Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(S)C=CC=1Cl.ClCCO.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][O:12][S:34]([CH3:33])(=[O:36])=[O:35])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)Cl
Reactant: OCCSc1ccc(Cl)c(Cl)c1
Agent: OCCCl
Agent: Sc1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCSc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
A solution of 2-[(3,4-dichlorophenyl)thio]ethanol (117.97 g, 0.53 mole) prepared from 3,4-dichlorothiophenol and 2-chloroethanol, in benzene (500 ml) with triethylamine (53.5 g, 0.53 mole) was prepared. To this solution was added dropwise a benzene solution of methanesulfonyl chloride (60.9 g, 0.53 mole) over 1 hr (in an ice bath). The reaction mixture was stirred at room temperature overnight and then filtered. Solvent was removed by evaporation to give an oil which crystallized. A 5 g portion was recrystallized from isopropyl ether to give 4.61 g (47.9% yield based on aliquot) of white crystalline solid, m.p. 53°-55° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[CH2:14]([Li])[CH2:15][CH2:16]C.[CH:19]([C:21]1[N:22]=[CH:23][N:24](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:25]=1)=[O:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCCCCC>[NH:24]1[CH:25]=[C:21]([C:19]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=3)[CH:3]=2)([OH:20])[CH:15]([CH3:16])[CH3:14])[N:22]=[CH:23]1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: [Li]CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-6-methoxynaphthalene (30 g) was dissolved in THF (400 ml) and cooled to −78° C. A solution (1.6 M; 99 ml) of n-butyl lithium in hexane was added dropwise, and the mixture was stirred at −78° C. for 30 min. A solution (300 ml) of 4-formyl-1-trityl-1H-imidazol (38.9 g) in THF was slowly added dropwise. After stirring at −78° C. for 30 min, the reaction mixture was poured into 3% aqueous citric acid solution (600 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer was combined and the mixture was washed with saturated brine, dried and concentrated. The residue was washed with ethyl acetate to give the title compound (35.0 g) as a colorless solid.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([NH2:17])(=[S:16])[CH2:14][CH3:15]>C1C=CC=CC=1>[N:10](=[C:4]([C:3]1[N:17]=[C:13]([CH2:14][CH3:15])[S:16][CH:2]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[OH:11]
Reactant: CCOC(=O)C(=NO)C(=O)CCl
Reactant: CCC(N)=S
Solvent: c1ccccc1
Product: CCOC(=O)C(=NO)c1csc(CC)n1
Reaction time: 4 h
Yield: 35.3 %

Procedure:
A solution of ethyl γ-chloro-α-oximinoacetoacetate (2.00 g, 10.3 mmol) and thiopropionamide (0.92 g, 10.3 mmol) in dry benzene (15 mL) was heated to reflux. After 4 hours, the reaction mixture was poured onto NaHCO3 (sat. aq., 50 mL), The resulting mixture was extracted with ethyl acetate (2×50 mL), and the combined extracts dried over MgSO4 and evaporated under reduced pressure. Flash chromatography (ethyl acetate:hexane 1:4) then afforded impure ethyl α-oximino-2-ethylthiazole-4-acetate (0.83 g). The crude oxime was then dissolved in methanol (25 mL) and formic acid (50% aq., 10 mL) was added. The mixture was cooled to 0° C. and zinc dust (1.00 g, 15.3 mmol) was added portionwise over 30 mins. The reaction mixture was allowed to warm to room temperature, and stirred for 6 hours. The solution was then filtered, basified to pH 9 with solid NaHCO3, and extracted with ethyl acetate (3×80 mL). The combined extracts were then dried and evaporated to afford DL-2-ethylthiazol-4-ylglycine ethyl ester (0.56 g, 2.6 mmol). The ester (560 mg, 2.6 mmol) was then dissolved in tetrahydrofuran (50 mL). Triethylamine (0.4 mL, 3.9 mmol) was added, followed by di-t-butyl dicarbonate (0.57 g, 2.6 mmol). After stirring at room temperature overnight the mixture was concentrated, water (20 mL) was added and the solution extracted with ethyl acetate (2×20 mL). The combined extracts were evaporated to afford N-t-butyloxycarbonyl-D/L-2-ethylthiazol-4-ylglycine ethyl ester (824 mg,) as a golden oil. The oil was dissolved in methanol (25 mL) and aqueous sodium hydroxide (2 M, 5 mL) was added. After stirring at room temperature for 2 hours, the solution was concentrated, water (30 mL) was added, and the solution extracted with ethyl acetate (30 mL). The aqueous layer was then acidified to pH 4 with 2 N HCl, and extracted with ethyl acetate (2×20 mL), The latter extracts were combined and evaporated to afford N-t-butyloxycarbonyl-D/L-2-ethylthiazol-4-ylglycine (450 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11].[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=CC=C[CH:14]=1.C(O)(C)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH:13]([CH3:18])[CH3:14]
Reactant: COC(=O)c1ccc(C)cc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COC(=O)c1ccc(C)cc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 112 %

