Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9][C@H:8]([O:20][CH2:21][C@H:22]2[O:29][C@H:26]([O:27][CH3:28])[C@H:25]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:24]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:23]2[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:7]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@H:6]1[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)(=O)C.CO>C1(C)C=CC=CC=1.C[O-].[Na+]>[CH2:31]([O:30][C@@H:25]1[C@@H:24]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:23]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:22]([CH2:21][O:20][C@H:8]2[O:9][C@H:10]([CH2:11][O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@H:5]([OH:4])[C@H:6]([O:62][CH2:63][C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C@H:7]2[O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[O:29][C@@H:26]1[O:27][CH3:28])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CO[C@H]1O[C@H](CO[C@H]2O[C@H](COCc3ccccc3)[C@H](OC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CO[C@H]1O[C@H](CO[C@H]2O[C@H](COCc3ccccc3)[C@H](O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 6-O-(4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (2.314 g, 2.46 mmol) is dissolved in hot toluene (20 ml) and methanol (80 ml) is added, followed by a few drops of 1 M methanolic sodium methoxide. The mixture is stirred at room temperature during 2 h. The reaction mixture is made neutral with Amberlite IR 120 (H+) resin, filtered and concentrated under reduced pressure so as to afford methyl 2,3,4-tri-O-benzyl-6-O-(2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-α-D -glucopyranoside as an amorphous solid.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][O:10][C:11]1[C:16]2[C:17](=[O:27])[N:18]3[CH2:25][C@H:24]([OH:26])[CH2:23][C@H:19]3[C:20](=[O:22])[NH:21][C:15]=2[CH:14]=[CH:13][C:12]=1[O:28][CH3:29].N1C=CN=C1.O>CN(C=O)C>[CH3:9][O:10][C:11]1[C:16]2[C:17](=[O:27])[N:18]3[CH2:25][C@H:24]([O:26][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:23][C@H:19]3[C:20](=[O:22])[NH:21][C:15]=2[CH:14]=[CH:13][C:12]=1[O:28][CH3:29]
Reactant: COc1ccc2c(c1OC)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1OC)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Solid TBDMS Chloride (8.22 g, 54.44 mmol) was added in one portion to a solution of 4 (7.23 g, 24.74 mmol) and imidazole (8.42 g, 123.72 mmol) in anhydrous DMF (75 mL) and allowed to stir at room temperature for 16 hours. The reaction mixture was poured into water (500 mL) and filtered to afford the crude product (5), which was purified by recrystallisation from EtOH (800 mL) as fine white needles (6.995 g, 17.21 mmol, 70%). 1H NMR (270 MHz, CDCl3) δ 10.06 (s, 1H, NH), 7.37 (s, 1H, ArH), 6.68 (s, 1H, ArH), 4.19-4.14 (m, 1H, 2), 4.06-4.01 (m, 1H, 11a), 3.90 (s, 3H, OMe), 3.88 (s, 3H, OMe), 3.69-3.63 (m, 2H, 3), 2.85-2.80 (m, 1H, 1), 2.05-2.01 (m, 1H, 1); 13C NMR (67.8 MHz, CDCl3) δ 170.4, 170.2, 165.9, 152.1, 145.8, 145.6, 131.1, 130.7, 118.1, 111.9, 104.3, 104.1, 69.2, 69.1, 56.0, 55.9, 55.7, 54.3, 54.0, 35.0, 25.8, 25.7, 25.6, 17.9, −3.0, −3.5, −4.9, −5.0.
