Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:11]4[CH:23]=[CH:22][S:21][C:12]=4[C:13](=[O:20])[NH:14][C:15]=3[CH:16]=[CH:17][C:18]=2[OH:19])=[CH:5][CH:4]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:19][C:18]1[CH:17]=[CH:16][C:15]2[NH:14][C:13](=[O:20])[C:12]3[S:21][CH:22]=[CH:23][C:11]=3[C:10]=2[C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:8][CH:7]=1
Reactant: NCc1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Reaction time: 1.5 h
Yield: 43.7 %

Procedure:
A solution of 9-[4-(aminomethyl)phenyl]-8-hydroxythieno[2,3-c]quinolin-4(5H)-one (50 mg, 0.16 mmol) and methanesulfonyl chloride (43 mg, 0.37 mmol) in methylene chloride (5 mL) was stirred at room temperature for 10 min. N,N-diisopropylethylamine (48 mg, 0.37 mmol) was added and the reaction mixture was stirred for 1.5 h, concentrated under reduced pressure and the residue was purified by preparatory HPLC (C18 silica, water/acetonitrile w/0.05% TFA gradient) to afford the desired product (28 mg, 45%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.77 (s, 1H), 9.22 (s, 1H), 7.70-7.67 (m, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.9 Hz, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.9 Hz, 1H), 5.89 (d, J=5.4 Hz, 1H), 4.29 (d, J=6.4 Hz, 2H), 2.94 (s, 3H); ESI MS m/z 401 [C19H16N2O4S+H]+; HPLC >99% (AUC), tR=12.12 min.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[OH:15][C:16]1[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>>[OH:15][C:16]1[CH:25]=[C:24]([NH:26][C:12]([C:6]2[O:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:14])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Reactant: COC(=O)c1ccc(N)cc1O
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1O
Yield: 71.7 %

Procedure:
In the same manner as that of Example 24, 4,5-diisopropylfuran-2-carboxylic acid (80 mg, 0.408 mmol) and methyl 2-hydroxy-4-aminobenzoate (123 mg, 0.736 mmol) were condensed, the reaction mixture was treated in a conventional manner, and then the residue was purified by silica gel chromatography [hexane-ethyl acetate (50:1)] and recrystallized to obtain methyl 2-hydroxy-4-[(4,5-diisopropylfuran-2-carbonyl)amino]benzoate (101 mg, 72%) as colorless prisms.
Reaction SMILES: [NH2:1][C:2]1[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][N:4]2[N:3]=1.C1([SiH3])C=CC=CC=1>C(Cl)Cl.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>[NH2:1][C:2]1[C:14]([C:15]([OH:17])=[O:16])=[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:11])[F:12])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: C=CCOC(=O)c1c(N)nn2ccc(C(F)(F)F)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: Nc1nn2ccc(C(F)(F)F)nc2c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
Allyl 2-amino-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate 4a (240 mg, 0.8385 mmol) and phenylsilane (181.5 mg, 206.7 μL, 1.677 mmol) were dissolved in dry DCM (6 mL). Pd(PPh3)4 (38.76 mg, 0.03354 mmol) was added and the resulting solution was stirred at RT for 2 hrs. The suspension was filtered and the collected solid was washed with DCM (3×1 mL). The solid was dried under vacuum at 40° C. to yield compound 5a (117 mg, 56%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20](O)=[O:21])[CH2:3][CH2:2]1.Cl.Cl.[CH3:25][C:26]1([CH3:37])[CH:31]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:30][CH2:29][NH:28][CH2:27]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:28]2[CH2:29][CH2:30][CH:31]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:26]([CH3:37])([CH3:25])[CH2:27]2)=[O:21])[CH2:2][CH2:3]1
Reactant: CC1(C)CNCCC1N1CCCC1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)O
Agent: Cl
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(N2CCCC2)C(C)(C)C1

Procedure:
The title compound was prepared from 5-cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid (Example 181A) and 3,3-dimethyl-4-pyrrolidin-1-yl-piperidine dihydrochloride in direct analogy to the general procedure used in example 150. MS: 457.4 (MH+).
Reaction SMILES: [P:1]([O-:10])([O:6][CH2:7][CH2:8][Br:9])[O:2][CH2:3][CH2:4][Br:5].C(Cl)(Cl)(Cl)[Cl:12]>C(N(CC)CC)C>[P:1]([Cl:12])(=[O:10])([O:6][CH2:7][CH2:8][Br:9])[O:2][CH2:3][CH2:4][Br:5]
Reactant: [O-]P(OCCBr)OCCBr
Reactant: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: O=P(Cl)(OCCBr)OCCBr

