Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](B(O)O)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH2:1]([N:8]1[CH:12]=[C:11]([C:17]2[CH:18]=[C:19]([NH2:20])[CH:21]=[CH:22][CH:23]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cnn(Cc2ccccc2)c1
Reactant: Nc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2cnn(Cc3ccccc3)c2)c1
Temperature: 25 °C
Yield: 94 %

Procedure:
1-benzyl-1H-pyrazole-4-boronic acid (0.176 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (10-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.137 g in 94% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:16](=O)[CH3:17])[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH3:2].[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]([NH:25][S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])[CH3:17])[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH3:2]
Reactant: CCOc1cc(C(C)=O)cnc1OCC(F)(F)F
Reactant: CC(C)(C)[S@](N)=O
Product: CCOc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)(F)F
Yield: 93 %

Procedure:
The title compound is prepared in 93% yield (0.75 g, colorless oil) from 1-(5-ethoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.58 g, 2.19 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:16]=[CH:17][C:18]=1[CH3:19])[N:10]=2
Reactant: N#C[S-]
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc(N)cn1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To a solution of potassium thiocyanate (62.9 g, 647 mmol) in acetic acid (500 ml) was added benzyl {3-[(5-aminopyridin-2-yl)oxy]-4-methylphenyl}carbamate (56.5 g, 162 mmol), and a solution of bromine (27.1 g, 170 mmol) in acetic acid (100 mL) was added dropwise. The reaction mixture was stirred at room temperature for 18 hr, and the insoluble material was filtered off through a celite pad. The filtrate was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate (500 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (300 mL). The obtained aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with saturated brine (100 mL), and purified by silica gel (ethyl acetate). The obtained solution was concentrated under reduced pressure, and the crystals precipitated during concentration were collected by filtration to give the title compound (48.4 g, 74%) as a pale-brown solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[CH2:5]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:3])=[O:17])=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCOc1ccc(C(=O)O)cc1
Product: CCCCCCOc1ccc(C(=O)Cl)cc1
Yield: 97.9 %

