Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.Cl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=3)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2
Reactant: CC(Oc1ccc(Oc2ccc3cc(Cl)ccc3n2)cc1)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ccc3cc(Cl)ccc3n2)cc1)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5 mmol of 2-(4-((6-chloro-2-quinolinyl)oxy)phenoxy)propionyl chloride, prepared as in Step A of Example 1 employing the corresponding acid, in 10 ml of methylene chloride was added dropwise to an ice-cooled solution of 1.09 g (5.5 mmol) of 4-aminobenzotrifluoride, hydrochloride, 1.21 g (12.0 mmol) of triethylamine and 50 ml of methylene chloride. The reaction mixture was stirred at room temperature for 3 hours and then poured into a dilute aqueous HCl solution. The organic layer was separated, washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and evaporated to dryness. The residual solid was recrystallized from methylcyclohexane to give 1.79 g (74 percent of theoretical) of the desired product as colorless crystals melting at 142°-146° C. The structure of the compound was confirmed by its IR and NMR spectrum. (Compound 6). The carbon, hydrogen and nitrogen contents were determined to be as follows:
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[Cl:20][C:21]1[N:22]=[C:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[S:24][CH:25]=1>>[Cl:20][C:21]1[N:22]=[C:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][N:1]2[CH:2]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[F:19])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])[S:24][CH:25]=1
Reactant: O=Cc1cccc(-c2nc(Cl)cs2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1cccc(-c2nc(Cl)cs2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with 3-(4-chlorothiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 430.96 g/mol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=O)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc(-c2n[nH]c(=O)c3ccccc23)n1
Product: Cc1cccc(-c2nnc(Cl)c3ccccc23)n1
Temperature: 0 °C

Procedure:
A dry RBF set up with stirring bar and reflux condenser was charged with 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-one (780 mg, 3.29 mmol) and POCl3(10.7 ml, 115 mmol). This was stirred under reflux for 18 h. Excess POCl3 was removed under vacuum with an aid of toluene. The residue was cooled to 0° C. and basified with cold 6 N NaOH until pH=9. Occasionally, ice was added to keep the mixture cold to prevent the hydrolysis. Stirring, agitation, and sonication eventually provided a solid material at basic pH. The solids were filtered, washed with ample amount of water and dried under vacuum to afford a white solid. MS Calcd for C14H10ClN3: [M]+=255. Found: [M+H]+=256.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:14])([F:13])[O:7][C:8]2([F:12])[F:11])=[CH:4][C:3]=1[OH:15].[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[F:13][C:6]1([F:14])[C:5]2[C:9](=[CH:10][C:2]([NH:1][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:3]([OH:15])[CH:4]=2)[C:8]([F:11])([F:12])[O:7]1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cc2c(cc1O)C(F)(F)OC2(F)F
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc2c(cc1O)C(F)(F)OC2(F)F)c1ccncc1
Temperature: 80 °C
Yield: 45.7 %

Procedure:
A mixture of 2.0 g of 6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran, 1.1 g of isonicotinic acid, 2.23 g of WSC and 15 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was poured into the reaction mixture. Precipitated solid was filtered and washed with water and dried under reduced pressure to give 1.34 g of N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH:25]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 8 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.32–7.24 (m, 7H), 6.91 (d, 1H, J=7.2 Hz), 6.67 (m, 1H), 3.31 (q, 2H, J=5.5 Hz), 2.92–2.85 (m, 2H), 2.53 (septet, 1H, J=6.7 Hz), 2.43 (tt, 1H, J=11.6, 3.0 Hz), 2.33 (t, 2H, J=6.7 Hz), 1.91 (dt, 2H, J=11.7, 1.8 Hz), 1.78–1.72 (m, 2H), 1.65–1.59 (m, 2H), 1.56 (s, 6H), 1.52–1.45 (m, 2H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 484.3 (M+H)+; Anal. Calc. for (HCl salt) C28H38ClN3O2.HCl.0.30 CHCl3: C, 61.10; H, 7.12; N, 7.55. Found: C, 60.90; H, 7.20; N, 7.64.
Reaction SMILES: O[C:2]1([CH3:21])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:21]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(C)(O)c1ccccc1CO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C=C1c2ccccc2COc2ccc(C(=O)OC)cc21

