Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:3]1.[NH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1.C(OCC)C>O1CCOCC1>[C:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][CH:29]([NH:28][C:11]2[N:10]=[CH:9][C:8]3[CH2:7][CH2:6][C:5]4[C:4]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:3][N:2]([CH3:1])[C:14]=4[C:13]=3[N:12]=2)[CH2:30]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(OS(=O)(=O)C(F)(F)F)nc1-2
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(C(=O)OC(C)(C)C)C3)nc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of 1.5 g (3.7 mmol) of ethyl 1-methyl-8-{[(trifluoromethyl)sulfonyl]oxy}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate in 150 mL of anhydrous dioxane, 756 mg (4.1 mmol) of tert-butyl 3-aminopyrrolidine-1-carboxylate were added. The reaction mixture was stirred at room temperature overnight. The solvent was then removed under reduced pressure, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over sodium sulfate and evaporated. 1.2 g (88% yield) of the title compound was collected by filtration after trituration with diethylether.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2].C(O)(=O)C1C=CC=CC=1.[CH2:28]([O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=1)[CH3:29]>C(N(CC)CC)C.[Cu]I.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>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:35]3[CH:36]=[CH:37][C:32]([C:31]([O:30][CH2:28][CH3:29])=[O:39])=[CH:33][CH:34]=3)=[CH:9][C:8]=2[C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:6][CH2:5]1)[CH3:2]
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(C)(C)C)c1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-tert-butylbenzene (Intermediate 112, 70.0 mg, 0.30 mmol) and ethyl-4-iodo benzoate (Reagent A, 85.0 mg, 0.30 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (19.0 mg, 0.01 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (70 mg, 0.01 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (1-2% EtOAc-hexanes) afforded 70.0 mg (73%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[O:15][P:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(CC(C1C(O)=CC(O)=C(CC=C(C)C)C=1[O-])=O)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([P:16](=[O:15])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COP(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: CC(C)=CCc1c(O)cc(O)c(C(=O)CC(C)C)c1[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)P(=O)(c2ccccc2)c2ccccc2)cc1

Procedure:
41.3 parts of p-tert.-butylbenzoyl chloride are reacted with 45.4 parts of methoxydiphenylphosphine, dissolved in 20 parts of toluene, in 90 minutes at 50° C., by a method similar to that described for compound X. After evaporating off the solvent on a rotary evaporator, the product is recrystallized from cyclohexane.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH2:19][C:20]([NH:22][CH3:23])=O.[OH-].[Na+]>C(OCC)C.C1COCC1.O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH2:19][CH2:20][NH:22][CH3:23]
Reactant: CNC(=O)Cc1cc(F)ccc1Br
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CNCCc1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Lithium aluminum hydride (7.50 g, 197 mmol) is suspended in dry diethyl ether (75 mL) and cooled to 0° C. Aluminum (III) chloride (8.80 g, 65.8 mmol) dissolved in dry diethyl ether (75 mL) is added dropwise at 0-5° C. The cooling bath is removed and the mixture is stirred at ambient temperature for 1 hour. The resulting aluminum hydride reagent solution is cooled to 0° C. followed by dropwise addition of 2-(2-bromo-5-fluoro-phenyl)-N-methyl-acetamide (16.2 g, 65.8 mmol) dissolved in dry THF (150 mL). After complete addition the solution is allowed to heat to ambient temperature and stirring is continued for 16 hours. The mixture is cooled to 10° C. followed by slow dropwise addition of water (16 mL) followed by 2M sodium hydroxide (16 mL) and water (80 mL) to quench excessive reducing agent. The mixture is filtered and concentrated in vacuo. The remanence is redissolved in ethyl acetate (200 mL), dried (MgSO4) and concentrated again to give 14.6 g (95%) of the title compound as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]([NH:22][CH3:23])=[O:21])=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]([NH:22][CH3:23])=[O:21])=[O:17])[CH2:14][CH2:15]2)=[N:8][CH:9]=1
Reactant: CNC(=O)COC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNC(=O)COC(=O)N1CCN(c2ccc(N)cn2)CC1
Reaction time: 14 h
Yield: 80.9 %

Procedure:
0.24 g of 10% palladium on charcoal is added to a suspension of 0.64 g (1.98 mmol) of 2-(methylamino)-2-oxoethyl 4-(5-nitro-2-pyridyl)-1-piperazinecarboxylate, prepared in step 5.3., in 90 ml of ethyl acetate. Stirring is continued at room temperature under a hydrogen atmosphere of 60 psi for 14 hours. After filtering off the catalyst, the filtrate is concentrated under reduced pressure and the residue thus obtained is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. 0.47 g of product is obtained in the form of a violet-colored oil, and is used without further purification in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][NH:7][C:8]1O[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[N:11][N:12]=1.O.[NH2:26][NH2:27]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][NH:7][C:8]1[N:26]([NH2:27])[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[N:11][N:12]=1
Reactant: COc1cccc(CNc2nnc(-c3c[nH]c4ncccc34)o2)c1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: COc1cccc(CNc2nnc(-c3c[nH]c4ncccc34)n2N)c1
Reaction time: 120 h
Yield: 31.8 %

