Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: COCCCCCOC1CCNCC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCCCOC1CCN(c2ccc(C#N)cc2)CC1
Yield: 31.6 %

Procedure:
A solution of 4-fluorobenzonitrile (0.38 g), 4-(5-methoxypentyloxy)piperidine (0.62 g) and potassium carbonate (0.87 g) in DMF (8 ml) was stirred at 90-95° C. for 6 hours. The reaction mixture was poured into water (50 ml) and extracted twice with a mixture of ethyl acetate and n-hexane (50 ml:20 ml). The extracts were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v-2:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-(5-methoxypentyloxy)-N-(4-cyanophenyl)piperidine (294 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14]([OH:16])=O)[CH3:2].CCN(C(C)C)C(C)C.Cl.[CH2:27]1[C:39]2[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:32]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:31]=2[CH2:30][CH2:29][NH:28]1>C1COCC1.CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14]([N:28]1[CH2:29][CH2:30][C:31]2[N:32]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[C:39]=2[CH2:27]1)=[O:16])[CH3:2]
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Reactant: CCOc1ccc2ccccc2c1C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c2c(c3ccccc31)CN(C(=O)c1c(OCC)ccc3ccccc13)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
Step a): To a solution of 2-ethoxynaphthoic acid (22 mg, 0.1 mmol), N′,N′,N′,N′tetramethyl-O-(7-azabenzotriazole-1-yl)-uronium-hexafluorophosphate (38 mg, 0.1 mmol) and DIEA (51 μl, 0.3 mmol) in THF/DMF (4:1, 1 ml) is added Intermediate 1 (29 mg, 0.1 mmol) in one portion and the reaction mixture is stirred at rt overnight. Then, the solvent is evaporated and the residue purified by silica gel column chromatography (6% MeOH in CH2Cl2/aqueous NH4OH 9:1) affording ethyl [2-(2-ethoxy-naphthalene-1-carbonyl)-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl]-acetate (43 mg) as a glassy brown solid in 93% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:48]=[CH:47][C:19]([C:20]([NH:22][C@@H:23]([C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([Br:46])[CH:40]=3)[CH2:24][N:25]([CH3:38])S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)=[O:21])=[C:18]([F:49])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].SC1C=CC(C(O)=O)=CC=1.O>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:16]2[CH:48]=[CH:47][C:19]([C:20]([NH:22][C@@H:23]([C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([Br:46])[CH:40]=3)[CH2:24][NH:25][CH3:38])=[O:21])=[C:18]([F:49])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CN(C[C@@H](NC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O)[C@@H](F)C3)cnc2N)cc1F)c1cc(F)cc(Br)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C(O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC[C@@H](NC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O)[C@@H](F)C3)cnc2N)cc1F)c1cc(F)cc(Br)c1
Temperature: 45 °C
Yield: 68.2 %

Procedure:
To a solution of 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(N-methyl-2-nitrophenylsulfonamido)ethyl)-2-fluorobenzamide (293 mg, 0.38 mmol) in DMF (3.8 mL) was added K2CO3 (371 mg, 2.69 mmol) and 4-mercaptobenzoic acid (207 mg, 1.34 mmol). The reaction mixture was heated in microwave synthesizer at 45° C. for 55 min. After the reaction, water was added, and the mixture was extracted with EtOAc three times. The organic layers were combined and washed with water three times. The combined organic layer was dried over sodium sulfate, filtered off, and concentrated in vacuo. The residue was purified with flash chromatography eluting with EtOAc (containing 20% MeOH and 0.5% ammonia in water)/DCM to provide 150 mg of 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide. LCMS (m/z): 578, 580 (MH+), 0.64 min. 1H NMR (400 MHz, CD3OD) δ ppm 7.80 (s, 1H), 7.76-7.68 (m, 1H), 7.59 (dd, J=1.6, 7.8 Hz, 1H), 7.53 (dd, J=1.2, 11.7 Hz, 1H), 7.37 (s, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.11 (d, J=9.4 Hz, 1H), 5.27-5.10 (m, 1H), 4.42-4.13 (m, 1H), 3.65-3.49 (m, 1H), 2.97-2.88 (m, 1H), 2.87-2.79 (m, 1H), 2.74 (t, J=11.7 Hz, 1H), 2.35 (s, 3H), 2.22-2.11 (m, 1H), 2.04-1.92 (m, 1H), 1.85-1.68 (m, 2H), 1.55 (dq, J=3.1, 12.9 Hz, 1H), 1.46-1.33 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:22]([NH:25][C:26]2[S:30][N:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=1I)#[N:2].C(OC[N:35]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=[N:36]1)C.C(=O)([O-])[O-].[Na+].[Na+].ClCCl.CO.C(O)(=O)C>O.O1CCOCC1.Cl>[C:1]([C:3]1[CH:4]=[C:5]([S:22]([NH:25][C:26]2[S:30][N:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=1[C:37]1[NH:36][N:35]=[CH:39][CH:38]=1)#[N:2]
Reactant: CCOCn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(OC(F)(F)F)cc1I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(OC(F)(F)F)cc1-c1ccn[nH]1
Temperature: 85 °C
Reaction time: 18 h
Yield: 46.9 %

