z 410 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:7][CH:6]=1)C.[OH-].[K+]>C(O)C.O>[C:14]([C:8]1[CH:9]=[C:10]([O:11][CH2:12][CH3:13])[C:5]([C:4]([OH:18])=[O:3])=[CH:6][N:7]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)cc1OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1cc(C(C)(C)C)ncc1C(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-tert-Butyl-4-ethoxy-nicotinic acid ethyl ester (100 mg, 0.4 mmol) was dissolved in ethanol. Potassium hydroxide (46 mg, 0.8 mmol) in 1 mL of water was added. It was stirred at 80° C. for 1 hr, checked by thin layer chromatography and LC-MS until the reaction was completed. The mixture was concentrated at high vacuum and dried overnight to give 6-tert-butyl-4-ethoxy-nicotinic acid as a white solid which was used in the next reaction with out further purification. The 6-tert-butyl-4-ethoxy-nicotinic acid was heated at 70° C. in 3 mL of SOCl2 for 2 hrs. The reaction mixture containing 6-tert-butyl-4-ethoxy-nicotinoyl chloride was concentrated to dryness then suspended in tetrahydrofuran (6 mL) with 0.1 mL of triethylamine and used for the next reaction immediately.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[N:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:8][N:9]=1)(=[O:3])[NH2:2].[Cl:40]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([C:4]1[C:5]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]3)=[C:25]([Cl:40])[CH:26]=2)=[N:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:8][N:9]=1)(=[O:3])[NH2:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2)CC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2Cl)CC1
Temperature: 50 °C
Reaction time: 15 h
Yield: 98.7 %

Procedure:
To a mixture of tert-butyl 4-(4-{[3-carbamoyl-6-(3-nitrophenoxy)pyrazin-2-yl]amino}phenyl)piperazine-1-carboxylate (1 g) and chloroform (30 mL) was added N-chlorosuccinimide (262 mg), and the reaction mixture was stirred at 50° C. for 15 hours and further, at 60° C. for 24 hours. To the reaction mixture was added silica gel, and the solvent was evaporated under reduced pressure and then purified by silica gel column chromatography (eluent; chloroform) to obtain tert-butyl 4-(4-{[3-carbamoyl-6-(3-nitrophenoxy)pyrazin-2-yl]amino}-2-chlorophenyl)piperazine-1-carboxylate (1.05 g) as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:4].O.[OH-].[Li+].Cl>O1CCCC1.O>[F:27][C:24]([F:25])([F:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[N:7]=[N:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH2:12][CH2:13]1)=[O:28]
Reactant: COC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 23 h
Yield: 84.1 %

Procedure:
To a solution of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid methyl ester (4.436 g, 11.25 mmol) in tetrahydrofuran (50 mL) and water (25 mL) was added lithium hydroxide monohydrate (2.30 g, 54.81 mmol). The reaction mixture was stirred at ambient temperature for 23 h and the pH of the solution was adjusted to ˜3 with concentrate hydrochloric acid (5.3 mL) at 0° C. The mixture was concentrated. Ethyl acetate (100 mL) was added to the residue and the product was precipited. The solid was collected by filtration, washed with ethyl acetate and dried in vacuo to afford the title compound (3.60 g). The aqueous layer was extracted with ethyl acetate, dried over Na2SO4 and concentrated to give the second portion of title compound (0.463 g). The total amount of product was 4.063 g (95% yield).
Reaction SMILES: C(OC(=O)[CH:5]([N:11]=[C:12]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1OC(=O)C)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C=CC(C(=O)C2C=C(C)C=CC=2O)=CC=1.ClC1C=CC(C(=N)C2C=C(C)C=CC=2O)=CC=1>>[CH2:9]([O:8][C:6]([C:5]1[NH:11][C:12]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[C:13]2[C:14]=1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18]2)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(N=C(c1ccc(Cl)cc1)c1cc(C)ccc1OC(C)=O)C(=O)OCC
Agent: Cc1ccc(O)c(C(=N)c2ccc(Cl)cc2)c1
Agent: Cc1ccc(O)c(C(=O)c2ccc(Cl)cc2)c1
Product: CCOC(=O)c1[nH]c(-c2ccc(Cl)cc2)c2cc(C)ccc12

Procedure:
The starting material, {[2-acetoxy-5-methyl-α-(4-chlorophenyl)benzyliden]-amino}malonic acid diethyl ester (colorless crystals from heptane, melting point 82°-84° C.), can be prepared as described in Example 1 from 4'-chloro-2-hydroxy-5-methyl-benzophenone via 4'-chloro-2-hydroxy-5-methyl-benzophenone imine (orange crystals from ethanol, melting point 134°-136° C.).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(Cl)(=O)C(C)(C)C.[CH:34]([N:37](CC)C(C)C)([CH3:36])[CH3:35].C(N)(C)C>C(Cl)Cl.C(N(CC)CC)C>[CH:34]([NH:37][C:22]([C:21]1[CH:25]=[CH:26][C:18]([C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:15][CH2:14]2)=[O:17])=[N:19][CH:20]=1)=[O:24])([CH3:36])[CH3:35]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(C(=O)N2CCN(c3ncccc3[N+](=O)[O-])CC2)nc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)N
Solvent: ClCCl
Product: CC(C)NC(=O)c1ccc(C(=O)N2CCN(c3ncccc3[N+](=O)[O-])CC2)nc1
Reaction time: 2 h
Yield: 78 %