Procedure:
To a mixture of 2-hydroxy-4-methyl-benzoic acid methyl ester (1.0 g, 6.0 mmol), triphenylphosphine (1.9 g, 7.2 mmol), and isopropanol (0.72 g, 12.0 mmol) in THF (10.0 mL) is added DIAD (1.45 g, 7.2 mmol) dropwise at 0° C. The mixture is stirred at room temperature overnight. The mixture is evaporated to dryness under reduced pressure. The residue is partitioned between EtOAc (50 mL) and water (50 mL). The organic phase is washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to afford the title compound as white solid (1.4 g, 96%). LC-ES/MS m/e 209.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>ClCCl.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N2CCNCC2)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
A solution of t-butyl 4-(4-methoxyphenyl)piperazine-1-carboxylate (1.412 g, 4.84 mmol, 1.00 equiv) in dichloromethane (17 mL) and trifluoroacetic acid (6 mL) was placed in a 50-mL round bottom flask and stirred for 2 h at 20° C. in an oil bath. The pH of the solution was adjusted to 7-8 with saturated aqueous sodium bicarbonate. The resulting mixture was concentrated under vacuum yielding 0.92 g (65%) of 1-(4-methoxyphenyl)piperazine as a yellow solid.
Reaction SMILES: C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:20]([C:22]1[C:23]([N-:37][CH2:38][CH:39]([CH3:41])[CH3:40])=[C:24]([OH:36])[C:25]([F:35])=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:27]=1[CH3:28])#[N:21]>C(OCC)(=O)C>[F:35][C:25]1[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:27]([CH3:28])[C:22]([C:20]#[N:21])=[C:23]2[C:24]=1[O:36][C:38]([CH:39]([CH3:41])[CH3:40])=[N:37]2
Reactant: Cc1c(C#N)c([N-]CC(C)C)c(O)c(F)c1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(C)C)nc2c1C#N

Procedure:
Toluene (10 ml), p-toluenesulfonic acid monohydrate (5.3 mg, 28 μmol) were added to N-(5-cyano-2-fluoro-3-hydroxy-6-methylbiphenyl-4-yl)isobutylamide (I-51) (87 mg, 279 μmol), followed by refluxing with a Dean-Stark condenser for 3.5 hours. During the course, p-toluenesulfonic acid monohydrate (5.3 mg, 28 μmol) was added. Alter cooled, ethyl acetate (50 ml) was added to the reaction liquid, the organic layer was successively washed with saturated sodium bicarbonate water (30 ml), saturated brine (30 ml×2), then dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the entitled compound (82 mg, quant.) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:33][C:34]1[S:35][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:37][N:38]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18](=[O:20])[NH:33][C:34]3[S:35][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[N:37][N:38]=3)=[CH:21][CH:22]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: Nc1nnc(-c2ccccc2)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4nnc(-c5ccccc5)s4)cc3)c(C#N)cc21
Reaction time: 0.25 h
Yield: 57.9 %