Procedure:
A total of 0.68 mole of bis(2-bromoethyl) phosphite was reacted with excess carbon tetrachloride in the presence of a small amount of triethylamine. The bis(2-bromoethyl) phosphorochloridate thus formed was reacted with 0.31 mole of ethylene glycol in the presence of 0.68 mole of pyridine. The reaction product was washed with aqueous sulfuric acid, water, aqueous sodium bicarbonate, and again with water. The volatiles (chloroform and carbon tetrachloride) were removed by evaporation at reduced pressure to give a 100% yield of product identified by IR as tetrakis(2-bromoethyl) ethylene diphosphate. On analysis, the product was found to contain 49.83% bromine and 9.05% phosphorus (compared to calculated percentages in C10H20Br4O8P2 of 49.23% bromine and 9.54% phosphorus).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]#[N:20])[NH:14]1.N1C=CC=CC=1.[F:27][C:28]([F:32])([F:31])[S:29]Cl>ClCCl>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:29][C:28]([F:32])([F:31])[F:27])[C:15]([C:19]#[N:20])=[N:14]1
Reactant: FC(F)(F)SCl
Reactant: N#Cc1cc(=O)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1SC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.1 %

Procedure:
To a solution of 0.25 g (0.78 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyanopyrazol-5-one in 15 ml of dichloromethane and 0.069 ml (0.86 mmole) of pyridine, cooled to -70° C. and kept under nitrogen, was added 0.1 ml (1.0 mmole) of trifluoromethanesulfenyl chloride. After stirring for 3 hrs., the reaction was allowed to warm to ambient temperature. The excess of trifluoromethanesulfenyl chloride was removed and the reaction mixture was diluted with ethyl acetate, washed with water, dried and concentrated to an orange colored oil. Chromatographic purification afforded 0.04 g of white solid, m.p. 325° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:34](=[O:36])[CH3:35])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCCc2ccccc2)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CCc2ccccc2)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [6-methoxy-2′-(phenethylamino-methyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]#[N:13].[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[CH2:7]([N:6]1[C:2]([NH:1][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[F:14])=[C:3]([C:12]#[N:13])[C:4]([CH3:11])=[N:5]1)[CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CCCCn1nc(C)c(C#N)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCn1nc(C)c(C#N)c1NC(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
5-Amino-1-butyl-3-methyl-1H-pyrazole-4-carbonitrile (10.0 g, 56 mmole) was dissolved in a mixture of dichloromethane/pyridine (45 ml/15 ml) and cooled to 0° C. 2-fluorobenzoyl chloride (8.87 g, 56 mmole) was added dropwise and reaction mixture stirred for 1 hour at 0° C., the at room temperature overnight. Removed solvent under vacuum. Residue was taken up in ethyl acetate, washed with dilute hydrochloric acid, 0.1M sodium hydroxide, water and dried over sodium sulfate (anh). Removed solvent and triturated solid in 30% ethyl acetate/hexanes. Filtered product to obtain 4.16 g product (yield: 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN1CCNCC1
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OCC2)c1ccc(Cl)cc1Cl
Product: CN1CCN(C(=O)c2ccc3c(c2)-c2sc(C(=O)N(C)c4ccc(Cl)cc4Cl)cc2CCO3)CC1

Procedure:
2-[(2,4-dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and N-methylpiperazine were reacted by General Procedure B to give 359. NMR: (CDCl3): 2.40 (3 H, s, Me), 2.49-2.58 (4 H, br m), 3.06-3.09 (2 H, m), 3.38 (3 H, s, Me), 3.49-3.90 (4 H, br m), 4.26-4.29 (2 H, m), 6.83 (1 H, s, Ar), 7.02 (1 H, d, J 8.2, Ar), 7.25 (1 H, dd, J 8.3 and 1.9, Ar), 7.31 (1 H, d, J 8.4, Ar), 7.37 (1 H, dd, J 8.4 and 2.2, Ar) and 7.55-7.57 (2 H, m, Ar). MS: (ESI+) MH+=530.13
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[CH:12][C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]#[N:11].ClC1C(Cl)=CC2N[C:27](=O)[C:26]3=CC=[CH:32][N:25]3[CH2:24][C:23]=2C=1>>[Cl:17][C:13]1[C:14]([Cl:16])=[CH:15][C:2]2[N:1]=[C:10]([N:11]3[CH2:27][CH2:26][N:25]([CH3:32])[CH2:24][CH2:23]3)[C:6]3=[CH:7][CH:8]=[CH:9][N:5]3[CH2:4][C:3]=2[CH:12]=1
Reactant: N#Cc1cccn1Cc1cc(Cl)c(Cl)cc1N
Reactant: O=C1Nc2cc(Cl)c(Cl)cc2Cn2cccc21
Product: CN1CCN(C2=Nc3cc(Cl)c(Cl)cc3Cn3cccc32)CC1

