Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](O)[CH:6]=[CH:5]2.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(=O)C.[Na+]>C(O)C.C1(C)C(C)=CC=CC=1>[C:14]1([NH:13][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[CH:8]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: Nc1ccccc1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1C
Product: Brc1ccc2cc(Nc3ccccc3)ccc2c1
Temperature: 85 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
Xylene was distilled from a mixture of 6-bromo-2-naphthol (16.4 g., 0.0735 mol.), aniline (25 ml, 0.274 mol.), xylene (25 ml), and p-toluene sulfonic acid monohydrate (2.7 g., 0.014 mol.) until the reaction temperature reached 190° C. The mixture was held at this temperature for 5 hours, and then cooled to 85° C. Sodium acetate (3.7 g.) and ethanol (100 ml) were added and the mixture was heated to reflux. The solution was cooled to 5° C. and the resulting slurry was filtered. The solids were washed with cold ethanol (50 ml). The air-dried solids (19.5 g.) were reslurried in hot water (150 ml) and filtered to give a gray solid, 19.3 g, 88% yield, m.p. 126.2-128.3° C. Two successive recrystalizations from heptane-ethyl acetate (19:1) gave a sample for analysis, m.p. 131-133° C. Mass Spec: m/z 297, 299 (M+). Analysis: Calculated for C16H12NBr: C, 64.45; H, 4.06; N, 4.70, Br, 26.80. Found: C, 64.36; H, 4.02; N, 4.67; Br, 27.04.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]2[N:25]3[C:20]([C:21]([NH2:26])=[N:22][CH:23]=[N:24]3)=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]2[N:25]3[C:20]([C:21]([NH2:26])=[N:22][CH:23]=[N:24]3)=[C:19]([Br:27])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c([C@@H]3CCCN(C(=O)OCc4ccccc4)C3)ccc12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1ncnn2c([C@@H]3CCCN(C(=O)OCc4ccccc4)C3)cc(Br)c12
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 194.6 %

Procedure:
The product of step 6 (3.59 g, 10.22 mmoL) was dissolved in 40 mL of DMF and cooled in an Ice/isopropanol/dry ice bath to −20° C. and 1,3-dibromo-5,5-dimethylhydantoin (1.46 g, 5.11 mmol) was added in 4 equal portions 15 minutes apart. The mixture was stirred for 10 minutes past the last addition and quenched by addition to a mixture of ice (400 g), saturated, aqueous Na2SO3 (20 mL) and 2M aq. Na2CO3 (20 mL) and the mixture was allowed to reach rt and vigorously stirred for 30 minutes. The solid was collected by filtration dried in a vacuum oven until a constant weight was obtained. The title compound (4.28 g) was obtained as a freely flowing solid. 1H NMR (300 MHz, CD3OD) δ 7.83 (s, 1H), 7.40-7.25 (m, 5H), 6.66 (s, 1H), 5.06 (bs, 2H), 4.19 (d, 1H), 3.92 (m, 1H), 3.22 (m, 1H), 3.12-2.83 (m, 3H), 1.99, (m, 1H), 1.78-1.62 (m, 2H), 1.48 (m, 1H). ES-MS m/z 430.1, 432.0 [M+H]+, HPLC RT (min) 2.98.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH:8]1([C:17]#[N:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[O:4]1[CH2:5][CH2:6][O:7][CH:3]1[CH2:2][C:8]1([C:17]#[N:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: N#CC1CCc2ccccc21
Reactant: BrCC1OCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(CC2OCCO2)CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.8 %