Procedure:
Dissolve 1 gm. of methyl 11-hydroxy-11-methyl-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate in 100 ml. of benzene containing a few crystals of p-toluenesulfonic acid for 10 minutes. Strip the reaction mixture to dryness to obtain the title product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:37]([O:39]C)=[O:38])=[N:11][C:12]([N:19]([CH3:36])[S:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[O:22])=[O:21])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C.Cl>CO.O>[CH2:1]([O:8][C:9]1[C:10]([C:37]([OH:39])=[O:38])=[N:11][C:12]([N:19]([CH3:36])[S:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])(=[O:21])=[O:22])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(N(C)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C)c2cccnc2c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(c1nc(C(=O)O)c(OCc2ccccc2)c2ncccc12)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 94 %

Procedure:
To a solution of methyl 8-(benzyloxy)-5-(5-(tert-butoxycarbonylamino)-N-methylpentylsulfonamido)-1,6-naphthyridine-7-carboxylate (Example 2.3; 4.05 mmol) in methanol (8 ml) and water (8 ml) at rt was added sodium hydroxide (16.2 mmol). The reaction was heated at 50° C. Ethyl acetate was added and the aquous phase was treated with HCl 1N until pH=6-7. Ethyl acetate was added again, the layers were separated and the organic phase was dried with MgSO4 and concentrated. The crude product was obtained in 94% yield, and used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:41])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([CH2:15][O:14][C:12]2[C:11]([C:19]([F:21])([F:22])[F:20])=[CH:10][C:9]3[NH:23][C:24](=[O:41])[CH2:25][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=5)[CH:29]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:17][CH2:18]1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC4CC4)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(OCC5CC5)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-cyclopropylmethoxy-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M177) (279 mg, 0.48 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (144 mg, 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.C([C:22]1[C:23]([N:31]=[CH:32][N:33]([CH3:35])C)=[N:24][C:25]([CH2:28][CH2:29][CH3:30])=[CH:26][CH:27]=1)#N>C(O)(=O)C>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)=[C:2]([NH:1][C:35]2[C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH3:30])=[N:24][C:23]=3[N:31]=[CH:32][N:33]=2)[CH:7]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: CCCc1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)ncnc2n1
Temperature: 130 °C
Yield: 78.1 %

Procedure:
The product from Example 7b (49 mg 0.231 mmol) and the product from Example 128A (50 mg, 0.231 mmol) were dissolved in acetic acid (1 mL) and heated to 130° C. for 1.5 hours. After cooling to room temperature and removal of the acetic acid solvent under vacuum methanol (3 mL) was added to the oil which caused a solid to form which was triturated with methanol to provide the title compound 80 mg, 78%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.95 (t, J=7.4 Hz, 3H), 1.89 (m, 2H), 2.02 (s, 3H), 2.32 (s, 3H), 2.89 (t, J=7.5 Hz, 2H), 7.06 (s, 2H), 7.21 (t, J=8.5 Hz, 2H), 7.30 (s, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.52 (m, 1H), 8.52 (s, 1H), 8.74 (d, J=7.7 Hz, 1H), 10.00 (s, 1H); MS (ESI)+ m/z 444 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[NH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.CS(O)(=O)=O>CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:21][CH2:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: NCc1cccnc1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3cccnc3)c3ccccc3nc21
Temperature: 90 °C
Yield: 76.7 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]-quinoline (1.0 g, 0.0043 mol), DMSO (1 ml) and 3-aminomethylpyridine (0.97 ml, 0.0093 mol) is heated at 90° C. for 4 hours. The reaction mixture is poured into water, and the solid that forms is collected by filtration and recrystallized from ether/CH2Cl2/hexane to afford the product as the free base. The free base is dissolved in methanol (100 ml) and then is treated with methanesulfonic acid (1 ml). The methanol is evaporated, and then the residue is crystallized from 2-propanol/ether. The product is collected by filtration, washed with ether and dried in vacuo to afford 1.0 g of 1-ethyl-N-(3-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine.2CH3SO3H, m.p. 282°-284° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([Br:15])=[CH:12][C:13]=1[I:14])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:15][C:11]1[N:10]=[CH:9][C:8]([NH2:7])=[C:13]([I:14])[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Br)cc1I
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnc(Br)cc1I
Yield: 98.1 %

Procedure:
(6-Bromo-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (13.6 g, 34.1 mmol) was dissolved in dichloromethane (150 mL) and trifluoroacetic acid (50 mL) was then added. The resultant solution was stirred at ambient temperature for 2 h then evaporated under reduced pressure. The resultant residue was treated with a saturated solution of sodium hydrogen carbonate and the resultant solid was treated with water (50 mL) then extracted with ethyl acetate (2×200 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford the title compound as an off-white solid (10.0 g, 98%). 1H NMR (CDCl3, 300 MHz): 7.81 (s, 1H), 7.73 (s, 1H), 4.14 (s, 2H). LCMS (Method B): RT=3.03 min, M+H+=299/301.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][O:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2OC)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1CCO[CH2:24]1>>[CH3:24][O:23][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:1][O:8][C@H:9]1[CH2:10][O:11][C@@H:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:13][CH2:14]1
Reactant: C1COCO1
Reactant: COc1ccccc1C1OCC(OCc2ccccc2)CO1
Product: COc1ccccc1CO[C@H]1CO[C@@H](c2ccccc2)OC1

