Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27](OC)=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:32][CH2:31]2)[N:25]=[C:24](C)[N:23]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[C:54]1(C)C=CC=CC=1>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH3:54])=[C:26]([N:30]2[CH2:31][CH2:32][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:34][CH2:35]2)[N:25]=[C:24]([O:50][CH3:49])[N:23]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)nc(C)nc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Reactant: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(NCC(NC(=O)OCc2ccccc2)C(=O)O)c(C)c(N2CCC(c3ccc4c(n3)NCCC4)CC2)n1

Procedure:
280 mg (0.443 mmole) of tert-butyl 2-benzyloxycarbonylamino-3-{5-methoxy-2-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate in 15 ml of dichloromethane with 3 ml of trifluoroacetic acid is stirred at ambient temperature for 18 hours. Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane then poured into diisopropyl ether. 210 mg of expected product is obtained by filtration in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(O)(=O)C>C(O)C.[Fe]>[CH3:1][C:2]1[S:3][C:4]2[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cccc([N+](=O)[O-])c2s1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc2cccc(N)c2s1
Yield: 68.5 %

Procedure:
To a solution of 3.8 g of the product from Example 6 and 8.1 g of glacial acetic acid in 56 mL absolute ethanol at reflux temperature was added 3.8 g of iron powder in small portions. The reaction mixture was heated at reflux temperature for about 36 hours, and was then cooled and filtered. The filtrate was concentrated in vacuo and the residue treated with several mL cold water to give a solid. Filtration and drying gave 2.2 g of the title compound as a tan-colored solid, m.p. 100°-101° C.; NMR (CDCl3): δ 2.8 (3H, s), 3.9 (2H, br s), 6.65 (1H, d, J=8 Hz), 7.2 (1H, t, J=8 Hz), 7.5 (1H, d, J=8 Hz).
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH2:6]([O:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1)[CH2:7][CH:8]([CH3:10])[CH3:9]>CO>[CH2:6]([O:11][C:12]1[N:13]=[N:14][C:15]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:16][CH:17]=1)[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)CCOc1ccc(Cl)nn1
Reactant: C=CCS
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(OCCC(C)C)nn1

Procedure:
1.15 g(0.05 mol) of metallic sodium was dissolved in 150 ml of absolute methanol and then mixed with 4.98 ml(0.05 mol) of allylmercaptan. To this mixture was added 10.03 g(0.05 mol) of 3-isopentyloxy-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]([NH2:9])=[O:8])=[CH:5][N:6]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:15]([C:14]1[CH:17]=[CH:18][C:11]([O:10][C:2]2[S:3][C:4]([C:7]([NH2:9])=[O:8])=[CH:5][N:6]=2)=[CH:12][CH:13]=1)=[O:16]
Reactant: NC(=O)c1cnc(Cl)s1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(Oc2ccc(C=O)cc2)s1

Procedure:
Dissolve 2-chlorothiazole-5-carboxamide (0.771 g, 4.78 mmol) and 4-hydroxybenzaldehyde (0.584 g, 4.78 mmol) in DMF (15.9 mL). Add K2CO3 (1.651 g, 11.95 mmol) and heat at 100° C. for 2 hours. Concentrate the reaction mixture. Take the solid up in dichloromethane:methanol (5:1). Add ethyl acetate to precipitate out a white solid. Filter and collect the solid as the title compound: 1H NMR (DMSO): 10.00 (s, 1H), 8.11 (s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.94 (s, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.41 (s, 1H); HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.4 min, 98.2% purity.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][C:4]([C:13]([O:15]C)=[O:14])=[N:3]1.CO.O>>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=[O:14])[NH:3]1
Reactant: COC(=O)c1nc(=O)n(-c2ccccc2)[nH]1
Solvent: O
Solvent: CO
Product: O=C(O)c1nn(-c2ccccc2)c(=O)[nH]1
Yield: 64.4 %

