Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:22][C:23]#[N:24])=[N:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[C:27](=[O:48])([O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH3:47])[O:28][CH:29](Cl)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCOC(C)=O.CCOCC>ClCCl>[CH3:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][O:37][C:27]([O:28][CH:29]([N:19]1[CH:20]=[CH:21][C:16](=[N:15][C:14]([NH:22][C:23]#[N:24])=[N:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]2[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:17]=[CH:18]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:48]
Reactant: N#CNC(=Nc1ccncc1)NCCCCCCOc1ccc(Cl)cc1
Reactant: COCCOCCOCCOC(=O)OC(Cl)c1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCOCCOCCOC(=O)OC(c1ccccc1)n1ccc(=NC(=NCCCCCCOc2ccc(Cl)cc2)NC#N)cc1
Temperature: 25 °C

Procedure:
A mixture of N-(6-(4-chlorophenoxy)-hexyl)-N′-cyano-N″-(4-pyridyl)-guanidine (67 mg) and α-chlorobenzyl 2-(2-(2-methoxyethoxy)-ethoxy)-ethyl carbonate (150 mg) was placed in a preheated oil bath at 90° C. After 10 minutes a clear yellow melt was formed and after a further 20 minutes the mixture was cooled to room temperature and EtOAc (4 ml) was added. Decantation and evaporation in vacuo gave a residue which was treated with ether. After decantation of the ether, the residue was taken up in dichloromethane and washed with an excess of sodium bicarbonate. Chromatography on silica gel with dichloromethane/methanol (98:2) as eluent gave the title compound as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:5]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:22]>C1COCC1>[CH3:22][N:11]([CH2:10][CH2:9][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCn1ccc([N+](=O)[O-])n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCn1ccc([N+](=O)[O-])n1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a solution of 206c (5 g, 19.5 mmol) in THF (40 mL) was added NaH (938 mg, 23.4 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Iodomethane (1.7 mL, 25.4 mmol) was added and the mixture was stirred for additional 15 hours. It was then evaporated and purified by silical-gel column eluting with 2:1 petroleum ether/ethyl acetate to give 206d as a white solid (4.5 g, 85%). MS: (M+H)+ 271.
Reaction SMILES: [OH-].[Na+].CS(O[C@@H:8]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1)[CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(=O)=O.CCOCC>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C@@H:8]2[CH2:9][N:10]2[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:24][CH:25]=1)#[N:30]
Reactant: CS(=O)(=O)O[C@H](CNC(=O)OCc1ccccc1)COc1ccc(C#N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: N#Cc1ccc(OC[C@@H]2CN2C(=O)OCc2ccccc2)cc1
Yield: 69 %

Procedure:
A solution of NaOH in water (11 mL of 50 wt. %) was added under vigorous stirring to a solution of (1R)-2-{[(benzyloxy)carbonyl]amino}-1-[(4-cyanophenoxy)-methyl]ethyl methanesulfonate (see step (iv) above; 5.7 g, 14.1 mmol) and tetrabutylammonium hydrogensulfate (0.6 g, 1.7 mmol) in DCM (34 mL). The mixture was stirred for 1 h before water (200 mL) and ether (200 mL) were added. The organic phase was washed with water and then dried. The solvents were evaporated and the resulting residue was purified by chromatography (DCM eluant) to yield 3.0 g (69%) of the sub-title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24](C#N)[CH:23]=4)[N:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:30]C1C=C(C2N=C(OS(C(F)(F)F)(=O)=O)C=C3C=2N=CC=C3)C=CC=1>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:30])[CH:23]=4)[N:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(C#N)c3)n2)CC1
Reactant: O=S(=O)(Oc1cc2cccnc2c(-c2cccc(F)c2)n1)C(F)(F)F
Product: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(F)c3)n2)CC1

Procedure:
This compound is prepared in an analogous way to compound 4-[8-(3-cyano-phenyl)-[1,7]naphthyridin-6-yl]-cyclohexanecarboxylic acid ethyl ester from trifluoromethanesulfonic acid 8-(3-flurophenyl)-[1,7]naphthyridin-6-yl ester. Purification is by chromatography followed by trituration with ether to yield a white solid. MS (AP+) 378.98
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].[CH3:18][N:19]=[C:20]=[O:21].C(N(CC)CC)C>CCOCC>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][C:20](=[O:21])[NH:19][CH3:18])[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: CN=C=O
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CNC(=O)OC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C
Reaction time: 2 h