Reaction SMILES: [Br:1][C:2]1[C:15]([F:16])=[CH:14][C:13]2[CH:12]3[CH2:17][CH:10]([CH2:11]3)[N:9]3[C:5](=[N:6][C:7]([C:20]([O:22]C)=[O:21])=[C:8]3[CH:18]=[O:19])[C:4]=2[CH:3]=1.[Li+].[OH-]>O.CO>[Br:1][C:2]1[C:15]([F:16])=[CH:14][C:13]2[CH:12]3[CH2:11][CH:10]([CH2:17]3)[N:9]3[C:5](=[N:6][C:7]([C:20]([OH:22])=[O:21])=[C:8]3[CH:18]=[O:19])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=Cc1c(C(=O)O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 74.8 %

Procedure:
Methyl 9-bromo-10-fluoro-3-formyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxylate (125 mg) was saponified with LiOH in H2O/MeOH to give 90 mg of 9-bromo-10-fluoro-3-formyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:13]([F:14])([F:15])[F:16]
Reactant: CC(C)C(O)c1ccc(F)c(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)=Cc1ccc(F)c(C(F)(F)F)c1

Procedure:
4.3 g (18.2 mmol) 1-(4-fluoro-3-trifluoromethyl-phenyl)-2-methyl-propan-1-ol and 1.0 g (5.3 mmol) p-toluenesulphonic acid monohydrate in 100 mL toluene are refluxed for 3 hours using the water separator. Then the reaction mixture is combined with water and made alkaline with 1 N sodium hydroxide solution. After separation of the organic phase this is washed with water, dried with sodium sulphate and evaporated down. The oil remaining is further reacted directly.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C:13](=C)[CH2:12][C@H:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[OH:23]>>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C:13](=[O:23])[CH2:12][C@H:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](c2ccccc2)C1
Reactant: CO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=O)C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into a solution of (+−)-trans-1-t-butyldimethylsilyloxymethyl-4-methylene-2-phenylcyclopentane from Step C (2.2 g, 7.3 mmol) in methanol (100 mL) cooled in a dry ice/acetone bath was bubbled ozone until the blue color persisted. The excess ozone was removed with a stream of nitrogen and then dimethylsulfide (5 mL) was added. After 10 min, the bath was removed and the reaction was allowed to warm to RT over 2 h. The volatiles were removed in vacuo and the residue was purified by FC (15-30% ethyl acetate in hexanes) to give the title compound (1.9 g).
Reaction SMILES: C(=O)(O[CH2:6][CH3:7])OCC.C[O-].[Na+].[CH:12]([O:14][CH:15]1[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18][CH2:17][CH2:16]1)=[O:13]>O>[CH:12]([O:14][C:15]1([CH:7]2[CH2:6][CH2:18][CH2:17][CH2:16][CH2:15][CH2:22][CH2:21]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13]
Reactant: CCOC(=O)OCC
Reactant: O=COC1CCC=CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: O=COC1(C2CCCCCCC2)CCCCCCC1
Temperature: 85 °C

Procedure:
Into a 2 liter reaction flask equipped with heating mantle, stirrer, Bidwell water trap, reflux condenser, thermometer and nitrogen blanket apparatus is placed 1,000 ml (8.4 moles) of diethyl carbonate, and 25 grams (0.45 moles) of sodium methoxide. The resulting mixture is heated to 85° C. While maintaining the reaction mass at 85°-86° C. over a period of 1 hour, 695 grams (4.5 moles) of a composition containing a major proportion of 4-cyclooctenyl formate having the structure: ##STR78## and a minor proportion of bicyclooctanyl formate having the structure: ##STR79## produced according to Example I, is added while removing ethyl formate reaction product from the reaction mass using the Bidwell trap. At the end of the 1 hour period, the reaction mass is stirred at a temperature of 85°-86° C. for an additional 1 hour.
Reaction SMILES: [NH2:1][C:2](=[O:72])[C@H:3]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[NH:4][C:5](=[O:64])[C@H:6]([CH2:51][NH:52][C:53](=[O:63])[CH2:54][NH:55][C:56]1[S:57][C:58]([CH:61]=[O:62])=[CH:59][N:60]=1)[NH:7][C:8](=[O:50])[CH2:9][NH:10][C:11](=[O:49])[C@H:12]([CH3:48])[NH:13][C:14](=[O:47])[C@H:15]([CH3:46])[NH:16][C:17](=[O:45])[C@@H:18]([NH:27][C:28](=[O:44])[O:29][CH2:30][CH:31]1[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.[BH4-].