Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:20]([F:23])([F:22])[F:21])=[C:15]([CH:19]=1)[C:16]([OH:18])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:46]=[C:47]([N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[CH2:48][NH:49][C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:53]=1)=[O:51]>CN(C=O)C.O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:20]([F:23])([F:22])[F:21])=[C:15]([CH:19]=1)[C:16]([N:67]1[CH2:66][CH2:65][N:64]([C:47](=[O:46])[CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)=[O:51])[CH2:69][CH2:68]1)=[O:18]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(F)ccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 5-fluoro-2-trifluoromethyl-benzoic acid (53.6 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 58 mg (43.8% yield) of biphenyl-4-carboxylicacid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 98.5%, 1H NMR: (DMSO) δ 8.7 (s, 1H), 8.0-7.9 (d, 3H), 7.84-7.7 (q, 4H), 7.6-7.4 (m, 5H), 4.2 (d, 2H), 3.8-3.4 (m, 6H), 3.24-3.06 (m, 2H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][CH2:19][NH:20][C:21]([P:23]([O:29]C(C)C)([O:25]C(C)C)=[O:24])=[O:22])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](Br)(C)C.CC#N>C(Cl)(Cl)Cl>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][CH2:19][NH:20][C:21]([P:23]([OH:29])([OH:25])=[O:24])=[O:22])(=[O:15])=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OP(=O)(OC(C)C)C(=O)NCCNS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C(NCCNS(=O)(=O)c1ccc(Oc2ccccc2)cc1)P(=O)(O)O
Temperature: 50 °C
Yield: 77.9 %

Procedure:
To the 1-[4-phenoxybenzenesulfonamido]-2-[diisopropylphophonoform amido]ethane (0.45 g, 0.93 mmol) in 10 ml CHCl3 was added TMSBr (5 eq, 0.62 ml, 4.6 mmol) and reaction was stirred and heated at 50° C. for 2.5 hours. The reaction mixture was monitored by 31P NMR. The solvent was evaporated and to the mixture reaction was added 5 ml MeOH for one hour. The solvent was evaporated to give a yellow oil. The product was solidified from MeCN to give 0.29 g (78%) a white solid, m.p.=166-169° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([O:15][CH3:16])([CH2:12][O:13][CH3:14])[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.Br[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1>>[CH3:16][O:15][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[CH:3]=1)([CH2:12][O:13][CH3:14])[CH2:9][CH2:10][OH:11]
Reactant: COCC(CCO)(OC)c1cccc(O)c1
Reactant: BrCc1ccc2ccccc2c1
Product: COCC(CCO)(OC)c1cccc(OCc2ccc3ccccc3c2)c1
Yield: 87 %

Procedure:
Using the procedure described in Example 12, 3-(3-hydroxyphenyl)-3,4-dimethoxybutan-1-ol was reacted with 2-bromomethylnaphthalene to give 3,4-dimethoxy-3-[3-(naphth-2-ylmethoxy)phenyl]butan-1-ol in 87% yield, m.p. 64°-65° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][NH:7][C:8](=[O:22])[NH:9][C:10]1[CH:15]=[C:14](Cl)[CH:13]=[C:12]([S:17]([OH:20])(=[O:19])=[O:18])[C:11]=1[OH:21])[C:3]([OH:5])=[O:4].[H][H]>O.CO.[Pd]>[NH2:1][C@@H:2]([CH2:6][NH:7][C:8](=[O:22])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:17]([OH:20])(=[O:18])=[O:19])[C:11]=1[OH:21])[C:3]([OH:5])=[O:4]
Reactant: [H][H]
Reactant: N[C@@H](CNC(=O)Nc1cc(Cl)cc(S(=O)(=O)O)c1O)C(=O)O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: N[C@@H](CNC(=O)Nc1cccc(S(=O)(=O)O)c1O)C(=O)O

Procedure:
The compound obtained in Example 6 was dissolved in water and methanol, to which a catalyst amount of Pd/C was added, and the resultant was stirred for three days in a hydrogen atmosphere. After filtrating the catalyst, the solvent was distilled away, and the resultant was purified using purification step A to obtain the title compound.
