Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][CH:8]=O)[CH2:2]1.[CH3:10][NH2:11]>CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7]/[CH:8]=[N:11]/[CH3:10])[CH2:2]1
Reactant: CN
Reactant: O=CC[C@H]1CCCOC1
Solvent: CCOCC
Product: C/N=C/C[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a magnetically stirred solution of (R)-2-(tetrahydro-2H-pyran-3-yl)acetaldehyde (11 g, 85.8 mmol) in Et2O (215 mL) at room temperature was added MeNH2 (2M in THF, 215 mL, 429.2 mmol) and molecular sieves (4 Å, powdered, activated, 21.5 g). The reaction was stirred at room temperature for 1 h. The resulting mixture was then filtered and concentrated under reduced pressure to furnish (R,E)-N-(2-(tetrahydro-2H-pyran-3-yl)ethylidene)methanamine as a yellow oil (11.3 g, 80 mmol, 93%). The crude material was carried on without further purification. 1H NMR (400 MHz, CDCl3) δ 7.67 (m, 1H), 3.86-3.91 (m, 2H), 3.36-3.43 (m, 1H), 3.29 (s, 3H), 3.13 (dd, J=11.0, 9.8 Hz, 1H), 1.95-2.14 (m, 2H), 1.86-1.91 (m, 2H), 1.62-1.68 (m, 2H), 1.21-1.30 (m, 1H).
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1NC(C2C=CC3C(=CC=C(C4C=CC([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:65])[CH:48]([C:59]6[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=6)[NH:49][C:50](=[O:58])[CH2:51][CH:52]6[CH2:57][CH2:56][O:55][CH2:54][CH2:53]6)=[N:40][CH:41]=5)=CC=4)C=3)C=2)=CN=1)=O)C(C)C.[CH3:67][O:68][C:69](=[O:125])[NH:70][CH:71]([C:75]([N:77]1[CH2:81][CH2:80][CH2:79][CH:78]1[C:82]1[NH:86][C:85]2[C:87]3[C:92]([CH2:93][CH2:94][C:84]=2[N:83]=1)=[CH:91][C:90]([C:95]1[CH:104]=[CH:103][C:102]2[C:97](=[CH:98][CH:99]=[C:100](C4NC(C5CCCN5C(=O)C(N)C5C=CC=CC=5)=NC=4)[CH:101]=2)[CH:96]=1)=[CH:89][CH:88]=3)=[O:76])[CH:72]([CH3:74])[CH3:73]>>[CH3:67][O:68][C:69](=[O:125])[NH:70][CH:71]([C:75]([N:77]1[CH2:81][CH2:80][CH2:79][CH:78]1[C:82]1[NH:86][C:85]2[C:87]3[C:92]([CH2:93][CH2:94][C:84]=2[N:83]=1)=[CH:91][C:90]([C:95]1[CH:104]=[CH:103][C:102]2[C:97](=[CH:98][CH:99]=[C:100]([C:37]4[NH:38][C:39]([CH:42]5[CH2:46][CH2:45][CH2:44][N:43]5[C:47](=[O:65])[CH:48]([C:59]5[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=5)[NH:49][C:50](=[O:58])[CH2:51][CH:52]5[CH2:57][CH2:56][O:55][CH2:54][CH2:53]5)=[N:40][CH:41]=4)[CH:101]=2)[CH:96]=1)=[CH:89][CH:88]=3)=[O:76])[CH:72]([CH3:74])[CH3:73]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)CC6CCOCC6)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(N)c6ccccc6)[nH]5)ccc4c3)cc1CC2)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)CC6CCOCC6)c6ccccc6)[nH]5)ccc4c3)cc1CC2)C(C)C
Yield: 15 %