Procedure:
Triethylamine (0.85 ml) was added to 6-[1-(3-nitro-2-pyridyl)piperazin-4-yl-carbonyl]nicotinic acid (2 g) in methylene chloride (25 ml) for dissolution and cooled. With the slow addition of pivaloyl chloride (0.7 ml) at 0° C.˜5° C., the mixture was stirred at 5° C.˜10° C. for 2 hours. With the addition of N,N-diisopropylethylamine (1.1 ml) and isopropylamine (0.55 ml), the mixture was stirred at 10° C.˜15° C. for 3 hours. The reaction mixture was washed with an aqueous sodium bicarbonate and water twice. The separated organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in chloroform (15 ml) and with the slow addition of ether, crystals were precipitated. For 2-hours stirring, the precipitate was filtered, washed (ether) and dried to give a desired compound of 1.74 g (yield: 78%).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH3:19])[C:10]3[C:15]([S:16][C:17]=2[CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4].C1COCC1>C(O)C>[OH:4][CH2:3][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH3:19])[C:10]3[C:15]([S:16][C:17]=2[CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CN1c2ccccc2Sc2cc(C=O)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1c2ccccc2Sc2cc(CO)ccc21
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
With ice-cooling, sodium borohydride (4.16 g, 110 mmol) was added to a mixture of 3-formyl-10-methylphenothiazine (24.6 g, 102 mmol), THF (100 ml) and ethanol (100 ml), the mixture was stirred for 10 minutes and then at room temperature for 20 minutes. The solvent was evaporated under a reduced pressure, water and 2N hydrochloric acid were added to the residue in that order, and then the reaction product was extracted with ethyl acetate. The extract was washed with a saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in that order, dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure. By recrystallizing the resulting residue from ethyl acetate-hexane, the title compound (18.9 g, 77.7 mmol, 76%) was obtained as yellow crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][N:23]3[C:31](O)([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:40])[CH2:18][CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([BH3-])#N.[Na+].CN(C)CCN(C)C.[C:53]([OH:58])(=[O:57])[C:54]([OH:56])=[O:55]>C(Cl)Cl.O1CCCC1.C(#N)C>[C:53]([OH:58])(=[O:57])[C:54]([OH:56])=[O:55].[CH2:32]([CH:31]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:40])[N:23]1[CH2:22][CH2:21][CH2:20][N:17]1[CH2:16][CH:15]=[C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:19][CH2:18]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C1c2ccccc2C(O)(Cc2ccccc2)N1CCCN1CC=C(c2ccccc2)CC1
Agent: CN(C)CCN(C)C
Agent: O=C(O)C(=O)O
Agent: [BH3-]C#N
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccccc2C(Cc2ccccc2)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 4 h
Yield: 115.4 %

Procedure:
75 cc of trifluoroacetic acid is added in the course of 45 minutes to 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-3-hydroxy-3-benzyl-1-isoindolinone (15.2 g) and sodium cyanoborohydride (4.6 g) cooled to a temperature close to -25° C. Agitation is continued for 4 hours at a temperature close to 20° C. The solution is diluted with methylene chloride (150 cc) then washed with saturated aqueous sodium bicarbonate solution (200 cc). The aqueous phase is extracted with methylene chloride (4×150 cc). The organic extracts are combined, washed with 1N hydrochloric acid solution (3×50 cc), dried over anhydrous magnesium sulphate, treated with animal charcoal, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in tetrahydrofuran (150 cc). Tetramethylethylenediamine (3.1 cc) is added and the solution heated to a temperature close to 65° C. for 1 hour. After cooling to a temperature close to 20° C., the solution is diluted with methylene chloride (300 cc), and washed with distilled water (5×50 cc). The organic extract is dried over anhydrous magnesium sulphate, filtered and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in acetonitrile (20 cc). A solution of oxalic acid (0.7 g) in acetonitrile (20 cc) is added and agitation is continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration and recrystallized from boiling methanol (280 cc). 4.6 g of 3-benzyl-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 219° C.
Reaction SMILES: [CH:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([O:14]C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ncoc1C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ncoc1C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirred solution of methyl 5-cyclohexyl-1,3-oxazole-4-carboxylate (6.40 g, 30.6 mmol) in methanol (370 mL) was added 1 M NaOH solution (92 mL). After being stirred at room temperature for 2 h, and at 50° C. for 1 h, the reaction mixture was cooled to 0° C., and then acidified with 1 M HCl solution. The mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting light yellow solid was triturated with hexane to give the title compound (5.29 g, 89%) as a white solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.Cl.[NH2:10][OH:11].C([O-])(=O)C.[Na+]>C(O)C>[OH:11]/[N:10]=[C:2](\[CH3:4])/[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: NO
Reactant: CCOC(=O)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)/C(C)=N/O
Yield: 59 %