Reaction SMILES: [C:1]1([CH:7]2[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10][C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22](=[O:25])[CH:23]=[CH2:24].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO>[CH3:20][O:21][C:22](=[O:25])[CH2:23][CH2:24][N:13]1[CH2:12][CH:11]2[CH:15]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=3[CH2:10]2)[CH2:14]1
Reactant: c1ccc(C2c3ccccc3CC3CNCC32)cc1
Reactant: C=CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Product: COC(=O)CCN1CC2Cc3ccccc3C(c3ccccc3)C2C1
Reaction time: 4 h

Procedure:
A mixture of 15 g of (3aRS,4SR,9aSR)-3a,4,9,9a-tetrahydro-4-phenyl-benz[f]isoindoline, 5.9 g of acrylic acid methyl ester and 1 cc of a 40% solution of benzyl trimethyl ammonium hydroxide in methanol is stirred at 50° for 4 hours and is then concentrated by evaporation. The evaporation residue is reduced to a slime with silica gel in benzene/ethyl acetate (9:1) and filtration is effected. Upon concentrating the filtrate by evaporation, the title compound, having a M.P. of 75°-76° (after crystallization from ether/petroleum ether), is obtained.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].[OH-].[Na+].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[C:20]([CH3:21])=[C:19]([N+:22]([O-:24])=[O:23])[C:18]([CH3:25])=[C:17]([N+:26]([O-:28])=[O:27])[C:16]=2[CH3:29])[CH2:12][C:11](=[O:30])[C:10]=1[C:31](=O)[CH2:32][CH3:33]>C(O)C>[CH2:2]([O:4][N:5]=[C:31]([C:10]1[C:9](=[O:8])[CH2:14][CH:13]([C:15]2[C:16]([CH3:29])=[C:17]([N+:26]([O-:28])=[O:27])[C:18]([CH3:25])=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=2[CH3:21])[CH2:12][C:11]=1[OH:30])[CH2:32][CH3:33])[CH3:3]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)c([N+](=O)[O-])c(C)c([N+](=O)[O-])c2C)CC1=O
Reactant: CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2c(C)c([N+](=O)[O-])c(C)c([N+](=O)[O-])c2C)CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.7 %

Procedure:
Ethoxyaminehydrochloride (0.36 g, 3.7 mmole) and then sodium hydroxide (0.15 g, 3.7 mmole) were added to a solution of 3-hydroxy-5-(2,4,6-trimethyl-3,5-dinitrophenyl)-2-propionylcyclohex-2-en-1-one (1.0 g; 2.7 mmole) in absolute ethanol (80 ml). The mixture was stirred at room temperature for a period of 24 hours and then the ethanol was removed by evaporation under reduced pressure. The residue was treated with dichloromethane and the organic phase was washed twice with water and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the product recrystallized from ethanol to give 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethyl-3,5-dinitrophenyl)cyclohex-2-en-1-one (0.45 g; 39.8%) as a white solid, mp 170° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][Si:26]([CH3:76])([CH3:75])[CH2:27][CH2:28][O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH2:39][C:40]2[CH:45]=[C:44]([C:46]3[CH:73]=[CH:72][C:49]4[N:50]([C:53]([C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=5)([C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=5)[C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=5)[N:51]=[N:52][C:48]=4[CH:47]=3)[CH:43]=[CH:42][C:41]=2[F:74])[CH2:34][CH2:33]1)=[O:31].[F:77][C:78]1[CH:86]=[CH:85][C:81]([C:82](O)=[O:83])=[CH:80][CH:79]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[CH3:25][Si:26]([CH3:76])([CH3:75])[CH2:27][CH2:28][O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([N:38]([C:82](=[O:83])[C:81]2[CH:85]=[CH:86][C:78]([F:77])=[CH:79][CH:80]=2)[CH2:39][C:40]2[CH:45]=[C:44]([C:46]3[CH:73]=[CH:72][C:49]4[N:50]([C:53]([C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=5)([C:60]5[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=5)[C:66]5[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=5)[N:51]=[N:52][C:48]=4[CH:47]=3)[CH:43]=[CH:42][C:41]=2[F:74])[CH2:36][CH2:37]1)=[O:31]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: C[Si](C)(C)CCOC(=O)N1CCC(NCc2cc(-c3ccc4c(c3)nnn4C(c3ccccc3)(c3ccccc3)c3ccccc3)ccc2F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOC(=O)N1CCC(N(Cc2cc(-c3ccc4c(c3)nnn4C(c3ccccc3)(c3ccccc3)c3ccccc3)ccc2F)C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU was added to a solution of 4-[2-fluoro-5-(1-trityl-1H-benzotriazol-5-yl)-benzylamino]-piperidine-1-carboxylic acid 2-trimethylsilany-1-ethyl ester, 4-fluorobenzoic acid and diisopropylethylamine and the resulting mixture stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate washed with 1 M sodium carbonate solution. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with diethyl ether/hexane, followed by ethyl acetate/hexane) provided 740 mg of product.
Reaction SMILES: C(OC(C)(C)C)(=O)[NH:2][NH2:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:43][C:44]1[CH:45]=[C:46]([C:50]([OH:52])=O)[O:47][C:48]=1[CH3:49]>C(Cl)Cl>[CH3:43][C:44]1[CH:45]=[C:46]([C:50]([NH:2][NH2:3])=[O:52])[O:47][C:48]=1[CH3:49]
Reactant: Cc1cc(C(=O)O)oc1C
Reactant: CC(C)(C)OC(=O)NN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)NN)oc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl carbazate (350 mg, 2.65 mmol), HBTU (1.01 g, 2.66 mmol), and N,N-diisopropylethylamine (923 μL, 5.30 mmol) were added to a methylene chloride (5 mL) solution of commercially available 4,5-dimethylfurancarboxylic acid (248 mg, 1.77 mmol), and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated, to the residue, a saturated aqueous solution of sodium bicarbonate was added, and the mixture was subjected to extraction with methylene chloride and dried over anhydrous sodium sulfate, and then, the solvent was distilled off. The obtained residue was dissolved in methylene chloride (6 mL). To the solution, trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated to obtain 4,5-dimethylfuran-2-carbohydrazide.
Reaction SMILES: [CH3:1][C@@:2]12[C:22]([CH3:24])([CH3:23])[C@@H:5]([C:6]3[C:7](=[O:21])[N:8]([C:11]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:14]=[CH:13][CH:12]=4)[NH:9][C:10]=31)[CH2:4][CH2:3]2.[CH2:25](I)[CH:26]=[CH2:27]>CN(C)C=O>[CH2:27]([N:9]1[C:10]2[C@@:2]3([CH3:1])[C:22]([CH3:24])([CH3:23])[C@H:5]([CH2:4][CH2:3]3)[C:6]=2[C:7](=[O:21])[N:8]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH:26]=[CH2:25]
Reactant: C=CCI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cccc4ccccc34)c(=O)c12
Solvent: CN(C)C=O
Product: C=CCn1c2c(c(=O)n1-c1cccc3ccccc13)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 46.3 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-naphthalen-1-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 46; 150 mg, 0.47 mmol) and allyl iodide (204 μL, 1.88 mmol) in dimethylformamide (5 mL) was heated in an oil-bath at 100° C. for 8 h. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with water (5×100 mL) and aqueous sodium thiosulfate (100 mL). The solvent was evaporated and the residue was purified using an ISCO 12 g column, eluting with 90-100% ethyl acetate/hexanes to give (4S,7R)-1-allyl-7,8,8-trimethyl-2-naphthalen-1-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (78 mg, 46%) as a white foam. ES(+)-MS (M+H) 359.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.Cl.Cl.[N:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][C:40]=1[CH2:49][NH2:50]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:50][CH2:49][C:40]1[CH:41]=[CH:42][C:43]2[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:39]=1)=[O:25]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NCc1ccc2ccccc2n1
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2ccc3ccccc3n2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with C-quinolin-2-yl-methylamine dihydrochloride.