Procedure:
3-cyano-N-(1,2,4-thiadiazol-5-yl)-4-[2-iodo-4-(trifluoromethoxy)phenoxy]benzenesulfonamide (Preparation 760, 500 mg, 0.88 mmol), 1-(ethoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 337, 600 mg, 1.4 mmol), palladium (0) tetrakis triphenylphosphine (78 mg, 0.067 mmol) and sodium carbonate (420 mg, 3.963 mmol) were dissolved in a mixture of water (4 mL) and 1,4-dioxane (12 mL) and heated to 85° C. under N2 for 7 hours. Further 1-(ethoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg 0.23 mmol) and palladium (0) tetrakis triphenylphosphine (10 mg, 0.008 mmol) were added and the reaction stirred at 85° C. under N2 for 18 hours. The reaction was quenched by the addition of ethyl acetate (20 mL) and saturated aqueous brine solution (20 mL). The organic layer was collected, dried over sodium sulphate and concentrated in vacuo before purification using silica gel column chromatography (v/v/v dichloromethane:methanol:acetic acid v/v/v 100:0:0 to 95:5:0.5) to afford a white solid. This was dissolved in 4M HCl in 1,4-dioxane (5 mL) and stirred at room temperature for 4 hours before concentration in vacuo and purification using silica gel column chromatography (v/v/v dichloromethane:methanol:acetic acid 100:0:0 to 90:10:1 to afford a residue that was triturated in dichloromethane (5 mL) to afford 210 mg of the title compound as a white solid as the HCl salt.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:12][C:11]=1[O:23][CH3:24])=[O:8].[CH:27]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH2:28]>O1CCOCC1>[F:26][C:6]([F:5])([F:25])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:28][CH2:27][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:19][CH2:18]2)=[CH:12][C:11]=1[O:23][CH3:24])=[O:8]
Reactant: C=CS(C)(=O)=O
Reactant: COc1cc(C2CCNCC2)c(C)cc1NC(=O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cc(C2CCN(CCS(C)(=O)=O)CC2)c(C)cc1NC(=O)C(F)(F)F
Temperature: 90 °C
Yield: 28.4 %

Procedure:
To 2,2,2-trifluoro-N-[5-methyl-2-(methyloxy)-4-(4-piperidinyl)phenyl]acetamide acetate (1.5 g, 4.0 mmol) in 30 mL of dioxane was added, TEA (2 g, 20 mmol), and methyl vinyl sulfone (1.06 g, 10 mmol). The mixture was heated to 90° C. for 72 h. The solvent was rotovaped down and the crude product was purified by flash chromatography to give 480 mg of 2,2,2-trifluoro-N-(5-methyl-2-(methyloxy)-4-{1-[2-(methylsulfonyl)ethyl]-4-piperidinyl}phenyl)acetamide and the title compound of step D (0.40 g, 1.2 mmol, 31%). 1H NMR (400 MHz, CDCl3) δ ppm 6.62 (s, 1H), 6.51 (s, 1H), 5.22 (s, 2H), 3.80 (bs, 3H), 3.29 (t, J=6.87 Hz, 2H), 3.13 (d, J=11.17 Hz, 2H), 3.04 (s, 3H), 2.98 (t, J=6.96 Hz, 2H), 2.61-2.70 (m, 1H), 2.24-2.31 (m, 2H), 2.17 (s, 3H), 1.73-1.81 (m, 4H).
Reaction SMILES: [C:1](O)(=O)C.O.[CH:6](=[O:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C=O>[CH2:1]=[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[O:15]
Reactant: CCCCCCCCC=O
Reactant: CC(=O)O
Agent: C=O
Solvent: O
Product: C=C(C=O)CCCCCCC
Temperature: 50 °C