Procedure:
Following the general procedure of Example 1, 1-(2-amino-4,5-dichlorobenzyl)-2-pyrrolecarbonitrile is converted to 7,8-dichloro-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one and thence to the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]([CH3:23])=O.CCCBr>O>[CH2:20]([O:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:21][CH3:23]
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])c(O)c1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCBr
Product: CCCOc1cc([N+](=O)[O-])ccc1[N+](=O)[O-]
Reaction time: 96 h

Procedure:
A mixture of 2,5-dinitrophenol (10 g), potassium carbonate (15 g) and acetone (100 ml) is stirred and n-propyl bromide (13.36 g) added to the mixture. The mixture is stirred at room temperature for 3 hours and then heated at reflux for 16 hours. More n-propyl bromide (6.68 g) is then added and refluxing continued for 96 hours. The mixture is filtered and the filtrate evaporated to dryness to afford a dark brown solid. This material is stirred with water (300 ml) and filtered. Recrystallization from methanol yields 8.9 g of 1-n-propoxy-2,5-dinitrobenzene, m.p. 52°-54° C. This compound (8.4 g) is reduced with hydrogen in a pressure vessel in the presence of methanol (250 ml) and 5% Pd/C catalyst (0.85 g); starting pressure: 3.36 kg/cm2, final pressure: 2.52 kg/cm2. The mixture is filtered and evaporated to dryness to afford 6.1 g of oily title compound, which is used in subsequent reactions without further purification.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.I[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[F:20][C:2]([F:19])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: Nc1nc2c(-c3cccc(C(F)(F)F)c3)cccn2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Nc2nc3c(-c4cccc(C(F)(F)F)c4)cccn3n2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
A suspension of 8-(3-(trifluoromethyl)phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-amine (1.0 g, 3.6 mmol, 1 equiv), methyl 4-iodobenzoate (0.95 g, 3.6 mmol, 1.0 equiv), palladium (II) acetate (0.080 g, 0.36 mmol, 0.10 equiv), cesium carbonate (2.34 g, 7.18 mmol, 2.0 equiv), and Xantphos (0.10 g, 0.17 mmol, 0.047 equiv) in 1,4-dioxane (20 mL) was heated to 80° C. After 16 h, the reaction mixture was concentrated in vacuo, and the resulting residue was diluted with methanol and water. The solid was collected by filtration and rinsed sequentially with water, isopropanol, and hexanes to afford crude methyl 4-(8-(3-(trifluoromethyl)phenyl)[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoate (1.07 g, 72%). LCMS (ESI) m/z: 413.0; 1H NMR (400 MHz, DMSO-d6) δ: 10.29 (s, 1 H), 8.88 (m, 1 H), 8.63 (s, 1 H), 8.40 (m, 1 H), 8.02 (m, 1 H), 7.78-7.90 (m, 6 H), 7.20 (m, 1 H), 3.80 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:13]2[CH:14]=[C:15]([CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH:16]=[CH:17][C:12]=2[O:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN.C(Cl)Cl.CCOC(C)=O>C(O)CCC>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[C:13]2[CH:14]=[C:15]([CH2:18][NH2:19])[CH:16]=[CH:17][C:12]=2[O:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1noc2ccc(CN3C(=O)c4ccccc4C3=O)cc12
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1noc2ccc(CN)cc12
Temperature: 25 °C

