Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[N:19]=3)[N:14]=[CH:13][CH:12]=2)[OH:10])[CH2:4]1.[O:23]=[C:24]1[CH2:29][S:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[OH:10][C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[N:19]=2)[N:14]=[CH:13][CH:12]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@@H:3]([CH2:2][NH:1][CH2:34][C:32]2[CH:31]=[CH:30][C:27]3[S:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=3[N:33]=2)[CH2:4]1
Reactant: COc1ccc2nccc([C@H](O)CN3CC[C@@H](CN)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2nccc([C@H](O)CN3CC[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 24 h
Yield: 52.9 %

Procedure:
To a stirred solution of (1S)-2-[(3S)-3-(aminomethyl)-1-pyrrolidinyl]-1-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethanol (72 mg, 0.24 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (20 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (47 mg, 0.24 mmole). After 24 h at RT, was added NaBH4 (10 mg, 0.26 mmole). After 2 h, silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (61 mg, 54%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J=4.5 Hz, 1H), 8.23 (d, J=9.1 Hz, 1H), 7.84 (d, J=4.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.12 (d, J=9.1 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 5.74 (m, 1H), 4.04 (s, 3H), 3.82 (s, 2H), 3.46 (s, 2H), 3.00-3.11 (m, 1H), 2.58-2.83 (m, 6H), 2.33-2.58 (m, 1H), 2.01 (m, 2H), 1.65 (m, 1H). LC-MS (ES) m/e 481 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][C:8]([OH:10])=[O:9])[N:3]=1.[CH:11]1(O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.P(Cl)(Cl)(Cl)=O.[OH-].[K+]>C(OCC)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])[N:3]=1
Reactant: OC1CCCCC1
Reactant: Cc1nc(CC(=O)O)no1
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: Cc1nc(CC(=O)OC2CCCCC2)no1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62 %

Procedure:
8 g (56.3 mmol) of 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid were suspended in 8 g (80 mmol) of re-distilled, dry cyclohexanol and 8 g (52.2 mmol) of phosphorous oxychloride were added dropwise under anhydrous conditions over about 7 minutes to the mixture. During the addition, the mixture was heated on a steam bath and heating was continued for 45 minutes. After the reaction mixture had cooled to room temperature, 75 ml of ice-water and 50 ml of diethyl ether were added and the mixture was stirred until a clear two-layer system was obtained. The flask was placed in an ice-salt bath and solid potassium hydroxide was added until a pH of 10.5 was reached. The layers were separated and the aqueous layer was extracted three times with 40 ml portions of diethyl ether. The four ethereal extracts were combined, washed once with a small volume of ice-water and subsequently concentrated in vacuo. The 10 g of residue was distilled in vacuo to obtain 7.9 g (62% yield) of cyclohexyl 5-methyl-1,2,4-oxadiazol-3-yl-acetate with a b.p. of 120°-121° C. at 0.9-1.0 mm and a refractive index nD25 =1.4715.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[CH3:3].S(Cl)([Cl:21])=O>>[ClH:21].[CH2:2]([N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([Cl:1])=[O:11])[CH3:3]
Reactant: CCN(CC)CCOc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CCN(CC)CCOc1ccccc1C(=O)Cl

Procedure:
Reaction of 2-(2-diethylaminoethoxy)benzoate hydrochoride with thionyl chloride as described in the procedure of Example 6 gives 2-(2-diethylaminoethoxy)benzoyl chloride hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH:12]2[CH2:14][CH2:13]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(Br)cc1F
Product: O=C(NC1CC1)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using) 4-bromo-2-fluorobenzoic acid, and cyclopropylamine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([OH:11])[CH:3]=1.[Cl-].[C:13]([C:15]1[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][NH2+:22][CH3:23])[CH:16]=1)#[N:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([C:15]1[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][N:22]([CH3:23])[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=2[OH:11])[CH:16]=1)#[N:14]
Reactant: C[NH2+]Cc1cc(C#N)n(C)n1
Reactant: O=C(O)c1ccc(F)cc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cc(C#N)n(C)n1)C(=O)c1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 40.1 %