Procedure:
A 5-liter flask fitted with an overhead stirrer and condenser was charged with di-N-butyl amine (61 g, 0.47 mol) and acetic acid (56 g, 0.9 mol). Roughly 900 ml of 37% formaldehyde solution in water (351 g formaldehyde, 11.7 mol) was then added and the resulting solution was heated to 50° C. with stirring. After this temperature was reached nonanal (1000 g, 7.0 mol) was fed in over about 2 h. A slight exotherm was noticed during the feed. Monitoring by GC showed the consumption of nonanal and the production of 2-methylene nonanal, finally reaching roughly 95% conversion after the addition was complete. The reaction mixture was allowed to cool to room temperature, poured into a separatory funnel, and washed once with 5% HCl solution. The organic layer was then washed once with saturated sodium bicarbonate, then taken directly on to the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1.[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)=[O:15]
Reactant: NCCSCc1cnccn1
Reactant: CN=C=O
Product: CNC(=O)NCCSCc1cnccn1

Procedure:
By the procedure of Example 24, 2-[(2-aminoethyl)-thiomethyl]pyrazine is reacted with methyl isocyanate to give the title compound.
Reaction SMILES: CN1CCOCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C@H:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([OH:22])=O)=[O:17])=[CH:11][CH:10]=1.[CH3:29][O:30][N:31]=[C:32]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]1[C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1.Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([O:18][C@H:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([NH:44][C:41]2[CH:42]=[CH:43][C:38]([N:33]3[CH2:34][CH2:35][CH2:36][CH2:37][C:32]3=[N:31][O:30][CH3:29])=[CH:39][CH:40]=2)=[O:22])=[O:17])=[CH:13][CH:14]=1
Reactant: O=C(Nc1ccc(Cl)cc1)O[C@@H](C(=O)O)c1ccccc1
Reactant: CON=C1CCCCN1c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CON=C1CCCCN1c1ccc(NC(=O)[C@H](OC(=O)Nc2ccc(Cl)cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.2 101 mg (1.00 mmol) of 4-methylmorpholine are added to a solution of 183 mg (0.600 mmol) of (R)-(4-chlorophenylcarbamoyloxy)phenylacetic acid, 129 mg (0.588 mmol) of 1-(4-aminophenyl)piperidin-2-one O-methyl oxime, 192 mg (1.00 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) and 91.9 mg (0.600 mmol) of hydroxybenzotriazole hydrate (HOBt) in 1 ml of DMF, and the mixture is stirred at room temperature for 24 hours. The reaction mixture is introduced into saturated sodium hydrogencarbonate solution, and the resultant precipitate is filtered off. The precipitate is chromatographed on a silica-gel column with petroleum ether/ethyl acetate as eluent, giving (R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(2-methoxyiminopiperidin-1-yl)phenyl]-2-phenylacetamide (“AA”) as a colourless solid; ESI 507.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]2[C:8]3[C:9]([CH3:16])=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([CH3:15])=[C:6]2[C:5](=O)[NH:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>CCOCC>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[CH3:1][C@H:2]1[N:7]2[C:8]3[C:9]([CH3:16])=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([CH3:15])=[C:6]2[CH2:5][NH:4][CH2:3]1
Reactant: Cc1c2n(c3c(C)cccc13)[C@H](C)CNC2=O
Agent: O=C(O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: Cc1c2n(c3c(C)cccc13)[C@H](C)CNC2
Yield: 74 %

Procedure:
(R)-4,6,10-Trimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (200 mg, 0.88 mmol) was reacted with lithium aluminum hydride in accordance with the general method of example 15a). The crude material obtained was dissolved in ether (10 mL) and treated with oxalic acid solution (20% in ethanol, 7 mL). The precipitate was collected by filtration and dried to afford the title compound (196 mg, 74%). White solid. Anal. calc. for C16H20N2O4: C, 63.14; H, 6.62; N, 9.20; found: C, 62.86; H, 6.87; N, 8.92.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>C(O)(=O)C>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:21]/[N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C=O)cc1OC
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc(/C=C/[N+](=O)[O-])cc1OC

