Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.[ClH:24].C(OCC)C>O1CCOCC1>[ClH:24].[N:12]1([C:10](=[O:11])[C@@H:9]([NH2:8])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCOCC1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N[C@H](C(=O)N1CCOCC1)c1ccccc1
Yield: 90 %

Procedure:
1.327 g of N-(tert-butoxycarbonyl)-(1S)-2-morpholin-4-yl-2-oxo-1-phenylethylamine was dissolved in 15 mL of dioxane and treated with 3.5 mL of HCl 4 M in dioxane overnight. The solvent was removed and the solid was triturated with diethylether yielding 920 mg of the product (yield 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[S:10]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11]1>CC(O)C>[S:10]1[CH:14]=[CH:13][C:12]([CH:15]2[O:5][CH2:4][C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[NH:1]2)=[CH:11]1
Reactant: Nc1ccccc1CO
Reactant: O=Cc1ccsc1
Solvent: CC(C)O
Product: c1ccc2c(c1)COC(c1ccsc1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A mixture of 2-aminobenzyl alcohol (0.1218 mol), 3-thiophenecarboxaldehyde (0.1218 mol) and molecular sieves (3 Å) in 2-propanol (150 ml) was stirred overnight at room temperature. The crude reaction mixture was filtered, the residue was treated with CH2Cl2, and the mixture was filtered again. The solvent was evaporated, yielding 21.53 g (81%) of (±)-1,4-dihydro-2-(3-thienyl)-2H-3,1-benzoxazine (interm. 3).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][N:9]=1)=[O:7].[OH-].[Na+]>C(O)C>[F:19][C:2]([F:1])([F:18])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1)=[O:7]
Reactant: COC(=O)c1ccc(C(=O)NCCC(F)(F)F)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C(=O)NCCC(F)(F)F)nc1

Procedure:
A solution of methyl 6-[(3,3,3-trifluoropropyl)carbamoyl]nicotinate (0.265 g, 0.96 mmol), sodium hydroxide (9.60 ml, 9.60 mmol), and ethanol (10 mL) was heated to 50° C. for 3.5 h. The volatiles were removed in vacuo. The residue was suspended in water (20 mL) and insoluble material was filtered off. The filtrate was cooled on ice and 6 M hydrochloric acid was added while stirring until an acidic pH was reached. The precipitate was filtered off, washed with ice-water and dried in vacuo to yield 78 mg (31%); MS (APPI/APCI) m/z 263[M+H+].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([N@@:44]2[CH2:46][CH:45]2[CH3:47])=[O:43])=[CH:38][C:37]=1[O:48][CH3:49].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:30]1([O:29][C:4]2[C:5]3[C:10]([C:11]4[CH:20]=[CH:19][C:14]5[N:15]=[C:16]([CH3:18])[O:17][C:13]=5[CH:12]=4)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=3[N:7]=[C:2]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]([N@@:44]4[CH2:46][CH:45]4[CH3:47])=[O:43])=[CH:38][C:37]=3[O:48][CH3:49])[N:3]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(C(=O)N2CC2C)ccc1N
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CC2C)ccc1Nc1nc(OC2CCCC2)c2c(-c3ccc4nc(C)oc4c3)cn(COCC[Si](C)(C)C)c2n1
Temperature: 110 °C
Yield: 75 %

Procedure:
To a degassed mixture of 2-chloro-4-cyclopentyloxy-5-(2-methyl-benzooxazol-6-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), (R)-(4-amino-3-methoxyphenyl)(2-methylaziridin-1-yl)methanone (1.2 equiv) and cesium carbonate (2 equiv) in 1,4-dioxane (0.05M) were added palladium acetate (0.2 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.4 equiv). The reaction mixture was refluxed at 110° C. for 1 h. The reaction mixture was filtered, concentrated under reduced pressure, and the crude product was purified by preparative thin layer chromatography (5% MeOH in DCM) to afford the desired product (75% yield). MS (ESI) m/z 669.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:22][C:23]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH:10]1[CH2:14][CH3:15])=[O:25]
Reactant: CCC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 190.4 %

