Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:37])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:20][N:21]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:22]([NH:24]CCC)=[O:23])=O)=[CH:11][CH:10]=1)[CH3:7])=[O:5])[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(OCC)(=O)C>[Cl:36][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[Cl:35])[CH2:28][N:21]1[C:22](=[O:23])[NH:24][C:18]([CH2:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]([CH3:37])([CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:10][CH:11]=2)=[N:20]1
Reactant: CCCNC(=O)N(Cc1ccc(Cl)c(Cl)c1)NC(=O)CCCc1ccc(OC(C)(C)C(=O)OCC)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCc2nn(Cc3ccc(Cl)c(Cl)c3)c(=O)[nH]2)cc1

Procedure:
To substrate 1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(3,4-dichlorophenylmethyl)-4-(propyl)semicarbazide (0.4976 g, 0.901 mmol) and camphorsulfonic acid (0.2078 g, 0.895 mmol) was added ethyl acetate (10 mL) and the resulting solution heated to reflux for 12 h. The solution was diluted with ethyl acetate, then washed with sat'd aq. NaHCO3 followed by sat'd aq. NaCl. It was then dried (MgSO4), filtered and concentrated to afford the title compound as an oil (0.4532 g (0.848 mmol, 94%): 1H NMR (DMSO-d6) δ 7.59 (d, 1H, J=8.5 Hz), 7.47 (d, 1H, J=2 Hz), 7.19 (dd, 1H, J=8.5, 2 Hz), 7.03 (d, 2 H, J=8.5 Hz), 6.69 (d, 2H, J=8.5 Hz), 4.85 (s, 2H), 4.13 (q, 2H, J=7 Hz), 3.48 (t, 2H, J=8 Hz), 2.55 (t, 2H, J=7 Hz), 1.83 (m, 2H), 1.52 (q, 2H, J=7 Hz), 1.47 (s, 6H), 1.14 (t, 3H, J=7 Hz), 0.79 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ 174.0, 154.1, 153.8, 147.3, 139.2, 135.6, 131.7, 131.5, 130.8, 130.1, 129.8, 128.4, 119.6, 79.3, 61.6, 47.3, 42.9, 34.0, 27.7, 25.7, 24.7, 22.4, 14.6, 11.5; IR (CHCl3) 3003, 2939, 1728, 1696, 1509 cm−1; HRMS calcd. for C27H34Cl2N3O4 (M+H)+: 524.1926. Found: 534.1935
Reaction SMILES: [CH2:1]([C@:3]1([C:31]([O:33][CH3:34])=[O:32])[CH2:7][CH2:6][CH2:5][C@H:4]1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH3:2].[H-].[Na+].I[CH3:38]>C1COCC1>[CH2:1]([C@:3]1([C:31]([O:33][CH3:34])=[O:32])[CH2:7][CH2:6][CH2:5][C@H:4]1[N:8]([CH3:38])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:11])[CH3:2]
Reactant: CI
Reactant: CC[C@]1(C(=O)OC)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@]1(C(=O)OC)CCC[C@H]1N(C)S(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To 204 mg (0.423 mmol) of methyl (1S,2R)-1-ethyl-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate (Example 56, Step 3) in THF (1.5 mL) was added 60% sodium hydride (22 mg, 0.55 mmol) and the resulting mixture was stirred at room temperature for 1 h. Iodomethane (35 μL, 80 mg 0.56 mmol) was added and the reaction was stirred overnight and then quenched with saturated aqueous ammonium chloride. These steps were repeated twice more, until starting material was consumed, and the residue was purified by column chromatography on silica gel eluting with 50% ethyl acetate/hexanes to give methyl (1S,2R)-l -ethyl-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate (174 mg, 0.350 mmol, 83%) as a colorless solid. 1H NMR (400 MHz, CHLOROFORM-D) □ ppm 0.85 (t, J=7.33 Hz, 3H) 1.29-1.40 (m, 1H) 1.48-1.60 (m, 4H) 1.78-1.87 (m, 1H) 2.20-2.30 (m, J=7.01, 7.01, 7.01, 7.01 Hz, 2H) 2.57 (s, 3H) 2.75 (s, 3H) 3.71 (s, 3H) 5.55 (s, 2H) 7.11 (ddd, J=9.41, 2.78, 2.46 Hz, 2H) 7.42 (s, 1H) 7.55 (ddd, J=8.27, 6.88, 1.26 Hz, 1H) 7.70-7.76 (m, 3H) 7.90 (d, J=7.58 Hz, 1H) 8.09 (d, J=7.83 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:17][C:18]([N:20]1[CH2:25][C@H:24]([CH3:26])[N:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:22][C@H:21]1[CH3:35])=[O:19])=[O:8])C.O1CCCC1.CO.O.[OH-].[Li+]>O>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH2:17][C:18]([N:20]2[CH2:25][C@H:24]([CH3:26])[N:23]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:22][C@H:21]2[CH3:35])=[O:19])=[C:9]([C:7](=[O:8])[CH2:6][CH2:5][C:4]([OH:36])=[O:3])[CH:14]=1
Reactant: CCOC(=O)CCC(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.7 %

