Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9](=[O:11])[CH3:10])[CH:5]=1.[C:12]([Mg]Br)#[CH:13]>C1COCC1>[CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]([OH:11])([C:12]#[CH:13])[CH3:10])[CH:5]=1
Reactant: C#C[Mg]Br
Reactant: COCc1cc(C(C)=O)no1
Solvent: C1CCOC1
Product: C#CC(C)(O)c1cc(COC)on1
Reaction time: 1.5 h

Procedure:
To a solution of 1-[5-(methoxymethyl)isoxazol-3-yl]ethanone (220 mg, 1.42 mmol) in dry THF (4 mL) at 0° C. under an atmosphere of nitrogen, was introduced ethynylmagnesium bromide (4.4 mL of a 0.5M solution in THF, 2.20 mmol) dropwise over 5 min. After 1.5 hr at this temperature, the reaction was carefully quenched with water (0.2 mL) and the resulting suspension concentrated in vacuo. The residual syrup was slurried in water (5 mL) and the pH adjusted to 2 with 5M aqueous hydrochloric acid for 5 min., then saturated sodium bicarbonate solution introduced until the pH was ˜7.5. Following extraction of the basic aqueous solution with EtOAc (2×100 ml), the combined EtOAc extracts were dried (Na2SO4), filtered and the filtrate concentrated in vacuo to furnish the crude title compound as a pale brown oil: 1H NMR (500 MHz, CDCl3) delta 1.89 (3H, s), 2.66 (1H, s), 3.02 (1H, br. s), 3.45 (3H, s), 4.55 (2H, s), 6.39 (1H, s); LC-MS: m/z=+181.95 (M+H)+.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N:16]=[N+:17]=[N-:18])(C)C>CN(C=O)C.CO.[Cu]I>[N:16]1[NH:17][N:18]=[C:10]([CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH:11]=1
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cn[nH]n1
Temperature: 100 °C
Yield: 98 %

Procedure:
To a solution of N-Boc-propargyl amine (1.60 g, 10.3 mmol) in a mixture of DMF:MeOH (4:1, 10 mL) was added trimethylsilylazide (2.0 mL, 15.2 mmol) and CuI (95 mg, 0.50 mmol). The resulting mixture was heated to 100° C. for 16 h, whereupon it was concentrated in vacuo and purified via silica gel chromatography, affording the title compound (2.0 g, 99%) as a light yellow oil; LCMS: m/z=196.9 (M−1).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](Cl)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1>>[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]1[C:17]([CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[O:18]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(C1CCNCC1)N1CCc2ccccc2C1

Procedure:
This compound was prepared similarly to Preparation C, starting from 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and 1,2,3,4-tetrahydroisoquinoline, and was used directly in Example 13. This intermediate was characterised as the hydrochloride salt, m.p. 245°-247°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[OH-].[Na+].[CH2:15](I)[CH3:16]>C(O)C.Cl>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12])[CH3:16]
Reactant: O=C1CCCc2c(O)cccc21
Reactant: CCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cccc2c1CCCC2=O

Procedure:
A mixture of 5-hydroxy-1-tetralone (2.00 g) and sodium hydroxide (493 mg) was warmed in ethanol (40 mL) to 50° C. Ethyl iodide (3.94 mL) was then added and the reaction mixture was heated at reflux for 16 hours. The reaction mixture was diluted with 2N hydrochloric acid, extracted into ethyl acetate, dried and the solvent removed in vacuo to yield 5-ethoxy-1-tetralone as a white solid (2.06 g)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])[CH3:2].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:18])[C:5]([C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:14])[F:15])=[CH:21][N:22]([CH3:24])[CH3:23])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1ccccc1C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1C(F)(F)F
Yield: 83 %

