Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[C:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:14][CH:13]=2)[CH:11]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1.C1(C)C=CC=CC=1.C1C=CC=CC=1>CCOCC>[F:1][C:2]([F:36])([F:35])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[C:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:14][CH:13]=2)[CH:11]=1)=[S:46]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)NCC(F)(F)F)nc3-c3ccccc3Cl)cc2)c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=S)NCC(F)(F)F)nc3-c3ccccc3Cl)cc2)c1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a 25 mL round bottom flask attached with Vigreux column and magnetic stir bar was added 2-(2-Chloro-phenyl)-1-(3′-methanesulfonyl-biphenyl-4-yl)-1H-imidazole-4-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (65 mg, 127 μmol), Lawesson's Reagent (230 mg, 570 μmol), and anhydrous toluene (6 mL). The reaction solution was allowed to stir at reflux 5 hrs prior to TLC analysis showing full transformation of starting material. The reaction solution was allowed to cool to room temperature prior to addition of a 1:1 mixture of benzene and Et2O. The resulting precipitate was removed by vacuum filtration through a Buchner funnel. The filtrate was concentrated on the Rotavapor and the crude residue was chromatographed through a 12 g SiO2 column using a mobile phase gradient of 100% Hx to 50% EtOAc to afford 55 mg (79% yield) of the title compound. 1H NMR (400 MHz, CDCl3) 9.21 (t, 1H), 8.11 (s, 1H), 8.04 (t, 1H), 7.85 (d, 1H), 7.75 (d, 1H), 7.59 (t, 1H), 7.53-7.46 (m, 4H), 7.34-7.311 (m, 3H), 7.18 (d, 2H), 4.56 (m, 2H), 3.02 (s, 3H); 19F NMR (400 MHz, CDCl3) 6-70.8 ppm; MS (ES): 550.3, 552.3 [M+H]+.
Reaction SMILES: C([BH3-])#N.[Na+].[CH:5]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)([CH3:7])[CH3:6].O.[OH-].[Na+]>C(O)(=O)C>[CH:5]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1)([CH3:7])[CH3:6]
Reactant: CC(C)c1cc2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C1Cc2ccccc2N1
Temperature: 15 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
4.65 g of sodium cyanoborohydride are gradually added to a solution of 5.0 g of 2-isopropylindole in 50 ml of acetic acid under argon cooled to a temperature of about 15° C. The reaction mixture is stirred at a temperature of about 15° C. for 2 hours and is then treated with 25 ml of water. It is then cooled to a temperature of about 5° C. and alkalinized by gradual addition of powdered sodium hydroxide. The reaction mixture is allowed to warm up to ambient temperature and is then stirred for 16 hours. The precipitate is filtered off through sintered glass and washed with 50 ml of water and then 50 ml of ethyl acetate. The filtrate is diluted with 50 ml of water and 70 ml of ethyl acetate and then separated by settling out. The organic phase is separated and the aqueous phase is extracted with 2×100 ml of ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 90 g cartridge of 15-40 μm silica, elution being carried out with a 95/5 v/v cyclohexane/ethyl acetate mixture, at a flow rate of 50 ml/min. 4.0 g of (±)-2-isopropylindoline are thus obtained in the form of a colorless oil which crystallizes into a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[S:9](=[O:11])(=[O:10])[NH:8][C:7]2[N:12]=[CH:13][CH:14]=[CH:15][C:6]=2[C:5]1=[O:16])[CH3:3].[H-].[Na+].S(OC)(O[CH3:23])(=O)=O>COCCOCCOC>[CH3:23][N:8]1[C:7]2[N:12]=[CH:13][CH:14]=[CH:15][C:6]=2[C:5](=[O:16])[N:4]([CH:2]([CH3:1])[CH3:3])[S:9]1(=[O:10])=[O:11]
Reactant: CC(C)N1C(=O)c2cccnc2NS1(=O)=O
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CC(C)N1C(=O)c2cccnc2N(C)S1(=O)=O