Procedure:
To a solution of 4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-4-oxo-butyric acid ethyl ester (0.082 g, 0.16 mmol) in 2:2:1 tetrahydrofuran:methanol:water(1.5 mL) was added lithium hydroxide monohydrate (0.34 g, 0.79 mmol). The resulting solution was stirred 12 hours at ambient temperature, then concentrated in vacuo. The crude product was dissolved in ethyl acetate and washed with 1 M hydrochloric acid. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (0.072 g, LRMS: 489.4, 491.4).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([C:23](=[O:34])[N:24]([CH3:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:11][N:10]=1)(C)(C)C.[ClH:36]>CCOC(C)=O>[ClH:36].[CH3:33][N:24]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:23]([C:12]1[C:13]2[C:18](=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)[C:9]([CH2:8][NH2:7])=[N:10][CH:11]=1)=[O:34]
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N(C)CCc3ccccn3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(CN)ncc(C(=O)N(C)CCc3ccccn3)c2c1
Yield: 100 %

Procedure:
As described in example 1, 57 mg of {6,8-dimethoxy-4-[methyl-(2-pyridin-2-yl-ethyl)-carbamoyl]-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester was treated with HCl in EtOAc to give 74 mg (>100%) of 1-aminomethyl-6,8-dimethoxy-isoquinoline-4-carboxylic acid methyl-(2-pyridin-2-yl-ethyl)-amide hydrochloride. MS: APCI (M+H) calc'd for C21H24N4O3+H 381.4; found 381.2.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[CH:5]=[CH:4][N:3]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O.O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C@H:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24]3)[CH:7]=2)[CH3:14])=[CH:16][CH:17]=1
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2ccnc(Br)c2)cc1
Reactant: c1ccc2c(c1)CCN2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc([C@@H](C)N2CCC[C@H]2c2ccnc(N3CCc4ccccc43)c2)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
To a solution of 2-Bromo-4-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (0.15 g, 0.41 mmol) in toluene (30 mL) are added indoline (0.10 g, 0.83 mmol), 2-(dicyclohexylphosphino)-biphenyl (14 mg, 0.04 mmol), Pd2(dba)3 (19 mg, 0.02 mmol) and potassium tert-butoxide (0.11 g, 1.04 mmol). The reaction mixture is stirred at 85° C. for 3 h and cooled to room temperature. Water and EtOAc are added to the mixture. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by flash chromatography on silica gel (EtOAc/Hexane: 5%˜25%) to give (1-(4-{(S)-1-[(R)-1-(4-Methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-2-yl)-2,3-dihydro-1H-indole (140 mg, 84%) as an oil. M/Z=400.2 [M+1]
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.[Cu](I)I>[Cl:1][C:2]1[C:7]([C:23]#[C:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: Clc1ncncc1I
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1ncncc1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2.1 g of 4-chloro-5-iodopyrimidine, 10 mL of triethylamine, 1.2 mL phenylacetylene, 80 mg copper iodide and 160 mg of dichlorobis(triphenylphosphine was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane and evaporated in vacuo. The residue was redissolved in a few mL of dichloromethane, 10 mL of triethylamine added and the mixture heated at reflux for one hour. The heterogeneous mixture was evaporated in vacuo and the residue obtained was partitioned between water and dichloromethane. A gelatinous precipitate which formed on shaking the two layers was filtered off, enabling separation of the two layers. The organic extracts were dried over sodium sulfate, filtrated and evaporated in vacuo to yield 2.5 g of a dark brown syrup. The syrup was purified by column chromatography on silica gel, twice, eluting with hexanes, 1:1 hexanes/dichloromethane, dichloromethane and finally ethyl acetate. Like fractions from dichloromethane elution were pooled, obtaining 350 mg of the product, 5-phenylethynyl-4-chloropyrimidine as an oil which solidified to white rosettes.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][NH:18][C:17](=[O:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([F:33])[CH:29]=2)[N:24]=1>>[F:33][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([CH2:22][N:18]1[CH2:19][CH:15]([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:8]=3)[CH2:16][C:17]1=[O:20])[CH:32]=[CH:31]2
Reactant: Fc1ccc2nc(CCl)ccc2c1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC1CCCC1
Product: COc1ccc(C2CC(=O)N(Cc3ccc4cc(F)ccc4n3)C2)cc1OC1CCCC1