Procedure:
This compound was prepared using the same procedure used to make {2-Methyl-1-[2-(5-{6-[4-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester using (1-{2-[7-(6-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.020 g, 0.022 mmol) to give [2-Methyl-1-(2-{7-[6-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (0.003 g, 15% yield). LCMS-ESI+: calc'd for C54H60N8O6: 916.46 (M+); Found: 917.44 (M+H+).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.COCC(OC1C=C(C=C(OC2C=CC(C3OC(C)=NN=3)=CC=2)C=1)C(O)=O)C.[CH3:41][C:42]1[O:46][C:45]([C:47]2[CH:70]=[CH:69][C:50]([O:51][C:52]3[CH:53]=[C:54]([CH:58]=[C:59]([O:61][CH:62]4[CH2:66][CH2:65][N:64]([CH3:67])[C:63]4=[O:68])[CH:60]=3)[C:55]([OH:57])=O)=[CH:49][CH:48]=2)=[N:44][N:43]=1.[CH:71]1([C:74]2[S:78][C:77]([NH2:79])=[N:76][N:75]=2)[CH2:73][CH2:72]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:71]1([C:74]2[S:78][C:77]([NH:79][C:55](=[O:57])[C:54]3[CH:58]=[C:59]([O:61][CH:62]4[CH2:66][CH2:65][N:64]([CH3:67])[C:63]4=[O:68])[CH:60]=[C:52]([O:51][C:50]4[CH:69]=[CH:70][C:47]([C:45]5[O:46][C:42]([CH3:41])=[N:43][N:44]=5)=[CH:48][CH:49]=4)[CH:53]=3)=[N:76][N:75]=2)[CH2:73][CH2:72]1
Reactant: Nc1nnc(C2CC2)s1
Reactant: Cc1nnc(-c2ccc(Oc3cc(OC4CCN(C)C4=O)cc(C(=O)O)c3)cc2)o1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: COCC(C)Oc1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(C(=O)O)c1
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(Oc3cc(OC4CCN(C)C4=O)cc(C(=O)Nc4nnc(C5CC5)s4)c3)cc2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(Dimethylamino)pyridine (DMAP) (0.149 g), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI.HCl) (0.524 g) were added to a solution of 3-(1-methoxypropan-2-yloxy)-5-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)benzoic acid (0.5 g) (Intermediate 1) in dry DCM under nitrogen at 0-5° C. 5-cyclopropyl-1,3,4-thiadiazol-2-amine (0.134 g) was added and the mixture was stirred for 16 h at room temperature. It was diluted with commercially available DCM. Organic phase was washed with dil HCl, saturated solution of NaHCO3, Water, brine, dried over Na2SO4, filtered and concentrated in vacuo to get the crude residue. The residue was chromatographed using silica gel as stationary phase and MeOH: CHCl3 gradient as mobile phase up to yield the product (0.3 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([O:24][CH3:25])[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([O:24][CH3:25])[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1nc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)ccc1N
Yield: 96.6 %

Procedure:
A solution of (S)-2-(6-methoxy-5-nitro-pyridin-2-yloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.11 g, 0.32 mmol) in methanol (11 ml) was hydrogenated using the ThalesNano H-Cube® hydrogenation reactor employing a 10% palladium on charcoal catalyst cartridge. After concentration of the solution under reduced pressure 0.10 g (92.6%) of the title compound were obtained.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:18]1([CH2:28][NH2:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.O>C1(C)C(C)=CC=CC=1>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:29][C:28]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: NCc1cccc2ccccc12
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc(C)cc1
Reaction time: 9 h
Yield: 12 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate (13.7 g) and 1-naphthalenemethylamine (11.0 g) were dissolved in xylene (137 ml), andrefluxed underheating for 9 hr whiledehydrating with Dean-stark trap. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was concentrated under reduced pressure and isopropyl alcohol was added to the obtained residue to allow crystallization. The crystals were collected by filtration to give ethyl 5-(4-methylphenyl)-2-(1-naphthyl)-imidazole-4-carboxylate (2.5 g), melting point 190-192° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31](=[O:45])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[C:34]([NH2:44])[CH:33]=1>CN(C=O)C.O.C(Cl)CCl>[CH3:29][O:30][C:31](=[O:45])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]([CH2:40][CH3:41])[CH2:42][CH3:43])=[C:34]([NH:44][C:7](=[O:9])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:33]=1
Reactant: CCC(CC)Nc1ccc(C(=O)OC)cc1N
Reactant: O=C(O)Cc1cccs1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CCC(CC)Nc1ccc(C(=O)OC)cc1NC(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
To a solution of 1.56 g of thiophen-2-yl-acetic acid in 25 ml of dry DMF 1.49 g of HOBT, 2.11 g of EDC and 2.6 ml of DIPEA were added at 0° C. After 30 min 2.36 g of 3-amino-4-(1-ethyl-propylamino)-benzoic acid methyl ester and 2.6 ml of DIPEA were added and the reaction was stirred at rt for 16 h. The reaction was then poured into water and extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated. The crude product was purified by crystallization from diethylether to yield 2.78 g (77%) of 4-(1-ethyl-propylamino)-3-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12].Br[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[C:38]([F:41])([F:40])[F:39].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[C:38]([F:39])([F:41])[F:40])[CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12]
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1cc2ccccc2o1
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3C(F)(F)F)CC2O)CCCCC1)c1cc2ccccc2o1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To the suspension of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride (300 mg) obtained in Step 2 of Example 1 in 5 ml of toluene, were added 1-bromo-4-fluoro-2-trifluoromethylbenzene (0.198 ml), cesium carbonate (1.42 g), (S)-2,2-bis(diphenylphospino)-1,1-binaphtyl (BINAP; 45.4 mg) and tris(dibenzylideneacetone)dipalladium (1.42 g). The reaction mixture was stirred for about 4 hours at 100° C. under nitrogen atmosphere, was diluted with 30 ml of ethyl acetate, filtered, and concentrated. The resulting residue was purified with column chromatography to give 179 mg of the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:14]([NH2:16])[CH3:15].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:14]([NH:16][CH2:4][C:3]1[CH:6]=[C:7]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:8]=[CH:9][C:2]=1[OH:1])[CH3:15]
Reactant: CS(=O)(=O)c1ccc(O)c(C=O)c1
Reactant: CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNCc1cc(S(C)(=O)=O)ccc1O
Reaction time: 1 h