Procedure:
To a solution of 4-fluoro-2-hydroxybenzoic acid 136 (500 mg, 3.2 mmol), (5-cyano-1-methyl-1H-pyrazol-3-yl)-N-methylmethanaminium chloride 137 (600 mg, 3.2 mmol), and HATU (1.4 g, 3.5 mmol) in DMF (21 mL) was added DIEA (2.8 mL, 16 mmol). After stirring at room temperature for 14 hours, the solution was concentrated and purified by column chromatography over silica gel eluting with heptane/ethyl acetate(0-75%) to afford compound 138 (370 mg, 40%) as a semi-solid. 1H NMR (400 MHz, 80° C., DMSO-d6) δ 10.08 (s, 1 H) 7.19 (m, 1 H) 6.94 (s, 1 H) 6.70-6.59 (m, 2 H) 4.52 (s, 2 H) 3.98 (d, J=0.8 Hz, 3 H) 2.86 (s, 3 H). LCMS APCI m/z 298 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][C:25]1[O:26][C:27]([CH3:33])=[C:28]([C:30](O)=[O:31])[N:29]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:30]([C:28]3[N:29]=[C:25]([CH3:24])[O:26][C:27]=3[CH3:33])=[O:31])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: Cc1nc(C(=O)O)c(C)o1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cc1nc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)c(C)o1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 2,5-dimethyl-oxazole-4-carboxylic acid. LC-MS (basic): tR=0.78 min; [M+H]+=456.1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12]2)=[N:3][CH:2]=1.C(OCC)C>[Pd].C1(OC2C=CC=CC=2)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12]2)=[N:3][CH:2]=1
Reactant: CCOC(=O)CC1CN(c2ncnc3ccccc23)c2ccccc21
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: CCOC(=O)Cc1cn(-c2ncnc3ccccc23)c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of ethyl 1-quinazolin-4-ylindolin-3-yl-acetate (2.6g.) and 10% w/w palladium on charcoal catalyst (1.3g.) in diphenyl ether (20ml.) was heated under reflux for 30 minutes. The mixture was cooled to room temperature, mixed with diethyl ether (50ml.) and filtered through diatomaceous earth. The solid residue was washed with diethyl ether (50ml.). The combined diethyl ether solution was evaporated in vacuo, and the residue was chromatographed on silica gel (ca 150g.) using, as eluant, petroleum ether (b.p. 40°-60° C.) containing an increasing proportion of diethyl ether. Diphenyl ether was recovered from the first fractions (rich in petroleum ether). Evaporation in vacuo of later fractions gave a syrup which crystallised from a mixture of diethyl ether and petroleum ether (b.p. 40°-60° C.) to give ethyl 1-quinazolin-4-ylindol-3-ylacetate, m.p. 65°-67° C.
Reaction SMILES: [CH3:1][C:2]([CH3:31])=[C:3]([N:8]1[C@H:11](SC)[C@@H:10]([C@H:14]([O:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[CH3:15])[C:9]1=[O:30])[C:4]([O:6][CH3:7])=[O:5].[Cl:32]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:32][CH:11]1[N:8]([C:3](=[C:2]([CH3:31])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])[C:9](=[O:30])[C@@H:10]1[C@H:14]([O:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])[CH3:15]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1SC
Reactant: ClCl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C1Cl
Temperature: 0 °C

Procedure:
To a solution of methyl 3-methyl-2-[(3S,4R)-4-methylthio-3-{(1R)-1-(p-nitrobenzyloxycarbonyloxy)-ethyl}-2-oxoazetidin-1-yl]but-2-enoate (481 mg) in dichloromethane (5 ml) was added a solution of chlorine (83 mg) in carbon tetrachloride (0.65 ml) at -78° C. The solution was allowed to warm to 0° C. during 45 minutes and evaporated in vacuo. The residue was chromatographed on silica gel (12 g) eluting with 10-33% ethyl acetate in hexane to give methyl 2-[(3S)-4-chloro-3-{(1R)-1-(p-nitrobenzyloxycarbonyloxy)-ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate [a mixture (55:45) of (4R) isomer and (4S) isomer] (394 mg).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:12][C@H:13]1[CH2:17][CH2:16][CH2:15][NH:14]1.F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([C:28]([F:31])([F:30])[F:29])[CH:20]=1.C(N(CC)CC)C>C(#N)C>[CH3:12][C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([C:28]([F:29])([F:31])[F:30])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: C[C@H]1CCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H]1CCCN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 82 °C
Yield: 100.1 %

Procedure:
To a solution of (S)-2-methylpyrrolidine tosylate (10.6 g, 41.2 mmol) in acetonitrile (85 mL) was added 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (6.6 g, 31.7 mmol) dropwise and followed by triethylamine (11.0 mL, 79.3 mmol) dropwise. The reaction was heated at 82° C. for 16 h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with 1N HCl, then dried over Na2SO4 and concentrated in vacuo to yield (S)-2-methyl-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (8.7 g, quantitative yield). LC/MS m/z 275.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][NH:11][CH2:10][C@@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25](Br)[CH:26]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]>>[C:16]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25]([N:11]3[CH2:12][C@H:13]([CH3:14])[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C@H:9]([CH3:15])[CH2:10]3)[CH:26]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: C[C@@H]1CNC[C@H](C)N1Cc1ccccc1
Reactant: COc1cc2c(cc1Br)N(C(C)=O)CC2
Product: COc1cc2c(cc1N1C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C1)N(C(C)=O)CC2
Yield: 43 %