Procedure:
A mixture of 2-[3-(tert-butoxycarbonyl)amino-benzo[d]isoxazol-5-ylmethyl]-isoindole-1,3-dione (1.31 g) and hydrazine hydrate (2.52 mL, 52 mmol) in 1-butanol (10 mL) was stirred at room temperature. The mixture turned into a translucent orange solution. After stirring for about 1 hr, white precipitate formed. The mixture was then heated to reflux for 5 min and all solid dissolved. After cooling, DCM was added, after which time white precipitate formed. The solid was filtered off and washed with DCM. Rotary evaporation afforded a yellow oil. The oily residue was taken up with EtOAc (100 mL) and washed with water (3×30 mL), brine (30 mL) and dried over anhydrous sodium sulfate. Most solvent was removed on a rotary evaporator and the remainder was loaded onto a 20 g ISOLUTE silica cartridge. The product was eluted with (2 M ammonia in methanol)/DCM (4:96). A light yellow solid was obtained (330 mg). 1H-NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.53 (d, 1H), 7.45 (d, 1H), 7.31 (s, 1H), 3.40 (s, 2H), 1.57 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][CH2:6][CH2:7][N:8]1[CH:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:15])C.[OH-].[Na+].Cl>O.CO>[CH3:14][CH:13]1[CH2:12][CH2:11][CH2:10][CH:9]([CH3:15])[N:8]1[CH2:7][CH2:6][CH2:5][C:4]([OH:16])=[O:3]
Reactant: CCOC(=O)CCCN1C(C)CCCC1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CCCC(C)N1CCCC(=O)O
Temperature: 25 °C
Yield: 71.1 %

Procedure:
To a suspension of 4-(2,6-dimethyl-piperidin-1-yl)-butyric acid ethyl ester (1.5 g, 6.7 mmol) in water (5 mL) and MeOH (1 mL), NaOH (266 mg, 6.7 mmol, 1.0 eq) was added and the mixture was heated at reflux for 22 hours. The reaction was then allowed to cool down to room temperature, the pH adjusted to 4 at 0° C. with HCl 2N and the mixture was concentrated under reduced pressure. The residue was treated with EtOH, and the sodium chloride precipitated was filtered off. Evaporation of the solvent under reduced pressure afforded 950 mg of the title compound as a white solid (51% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:31])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:30]=[CH:29][O:28][CH:27]=3)[CH:21]=2)=[O:19])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:31])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:30]=[CH:29][O:28][CH:27]=3)[CH:21]=2)=[O:19])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CCCNC(=O)c1cccc(-c2ccoc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CCCNC(=O)c1cccc(-c2ccoc2)c1)Nc1ccc(Cl)cc1C(=O)O
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
1.22 g (2.8 mmol) of methyl 5-chloro-2-{[4-({[3-(furan-3-yl)phenyl]carbonyl}amino)butanoyl]amino}benzoate was dissolved in 12 mL of tetrahydrofuran (THF). 1N aqueous sodium hydroxide was added at room temperature, and the mixture was stirred at 50° C. for 1.5 hours. After cooling the mixture, 1N hydrochloric acid was added to acidify the reaction mixture, and the solvent was distilled off under reduced pressure. Thereafter, water was added to the residue. Solids were collected by filtration, followed by washing with water, thereby giving 1.07 g of the target 5-chloro-2-{[4-({[3-(furan-3-yl)phenyl]carbonyl}amino)butanoyl]amino}benzoic acid (yield: 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[C:11](C1C2C=CC=C(Br)C=2SC=1)(=[O:13])[CH3:12]>>[C:11]([C:7]1[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[S:9][CH:8]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)c1csc2c(Br)cccc12
Reactant: Brc1ccc2sccc2c1
Product: CC(=O)c1csc2ccc(Br)cc12
Yield: 70 %

Procedure:
Prepared in 70% yield from 5-bromo-benzothiophene (See Ple, P. A.; Marnett, L. J. J. Heterocycl. Chem., vol. 25, pp. 1271-1272 (1988), incorporated herein by references), analogous to the procedure for the preparation of 3-acetyl-7-bromo-benzo[b]thiophene. 1H NMR (300 MHz, CDCl3) δ8.04 (d, H. J=1.8Hz), 7.86 (s, 1H), 7.74 (d, 1H, J=8.4Hz), 7.56 (dd, 1H, J=8.4, 1.8Hz), 2.67 (s, 3H). Anal. (C10H7BrOS) C, H, Br, S. Calculated C=47.07, H=2.77, Br=31.32, S=12.57; found C=47.18, H=2.76, Br=31.42, S=12.55.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.CC1(C)C(C)(C)OB([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[O:22][CH2:21][CH2:20][CH2:19]3)O1.Br[C:28]1[S:32][C:31]([CH3:33])=[N:30][C:29]=1[CH:34]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:35]([O:37][CH3:38])=[O:36]>CN(C)C=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:40]([O:39][CH:34]([C:29]1[N:30]=[C:31]([CH3:33])[S:32][C:28]=1[C:16]1[CH:25]=[CH:24][C:23]2[O:22][CH2:21][CH2:20][CH2:19][C:18]=2[CH:17]=1)[C:35]([O:37][CH3:38])=[O:36])([CH3:43])([CH3:42])[CH3:41]
Reactant: COC(=O)C(OC(C)(C)C)c1nc(C)sc1Br
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1nc(C)sc1-c1ccc2c(c1)CCCO2
Temperature: 110 °C
Yield: 61.9 %