Procedure:
Reaction of 4-[3-(cyclopentyloxy)-4-methoxyphenyl]pyrrolidinone with 2-chloromethyl-6-fluoroquinoline, analogous to the procedure of Example 29, yielded the title compound. M.P.: 65°-68° C. High Resolution Mass Spectra: Calc'd: 434.1983. Found: 434.2005.
Reaction SMILES: [CH3:1][CH:2]([C@@:4]12C[CH:8]1[C@:7]([OH:11])(C)[CH2:6][CH2:5]2)[CH3:3].CC(C12CC1C(=O)CC2)C>>[CH:2]([C:4]1[CH2:5][CH2:6][C:7](=[O:11])[CH:8]=1)([CH3:3])[CH3:1]
Reactant: CC(C)[C@]12CC[C@](C)(O)C1C2
Agent: CC(C)C12CCC(=O)C1C2
Product: CC(C)C1=CC(=O)CC1

Procedure:
In the process, however, a relatively greater number of steps have to be pursued up to the course of synthesis of sabina ketone (6). In addition, since sabine ketone is obtainable from the starting material 3-isopropyl-2-cyclopenten-1-one only in about 57% yield, the total yield of sabinene hydrate results in lower value. Moreover, according to the process, operations and works are complicated and laborious, as it requires isolation procedures for each intermediate. Further, it is necessary to use valuable reagents and chromate compound hazardous in handling. Therefore, sabinene hydrates cannot be produced efficiently or economically, in particular, in large scale. Furthermore, by the process, cis-sabinene hydrate (formula 8) is produced preferentially and trans-sabinene hydrate (formula 7) appears only in a considerably minor amount. That is to say, a ratio of formation of trans-compound to cis-compound is 1:8.5, so that the process does not suit an industrial synthesis of trans-sabinene hydrate. Also, yield of trans- and cis-sabinene hydrates from sabina ketone is about 11%, and yield from 3-isopropyl-2-cyclopenten-1-one is about 6.3%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=O)[CH:5]=[CH:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:10]1([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Nc1cc(C(=O)N2CCCCC2)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cc(CN2CCCCC2)ccn1
Temperature: 0 °C

Procedure:
To a stirred solution of (2-amino-pyridin-4-yl)-piperidin-1-yl-methanone (100 mg, 0.487 mmol) in dry THF (10 mL) at 0° C. was added LAH (1.5 mL, 1.46 mmol) dropwise. The mixture was heated to reflux for 20 h. The resulting mixture was cooled to 0° C. and quenched with H2O (1.5 mL) dropwise followed by 10% NaOH (1.5 mL). Solvent was removed and the residue was partitioned between H2O and CHCl3. The organic layer was washed with H2O, brine, dried over MgSO4. Concentration in vacuo gave a light brown liquid. MS m/z: 192.2 (M+H). Calc'd. for C11H17N3-191.14.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:21](=[O:24])[CH2:22]Br)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>CCO>[F:20][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][N:10]2[CH2:9][CH2:8][NH:7][CH2:22][C:21]2=[O:24])[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CC(C)(C)OC(=O)NCCN(CCc1ccc(F)c(F)c1)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNCCN1CCc1ccc(F)c(F)c1
Yield: 91.6 %