Procedure:
The title compound was prepared in 43% yield from cis-1-benzyl-2,6-dimethylpiperazine (Org. Prep. Proc. 1976, 8, 19) and D1 using a similar procedure to Description 2.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[CH:17][CH:16]=1>CS(C)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[S:23])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)=[CH:17][CH:16]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CS(C)=O
Product: CCOC(=O)C(=O)c1csc(NC(=S)Nc2ccc(F)cc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.6 g of p-fluorophenyl isothiocyanate and 20 ml of dimethyl sulfoxide. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].P(Br)(Br)[Br:22]>CCOCC>[Br:22][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: COc1ccc(CO)cc1C(=O)OCc1ccccc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: COc1ccc(CBr)cc1C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 179.6 %

Procedure:
Benzyl 5-hydroxymethyl-2-methoxybenzoate (Patent Application No. Hei 11-162235) (15.5 g, 56.9 mmol) and 300 ml of dehydrated ether were mixed and phosphorus tribromide (2.0 ml, 21.1 mmol) was added dropwise under stirring and cooling with ice, which was further stirred for 1 hour. Ice water was added to the reaction mixture and ether layer was separated. The ether layer was washed with water, saturated sodium hydrogencarbonate and brine in sequence, then dried over anhydrous sodium sulfate and concentrated. The crystals obtained were recrystallized from diisopropyl ether to obtain 12.7 g (66%) of the aimed compound as colorless prisms.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25]Cl)=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:30].[Na+]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25][I:30])=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cccc(C(=O)OCCl)c1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cccc(C(=O)OCI)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate (2.0 g, 4.76 mmole) in dry acetone (30 ml) was added sodium iodide (3.15 g, 21 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl actate/water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Yield: 2.3 g=94%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:5]=[CH:4][C:3]=1F.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[O:14].O.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8](=[CH2:9])[CH2:10][CH:13]([OH:14])[C:12]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=O
Reactant: C=C(C)c1ccc(F)c(Br)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: O
Product: C=C(CC(O)C(=O)OCC)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 2-bromo-1-fluoro-4-(prop-1-en-2-yl)benzene (12.3 g, 62.2 mmol, 1.0 equiv) in acetonitrile (124 mL, 0.5 M) are added ethyl glyoxalate (38.1 g, 37 mL, 187 mmoles, 3 equiv) and ytterbium trifluoromethanesulfonate, hydrate (7.72 g, 12.4 mmoles, 0.2 equiv). The mixture is stirred overnight at room temperature. The mixture is concentrated under reduced pressure and diluted with diethyl ether. The resulting solution is washed twice with water. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via flash column chromatography on silica gel (330 g) in two batches using a gradient of 0-100% ethyl acetate/hexanes to yield the title compound (87% yield): 1H NMR (CDCl3, 400 MHz): δ 7.53 (t, 1H, J=1.9 Hz), 7.41-7.37 (dt, 1H), 7.33-7.30 (dt, 1H), 7.18 (t, 1H, J=7.6 Hz), 5.37 (s, 1H), 5.22 (s, 1H), 4.26-4.21 (m, 1H), 4.17-3.99 (m, 2H), 2.99 (dd, J=14.8, 4.8 Hz), 2.83-2.72 (m, 2H), 1.23 (t, 3H, J=7.6 Hz).
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][C:24]([OH:26])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:24](=[O:26])[CH2:23][CH2:22][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)CCc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (80 mg, 0.41 mmol) and Et3N (58 μL, 0.41 mmol) in anhydrous DCM (2.0 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (70 mg, 0.29 mmol) and DMAP (5 mg, 0.04 mmol) and stir the resulting solution for 10 min. Add 4-Amino-benzoic acid methyl ester (77) (42 mg, 0.27 mmol) and stir the reaction solution 2d at rt. Quench reaction solution with water, separate layers and extract aqu. layer with DCM (3 times). Wash combined organic layer with brine, dry with Na2SO4 and filtrate it through a short pad of silica gel using EtOAc to obtain 4-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-benzoic acid methyl ester (78) (91 mg, 88%) as a white solid. No further purification. 1H NMR (400 MHz, CDCl3): 2.60 (t, 2H, J=7.6 Hz); 2.91 (t, 2H, J=7.6 Hz); 3.70 (s, 6H); 3.76 (s, 3H); 3.83 (s, 3H); 6.35 (s, 2H); 7.55 (d, 2H, J=8.3 Hz); 7.91 (d, 2H, J=8.6 Hz); 8.09 (s, 1H).
Reaction SMILES: I[C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:14]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>>[CH:14]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: O=C(O)c1cccc(C(=O)O)c1I
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(Nc2c(C(=O)O)cccc2C(=O)O)cc1
Yield: 62 %