Procedure:
Methyl 2,5-dihydro-5-oxo-1-phenyl-1h-1,2,4-triazole-3-carboxylate (300.0 mg, 1.4 mmol) was mixed with MeOH (4.5 mL, 110 mmol) and water (0.5 mL, 30 mmol) at room temperature, then treated with LiOH monohydrate (0.1 g, 2.7 mmol) at room temperature overnight. The mixture was concentrated and the resulting residue was acidified to pH˜1 with 1N aqueous HCl. The resulting solids were filtered and rinsed with water, then dried in vacuo to give the title compound as a yellowish solid (185 mg), which was used without further purification.
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:11][CH2:10][C:9]2[S:12][C:13]([NH2:22])=[C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]=2[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[C:18]([O:17][C:15]([C:14]1[C:8]2[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[O:11][CH2:10][C:9]=2[S:12][C:13]=1[NH2:22])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C1Cc2c(sc(N)c2C(=O)OC(C)(C)C)CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C(=O)O)OC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The above 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester 5-ethyl ester (275 mg, 0.84 mmol) was dissolved in a mixture of ethanol (4 ml) and tetrahydrofuran (1 ml). Sodium hydroxide (1N, 1.6 ml, 1.68 mmol) was added and the reaction stirred at ambient temperature for 5 hours after which TLC analysis indicated that the reaction was complete. The reaction was monitored with a pH meter and neutralized with 1N hydrochloric acid until pH=6.9. The solution was concentrated in vacuo to give 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester as a solid. Sodium chloride remained as an impurity.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:29])C1C=CC=CC=1OC.[Li+].[OH-:31].Cl>O.C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([C:10](=[O:11])[NH:12][CH:13]3[CH2:14][CH2:15]3)[CH:16]=[CH:17][C:18]=2[CH3:19])[N:5]=[CH:4][C:3]=1[C:20]([OH:29])=[O:31]
Reactant: COc1ccccc1C(=O)c1cnn(-c2cc(C(=O)NC3CC3)ccc2C)c1N
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)O)c1N
Yield: 88 %

Procedure:
A solution of 5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.0 g, see Example 44), LiOH (1.2 g) in water/ethanol (15 ml/20 ml) was heated at 50° C. overnight. The solution was neutralized with dilute HCl (2M), and extracted with ethyl acetate (200 ml×2), dried over Na2SO4. The solvent was evaporated under reduced pressure and ethyl acetate and diethyl ether was added. The resulting solid was filtered to give the desired 5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylic acid. (0.8 g; yield: 88%.).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][C:4]#[N:5].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.O>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:4](=[NH:5])[CH2:3][CH:2]([CH3:6])[CH3:1])=[CH:14][CH:13]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)CC#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CC(=N)Nc1ccc(Cl)cc1
Yield: 57.6 %

Procedure:
To a solution of 3-methylbutanenitrile (250 mg, 3.0 mmol) and AlCl3 (400 mg, 3.0 mmol) in toluene (6 mL) was added 4-chloroaniline (383 mg, 3.0 mmol). The resulting solution was stirred at reflux for 2 h, diluted with water, and extracted with EtOAc. The aqueous layer was neutralized with saturated NaHCO3 solution and extracted with EtOAc. The combined extracts were dried over MgSO4, filtered, and concentrated. The crude product (364 mg, 58% yield) was used for the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C)C=O.O>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:4]([CH2:5][N:6]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[CH:8]=[C:7]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1)[CH3:38]
Reactant: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(Cn2c(-c3ccccc3)cc3cc(OC)ccc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(3-hydroxybenzyl)-5-methoxy-2-phenylindole (108 mg) in N,N-dimethylformamide (1.3 mL) was added potassium carbonate (68.2 mg) at room temperature. Then ethyl bromoacetate (0.047 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (129 mg).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C@H:27]([CH3:31])[CH2:28][C:29]#[N:30])[CH2:23][CH2:22]2)=[CH:16][CH:15]=1>>[C:29]([CH2:28][C@H:27]([N:24]1[CH2:23][CH2:22][CH:21]([N:20]([C:17]2[CH:18]=[CH:19][C:14]([S:13][CH3:12])=[CH:15][CH:16]=2)[C:9](=[O:11])[C:8]2[C:3]([CH3:2])=[CH:4][CH:5]=[N:6][CH:7]=2)[CH2:26][CH2:25]1)[CH3:31])#[N:30]
Reactant: CSc1ccc(NC2CCN([C@H](C)CC#N)CC2)cc1
Reactant: Cc1ccncc1C(=O)O
Agent: Cl
Product: CSc1ccc(N(C(=O)c2cnccc2C)C2CCN([C@H](C)CC#N)CC2)cc1
Yield: 67.4 %