Procedure:
a solution of (RS) 4-tert-butoxycarbonyl-2-ethylpiperazine (3.95 g) and pyridine (1.64 ml) in DCM (35 ml) was added dropwise to a stirred solution of triphosgene (2.1 g) in DCM (100 ml) at 0° C. under Ar. The mixture was warmed to room temperature, stirred for 30 min then washed with water (100 ml) and brine (100 ml). The organic solution was dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in isohexane, filtered and concentrated in vacuo to give the product as a clear oil (3.73 g) which was used without further purification; δH (400 MHz, CDCl3) 4.39–3.80 (4H, m), 3.39–2.69 (3H, m), 1.66 (2H, m), 1.47 (9H, s), 0.96 (2.7H, d, J 7 Hz) and 0.89 (0.3H, d, J 7 Hz); GC (150° C.-10 min-320° C.) 83%, 8.72 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH:29]=O)=[N:24]2)=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:29][CH2:28][S:27][C:23]2[CH:22]=[N:21][C:20]3[C:25](=[CH:26][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[N:24]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1ccc2ncc(SCC=O)nc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)OC(C)(C)C)CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.2 %

Procedure:
Piperidin-4-yl-carbamic acid tert-butyl ester (2.82 g, 14.09 mmol, 1.5 eq) is added at room temperature to a stirred solution of (7-methoxy-quinoxalin-2-ylsulfanyl)-acetaldehyde (2.2 g, 9.39 mmol, 1.0 eq) in 1,2-dichloroethane (80 mL), followed by sodium triacetoxyborohydride (3.98 g, 18.78 mmol, 2.0 eq). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×60 mL) and a saturated sodium hydrogen carbonate aqueous solution (60 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: ethyl acetate:hexane, 1:1, v/v) to give a yellow solid that is further recrystallized with ethyl acetate:hexane (1:6, v/v) to afford {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as light yellow needles (2.6 g, 66% yield).
Reaction SMILES: C1(C2C=C(CCCC(O)=O)C3C(=CC=CC=3)N=2)C=CC=CC=1.O=[C:24]([C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[C:33]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:32]=1)[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].O.NN.[OH-].[K+]>C(O)COCCO>[C:41]1([C:33]2[CH:32]=[C:31]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(O)CCCC(=O)c1cc(-c2ccccc2)nc2ccccc12
Agent: NN
Agent: O=C(O)CCCc1cc(-c2ccccc2)nc2ccccc12
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: O=C(O)CCCCc1cc(-c2ccccc2)nc2ccccc12
Yield: 90.9 %

Procedure:
The procedure is the same as that used for preparing 2-phenyl-4-quinolinebutanoic acid described in Example 24, but starting with δ-oxo-2-phenyl-4-quinolinepentanoic acid (4.6 g), 98% pure hydrazine hydrate (2.15 g), potassium hydroxide pellets (2.4 g) and diethylene glycol (14 cc). 2-Phenyl-4-quinolinepentanoic acid (4 g) is thereby isolated, its proton NMR spectrum in deuterated chloroform showing the following characteristics:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]=[CH2:15])=[CH:8][CH:7]=1)[CH3:5].[H-].[Na+].[CH3:19]I>CN(C)C=O>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH:14]=[CH2:15])=[CH:10][CH:11]=1)([CH3:19])[CH3:5]
Reactant: CI
Reactant: C=CCOc1ccc(C(C)C(=O)OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(C)(C)C(=O)OC)cc1
Temperature: 0 °C

Procedure:
A 0° C. solution of the product of Example 46B (1.9 g, 8.6 mmol) in anhydrous dimethylformamide (10 mL) was treated portion-wise with 60% sodium hydride (410 mg, 10 mmol) in mineral oil. The reaction mixture was stirred twenty minutes at 0° C., and methyl iodide (1.4 mL, 22 mmol) was then added. Ice bath was removed, and reaction mixture stirred 16 hours at room temperature. Reaction mixture quenched with saturated ammonium chloride, and product extracted with ethyl acetate (2×). The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Residue purified by normal phase HPLC on silica gel eluting with 3% ethyl acetate/hexane to provide the title compound.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:10].[CH3:20][S:21](Cl)(=[O:23])=[O:22].[Cl-].[Na+]>C(Cl)Cl>[CH3:20][S:21]([O:8][CH:9]([C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:10])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1nc2ccccc2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1nc2ccccc2s1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
0.33 ml of triethylamine were added to a solution of 384.4 mg of 2-(1-hydroxyethyl)-benzothiazole [prepared as described in step (b) above] in 4 ml of methylene chloride cooled in an ice-water bath, and then 0.18 ml of methanesulfonyl chloride were added thereto. The temperature of the resulting mixture was elevated to room temperature, and the mixture was then stirred for 2 hours. At the end of this time, a saturated aqueous sodium chloride solution was added to the reaction mixture and the resulting mixture was then extracted with methylene chloride. The resulting extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to given 519.4 mg (yield 94.3%) of the title compound as an oil.
Reaction SMILES: C([O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:18](\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)/[CH2:19][CH2:20][Cl:21])=[CH:13][CH:12]=1)(=O)C(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1>[CH:25]1[CH:26]=[CH:27][C:22](/[C:18](/[CH2:19][CH2:20][Cl:21])=[C:17](\[C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][OH:7])=[CH:12][CH:13]=2)/[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)C(=O)OCCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: OCCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.1 %

