Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.[CH2:25]1[O:33][C:32]2[CH:31]=[CH:30][C:29]([CH:34]3[C:38]4[NH:39][C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=5[C:46](=[O:47])[C:37]=4[CH2:36][NH:35]3)=[CH:28][C:27]=2[O:26]1>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C.C1COCC1.C(Cl)Cl.C(N(CC)CC)C>[CH2:25]1[O:33][C:32]2[CH:31]=[CH:30][C:29]([CH:34]3[C:38]4[NH:39][C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=5[C:46](=[O:47])[C:37]=4[CH2:36][N:35]3[C:14]([C:12]3[O:13][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:18])[F:17])[CH:4]=4)=[CH:10][CH:11]=3)=[O:16])=[CH:28][C:27]=2[O:26]1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)NC2
Reactant: O=C(O)c1ccc(-c2cccc(C(F)(F)F)c2)o1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccc(-c2cccc(C(F)(F)F)c2)o1)N1Cc2c([nH]c3ccccc3c2=O)C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(3-trifluoromethylphenyl)-2-furoic acid (80.44 mg, 0.314 mmol) in 1:1 DCM:THF (5 mL, anhydrous) was added oxalyl chloride (43.85 mg, 0.345 mmol), followed by two drops of DMF. The mixture was stirred at room temperature for 1 h. A suspension of 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one (96.2 mg, 0.314 mmol) (prepared as in Example 5), triethylamine (0.13 mL), and DMAP (trace) in 1:1 DCM:THF (5 mL) was added. The resulting mixture was stirred at room temperature for 16 h. Ethyl acetate (50 mL) was added, and the solution was washed with aq. NaHCO3, brine, 1N HCl, brine and then dried with MgSO4. The solvent was evaporated and the residue triturated with ethyl acetate to yield the product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:27])[C:11](=O)[C:12]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:13]=23)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:27])[CH2:11][C:12]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:13]=23)=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=O)C(=O)c2c3n(c4ccccc24)CCNCC3)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NC(=O)Cc2c3n(c4ccccc24)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.3 %

Procedure:
(Chart C, Step 1): A solution of N-(4-methoxyphenyl)-2-oxo-2-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)acetamide (355 mg, 0.98 mmol) in 1,2-dichloroethane (20 mL) is treated with TFA (2.5 mL) and triethylsilane (2.5 mL). The resulting clear golden solution is heated to reflux. After 18 hrs, the reaction is cooled to rt, washed twice with saturated sodium bicarbonate (50 mL), once with brine (50 mL), dried over MgSO4, filtered, and concentrated to give a golden oil. This material is purified by LC (230-400 silica gel) eluting with 5:0.5:94.5 methanol/NH4OH/dichloromethane to afford 275 mg of N-(4-methoxyphenyl)-2-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)acetamide as a white foam. IR (drift) 1662, 1602, 1535, 1512, 1467, 1411, 1372, 1358, 1323, 1297, 1243, 1180, 1032, 830, 740 cm−1; OAMS supporting ions at: ESI+350.2.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[OH:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:40][C:41]([NH2:43])=[O:42]>CC(C)=O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH2:40][C:41](=[O:42])[NH2:43])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: NC(=O)CCl
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)COc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1
Yield: 95.4 %

Procedure:
To a solution of 5-oxo-1-[4-(2-hydroxybenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (400 mg) in acetone (20 ml) are added potassium carbonate (210 mg), potassium iodide (250 mg) and 2-chloroacetamide (120 mg), and the mixture is refluxed for 2 hours. The insoluble materials are removed by filtration, and the filtrate is distilled off. Dichloromethane is added to the resulting residue, and the mixture is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is recrystallized from ethyl acetate/n-hexane to give 5-oxo-1-[4-(2-carbamoylmethoxybenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (436 mg) as white powder, m.p. 226°-228° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C.O>[Br:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)nn1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Clc1ccc(CNc2ccc(Br)nn2)cc1

