Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])C2C=CC(C#CC3C=CC(C(OCC)=O)=CC=3)=CC=2[C:5]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH2:3]1.FC(F)(F)S(OC1[C:37]2[CH:38]=[CH:39][C:40]([C:48]#[C:49][C:50]3[CH:60]=[CH:59][C:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:52][CH:51]=3)=[CH:41][C:42]=2C(C)(C)CC=1)(=O)=O>>[CH3:29][C:2]1([CH3:1])[C:38]2[CH:39]=[C:40]([C:48]#[C:49][C:50]3[CH:51]=[CH:52][C:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:59][CH:60]=3)[CH:41]=[CH:42][C:37]=2[C:5]([C:25]([CH3:26])([CH3:27])[CH3:28])=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OS(=O)(=O)C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3C(C)(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate (Compound 71), 300 mg (0.63 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) was converted into the title compound (colorless oil) using 84 mg (0.94 mmol) of cuprous cyanide, 40 mg (0.94 mmol) of lithium chloride and 120 mg (1.1 ml, 1.88 mmol) of tert-butyllithium (1.7M solution in pentane).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](=[NH:7])[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[O:15][C:10]=3[CH:9]=2)[CH:3]=1.C(N(CC)CC)C.[CH:29]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30]1>C(#N)C>[CH3:1][C:2]1[S:6]/[C:5](=[N:7]\[C:33]([CH:29]2[CH2:32][CH2:31][CH2:30]2)=[O:34])/[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[O:15][C:10]=3[CH:9]=2)[CH:3]=1
Reactant: O=C(Cl)C1CCC1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)c(=N)s1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)C2CCC2)s1
Temperature: 65 °C

Procedure:
The imine (Example 26A, 30 mg, 0.09 mmol) was dissolved in 1.5 ml acetonitrile (1.5 mL). Triethylamine (19 μl, 0.18 mmol) was added followed by the cyclobutanecarbonyl chloride (0.11 mmol). The reaction was heated at 65° C. overnight. The reaction mixture was cooled down and passed through a Si-amine cartridge (1 g, 1.6 mmol/g) to remove the excess carbonyl chloride eluting with additional acetonitrile. The resulting solution was dried and purified by reverse phase HPLC. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.75 (1H), 1.88 (1H), 2.10 (4H), 2.26 (3H), 3.15 (1H), 7.44 (1H), 7.63 (1H), 7.68 (1H), 7.90 (1H); MS (ESI) m/z 403.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[N:46]1([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([N:49]2[CH2:48][CH2:47][N:46]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:51][CH2:50]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1cccc(Cl)c1)C1(O)CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2cccc(Cl)c2)C2(O)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A solution of (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) (5.4 g, 20.1 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (14.22 g, 32.15 mmol), and tert-butyl 1-piperazinecarboxylate (5.99 g, 32.15 mmol) in methylene chloride (20 mL) was treated with triethylamine (8.4 mL, 60.3 mmol). The reaction was stirred at 25° C. for 16 h, after which time the solvent was removed in vacuo and the product was purified via Biotage Horizon (FLASH 40 M, silica, gradient from 0% EtOAc/hexane to 30% EtOAc/hexane) to yield 7.10 g (81%) tert-butyl 4-[(3-chlorophenyl)(1-hydroxycyclohexyl)acetyl]piperazine-1-carboxylate as a white foam. HRMS: calcd for C23H33ClN2O4, 436.2129; found (ESI_FT), 437.21996.
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:57])=[C:11]([N:17]([CH2:26][C:27]2[N:28]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:31]=2)[C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:15]([C:13]1[CH:14]=[C:9]([OH:8])[C:10]([F:57])=[C:11]([N:17]([CH2:26][C:27]2[N:28]([C:38]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:31]=2)[C:18]2[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=2)[CH:12]=1)[CH3:16]
Reactant: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(N(Cc2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(C#N)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1cc(O)c(F)c(N(Cc2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a solution of Intermediate 191.1 (72 mg, 0.0936 mmol) in 1 mL THF at rt, was added TBAF (1 M in THF, 0.094 mL, 0.094 mmol). The mixture was stirred at rt for 30 min, then concentrated. The mixture was diluted with EtOAc, washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 75% EtOAc/hexanes gradient) to afford 42 mg of Intermediate 191.2 as a colorless residue.
Reaction SMILES: C(OC/C=C(/CCC=C(C)C)\C)(=O)C.Cl[N:16]1[C:21](=[O:22])[N:20](Cl)[C:19](=[O:24])[N:18](Cl)[C:17]1=[O:26]>CCCCCC>[NH:16]1[C:21](=[O:22])[NH:20][C:19](=[O:24])[NH:18][C:17]1=[O:26]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: CC(=O)OC/C=C(\C)CCC=C(C)C
Solvent: CCCCCC
Product: O=c1[nH]c(=O)[nH]c(=O)[nH]1