Procedure:
Thionyl chloride (485 g of 98%, 4.00 mol) was added dropwise to 300 g (1.35 mol) of 4-hexyloxybenzoic acid. The resulting mixture was refluxed under nitrogen for 2 hours. Distillation yielded 318 g (98%) of 4-hexyloxybenzoyl chloride [boiling point 149°-153° C. (7.5 mm)].
Reaction SMILES: Cl.C=O.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].[CH2:15](NCC)C>>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12]([CH2:15][O:10][C:9]2=[O:11])=[CH:13][CH:14]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: CCNCC
Agent: C=O
Agent: Cl
Product: COc1ccc2c(c1)C(=O)OC2
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
Concentrated HCl (1l) was added with 40% w/v formaldehyde (65 ml, 0.86 mole) under vigorous stirring, then with 3-methoxybenzoic acid (100 g, 0.66 mole) and the mixture was heated to 100° C. controlling the generation of gas, for 30 minutes. The cooling of the mixture yielded a precipitate which was filtered and stored, while the mixture was washed with water, then with 5% NaOH. The new precipitate was twice extracted with CH2Cl2, the extract anhydrified, concentrated, joined to the previously filtered solid and both were dissolved in CH2Cl2 and treated with diethylamine (120 ml, 1.15 moles). After 24 hours it was extracted with 10% HCl and the phases were separated and extracted with CH2Cl2. The organic phase was washed with 10% NaOH, discoloured with charcoal, anhydrified and concentrated. The residue was dissolved in CH2Cl2 and treated, under stirring, with 10% HCl for 30 minutes. The organic phase was washed with water, anhydrified and dried. The residue was dissolved in CH2Cl2 and treated with 10% NaOH under stirring for 30 minutes. The organic phase was washed with water, anhydrified and concentrated to give a solid which was crystallised from CH3OH/H2O 65:35 and dried at 50° C. over P2O5, then crystallised again from CH3OH/H2O 6:4 to give 35.28 g of the title compound (yield: 32%). m.p.: 115-117° C.
Reaction SMILES: N.[K].[C:3]1([CH3:11])[C:4]([C:9]#[N:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>O.O1CCCC1>[NH2:10][C:9]1[C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:13]=1
Reactant: Cc1ccccc1C#N
Reactant: N#Cc1ccccn1
Agent: N
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(-c2ccccn2)cc2ccccc12
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To 250 ml. of liquid ammonia under a nitrogen atmosphere are added 7.5 g. (0.19 gram atom) of potassium in small portions and a few crystals of ferric nitrate. When all the potassium has been converted into the amide (i.e. when the blue color disappears), 11.1 g. (0.095 mole) of o-toluonitrile in 30 ml. of anhydrous tetrahydrofuran are added, upon which the solution immediately takes on a red color. 19.8 g. (0.19 mole) of 2-cyanopyridine in 100 ml. of anhydrous tetrahydrofuran are then added. The mixture is left standing overnight and then decomposed with water. The tetrahydrofuran is evaporated and the residue is extracted with chloroform. The extract is washed with water, dried with magnesium sulphate and the solvent is removed by evaporation. The residue is purified by sublimation. 5.2 g. of 1-amino-3-(2-pyridyl)isoquinoline are obtained. Yield 24.8%, m.p. 152°-153° C. The base is dissolved in diethyl ether and an etheral hydrogen chloride solution is added. The precipitate formed is filtered off and crystallised from ethanol (96%) to yield the monohydrochloride, m.p. 266° C., (with decomposition). 0.95 g. (4.30 mmol) of the base and 2.44 g. (17.2 mmol) of methyl iodide, dissolved in 20 ml of acetone are heated at 43° C under a nitrogen atmosphere for 4 days. The solvent is distilled off and the residue is crystallised from methanol. 1-Amino-3-(2-pyridyl)isoquinoline methyliodide is obtained. Melting point 206° C with decomposition.
Reaction SMILES: CO.S(=O)(=O)(O)O.[CH3:8][NH:9][S:10]([C:13]1[CH:14]=[C:15]([C:23]([OH:25])=[O:24])[C:16]2[O:21][CH2:20][CH2:19][O:18][C:17]=2[CH:22]=1)(=[O:12])=[O:11].[C:26](=O)([O-])[O-].[Na+].[Na+]>O>[CH3:26][O:24][C:23]([C:15]1[C:16]2[O:21][CH2:20][CH2:19][O:18][C:17]=2[CH:22]=[C:13]([S:10](=[O:11])(=[O:12])[NH:9][CH3:8])[CH:14]=1)=[O:25]
Reactant: O=C([O-])[O-]
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNS(=O)(=O)c1cc2c(c(C(=O)OC)c1)OCCO2
Yield: 85 %

Procedure:
750 ml of methanol were introduced into a balloon flask provided with a condenser. Then, under cooling, 273 g of concentrated sulfuric acid and 160 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were added. The mixture was heated under reflux, cooled and poured into water and sodium carbonate. The precipitate was dried off, washed and dried. 143 g of methyl-7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate were obtained (M.P.: 159°-160° C.; yield: 85%).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][O:2]1.Br[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[C:13]2[NH:20][C:21]([NH:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)=[O:22]>>[CH2:1]1[CH:5]2[CH2:6][N:7]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[C:13]4[NH:20][C:21]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)=[O:22])[CH2:8][CH:4]2[CH2:3][O:2]1
Reactant: C1NCC2COCC12
Reactant: O=C(Nc1cnccn1)Nc1ccnc2ccc(Br)cc12
Product: O=C(Nc1cnccn1)Nc1ccnc2ccc(N3CC4COCC4C3)cc12

Procedure:
The compound was prepared by the method described for Example 1 using hexahydro-furo[3,4-c]pyrrole and 1-(6-bromoquinolin-4-yl)-3-(pyrazin-2-yl)urea as starting compounds.
Reaction SMILES: [CH3:1][O:2][CH:3](C)[C:4]([CH3:11])=[CH:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9].[CH:13]([Mg]Cl)=[CH2:14].O>O1CCCC1>[CH3:1][O:2][CH2:3][C:4]([CH3:11])=[CH:5][CH2:6][CH2:7][C:8]([CH3:9])([OH:10])[CH:13]=[CH2:14]
Reactant: COC(C)C(C)=CCCC(C)=O
Reactant: C=C[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CC(C)(O)CCC=C(C)COC
Yield: 85 %

