Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.Cl.[NH2:27][C@@H:28]([C:31]1[CH:36]=[C:35]([I:37])[CH:34]=[C:33]([F:38])[CH:32]=1)[CH2:29][OH:30].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:27][C@@H:28]([C:31]3[CH:36]=[C:35]([I:37])[CH:34]=[C:33]([F:38])[CH:32]=3)[CH2:29][OH:30])=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: N[C@H](CO)c1cc(F)cc(I)c1
Reactant: Nc1ncc([C@H]2CC[C@H](O)[C@@H](F)C2)nc1-c1ccc(C(=O)O)c(F)c1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc([C@H]2CC[C@H](O)[C@@H](F)C2)nc1-c1ccc(C(=O)N[C@H](CO)c2cc(F)cc(I)c2)c(F)c1
Reaction time: 15 h
Yield: 33 %

Procedure:
To a solution of 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (16 mg, 0.046 mmol) in DMF (0.46 mL) was added (S)-2-amino-2-(3-fluoro-5-iodophenyl)ethanol hydrochloride (17.5 mg, 0.055 mmol), HOAt (9.35 mg, 0.069 mmol), EDC (17.6 mg, 0.092 mmol), and DIEA (24 μl, 0.137 mmol). The reaction mixture was stirred for 15 h. After water was added, the reaction mixture was extracted with EtOAc and the organic layer was washed with water twice. The organic layer was separated and dried over Na2SO4, filtered off and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 0-100% EtOAc/heptane to provide crude product, which was triturated with 70% of DCM/ether to provide 9.3 mg of 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluoro-N—((S)-1-(3-fluoro-5-iodophenyl)-2-hydroxyethyl)benzamide as a TFA salt (28%). LCMS (m/z): 613.1 (MH+), 0.74 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.93-7.78 (m, 2H), 7.76-7.57 (m, 3H), 7.73-7.56 (m, 3H), 7.43 (d, J=7.8 Hz, 1H), 7.21 (d, J=9.4 Hz, 1H), 5.15 (t, J=5.9 Hz, 1H), 4.37 (m, 1H), 3.83 (m, 2H), 3.63 (m, 1H), 2.84 (t, J=11.7 Hz, 1H), 2.27 (dd, J=2.9, 9.2 Hz, 1H), 2.14-1.98 (m, 1H), 1.96-1.75 (m, 2H), 1.65 (dq, J=3.3, 13.0 Hz, 1H), 1.56-1.34 (m, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].P([O-])([O-])(O)=O.[Na+].[Na+].[Cl:19]CCl.ClCl>O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([Cl:19])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: ClCCl
Reactant: CC(=O)Nc1cc(C)ccn1
Agent: ClCl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1cc(C)c(Cl)cn1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
In 300 ml of water, 15.0 g (0.1 mol) of 2-acetamido-4-methylpyridine (Ia) was dissolved. To this solution, 35.5 g (0.25 mol) of disodium hydrogenphosphate and 100 ml of dichloromethane were added in this order. While this mixture was stirred, 8.0 g (0.11 mol) of chlorine was introduced thereto at 0° C. for one hour. After having further been stirred at the same temperature for 2 hours, the mixture was separated into a water layer and an extract layer. After the water layer was further extracted with 100 ml of dichloromethane, the newly-separated extract layer was combined with the previously-separated extract layer and washed with saturated brine. Then the washed mixture was desiccated with sodium sulfate anhydride. When the solvent was evaporated off, 18.0 g (yield: 97.3%) of 2-acetamido-4-methyl-5-chloropyridine (IIk) was obtained as a pale yellow crystal.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28](C)([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.ClC(OC(C)C)=O>C(Cl)Cl.CCOC(C)=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Agent: CC(C)OC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
1,1-Dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (prepared as in Example 73, 0.132 g, 0.30 mmol) was dissolved in CH2Cl2 (9 mL). TFA (0.30 mL) was added to this solution and the mixture was stirred at ambient temperature overnight. The excess TFA and CH2Cl2 were removed under reduced pressure. The residue was redissolved in CH2Cl2 (9 mL). The solution was cooled to 0° C. in an ice bath, and diisopropylethylamine (1.5 mL) was added, followed by addition of isopropyl chloroformate (1.0M in toluene, 0.36 mL, 0.36 mmol). The reaction mixture was allowed to warm to ambient temperature, and stirred for 2 h, then diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light yellow solid. The crude product was purified by chromatography on a silica gel column eluted with 9:4 EtOAc/hexane to give 0.12 g (93%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.40 (d, 1H, J=2.7 Hz), 8.14 (d, 2H, J=8.3 Hz), 8.01 (d, 2H, J=8.6 Hz), 7.74 (d, 1H, J=8.8 Hz), 7.35-7.25 (m, 1H), 4.92 (septet, 1H, J=6.2 Hz), 4.23 (bs, 2H), 3.92 (d, 2H, J=6.3 Hz), 3.08 (s, 3H), 2.85-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.40-1.20 (m, 8H); LRMS (APCI), m/z 433 (M+H).