Procedure:
A mixture of 50 mg of (3-methoxybenzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,3,4-oxadiazol-2-yl]amine (prepared by method 1) and 75 μl of hydrazine hydrate in 1 ml of 2-propanol is stirred at a bath temperature of 100° C.-120° C. for 5 days in a sealed screw-lid vial. The reaction mixture is evaporated and purified by prep. HPLC (RP-18, water/acetonitrile), giving 16.6 mg of N*3*-(3-methoxybenzyl)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2,4-triazole-3,4-diamine (31.8%) MS-FAB (M+H+)=336.4 Rf (polar method): 1.34 min;
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([NH2:19])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[O:25][CH:24]=[N:23][C:22]=1[C:26](O)=[O:27]>>[CH:1]1([C:7]2[CH:8]=[C:9]([NH:19][C:26]([C:22]3[N:23]=[CH:24][O:25][C:21]=3[CH3:20])=[O:27])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: Cc1ocnc1C(=O)O
Product: Cc1ocnc1C(=O)Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Yield: 48.5 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 8b) (100 mg, 0.36 mmol) and 5-methyl-4-oxazolecarboxylic acid (71 mg, 0.55 mmol) as starting materials. The title compound (67 mg, 47.2%) was isolated as off white solid; MS (ESI): 384 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[N:5]1)([CH3:3])[CH3:2].[NH2:16][C@H:17]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:20]([CH2:30][C:31]2([OH:37])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[OH:37][C:31]1([CH2:30][C@H:20]2[CH2:19][CH2:18][C@@H:17]([NH:16][C:13]([C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=3)=[O:15])[CH2:22][N:21]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)CC[C@@H]1CC1(O)CCOCC1
Reactant: CC(C)n1nc(C(=O)O)c2ccccc21
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1nc(C(=O)N[C@@H]2CC[C@H](CC3(O)CCOCC3)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Reaction time: 18 h
Yield: 94.2 %

Procedure:
To a stirred solution of 1-isopropyl-1H-indazole-3-carboxylic acid (126 mg, 0.619 mmol), tert-butyl cis-5-amino-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidine-1-carboxylate (234 mg, 0.743 mmol, step 5 of Example 2), N,N-diisopropylethylamine (96 mg, 0.743 mmol) in N,N-dimethylformamide (3 mL) was added diethyl cyanophosphonate (121 mg, 0.743 mmol) at room temperature, and the mixture was stirred at the same temperature for 18 h. The mixture was concentrated under reduced pressure and the resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (1:1) to give 292 mg (94%) of the title compound as a colorless oil.
Reaction SMILES: FC(F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14](C(=O)C(F)(F)F)=[CH:13][CH:12]=2)[N:7]=1)=[O:4].C(O)=O.ClC1C=C(N2CC(C)C(NC=O)=N2)C=CC=1Cl>O>[C:11]1([N:8]2[CH2:9][CH2:10][C:6]([NH:5][CH:3]=[O:4])=[N:7]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(NC1=NN(c2ccc(C(=O)C(F)(F)F)cc2)CC1)C(F)(F)F
Agent: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Solvent: O
Solvent: O=CO
Product: O=CNC1=NN(c2ccccc2)CC1
Reaction time: 3 h

Procedure:
A mixture of 10.0 g. of 3-amino-1-phenyl-2-pyrazoline (prepared in Example 8) and 50.0 ml. of a mixture of formic acid and acetic anhydride (Example 15) is allowed to stand at room temperature for 3 hours. Water is added and the white crystals are collected by filtration. The solid is dissolved in dichloromethane. The solution is dried over magnesium sulfate and filtered through a hydrous magnesium silicate. The filtrate is evaporated in vacuo to give pink crystals. A 500 mg. portion of crude product is recrystallized from dichloromethane-hexane to give 403 mg. of the desired product as a white solid, m.p. 140°-141° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: [H][H]
Reactant: CCOC(=O)C=C(CCCCc1ccccc1)c1ccc(OC)c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(CCCCc1ccccc1)c1ccc(OC)c(OC)c1
Yield: 73.6 %