[Na+]>CCO.O>[NH2:1][C:2](=[O:72])[C@H:3]([CH2:65][C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1)[NH:4][C:5](=[O:64])[C@H:6]([CH2:51][NH:52][C:53](=[O:63])[CH2:54][NH:55][C:56]1[S:57][C:58]([CH2:61][OH:62])=[CH:59][N:60]=1)[NH:7][C:8](=[O:50])[CH2:9][NH:10][C:11](=[O:49])[C@H:12]([CH3:48])[NH:13][C:14](=[O:47])[C@H:15]([CH3:46])[NH:16][C:17](=[O:45])[C@@H:18]([NH:27][C:28](=[O:44])[O:29][CH2:30][CH:31]1[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(=O)N[C@@H](CNC(=O)CNc1ncc(C=O)s1)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(=O)N[C@@H](CNC(=O)CNc1ncc(CO)s1)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Following the procedure as described in Example 32, except using material from Example 87 (16 mg, 0.014 mmol), EtOH/H2O (4:1) (5 mL), sodium borohydride (6.3 mg, 0.167 mmol) and stirring at room temp for 2.5 h, the title compound is isolated (quantitative yield) that is used crude in the next step. LC/MS (Condition A): ret. T=3.37 min, (2M+Na) 1005.75.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][NH:6][C:7](=[O:34])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:15][CH3:16])=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[F:31][C:30]([F:32])([F:33])[C:27]1[CH:26]=[CH:25][C:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[O:34])=[CH:13][CH:12]=3)[CH2:15][CH3:16])=[CH:19][CH:20]=2)=[CH:29][CH:28]=1
Reactant: CCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Reaction time: 5 h
Yield: 95.4 %

Procedure:
To a mixture of 3-{4-[1-(4′-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propionic acid methyl ester (60 mg, 0.12 mmol) in methanol (2 mL) is added sodium hydroxide (5 N aqueous, 0.5 mL) and stirred for 5 hours. The reaction mixture is concentrated and acidified by 5 N HCl (0.5 mL), extracted with ethyl acetate. Combined organic layers are washed with water and brine, dried over sodium sulfate. Concentration gives the title compound (54 mg). MS (ES): 472.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].[H][H].C(OCC)(=O)C>[Pd].CO>[NH2:13][C:12]1[C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(c1ncccc1[N+](=O)[O-])S(C)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(c1ncccc1N)S(C)(=O)=O

Procedure:
N-(3-Amino-pyridin-2-yl)-N-methyl-methanesulfonamide was prepared from N-methyl-N-(3-nitro-pyridin-2-yl)-methanesulfonamide (6.20 g, 26.8 mmol)(prepared as described in J. Med. Chem., 2007, 50, 3431) via hydrogenation using a Paar apparatus with 10% Palladium on Carbon (50% Wet)(5:45:50, Palladium:carbon black:Water, 5.71 g, 2.68 mmol) and Hydrogen (50 psi) in 2:1 ethyl acetate:methanol (150 mL). The mixture was shaken on a Paar apparatus until adsorption of hydrogen ceased. The mixture was degassed, backflushed with nitrogen, filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated under reduced pressure. Product isolated as brown solid (5.15 g, 95%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.85 (dd, J=3.7, 2.5 Hz, 1H), 7.10-7.08 (m, 2H), 4.24 (br s, 2H), 3.23 (s, 3H), 3.08 (s, 3H). MS=202 (MH)+. 111b) N-[3-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide was prepared from N-(3-amino-pyridin-2-yl)-N-methyl-methanesulfonamide (238.0 mg, 1.183 mmol) and 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (250.0 mg, 1.075 mmol) in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.185 g, 48%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.18-8.15 (m, 1H), 8.11 (d, J=6.8 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.32-7.25 (m, 1H), 7.17 (d, J=7.5 Hz, 1H), 6.93 (t, J=7.3 Hz, 1H), 3.31 (s, 3H), 3.07 (s, 3H). MS=353, 355 (MH)+. 111c) N-Methyl-N-(3-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-pyridin-2-yl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide (75.0 mg, 0.212 mmol) and 3-(4-methylpiperazin-1-yl)aniline (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.017 g, 16%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11-8.06 (m, 2H), 7.78 (d, J=7.5 Hz, 1H), 7.52 (s, 1H), 7.28-7.19 (m, 3H), 7.12 (d, J=7.5 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.84 (s, 1H), 6.78-6.73 (m, 1H), 6.57 (d, J=8.0 Hz, 1H), 3.32 (s, 3H), 3.29-3.24 (m, 4H), 3.09 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=518 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.FC(S(O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29](S(C(F)(F)F)(=O)=O)[CH:30]=[CH:31][N:32]=2)=[C:24]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=2[Cl:47])[N:23]=1)(=O)=O)(F)F>CN(C)C(=O)C>[Cl:47][C:41]1[CH:42]=[C:43]([Cl:46])[CH:44]=[CH:45][C:40]=1[C:24]1[N:23]=[C:22]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=2)[CH:27]=[CH:26][C:25]=1[C:28]1[NH:32][CH:31]=[CH:30][N:29]=1