Procedure:
To a solution of 2-hydroxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (12 parts) in ether (46 parts) was added methyl isocyanate (4.5 parts) and triethylamine (0.3 parts). The solution was left at room temperature for two hours and the solvent evaporated off. The crude product was recrystallised from a mixture of benzene and light petroleum to give 2-methylcarbamoyloxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate, melting point 126°-127° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10].[CH2:21](O)[CH2:22][OH:23].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:21][CH2:22][OH:23])(=[O:10])=[O:11]
Reactant: OCCO
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCO)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
A solution of 3-(2-methoxyphenylsulfonyloxy)-5-methylphenol (245 mg, 0.83 mmol, prepared in step b of example 8), ethylene glycol (0.23 mL, 4.1 mmol), 1,1'-(azodicarbonyl)dipiperidine (420 mg, 1.66 mmol) and anhydrous tetrahydrofuran (6 mL) was cooled to 0° C. under nitrogen. Tri-n-butylphosphine (0.41 mL, 1.66 mmol) was added dropwise over 2.5 minutes. The mixture was stirred at 0° C. for 5 hours, then more 1,1'-(azodicarbonyl)dipiperidine (210 mg) and tri-n-butylphosphine (0.21 mL) were added. The reaction was stirred overnight at ambient temperature, then more 1,1'-(azodicarbonyl)dipiperidine (420 mg) and tri-n-butylphosphine (0.41 mL) were added. The mixture was stirred overnight at ambient temperature, then diethyl ether (50 mL) was added and the mixture was filtered. The filtrate was concentrated, and the residue was purified by flash column chromatography through silica gel (3:2 ethyl acetate/hexane) to give the title compound as a colorless oil (190 mg, 67%). 1H-NMR (300 MHz, CDCl3) δ 7.82 (dd, 1H, J=1.7, 7.9 Hz), 7.62 (ddd, 1H, J=1.8, 7.4, 8.4 Hz), 7.09 (dd, 1H, J=0.8, 8.4 Hz), 6.99-7.05 (m, 1H), 6.60-6.61 (m, 1H), 6.53-6.55 (m, 1H), 6.46-6.48 (m, 1H), 4.02 (s, 3H), 3.89-4.01 (m, 4H), 2.25 (d, 3H, J=0.6 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C16H18O6S: 361.1 (M+Na). Found: 360.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1COc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(4-chlorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [F:1][C:2]([F:29])([C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:3][CH2:4][CH2:5][CH2:6]OC1(C)C=CC(S([O-])(=O)=O)=CC1.[CH2:30](OC1C=CC2C(=CC=C(Br)C=2)C=1)[C:31]1C=CC=[CH:33][CH:32]=1>C1COCC1.[Cu]Br>[F:29][C:2]([F:1])([C:19]([F:27])([F:28])[C:20]([F:25])([F:26])[C:21]([F:22])([F:23])[F:24])[CH2:3][CH2:4][CH2:5][CH2:6][C:31]([CH:32]=[CH2:33])=[CH2:30]
Reactant: Brc1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: CC1(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C=CC(S(=O)(=O)[O-])=CC1
Agent: [Cu]Br
Solvent: C1CCOC1
Product: C=CC(=C)CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyl)-tosylate (10), (1 equi) and copper (I) bromide (0.05 equi.) in THF (2 mL/mmole), a solution of buta-1,3-diene-2-magnesium chloride, prepared as described in (3), (38) (0.5M in THF) (1.3 equi.) was added at ice temperature over a period of 20 min. The reaction mixture was stirred at room temperature for 24 h, quenched with 5% aqueous ammonium chloride (1 mL/mmole), extracted with hexane, washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (hexane) gave 2-(5,5,6,6,7,7,8,8,8-nona fluoro-octyl)-buta-1,3-diene (39) a colorless oil (96%).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:29]=[CH:28][N:27](COCC[Si](C)(C)C)[N:26]=4)=[C:21]([CH3:38])[CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2].C([C@H]1COC(=O)N1C1C=CN2N=CC(C3C=CC(C4N(COCC[Si](C)(C)C)N=CN=4)=C(C)C=3)=C2N=1)(C)C>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:29]=[CH:28][NH:27][N:26]=4)=[C:21]([CH3:38])[CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(-c2cnn3ccc(N4C(=O)OC[C@@H]4C(C)C)nc23)ccc1-c1ncn(COCC[Si](C)(C)C)n1
Agent: Cc1cc(-c2cnn3ccc(N4C(=O)OC[C@@H]4C(C)C)nc23)ccc1-c1ncnn1COCC[Si](C)(C)C
Product: Cc1cc(-c2cnn3ccc(N4C(=O)OC[C@@H]4C(C)C)nc23)ccc1-c1nc[nH]n1
Yield: 64 %