Reaction SMILES: [ClH:1].Cl.Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:15][C@@H:14]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[NH2:30])[CH2:19][CH2:18]3)[CH2:13][O:12]2)=[CH:7][CH:6]=1.[O-:31][C:32]#N.[K+]>C(O)C>[ClH:1].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:15][C@@H:14]([CH2:16][N:17]3[CH2:18][CH2:19][CH:20]([N:23]4[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[NH:30][C:32]4=[O:31])[CH2:21][CH2:22]3)[CH2:13][O:12]2)=[CH:7][CH:6]=1
Reactant: Nc1ccccc1NC1CCN(C[C@H]2CO[C@@H](c3ccc(F)cc3)C2)CC1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=c1[nH]c2ccccc2n1C1CCN(C[C@H]2CO[C@@H](c3ccc(F)cc3)C2)CC1
Reaction time: 8 h

Procedure:
A mixture of 9.56 g of 1-[cis-2-(4-fluorophenyl)-tetrahydro-4-furylmethyl]-4-(2-aminoanilino)piperidine trihydrochloride and 2.0 g of potassium cyanate in 100 ml of ethanol is heated under reflux with stirring for 8 hours. The ethanol is then distilled off under reduced pressure, and 10 ml of 10% aqueous sodium hydroxide solution and 50 ml of water are added to the residue and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in a small amount of ethanol, and ethanolic hydrochloric acid is added thereto. The crystals precipitated are collected by filtration and recrystallized from ethanol-water to give 1-[1-(cis-2-(4-fluorophenyl)-tetrahydro-4-furylmethyl)-4-piperidyl]benzimidazolin-2-one hydrochloride, melting at 276° C. with decomposition.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1>CN(C)C=O>[OH:19][C:15]1[CH:14]=[C:13]([N:12]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cccc(O)c1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1c1cccc(O)c1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
452 g (3.0 mol) of phthalic anhydride are used as initial charge in 1.6 l of DMF (dimethylformamide) in a round-bottomed flask. 334 g (3.0 mol) of 3-aminophenol are added slowly to this mixture. The mixture is stirred at 140° C. for 8 hours. During this period, water is removed by distillation by way of the head of a column. The mixture is permitted to cool to room temperature, and the precipitated solid is removed by suction filtration. The solid is washed first with water and then with ethanol, and is then dried in vacuo. This gives 650 g of a beige-coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]([C:11](=O)[C:12]#[C:13]C)=[C:4]2[CH:3]=1.Cl.[CH:24]1([NH:29][C:30]([NH2:32])=[NH:31])[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:10]([C:11]3[CH:12]=[CH:13][N:32]=[C:30]([NH:29][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:31]=3)=[C:4]2[CH:3]=1
Reactant: N=C(N)NC1CCCC1
Reactant: CC#CC(=O)c1c(-c2ccc(F)cc2)nn2ccc(Cl)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 80 °C

Procedure:
To a solution of 1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-one (0.61 g, 2.0 mmol) in N,N-dimethylformamide was added N-cyclopentyl guanidine hydrochloride (0.67 g, 4.1 mmol) followed by potassium carbonate (0.57 g, 4.1 mmol). The resulting mixture was heated at 80° C. for 12 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:1 ethyl acetate-hexane) to give, after recrystallization from acetonitrile, 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (0.6 g, 74%) as a white solid. 1H NMR (CDCl3): δ 8.54 (broad s, 1H), 8.40 (d, 1H), 8.04 (d, 1H), 7.60 (q, 2H), 7.16 (t, 2H), 6.88 (dd, 1H), 6.28 (d, 1H), 5.22 (d, 1H), 4.40 (m, 1H), 1.4–2.2 (m, 8H; 19F NMR (CDCl3); δ −112.5; MS m/z 408 (M+1).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([N:22]([CH:32]([CH3:34])[CH3:33])[C:23]1[N:24]=[C:25]([Cl:31])[C:26]([CH:29]=O)=[N:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:35]([NH:42][CH2:43][CH2:44][OH:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:35]([N:42]([CH2:29][C:26]1[C:25]([Cl:31])=[N:24][C:23]([N:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:32]([CH3:34])[CH3:33])=[CH:28][N:27]=1)[CH2:43][CH2:44][OH:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)N(Cc1ccccc1)c1cnc(C=O)c(Cl)n1
Reactant: OCCNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)N(Cc1ccccc1)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
Sodium triacetoxyborohydride (2.65 g) was added to a solution of 5-[benzyl(1-methylethyl)amino]-3-chloropyrazine-2-carbaldehyde (2.42 g), N-benzylethanolamine (1.42 g) and acetic acid (1.43 mL) in acetonitrile (14 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 20-÷50% ethyl acetate/hexane) to give the title compound (3.32 g, 94%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.ClCCl.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C>O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:13])=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1cnc(Cl)nc1C(F)(F)F)N1CCOCC1