Procedure:
141 g (0.9 mole) of 7-methoxy-6-methyl-oct-5-en-2-one are added to 1 mole of a 1.5 normal solution of vinyl-magnesium chloride in tetrahydrofuran, at below 20° C, in the course of one hour. After a further 2 hours' reaction, hydrolysis is carried out with 100 ml of water, whilst cooling with ice. After a homogeneous salt suspension has formed, the salt and the tetrahydrofuran solution are separated by filtering or centrifuging. The tetrahydrofuran is distilled off under reduced pressure and the reaction product which remains is purified by fractional distillation. 164 g of 8-methoxy-3,7-dimethyl-octa-1,6-dien-3-ol (yield 85%) are obtained. Boiling point 73°-75° C/0.01 bar; nD25 = 1.4676.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[CH2:20][CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:33]1[CH2:38][CH:37]=[C:36]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)[CH2:35][CH2:34]1>O1CCCC1.CN(C)C=O>[O:14]1[C:15]2[C:24]3[O:23][CH2:22][CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][C:16]=2[O:25][CH2:26][CH:13]1[CH2:12][N:33]1[CH2:34][CH:35]=[C:36]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)OCCC4)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4c(c3O2)OCCC4)C1

Procedure:
To a mixture of (2R)-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-h]chromen-2-yl-methyl 4-methylbenzenesulfonate (0.30 g, 0.80 mmole) and potassium carbonate (0.22 g, 1.55 mmole) in 1:1 tetrahydrofuran/dimethylformamide (20 mL) was added 0.47 g (2.38 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H-indole. The reaction mixture was refluxed under nitrogen for 6 hours. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure and the residue was column chromatographed on silica gel with methylene chloride to remove impurities and with 3% methanol/methylene chloride to elute the desired product as an as an oil, which was crystallized from isopropanol with the addition of a solution of oxalic acid in hot isopropanol to give 0.070 g (6%) of the (S)-enantiomer of the title compound as an orange solid, m.p. 140° C.
Reaction SMILES: ClC1N=C2C(N=C(C(O)(C)C)N2)=C(N2CCOCC2)N=1.[Si]([O:28][CH2:29][CH2:30][CH2:31][N:32]1[C:40]([C:41]([OH:44])([CH3:43])[CH3:42])=[N:39][C:38]2[C:33]1=[N:34][C:35](Cl)=[N:36][C:37]=2[N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1)(C(C)(C)C)(C)C.[NH2:52][C:53]1[N:58]=[CH:57][C:56](B(O)O)=[CH:55][N:54]=1>>[NH2:52][C:53]1[N:58]=[CH:57][C:56]([C:35]2[N:34]=[C:33]3[C:38]([N:39]=[C:40]([C:41]([OH:44])([CH3:43])[CH3:42])[N:32]3[CH2:31][CH2:30][CH2:29][OH:28])=[C:37]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)[N:36]=2)=[CH:55][N:54]=1
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1CCCO[Si](C)(C)C(C)(C)C
Reactant: Nc1ncc(B(O)O)cn1
Agent: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Product: CC(C)(O)c1nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc2n1CCCO