Procedure:
2-bromomethyl-1,3-dioxolane (12.94 ml, 125.0 mmole) was added to a solution of 1-indanecarbonitrile (16.27 g, 113.6 mmole) in 100 ml of THF and cooled to 0° C. After the dropwise addition of 1M LHMDS (125 ml) the solution was stirred at 0° C. for 20 min then at room temperature for 20 min. After the removal of solvent the residue was flashed of silica using 15% EtOAc and Hexanes to afford 19.23 g of 1-(1,3-dioxolan-2-ylmethyl)-1-indanecarbonitrile (74% yield) as a thick oil.
Reaction SMILES: [CH3:1][CH:2]([N:14]([CH3:16])[CH3:15])[CH2:3][CH2:4][C:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH2:7][C:6]=1[CH3:13].[CH3:17][I:18]>CCOCC>[I-:18].[CH3:1][CH:2]([N+:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][CH2:4][C:5]1[C:10]([CH3:11])([CH3:12])[CH2:9][CH2:8][CH2:7][C:6]=1[CH3:13]
Reactant: CI
Reactant: CC1=C(CCC(C)N(C)C)C(C)(C)CCC1
Solvent: CCOCC
Product: CC1=C(CCC(C)[N+](C)(C)C)C(C)(C)CCC1
Product: [I-]
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of [1-methyl-3-(2,6,6-trimethyl-1-cyclohexenyl)propyl]dimethylamine (2.0 g) in dry ether (20 cc) was added methyliodide (2.0 g), and the mixture was allowed to stand overnight. Precipitated crystals were gathered by filtration and recrystallized from a mixed solvent of ethanol, benzene and ether to give colorless crystals (3.0 g) of [1-methyl-3-(2,6,6-trimethyl-1-cyclohexenyl)propyl]trimethylammonium iodide, m.p. 220°-222° C.
Reaction SMILES: C1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:16])=O)C=CC=CC=1.[NH2:23][OH:24].Cl.NO.[C:28]([O-])(=O)[CH3:29].[Na+]>O.CO>[C:29]1([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:16])[C:13](=[N:23][OH:24])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:7]=2)[CH:28]=[CH:9][CH:8]=[CH:7][CH:12]=1
Reactant: O=C(c1ccccc1-c1ccccc1)C(O)c1ccccc1
Reactant: NO
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=C(c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 40 %

Procedure:
180 g (0.625 mol) of phenylbenzoin was added to a 3 liter, one necked, round bottomed flask fitted with a reflux condenser and a nitrogen bypass. 1.45 liters of methanol was added to dissolve the phenylbenzoin and free hydroxylamine was prepared by treating 177.9 g. (2.56 moles) hydroxylamine hydrochloride with 209.9 g (2.56 moles) of sodium acetate in water. The result solution was added to the phenylbenzoin and the reaction mixtur was stirred for 48 hours at reflux at which time an additional 1.24 moles of hydroxylamine was added. The solution was cooled and filtered. The solids were then placed in a Soxhlet extracted and treated with refluxing hexane. After 72 hours the solid remaining in the extraction thimble was collected to yield 40% of the theoretical yield of pure alpha-phenylbenzoin oxime, m.p. 150°-52° C. (lit. 153.5). The hexane extract can be concentrated yield unreacted phenylbenzoin (50% of theory) which may be recycled to afford additional phenylbenzoin oxime. This material was employed to polymerize 2,6 -xylenol using the following composition:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:14]3=[N:15][C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][C:18](=[O:19])[N:13]3[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1.F[B-](F)(F)F.[O:31]=[N+:32]=[O:33]>ClCCl>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:14]3=[N:15][C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:17]([N+:32]([O-:33])=[O:31])[C:18](=[O:19])[N:13]3[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]=O
Reactant: CSc1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CSc1nccc(N2CCCn3c2nc(-c2ccccc2)c([N+](=O)[O-])c3=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 9-(2-methylsulfanyl-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (500 mg, 1.42 mmol) in dichloromethane (10 mL) at 0° C. under nitrogen was added nitronium tetrafluoroborate in a 0.5M solution (7 mL, 3.55 mmol). External cooling removed and reaction warmed to room temperature while stirring for 1 h. Reaction washed with 5% sodium bicarbonate and saturated ammonium chloride. Organic concentrated under vacuum and orange solid isolated after purification on silica. M+1=397.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[CH:24]=[N:23][CH:22]=[C:21]([CH:25]6[CH2:27][CH2:26]6)[N:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[Na+].[Cl-]>O1CCOCC1.CCOC(C)=O>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[CH:24]=[N:23][CH:22]=[C:21]([CH:25]6[CH2:27][CH2:26]6)[N:20]=5)[CH:17]=4)[NH:12][CH:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4cncc(C5CC5)n4)ccc32)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1cc2[nH]cc(-c3cncc(C4CC4)n3)c2cc1-c1cncc(C2CC2)n1
Temperature: 120 °C
Yield: 50 %