Procedure:
3-(1-Methylethyl)pyrido(2,3-c)(1,2,6)thiadiazin-4(3H)-one-2,2-dioxide (5.0 grams; 0.0208 mole) was mixed with 50 ml of diethylene glycol dimethyl ether. The system was flushed with nitrogen and sodium hydride (1.0 gram; 0.02 mole), previously washed with n-hexane, was added portionwise to the reaction mixture. After the effervescence of hydrogen ceased, 2.2 ml of dimethyl sulfate (0.023 mole, 1.33g/ml) was added and the reaction mixture heated at reflux temperatures for a period of 4 hours. During the reaction, the color of the reaction mixture changed from light yellow to deep red and gradually back to yellow.
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>C1COCC1>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:15](=[O:16])[NH:13][C:10]2[CH:11]=[N:12][C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:8][CH:9]=2)=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: Nc1ccc(OC2CCCC2)nc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OC2CCCC2)nc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of 6-cyclopentyloxy-pyridin-3-ylamine (0.248 g, 1.39 mmol) in THF (2 mL) was added 4-nitrophenyl chloroformate (0.280 g, 1.39 mmol) portionwise. After stirring at rt for 1 h, a heavy precipitate formed in the organic layer. Filtration of the organic layer provided the title compound as a light pink solid (0.368 g, 77%). 1H-NMR (400 MHz, CDCl3): δ 11.1 (s, 1H), 9.11 (s, 1H), 9.04 (d, 1H), 8.26 (d, 2H), 7.40 (d, 2H), 7.14 (d, 1H), 5.36 (m, 1H), 2.11 (m, 2H), 1.97 (m, 2H), 1.84 (m, 2H), 1.71 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:8][C:5]2[C:4]([O:9][CH3:10])=[N:3][C:2]([Cl:1])=[CH:7][N:6]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: COc1nc(Cl)cnc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.1 g) and 4-chlorobenzenesulphonyl chloride (0.13 g).
Reaction SMILES: B(Br)(Br)Br.C(Cl)Cl.C[O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]2>C(Cl)Cl>[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]2
Reactant: COc1ccc2c(c1)CCC(=O)N2C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1C(=O)CCc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
5.74 ml of 1.0 M BBr3/CH2Cl2 solution was added to a dry CH2Cl2 solution of 6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (500 mg, 2.62 mmol) under nitrogen. The reaction mixture was stirred for 2 hours, poured into ice water and extracted with ethyl acetate (150 ml). The combined organic extract was washed with brine,dried (MgSO4) and the solvent was evaporated under reduced pressure to yield the title compound as a pink solid (392 mg, 84%). 1H NMR (400 MHz, CD3OD) δ 2.52–2.56 (2H, m), 2.77–2.81 (2H, m), 3.28 (3H, s), 6.62–6.67 (2H, m), 6.92 (1H, d, J=8.72 Hz). m/z (APCI−) 176 (M−1). HPLC (aqueous 200 Mm ammonium acetate buffer/acetonitrile gradient, 3.0 ml/min, Hewlett Packard ODS Hypersil 5 μM, 125×4 mm column), 2.51 minutes.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:10]3[CH:16]=[CH:15][C:14](=[O:17])[CH:13]=[CH:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:21]2[CH2:20][CH2:19][N:18]([C:9]3[N:10]4[CH:16]=[CH:15][C:14](=[O:17])[CH:13]=[CH:12][C:11]4=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[CH2:23][CH2:22]2)=[CH:27][CH:28]=1)#[N:33]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=c1ccc2c(-c3ccccc3)cc(N3CCNCC3)n2cc1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(CN2CCN(c3cc(-c4ccccc4)c4ccc(=O)ccn34)CC2)cc1
Yield: 12.9 %

Procedure:
By working as in Example 2, but starting with 1-phenyl-3-(1-piperazinyl)-7H-pyrrolo[1,2-a]azepin-7-one (3.05 g), α-bromo-p-toluonitrile (2.35 g) and 4-dimethylaminopyridine (1.48 g) in solution in chloroform (80 cc), 3-[4-(4-cyanobenzyl)-1-piperazinyl]-1-phenyl-7H-pyrrolo[1,2-a]azepin-7-one (0.54 g), m.p. 196° C., is obtained after recrystallization in ethanol (25 cc).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH2:49]([CH2:51][NH2:52])[OH:50]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:52][CH2:51][CH2:49][OH:50])=[O:20])=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCO)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 62.7 %

Procedure:
A dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (100 mg, 0.236 mmol) obtained in Example 50 were added triethylamine (80 μl, 0.566 mmol), 4-dimethylaminopyridine (15 mg, 0.118 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg, 0.283 mmol) and ethanolamine hydrochloride (28 mg, 0.283 mmol). The resulting mixture was stirred at room temperature for 17.5 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the dichloromethane:methanol=30:1 eluate was concentrated under reduced pressure to give the title compound (69 mg, 0.148 mmol, 63%) as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)(O)[CH3:7])C.I.OS([O-])=O.[Na+]>C(O)(=O)C>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([CH:6]([CH3:7])[CH2:5][C:4]([OH:23])=[O:3])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
1 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester, or the corresponding free hydroxy acid or 3-(2',4°-difluoro-4-biphenylyl)-2-butenoic acid, is heated with 2 ml. of 67% hydriodic acid and 4 ml of acetic acid at 150° for 1 hour and the mixture is poured onto ice and decolorized with NaHSO3 solution. After the customary work up, 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°, is obtained.
Reaction SMILES: [CH2:1](N(C(C)C)C(C)C)[CH3:2].[OH:10][C@@H:11]([C@H:13]1[C:19](=[O:20])[N:18]2[CH:14]1[S:15][C:16](=[S:34])[CH:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:12].ICC>O1CCCC1>[CH2:1]([S:34][C:16]1[S:15][CH:14]2[N:18]([C:19](=[O:20])[C@@H:13]2[C@H:11]([OH:10])[CH3:12])[C:17]=1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=S)SC12
Solvent: C1CCOC1
Solvent: CCI
Product: CCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)C2S1
Reaction time: 16 h