Reactant: O=S(=O)(Oc1ccc(-c2nccn2S(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)cc2Cl)n1)C(F)(F)F
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Temperature: 40 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
A suspension of (2-aminoethyl)(5-nitro(2-pyridyl))amine (255 mg, 1.40 mmol) in N,N-dimethylacetamide (3 ml) containing dry powdered 4 Å molecular sieves (50 mg) was added to a suspension of 6-(2,4-dichlorophenyl)-5-{1-[(trifluoromethyl)sulfonyl]imidazol-2-yl}-2-pyridyl (trifluoromethyl)sulfonate (200 mg, 0.35 mmol) in N,N-dimethylacetamide (3 ml) containing dry powdered 4 Å molecular sieves (50 mg). After stirring at 40° C. for 24 h, ethylenediamine (0.5 ml) and water (0.5 ml) were added to the reaction to hydrolyze the one remaining triflate from the product. The reaction was stirred at 85° C. for 2 h and left at room temperature for 12 h. The reaction was then diluted with ethyl acetate (100 ml), filtered, extracted with sat. aq. NaHCO3 (6×30 ml), brine (30 ml), dried with Na2SO4, filtered, and concentrated under reduced pressure. The product [6-(2,4-dichlorophenyl)-5-imidazol-2-yl(2-pyridyl)]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine (79859) was obtained as a yellow glass weighing 143 mg in 85% yield.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]([CH3:13])([CH3:12])[CH2:10]O>>[CH3:10][C:9]1([CH3:13])[NH:8][C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:7][CH2:12]1
Reactant: O=C1CCCCC1
Reactant: CC(C)(N)CO
Product: CC1(C)COC2(CCCCC2)N1

Procedure:
Reaction of cyclohexanone with 2-amino-2-methyl-1-propanol to form 3,3-dimethyl-1-oxa-4-azaspiro[4.5]decane.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[F:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:16])[C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc(=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
A solution of Compound 35 (3 g, 16.57 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 0.729 g, 18.23 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat methyl iodide (1.14 mL, 18.23 mmol) was added and the solution further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 1.84 g (57%) of white solids. M.P. 133° C. 1H NMR (DMSO-d6): δ 3.90 (s, 3H), 7.51 (dd, J=4.0, 8.8 Hz, 1H), 7.77 (m, 12). Anal. (C9H6FNO3) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][CH:10]=2)[CH:7]=1.C(=O)(O)[O-].[Na+].[I:16]I>CCO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][C:10]=2[I:16])[CH:7]=1
Reactant: II
Reactant: Clc1ccc2cncn2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1ccc2c(I)ncn2c1
Temperature: 25 °C
Yield: 35.6 %

Procedure:
To a solution of 6-chloroimidazo[1,5-a]pyridine (417 mg, 2.73 mmol) in EtOH (5 mL) and water (2.4 mL) was added sodium bicarbonate (861 mg, 10.2 mmol) and iodine (832 mg, 3.28 mmol) and the mixture stirred at room temperature under N2. After 16 h the reaction mixture was quenched with sodium thiosulfate, then extracted into ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated. Purification of the filtrate by chromatography (silica, 20-60% ethyl acetate/hexanes) gave 6-chloro-1-iodoimidazo[1,5-a]pyridine (271 mg, 973 μmol, 36%) as a brown solid. MS (M+H)+=278.8; 1H NMR (CDCl3) δ: 8.10 (s, 1H), 8.0 (m, 1H), 7.30 (d, J=9.5 Hz, 1H), 6.76 (9.5 m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[CH2:9]1)=O)(C)(C)C.[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19]>ClCCl>[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19].[NH:8]1[CH2:11][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC1CNC1
Temperature: 25 °C

Procedure:
2-(1-(tert-Butoxycarbonyl)azetidin-3-yl)acetic acid (0.308 g, 1.43 mmol) was dissolved in 5 mL dichloromethane and was stirred at room temperature. Trifluoroacetic acid (1.47 mL) was added dropwise to the reaction mixture at 0° C. The reaction mixture was allowed to stir at room temperature for 2 h. Trifluoroacetic acid was removed in vacuo to give 2-(azetidin-3-yl)acetic acid trifluoroacetic acid salt. 1H-NMR (400 MHz, CDCl3) δ ppm 4.18-4.13 (m, 2H), 3.93-3.88 (m, 2H), 3.25-3.19 (m, 1H), 2.71 (d, 2H, J=7.6 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@@H:9]1[C:15](=[O:27])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][O:25][C:23](=[O:24])[C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:15]([C@H:9]2[CH2:10][C@@H:11]([O:13][CH3:14])[CH2:12][NH:8]2)=[O:27])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@H]2C[C@@H](OC)CN2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@H]2C[C@@H](OC)CN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Into a solution of 7 (12.5 g, 33.0 mmol) in anhydrous CH2Cl2 (70 mL) was added TFA (20 mL). The solution was stirred at RT overnight before concentrating under reduced pressure to give 8 (9.19 g, 100%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(N(CC)CC)C.[C:25]([N:29]=[C:30]=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:30]([NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(C)N=C=O
Reactant: Brc1cnc2ccc(NC[C@@H]3CCCN3)nn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)N1CCC[C@H]1CNc1ccc2ncc(Br)n2n1
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of (S)-3-bromo-N-(pyrrolidin-2-ylmethyl)imidazo[1,2-b]pyridazin-6-amine (400 mg, 1.2 mmol) and triethylamine (0.5 mL, 3.5 mmol) in DCM (10 mL) was added t-butyl isocyanate (0.2 mL, 1.75 mmol) dropwise. After stirring at it for 2 h, the reaction mixture was concentrated and purified by ISCO column chromatography (10% MeOH/DCM) to give (S)-2-(((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)methyl)-N-(tert-butyl)pyrrolidine-1-carboxamide (360 mg, 76% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.58 (d, J=9.60 Hz, 1H), 7.42 (s, 1H), 6.72 (d, J=9.85 Hz, 1H), 5.07 (s, 1H), 4.26 (dd, J=6.57, 1.77 Hz, 1H), 3.35-3.48 (m, 4H), 2.09-2.20 (m, 1H), 1.90-2.05 (m, 3H), 1.26 (s, 9H); LRMS (ESI) m/e 395.2 [(M+H)+, calcd for C16H24BrN6O 396.3].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.CON(C)[C:17]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:26][CH:25]=[CH:24][C:23]=2[C:35]([F:38])([F:37])[F:36])=[O:18].Cl>C1COCC1.CO>[CH3:8][C:4]1[CH:3]=[C:2]([C:17]([C:19]2[CH:20]=[N:21][C:22]3[C:27]([C:28]=2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][CH:25]=[CH:24][C:23]=3[C:35]([F:38])([F:37])[F:36])=[O:18])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)c2cnc3c(C(F)(F)F)cccc3c2-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
3-Bromotoluene (0.078 mL, 0.64 mmol) was taken into THF (3 mL) and cooled to −78° C. Next, BuLi (0.32 mL of a 2.0 M Solution, 0.64 mmol) was added dropwise and then stirred for 30 minutes. Next, N-methoxy-N-methyl-4-phenyl-8-(trifluoromethyl)quinoline-3-carboxamide (0.231 g, 0.64 mmol) in THF (2 mL) was added quickly via syringe and allowed to stir overnight. MeOH and 2 N HCl were added and stirred for 5 minutes. Then the mixture was extracted with ethyl acetate and dried over magnesium sulfate and concentrated. The resulting material was purified via column chromatography using 10% ethyl acetate in hexane as the eluent to afford 0.060 g of desired product as an off white solid. MS (ESI) m/z 392 ([M+H]+); Anal. Calcd. for C24H16F3NO: C, 73.65; H, 4.12; N, 3.58. Found: C, 73.34; H, 4.08; N, 3.31.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].ClC(Cl)(Cl)C[O:19][C:20](=[O:41])[CH:21]([S:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=1>>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][S:31][CH:21]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][O:13][C:12](=[O:14])[CH:11]([C:8]3[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=3)[CH3:15])=[CH:27][CH:28]=2)[C:20]([OH:41])=[O:19])=[CH:35][CH:36]=1
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CO)cc1)SCCc1ccc(F)cc1
Product: CC(C)Cc1ccc(C(C)C(=O)OCc2ccc(CC(SCCc3ccc(F)cc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared starting from 2-(4-isobutyl-phenyl)-propionic acid and 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-(4-hydroxymethyl-phenyl)-propionic acid 2,2,2-trichloro-ethyl ester in the same manner as described for example 7 (yield: 5.6 mg, 17%). 1H-NMR (300 MHz, CDCl3): δ 0.90 (d, 6H), 1.50 (d, 3H), 1.77-1.92 (m, 1H), 2.45 (d, 2H), 2.75-2.96 (m, 5H), 3.12-3.23 (m, 1H), 3.41-3.50 (m, 1H), 3.74 (q, 1H), 5.00-5.13 (m, 2H), 6.91-6.99 (m, 2H), 7.04-7.23 (m, 10H); Mass Spectrum: M−H+ 521.