Procedure:
A glass microwave reaction vessel was charged with 3,5-bis(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indole (72 mg, 0.14 mmol) and 1 M NaOH (aq., 0.71 mL, 0.71 mmol) in dioxane (1.5 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 min. Saturated NaCl (aq.) was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 0-70% EtOAc in hexanes, to the title compound (25 mg, 0.07 mmol, 50% yield) as a light-yellow solid. MS (ESI, pos. ion) m/z: 354.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (s, 1H), 9.07-9.14 (m, 1H), 8.95 (d, J=6.46 Hz, 2H), 8.53 (s, 1H), 8.37 (d, J=3.91 Hz, 2H), 7.89-7.97 (m, 1H), 7.60 (s, 1H), 2.22-2.33 (m, 2H), 1.06-1.26 (m, 8H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[C:14]([O:18][C:19]([NH:21][C@H:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>C(O)CCCC>[C:14]([O:18][C:19](=[O:20])[NH:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:23]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: COc1ccc2nccc(Br)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCO
Product: COc1ccc2nccc(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c2n1
Temperature: 80 °C
Yield: 86.1 %

Procedure:
A mixture of 8-bromo-2-methoxy-[1,5]naphthyridine (1.50 g, 6.27 mmol, prepared as in WO 2006/032466) and (S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (1.17 g, 6.27 mmol) in pentanol (5 mL) and DIPEA (1.24 mL, 1.2 eq) was heated at 80° C. over night. The majority of the solvent was removed in vacuo at elevated temperature (50-60° C.). The residue was triturated with ether to remove residual amine. The mother liquor was concentrated and the residue was chromatographed over SiO2 (DCM-MeOH—NH4OH 1000:50:4) to afford the desired intermediate as a beige foam (1.86 g, 86%).
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[CH3:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])(=[O:15])=[O:14])[CH2:10][N:9]1[C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([CH3:26])=[CH:28][CH:29]=1)=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: Cc1ccc(C(=O)N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)NCC#N)cc1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K2 was coupled with 4-methyl-benzoic acid in analogy to experiment A1 to give (2S,4R)-1-(4-methyl-benzoyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 480.1 [M+H]+.
Reaction SMILES: [Li+].[OH-].C([O:16][CH2:17][C:18]1[C:22]([OH:24])([CH3:23])[O:21][C:20](=[O:25])[C:19]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)CCCCCCCCCCC.C(O)(=O)C>C1COCC1>[OH:16][CH2:17][C:18]1[C:22]([OH:24])([CH3:23])[O:21][C:20](=[O:25])[C:19]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCCCCCCCCCC(=O)OCC1=C(c2ccccc2)C(=O)OC1(C)O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(O)OC(=O)C(c2ccccc2)=C1CO
Reaction time: 3 h