Reaction SMILES: C(OC(=O)[C:5]([NH:25][C:26]([O:28][CH3:29])=[O:27])([CH3:24])[CH2:6][CH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)C.[Cl-].[Li+].[BH4-].[Na+].Cl>C(O)C.O1CCCC1>[CH3:24][C:5]1([CH2:6][CH2:7][C:8]2[S:9][CH:10]=[C:11]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:12]=2)[CH2:29][O:28][C:26](=[O:27])[NH:25]1
Reactant: CCOC(=O)C(C)(CCc1cc(C#CCCCc2ccccc2)cs1)NC(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(CCc2cc(C#CCCCc3ccccc3)cs2)COC(=O)N1
Temperature: 70 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
2-Methoxycabonylamino-2-methyl-4-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]butanoic acid ethylester (0.82 g, 1.92 mmol) obtained in Example 25(g) was dissolved in a mixture of ethanol (15 ml) and tetrahydrofuran (10 ml), and lithium chloride (0.24 g, 5.75 mmol) and sodium borohydride (0.22 g, 5.75 mmol) were added thereto in an ice bath, and then the reaction mixture was stirred for 2 hours at 70° C. under a nitrogen atmosphere. After the reaction solution was acidified with 1N hydrochloride acid, the resulting solution was extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacua. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=4:1-1:1) to give the title compound (0.65 g, 96% yield).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([NH2:19])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>>[CH:1]1([C:7]2[CH:8]=[C:9]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=3)[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1)c1cccnc1
Yield: 43.1 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 8b) (100 mg, 0.36 mmol) and nicotinic acid (40.6 mg, 0.33 mmol) as starting materials. The title compound (54 mg, 39.9%) was isolated as off white solid; MS (ESI): 380 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:63]1([CH2:68][CH:69]2[CH2:74][CH2:73][CH2:72][NH:71][CH2:70]2)[CH2:67][CH2:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:71]1[CH2:72][CH2:73][CH2:74][CH:69]([CH2:68][N:63]3[CH2:64][CH2:65][CH2:66][CH2:67]3)[CH2:70]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: C1CNCC(CN2CCCC2)C1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCC(CN4CCCC4)C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-(pyrrolidin-1-ylmethyl)-piperidine in DMSO at ambient temperature.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17]([N:19]4[CH2:23][CH2:22][C@@:21]5([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[C:25](=[O:32])[O:24]5)[CH2:20]4)=[O:18])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.CO.Cl>O1CCOCC1>[O:1]=[C:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([N:19]3[CH2:23][CH2:22][C@@:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[C:25](=[O:32])[O:24]4)[CH2:20]3)=[O:18])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)C(=O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCNCC5=O)cc4)CC3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 3-oxo-4-[4-(1-{[(1R)-3-oxo-1H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate (180 mg, 0.00034 mol) in methanol (2 mL, 0.05 mol) was added 4 M of hydrogen chloride in 1,4-dioxane (0.4 mL) and the mixture was stirred at rt for 3 hours and then concentrated. LC/MS: 432.2 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:9][CH:8]([C:10]2[S:11][C:12]([Br:15])=[CH:13][CH:14]=2)[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:6]=1)=[O:4].[OH-].[K+].CO>O>[Br:15][C:12]1[S:11][C:10]([CH:8]2[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH2:9]2)=[CH:14][CH:13]=1
Reactant: COC(=O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)s2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)s2)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 99.2 %

Procedure:
5-(5-Bromo-thiophen-2-yl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester (18.9 g, 47.3 mmol) prepared in Step 3 and a solution of potassium hydroxide (5.3 g, 94.6 mmol) in distilled water (200.0 mL) were added to methanol (200.0 mL). The reaction mixture was stirred at 80° C. for 12 hours and then concentrated under reduced pressure to discard methanol. The resulting residue was washed with diethyl ether, acidified by a 1N hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 18.1 g of the titled compound as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N+:16]=2[O-:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:23]1[N:27]2[CH:28]=[CH:29][CH:30]=[N:31][C:26]2=[C:25]([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N+:16]=2[O-:22])[C:36](=[O:37])[C:35]2[CH:34]=[CH:33][C:32]([C:25]3[CH:24]=[N:23][N:27]4[CH:28]=[CH:29][CH:30]=[N:31][C:26]=34)=[CH:40][CH:39]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(-c2cnn3cccnc23)cc1
Reactant: Cc1ccc[n+]([O-])c1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc[n+]([O-])c1N(C(=O)c1ccc(-c2cnn3cccnc23)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Preparation 14 (R)-2-(1-(tert-butoxycarbonyl)piperidin-3-ylamino)-3-methylpyridine 1-oxide (540 mg, 1.76 mmol) and Preparation 19 4-(pyrazolo[1,5-a]pyrimidin-3-yl)benzoic acid (420 mg, 1.76 mmol) in DMF (10 mL) was added HATU (803 mg, 2.11 mmol) at 30° C. The reaction was stirred at room temperature for 30 min. Diisopropylethyl amine (682 mg, 5.28 mmol) was then added at 0° C. dropwise. The reaction was stirred at 30° C. for 2 h. The resulting mixture poured into water then extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography to deliver the title compound (760 mg, 82%) as a brown oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:4][CH2:3]1.[C:19]([NH:26][C:27](N)=[O:28])([C:21]1[S:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>N1C=CC=CC=1>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:27]([NH:26][C:19]([C:21]2[S:25][CH:24]=[CH:23][CH:22]=2)=[O:20])=[O:28])[CH2:7][CH2:6]1
Reactant: NC(=O)NC(=O)c1cccs1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Solvent: c1ccncc1
Product: O=C(NC(=O)c1cccs1)NC1CCN(Cc2ccc3ccccc3c2)CC1

Procedure:
4-Amino-1-(naphth-2-ylmethyl)piperidine (1.0 g, 0.0047 m) and 1-(then-2-oyl)urea (0.65 g, 0.0042 m) in pyridine (5 cm3) was refluxed for 9.5 hours. The solvent was evaporated, water added, and the precipitated title compound filtered and washed well with water. This was recrystallised from ethanol, converted to the hydrochloride salt in ethanol with ethanolic HCl, and recrystallised from ethanol, 0.5 g, at the hydrochloride, m.p. 217°-219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:28]3[O:29][C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: OCCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1
Reactant: Clc1nc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(C(OC2CCN(CCOc3nc4ccccc4o3)CC2)c2ccccn2)cc1
Yield: 35 %

Procedure:
To a solution of 2.35 g (6.78 mmol) of 2-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1piperidyl]ethanol obtained in Example 10 dissolved in 20 ml of toluene was added 0.53 g (13.25 mmol) of sodium hydride (60% dispersion in mineral oil), and 1.25 g (8.14 mmol) of 2-chlorobenzoxazole was added to the mixed solution. The mixture stirred under reflux for 7 hours. After the reaction, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using a mixture of chloroform and methanol in the volume ratio of 40:1 as the developing solvent. The desired fractions was concentrated under reduced pressure to give 1.10 g (35%) of 2-[2-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]ethoxy]benzoxazole as an oil.