Procedure:
A solution of 3-oxo-3-(2-trifluoromethyl-phenyl)-propionic acid ethyl ester, prepared following an analogous procedure to that outlined in Example 231, (3.14 g, 12.1 mmol, 1.0 equiv) and 1,1-dimethoxy-N,N-dimethylmethanamine (5.60 mL, 42.2 mmol, 3.5 equiv) in N,N-dimethylformamide was heated to reflux for 5 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic phase was separated and washed sequentially with water (4×) and saturated aqueous sodium chloride. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 3.20 g (83%) of 3-dimethylamino-2-(2-trifluoromethyl-benzoyl)-acrylic acid ethyl ester as an orange waxy solid. 1H NMR (400 MHz, CDCl3) δ: 7.86 (s, 1H), 7.67-7.64 (m, 1H), 7.51-7.41 (m, 2H), 7.35 (d, 1H), 3.81 (q, 2H), 3.42-3.17 (m, 3H), 3.11-2.93 (m, 3H), 0.78-0.69 (t, 3H).
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][CH2:16][C:17]1[C:18]([F:34])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:28]#[N:29])[C:20]([Cl:23])=[CH:21][CH:22]=1.[CH3:35][C:36]([O:39][C:40]([N:42]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:43]1[NH:44][CH:45]=[C:46]([C:48](O)=[O:49])[N:47]=1)=[O:41])([CH3:38])[CH3:37].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:38][C:36]([O:39][C:40]([N:42]([C:43]1[NH:44][CH:45]=[C:46]([C:48]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][C:25]3[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[C:31]([Cl:33])[CH:32]=3)[C:18]=2[F:34])=[O:49])[N:47]=1)[C:51]([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:52])=[O:41])([CH3:35])[CH3:37]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C(=O)O)c[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)c[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (0.035 g, 0.183 mmol) and HOBT (0.025 g, 0.183 mmol) were added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.048 g, 0.153 mmol) and 2-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-imidazole-4-carboxylic acid (0.050 g, 0.153 mmol) in DMF (2 mL). The mixture was stirred at RT overnight. Saturated aqueous sodium bicarbonate was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give crude bis(1,1-dimethylethyl)(4-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate as an oil. Trifluoroacetic acid (0.3 mL, 3.89 mmol) was added to a solution of bis(1,1-dimethylethyl)(4-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate (0.066 g, 0.106 mmol) in dichloromethane (2 mL). The mixture was stirred at RT overnight, concentrated and purified by reverse phase HPLC (acetonitrile:water with 0.1% formic acid) to give the title compound (0.017 g, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09-8.18 (m, 2H), 7.81 (s, 1H), 7.51 (s, 1H), 7.44-7.50 (m, 2H), 7.30 (t, 1H), 7.10 (s, 1H), 5.45 (br. s., 2H), 4.44 (d, 2H). MS m/z 420 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][C:16]([OH:18])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([NH:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:19]([N:22]([C:16](=[O:18])[CH2:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[NH:23][C:24](=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([CH3:21])[CH3:20]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)CCc1ccccc1Oc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Oc1ccccc1
Yield: 22.1 %

Procedure:
A solution of 3-(2-phenoxy-phenyl)-propionic acid (110 mg, 0.45 mmoles) and benzoic acid N′-isopropyl-hydrazide (97 mg, 0.54 mmoles) in DMF (5 mL) was treated with diisopropylethylamine (0.20 mL, 1.13 mmol), and PyBroP (315 mg, 0.68 mmol) at room temperature for 18 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (40 mg, 22%). LC-MS m/e 425.44 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClC(Cl)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[F:10]
Reactant: C1COCCN1
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Fc1cc(CN2CCOCC2)ccc1Cl
Temperature: 25 °C
Yield: 60.4 %

Procedure:
4-Chloro-3-fluorobenzaldehyde (1.0 g, 6.31 mmol), morpholine (0.546 ml, 6.31 mmol) and sodium triacetoxyborohydride (1.938 g, 9.14 mmol) were mixed in dichloroethane (19 ml) and the reaction stirred at ambient temperature under an atmosphere of argon over night. 1M HCl (aq, 25 ml) was added. The mixture was extracted with dichloromethane (×4). The pH was adjusted to ca 12 by adding KOH (s). The mixture was extracted with dichloromethane (×4). The combined organic phases were dried over MgSO4 filtered and concentrated in vacuo to give 4-(4-chloro-3-fluorobenzyl)morpholine (0.875 g, 60%) as a liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH3:47][O:48][C:49]1[CH:50]=[C:51]([N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH:52]=[CH:53][CH:54]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:10]([N:58]1[CH2:57][CH2:56][N:55]([C:51]2[CH:52]=[CH:53][CH:54]=[C:49]([O:48][CH3:47])[CH:50]=2)[CH2:60][CH2:59]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1cccc(N2CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc3ccccc3)CC2)c1
Reaction time: 16 h

Procedure:
To a solution of 2 g of (S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester 2.7 g of NEM and 1.9 g of TOTU in 10 ml of DMF, 1.1 g of 1-(3-Methoxy-phenyl)-piperazine was added at RT and stirred for 16 h. The reaction mixture was diluted with 150 ml of ethyl and subsequently extracted with aqueous LiCl (4% w/w), 0.1 M HCl and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was pure enough for the further manipulations. Yield: 4 g.
Reaction SMILES: COC1C=CC(N2CCN([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)CC2)=CC=1C.C1(CC[N:32]2[CH2:37][CH2:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([O:44]C)=[C:40]([F:46])[CH:39]=3)[CH2:34][CH2:33]2)CCCCC1>>[CH:17]1([CH2:16][CH2:15][CH:34]2[CH2:33][NH:32][CH2:37][CH2:36][N:35]2[C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([F:46])[CH:39]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccc(N2CCN(CCC3CCCCC3)CC2)cc1F
Reactant: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Product: Oc1ccc(N2CCNCC2CCC2CCCCC2)cc1F

