Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])[CH2:6][CH2:5]2)[O:3]C1.Cl>C(O)(=O)C.O>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1
Reactant: COc1ccccc1N1CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1N1CCC(=O)CC1

Procedure:
A solution of 19 (570 mg, 2.28 mmol) in acetic acid (20 mL), water (20 ml), and concetrated HCl (5 mL) was heated in an oil bath (50° C.) overnight. The solvent was removed in vacuo and the residue dissolved in ether and sodium carbonate solution. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 2 mm, CHCl3) afforded the title compound (20)
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[N:11]=[CH:10][CH:9]=1>CN(C=O)C>[Br:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[O:5][CH2:4][CH2:3][OH:6]
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCOc1ccnc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
To a suspension of sodium hydride (60% suspension, 40 mg, 0.99 mmol) in DMF (3 mL) under nitrogen atmosphere was added ethylene glycol dropwise. The reaction mixture was stirred for 20 min before adding 4-chloro-6-bromoquinoline (200 mg, 0.825 mmol) in one portion. The reaction mixture was stirred at 90° C. for 22 h. Another 20 mg of sodium hydride was added after 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in methanol and the solution was adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-10% methanol/dichloromethane afforded 127 mg of 2-(6-bromo-quinolin-4-yloxy)-ethanol as a white solid (57% yield): 1H NMR (DMSO-d6) δ 3.93 (q, 2H), 4.32 (t, 2H), 5.21 (t, 1H), 7.14 (d, 1H), 7.94 (m, 2H), 8.50 (d, 1H), 8.82 (d, 1H); MS (m/z) 268, 270 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([O:12][C:13]2[C:18]3[C:19]([O:22][CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[N:20][O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2].[CH:30]([C:32]1([C:37]([O:39][CH3:40])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1)=O.C(C1(C(OC)=O)CCC1)=O>>[C:1]([O:4][CH2:5][C@@H:6]1[CH2:7][CH2:8][C@H:9]([O:12][C:13]2[C:18]3[C:19]([O:22][CH2:23][CH:24]4[CH2:25][CH2:26][N:27]([CH2:30][C:32]5([C:37]([O:39][CH3:40])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]5)[CH2:28][CH2:29]4)=[N:20][O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1CC[C@@H](Oc2cccc3onc(OCC4CCNCC4)c23)CC1
Reactant: COC(=O)C1(C=O)CCCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(O[C@H]5CC[C@@H](COC(C)=O)CC5)c34)CC2)CCCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using (cis-4-{[3-(piperidin-4-ylmethoxy)-1,2-benzisoxazol-4-yl]oxy}cyclohexyl)methyl acetate (EXAMPLE 46, Step 3) and methyl 1-formylcyclopentanecarboxylate (Synthesis 1997, 32-34) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:19][N:18]=[C:17]([C:20]([NH:22][CH2:23][C:24]([OH:26])=O)=[O:21])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[NH:67][CH:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1>CN(C=O)C.O>[Cl:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[NH:67][CH:68]1[CH2:73][CH2:72][N:71]([C:24](=[O:26])[CH2:23][NH:22][C:20]([C:17]2[CH:16]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:19][N:18]=2)=[O:21])[CH2:70][CH2:69]1
Reactant: Clc1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a stirred solution of {[5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (0.15 g, 0.00039 mol) in DMF (2 mL) was added DIPEA (0.224 g, 0.00174 mol), HOBt (0.065 g, 0.00048 mol) and EDCI.HCl (0.0925 g, 0.00048 mol) at ambient temperature. After 5 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00041 mol) was added to the reaction mixture continued stirring at the same temperature for overnight. The reaction mixture was diluted with cold water, filtered the solid precipitated and dried to afford 0.205 g (98%) of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 544.2 (M+1)+, 92.2%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:25]([OH:27])=[O:26])[CH2:14][CH2:15][CH2:16][NH:17]C(OC(C)(C)C)=O)=[O:11].[ClH:28].O1CCOCC1>C(Cl)Cl>[ClH:28].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:25]([OH:27])=[O:26])[CH2:14][CH2:15][CH2:16][NH2:17])=[O:11]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)C=Cc1ccccc1F)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCC[C@H](NC(=O)C=Cc1ccccc1F)C(=O)O
Yield: 90 %