Procedure:
In the same way as that described in Example 2, Step 3 using 2-[(bromoacetyl)(2-(3,4-difluorophenyl)ethyl)amino]ethyl carbamic acid tert-butyl ester (549 mg, 1.3 mmol), trifluoroacetic acid (2.5 mL) and CH2Cl2 (25 mL), followed by K2CO3 (0.36 g, 2.6 mmol) and EtOH (50 mL). The piperazinone (286 mg, 91%) was isolated as a yellow oil. 1H NMR (250 MHz, CDCl3) δ 2.85 (2H, t, J=7.3Hz), 2.99-3.03 (2H, m), 3.17-3.21 (2H, m), 3.52 (2H, s), 3.56 (2H, t, J=7.3Hz), 6.90-7.16 (3H, m). MS (ES+) (241, M+1).
Reaction SMILES: C(OC(=O)[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[C:10]([F:16])[N:9]=1)(C)(C)C.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]([Si](C(C)C)(C(C)C)C(C)C)[CH:28]=1>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:27]2[C:35]3[C:30](=[N:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[NH:29][CH:28]=2)=[C:10]([F:16])[N:9]=1
Reactant: COc1cnc2c(c1)c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1Cl)c1ccc(C=O)c(F)n1
Product: COc1cnc2[nH]cc(Cc3ccc(NCc4ccccc4Cl)nc3F)c2c1

Procedure:
(2-Chloro-benzyl)-[6-fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine P-2034 was prepared in two steps from (2-chloro-benzyl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 48 and 3-iodo-5-methoxy-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 5 as shown in Scheme 25.
Reaction SMILES: Br[CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([F:15])[CH:6]=1)[OH:4].[CH3:16][NH2:17]>C1COCC1>[F:15][C:7]1[CH:6]=[C:5]([C@@H:3]([OH:4])[CH2:2][NH:17][CH3:16])[CH:10]=[CH:9][C:8]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O[C@@H](CBr)c1ccc(C(F)(F)F)c(F)c1
Reactant: CN
Solvent: C1CCOC1
Product: CNC[C@H](O)c1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of 258 (1.0 g, 3.5 mmol) and THF (20 mL) at RT was added methylamine (2.7 g, 35 mmol, 40% in water) and the reaction was sealed and stirred for 24 h at RT. The reaction was then concentrated to afford 0.83 g (100%) of (R)-1-(3-fluoro-4-(trifluoromethyl)phenyl)-2-(methylamino)ethanol (260) which was used without further purification.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[CH:16]=[C:17]([Cl:37])[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25]([OH:27])=O)=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:38][C:39]1[S:40][CH:41]=[C:42]([CH3:44])[N:43]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[CH:16]=[C:17]([Cl:37])[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25]([NH:38][C:39]3[S:40][CH:41]=[C:42]([CH3:44])[N:43]=3)=[O:27])=[N:19][CH:20]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: O=C(O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(O[C@H]2CCOC2)c1
Reactant: Cc1csc(N)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1csc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@H]3CCOC3)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.70 mL, 0.53 mmol) was added to a solution of 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (200 mg, 0.48 mmol) in DCM (6 mL) and stirred at RT for 2 hours. 2-Amino-4-methylthiazole (110 mg, 0.96 mmol) and pyridine (0.078 mL, 0.96 mmol) were added and the reaction stirred at RT for 16 hours. The solvent was removed in vacuo, water (20 mL) added and the mixture extracted with ethyl acetate (3×20 mL). The extracts were combined and washed with 2N hydrochloric acid (20 mL), saturated aqueous sodium bicarbonate solution (20 mL), water (20 mL), brine (20 mL), dried (MgSO4), filtered, and evaporated in vacuo. The residue was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (78 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[C:11]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH:17]2[CH2:18][CH2:19][N:20]([C:2]3[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=3)[CH2:21][CH2:22]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: c1ccc(C2CCNCC2)cc1
Product: Nc1ccc(N2CCC(c3ccccc3)CC2)nc1

Procedure:
Intermediate B-6 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and 4-phenylpiperidine as starting materials. LCMS (ESI) calcd for [M+1]+ 254.2. found 254.1.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:6][C:3]=1[CH:4]=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]#[N:26]>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]1[C:25]([NH2:26])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][C:7]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:8][CH:9]=2
Reactant: COc1ccccc1CCC#N
Reactant: COCCOc1ccc(N)c(C=O)c1
Product: COCCOc1ccc2nc(N)c(Cc3ccccc3OC)cc2c1