Procedure:
5-benzyloxy-2-(2-methoxyphenyl)-1,3-dioxane (b.p. 190°-195° C at 10-5 mm; VPC analysis indicated that it contained 14% cis, 31% trans, and 55% of the isomeric dioxolane);
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:19]=[CH:18][C:11]2[CH:12]=[C:13]([C:15]([OH:17])=O)[O:14][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]([F:35])([F:34])[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[NH2:23].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl>CN(C)C=O>[F:20][C:21]([F:34])([F:35])[CH:22]([NH:23][C:15]([C:13]1[O:14][C:10]2[CH:9]=[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:19]=[CH:18][C:11]=2[CH:12]=1)=[O:17])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=1
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)c1ccc2cc(C(=O)O)oc2c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 6-(tert-butoxycarbonyl)-1-benzofuran-2-carboxylic acid (350 mg, 1.33 mmol) and 2,2,2-trifluoro-1-[3-trifluoromethylphenyl]ethanamine (357 mg, 1.46 mmol) in N,N-dimethylformamide (5 ml) was admixed with 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (304 mg, 1.46 mmol) and stirred in a closed vessel at 50° C. overnight. The cooled reaction solution was admixed with hydrochloric acid (1 M) and extracted with ethyl acetate. The organic phase was washed with sat. sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. This leaves 453 mg as a mixture of the tert-butyl ester and of the free acid, which was used for the next step without further purification.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(N(CC)CC)C.[C:18]([C:20]1(Cl)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)#[CH:19].C(C1(O)CCCCC1)#C>CCOCC.O.CCOCC.Cl[Cu]>[CH2:2]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:20]2([C:18]#[CH:19])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:6][CH:5]=1)[CH3:1]
Reactant: CCOc1ccc(N)cc1
Reactant: C#CC1(Cl)CCCCC1
Agent: Cl[Cu]
Agent: C#CC1(O)CCCCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: C#CC1(Nc2ccc(OCC)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution, cooled to 10° C., of 18.2 mmol (2.5 g) of p-phenetidine in a mixture of ether:water (4:1; 30 ml) containing 24.5 mmol (3.42 ml) of triethylamine there are added, in succession, 0.25 mmol (0.025 g) of CuCl, 0.39 mmol (0.025 g) of Cu and, dropwise, 28.0 mmol (4.0 g) of 1-ethynyl-1-chlorocyclohexane prepared according to the method described in J. Am. Chem. Soc., 83, 725, 1961, starting from 1-ethynylcyclohexanol. After stirring for 4 hours (allowing the temperature to increase towards ambient temperature) the reaction mixture is diluted with ether and then washed with 1N sulphuric acid solution. The ethereal phase is removed and the aqueous phase is neutralised (at 0° C.) using potassium hydroxide pellets and then re-extracted with ether. The organic phase is dried and then concentrated to yield the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].I[CH2:11][CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH3:12]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOc1ccc(Cl)cc1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of 2-Bromo-4-chlorophenol (2.12 g, 10.2 mmol) in 25 mL acetone was added iodoethane (0.850 mL, 10.6 mmol) and cesium carbonate (4.08 g, 12.5 mmol). The reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated to yield 2.37 g (98%) of 2-bromo-4-chloro-1-ethoxybenzene as a yellow oil, which was carried forward without further purification. LCMS (ESI) no m/z signal; 1H NMR (400 MHz, DMSO-d6) δ: 7.67 (d, J=2.6, 1H), 7.39 (dd, J=8.8, 2.6, 1H), 7.12 (d, J=8.9, 1H), 4.11 (q, J=7.0, 2H), 1.35 (t, J=7.0, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:21]1([Mg]Cl)[CH2:25][CH2:24][CH2:23][CH2:22]1.[Br:28]Br.C(N(CC)CC)C>C1COCC1.CCOCC>[Br:28][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:6][C:7]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: BrBr
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2)cc1
Reactant: Cl[Mg]C1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)Nc2cc(C3CCCC3)c([N+](=O)[O-])cc2Br)cc1