Temperature: -70 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2-chloro-4-(trifluoromethyl)pyrimidine-5-carbonyl chloride (2.8 g) and dichloromethane (56 mL) was cooled in a dry ice-acetone bath, and morpholine (990 μL) and triethylamine (1.9 mL) were added dropwise thereto while keeping the temperature at −50° C. or lower. The reaction mixture was stirred at −70° C. for 2.5 hours, and then ethyl acetate and water were added thereto. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}morpholine (2.8 g) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]=1[C:32](O)=[O:33]>>[CH3:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]=1[C:32]([N:17]1[CH2:16][CH:15]2[CH:19]([CH2:20][N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:18]1)=[O:33]
Reactant: Cc1ccc2ccccc2c1C(=O)O
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Product: Cc1ccc2ccccc2c1C(=O)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2-methyl-naphthalene-1-carboxylic acid. MS (ESI) mass calcd. for C28H26N4O, 434.51; m/z found, 435.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([OH:13])=O)[C:4]=2[CH:3]=1.[Br:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[C:22]=1[NH2:23]>>[Br:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[C:22]=1[NH:23][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:13]
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Reactant: Nc1c(Br)cccc1Br
Product: Cc1ccc2c(c1)C(C(=O)Nc1c(Br)cccc1Br)c1ccccc1CO2
Yield: 58.7 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.40 g of Compound A and 1.28 g of 2,6-dibromoaniline in place of aniline to obtain 1.46 g of Compound 7.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>S(=O)(=O)(O)O>[C:1]1([CH:7]2[C:9]3[CH:10]=[N:11][CH:12]=[N:13][C:14]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1cncnc1
Agent: O=S(=O)(O)O
Product: c1ccc(C2c3ccccc3-c3ncncc32)cc1
Yield: 118.1 %

Procedure:
Ten grams of α, α-diphenyl-5-pyrimidinemethanol were stirred in 50 ml of sulfuric acid for approximately 18 hours. The solution was poured onto ice and the resulting solids were recovered by filtration providing 11 g of the desired title product. Recrystallization from diethyl ether provided material with a melting point of 148°-150° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([CH:21]=3)[C:19]#[N:20])[N:10]=2)=[CH:5][CH:4]=1)=O.[NH:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1.C(O)(=O)C.C([BH3-])#N>CO.ClCCCl>[C:19]([C:18]1[CH:21]=[C:14]([C:11]2[N:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][N:26]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]4)=[CH:8][CH:7]=3)[O:13][N:12]=2)[CH:15]=[CH:16][C:17]=1[O:22][CH:23]([CH3:25])[CH3:24])#[N:20]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(C=O)cc3)n2)cc1C#N
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Solvent: ClCCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(CN4CC(C(=O)O)C4)cc3)n2)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
5-(5-(4-formylphenyl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile (0.077 g, 0.231 mmol) and azetidine-3-carboxylic acid (0.028 g, 0.277 mmol) were combined in methanol (11.55 ml) and DCE (11.55 ml) in a sealed vial. Acetic acid (0.066 ml, 1.155 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hr. MP-cyanoborohydride (0.265 g, 0.570 mmol) was added and the reaction stirred for about 24 h. The solution was filtered, the solid was washed with methylene chloride and methanol, and the filtrate was concentrated to afford a white solid, which was recrystallized by methanol (5 mL) to give 1-(4-(3-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)azetidine-3-carboxylic acid (0.025 g, 0.060 mmol, 25.9% yield) as white solid: LC/MS (Table 1, Method a) Rt=2.10 min.; MS m/z: 420.26 (M+H)+. 1H NMR (400 MHz, Solvent d-DMSO) ppm 8.35-8.28 (m, 2H), 8.17-8.11 (d, J=8.00 Hz, 2H), 7.56-7.50 (m, 8.69 Hz, 3H), 4.98-4.89 (m, 1H), 3.68 (s, 2H), 3.43 (s, 2H), 3.25-3.23 (m, 3H), 1.38 (d, J=6.03 Hz, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=2[C:13](O)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+].Cl>C1COCC1.CO>[C:1]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=2[CH2:13][OH:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(COc2ccc(F)cc2C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(COc2ccc(F)cc2CO)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