Procedure:
In 100 ml of n-hexane was dissolved 40 g (0.204 mol) of geranyl acetate, and 17.1 g (0.071 mol) of trichloroisocyanuric acid was added slowly and maintained between -10° C. to 0° C. for six hours. After the reaction, excessive trichloroisocyanuric acid and by-produced isocyanuric acid were removed by filtration. The filtrate was washed with an aqueous sodium hydrogencarbonate solution and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated to yield a crude product. The crude product obtained was purified by silica gel chromatography to provide 6-chloro-3,7-dimethyl-2,7-octadiene-1-acetate (hereinafter, compound (a)) in a yield of 86% in the form of pale yellow oil.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][C:44]([CH3:69])([CH3:68])[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([F:58])=[CH:53][C:52]=2[NH:59][S:60]([C:63]1[S:64][CH:65]=[CH:66][CH:67]=1)(=[O:62])=[O:61])=O)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:68][C:44]1([CH3:69])[S:43][C:47]([C:49]2[NH:50][C:51]3[C:56]([CH:57]=2)=[CH:55][C:54]([F:58])=[CH:53][C:52]=3[NH:59][S:60]([C:63]2[S:64][CH:65]=[CH:66][CH:67]=2)(=[O:62])=[O:61])=[N:46][CH2:45]1
Reactant: CC(C)(CNC(=O)c1cc2cc(F)cc(NS(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CN=C(c2cc3cc(F)cc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Reaction time: 0.25 h
Yield: 12.6 %

Procedure:
A mixture of triphenylphosphine oxide (0.71 g), trifluoromethanesulfonic anhydride (0.22 mL), and dichloromethane (20 mL) was stirred for 15 min under ice-cooling. Then, N-[2-(benzylthio)-2-methylpropyl]-5-fluoro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.23 g) was added, and the mixture was stirred for 5 hr under ice-cooling. The reaction solution was poured into aqueous sodium hydrogencarbonate solution and the mixture was extracted with dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined dichloromethane layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-3:7), and the obtained oil was crystallized from diethyl ether-hexane to give the title compound (23 mg, yield 13%) as colorless prism crystals. melting point 175-176° C.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[C:16]([F:17])=[CH:15][C:14]([C:18](=[O:38])[CH:19]([N:21]2[CH2:26][CH2:25][C:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)([OH:27])[CH2:23][CH2:22]2)[CH3:20])=[CH:13][C:12]=1[F:39])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([O:10][C:11]1[C:12]([F:39])=[CH:13][C:14]([CH:18]([OH:38])[CH:19]([N:21]2[CH2:22][CH2:23][C:24]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:32][CH:33]=3)([OH:27])[CH2:25][CH2:26]2)[CH3:20])=[CH:15][C:16]=1[F:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C(=O)c1cc(F)c(OCc2ccccc2)c(F)c1)N1CCC(O)(c2ccc(C(F)(F)F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C(O)c1cc(F)c(OCc2ccccc2)c(F)c1)N1CCC(O)(c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 0.17 h

Procedure:
A mixture of sodium borohydride (0.085 g, 2.25 mmol) and ethanol (5 mL) was stirred 10 min and then 1-(4-benzyloxy-3,5-difluorophenyl)-2-(4-(4-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (1.02 g, 1.96 mmol in 30 mL of ethanol) was added. The reaction was stirred at ambient temperature overnight. The white solid which precipitated was collected by filtration and dried to yield 0.66 g (65%) of (1R*, 2R*)-1-(4- benzyloxy-3,5-difluorophenyl)-2-(4-(4-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol which was suitable for use without further purification and had: mp 201-202° C. Analysis calculated for C28H28F5NO3.0.25 H2O: C, 63.93; H, 5.46; N, 2.66. Found: C, 63.98; H, 5.49; N, 2.70.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH:21]1([CH2:20][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6])[CH2:23][CH2:22]1
Reactant: BrCC1CC1
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CC1CC1)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.4 g of bromomethylcyclopropane were dissolved in 10 ml of dimethyl sulfoxide, 1.4 g of potassium carbonate was added, and the mixture was stirred at room temperature for 2 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.35 g of 2-cyclopropylmethyl-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (72)).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:17]([CH3:19])[CH3:18].O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)ccc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(Br)ccc1OC(C)C
Temperature: 100 °C
Yield: 84.7 %