Procedure:
(S)-4-isopropyl-3-(3-(3-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (0.138 g, 64%) was prepared by the procedure described in Example 1, Step 9, using a mixture of (S)-4-isopropyl-3-(3-(3-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl) oxazolidin-2-one and (S)-4-isopropyl-3-(3-(3-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (0.285 g, 0.534 mmol), to produce a yellow solid. LCMS (APCI+) m/z 404.6 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 11.40 (broad s, 1H), 8.60 (d, J=7.8 Hz, 1H), 8.41 (s, 1H), 8.22 (s, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.94 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 4.97-4.93 (m, 1H), 4.48-4.38 (m, 2H), 2.94-2.87 (m, 1H), 2.65 (s, 3H), 1.07 (d, J=7.0 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[N:9][OH:10])[S:2]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:10][N:9]=[C:3]1[CH:4]2[CH2:7][CH2:8][CH:1]([CH:6]=[CH:5]2)[S:2]1
Reactant: ON=C1SC2C=CC1CC2
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C1=CC2CCC1SC2=NOC1CCCCO1
Yield: 93.4 %

Procedure:
A solution of 10 g (0.06 m) of 2-thiabicyclo[2.2.2]oct-5-en-3-one oxime, 9 g (0.1 m) of 98% dihydropyran, and a catalytic amount of p-toluenesulfonic acid in 30 ml of methylene chloride was heated under reflux overnight. Sodium bicarbonate was added to neutrality. The residue after removal of solvent was purified by dry column chromatography (silica gel-ethyl acetate:hexane::1:1) to give 14.4 g of yellow solid. Recrystallization from ether-hexane yielded 10.1 g of the title compound as a white solid, m. 84°-5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CCOC(C)=O.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:11][C:12]([OH:14])=[O:13])=[CH:3][C:2]=1[F:1]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(CC(=O)O)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-fluoro-4-nitrophenyl)acetic acid (1 g, 5 mmol) in 30 mL of EtOAc was added 180 mg of Pd/C was stirred at room temperature under H2 atmosphere overnight. The reaction mixture was filtrated and concentrated to give (4-amino-3-fluorophenyl)acetic acid.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:9]([O:11]CC)=O.CC[O-].[Na+].[N:23]1([C:29]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[NH:37][C:36](=[O:41])[CH2:35][CH2:34]3)=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:9]([N:26]1[CH2:27][CH2:28][N:23]([C:29]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[NH:37][C:36](=[O:41])[CH2:35][CH2:34]3)=[O:30])[CH2:24][CH2:25]1)=[O:11]
Reactant: CCOC(=O)c1ccc(OC)c(OC)c1
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Yield: 6.5 %

Procedure:
To 100 ml of ethanol was added 1.9 g of ethyl 3,4-dimethoxybenzoate, 0.5 g sodium ethylate and 2.4 g of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril, the mixture was reacted in an autoclave under 110 atmospheric pressure at 140°-150° C. for 6 hours. After the reaction was completed, the reaction mixture was cooled and concentrated under a reduced pressure. The residue thus obtained was dissolved in 200 ml of chloroform and the chloroform solution was washed with 1%-potassium carbonate aqueous solution, a dilute hydrochloric acid and water in this order, then dried with anhydrous sodium sulfate. The solvent was removed by distillation and the residue was treated by means of a silica gel column chromatography (Silica gel: Wako C-200, eluent: chloroform:methanol (volume/volume)=20:1) and the crude crystals were recrystallized from ethanol-chloroform to obtain 250 mg of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:28][CH2:27][C:5]2[N:6]([CH2:14][CH:15](OS(C)(=O)=O)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:29]([NH2:31])[CH3:30]>O>[CH3:1][N:2]1[CH2:28][CH2:27][C:5]2[N:6]([CH2:14][CH:15]([NH:31][CH2:29][CH3:30])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCN
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Solvent: O
Product: CCNC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C

Procedure:
Methanesulfonicacid-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester (300 mg, 0.75 mmol) in 70% ethylamine in water (15 mL) was heated at 100° C. for 18 h. The reaction mixture was cooled to RT and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (2×20 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 55 mg of [2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl]-ethyl-amine. 1H NMR (DMSO, TFA salt): δ (ppm): 8.5 (d, 2H), 7.3 (d, 1H), 7.2 (m, 3H), 6.9 (d, 1H), 4.7 (m, 2H), 4.43 (m, 2H), 4.1 (d, 1H), 3.3 (m, 1H), 3.0 (m, 2H), 2.85 (d, 6H), 2.8 (m, 1H), 2.5 (m, 2H), 2.3 (s, 3H), 1.22 (s, 3H). Chiral HPLC separates the racemate into enantiomers II-8a-b.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12](O)(=[O:14])[CH3:13]>S(=O)(=O)(O)O.O>[C:12]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)O
Reactant: O=C(O)c1ccc(O)cc1F
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Temperature: 80 °C