Procedure:
100 mg of 2-(2-chloro-6-morpholino-9H-purin-8-yl)propan-2-ol was treated with TBDMS-protected bromopropanol via General Procedure C. Crude intermediate 2-(9-(3-(tert-butyldimethylsilyloxy)propyl)-2-chloro-6-morpholino-9H-purin-8-yl)propan-2-ol was treated with 2-aminopyrimidine-5-boronic acid, pinacol ester via General Procedure A and was purified via reverse phase HPLC to give 36 mg of 105 as a white solid. MS (Q1) 415.2 (M)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C@:6]1([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][CH:9](OC(=O)C)[C@H:8]([O:15][C:16](=[O:18])[CH3:17])[C@@H:7]1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].[NH:36]1[CH:44]=[C:42]([CH3:43])[C:40](=[O:41])[NH:39][C:37]1=[O:38].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>C(#N)C>[C:1]([O:4][CH2:5][C@:6]1([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][C@@H:9]([N:36]2[CH:44]=[C:42]([CH3:43])[C:40](=[O:41])[NH:39][C:37]2=[O:38])[C@H:8]([O:15][C:16](=[O:18])[CH3:17])[C@@H:7]1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of the anomeric mixture 33 (736 mg, 1.51 mmol) and thymine (381 mg, 3.03 mmol) in anhydrous acetonitrile (14.5 cm3) was added N,O-bis(trimethylsilyl)acetamide (2.61 cm3, 10.6 mmol). The reaction mixture was stirred at reflux for 1 h, then cooled to 0° C. Trimethylsilyl triflate (0.47 cm3, 2.56 mmol) was added dropwise under stirring and the solution was stirred at 65° C. for 2 h. The reaction was quenched with a cold saturated aqueous solution of sodium hydrogen carbonate (15 cm3) and extraction was performed with dichloromethane (3×10 cm3). The combined organic phase was washed with saturated aqueous solutions of sodium hydrogen-carbonate (2×10 cm3) and brine (2×10 cm3), and was dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98:2, v/v) as eluent to give nucleoside 34 as a white solid material (639 mg, 76%). δH (CDCl3) 8.98 (1 H, br-s, NH), 7.39-7.26 (11 H, m, Bn, 6-H), 6.22 (1 H, d, J 5.3, 1′-H), 5.42 (1 H, t, J 5.4, 2′-H), 4.63-4.43 (5H, m, 3′-H, Bn), 4.41 (1 H, d, J 12.2, 5′-Ha), 4.17 (1H, d, J 12.1, 5′-Hb), 3.76 (1 H, d, J 10.2, 1-″H), 3.51 (1 H, d, J 10.4, 1″-Hb), 2.09 (3 H, s, COCH3), 2.03 (3 H, s, COCH3), 1.53 (3 H, d, J 0.9, CH3). δC (CDCl3) 170.8, 170.4 (C═O), 163.9 (C-4), 150.6 (C-2), 137.4 (C-6) 137.4, 136.1, 128.9, 128.8, 128.4, 128.2, 127.9 (Bn), 111.7 (C-5), 87.2, 87.2, 86.1 (C-1′, C-3′, C-4′), 77.6 (C-2′), 74.8, 73.9, 71.1, 63.8 (Bn, C-1″, C-5′), 20.9, 20.8 (COCH3), 12.0 (CH3). FAB-MS m/z 553 [M+H]+. Found: C, 62.7; H, 5.9; N, 4.7; C29H32N2O9 requires C, 63.0; H, 5.8; N, 5.1%.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C@@H:4]1[CH3:13].C(N(CC)CC)C.[CH3:21][C:22]1[N:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41](Cl)=[O:42])[N:40]=3)[CH2:32][CH2:31]2)=[O:29])[N:25]=[C:24]([C:44]([F:47])([F:46])[F:45])[CH:23]=1>ClCCl>[CH3:1][N:2]([C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C@@H:4]1[CH3:13])[C:41]([C:39]1[N:40]=[C:36]([CH:33]2[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][N:26]3[C:22]([CH3:21])=[CH:23][C:24]([C:44]([F:45])([F:47])[F:46])=[N:25]3)[CH2:31][CH2:32]2)[S:37][CH:38]=1)=[O:42]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Reactant: CN[C@H]1c2ccccc2CC[C@@H]1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@H]3c4ccccc4CC[C@@H]3C)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1R,2S)-1,2,3,4-tetrahydro-N,2-dimethyl-naphthalenamine and its enantiomer (0.043 g, 0.25 mmol) (prepared by the method described from Example 6, Step A) and triethylamine (0.104 mL, 0.74 mmol) in 2 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (85 mg, 0.2 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 16 h, diluted with 4 mL of dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by medium-pressure liquid chromatography on silica gel using 60-100% of ethyl acetate in hexanes as eluant to give 43 mg of the title compounds, compounds of the present invention as white foam.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:14]([OH:16])=O)[C:8]=2[CH:7]=[CH:6]1)[CH3:2].[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[CH:17]1([NH:20][C:14]([C:9]2[C:8]3[CH:7]=[CH:6][N:5]([CH2:4][O:3][CH2:1][CH3:2])[C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:16])[CH2:19][CH2:18]1
Reactant: CCOCn1ccc2c(C(=O)O)cccc21
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOCn1ccc2c(C(=O)NC3CC3)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 1-(ethoxymethyl)-1H-indole-4-carboxylic acid (123 g, 0.56 mol) in THF (1.5 L) is added cyclopropylamine (58 mL, 0.84 mol) and triethylamine (TEA, 167 mL, 1.12 mol), followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (240 g, 0.62 mol) at 0° C. The reaction mixture is stirred at ambient temperature overnight. The volatiles are removed in vacuo. The residue is stirred in EA (1.5 L) and HCl (0.5%, 1 L) for 10 minutes. The organic layer is separated, washed with aqueous saturated sodium chloride (3×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by chromatography on silica gel to give the title compound (110 g, 77%). MS (m/z): 259 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:10][CH2:11][CH2:12][O:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8]
Reactant: Oc1c(F)cccc1F
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cccc(F)c1OCCBr
Temperature: 75 °C