Procedure:
LiOH (0.5M, 19.7 mL, 9.83 mmol) was added to a solution of 4-dodecoyloxymethyl-5-hydroxy-5-methyl-3-phenyl-2-furanone (Compound 5, see improved process for preparation below), in THF (20 mL) at room temperature. After stirring for 3 hours the reaction was quenched with glacial acetic acid (590 mg, 9.83 mmol) and the THF was removed by rotary evaporator. Solids were removed from the residual aqueous slurry. The clear aqueous solution containing the crude product was lyophylized, adhered to silica with methanol and purified by flash chromatography using 60% ethyl acetate/hexane to give the title alcohol.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:4]=2[C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=O.[C:21]([O:28][CH3:29])(=[O:27])[CH2:22][CH2:23][C:24]([CH3:26])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:26][C:24]1[N:1]=[C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][CH2:11][C:4]=3[C:3]2=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:23]=1[CH2:22][C:21]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CCC(C)=O
Reactant: Cc1ccc(C(=O)c2c(N)sc3c2CCCCC3)cc1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CC=CC=C3
Yield: 54.3 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-3-yl)(p-tolyl)methanone (0.713 g; 2.5 mmol), methyl levulinate (0.350 mL; 2.75 mmol), chlorotrimethylsilane (1.27 mL; 10 mmol) in DMF (10 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.510 g (52%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)(=O)[CH3:2].[CH2:19]([NH2:22])[CH2:20][NH2:21]>C(O)(=O)C>[NH2:21][CH2:20][CH2:19][NH:22][CH:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(OCC(=O)N2CCCC2)cc1
Reactant: NCCN
Solvent: CC(=O)O
Product: CC(NCCN)c1ccc(OCC(=O)N2CCCC2)cc1

Procedure:
By using 2-(4-acetylphenoxy)-1-(pyrrolidin-1-yl)ethanone (250 mg), ethylenediamine (400 μl) and acetic acid (700 μl) as starting materials, the title compound (163.8 mg) was obtained in the same manner as that of Reference Example 64, (1).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:7]=1[C:6]=2[CH3:17])[CH3:2].[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][S:23][C:24]1[N:25]([CH3:40])[C:26]([C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([CH3:39])=[N:34]3)=[N:27][N:28]=1>>[ClH:18].[CH2:1]([C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][N:11]([CH2:19][CH2:20][CH2:21][CH2:22][S:23][C:24]3[N:25]([CH3:40])[C:26]([C:29]4[CH:38]=[CH:37][CH:36]=[C:35]5[C:30]=4[CH:31]=[CH:32][C:33]([CH3:39])=[N:34]5)=[N:27][N:28]=3)[CH2:12][CH2:13][C:7]=1[C:6]=2[CH3:17])[CH3:2]
Reactant: CCc1nc2cc3c(c(C)c2o1)CCNCC3
Reactant: Cc1ccc2c(-c3nnc(SCCCCCl)n3C)cccc2n1
Product: CCc1nc2cc3c(c(C)c2o1)CCN(CCCCSc1nnc(-c2cccc4nc(C)ccc24)n1C)CC3
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-ethyl-10-methyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (85 mg) and 5-{5-[(4-chlorobutyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline (153 mg) and was obtained as a colourless slightly hygroscopic solid (136 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:7]([NH:9][NH2:10])=O)[CH3:2].[CH3:17][N:18]=[C:19]=[S:20].C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[N:18]([CH3:17])[C:19]([SH:20])=[N:10][N:9]=2)[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH3:2]
Reactant: CCOc1cc(C(=O)NN)ccc1[N+](=O)[O-]
Reactant: CN=C=S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1cc(-c2nnc(S)n2C)ccc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 22 h
Yield: 72.3 %

Procedure:
3-Ethoxy-4-nitrobenzohydrazide (Preparation 219, 1287 mg 5.72 mmole) was stirred in THF (26 mL) and a solution of methyl isothiocyanate (422 mg 5.78 mmole) in THF (5 mL) was added. Triethylamine (102 uL, 0.71 mmole) was added and the reaction was stirred at 20° C. for 22 hours. The solvent was evaporated and replaced with 1M sodium hydroxide solution (85 mL) and the reaction was stirred at 45° C. for 2.5 hours. The reaction was filtered through Celite and the filtrate extracted with ether (2×45 mL). The aqueous was acidified using conc. hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined ethyl acetate extracts were washed with water and with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound (1.16 g, 72%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:30]([CH2:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH3:29]>>[C:34]([O:33][C:31]([N:30]([CH2:38][C:39]1[CH:45]=[CH:44][C:42]([NH:43]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:41][CH:40]=1)[CH2:28][CH3:29])=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CCN(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: CCN(Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1)C(=O)OC(C)(C)C