Procedure:
Similar reaction of 2-iodoisophthalic acid and 4-isopropylaniline gave 2-[(4-isopropyl)phenylamino]isophthalic acid (62%), mp (EtOAc/petroleum ether) 208° C. (dec). 1H NMR [(CD3)2SO] δ 1.16 (d, J=6.9 Hz, 6 H, 2×CH3), 2.78-2.82 (m, 1 H, CH), 6.83 (d, J=8.4 Hz, 2 H, H-2' and H-6' or H-3' and H-5'; 6.97 (t, J=7.7 Hz, 1 H, H-5), 7.07 (d, J=8.5 Hz, 2 H, H-3' and H-5' or H-2' and H-6'), 7.92 (d, J=7.7 Hz, 2 H, H-4 and H-6), 9.66 (br s, 1 H, NH), 12.89 (br s, 2 H, 2×COOH). Anal. (C17H17NO4) C, H, N.
Reaction SMILES: C([C:5]1[C:13]([CH2:14][N:15]([C:17](=[O:24])[CH:18]([OH:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:16])=[C:12]([NH2:25])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[NH2:25][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:13]=1[CH2:14][N:15]([C:17](=[O:24])[CH:18]([OH:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:16]
Reactant: CC(C)CC(O)C(=O)N(C)Cc1c(N)ccc(C(=O)O)c1C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(O)C(=O)N(C)Cc1cc(C(=O)O)ccc1N
Reaction time: 12 h

Procedure:
To a stirred solution of t-butyl-4-amino-3-[(2-hydroxy-4,N-dimethylpentanoylamino)methyl]benzoic acid (3.50 g, 10.0 mmole) in CH2Cl2 (20 mL) at RT was added TFA (20 mL). After 12 hr, the reaction contents were evaporated, washed with hexanes and dried under high vacuum overnight affording the title compound as an orange oil (4.42 g, 10.8 mmol). This product was used without further purification: MS (ES) m/de 295 (M+H-TFA)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]([F:21])([F:20])[F:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:17])[C:13]([O:15]C)=[O:14])[CH:7]=[CH:6]2)#[N:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:3]1[C:4]([C:18]([F:21])([F:20])[F:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:17])[C:13]([OH:15])=[O:14])[CH:7]=[CH:6]2)#[N:2]
Reactant: COC(=O)C(C)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C(=O)O)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 60 °C
Yield: 99.6 %

Procedure:
To methyl 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]propanoate (0.055 g, 0.185 mmol) in 1:1 THF/MeOH (4 mL) was added 5N NaOH (0.185 mL) and the resulting mixture was heated to 60° C. for 30 min. The cooled mixture was partitioned between Et2O and 0.1 N HCl. The separated organic portion was washed with brine, dried over Na2SO4, and filtered. Concentration afforded the title compound (0.052 g, 99% yield): MS (APCl) m/z 283 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)#[CH:11]>C(NC(C)C)(C)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]#[C:11][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)=[CH:13][CH:14]=1
Reactant: COc1cncc(Br)c1
Reactant: C#Cc1ccc(F)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: COc1cncc(C#Cc2ccc(F)cc2)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 59.2 %

Procedure:
Dissolve 3-bromo-5-methoxypyridine (1.0 g, 5.35 mmol) in diisopropylamine (17 mL) and toluene (10 mL) under nitrogen. Add tetrakis(triphenylphosphine)palladium (0.200 g, 0.16 mmol). Heat at 60° C. and add 1-ethynyl-4-fluorobenzene (642 mg, 5.35 mmol) and copper (I) iodide (20 mg, 0.11 mmol). After 20 h, concentrate, and purify using silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes, to give the title compound (720 mg, 60%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]([CH3:19])[NH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1.[OH-].[Na+].[ClH:22]>O>[ClH:22].[NH:5]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]([CH3:19])[NH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:10][CH:11]=1)[NH2:1]
Reactant: O=N[O-]
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1NC(=O)NN=C1c1ccc(NN)cc1
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (3.6 g) in water (10 ml) was added dropwise to a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (9.8 g), concentrated hydrochloric acid (10 ml) and water (30 ml) at 0° C. After stirring for 0.5 hours, a solution of stannous chloride dihydrate (43.12 g) in conc. hydrochloric acid (43 ml) was added thereto at 0° C. After stirring for 2 hours, the mixture was made alkaline with an aqueous solution of sodium hydroxide and the resultant precipitates were collected by filtration and washed with water. The crude product was dissolved in 10% hydrochloric acid under warming, and then allowed to stand at room temperature. The precipitates were collected by filtration and then dissolved in water. The aqueous solution was washed with ethyl acetate, treated with activated charcoal, and made alkaline with an aqueous solution of sodium hydroxide. The resultant precipitates were collected by filtration, washed with water, and recrystallized from 10% hydrochloric acid to give 6-(4-hydrazinophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one hydrochloride (3.2 g).