Procedure:
To 6-bromo-pyridazin-3-ylamine (521, 0.85 g, 0.0049 mol) in acetonitrile (30.0 mL) were added 4-chlorobenzaldehyde (40, 0.82 g, 0.0058 mol), triethylsilane (4.0 mL, 0.025 mol) and trifluoroacetic acid (2.0 mL, 0.026 mol). The reaction was heated to reflux for 4 hours, then poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and washed with ethyl acetate to give a white solid (522, 1.0 g). MS (ESI) [M+H+]+=298.3, 300.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:22])([F:21])[CH2:18][CH:19]=O.CC(O)=O.C([BH3-])#N.[Na+]>C1COCC1.CO>[CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([CH2:19][CH2:18][C:17]([F:22])([F:21])[F:16])[CH2:10][C@@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCC(F)(F)F
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1CCC(F)(F)F
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of (2S,5R)-1-benzyl-2,5-dimethylpiperazine (2.00 g, 7.21 mmol) in THF (10 mL), MeOH (10 mL), and TEA (1.0 mL) was added 3,3,3-trifluoropropionaldehyde (1.62 g, 14.4 mmol) and AcOH (0.826 mL, 14.4 mmol) followed by sodium cyanoborohydride (0.907 g, 14.4 mmol). The reaction was allowed to stir for 2 h, at which time the reaction was quenched with water (15 mL) then made basic with NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated in vacuo to yield a white powder (2.0 g, 90%). Mass Spectrum: Calcd for C16H24N2F3 (M+H): 301. Found: 301.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.S(Cl)([Cl:17])=O>C(Cl)Cl>[OH:1][C:2]1[C:11]([C:12]([Cl:17])=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2ccccc2cc1O
Solvent: ClCCl
Product: O=C(Cl)c1cc2ccccc2cc1O
Reaction time: 4 h

Procedure:
To 30 grams (0.16 moles) of 2-hydroxy-3-naphthoic acid in 125 milliliters of methylene chloride was added 24 grams of thionyl chloride. The reaction mixture was maintained at reflux under a nitrogen atmosphere. After 4 hours, a dark brown solution of 2-hydroxy-3-naphthoic acid chloride was obtained. The solution was cooled to room temperature, placed in a 125 milliliter pressure equalizing funnel, and added slowly to a 200 milliliter methylene chloride solution of 24 grams of N,N-diethylaniline and 27 grams of 2,3-dichloroaniline (0.16 moles). The mixture was heated to reflux. The reaction was substantially complete after approximately 3 hours; and allowing the reaction to continue for up to 20 hours was not observed to affect the product. Half of the reacting solvent was distilled off and 50 to 100 milliliters of ethanol was introduced. After cooling the mixture to room temperature, the precipitated product was collected by filtration and washed twice with 50 milliliter portions of methanol. The crude product was then recrystallized from a mixture of duimethylformamide and methanol. Yield of the coupler compound 2-hydroxy-3-naphtho-2',3'-dichloroanilide was 37 grams (70 percent). The coupler compound exhibited the following properties:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][C:11]([Br:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:18]([O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([CH3:20])[CH3:19]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:23][CH:24]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][C:11]([Br:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1C=O
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Product: CCOC(=O)c1c(C=O)c2cc(Br)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 5-bromo-3-formylindole-2-carboxylic acid ethyl ester (4 g, 13.51 mmol; see step (a) above) and 4-isopropoxyphenylboronic acid (4.86 g, 27.02 mmol). Yield 4.1 g (710%).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][C:6]([F:12])([F:11])[C:7]([O:9]C)=[O:8].CCOCC>O>[Br:2][CH2:3][CH:4]=[CH:5][C:6]([F:12])([F:11])[C:7]([OH:9])=[O:8]
Reactant: COC(=O)C(F)(F)CCCBr
Agent: Br
Solvent: CCOCC
Solvent: O
Product: O=C(O)C(F)(F)C=CCBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
HBr gas was introduced into 48% HBr in H2O (100 ml) with occasional cooling in an ice bath until the weight became 180 g. The HBr solution was then added to Part (5) compound (8.4 g, 36.3 mmole) at room temperature and the reaction was stirred for 5 hours at room temperature. The reaction was cooled to 0° C. and poured into Et2O (900 ml) in an ice bath. The products were extracted into the Et2O layer. The water layer was further extracted with Et2O (200 ml and 100 ml). The combined ether layers were washed with H2O (200 ml). The H2 wash was backwashed with Et2O (100 ml). The Et2O layers were combined and dried over MgSO4. Filtration and evaporation of solvent gave the title compound (7.8 g, quant.) as a colorless liquid.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.Br[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].[Cl-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C=CC=CC=1.O1CCCC1>[CH3:23][Si:24]([C:27]#[C:28][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)([CH3:26])[CH3:25]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd+2]
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1ccc(C=O)cc1
Yield: 88.3 %