Procedure:
A solution of ethyl 3-(3,4-dimethoxyphenyl)-7-phenyl-2-heptenoate (0.4 g, 1.1 mmol) in ethanol (20 mL) containing 10% Pd/C (few mg) is stirred under a balloon of hydrogen for 4 hours at room temperature. The catalyst is filtered and the solvent is removed in vacuo to produce ethyl 3-(3,4-dimethoxyphenyl)-7-phenylheptanoate (0.3 g, 73%) as an oil. 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.11-1.20 (t, 3H), 1.20-1.65 (m, 6H), 2.45-2.59 (m, 4H), 2.92-3.10 (m, 1H), 3.82 (s, 6H), 4.00-4.08 (q, 2H), 6.62-6.82 (m, 3H), 7.02-7.28 (m, 5H); MS (EI) m/e 370 (M+).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[C:14]([CH3:16])([CH3:15])[C:13]2([Cl:18])[Cl:17])(=O)=O)=CC=1.[C-:20]#[N:21].[K+].O>CN(C)C=O>[Cl:18][C:13]1([Cl:17])[C:14]([CH3:15])([CH3:16])[CH:12]1[CH2:11][C:20]#[N:21]
Reactant: Cc1ccc(S(=O)(=O)OCC2C(C)(C)C2(Cl)Cl)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(CC#N)C1(Cl)Cl
Temperature: 100 °C
Yield: 106.5 %

Procedure:
6.48 g of 2,2-dichloro-3,3-dimethylcyclopropylmethyl p-toluenesulfonate and 2.0 g of potassium cyanide were suspended in 20 ml of dimethyl formamide, and the mixture was heated at 100° C. for 24 hours with stirring. After cooling, 50 ml of water was added to the reaction mixture. The mixture was extracted with hexane. The hexane layer was washed with water, and dried over sodium sulfate. After drying, the hexane was evaporated under reduced pressure to give 3.8 g of 2,2-dichloro-3,3-dimethylcyclopropylacetonitrile, the desired compound shown above. The boiling point of the product was 96° to 98° C. at 14 mmHg.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH2:26][S:27][CH3:28])[NH2:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.COC(=O)[C@H](CCSC)N(C(=O)C1C=CC(N)=CC=1)C(OC(C)(C)C)=O>C(Cl)Cl.CCN(CC)CC>[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH2:26][S:27][CH3:28])[NH:24][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Yield: 85.8 %

Procedure:
4-nitro-2-phenylbenzoic acid (0.30 g, 1.23 mmol), methionine methyl ester hydrochloride salt (0.27 g, 1.35 mmol), EDCI (0.26 g, 1.35 mmol), HOBT (0.18 g, 1.35 mmol) and Et3N (0.19 ml) in dry CH2Cl2 (4.9 ml) were reacted according to the above procedure and worked up as described for N-BOC-4-aminobenzoyl methionine methyl ester in Example 1. After recrystallization from ethyl acetate and hexanes, 0.41 g (85.5%) of pure product was isolated. mp 98°-101° C.; 1H NMR (CDCl3) 1.62-1.73 (1 H, m), 1.79-1.88 (1 H, m), 1.91 (3 H, s), 1.99 (2 H, t, J=7.2 Hz), 3.59 (3 H, s), 4.53 (1 H, m), 6.45 (1 H, d, J=7.8 Hz), 7.33-7.40 (5 H, m), 7.67 (1 H, d, J=8.3 Hz), 8.07-8.12 (2 H, m); 13C NMR (CDCl3) 14.92, 29.11, 30.67, 51.51, 52.29, 121.86, 124.74, 128.27, 128.60, 128.69, 129.52, 137.50, 140.56, 141.02, 148.09, 167.23, 171.23; m/ z (FAB) , 389 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][N:29]=2)[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:31]3[CH:30]=[N:29][C:28]([N:25]4[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]4)=[CH:33][CH:32]=3)=[CH:14][C:6]1=2
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3Cl)CCN4)cn2)CC1
Yield: 50 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (94 mg) was coupled to 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4B to give the title compound as a brown solid (50% yield). LCMS: m/z=468.97 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (3H, s), 2.51 (4H, t, J=5.1 Hz), 3.48 (2H, m), 3.55 (4H, t, J=5.1 Hz), 3.64 (2H, t, J=4.7 Hz), 4.46 (2H, s), 5.20 (1H, bs), 6.52 (1H, d, J=1.5 Hz), 6.65 (1H, d, J=8.8 Hz), 7.19 (1H, dd, J=8.5, 2.4 Hz), 7.26 (1H, d, J=2.3 Hz), 7.33 (1H, d, J=8.3 Hz), 7.52 (1H, dd, J=8.6, 2.5 Hz), 7.62 (1H, d, J=1.5 Hz), 8.20 (1H, d, J=2.5 Hz).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][SH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=1.CO>O1CCCC1.ClCCl.O>[CH2:9]([S:10][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cccc(C(F)(F)F)n1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc(SCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.4 %