Procedure:
(Z)-2-(4-(4-Chloro-1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl pivalate (3.5 g, 7.56 mmol) was dissolved in toluene (35 ml) and stirred under nitrogen for 5 min at room temperature. Lithium aluminium hydride solution (1 M in THF) (7.56 ml, 7.56 mmol) was added dropwise to the reaction and the mixture was stirred at room temperature for 30 min. After HPLC indicated completion, the reaction was quenched by addition of saturated NH4Cl-solution (75 ml). Additional amount of toluene (30 ml) was added and the phases were separated. The organic phase was washed with water (50 ml), brine (50 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was crystallized froth 90% MeOH yielding ospemifene (1.75 g, 61%) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:42]=[CH:43][C:44]=1[NH:45][C:46]([NH:48][CH:49]1[CH2:51][CH2:50]1)=[O:47])[O:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:40][CH3:41])=[C:20]([C:23]([NH:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33](OC(C)(C)C)=O)[CH2:29][CH2:28]3)=[O:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+].C=O.C([BH3-])#N.[Na+]>C(OCC)(=O)C.C(O)(=O)C>[CH3:33][N:30]1[CH2:29][CH2:28][CH:27]([CH2:26][NH:25][C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][C:19]=2[O:40][CH3:41])[N:16]=[CH:15][CH:14]=[C:13]3[O:12][C:11]2[CH:42]=[CH:43][C:44]([NH:45][C:46]([NH:48][CH:49]3[CH2:51][CH2:50]3)=[O:47])=[C:9]([Cl:8])[CH:10]=2)=[O:24])[CH2:32][CH2:31]1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(=O)NCC1CCN(C)CC1
Reaction time: 2 h
Yield: 58.3 %

Procedure:
After adding trifluoroacetic acid (1 ml) to tert-butyl 4-((((4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolyl)carbonyl)amino)methyl)-1-piperidinecarboxylate (249 mg, 0.40 mmol) at room temperature, the mixture was stirred for 2 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate for neutralization and extracted 3 times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was dissolved in tetrahydrofuran (5 ml)-methanol (5 ml), and then 37% aqueous formaldehyde (0.5 ml), acetic acid (0.05 ml) and sodium cyanoborohydride (50 mg, 0.8 mmol) were added in that order at room temperature and the mixture was stirred for 1 hour. The reaction solution was distributed between ethyl acetate and saturated aqueous sodium bicarbonate, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline and dried over anhydrous sodium sulfate. After distilling off the solvent, ethyl acetate was used for crystallization and the crystals were filtered out and blow-dried to obtain the title compound (125.6 mg, 0.233 mmol, 58.4%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.[Br-].[Li+].N1CCNCC1.Cl>CN(C)C=O.O>[Br:10][C:6]1[CH:5]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=4)=[CH:22][C:14]2=3)=[O:12])[CH:3]=[C:2]([Br:1])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccc(C(F)(F)F)cc4)cc32)cc1Br
Agent: C1CNCCN1
Agent: Cl
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ncc(-c3ccc(C(F)(F)F)cc3)cc21
Reaction time: 2 h
Yield: 50.3 %

Procedure:
In a 10 ml flask, (3,5-dibromo-4-methoxy-phenyl)-[7-(4-trifluoromethyl-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone (122 mg, 0.21 mmol), lithium bromide (148 mg, 1.71 mmol) and piperazine (28 mg, 0.32 mmol) were dissolved in 3 ml of N,N-dimethyl formamide and then stirred at 1000 for 2 hours. After completion of the reaction by adding water dropwise, the mixture was adjusted to weak acidic condition (pH=6) by using 1N hydrochloric acid. The formed solid was filtered and washed with distilled water. The resulting solid was recrystallized from tetrahydrofuran and methanol to obtain the target compound 45, i.e., (3,5-dibromo-4-hydroxy-phenyl)-[7-(4-trifluoromethyl-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone (59 mg, 50%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([CH3:24])[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[N:17]2)[CH:11]=1.CC1C=C(C=CC=1)N.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:55][CH2:56][C:57]([N:59]1[CH2:64][CH2:63][CH:62]([O:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([C:72]([F:75])([F:74])[F:73])[CH:67]=2)[CH2:61][CH2:60]1)=[O:58]>CN(C=O)C.CO.CCCCCC.O>[O:58]=[C:57]([N:59]1[CH2:60][CH2:61][CH:62]([O:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([C:72]([F:75])([F:73])[F:74])[CH:67]=2)[CH2:63][CH2:64]1)[CH2:56][NH:55][C:21]([C:19]1[N:18]=[N:17][N:16]([C:12]2[CH:11]=[C:10]([CH3:24])[CH:15]=[CH:14][CH:13]=2)[CH:20]=1)=[O:23]
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: Cc1cccc(-n2cc(C(=O)O)nn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CO
Solvent: Cc1cccc(N)c1
Product: Cc1cccc(-n2cc(C(=O)NCC(=O)N3CCC(Oc4cccc(C(F)(F)F)c4)CC3)nn2)c1
Reaction time: 0.03 h
Yield: 70.5 %