Procedure:
2-Hydroxy-5-methanesulfonyl-benzaldehyde (0.200 g, 1.0 mmol), ethylamine (2M in THF; 0.75 mL, 1.5 mmol), and sodium cyanoborohydride (0.095 g, 1.5 mmol) were combined in MeOH (10 mL). 4 Å Molecular sieves were added, followed by acetic acid (0.09 mL, 1.5 mmol), and the reaction was stirred for 1 hour. The mixture was filtered, and H2O (0.5 mL) was added and the solution was concentrated. The residue was partitioned between EtOAc (100 mL) and brine (20 mL), and the mixture was neutralized with 1N aqueous HCl (1 mL) and extracted six times with EtOAc, until minimal product was seen in the aqueous layer by analytical tlc. The combined organic layers were dried, filtered, and concentrated to give the title compound.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][C:24]=3[O:33][CH3:34])[CH2:15][CH2:14]2)=O)=[CH:6][CH:5]=1>[OH-].[Na+]>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH2:40]2)[CH2:11][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][C:24]=3[O:33][CH3:34])[CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: COc1ccc2ccccc2c1CCCCN1CCN(C(=O)C(c2ccc(F)cc2)C2CCNCC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2ccccc2c1CCCCN1CCN(CC(c2ccc(F)cc2)C2CCNCC2)CC1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 101.6 %

Procedure:
0.15 g of 4-(1-(4-Fluorophenyl)-2-{4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazin-1-yl}-2-oxoethyl)piperidine dihydrochloride was dissolved in 1M aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 5 ml of tetrahydrofuran, and 10 mg lithium aluminum hydride was added, followed by stirring at 50° C. for 15 minutes. The reaction solution was cooled to room temperature and diluted with ether, and 25% aqueous ammonia solution was added dropwise. The precipitate was removed by Celite filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=4:1) to give 0.13 g of 1-[2-(4-fluorophenyl)-2-piperidin-4-yl-ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine as an oil.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2].[CH3:18][CH:19]([NH2:23])[C:20]([OH:22])=[O:21].[OH-].[Na+].O>CC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:23][CH:19]([C:20]([OH:22])=[O:21])[CH3:18])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2]
Reactant: CC(N)C(=O)O
Reactant: N#Cc1nc(Cl)c(-c2ccccc2)nc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(Nc1nc(C#N)c(C#N)nc1-c1ccccc1)C(=O)O
Yield: 41.9 %