Procedure:
The same procedures as in Example 29 were carried out from the compound obtained in Example 111 (5.4 g), 4 mol/L of hydrogen chloride-dioxane (11 mL), and methylene chloride (200 mL), to give the captioned compound (4.1 g, 90%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][OH:16])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1.Cl[C:18]1[NH:22][C:21]2[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:26]([I:27])[C:20]=2[N:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][OH:16])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:18]2[NH:19][C:20]3[C:26]([I:27])=[CH:25][C:24]([C:28]([F:31])([F:29])[F:30])=[CH:23][C:21]=3[N:22]=2)[C@H:10]([CH3:14])[CH2:9]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1
Reactant: FC(F)(F)c1cc(I)c2nc(Cl)[nH]c2c1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(I)c2[nH]1

Procedure:
The piperazine from step (a) above (73 mg, 0.3 mmol) reacted with 2-chloro-4-iodo-6-(trifluoromethyl)-1H-benzoimidazole (69 mg, 0.2 mmol, Example 61c) under the conditions of Example 3c to give the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 552 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:16]=[CH:15][C:9]([N:10]([CH3:14])[C:11](=[O:13])[CH3:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH2:37]([N:44]1[CH2:49][CH2:48][C:47](=[O:50])[CH2:46][CH2:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCCC1.O>[CH2:1]([O:5][C:6]1[CH:16]=[CH:15][C:9]([N:10]([CH3:14])[C:11](=[O:13])[CH2:12][C:47]2([OH:50])[CH2:48][CH2:49][N:44]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:45][CH2:46]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(N(C)C(C)=O)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1ccc(N(C)C(=O)CC2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
A solution of 4′-n-butoxy-N-methylacetanilide (0.34 g) in anhydrous tetrahydrofuran (1.5 mL) was added to a solution of lithium diisopropylamide prepared from diisopropylamine (0.22 mL) and n-butyl lithium (1.58M hexane solution; 1.07 mL) in an anhydrous tetrahydrofuran (1.6 mL) under cooling with ice-water, and the mixture was stirred for 30 minutes. A solution of 1-benzylpiperidin-4-one (0.32 g) in anhydrous tetrahydrofuran solution (1.5 mL) was added to thereto under cooling with ice-water, followed by additional stirring for 30 minutes. After increasing the temperature to room temperature, water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off. The titled compound (0.33 g) was obtained by recrystallization of the residue from hexane.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][CH:17]=[CH:18][C:19]([N:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[N:22]=[CH:21]3)=[C:14]2[C:13]([CH:31]([CH3:33])[CH3:32])=[N:12]1)[C:6]#[N:7])=[O:2].C(C1C=C(C=CC=1N1C2=NC=CC(I)=C2C(C(C)C)=N1)C#N)=[O:35].Cl.CN1C=C(C2N=CNC=2)C=N1>>[CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][CH:17]=[CH:18][C:19]([N:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[N:22]=[CH:21]3)=[C:14]2[C:13]([CH:31]([CH3:33])[CH3:32])=[N:12]1)[C:6]([NH2:7])=[O:35])=[O:2]
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2C=O)c2nccc(-n3cnc(-c4cnn(C)c4)c3)c12
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2C=O)c2nccc(I)c12
Agent: Cl
Agent: Cn1cc(-c2c[nH]cn2)cn1
Product: CC(C)c1nn(-c2ccc(C(N)=O)cc2C=O)c2nccc(-n3cnc(-c4cnn(C)c4)c3)c12
Yield: 17 %

Procedure:
According to Example 97(2), 3-formyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile was prepared using compound (125a) instead of compound (97a) and using 4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole hydrochloride instead of 4-phenyl-1H-imidazole and was used in the subsequent reaction without being purified. According to Example 1(7), compound (125) (the second stage yield: 17%) was prepared as a white solid using 3-formyl-4-{(3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: C([O:5][C:6](=[O:16])[C@H:7]([CH3:15])[CH2:8][C:9]([NH:11][CH2:12][CH:13]=[CH2:14])=[O:10])(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:12]([NH:11][C:9](=[O:10])[CH2:8][C@@H:7]([CH3:15])[C:6]([OH:16])=[O:5])[CH:13]=[CH2:14]
Reactant: C=CCNC(=O)C[C@@H](C)C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCNC(=O)C[C@@H](C)C(=O)O
Reaction time: 3 h