Procedure:
Using general procedure F, 4-methylnicotinic acid hydrochloride (363 mg, 2.09 mmol) and (R)-3-[4-(4-methylsulfanyl-phenylamino)-piperidin-1-yl]-butyronitrile (see EXAMPLE 307) (304 mg, 0.93 mmol) afforded N-[1-((R)-2-cyano-1-methyl-ethyl)-piperidin-4-yl]-4-methyl-N-(4-methylsulfanyl-phenyl)-nicotinamide as a brown oil (256 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH:18]=1)=[O:13].Br[C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH:18]=2)[CH:4]=[CH:5][C:6]=1[O:9][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: O=C(CCc1ccc(O)c(Cl)c1Cl)c1cc(-c2ccc(C(F)(F)F)cc2)cs1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2cc(-c3ccc(C(F)(F)F)cc3)cs2)c(Cl)c1Cl

Procedure:
Tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(4-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate is prepared from 3-(2,3-dichloro-4-hydroxyphenyl)-1-(4-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([OH:14])[C:11]([O:15][CH3:16])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8].[N+:17]([O-])([OH:19])=[O:18]>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[C:3]2[C:13]([N+:17]([O-:19])=[O:18])=[C:12]([OH:14])[C:11]([O:15][CH3:16])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: COc1cc2sc(C(=O)O)c(Cl)c2cc1O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2sc(C(=O)O)c(Cl)c2c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Chloro-5-hydroxy-6-methoxy-benzo[b]thiophene-2-carboxylic acid (0.28 g) was dissolved in ethyl acetate and a solution of nitric acid in dichloromethane (2M, 0.75 ml) was gradually added at 20° C. into. The solution was stirred at room temperature for 10 min and then it was poured into ice-cold water and extracted with ethyl acetate and evaporated to dryness.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1/[CH:4]=[N:5]/[OH:6].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[O:6]1[C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[CH:4]=[N:5]1
Reactant: O/N=C/c1ccccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc2oncc2c1
Temperature: 4 °C
Reaction time: 1 h