Procedure:
A mixture of ethyl pyruvate (9.50 g), hydroxylamine hydrochloride (6.82 g), sodium acetate (10.1 g) and ethanol (150 ml) was heated under reflux for 17 hours. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then concentrated. The residual crystals were recrystallized from ethyl acetate-hexane to obtain ethyl E-2-hydroxyiminopropionate (6.33 g, yield 59%) as colorless crystals. m.p. 98-99° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]([NH:31]C(=O)OC(C)(C)C)[CH3:30])=[CH:25][CH:24]=1)=[O:22])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:31][CH:29]([C:26]1[CH:25]=[CH:24][C:23]([C:21]([NH:20][C:4]2[C:5]([CH3:19])=[CH:6][C:7]([C:9]([F:18])([C:10]([F:11])([F:12])[F:13])[C:14]([F:15])([F:16])[F:17])=[CH:8][C:3]=2[CH2:1][CH3:2])=[O:22])=[CH:28][CH:27]=1)[CH3:30]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C(C)N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-Butyl [1-(4-{[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]carbamoyl}phenyl)ethyl]carbamate (1.7 g) was dissolved in methylene chloride (20 ml). To the solution, trifluoroacetic acid (1.5 g) was added and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and the residue was neutralized by adding water and potassium carbonate followed by extraction twice with ethyl acetate. The organic phases were combined, washed with a saturated sodium bicarbonate aqueous solution and water in turns and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain 4-(1-aminoethyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]benzamide as a crude product (1.8 g).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[O:8][N:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl.F[CH2:39][C:40](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=CC(OC4CCNCC4)=CN=3)=CC=2)C=1)(C)[CH2:41]F>>[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:30][CH2:31][N:32]([CH:40]([CH3:41])[CH3:39])[CH2:33][CH2:34]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[O:8][N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)on1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)no4)cc3)nc2)CC1
Yield: 52 %

Procedure:
N-(4-(3-(3-tert-Butylisoxazol-5-yl)ureido)phenyl)-5-(1-isopropylpiperidin-4-yloxy)picolinamide (63 mg, 52%) was prepared using a procedure analogous to that described in Example 20, substituting N-(4-(3-(3-tert-butylisoxazol-5-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride from Step 2 of this example for N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 20. LC-MS (ESI) m/z 521 (M+H)+.
Reaction SMILES: [C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:31][CH:32]([CH3:34])[CH3:33])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:9]([C:27]([O:29]C)=[O:28])[CH2:8]2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:31][CH:32]([CH3:33])[CH3:34])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C:14]([CH3:15])([CH3:16])[CH3:17])[C@H:9]([C:27]([OH:29])=[O:28])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1C[C@@](SC(C)C)(c2ccc(-c3ccccc3)cc2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(isopropylthio)pyrrolidine-2-carboxylate (208 mg, 0.366 mmol) in THF (2 mL) and MeOH (2.000 mL) was added pre-made solution of Lithium hydroxide monohydrate (30.7 mg, 0.731 mmol) in water (2 mL). The resulting cloudy solution was stirred at room temperature overnight. Quenched with 5% citric acid, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated, to afford the desired product (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(isopropylthio)pyrrolidine-2-carboxylic acid (202 mg, 0.328 mmol, 90% yield) as a white foam. LC-MS (retention time: 3.39 min, method B), MS m/z 555 (M+H).
Reaction SMILES: [CH:1]1([NH:5][C@@H:6]2[CH2:11][C:10]3[C:12]([O:17][CH3:18])=[CH:13][CH:14]=[C:15]([F:16])[C:9]=3[O:8][CH2:7]2)[CH2:4][CH2:3][CH2:2]1.[CH3:19][CH2:20][CH:21]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:1]1([N:5]([C@@H:6]2[CH2:11][C:10]3[C:12]([O:17][CH3:18])=[CH:13][CH:14]=[C:15]([F:16])[C:9]=3[O:8][CH2:7]2)[CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4]1
Reactant: CCC=O
Reactant: COc1ccc(F)c2c1C[C@@H](NC1CCC1)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(C1CCC1)[C@H]1COc2c(F)ccc(OC)c2C1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
(R)-3-(N-Cyclobutylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (1.01 g, 4.02 mmol) was dissolved in anhydrous methanol (20 mL) and to this was n-propionaldehyde (3.0 mL, 40.2 mmol) added. After 1 h the reaction was cooled (ice-bath) then sodium cyanoborohydride (0.46 g, 7.24 mmol) was added, the pH was adjusted to 4-5 with acetic acid and the reaction was allowed to stir at room temperature over the weekend. The solvent was removed in vacuo, the remains were taken into a 2M solution of NH3 and then extracted thrice with diethyl ether. The combined ether portions were dried (MgSO4), filtered, and the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent 11% ethyl acetate/hexane) gave 0.95 g (80% yield) of the title compound as a clear oil. [α]21D =-95.4° (C=0.1; CHCl3). GC-MS (70 eV) M=293 (1%).