Procedure:
6-Bromo-2-methylpyridin-3-ol (10.5 g, 55.9 mmol) was dissolved in DMF (100 mL). K2CO3 (19.3 g, 139.6 mmol) and 2-bromopropane (13.1 ml, 139.6 mmol) were added to the solution and the reaction mixture was heated at 100° C. overnight. The reaction mixture was poured onto a mixture of water and EtOAc (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude oil was purified by silica gel column chromatography (0-20% ethyl acetate/heptanes) to give 6-bromo-3-isopropoxy-2-methylpyridine (10.9 g, 85%) as a yellow oil. 1H-NMR (300 MHz, CDCl3) 1.42 (d, 6H), 2.48 (s, 3H), 4.65 (m, 1H), 7.20 (d, 1H), 8.04 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]2)[CH2:9][CH3:10])=[CH:4][C:3]=1[N+:18]([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:18][C:3]1[CH:4]=[C:5]([CH:8]([C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]2)[CH2:9][CH3:10])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CCC(c1ccc(Cl)c([N+](=O)[O-])c1)C1(C(=O)OC)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(c1ccc(Cl)c(N)c1)C1(C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
224 mg (0.76 mmol) of methyl 1-[1-(4-chloro-3-nitrophenyl)propyl]cyclopropanecarboxylate were dissolved in 48 ml of ethyl acetate, the mixture was inertized with argon and 40 mg of palladium (10% on carbon) were added. At RT, the reaction mixture was stirred under an atmosphere of hydrogen at atmospheric pressure for a total of 24 h. The mixture was then filtered through Celite, the residue was washed thoroughly with ethyl acetate and the combined filtrate was concentrated under reduced pressure. This gave 195 mg of the target compound (96% of theory).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCCN(c2ccc(N)cc2)CC1

Procedure:
A solution 1-methyl-4-(4-nitrophenyl)-1,4-diazepane in ethanol is hydrogenated overnight at atmospheric pressure over 10% Pd/C. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give 4-(4-methyl-[1,4]-diazepan-1-yl)phenylamine as a dark maroon oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:12]
Reactant: OCCCc1cccc(Cl)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Fc1c(Cl)cccc1CCCBr
Yield: 87.1 %

Procedure:
Compound 63-2 (2.48 g) was dissolved in methylene chloride (45 ml), triphenylphosphine (3.80 g) and N-bromosuccinimide (2.57 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.88 g) as a colorless oil.
Reaction SMILES: CNN.[O:4]=[C:5]1[C@@H:11]([N:12]2C(=O)C3=CC=CC=C3C2=O)[CH2:10][S:9][CH2:8][C@@H:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:6]1[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>C(Cl)Cl>[NH2:12][C@H:11]1[CH2:10][S:9][CH2:8][C@@H:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:6]([CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[C:5]1=[O:4]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N2C(=O)c3ccccc3C2=O)CSC[C@H]1c1ccccc1
Agent: CNN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSC[C@H]1c1ccccc1
Reaction time: 2 h
Yield: 92.4 %

Procedure:
0.7 ml of methylhydrazine was added to a solution containing 1.65 g of t-butyl α-[5-oxo-3(R)-phenyl-6(R)-phthalimidoperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (f) above] dissolved in 20 ml of methylene chloride, and the mixture was allowed to stand at room temperature for 2 hours. The solvent and excess methylhydrazine were then distilled off, and the residue was dissolved in 10 ml of methylene chloride and 1 ml of methanol. The resulting solution was allowed to stand overnight at room temperature, after which the solvent was removed by distillation. A small amount of methylene chloride was added to the residue, and the precipitate was filtered off. The filtrate was subjected to silica gel column chromatography eluted with a 1:20 by volume mixture of methanol and methylene chloride, to give 1.1 g of the title compound as an amorphous substance.
Reaction SMILES: [ClH:1].[C:2]1([C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([CH2:17][OH:18])[CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[ClH:1].[C:2]1([C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([CH2:17][O:18][C:37](=[O:39])[CH3:38])[CH2:13][CH2:12]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1(c2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OCC1(c2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reaction time: 24 h