Procedure:
To a solution of 1.98 g (8.7 mmol) of (R)—N-allyl-2-methyl-succinamic acid tert-butyl ester in 30 ml of DCM are added 3.57 ml (21.8 mmol) of triethylsilane and 8.76 ml (113 mmol) of TFA, and the mixture is stirred for 3 h and then concentrated by co-evaporation with toluene (3×30 ml) to give the solid product.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]([C:14]1[N:21]2[C:17]([S:18][CH:19]=[CH:20]2)=[CH:16][N:15]=1)[NH:7][C:8](=[O:13])C(F)(F)F)(=O)C.[OH-].[Na+].N[C@H](C1N2C(SC=C2)=CN=1)CO.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O.C(O)=O.C(Cl)Cl>[CH:8]([NH:7][C@H:6]([C:14]1[N:21]2[C:17]([S:18][CH:19]=[CH:20]2)=[CH:16][N:15]=1)[CH2:5][OH:4])=[O:13]
Reactant: CC(=O)OC[C@H](NC(=O)C(F)(F)F)c1ncc2sccn12
Agent: N[C@@H](CO)c1ncc2sccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=CN[C@@H](CO)c1ncc2sccn12
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.1 %

Procedure:
To a solution of 0.310 g of the above-obtained 5-[(R)-2- acetoxy-1-(trifluoroacetylamino)ethyl]imidazo[5,1-b]thiazole in 10 ml of methanol was added a solution of 0.160 g of sodium hydroxide in 5 ml of water, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated to dryness under reduced pressure to give a solid containing 5-[(R)-1-amino-2-hydroxyethyl]imidazo[5,1-b]-thiazole. To this was added 50 ml of methylene chloride, and the mixture was thoroughly stirred. To this suspension was added with ice-cooling a mixture of 2.0 g of acetic anhydride and 0.5 g of formic acid, which had been heated to 50° C. for 10 minutes and then cooled to room temperature. The mixture was stirred at room temperature for 30 minutes, and then cooled with ice. To this were added 4 ml of water and 4 g of potassium carbonate, and the mixture was stirred at room temperature for 30 minutes. To this mixture was added 4 ml of methanol, and the resulting mixture was stirred for an additional one hour. The organic layer was separated by decantation. The aqueous layer containing the crystals was washed with methylene chloride (30 ml×3). The combined organic layers were dried over anhydrous magnesium sulfate, and then concentrated to dryness to give 0.200 g (quant.) of 5-((R)-1-formylamino-2-hydroxyethyl)imidazo[5,1-b]thiazole. NMR (DMSO-d6) d: 3.88 (2H, t, J=5.8 Hz), 5.01 (1H, t, J=5.8 Hz), 5.27 (1H, dr, J=8.4 Hz, 5.8 Hz), 6.97 (1H, s), 7.22 (1H, d, J=4.2 Hz), 7.80 (1H, d, J=4.2 Hz), 8.08 (1H, s), 8.61 (1H, d, J=8.4 Hz) MS (EI, DMSO, 200° C.): 211 (M+)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][CH2:14][OH:15])[CH2:9]1.C(N(CC)CC)C.[Mn]([O-])(=O)(=O)=O.FC1C=CC=CN=1>CO>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][CH2:14][OH:15])[CH2:9]1
Reactant: OCC[C@@H]1CCNC1
Reactant: Fc1ccccn1
Agent: O=[Mn](=O)(=O)[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: OCC[C@@H]1CCN(c2ccccn2)C1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
(S)-2-(Pyrrolidin-3-yl)ethanol 2-fluoropyridine (6.95 mmol, 0.598 ml, 0.674 g) and triethylamine (17.36 mmol, 2.420 ml, 1.757 g) were dissolved in MeOH (2.5 ml) and heated to 150° C. for 1 hour in the microwave. TLC (permanganate stain) suggested SM remained. Further 2-fluoropyridine (6.95 mmol, 0.598 ml, 0.674 g) was added and heating continued for 1 hour. The reaction mixture was concentrated in vacuo. The resulting residue was purified by silica chromatography, eluting with DCM—3% MeOH/DCM to afford (S)-2-(1-(pyridin-2-yl)pyrrolidin-3-yl)ethanol. 1H NMR (CDCl3) δ: 8.14 (d, 1H), 7.44 (m, 1H), 6.51 (m, 1H), 6.33 (d, 1H), 3.71 (m, 3H), 3.55 (m, 1H), 3.38 (m, 1H), 3.05 (m, 1H), 2.42 (m, 1H), 2.17 (m, 1H), 1.78 (m, 2H), 1.66 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](OCC)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1CCN(Cc2ccccc2)CC1
Reaction time: 2.5 h
Yield: 90.6 %