Procedure:
207.0 g of 3,4-dimethoxybenzaldehyde, 100.0 g of ammonium acetate and 125 ml of nitromethane are heated to boiling for 3-4 h in 1.01 of glacial acetic acid. After cooling in an ice bath, the precipitate is filtered off with suction, rinsed with glacial acetic acid and petroleum ether and dried. M.p.: 140-141° C. Yield: 179.0 g.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.ClCCl.C(=O)([O-])[O-].[K+].[K+].O=[Mn]=O>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Br)nc1
Agent: O=[Mn]=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC(=O)c1ccc(Br)nc1
Reaction time: 8 h

Procedure:
To a solution of 1-(6-bromo-pyridin-3-yl)-propan-1-ol (12.9 g, 59.93 mmol) in THF (200 mL) was added 85% activated MnO2 (6.4 g, 62.57 mmol) and the mixture was stirred overnight. The reaction was monitored by TLC (ethyl acetate-hexanes 4:6) indicating starting material and a new less polar product. To the mixture was added additional 85% activated MnO2 (6.0 g, 58.66 mmol) and the mixture stirred for 2 days. The reaction was monitored by TLC (ethyl acetate-hexanes 3:7) indicting starting material was still present. The mixture was warmed at reflux for 6 hours. The mixture was filtered through diatomaceous earth and concentrated. The residue was diluted with dichloromethane and Dess-Martin periodinane (19 g, 44.8 mmol) was added. After 1 hour, the mixture was diluted with saturated aqueous potassium carbonate (200 mL) and concentrated. The resulting solid was collected by filtration washing with water and dried by pulling vacuum through the filter cake. The solid was then suspended in dichloromethane and filtered and the filtrate was passed through a pad of silica gel eluting with ether to afford 1-(6-bromo-pyridin-3-yl)-propan-1-one as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3]1.[C:11]([OH:19])(=[S:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1CCCCC1>[C:11]([S:18][C@@H:3]1[C:2]([CH3:10])([CH3:1])[CH2:6][CH2:5][C@H:4]1[C:7]([OH:9])=[O:8])(=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)C=C(C(=O)O)CC1
Reactant: OC(=S)c1ccccc1
Solvent: C1CCCCC1
Product: CC1(C)CC[C@@H](C(=O)O)[C@@H]1SC(=O)c1ccccc1
Temperature: 120 °C
Yield: 51.6 %

Procedure:
A mixture of 3,3-dimethyl-1-cyclopentene-1-carboxylic acid (2 g) and thio-benzoic acid (2.37 g) is heated to 120° C. for 14 hours under Argon stream. The reaction mixture is cooled, taken up with a small amount of cyclohexane and filtered yielding 2.05 g of trans 2-benzoylthio-3,3-dimethylcyclopentyl carboxylic acid. M.p. 131° C. (from hexane).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:13][NH:14][O:15][CH3:16].C(N(CC)CC)C.C(Cl)CCl>ClCCl.CN(C)C=O>[CH3:16][O:15][N:14]([CH3:13])[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)=[O:12]
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: CNOC
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of Example 75A (1.6 g, 10 mmol) and N,O-dimethylhydroxylamine (1.1 g, 11 mmol) in dichloromethane (40 mL) and dimethylformamide (10 mL) was added triethylamine (1.67 mL, 12 mmol) and EDC (2.1 g, 11 mmol), and the mixture was stirred at room temperature for 24 hours. The solvents were evaporated under reduced pressure, and the resulting residue was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and purified by silica gel column chromatography in ethyl acetate to afford the title compound. MS (ESI+) m/z 206.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([Cl:40])[CH:39]=1)[C:34](Cl)=[O:35].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:34](=[O:35])[C:33]2[CH:32]=[C:31]([Cl:30])[CH:39]=[C:38]([Cl:40])[CH:37]=2)[C@H:10]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCN[C@H](Cc3c[nH]c4ccccc34)C2)cc1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CCN(Cc2ccccc2)C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled mixture of (3R)-1-benzyl-3-(1H-indol-3-yl-methyl)piperazine (305 mg) and potassium carbonate (207 mg) in dimethylformamide (1 ml) was added 3,5-dichlorobenzoyl chloride (210 mg). The mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added. The organic layer was washed successively with aqueous sodium bicarbonate solution and brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was dissolved in ethyl ether. After insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure and the residue was triturated with diisopropyl ether, collected by filtration and dried to give (2R)-4-benzyl-1-(3,5-dichlorobenzoyl)-2-(1H-indol-3-yl-methyl)piperazine.
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH2:17][O:18][CH3:19])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[BH:20]([OH:22])[OH:21]>>[CH3:19][O:18][CH2:17][O:16][C:3]1[CH:2]=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[C:4]=1[B:20]([OH:22])[OH:21]
Reactant: OBO
Reactant: COCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Product: COCOc1ccc2c(c1B(O)O)C(C)(C)CCC2(C)C