Procedure:
4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (20 mg, 0.057 mmol) was diluted with DCM (1 ml) followed by the addition of oxalyl chloride in DCM (2M) (31 μl, 0.062 mmol) and DMF (1 drop). After stirring for 15 minutes, 2-amino-5-phenyl-[1,3,4]-thiadiazole (10 mg, 0.057 mmol) and DIEA (25 μl, 0.14 mmol) were added. After stirring for 12 hours, the reaction was loaded directly onto a biotage 25 column and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield methyl 6-cyano-7-(4-(5-phenyl-1,3,4-thiadiazol-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (17 mg, 0.033 mmol, 59% yield).
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH:41]=O.[C:43]([BH3-])#[N:44].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:44]([CH2:43][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:26][CH:25]=[CH:24][N:23]=3)[CH2:41][C:32]3[CH:33]=[CH:34][C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:31]=3)=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ccc4ccccc4n3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (81.2 mg) obtained in Example 47-3 was dissolved in methanol (3.2 ml) and then added with quinoline-2-aldehyde (36.5 mg) and sodium cyanoborohydride (24.3 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (77.8 mg) of the subject compound as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:22](=[CH:23][CH:24]=1)[C:10]1[NH:11][N:12]=[C:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[C:9]=1[CH2:8]2)[CH:2]=[CH2:3].[N-:25]=[N+:26]=[N-:27].[Na+].N(CC)(CC)CC.Cl>CN(C=O)C>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:22](=[CH:23][CH:24]=1)[C:10]1[NH:11][N:12]=[C:13]([C:14]3[CH:15]=[CH:16][C:17]([C:18]4[NH:27][N:26]=[N:25][N:19]=4)=[CH:20][CH:21]=3)[C:9]=1[CH2:8]2)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc2c(c1)Cc1c(-c3ccc(C#N)cc3)n[nH]c1-2
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)Cc1c(-c3ccc(-c4nnn[nH]4)cc3)n[nH]c1-2
Reaction time: 8 h
Yield: 28.6 %

Procedure:
A mixture of Example 62B (61.5 mg, 0.196 mmol), NaN3 (19.1 mg, 0.294 mmol), and Et3N.HCl (40.5 mg, 0.294 mmol) in DMF (2 mL) was heated at 140° C. for 4 hours. To this mixture were added more NaN3 (60.0 mg) and Et3N.HCl (120 mg). The reaction mixture was stirred overnight, cooled, and concentrated. The crude material was purified using the HPLC condition in Example 8 to give 20.0 mg (29%) of the desired product as brown solid. MS (DCI/NH3) m/z: 357.1 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 3.90 (s, 2H), 4.53-4.71 (m, 2H), 5.29 (dd, J=10.51, 1.70 Hz, 1H), 5.44 (dd, J=17.29, 2.03 Hz, 1H), 6.07 (m, 1H), 6.98 (dd, J=8.31, 2.20 Hz, 1H), 7.22 (d, J=2.03 Hz, 1H), 7.57 (d, J=8.14 Hz, 1H), 8.02 (d, J=8.14 Hz, 2H), 8.16 (d, J=8.48 Hz, 2H), 13.22 (s, brd, 1H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:18][O:19][C:20]([C:22]1[CH:40]=[CH:39][CH:38]=[CH:37][C:23]=1[CH2:24][S:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([OH:36])=O)=[CH:28][CH:27]=1)=[O:21].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:34](=[O:36])[CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([S:25][CH2:24][C:23]2[CH:37]=[CH:38][CH:39]=[CH:40][C:22]=2[C:20]([O:19][CH3:18])=[O:21])=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccccc1CSc1ccc(CCC(=O)O)cc1
Reactant: CCCCCCCNCc1ccc(F)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(SCc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
N-(2,4-difluorobenzyl)-N-heptylamine (0.64 g, 2.65 mmol) was dissolved in DMF (10 ml), 3-(4-{[2-(methoxycarbonyl)benzyl]thio}phenyl)propanoic acid (0.80 g, 2.41 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)-(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.85 g, 2.65 mmol) and diisopropylethylamine (0.65 g, 5.05 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. EtOAc (15 ml) was added and the organic phase was washed with two portions of sodium hydrogencarbonate (aq, 10 ml). EtOAc was removed by evaporation and the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). The solvent was removed by evaporation and gave 1.10 gram of methyl 2-{[(4-{3-[(2,4-difluorobenzyl)(heptyl)amino]-3-oxopropyl}phenyl)thio]methyl}benzoate (yield 82.2%).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 97.8 %