Procedure:
A solution of 1-benzyl-4-carboethoxypiperidine (74.3 g, 0.300 mole) in anhydrous Et2O (740 mL) was stirred at 0° C. under N2. Lithium aluminum hydride (11.4 g, 0.300 mole) was added in small portions over 0.5 hours. After an additional 2.5 hours, the reaction was carefully quenched with H2O (740 mL). The mixture was filtered through a Celite pad and rinsed with ethyl acetate (EtOAc), then the layers were separated. The aqueous layer was saturated with NaCl, then extracted with EtOAc (3×100 mL). The combined organics were extracted with brine, dried (MgSO4), and concentrated in vacuo. The resulting crude product was vacuum distilled, bp ~144° C. at 0.1 mm Hg, to yield the alcohol (55.8 g,91%) as a colorless, viscous oil. Analysis: Calculated for C13H19NO: C,76.06; H,9.33; N,6.82; found: C,75.87; H,9.16; N,6.55.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[C:13]1([CH2:19][OH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]([O:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)OCc1ccccc1
Temperature: 5 °C
Reaction time: 5 h
Yield: 95.6 %

Procedure:
Triphosgene (29.8 g, 0.1 mol) and 50 mL of carbon tetrachloride were added into 250 mL of flask in sequence, the mixture was cooled to 5° C. below by ice bath, then the solution of phenylmethanol (10.8 g, 0.1 mol) and 20 mL of carbon tetrachloride were dropwise to the reaction solution followed by stirring for 5 hours at room temperature after removing ice bath. The reaction was monitored by thin-layer chromatography (TLC). Upon completion the mixture was added ethyl acetate, the organic phase was washed by water and then evaporated under reduced pressure to obtain 16.3 g of colorless of oil with yield of 95.6%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.I[CH:18]([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:10])=[O:11])[C:5]([O:8][CH:18]([CH3:20])[CH3:19])=[N:6][CH:7]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(Br)cnc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ncc(Br)cc1S(=O)(=O)NC(C)(C)C
Temperature: 100 °C
Yield: 38.7 %

Procedure:
To a solution of 5-bromo-N-(tert-butyl)-2-hydroxypyridine-3-sulfonamide (1.50 g, 4.85 mmol) in DMF (40 mL) was added 2-iodopropane (0.825 g, 4.85 mmol) followed by K2CO3 (1.34 g, 9.70 mmol) at RT. The reaction mixture was heated to 100° C. for 14 h. The reaction mixture was allowed to cool and the volatile components were removed under reduced pressure. The residue was diluted with cold water (150 mL) and extracted into ethyl acetate (2×100 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure and the residue was purified by CombiFlash (REDISEP®, silica gel, 24 g, 50% EtOAc/petroleum ether) to give 5-bromo-N-(tert-butyl)-2-isopropoxypyridine-3-sulfonamide (0.660 g, 37.7%) as a white solid. LCMS Condition B-22: retention time 1.92 min, [M+1]=351.0. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.13 (s, 9H), 1.35 (d, J=6.8 Hz, 6H), 5.06 (dt, J=13.6 Hz, J=6.8 Hz, 1H), 6.96 (s, 1H), 8.00 (d, J=2.6 Hz, 1H), 8.36 (d, J=2.6 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=3)=[CH:19][CH:18]=2)[C:12]([O:14]C)=[O:13])=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:30][CH:31]=3)=[CH:19][CH:18]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1)SCCc1ccc(O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc(OCCc2ccc(CC(SCCc3ccc(O)cc3)C(=O)O)cc2)cc1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
Methyl 2-{[2-(4-hydroxyphenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}-ethyl)phenyl]propanoate (105 mg, 0.2 mmol) was dissolved in 6.5 ml of a 7:1 mixture of THF and water and cooled on an ice-bath. Lithium hydroxide (9.4 mg, 0.4 mmol) was added. Water was added to the reaction mixture after 24 hours of stirring at room temperature. The THF was evaporated under reduced pressure and the residue was acidified with 1M hydrochloric acid. The water phase was extracted with EtOAc (×3), the organic phases were pooled, washed (water, brine), dried (MgSO4) and evaporated. The crude product was purified using preparative HPLC (eluent: CH3CN/5% CH3CN-waterphase containing 0.1M NH4OAc) to give 74 mg of the desired product (yield 97%) as an oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:27]=[CH:26][O:25][CH:24]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[O:25]1[CH:26]=[CH:27][C:23]([CH2:22][CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)=[CH:24]1
Reactant: c1ccc(CN2CCN(Cc3ccccc3)[C@@H](CCc3ccoc3)C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: c1cc(CC[C@H]2CNCCN2)co1
Reaction time: 3.5 h
Yield: 43.2 %