Procedure:
2,3-Dicyano-5-chloro-6-phenylpyrazine (4.82 g; 0.02 mole) was dissolved in 50 ml of acetone. The solution was cooled to 0° to 5° C., and with stirring, a solution prepared from 1.78 g (0.02 mole) of DL-α-alanine, 1.64 g (0.02 mole) of sodium hydroxide and 40 ml of water was added dropwise over the period of 30 minutes. The mixture was worked up in the same way as in Example 23, and recrystallized from benzene to afford 2.46 g (yield 42%) of 2,3-dicyano-5-(1-carboxyethyl)amino-6-phenylpyrazine.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.[OH-].[Na+]>Br.C(Cl)Cl.O>[C:24]1([C:21]2[CH:22]=[CH:23][C:18]3[N:19]([C:15]([CH2:14][NH:13][C:7]4[CH:8]=[CH:9][N:10]=[C:11]5[C:6]=4[N:5]=[CH:4][C:3]([OH:2])=[CH:12]5)=[N:16][N:17]=3)[N:20]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1cnc2c(NCc3nnc4ccc(-c5ccccc5)nn34)ccnc2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Oc1cnc2c(NCc3nnc4ccc(-c5ccccc5)nn34)ccnc2c1
Temperature: 100 °C
Yield: 79.6 %

Procedure:
In a 25 mL sealed tube was dissolved 7-methoxy-N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine (prepared according to General Method D) (300 mg, 782 μmol) in 5 mL of concentrated HBr then stirred and heated at 100° C. for 48 h. The reaction mixture was diluted with DCM and H2O then neutralized with NaOH (1N) to neutral pH. The aqueous phase was extracted 3× with DCM then the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by MPLC (ISCO) with DCM:MeOH:NH4OH (90:10:1) and then triturated with hot EtOH to afforded 8-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol (230 mg, 79.6% yield) as a tan solid. MS m/z=369.1 [M+1]+. Calc'd for C20H15N7O: 370.0.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]2)[CH:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][NH:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.Br[CH2:44][C:45]1[CH:46]=[C:47]([CH:52]=[CH:53][CH:54]=1)[C:48]([O:50][CH3:51])=[O:49]>CN(C)C=O.C(OCC)(=O)C>[CH3:51][O:50][C:48]([C:47]1[CH:46]=[C:45]([CH:54]=[CH:53][CH:52]=1)[CH2:44][N:3]1[CH2:4][CH:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1])=[O:49]
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCC2c1ccccc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN2CC(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Yield: 86.3 %

Procedure:
A mixture of benzyl 1-oxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-carboxylate (1 g, 3.03 mmol, 1 equiv), lithium bis(trimethylsilyl)amide, 1M in tetrahydrofuran (3.33 ml, 3.33 mmol, 1.1 equiv), and methyl 3-(bromomethyl)benzoate (694.08 g, 3.03 mmol, 1 equiv) in N,N-dimethylformamide was stirred for 16 h at ambient temperature. Reaction was diluted with ethyl acetate and the organic layer was washed with water and brine. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.6, gradient—10%-50% ethyl acetate in hexanes) to afford the title compound as a cream solid (1.34 g, 92%); 1H NMR (400 MHz, DMSO-d6): δ 0.87-0.92 (m, 1H); 1.33 (s, 9H); 1.46-1.51 (m, 2H); 1.54-1.65 (m, 1H); 3.03-3.07 (m, 1H); 3.34-3.40 (m, 3H); 3.46-3.48 (m, 1H); 3.57-3.61 (m, 1H); 3.69-3.71 (m, 1H); 3.86 (s, 3H); 4.56 (s, 2H); 7.14-7.16 (m, 2H); 7.20-7.28 (m, 3H); 7.52-7.59 (m, 2H); 7.89-7.91 (m, 2H); MS for C31H32N2O5 m/z 513.23 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[O:11]C(=O)[NH:9][CH:8]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[NH2:9][CH:8]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=1)[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[OH:11]
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccccc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1
Yield: 86.9 %