Procedure:
To a solution of 21.58 g of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 325 ml of ethyl alcohol is added 2.15 g of 10% Pd/C and 5.16 g of hydrazine followed by stirring and heating under reflux for 15 hours. The room temperature reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give 19.2 g of the desired product as a tan solid. The solid is purified by flash chromatography using 7:1 ethyl acetate-hexane to give 17.97 g of the desired product, m.p. 166-168° C.
Reaction SMILES: C(OC(=O)COC1C=CC(SCC2C=C(C3C=CC(C(F)(F)F)=CC=3)OC=2)=CC=1C)C.[CH2:32]([O:34][C:35](=[O:46])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=1[CH3:45])[CH3:33].[F:47][C:48]1[C:53]([F:54])=[C:52]([C:55]([F:58])([F:57])[F:56])[CH:51]=[CH:50][C:49]=1[C:59]1[S:63][C:62]([CH2:64]O)=[C:61]([CH3:66])[CH:60]=1>>[CH2:32]([O:34][C:35](=[O:46])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:64][C:62]2[S:63][C:59]([C:49]3[CH:50]=[CH:51][C:52]([C:55]([F:56])([F:57])[F:58])=[C:53]([F:54])[C:48]=3[F:47])=[CH:60][C:61]=2[CH3:66])=[CH:40][C:39]=1[CH3:45])[CH3:33]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(F)c2F)sc1CO
Reactant: CCOC(=O)COc1ccc(O)cc1C
Agent: CCOC(=O)COc1ccc(SCc2coc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(OCc2sc(-c3ccc(C(F)(F)F)c(F)c3F)cc2C)cc1C

Procedure:
The title compound was prepared by a method analogous to that used for the preparation of ethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate (example 1) using ethyl(4-hydroxy-2-methylphenoxy)acetate (intermediate 7) and {5-[2,3-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methanol (intermediate 122).
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH2:18].[C:19](Cl)(=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22]>ClC(Cl)C>[CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH:18][C:19](=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Reactant: CC(C)CC(=O)Cl
Solvent: CC(Cl)Cl
Product: CC(C)CC(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Yield: 66 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine (0.10 g, 0.42 mmol), isovaleryl chloride (0.051 mL, 0.42 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided 0.09 g of N-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-yl-3-methylbutanamide. MS (ES) m/z 325.2; HPLC purity 100% at 210-370 nm, 10.8 min.; 99.4% at 252 nm, 10.8 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C21H28N2O+H+, 325.22744; found (ESI, [M+H]+), 325.2269.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10](Cl)=[CH:9][C:8]([CH3:12])=[N:7][C:6]=1[Cl:13])[CH3:2].[CH3:15][CH2:16][O-:17].[Na+]>CCO.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([O:17][CH2:16][CH3:15])=[CH:9][C:8]([CH3:12])=[N:7][C:6]=1[Cl:13])[CH3:2]
Reactant: CC[O-]
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(OCC)cc(C)nc1Cl
Temperature: 60 °C