Procedure:
A mixture of 1.0 part of 1-(3,3,3-triphenylpropyl)-4-phenyl-4-piperidinemethanol hydrochloride, 10 parts by volume of pyridine and 3.0 parts by volume of acetic anhydride is allowed to stand for 24 hours. Volatile material is removed under reduced pressure and the resulting residue is partitioned between dilute sodium hydroxide and ether. The ether layer is separated, washed with water, dried over sodium sulfate and then treated with an excess of a solution of hydrogen chloride in 2-propanol. The solid which forms is separated by filtration and then washed successively with ether, water, and ether, and then air dried to give 1-(3,3,3-triphenylpropyl)-4-phenyl-4-acetoxymethylpiperidine hydrochloride melting at about 211°-213° C and having the following structural formula ##STR19## Replacement of acetic anhydride with 3.0 parts of propionic acid anhydride provides 1-(3,3,3-triphenylpropyl)-4-phenyl-4-propionyloxymethylpiperidine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C1C=CC(CC(NCN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1.[CH2:51]([NH2:57])[C:52]1[O:56][CH:55]=[CH:54][CH:53]=1>CS(C)=O.C(N(C(C)C)CC)(C)C.[Cl-].[Na+].O>[NH2:1][C:2]1[N:23]=[C:22]([NH:57][CH2:51][C:52]2[O:56][CH:55]=[CH:54][CH:53]=2)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: NCc1ccco1
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Agent: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Nc1nc(NCc2ccco2)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 135 °C
Yield: 68 %

Procedure:
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (180 mg, 0.5 mmol) was dissolved in a mixture solution of dimethylsulfoxide (2 mL) and diisopropylethylamine (1 mL), furfurylamine (0.663 mL, 7.5 mmol) was added, and the solution was heated in a sealed tube for 13 hours 30 minutes (oil bath temperature: 135° C.). The reaction mixture was allowed to room temperature, poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then concentrated, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=2:1), and the title compound (144 mg, 0.34 mmol, 68%) was obtained.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[O:9][CH2:10][C@@:11]2([N:28]=1)[C:24]1[CH:23]=[C:22]([OH:25])[CH:21]=[C:20]([F:26])[C:19]=1[O:18][C:17]1[C:12]2=[CH:13][C:14](Br)=[CH:15][CH:16]=1.[F:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:7][C:8]1[O:9][CH2:10][C@@:11]2([N:28]=1)[C:24]1[CH:23]=[C:22]([OH:25])[CH:21]=[C:20]([F:26])[C:19]=1[O:18][C:17]1[C:12]2=[CH:13][C:14]([C:35]2[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:15][CH:16]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(O)cc12
Temperature: 85 °C

Procedure:
Sodium carbonate (saturated, 2 mL), Pd(PPh3)4 (0.237 g, 0.205 mmol), (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (0.75 g, 2.054 mmol), and 2-fluoropyridine-3-boronic acid (310 mg, 2.18 mmol) were combined in DMF (5 mL). The solution was heated at 85° C. overnight before being cooled to rt. The solution was diluted with water (25 ml) and filtered. The solids were triturated with MeOH and dried under vacuum to afford (S)-2-amino-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as a tan solid. MS m/z=382.0 [M+H].
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].O.NN>C(O)C.C(Cl)Cl>[NH2:3][O:12][CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15]
Reactant: C[C@@H](CON1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: C[C@@H](CON)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
To a solution of tert-butyl {(1S)-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]-1-methylethyl}carbamate 58 (1.2 g, 3.74 mmol) in a mixture of ethanol (3 mL) and DCM (20 mL) was added hydrazine hydrate (0.215 mL, 3.74 mmol). The reaction mixture was stirred at room temperature for 6 h. Precipitate was filtered off, the filtrate was evaporated and the residue was subjected to chromatography to give 59 (0.55 g, 77%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([OH:9])[N:4]=1.[N:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.N12CCN(CC1)CC2.O>CN(C)C=O>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:18]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:19])[N:4]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Oc1nccc(C(F)(F)F)n1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1nccc(C(F)(F)F)n1)N1CCOCC1
Yield: 79.4 %

Procedure:
A solution of 4-(trifluoromethyl)-2-pyrimidol (0.49 g, 3.00 mmol), 4-morpholinecarbonyl chloride (0.45 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.51 g, 3.00 mmol) in N,N-dimethylformamide (15 ml) was stirred at room temperature for 2 hours. Water was added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70→50:50)) yielding the title compound (0.66 g, 80% yield) as a white solid.