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-ethyl-N-tert.butoxycarbonyl-aminomethyl)-aniline Rf value: 0.6 (silica gel, methylene chloride/methanol=10:1) C31H33N3O5
Reaction SMILES: [CH:1]1([CH:5]([C:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:18]=2[CH3:28])[O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:5]([C:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:18]=2[CH3:28])[O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2cc(-c3ccccc3)oc2C)C2CCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of cyclobutyl(2-methyl-5-phenylfuran-3-yl)methanol (364 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (274 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (757 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 12% ethyl acetate/hexane) to give methyl 4-[cyclobutyl(2-methyl-5-phenylfuran-3-yl)methoxy]benzoate as an oil. The obtained methyl 4-[cyclobutyl(2-methyl-5-phenylfuran-3-yl)methoxy]benzoate was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (1.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (276 mg, 47%) as an amorphous compound.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[N:30]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:31][CH3:32])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][N:9]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=[O:51].C(OCC)(=O)C>C(Cl)Cl>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1)[CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[N:30]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:31][CH3:32])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]([OH:51])=[O:18])=[CH:12][N:13]=1
Reactant: CCN(CC1CCCCC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCO)cn1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(CC1CCCCC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
3-(2-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-propan-1-ol (140 mg) is dissolved in methylene chloride (2 ml), and thereto is added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (188 mg) at room temperature and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, and the mixture is separated and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is dissolved in the mixed solvent of tert-butanol (4 ml) and water (1 ml) and thereto are added 2-methyl-2-butene (128 μl), sodium dihydrogenphosphate dihydrate (44 mg) and sodium chlorite (73 mg) and the mixture is stirred at room temperature for 30 minutes. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:3) to give 3-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-propionic acid (60 mg). The resulting carboxylic acid is dissolved in ethanol (0.5 ml), and thereto is added 1N-aqueous sodium hydroxide solution (85 μl) and the reaction solution is concentrated under reduced pressure to give 3-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-propionic acid sodium salt (60 mg). MS (m/z): 705 [M−Na]−.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:15]([NH:17][O:18]C3CCCCO3)=[O:16])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCO>[CH:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:29])([S:25]([CH3:28])(=[O:26])=[O:27])[C:15]([NH:17][OH:18])=[O:16])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@](CCn1cc(C2CCCCC2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@@](CCn1cc(C2CCCCC2)cn1)(C(=O)NO)S(C)(=O)=O
Yield: 65.6 %

Procedure:
To a solution of (2R)-4-(4-cyclohexyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (260 mg, 0.608 mmol, 1 eq) in EtOH (6 mL), was added PPTS (45.7 mg, 0.182 mmol, 0.3 eq), and the reaction mixture was heated at reflux overnight. The crude product mixture was purified by reverse phase HPLC (Column: Phenomenex Gemini NX 150×21.2 mm 5μ; Flow rate 28 mL/min; conditions: 5-95% Water/MeOH containing 0.1% NH4OH) to give (2R)-4-(4-cyclohexyl-1H-pyrazol-1-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (137 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.48 (s, 1H), 7.25 (s, 1H), 4.13-4.03 (m, 1H), 3.97-3.85 (m, 1H), 3.02 (s, 3H), 2.68-2.57 (m, 1H), 2.43-2.33 (m, 1H), 2.21-2.08 (m, 1H), 1.89-1.80 (m, 1H), 1.74-1.57 (m, 3H), 1.42 (s, 3H), 1.25 (s, 6H). LC-MS M+H+344.1.