Procedure:
A 50-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.034 g (0.15 mmol) of palladium (II) acetate, 0.019 g (0.1 mmol) of copper (I) iodide, 1.088 g (6 mmol) of dicyclohexylamine and 9 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.157 g (0.3 mmol) of tri-tert-butylphosphonium tetraphenylborate obtained in Example A-1 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 30° C. for 30 minutes. 0.925 g (5 mmol) of 4-bromobenzaldehyde and 0.589 g (6 mmol) of trimethylsilylacetylene were added, followed by stirring at 30° C. for 17 hours. After the completion of the reaction, 10 ml of tetrahydrofuran, 5 ml of toluene and 15 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.893 g of 4-[(trimethylsilyl)ethynyl]benzaldehyde (yield: 88 mol % based on 4-bromobenzaldehyde). The identification of the product was made by 1H-NMR and 13C-NMR.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH2:45][CH2:46][CH2:47][CH2:48][C:49](O)=[O:50])=[CH:37]1>CO>[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45][C:38]2[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[NH:36][CH:37]=2)[CH2:8][CH2:7]1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Reactant: O=C(O)CCCCc1c[nH]c2ccccc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)CCCCc2c[nH]c3ccccc23)CC1
Reaction time: 24 h
Yield: 70.9 %

Procedure:
The non-polar diastereoisomer of (4-aminomethyl-1-phenylcyclohexyl)dimethylamine (232 mg, 1.0 mmol.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (415 mg, 1.5 mmol.) were added to a solution of 5-(1H-indol-3-yl)pentanoic acid (217 mg, 1.0 mmol.) in abs. methanol. Stirring was then carried out for 24 h at RT. For working up, the mixture was concentrated, the residue was suspended in water (10 ml), the pH was adjusted to 11 with 5M NaOH, and extraction was carried out with EE (4×10 ml). The organic phase was washed with 1M NaOH, dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel (50 g) with methanol/EE (1 ml/3.5 l) and the non-polar diastereoisomer of 5-(1H-indol-3-yl)pentanoic acid (4-dimethylamino-4-phenylcyclohexylmethyl)amide (306 mg) was isolated. 190 mg (0.44 mmol.) thereof were dissolved in 2-butanone; chlorotrimethylsilane (84 μl, 0.7 mmol.) was added, and stirring was carried out for 2 h. The solvent was decanted off, and the tacky solid was washed with cold 2-butanone (2×1 ml) and cold ether (3×1.5 ml) and dried in vacuo. The hydrochloride of the non-polar diastereoisomer of 5-(1H-indol-3-yl)pentanoic acid (4-dimethylamino-4-phenylcyclohexylmethyl)amide was obtained in a yield of 184 mg (pale-pink solid, m.p. 120–130° C.).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:18])[CH:14]=2)[CH:9]1[C:19](=[O:29])[NH:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[F:28])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=1[NH:20][C:19]([CH:9]1[C:10]2[C:15](=[CH:14][C:13]([Cl:18])=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)ccc2C1C(=O)Nc1c(F)cccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1c(F)cccc1F)C1NCCc2cc(Cl)ccc21
Reaction time: 1 h
Yield: 85.9 %