Procedure:
This compound is prepared according to the procedure described in step A of Preparation 2.18, from 15 g of N-(4-nitrophenyl)-4-methylbenzenesulphonamide in 100 ml of THF and 64 ml of a 2M solution of cyclopentylmagnesium chloride in ether, followed by 6.8 ml of bromine and 35 ml of triethylamine. 6.1 g of the expected product are obtained, m.p.=122° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:6][CH:7]=1
Reactant: CCOC(=O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Product: CCOC(=O)[C@@H]1CCCN1c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
5-bromo-2-chloro-3-nitropyridine (5.94 g, 25 mmol) and (S)-ethyl pyrrolidine-2-carboxylate (7.52 g, 52.5 mmol) were combined and stirred at 90° C. for 10 min in a closed vial. The crude material was purified by flash column chromatography (20-30% EtOAc in hexanes to afford (S)-ethyl 1-(5-bromo-3-nitropyridin-2-yl)pyrrolidine-2-carboxylate (8.43 g, 24.49 mmol, 98% yield) as a yellow viscous oil. [M+H] calc'd for C12H14BrN3O4, 344. found, 344.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:21]([O:26]CC1OC1)(=[O:25])[C:22]([CH3:24])=[CH2:23]>CO>[C:21]([O:26][CH:3]([N:2]([CH2:23][CH2:22][CH2:21][OH:25])[CH3:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: C=C(C)C(=O)OCC1CO1
Solvent: CO
Product: C=C(C)C(=O)OC(CCCCCCCCCCCCCCCCC)N(C)CCCO

Procedure:
Equimolar quantities of N-methyl-N-octadecyl amine and glycidyl methacrylate were reacted together in methanol to form methacryloyloxyhydroxypropyl methyl octadecyl amine. 14.3 grams of the resultant amine were dissolved in 20 grams of dimethyl formamide and 4.2 grams of dimethyl sulfate were added slowly with stirring. After 10 days' standing at 25° C, 9 grams of crystalline material was isolated, washed with ether, and dried. The sulfate band in the crystalline product was identified in the I.R. spectrum.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:19]O>>[Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CC(=O)O)s1
Product: COC(=O)Cc1ccc(CO[Si](C)(C)C(C)(C)C)s1
Reaction time: 0.5 h

Procedure:
To 2-(5-((tert-butyldimethylsilyloxy)methyl)thiophen-2-yl)acetic acid (E231) in MeOH at 0° C. was added TMS-CH2N2 until the solution persisted in a yellow color and TLC indicated completion of the reaction. The solution stirred for 30 min and then was quenched with a few drops of AcOH. The solvents were evaporated and column chromatography (SiO2, 0-15% EtOAc/Hexanes) gave pure methyl 2-(5-((tert-butyldimethylsilyloxy)methyl)thiophen-2-yl)acetate (E232).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[C:8](=[O:18])[NH:9][C:10](=[O:17])[N:11]([CH2:13][CH2:14][CH:15]=O)[CH:12]=2)[S:5][CH:6]=1.C(O)(=O)C.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:30]=[CH:29][C:28]([C@:31]23[CH2:36][C@H:35]2[CH2:34][NH:33][CH2:32]3)=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]([C:7]2[C:8](=[O:18])[NH:9][C:10](=[O:17])[N:11]([CH2:13][CH2:14][CH2:15][N:33]3[CH2:34][C@H:35]4[C@:31]([C:28]5[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:38])[F:37])=[CH:30][CH:29]=5)([CH2:36]4)[CH2:32]3)[CH:12]=2)[S:5][CH:6]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: Cc1csc(-c2cn(CCC=O)c(=O)[nH]c2=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1csc(-c2cn(CCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 13.1 %

Procedure:
3-[5-(4-methyl-1,3-thiazol-2-yl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]propanal (Prep.45, 0.109 mmol) was suspended in 1,2-Dichloroethane (DCE) (1 ml) and Acetonitrile (1 ml). Acetic acid (9.36 μl, 0.164 mmol) followed by (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (P4 24.77 mg, 0.109 mmol) were added and the mixture was stirred at rt for 20 minutes. Then the resulting solution was cooled to 0° C. and SODIUM TRIACETOXYBOROHYDRIDE (25.4 mg, 0.120 mmol) was added. The mixture was allowed to reach r.t. under stirring and left at rt overnight. The mixture was treated with NaHCO3 aqueous saturated solution (5 mL) and extracted with EtOAc (3×5 mL). The organic was dried (Na2SO4 and rotary) to afford a yellow solid that was submitted to LC preparative purification. Fractions were collected, dried under vacuum to afford the title compound as a white solid (6.8 mg, 12%).