Procedure:
Under a nitrogen atmosphere, sodium carbonate (22 mg, 0.21 mmol), water (1 mL), palladium tetrakis(triphenylphosphine) (32 mg, 0.03 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (55 mg, 0.21 mmol) were added to a solution of methyl 2-(5-bromo-2-methyl-1,3-thiazol-4-yl)-2-(tert-butoxy)acetate (15d) (70 mg, 0.21 mmol) in N,N-dimethylformamide (4 mL). The mixture was heated at 110° C. for 1 hour. The mixture was then cooled at room temperature, concentrated and water (20 mL) was added. The aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 90/10) to afford the desired product as a white solid (48 mg, 0.13 mmol, 61%).
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[F:13][C:14]([F:24])([F:23])[C:15]1[S:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[F:13][C:14]([F:24])([F:23])[C:15]1[S:19][C:18]([C:5]2[N:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:17][CH:16]=1
Reactant: O=Cc1cccnc1Br
Reactant: OB(O)c1ccc(C(F)(F)F)s1
Agent: OBO
Product: O=Cc1cccnc1-c1ccc(C(F)(F)F)s1

Procedure:
2-(5-(trifluoromethyl)thiophen-2-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (5-(trifluoromethyl)thiophen-2-yl)boronic acid (47.7 mg, 62.3 mg theoretical, 76.6%). LC-MS m/z 258.2 (M+1).
Reaction SMILES: [ClH:1].Cl.[C:3]1([C:9]2[C:10]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:11][CH:12]=[CH:13][N:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21][C:22]1[C:26]([CH:27]=O)=[CH:25][NH:24][N:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].Cl>O1CCCC1.C(#N)C.C(Cl)Cl>[ClH:1].[CH3:21][C:22]1[C:26]([CH2:27][N:18]2[CH2:19][CH2:20][N:15]([C:10]3[C:9]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[N:14][CH:13]=[CH:12][N:11]=3)[CH2:16][CH2:17]2)=[CH:25][NH:24][N:23]=1
Reactant: Cc1n[nH]cc1C=O
Reactant: c1ccc(-c2nccnc2N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1n[nH]cc1CN1CCN(c2nccnc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 70 h
Yield: 33.5 %

Procedure:
To a stirred suspension of 3′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (0.4 g, 1.28 mmol, 1 eq) and 3-methyl-1H-pyrazole-4-carbaldehyde (0.27 g, 2.45 mmol, 1.92 eq) in tetrahydrofuran (20 mL) add sodium triacetoxyborohydride (0.88 g, 4.15 mmol, 3 eq) in one portion as a solid. Stir the mixture at room temperature under nitrogen for 70 hr. Add a further portion of 3-methyl-1H-pyrazole-4-carbaldehyde (70 mg, 0.639 mmol, 0.5 eq) and sodium triacetoxyborohydride (271 mg, 1.28 mmol, 1 eq) and stir for a further 21 hr. Add 2M aqueous sodium hydroxide solution (10 ml) and DCM (20 ml) separate and extract the aqueous layer with DCM (20 ml). Combine the organics, dry over magnesium sulfate, filter and concentrate. Purify by flash chromatography on silica gel column, eluting with 5% methanol in DCM, and then 5-10% methanol in DCM. Dissolve this material (157 mg, 0.47 mmol) in the minimum quantity of 50% aqueous acetonitrile. Add 2M aqueous hydrogen chloride (235 μL, 0.47 mmol) and lyophilize to give the title compound (159 mg, 34%). MS (ES): m/z=335.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:9][C:12](=[O:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 3-trifluoromethyl-phenylamine (4 g, 24.8 mmol), acetic anhydride (10.1 g, 99.3 mmol), DMAP (0.9 g, 7.4 mmol) and triethyl amine (2.5 g, 24.8 mmol) was heated to reflux 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the combined organic layers were dried over sodium sulphate and concentrated to dryness. The obtained residue was purified by column chromatography using 30% ethylacetate in hexane to get the title compound as off-white solid.