Procedure:
In a 50 mL pear-shaped flask, 6-chloro-1-(2,6-difluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.6 g, 1.42 mmol, Eq: 1.00) was combined with DCM (25 mL) to give a light brown solution. TFA (4.85 g, 3.28 mL, 42.6 mmol, Eq: 30) was added. After 1 h, the reaction was concentrated, the residue dissolved in EtOAc and the mixture washed with 1 N NaOH and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford 0.3937 g 6-chloro-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2,6-difluoro-phenyl)-amide as a brown oil which was used without purification. 86.0% MS m/z 323.0 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:20]([C:17]5[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=5)[CH:21]=4)[CH2:26]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc(-c2ccc3c(c2)CCNC3)ccn1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2cc(-c3ccncc3)ccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[C@H:3]([C:8]1[CH:23]=[CH:22][C:11]([C:12]([NH:14][O:15]C2CCCCO2)=[O:13])=[CH:10][CH:9]=1)[NH:4][C:5]([NH2:7])=[S:6].Br[CH2:26][C:27]([C:29]1[O:33][N:32]=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=1)=O.Cl>O1CCOCC1.C(Cl)Cl>[OH:15][NH:14][C:12](=[O:13])[C:11]1[CH:10]=[CH:9][C:8]([C@H:3]([NH:4][C:5]2[S:6][CH:26]=[C:27]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:30]=3)[N:7]=2)[CH:2]([CH3:1])[CH3:24])=[CH:23][CH:22]=1
Reactant: CC(C)[C@@H](NC(N)=S)c1ccc(C(=O)NOC2CCCCO2)cc1
Reactant: O=C(CBr)c1cc(-c2ccccc2)no1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)[C@@H](Nc1nc(-c2cc(-c3ccccc3)no2)cs1)c1ccc(C(=O)NO)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 55.5 %

Procedure:
A mixture of 4-((R)-2-methyl-1-thioureidopropyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzamide (0.0252 g, 0.0717 mmol) and 5-(bromoacetyl)-3-phenylisoxazole (0.0191 g, 0.0717 mmol) in 1,4-dioxane (0.50 mL) was heated at 40° C. for 1 h. The solution was diluted with DCM (0.50 mL) and hydrochloric acid (0.20 mL, 0.80 mmol, 4.00 M of in 1,4-dioxane) was added. The reaction was stirred at rt for 3 h. The mixture was evaporated to dryness, the residue dissolved in DMSO and the solution purified on prep-HPLC to give (R)—N-hydroxy-4-(2-methyl-1-(4-(3-phenylisoxazol-5-yl)thiazol-2-ylamino)propyl)benzamide as a white solid (0.0173 g, 56%). LC-MS: (FA) ES+ 435. 1H NMR (dmso-d6, 400 MHz) δ11.13 (s, 1H), 9.00 (s, 1H), 8.52 (d, J=8.6 Hz, 1H), 7.90 (m, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.51 (dd, J=5.1, 1.9 Hz, 3H), 7.44 (d, J=8.3 Hz, 2H), 7.26 (s, 1H), 7.09 (s, 1H), 4.48 (t, J=8.1 Hz, 1H), 2.10 (m, 1H), 1.00 (d, J=6.6 Hz, 3H), 0.78 (d, J=6.7 Hz, 3H).
Reaction SMILES: B([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(O)O.Br[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:17]1[CH:18]=[CH:19][C:14]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)=[CH:15][CH:16]=1
Reactant: Brc1ccncc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc(-c2ccncc2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 90.4 %