6.65 g (22 mmol) of 2-(4-tert-butylbenzyloxy)-5-fluorobenzoic acid are suspended in 25 ml of THF and cooled to 0° C. 2.4 ml (22 mmol) of N-methylmorpholine and 2.1 ml (22 mmol) of ethyl chloroformate are added, and the solution is stirred at room temperature for 15 min. 2.50 g (66 mmol) of sodium borohydride are added and, after 3 h, methanol is added until gas evolution has subsided. The mixture is acidified with 1 N hydrochloric acid and concentrated in vacuo, and the residue is taken up in ethyl acetate. The organic phase is washed with saturated sodium chloride solution and then dried over sodium sulfate. The solvent is distilled out in vacuo, and the residue is chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 3.52 g (12.2 mmol, 55% of theory) of the title compound are isolated.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:12]([NH:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)(=[O:14])[CH3:13]>CC(N(C)C)=O.[Cu-]=O>[C:12]([NH:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:14])[CH3:13]
Reactant: COC(=O)c1ccccc1I
Reactant: CC(=O)Nc1cccc(O)c1
Agent: O=[Cu-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccccc1Oc1cccc(NC(C)=O)c1
Temperature: 180 °C
Yield: 55 %

Procedure:
To a stirred solution of methyl 2-iodobenzoate (10 g, 38.2 mmole) in dimethylacetamide (50 mL) was added 3-acetamidophenol (5 g, 33 mmole) and copper(I) oxide (2.5 g, 17 mmole), and the mixture was heated at reflux under argon (180° C. oil bath). After 24 h the reaction was cooled to RT and most of the solvent was distilled off. The remaining residue was purified by flash chromatography on silica gel (50% EtOAc/hexane) to give the crude title compound (4.95, 55%): MS (ES) m/e 286.2 (M+H)+. The title compound prepared in this way contained approximately 45% N,O-diarylated acetamidophenol as a contaminant: MS (ES) m/e 420.4 (M+H)+. The mixture was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(C)C.CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CC(=O)O)cc1Br
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CCO)cc1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of [3-bromo-4-(methyloxy)phenyl]acetic acid (10.0 g, 40.8 mmol) in anhydrous THF (50 mL) was added BH3.(CH3)2S (5.3 mL, 53 mmol) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 3 h. The mixture was then treated with MeOH until gas evolution subsided, and then concentrated under reduced pressure. The residue was then partitioned between water and EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to give crude 2-[3-bromo-4-(methyloxy)phenyl]ethanol, which was used without further purification for the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1I)[C:15]#[N:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23].C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]#[N:16])[CH:17]=[CH:18][C:19]=1[CH:23]=[CH:22][C:21]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1I
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(C#N)cc1OCCNC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
11.0 g (28.4 mmol) of 3-[2-(t-butoxycarbonylamino)ethoxy]-4iodobenzonitrile was dissolved in 200 ml of DMF. 15.4 ml (142 mmol) of ethyl acrylate, 20 ml (142 mmol) of triethylamine and 127 mg (0.567 mmol) of palladium acetate were added to the obtained solution. They were stirred at 100° C. overnight and then treated with ethyl acetate as the extraction solvent in an ordinary manner to obtain the crude product. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:62]=[CH:61][C:51]([CH2:52][NH:53][CH2:54][CH2:55][CH2:56][C:57]([F:60])([F:59])[F:58])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:62]=[CH:61][C:51]([CH2:52][N:53]([CH2:54][CH2:55][CH2:56][C:57]([F:60])([F:59])[F:58])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCCC(F)(F)F)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCCC(F)(F)F)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 104 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 82 mg (0.3 mmol) of (4-tert-butyl-benzyl)-(4,4,4-trifluoro-butyl)-amine in 1 ml DMF were added. After stirring for 19 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo to give 130 mg (99%) of an orange solid. MS (ISP) 416.2 (M+H)+.