Procedure:
To a solution of 2,4-dichloro-6-methylnicotinic acid ethyl ester (2.49 mmol) in 6 mL EtOH was added NaOEt (2.61 mmol). The reaction mixture was heated to 60° C. overnight in a closed vessel. At RT, the mixture was diluted with EtOAc and washed with aq. NH4Cl solution. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by (KP-SIL™ from Biotage) using Hept/EtOAc (1/1) gives the desired product as beige solid;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21](SC)=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:31])([F:30])[F:29])[CH:4]=1.[C:32]([O:36][C:37](=[O:45])[NH:38][C@H:39]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:45])[NH:38][CH:39]1[CH2:44][CH2:43][CH2:42][N:41]([C:21]2[S:22][C:18](=[CH:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][C:6]3[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:28]([F:31])([F:29])[F:30])[N:9]=[CH:10]4)[C:19](=[O:25])[N:20]=2)[CH2:40]1)([CH3:35])([CH3:33])[CH3:34].[NH2:38][C@H:39]1[CH2:44][CH2:43][CH2:42][N:41]([C:21]2[S:22][C:18](=[CH:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][C:6]3[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:28]([F:30])([F:31])[F:29])[N:9]=[CH:10]4)[C:19](=[O:25])[N:20]=2)[CH2:40]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: COc1ccc(Cn2ncc3cc(C=C4SC(SC)=NC4=O)ccc32)c(C(F)(F)F)c1
Product: COc1ccc(Cn2ncc3cc(C=C4SC(N5CCCC(NC(=O)OC(C)(C)C)C5)=NC4=O)ccc32)c(C(F)(F)F)c1
Product: COc1ccc(Cn2ncc3cc(C=C4SC(N5CCC[C@H](N)C5)=NC4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-3-yl)-carbamic acid tert-butyl ester was prepared from 5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperidin-3-(S)-yl-carbamic acid tert-butyl ester following General Procedure C. The compound was used directly following General Procedure H to provide 2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.
Reaction SMILES: C([O:5]C([NH:8][C@H:9]([C:22]([NH:24][C@@H:25]([C:31]([NH:33][CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:32])[CH2:26][CH2:27][C:28]([NH2:30])=[O:29])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C(C)(C)C)=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:43]>C(O)(=O)C>[OH2:5].[ClH:43].[NH2:8][C@H:9]([C:22]([NH:24][C@@H:25]([C:31]([NH:33][CH2:34][CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:32])[CH2:26][CH2:27][C:28]([NH2:30])=[O:29])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@H](CCC(N)=O)C(=O)NCCCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)CC[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCCCc1ccccc1
Product: O

Procedure:
A solution of [N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosyl]-N1 -(3-phenylpropyl)-D-glutamamide (700 mg.) in acetic acid saturated with hydrogen chloride (15 ml.) was stirred at room temperature for one hour, then stripped of volatiles under vacuum at 40° C. An aqueous solution of the residue was filtered and lyophilized, affording as an amorphous white solid L-tyrosyl-N1 -(3-phenylpropyl)-D-glutamamide monohydrochloride hydrate (4:3) (545 mg.; [α]D25 +46.4°, c=1, methanol), whose free base is the compound of Formula II wherein Q is Gln, R1, R2 and R5 are each hydrogen and R4 is (CH2)nY wherein n is 3 and Y is phenyl.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.O1[C:39]2[CH:40]=[CH:41][C:42]([NH2:44])=[CH:43][C:38]=2OCC1>>[CH2:2]1[C:38]2[C:39](=[CH:40][CH:41]=[C:42]([NH:44][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:43]=2)[CH2:5][CH2:4][NH:3]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: Nc1ccc2c(c1)OCCO2
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 2,3-dihydro-1,4-benzodioxin-6-amine in a manner analogous to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 4.20 (m, 4H), 6.45 (d, 1H, J=5.3 HZ), 6.72 (d, 1H, J=8.8 Hz), 7.10 (m, 2H), 7.22 (m, 2H), 7.28 (m, 2H), 7.35 (m, 2H), 7.46 (d, 1H, J=8.1 Hz), 7.98 (s, 1H), 8.20 (d, 1H, J=5.3 Hz), 8.83 (d, 1H, J=6.9 Hz), 9.35 (s, 1H), 10.93 (s, 1H); ESIMS (M+H)+=577.