Procedure:
To a suspension of sodium hydride (0.170 g, 4.24 mmol) in tetrahydrofuran (10 mL) was added phenylmethanethiol (0.338 ml, 2.88 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes then 2-fluoro-6-(trifluoromethyl)pyridine (0.365 ml, 3.03 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 minutes. Methanol (1 mL) was added carefully and the reaction mixture was stirred at 0° C. for a further 10 minutes then water (5 mL) and dichloromethane (10 mL) were added. The organic layer was recovered using a phase separator cartridge then concentrated in vacuo to give 2-(benzylthio)-6-(trifluoromethyl)pyridine (538 mg) as a colourless oil. LCMS (Method F, ES-API): RT 2.80 min, m+H=270.1.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20]>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:14])[N:15]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:5](=[O:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COCCCN
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Solvent: CC(=O)O
Product: COCCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O

Procedure:
A solution of 3-chloro-4-phenylfuran-2,5-dione (0.20 mmol, 42 mg) and 1-amino-3-methoxypropane (0.20 mmol, 18 mg) in glacial acetic acid (1 mL) was heated in a microwave reactor at 120° C. for two min. After cooling, the solvent was evaporated at reduced pressure. The crude product was used without purification.
Reaction SMILES: [C:1]([C:5]1[C:10]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:9][N:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([C:5]1[C:10]([CH:11]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[OH:19])=[CH:9][N:8]=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ncncc1C(=O)c1ccc(Cl)cc1
Solvent: CCO
Product: CC(C)(C)c1ncncc1C(O)c1ccc(Cl)cc1
Yield: 59.6 %

Procedure:
1 g of 4-t-butyl-5-(4-chlorobenzoyl)pyrimidine was dissolved in 20 ml of ethanol, and 0.8 g of a borane ammonia complex was added. The mixture was heated at 50° C.-60° C. for 1 hour, and further refluxed under heating for 30 minutes. After the solvent was distilled off under reduced pressure, water was added, and extraction with chloroform was carried out. The extract layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.6 g of the desired product as a viscous liquid. nD20.2 1.5474
Reaction SMILES: [CH2:1]([CH:3]([CH2:31][CH3:32])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:20](O)=[O:21])[CH2:15][CH2:14]2)=[C:9]([F:30])[CH:8]=1)=[O:5])[CH3:2].CO[C:35](=O)[CH:36]([N:44]1CCN(C2C=CC(NC(=O)C(CC)CC)=CC=2F)[CH2:46][CH2:45]1)C1C=CC=C(F)C=1.[OH-].[K+].CC(O)=O>O.CO.O>[CH2:36]([N:44]([CH2:45][CH3:46])[C:20]([CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[CH:3]([CH2:1][CH3:2])[CH2:31][CH3:32])=[CH:8][C:9]=2[F:30])[CH2:18][CH2:17]1)=[O:21])[CH3:35]
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)OC)c3cccc(F)c3)CC2)c(F)c1
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)O)c3cccc(F)c3)CC2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)N(CC)CC)c3cccc(F)c3)CC2)c(F)c1
Temperature: 25 °C

Procedure:
{4-[4-(2-Ethyl-butyrylamino)-2-fluoro-phenyl]-piperazin-1-yl}-(3-fluoro-phenyl)-acetic acid. A mixture of {4-[4-(2-ethyl-butyrylamino)-2-fluoro-phenyl]-piperazin-1-yl}-(3-fluoro-phenyl)-acetic acid methyl ester (0.22 g, 0.47 mmol) in water/MeOH (1:4, 5 mL) was treated with KOH (0.095 g, 1.70 mmol) and the resulting mixture was heated at reflux for 24 h. The mixture was cooled to rt and acidified to pH 6.5 with AcOH. The mixture was diluted with water and extracted with DCM. The organic layer was dried (Na2SO4) and concentrated to yield the title compound (0.24 g), which was carried forward to the next step.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C@@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[NH:28][CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:34][CH:33]=3)[N:31]=2)=[CH:23][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:14][C@@H:15]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[NH:28][CH:29]=[C:30]([C:32]4[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:36][CH:37]=4)[N:31]=3)=[CH:25][CH:26]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:11])=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: CCCCCCCOc1ccc(-c2c[nH]c(-c3ccc(C[C@H](N)C(=O)OC)cc3)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2c[nH]c(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)OC)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
To a solution of 4-(tert-butyl)benzoic acid (25 mg, 0.14 mmol), (S)-methyl 2-amino-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoate (55 mg, 0.13 mmol), and TEA (53 μl, 0.38 mmol) in DMF (1 mL) was added HATU (53 mg, 0.14 mmol). The reaction mixture was stirred at RT for 2 h, diluted in DCM, and washed aq. NaHCO3. The organic layer was dried, concentrated and purified by chromatography (EA/hexane) to provide 14 mg (17%) of methyl (S)-2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for C37H45N3O4: 595.8; found 596.4 [M+H]+, tR=2.33 min. (Method 8).