Procedure:
A mixture of 10 g of 2,6-difluorophenol, 40.5 cm3 of 1,2-dibromoethane and 15.3 g of potassium carbonate in 300 cm3 of acetonitrile was heated for 18 hours at a temperature in the region of 75° C., with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20° C., the reaction mixture was filtered and washed with 3 times 30 cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 200 cm3 of petroleum ether (40-65° C.), filtered and washed with 3 times 30 cm3 of petroleum ether (40-65° C.). The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 7 cm; height: 28 cm), eluting with petroleum ether (40-65° C.) and collecting 100-cm3 fractions. Fractions 22 to 58 were combined and then concentrated to dryness under the above conditions. 14.5 g of 1-(2-bromoethoxy)-2,6-difluorobenzene were obtained in the form of a thick colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:24][CH2:25][O:26][CH3:27])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[CH2:28][CH2:29][CH3:30])=[CH:4][C:3]=1[CH2:31]O.[CH3:33][C:34]1([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH:48]([CH3:50])[CH3:49])=[CH:43][CH:42]=2)[NH:38][C:37](=[O:39])[NH:36][C:35]1=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O1CCCC1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:24][CH2:25][O:26][CH3:27])([C:16]([F:17])([F:18])[F:19])[C:20]([F:23])([F:22])[F:21])=[CH:11][C:10]=2[CH2:28][CH2:29][CH3:30])=[CH:4][C:3]=1[CH2:31][N:36]1[C:35](=[O:40])[C:34]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH:48]([CH3:50])[CH3:49])=[CH:43][CH:42]=2)([CH3:33])[NH:38][C:37]1=[O:39]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(Cl)c(CO)c1
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(Cl)c(CN2C(=O)NC(C)(c3ccc(OC(C)C)cc3)C2=O)c1
Yield: 50 %

Procedure:
(2-Chloro-5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy) phenyl)methanol (10 mg, 0.0212 mmol), 5-methyl-5-(4-(1-methylethoxy)phenyl)imidazolidine-2,4-dione (16 mg, 0.0635 mmol) and triphenylphosphine (16 mg, 0.0635 mmol) were added and dried in vacuo. N, N-dimethylformamide (300 μL) was added, and under ice-cold conditions, a solution of diethyl azodicarboxylate in tetrahydrofuran (29 μL, 0.0635 mmol) was added. The resultant mixture was stirred at room temperature for 4 hours. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using preparative thin-layer chromatography (hexane/ethyl acetate). 3-(2-Chloro-5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy) benzyl)-5-(4-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione (7.6 mg, yield >100%) was obtained as a yellow oil.