Procedure:
To 0.200 ml of ethyl diisopropylamine was added to 0.426 g of 4-nitrobenzyl 6(S)-[1(R)-hydroxyethyl]-7-oxo-3-thioxo-4-thia-1-azabicyclo[3,2,0]heptane-2-carboxylate in dry tetrahydrofuran with stirring. 0.252 ml of iodoethane was then added and stirring was continued for 16 hours at room temperature. The reaction mixture was then evaporated to dryness and chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures, to give the title product as a mixture of 5R and 5S isomers.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[NH2:20])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[O:28]=[C:29](Cl)OC(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]2[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[NH:20][C:29]2=[O:28])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(Nc2ccc(F)cc2N)CC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(F)ccc32)CC1
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To a solution of 4-(2-amino-4-fluoro-phenylamino)-piperidine-1-carboxylic acid ethyl ester (0.100 g, 0.36 mmol) and triethylamine (0.110 mg, 1.08 mmol) in methylene chloride (2 mL) at 0° C. was added a solution of diphosgene (0.71 mg, 0.36 mmol) in methylene chloride (4 mL) at room temperature. The reaction mixture was stirred for 18 h then quenched with a saturated aqueous solution of sodium bicarbonate. The organic phase was separated and washed with brine. The organic phase was purified by passing it through a plug of silica gel, using ethyl acetate as the eluent. The filtrate was evaporated, in vacuo, to a residue. The residue was triturated with hexanes/dichlormethane (95:5) and the solid collected by filtration. Vaccum drying yielded 4-(5-fluoro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester (77.8 mg, 71%) as a light tan solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.N#N>COCCOC.C([O-])([O-])=O.[Na+].[Na+]>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][CH:10]=1
Reactant: Brc1cccnc1
Reactant: OB(O)c1ccc(F)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2cccnc2)cc1
Temperature: 80 °C
Yield: 109.6 %

Procedure:
A solution of 3-bromopyridine (2.5 g, 15.8 mmol) and 4-fluorophenylboronic acid (2.8 g, 20.0 mmol) in DME (20 ml) and 2N Na2CO3 (aq, 20 ml) was deoxygenated by evacuation/refill with N2 (×2). PdCl2dppf (600 mg, 0.8 mmol) was added and the mixture was deoxygenated again (×3). The reaction was stirred and heated at 80° C. under N2 for 16 hours. After cooling to RT the mixture was partitioned between EtOAc/H2O. The aqueous layer was extracted with EtOAc (×2). The combined extracts were washed with brine (×1), dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica (10→40% EtOAc/Petrol) to give the title compound (3.0 g, oil). 1H NMR (400 MHz, CDCl3): 8.83 (1H, brs), 8.61 (1H, brs), 7.85 (1H, d), 7.54 (2H, dd), 7.39 (1H, brs), 7.18 (2H, t).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:23]([O:21][C:20](=[O:22])[C@@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Finely divided t-butoxycarbonyl-D-tryptophan (3 g, 10 mmol) was suspended in methylene chloride and benzyl alcohol (1.08 mL, 10 mmol) and 4-dimethylaminopyridine (0.12 g, 1 mmol) were added and stirred at room temperature. Solid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g, 10 mmol) was then added in three roughly equal portions over 5 minutes. The reaction mixture was stirred for 3 hours at room temperature during which time the reaction mixture became a homogeneous solution. The reaction mixture was poured into water (100 mL) and extracted with methylene chloride (2×50 mL). The combined methylene chloride layers were washed with 5% aqueous citric acid solution (100 mL) and 5% aqueous sodium bicarbonate solution (100 mL). The resulting methylene chloride layer was dried over magnesium sulfate, filtered and evaporated under vaccum to give an off-white solid. This solid material was chromatographed on silica gel using ethyl acetate/hexanes (2:3 v/v) as eluant. This afforded 3.56 g (91%) of the desired benzyl ester as a white amorphous powder.
Reaction SMILES: [Si]([O:8][CH:9]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20](=[O:22])[CH3:21])[CH:15]=1)[C:10]([F:13])([F:12])[F:11])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C1COCC1>[F:13][C:10]([F:11])([F:12])[CH:9]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20](=[O:22])[CH3:21])[CH:15]=1)[OH:8]
Reactant: CC(=O)c1cc(C(O[Si](C)(C)C(C)(C)C)C(F)(F)F)ccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(O)C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
In THF (6 mL) was dissolved 1-(4-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)pyridin-2-yl)ethanone (645 mg, 1.93 mmol) obtained in Step 3. Tetrabutylammonium fluoride (1.0 mol/L solution in THF, 0.556 mL, 0.556 mmol) was added and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give 1-(4-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)ethanone (406 mg, 96% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].Cl.[CH:8]1([CH:14]=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>[Pd].CO>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:1][CH2:14][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=CC1CCCCC1
Reactant: COC(=O)CN
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)CNCC1CCCCC1