Procedure:
Production Example 10 was repeated except that 1-(4-methoxy-3-methylphenyl)-4-phenethylpiperazine was replaced with 1-(2-cyclohexylethyl)-4-(3-fluoro-4-methoxyphenyl)piperazine (218 mg) and the resulting crude product was purified on TLC (developer, chloroform: methanol=18:1) to provide 4-[4-(2-cyclohexylethyl-piperazin-1-yl]-2-fluorophenol (77 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1F)[C:15]#[N:16].C(=O)([O-])O.[Na+]>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:15]#[N:16]
Reactant: COc1ccc(CN)cc1
Reactant: N#Cc1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(CNc2ccc(C#N)cc2F)cc1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
4-Methoxybenzylamine (5.6 ml, 43.1 mmol) was added dropwise to a solution of commercially available 3,4-difluorobenzonitrile (2.0 g, 14.4 mmol) in anhydrous di(ethylene glycol) dimethyl ether (10 ml) cooled to 0° C. with stirring. The resulting mixture was stirred at 120° C. for 1 hour. At the end of this time, the reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution at room temperature. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane was added to the crystalline residue to give 3-fluoro-4-[(4-methoxybenzyl)amino]benzonitrile (2.26 g, yield 61%) as white fluffy crystals.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][C:11]([F:20])([F:19])[C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(O)CO.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.[Cu]I.C(O)(C)C>[F:20][C:11]([F:10])([F:19])[C:12]1[CH:13]=[CH:14][C:15]([S:18][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])=[CH:16][CH:17]=1
Reactant: FC(F)(F)c1ccc(S)cc1
Reactant: O=Cc1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Solvent: ClCCl
Product: O=Cc1cccc(Sc2ccc(C(F)(F)F)cc2)c1
Temperature: 85 °C
Yield: 44.5 %

Procedure:
To a sealed tube flushed with nitrogen, was added 3-iodobenzaldehyde 31.1 (300 mg, 1.29 mmol), 4-(trifluoromethyl)benzenethiol (230 mg, 1.29 mmol), copper (I) iodide (24.6 mg, 0.129 mmol), ethylene glycol (0.144 mL, 2.59 mmol), potassium carbonate (357 mg, 2.59 mmol), and isopropanol (6.50 mL). The reaction mixture was heated at 85° C. for 48 hours. The reaction was then cooled and diluted with DCM and filtered over a pad of diatomaceous earth. The filtrate was concentrated, and the residue was purified by medium pressure chromatography (silica gel, 0 to 20% diethyl ether:hexanes) to give 31.2 (162 mg). 1H NMR (400 MHz, CDCl3) δ ppm 9.92 (1H, s), 7.85 (1H, s), 7.77 (1H, d, J=7.4 Hz), 7.59 (1H, d, J=7.8 Hz), 7.44-7.50 (3H, m), 7.29 (2H, d, J=8.2 Hz).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1cccc(F)c1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 3-fluorobenzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](=O)[CH2:12]Cl)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:15]=[C:16]([NH2:18])[S:17][CH:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(CCl)c1c[nH]c2ncc(Br)cc12
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(-c2c[nH]c3ncc(Br)cc23)cs1
Yield: 98.5 %

Procedure:
A solution 1-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-chloro-ethanone (0.32 g, 1.17 mmol) and thio urea (0.097 g, 1.28 mmol) in ethanol (4 mL) was stirred at 80° C. for 1.5 hours. The resulting precipitate was filtered, washed with MeOH, and dried under vacuum to give 4-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-ylamine (0.34 g, 99% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[O:8]>CO>[CH3:1][O:2][C:3]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=1[CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C=Cc1ccc(OC)cc1OC
Solvent: CO
Product: COC(=O)CCc1ccc(OC)cc1OC

Procedure:
113.8 g of methyl 2,4-dimethoxycinnamate are dissolved in 1.5 1 of methanol while heating and are hydrogenated on 5 g of catalyst (10% Pd/C). The catalyst is removed by filtration and the filtrate is concentrated. 113 g of an oil remain and are immediately used in the subsequent Friedel-Crafts acylation.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][C@H:12]2[CH3:28])(=[O:10])=[O:9])=[C:4]([Cl:29])[CH:3]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH:82]1[CH2:87][CH2:86][O:85][CH2:84][CH2:83]1>CCOC(C)=O.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]>[Cl:29][C:4]1[CH:3]=[C:2]([N:82]2[CH2:87][CH2:86][O:85][CH2:84][CH2:83]2)[CH:7]=[CH:6][C:5]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[C:24]([F:27])([F:26])[F:25])[CH2:13][C@H:12]1[CH3:28])(=[O:10])=[O:9]
Reactant: C1COCCN1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(Br)cc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCOCC2)cc1Cl
Temperature: 75 °C