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-(2-methoxy-ethoxy)benzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [NH2:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1.C>C1C=CC=CC=1>[C:2]12([NH:1][C:15](=[O:16])[CH2:14][C:13](=[O:17])[CH3:12])[CH2:3][CH:4]3[CH2:10][CH:8]([CH2:7][CH:6]([CH2:5]3)[CH2:11]1)[CH2:9]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: C=C1CC(=O)O1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
19 g of 1-amino-adamantane were added to 200 ml of benzene and then 9.5 ml of diketene were added thereto over 10 minutes. The mixture was stirred for 21/2 hours at room temperature and after the addition of activated charcoal, the mixture was stirred and filtered. The filtrate was distilled to dryness under reduced pressure and the residue was added to isopropyl ether. The mixture was vacuum filtered to obtain 23.6 g of N-(1-adamantyl)-acetylacetamide melting at 80° C. 23.5 g of the said product and 1 g of p-toluene sulfonic acid were added to a mixture of 50 ml of methanol and 15 ml of methyl orthoformate and the mixture was stirred at room temperature for 24 hours and was then cooled. 2 ml of quinoline were added and the mixture was vacuum filtered. The precipitate was dried to obtain 25.1 g of N-(1-adamantyl)-3,3-dimethoxy-butyramide melting at 140° C.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:37][CH2:38][C@H:39]1[CH2:44][CH2:43][C@H:42]([CH2:45][N:46]2[CH2:51][CH2:50][CH:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:48][CH2:47]2)[CH2:41][CH2:40]1>C(#N)C.C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:52]1([CH:49]2[CH2:48][CH2:47][N:46]([CH2:45][C@H:42]3[CH2:43][CH2:44][C@H:39]([CH2:38][NH:37][C:13]([C:5]4[S:6][C:7]5[N:12]6[C:3](=[CH:2][N:1]=[C:11]6[CH:10]=[CH:9][CH:8]=5)[CH:4]=4)=[O:15])[CH2:40][CH2:41]3)[CH2:51][CH2:50]2)[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: NC[C@H]1CC[C@H](CN2CCC(c3ccccc3)CC2)CC1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C(NC[C@H]1CC[C@H](CN2CCC(c3ccccc3)CC2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 1 h

Procedure:
To a solution of 0.41 g (1.88 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 0.37 g (3.21 mM) of N-hydroxysuccinimide in acetonitrile (5 ml) was added 0.62 g (3.23 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide at room temperature, and the mixture was stirred for 1 hour. To this reaction mixture was added a suspension of 0.70 g (1.95 mM) of 1-(trans-4-aminomethyl-1-cyclohexylmethyl)-4-phenylpiperidine dihydrochloride and 1.0 ml (7.71 mM) of triethylamine in chloroform (10 ml) and the mixture was further stirred for 2 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and a small amount of ethanol and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. After concentration, the crude product obtained was purified by column chromatography (methanol/ethyl acetate 30-50%) and recrystallization from ethyl acetate to provide the title compound as red-purple crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19]C)=O)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[Li][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([C:17]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[OH:19])[CH2:15][CH2:16]2)=[CH:7][CH:8]=1
Reactant: COC(=O)C1CCN(CCc2ccc(OC)cc2)CC1
Reactant: [Li]c1cccs1
Solvent: C1CCOC1
Product: COc1ccc(CCN2CCC(C(O)(c3cccs3)c3cccs3)CC2)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Dissolve 1-[2-(4-methoxyphenyl)ethyl]-4-piperidinecarboxylic acid, methyl ester (4.0 g, 14.42 mmol) in anhydrous tetrahydrofuran (100 mL), place under an argon atmosphere and cool to -78° C. Add, by dropwise addition, 2-lithiothiophene (14.42 mL of a 1M solution in tetrahydrofuran, 14.42 mmol) and stir at -78° C. for 3 hours. Add additional 2-lithiothiophene (14.42 mL of a 1M solution in tetrahydrofuran, 14.42 mmol) and stir at -78° C. for 2 hours. Remove the ice bath and allow to warm to room temperature. Quench with saturated ammonium chloride (100 mL), separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (ethyl acetate) and recrystallize (ethyl acetate) to give the title compound as fluffy white crystals; mp 153°-155° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:15]([O-])=O.Br>C(O)C>[NH2:15][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=1[Br:1])[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7]
Reactant: O=C(O)CCC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: Br
Solvent: CCO
Product: Nc1cc(C(=O)CCC(=O)O)ccc1Br

Procedure:
A solution of 3-(4-bromo-3-nitrobenzoyl)propionic acid in ethanol was treated with ion filings and aqueous hydrobromic acid. The residue after evaporation under reduced pressure was treated with water to give 3-(3-amino-4-bromobenzoyl)-propionic acid.