Procedure:
Dissolve (S)-1,4-dibenzyl-2-(2-furan-3-yl-ethyl)-piperazine (810 mg, 2.25 mmol) in ethanol (5 mL). Add ammonium formate (850 mg, 13.5 mmol) and palladium (100 mg, 5 wt. % on carbon) and heat to reflux. After 3.5 h, filter the palladium and concentrate the filtrate. Purify by silica gel chromatography using 7N ammonia in methanol-methylene chloride (5%) as the eluent to give 175 mg (43%) of the title compound: mass spectrum (ion spray): m/z=181 (M+1). Analysis calculated for C10H16N2O: C, 66.63; H, 8.95; N, 11.54. Found: C, 66.53; H, 8.92; N, 11.14.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:12]([O:15][CH2:16][CH3:17])(=O)C>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:12][O:15][C:16]1[CH:17]=[CH:5][C:4]([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:3][CH:2]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: CCOC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3nc(N)nn23)cc1
Yield: 83 %

Procedure:
A solution of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (1.5 g, 7.0 mmol, 1 equiv) and bis(triphenylphosphine)palladium(II) chloride (500 mg, 0.7 mmol 0.1 equiv) in acetonitrile (10 mL) and 1M aqueous sodium carbonate solution (10 mL) was heated at 120° C. for 3 min in the microwave. The reaction mixture was diluted with ethyl acetate, and the resulting solution was washed water (2×) and saturated aqueous sodium chloride solution. Purification by flash column chromatography (2→10% methanol in dichloromethane) provided product (1.4 g, 83%). 1H NMR (400 MHz, CDCl3), δ: 7.90 (d, 2H), 7.48 (m, 1H), 7.39 (m, 1H), 7.05 (d, 2H), 6.88 (dd, 1H), 4.25 (s, 2H); ES-MS m/z 241.0.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl>[F:34][C:19]([F:18])([F:35])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([C:28]([N:12]3[CH2:13][CH2:14][CH2:15][N:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][N:7]=4)[CH2:10][CH2:11]3)=[O:29])[CH:31]=[CH:32][CH:33]=2)[N:21]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: FC(F)(F)c1ccc(N2CCCNCC2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.5 %

Procedure:
1-(5-(Trifluoromethyl)pyridin-2-yl)-1,4-diazepane (60 mg, 0.23 mmol), 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (68 mg, 0.28 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCl) (89 mg, 0.46 mmol) were dissolved in dichloromethane (3 mL) at room temperature. Diisopropylethylamine (DIEA) (0.085 mL, 0.93 mmol) was then introduced at room temperature and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (60 mL) and washed with water (1×20 mL) and brine (1×20 mL). The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was then purified on Prep TLC (30% Ethyl Acetate:Hexanes) to give (3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)(4-(5-(trifluoromethyl)pyridin-2-yl)-1,4-diazepan-1-yl)methanone (14 mg, 14% yield). 1H NMR (300 MHz, CDCl3) δ 8.41 (s, 1H), 8.19-8.06 (m, 2H), 7.88 (s, 1H), 7.66-7.44 (m, 2H), 6.55 (bs, 1H), 3.98-3.64 (m, 8H), 1.74 (m, 2H). MS (ESI) m/z: Calculated for C21H17F6N5O2S: 485.13. found: 486.1 (M+H)+.