Procedure:
Into a 1 L 3-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (E)-2-hydroxybenzaldehyde oxime (3 g, 21.90 mmol) in tetrahydrofuran (300 mL). To the mixture was added PPh3 (6.024 g, 22.99 mmol), while cooling to a temperature of 4° C. This was followed by the addition of a solution of DEAD (4 g, 22.99 mmol) in tetrahydrofuran (150 mL), while cooling to a temperature of 4° C. over a time period of 4 hours. The resulting solution was allowed to react, with stirring, for 1 hour while the temperature was maintained at 4° C. in a bath of H2O/ice. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluting through a column with a 1:100 ethyl acetate/petroleum ether solvent system. This resulted in 1.8 g (66%) of benzo[d]isoxazole as yellow oil.
Reaction SMILES: C(Cl)(=[O:3])C.[P:5]([O:14][CH2:15][CH2:16][Cl:17])([O:10][CH2:11][CH2:12][Cl:13])[O:6][CH2:7][CH2:8]Cl>C(Cl)CCl>[P:5]([O:14][CH2:15][CH2:16][Cl:17])([O:10][CH2:11][CH2:12][Cl:13])[O:6][C:7](=[O:3])[CH3:8]
Reactant: ClCCOP(OCCCl)OCCCl
Reactant: CC(=O)Cl
Solvent: ClCCCl
Product: CC(=O)OP(OCCCl)OCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The same equipment and procedure as in Example 1 was employed. The reaction flask was charged with 100 ml ethylene dichloride and 85 g acetyl chloride (1.1 mole). The addition of 270 g (1.0 mole) tris (β-chloroethyl) phosphite was commenced dropwise and continued for one hour during which there was a slow exotherm to 35° C. After addition of the triphosphite the reaction continued with a self-maintained exotherm at about 40° C. for three hours and then a slow return to ambient temperature while stirring overnight. The pink acetyl bis(β-chloroethyl) phosphite was isolated by rotary evaporatory at 50° C. and 15 torr. The yield was 261 g; acid number 2; purity by infrared analysis was about 75%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH:18]=[CH2:19]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:19][CH2:18][CH:17]=[CH2:16])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: C=CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCC(C(=O)OC)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of methyl 4-bromophenylacetate (1 g, 4.37 mmol) in DMF (12 ml) at room temperature was added 60% NaH (0.227 g, 5.68 mmol) and the mixture was stirred at room temperature for 1 hr then was added 4-bromo-1-butene (0.487 ml, 4.80 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched by sat. aq. NH4Cl and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0 to 30% DCM/Hep) to give the title compound 1.1 g (yield 89%). Retention time 1.54 min (condition A).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]([C:10]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:2]1([NH:1][CH2:8][C:10]2[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1cccc(C=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cccc(CNc2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.7 %

Procedure:
A mixture of aniline (128 mg, 1.38 mmol), methyl 6-formylpyridine-2-carboxylate (217 mg, 1.31 mmol) and acetic acid (75 μL, 1.31 mmol) in dichloromethane (10 mL) was stirred at room temperature for 24 h. After this time, sodium triacetoxyborohydride (695 mg, 3.28 mmol) was added in one portion and the resulting mixture was stirred at room temperature for 18 h. The reaction was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, passed through a hydrophobic fit and the solvent was removed in vacuo to afford the title compound (310 mg, 97%) as yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[I:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9](O)=[O:10]>C(Cl)(Cl)Cl>[I:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([Cl:3])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(=O)O)cc1I
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)Cl)cc1I
Temperature: 61 °C

Procedure:
Thionyl chloride (8.2 ml, 112.5 mmol) was added to a mixture of 3-iodo-4-methylbenzoic acid (18.5 g, 75 mmol) in chloroform (100 ml) and heated at 61° C. for 16 hours. The solvent was removed in vacuo and excess thionyl chloride removed by azeotroping with toluene (3×30 ml). The desired product was formed as a beige solid (19.5 g 93%) and used in subsequent reactions without further purification.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=[O:8].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CN(C)C=O>[C:17]1([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCCCCc1ccccc1
Reactant: O=C([O-])CCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCCOCCCCCc1ccccc1
Temperature: 60 °C
Yield: 2.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 228 mg, 5.7 mmol) was added to a solution of sodium 4-hydroxybutyrate (600 mg, 4.76 mmol) in N,N-dimethylformamide (5 mL). The reaction was heated at 60° C. for 1 h, then (5-bromopentyl)-benzene (1.15 g, 5.08 mmol) was added, then after 3 weeks 1 M aq. hydrochloric acid solution was added and the reaction mixture evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced 4-(5-phenyl-pentyloxy)-butyric acid (32 mg, 3%) as a colorless oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[CH:16].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].C(O)(=O)C>ClCCCl>[CH2:25]([N:27]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:15]#[CH:16])=[CH:18][CH:19]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCNCC
Reactant: C#Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C#Cc1ccc(CN(CC)CC)cc1
Reaction time: 18 h
Yield: 63.3 %