Procedure:
To a solution of 4-boronobenzoic acid (1.66 g, 10 mmol) and 4-bromopyridine (1.72 g, 11 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), Bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) was added. The mixture was degassed and purged withed nitrogen. The mixture was stirred at 100° C. for 24 h. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.8 g of white solid of 4-(pyridin-4-yl)benzoic acid. Yield: 90%. LC-MS (ESI) m/z: 200 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](Cl)=[O:6].[CH2:13]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)[CH2:14][CH2:15][CH3:16]>C(=S)=S>[CH2:13]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[C:21]=1[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([CH3:1])[CH:3]=1)[CH2:14][CH2:15][CH3:16]
Reactant: COc1ccc(C(=O)Cl)cc1C
Reactant: CCCCc1cc2ccccc2o1
Solvent: S=C=S
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(OC)c(C)c1
Temperature: 25 °C

Procedure:
To a cooled, stirred solution of 10.8 g. (0.058 mol.) of 3-methyl-4-methoxybenzoic acid chloride and 9.4 g. (0.054 mol.) of 2-n-butylbenzofuran in 40 ml. of carbon disulfide was added dropwise over a 20 minute interval 28.2 g. (0.108 mol.) of stannic chloride. After addition, the reaction mixture was warmed to ambient temperature and stirred for two hours. The mixture was then poured onto 100 ml. of ice-water and stirred for one hour. The solvent was removed, the product extracted into chloroform and the extracts were washed with water, dried (Na2SO4) and concentrated in vacuo to give 2-n-butyl-3-(3'-methyl-4'-methoxybenzoyl)benzofuran.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1.[CH3:14][O:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>CN(C=O)C>[CH3:14][O:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[CH:12]=[CH:13][C:4]([CH3:3])=[CH:5][C:6]=2[O:10][C:9]1=[O:11]
Reactant: COC(=O)CCCCCCCBr
Reactant: Cc1ccc2[nH]c(=O)oc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)oc2cc(C)ccc21

Procedure:
The product is produced as described in example 1 from 3.6 g. of NaH (of 80% suspension in mineral oil), 19.9 g. of 6-methylbenzoxazolin-2-one (produced in usual manners by subjecting 2-amino-5-methyl-phenol-hydrochloride to reaction with phosgene), 240 cc. of DMF, 28.4 g. of 8-bromo caprylic acid methyl ester and 3.6 g. NaJ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][CH:34]=[CH:33][C:4]=1[O:5][CH2:6][CH2:7][N:8]([CH3:32])[CH2:9][CH2:10][CH2:11][NH:12]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO.Cl>O>[CH3:1][O:2][C:3]1[CH:36]=[CH:35][CH:34]=[CH:33][C:4]=1[O:5][CH2:6][CH2:7][N:8]([CH3:32])[CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: COc1ccccc1OCCN(C)CCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccccc1OCCN(C)CCCN
Reaction time: 7.5 h
Yield: 87.7 %

Procedure:
12.9 g (0.0268 mol) of N-[2-(2-methoxyphenoxy)ethyl]-N-methyl-N'-(triphenylmethyl)-1,3-propanediamine and 250 ml of methanol are introduced into a 1 l round-bottomed flask. A stream of gaseous hydrochloric acid is passed for 15 min while cooling with a mixture of water and ice. The mixture is allowed to return to room temperature and is then brought to the reflux temperature for 7.5 h. The mixture is concentrated to dryness and the residue is taken up in ethanol and concentrated again. The residue is taken up in water, the mixture is basified, the supernatant oil is taken up in dilute hydrochloric acid and extraction is carried out with diethyl ether. The acidic aqueous phase is then treated with sodium hydroxide until the pH is basic and extraction is carried out with dichloromethane. The organic phase is washed with water, dried over sodium sulphate and concentrated under reduced pressure. There are obtained 5.6 g of a yellow oil which is used as is in the following stage.