Procedure:
To a solution of (4RS,5SR)-5-phenyl-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (6.0 g, 18.7 mmol) in ethanol (100 ml) was added 8N aqueous sodium hydroxide solution (11.7 ml, 93 mmol) and the mixture was heated under reflux for 4 hrs. The reaction solution was concentrated, diluted with water (300 ml) and extracted with ethyl acetate (300 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (1RS,2SR)-2-amino-1-phenyl-3-(4-(trifluoromethyl)phenyl)-1-propanol (4.8 g, 87%).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][C:10]([C:13]([O:15]C)=[O:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+]>C(O)C>[N+:1]([C:4]1[C:12]2[O:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc2cccc([N+](=O)[O-])c2o1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cccc([N+](=O)[O-])c2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To a suspension of methyl 7-nitrobenzofuran-2-carboxylate (4.12 g, 18.6 mmol) in ethanol (100 mL) was added potassium hydroxide (2.08 g, 37.1 mmol). The mixture was heated at reflux for 1 hour, cooled to room temperature and evaporated. The residue was diluted with water, acidified by concentrated hydrochloric acid (12 N). The suspension was stirred for another 30 minutes, and then filtrated. The precipitate was collected, washed with water and dried to afford the product 7-nitrobenzofuran-2-carboxylic acid (3.54 g, yield 92%). 1H NMR (400 MHz, CDCl3) δ ppm 8.28-8.30 (dd, 1H, J=0.8 Hz, 8.0 Hz), 8.06-8.08 (dd, 1H, J=0.8 Hz, 7.6 Hz), 7.641-7.642 (d, 1H, J=0.4 Hz), 7.47-7.51 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH3:12].[CH3:14][O:15][C:16](=[O:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])O.[Na+]>CC(=O)CC>[CH3:14][O:15][C:16]([C:17]1[C:3]([CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=2[CH3:12])=[CH:2][N:19]2[C:18]=1[CH:23]=[CH:22][CH:21]=[CH:20]2)=[O:24]
Reactant: Cc1c(F)cccc1CC(=O)CBr
Reactant: COC(=O)Cc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Product: COC(=O)c1c(Cc2cccc(F)c2C)cn2ccccc12
Yield: 61.3 %

Procedure:
The compound of step 1 (3.89 g, 15.88 mmol), pyridin-2-ylacetic acid methyl ester (1.65 g, 10.92 mmol) and sodium hydrogencarbonate (4.59 g, 54.60 mmol) in butan-2-one (43 ml) were heated under reflux for 24 h. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel chromatography (HEP/EA) to give 1.99 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([CH2:20][C:21](Cl)=[O:22])[CH:17]=[CH:18][CH:19]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:21](=[O:22])[CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:24])([F:12])[F:25])[CH:15]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]ccc1C
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2cccc(C(F)(F)F)c2)c1C

Procedure:
3-Methyl-4-[2-(3-trifluoromethylphenyl)acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (103) was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (3-trifluoromethylphenyl)-acetyl chloride following the procedure described in Example 32. Crude yield: 97%. 1H-NMR (400 MHz, CDCl3): δ 1.38 (t, 3H), 2.62 (s, 3H), 4.11 (s, 2H), 4.35 (q, 2H), 7.45 (m, 2H), 7.51 (m, 3H), 9.40 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ 11.73, 14.40, 46.73, 60.78, 123.70, 124.70, 126.82, 128.93, 129.71, 133.01, 135.85, 161.61, 192.58 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.73, 14.40; CH2 carbons: 46.73, 60.78; CH carbons: 123.70, 126.82, 128.93, 129.71, 133.01 ppm. LC/MS: 79.18%, m/z=339.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][CH3:27].O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH3:27])[CH2:14][CH2:13]2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1
Reactant: CS(=O)(=O)c1cc(F)cc(C2CCNCC2)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCN1CCC(c2cc(F)cc(S(C)(=O)=O)c2)CC1
Temperature: 150 °C
Yield: 46.5 %

Procedure:
To a solution of 4-[3-fluoro-5-(methylsulfonyl)phenyl]piperidine (0.5 g, 1.94 mmol) in acetonitrile (5 ml) was added potassium carbonate (0.53 g, 3.83 mmol) and 1-iodopropane (0.189 ml, 1.94 mmol) and the mixture was heated with microwave irradiation for 20 min at 150° C. The mixture was cooled to ambient temperature and water (50 ml) was added. The aqueous residue was extracted with ethylacetate (3×50 ml) and the combined organic phases was dried, concentrated, and purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (0.27 g, 46%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 187-189° C. MS m/z (relative intensity, 70 eV) 299 (M+, 3), 271 (15), 270 (bp), 147 (5) 133 (5).