Procedure:
Sodium triacetoxyborohydride (1.22 g, 5.76 mmol) was added to a solution of 4-ethynylbenzaldehyde (0.50 g, 3.84 mmol) in 1,2-dichloroethane (18.75 mL) at rt. Diethylamine (0.61 mL, 5.76 mmol) and acetic acid (0.12 mL, 1.92 mmol) were then added under N2 atmosphere to the mixture at rt and the reaction was stirred for 18 h. The reaction was quenched with sat. sodium bicarbonate solution (10 mL) and the mixture was stirred for 15 min. Dichloromethane (18.75 mL) was then added and the layers were separated. The aqueous layer was extracted using dichloromethane (10 mL), and the combined organic layers were washed with brine and dried over sodium sulfate. The solvent was then removed under vacuum at 40° C./200 mbar. The resultant oily residue was purified by silica gel column chromatography using dichloromethane: methanol (100 to 90:10) gradient to give the title compound as pale yellow thick oil (0.455 g, 63.2%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8.0 Hz, 2H), 7.76 (d, J=7.6 Hz, 2H), 3.78 (s, 2H), 3.08 (s, 1H), 2.72-2.66 (m, 4H), 1.13 (t, J=7.2 Hz, 6H); MS ESI 187.9 [M+H]+, calcd for [C13H7N+H]+ 187.14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl.Br>[Br:21][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(OC)cc1
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(OC)cc1
Yield: 101.8 %

Procedure:
To a mixture of methyl 4-methoxyphenylacetate (20 g, 0.11 mol) and NBS (0.11 mol) in CCl4 (0.2 l) were added 3 drops of 48% HBr and this mixture was heated to reflux for 8 h. The cooled solution was filtered through a pad of silica gel and the filtrate was evaporated in vacuo to give 29 g of the title compound as pale yellow oil, which was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.Cl.[C:25]1([CH2:41][NH:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH:26]=1.O>CN(C=O)C.C1C=CC2N(O)N=NC=2C=1>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([N:32]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)[CH2:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH2:41][NH:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[CH:26]=1)=[O:7]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1O
Reactant: Fc1ccc(CNCc2cccc(CNCc3ccc(F)cc3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1cccc(CNCc2ccc(F)cc2)c1
Yield: 21.4 %

Procedure:
To a solution of 3,5-dichloro-2-hydroxybenzoic acid (300 mg, 1.449 mmol) in DMF (5 mL) at rt was added EDCI.HCl (300 mg, 1.565 mmol) followed by N,N′-(1,3-phenylenebis(methylene))bis(1-(4-fluorophenyl)methanamine) (365 mg, 1.036 mmol) in 2 mL of DMF and hydrated HOBt.H2O (200 mg), and the reaction mixture was stirred at rt overnight. The mixture was directly purified by prep HPLC to provide a monoacylated product 3,5-dichloro-N-(4-fluorobenzyl)-N-(3-((4-fluorobenzylamino)methyl)benzyl)-2-hydroxybenzamide (0.12 g, 21.4%) and a diacylated product, N,N′-(1,3-phenylenebis(methylene))bis(3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxybenzamide) (0.245 g, 32.4%). 1H NMR (CD3OD): δ 7.34˜6.80 (m, 16H), 4.59 (s, 4H), 4.24 (s, 4H); MS (ESI): (M+H)+=731.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:9][CH2:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[C:7]=2[CH:8]=1
Reactant: COc1ccc(CCc2ccccc2C(=O)O)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc2c(c1)C(=O)c1ccccc1CC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 50 ml of a methylene chloride solution containing 1.80 g (7.0 mmol) of 2-[2-(4-methoxyphenyl)ethyl]benzoic acid were added 1.83 ml (13 mmol) of trifluoroacetic anhydride and 0.8 ml (6.3 mmol) of boron trifluoride ethyl ether complex and the mixture was stirred at room temperature for 5 hours.