Procedure:
In a similar manner to Example 3(a), starting with 8 g (24.4 mmol) of 3-bromo-2-methoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene, 5.5 g (77%) of the expected boronic acid are obtained, with a melting point of 133-4° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[H-].[Na+].CS(O[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CO>[O:11]=[C:3]1[N:4]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23][CH2:22]2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2]1
Reactant: O=C1COc2ccccc2N1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccccc32)CC1
Yield: 63 %

Procedure:
2H-1,4-Benzoxazin-3(4H)-one (298 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (2.0 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) gave the product in 63% yield as a yellow gum.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:13])[CH:3]=1.P(Cl)(Cl)([Cl:16])=O.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:16][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nc2nc(C)cc(O)n2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1nc2nc(C)cc(Cl)n2n1

Procedure:
The titled compound (Intermediate 5), was obtained by refluxing a suspension of Intermediate 4 (0.3 g, 1.684 mmol) in phosphorus oxychloride (ALDRICH, 1.88 mL, 20.2 mmol) for 2 h and then, adding the reaction mixture slowly to a mixture of water and ice. The solution was neutralized with solid Na2CO3 and extracted with DCM (25 mL). The aqueous layer was further extracted with DCM (2×5 mL) and the combined organic layers were washed with water (20 mL), then with brine (20 mL), and then dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified (silica gel column, eluting with Hexane/EtOAc mixtures from 100:0 to 40:60%) to obtain Intermediate 5 as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:43]=[CH:42][C:15]2[C:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:38]=[C:37]5[C:32]([C:33](=[O:41])[C:34]([CH2:39][OH:40])=[CH:35][O:36]5)=[CH:31][CH:30]=4)[CH2:21][CH2:20]3)=[N:17][O:18][C:14]=2[CH:13]=1.C(N(CC)CC)C>ClCCl.O>[F:11][C:12]1[CH:43]=[CH:42][C:15]2[C:16]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:38]=[C:37]5[C:32]([C:33](=[O:41])[C:34]([CH:39]=[O:40])=[CH:35][O:36]5)=[CH:31][CH:30]=4)[CH2:23][CH2:24]3)=[N:17][O:18][C:14]=2[CH:13]=1
Reactant: O=c1c(CO)coc2cc(OCCCN3CCC(c4noc5cc(F)ccc45)CC3)ccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: O=Cc1coc2cc(OCCCN3CCC(c4noc5cc(F)ccc45)CC3)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.8 %

Procedure:
To a solution of 2 mL (23 mmoles) of oxalyl chloride in 35 mL of dry dichloromethane, cooled at −70°C., was added drop by drop a solution of 3 mL (42 mmoles) of dimethyl sulfoxide dissolved in 10 mL of dichloromethane and the mixture was stirred for 5 minutes. Then 5 g (11 mmoles) of 7-[3-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidin-1-yl]propoxy]-3-(hydroxymethyl)-chromen-4-one (Patent ES 9600323) were added in several portions for 15 minutes and stirred for further 30 minutes at −70° C. 15 mL (107 moles) of triethylamine were added drop by drop and stirred overnight while allowed to warm to room temperature gradually. By cooling at −20° C., 50 mL of water were added, the mixture was allowed to warm to room temperature and the organic phase was decanted, dried over sodium sulphate and evaporated. The solid obtained was purified by chromatography on a silica gel column. Elution of the column with CHCl3:CH3OH (98:2, v/v) gave 2.12 g of 7-[3-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidin-1-yl]propoxy]-3-formyl-chromen-4-one in 43% yield, mp 163-5° C.