Procedure:
A 5-mL microwave vial was charged with a stirbar, (2R)-1-[(4-bromo-2-chlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazine (250 mg, 0.49 mmol), Sodium tert-butoxide (77 mg, 0.74 mmol), BINAP (31 mg, 0.05 mmol), and Pd2(dba)3 (25 mg, 0.03 mmol). The vial was sealed and vacuum-purged with N2 three times. Toluene (2.0 mL) was then added under N2, followed by morpholine (0.05 mL, 0.53 mmol). The reaction mixture was heated to 75° C. under thermal conditions for 30 minutes, upon which the reaction was judged complete by LCMS. The reaction mixture was diluted with EtOAc (100 mL), and filtered through celite to remove inorganics. The filtrate was concentrated in vacuo and the crude product was directly loaded onto a SiO2 column and purified via normal phase chromatography (5%-50% EtOAc/Hexanes gradient), affording the desired compound in >95% purity. HRMS: calcd for C22H24ClF4N3O3S+H+, 522.12358. found ([M+H]+), 522.12358. HPLC Method 1: room temperature, 7.125 min, 100%. HPLC Method 2: room temperature, 7.664 min, 100%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:21])[CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH3:21])[CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(CCN(C)C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(CCc1ccc(C(=O)O)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
The resulting methyl 4-{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}benzoate (200 mg, 0.682 mmol) was dissolved in tetrahydrofuran (4 mL), a 1 N aqueous sodium hydroxide solution (1 mL) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the aqueous layer was washed with ethyl acetate, the aqueous layer was adjusted to pH 3 with a 1 N aqueous hydrochloric acid solution, and then ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude title compound (140 mg; yield, 74%) as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][CH2:18][NH2:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.O1CCCC1.[CH:32]1[C:41]2[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=2[CH:35]=[CH:34][C:33]=1[CH2:42][C:43](Cl)=[O:44]>O>[CH2:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:17][CH2:18][NH:19][C:43](=[O:44])[CH2:42][C:33]2[CH:34]=[CH:35][C:36]3[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=3[CH:32]=2)=[CH:4][C:3]=1[O:2][CH3:1])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Reactant: O=C(Cl)Cc1ccc2c(c1)CCCC2
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CCNC(=O)Cc2ccc3c(c2)CCCC3)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
8.01 g (31.2 mmol) of crude 2-(3-methoxy-4-benzyloxyphenyl)ethylamine, 3.78 g (37.4 mmol) of triethylamine and 80 ml of tetrahydrofuran were mixed and cooled to 0° C. and then (5,6,7,8-tetrahydronaphthalen-2-yl)acetyl chloride was added dropwise thereto. The mixture was stirred at 0° C. for 30 minutes and further at room temperature for 2 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochloric acid and then saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1) to give 8.3 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acetamide.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)([O-])=O.[BH4-].[Na+]>CO>[NH2:2][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCNCc3cccc(Oc4ccccc4)c3)c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc2[nH]cc(CCNCc3cccc(Oc4ccccc4)c3)c2c1

Procedure:
Combine N-(2-(5-nitro-1H-indol-3-yl)ethyl)-3-phenoxybenzylamine hydrochloride (250 mg, 0.64 mmol) and NiCl2-6H2O (460 mg, 1.9 mmol) in 30 mL MeOH and treat with NaBH4 (73 mg, 1.9 mmol). After 1 hour concentrate to dryness, partition between EtOAc and concentrated NH4OH. Extract the aqueous layer with EtOAc, combine the organic layer, dry over MgSO4 and concentrate to dryness. Chromatograph on silica gel eluting with a stepwise gradient 20/75/5 THF/hexanes/Et3N then 40/55/5 THF/hexanes/Et3N gives the title compound as an oil. Additional chromatograph on silica gel eluting with 1% MeOH in CHCl3 mixed with conc. NH4OH gives the title compound as an oil. Treatment with in 10 mL EtOH with 0.25 mL 5 N HCl and 40 mL toluene then concentrating give the title compound as the hydrochloride: Analysis for C23H23N3O 2.6 HCl 0.6 EtOH: calcd: C, 59.66; H, 5.83; N, 9.07. found: C, 59.30; H, 5.48; N, 8.82. ISMS 358 (M+1).