Procedure:
6 Grams of 4-hydroxy-2-fluorobenzoic acid and 8.2 g of anhydrous acetic acid were placed in a two-necked flask, and mixed. While the mixture was cooled with water, 5 drops of sulfuric acid were added. After heat generation was terminated, the mixture was heated at 80° C. for 30 minutes. Then, the reaction mixture was poured into cold water, and a precipitated crystal was recovered by filtration. The crystal was vacuum-dried, and used in the next step. The yield of the crystal was 4.8 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].C(N(CC)C(C)C)(C)C.[NH2:21][C:22]1[CH:44]=[CH:43][C:25]([C:26]([N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[CH2:31][C:30]3[CH:39]=[CH:40][CH:41]=[CH:42][C:29]2=3)=[O:27])=[CH:24][CH:23]=1>C1(C)C(C)=CC=CC=1>[CH:39]1[C:30]2[CH2:31][C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[CH2:34][N:28]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:4](=[O:5])[C:3]4[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=4[Cl:11])=[CH:44][CH:43]=3)=[O:27])[C:29]=2[CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1c(Cl)cccc1Cl
Temperature: 110 °C
Yield: 76 %

Procedure:
A mixture of 335 mg of 2,6-dichlorobenzoyl chloride and 258 mg of N,N-diisopropylethylamine is stirred in 2 ml of xylene while 314 mg of 5-(4-amino-benzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is added. The reactants are refluxed in an oil bath at 110° C. for 18 hours. The xylene is evaporated in vacuo to a residue which is partitioned between methylene chloride and water. The organic layer is separated, washed with 1N HCl, 1H NaHCO3, and brine. The organic layer is dried with Na2SO4 and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 370 mg of the desired product as a crystalline solid, m.p. 257°-259° C.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:27])[CH3:28])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ncc(OCc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-yl)oxy)methyl)phenyl)propanoate (253 mg) in THF (4.0 mL) and methanol (2.0 mL) was added 1N aqueous sodium hydroxide solution (4.0 mL), and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was neutralized with 1N hydrochloric acid (4.0 mL) at room temperature, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (220 mg) as a white amorphous solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][CH:8]=[C:7]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[CH:6]=1)[CH3:3].[NH2:15][C:16]1[C:19](=[O:20])[C:18](=[O:21])[C:17]=1OC>CO>[NH2:15][C:16]1[C:19](=[O:20])[C:18](=[O:21])[C:17]=1[NH:14][CH2:13][CH2:12][S:11][CH2:10][C:7]1[CH:6]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:9][CH:8]=1
Reactant: CN(C)Cc1cc(CSCCN)cs1
Reactant: COc1c(N)c(=O)c1=O
Solvent: CO
Product: CN(C)Cc1cc(CSCCNc2c(N)c(=O)c2=O)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
A mixture of 2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamine (2.11 g, 8.68 mmoles) [prepared according to the procedure described in published European Patent Application 27,744] and 1-amino-2-methoxycyclobutene-3,4-dione (1.10 g, 8.68 mmoles) in methanol was stirred at ambient temperature for 18 hours and filtered. The crude product was recrystallized from 2-methoxyethanol to yield 1.30 g of the title compound as a colorless solid, m.p. 234°-236°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][CH:3]=1.Cl.[NH2:13][OH:14].C(=O)([O-])O.[Na+]>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7]/[C:8](=[N:13]/[OH:14])/[NH2:9])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#CCOc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N/C(COc1ccc(Cl)cc1)=N\O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(4-chlorophenoxy)acetonitrile (1.35 g, 8.06 mmol), hydroxylamine hydrochloride (0.840 g, 12.1 mmol), and sodium hydrogencarbonate (3.38 g, 40.3 mmol) in methanol (15 mL) was heated to reflux. After 16 hours, the reaction mixture was cooled to ambient temperature and filtered. The filtrate was diluted with ethyl acetate (125 mL) and washed with 1 N aqueous HCl and saturated aqueous NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo to furnish the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.28 (s, 1H), 7.36-7.28 (m, 2H), 7.06-6.98 (m, 2H), 5.60 (bs, 2H), 4.39 (s, 2H); MS (DCI+) m/z 201 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=C)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:31]=[O+][O-].C(N(CC)CC)C>ClCCl>[CH:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[O:31])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(C2CCCCC2)c1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(C2CCCCC2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To a solution of 3-(5-cyclohexyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 75A, 0.015 g, 0.036 mmol) in dichloromethane (5.0 mL) at −78° C. was passed ozone from an ozone generator until the solution turned a deep blue. The reaction mixture was then purged with oxygen until the blue color disappeared and then with nitrogen for 5 minutes. The reaction mixture was allowed to warm to room temperature, and triethylamine (5.07 μl, 0.036 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes. Concentration under vacuum provided 3-(5-cyclohexyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde [0.014 g, 0.0.036 mmol, 98%] as a tan solid. The product had an HPLC ret. time=4.44 min. (condition B). LC/MS M+1=417.07.