Procedure:
In a methanol solution containing 2.0 g of H-Gly-OMe.HCl, 2.12 ml of cyclohexanecarboxaldehyde was added and the resultant mixture was stirred overnight in H2) atomosphere in the presence of 200 mg of 10% palladium-charcoal. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give N-(cyclohexylmethyl)glycine methyl ester [H-(cHexm)Gly-OMe]. The CHCl3 solution of the amino ester obtained above was mixed with 3.32 ml of triethylamine and 4.18 g of Boc2O under ice cooling and the mixture was stirred for 3 hr. The stirred mixture was washed with 5% aqueous citric acid solution, 5% aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography (chloroform) to give oily Boc-(cHexm)Gly-OMe. The oily product was dissolved in methanol and 11.4 ml of 1N—NaOH aqueous solution was added and the resultant solution was stirred for 2 hr at room temperature. The obtained solution was neutralized with citric acid, evaporated and dissolved in ethyl acetate. The ethyl acetate solution was washed with 5% aqueous citric acid solution and saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure. The residue was dissolved in methanol and cyclohexylamine was added to the solution, then the resultant solution was evaporated and crystallized from ether to give 1.75 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[S:8][CH2:7][CH2:6][CH:5]2[OH:13].[CH2:15](O)[CH3:16]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[S:8][CH2:7][CH2:6][CH:5]2[O:13][CH2:15][CH3:16]
Reactant: Cc1cc(Br)c(C)c2c1SCCC2O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC1CCSc2c(C)cc(Br)c(C)c21

Procedure:
A 100 ml three-necked flask was charged with 5.9 g (0.022 mol) of 6-bromo-5,8-dimethylthiochroman-4-one, and then, 30 ml of methylene chloride and 10 ml of methanol were added and dissolved. The entire reaction system was cooled to 0° C. in an ice salt bath, and 0.42 g.(0.011 mol) of sodium borohydride was added by small portions. Thereafter, the mixture was allowed to react for 2 hours while it was cooled as above. The reaction mixture was poured into 100 ml of water, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and methylene chloride was distilled off under reduced pressure to give 6.0 g of 6-bromo-5,8-dimethyl-4-hydroxythiochroman as a solid. Then, 6.0 g of this 6-bromo-5,8-dimethyl-4-hydroxythiochroman was charged into a 100 ml eggplant-shaped flask, and 20 ml of ethanol was added to form a solution. Then, 10 drops of concentrated sulfuric acid was added, and the mixture was refluxed under heat for 1 hour. The reaction mixture was allowed to cool and poured into 100 ml of water, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and methylene chloride was distilled off under reduced pressure to give 5.8 g of 6-bromo-5,8-dimethyl-4-ethoxythiochroman as an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][C:10](=[O:12])[CH3:11]
Reactant: Nc1cc(F)ccc1F
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(F)ccc1F
Reaction time: 1 h

Procedure:
2,5-Difluoroaniline (100 g, 0.775 mol) is added dropwise to a mixture of concentrated sulfuric acid (4 drops) in acetic anhydride (250 mL) while maintaining the reaction mixture temperature below 15° C. After the addition is complete, the reaction mixture is stirred for one hour and filtered to obtain a solid. The solid is washed with diethyl ether and air dried to give the title product as a white solid, mp 124°-125° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])C.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:27][NH2:28])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:27][NH:28][C:7]2[C:6]([C:4]([OH:3])=[O:5])=[CH:11][N:10]=[C:9]3[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:8]=23)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: COc1ccc(CN)cc1Cl
Product: CCn1ncc2c(NCc3ccc(OC)c(Cl)c3)c(C(=O)O)cnc21
Yield: 87 %

Procedure:
4-Chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester and (3-chloro-4-methoxyphenyl)methylamine was used to afford the title compound (87%) as a white solid: mp 250 ° C.(decomposed).