Procedure:
DIPEA (171 mg, 1.32 mmol) was added to a stirred solution of 1-m-Tolyl-1H-[1,2,3]triazole-4-carboxylic acid (60 mg, 0.29 mmol) (prepared by the method used for the synthesis of Intermediate 64, starting from 3-methylaniline) in DMF (5 mL) followed by HOBt (44 mg, 0.32 mmol) and EDCI (141 mg, 0.73 mmol). After 2 minutes of stirring, 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (110 mg, 0.32 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Cold water was then added and the solid was collected to afford the crude solid. The crude solid obtained was purified by recrystallisation from a solvent system (3:7:0.2), EtOAc:hexane:MeOH to afford 100 mg (70.5% Yield) of 1-m-tolyl-1H-[1,2,3]triazole-4-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 488, 96.08%. 1H NMR (300 MHz, DMSO-d6): δ 9.3 (s, 1H), 8.5 (t, 1H), 7.84 (s, 1H), 7.8 (d, 1H), 7.56-7.44 (m, 2H), 7.38-7.24 (m, 4H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (s, 1H), 3.8 (s, 1H), 3.5 (s, 1H), 3.3 (s, 1H), 2.4 (s, 3H), 2.1 (t, 2H), 1.8 (d, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]#[C:11][C:12](=O)[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:15]([CH2:17][C:18]([NH2:20])=[O:19])#[N:16].N1(CC([O-])=O)CCCCC1>C(O)C.O>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH3:13])[NH:20][C:18](=[O:19])[C:17]=1[C:15]#[N:16])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(=O)C#CCO[Si](C)(C)C(C)(C)C
Reactant: N#CCC(N)=O
Agent: O=C([O-])CN1CCCCC1
Solvent: CCO
Solvent: O
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(C#N)c(=O)[nH]1
Yield: 32.4 %

Procedure:
To a stirred solution of compound 5-((tert-butyldimethylsilyl)oxy)pent-3-yn-2-one (13.0 g, 61.0 mmol) and cyanoacetamide (6.2 g, 73.2 mmol) in a mixture of ethanol and water (9:1) (270 mL) at room temperature was added piperidineacetate (catalytic) and the reaction mixture was heated to reflux for 5 h. After removal of solvent water was added and the solid product was filtered. The solid product on washing with water followed by ether and hexane afforded the desired compound (5.5 g, 32%).
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:22][C@@H:23]([C@@H:25]2[CH2:29][O:28]C(C)(C)[O:26]2)[CH3:24])[N:7]=1.C(O)(C(F)(F)F)=O>CO>[F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:22][C@H:23]([CH3:24])[C@@H:25]([OH:26])[CH2:29][OH:28])[N:7]=1
Reactant: C[C@@H](Oc1cc(NS(=O)(=O)N2CCOCC2)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCOCC2)nc(SCc2cccc(F)c2F)n1)[C@@H](O)CO
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of N-(2-[(2,3-difluorobenzyl)thio]-6-{(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy}pyrimidin-4-yl)morpholine-4-sulfonamide (0.20 g) in MeOH (2 ml) was added TFA (0.4 ml) and the reaction was stirred at room temperature for 20 h. The mixture was evaporated, suspended in saturated sodium carbonate solution and then re-acidified to pH5 with glacial acetic acid with stirring. The resulting solid was collected, washed with H2O and dried to give the title compound as a white solid. Yield 0.15 g.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[C:7]1[C:8]([Cl:14])=[N:9][C:10](Cl)=[N:11][CH:12]=1>C1COCC1.N1C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:10]1[N:11]=[C:12]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:7]=[C:8]([Cl:14])[N:9]=1)[CH3:2]
Reactant: CCNCC
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCN(CC)c1cc(Cl)nc(N(CC)CC)n1

Procedure:
Diethylamine (80 g) is reacted with trichloropyrimidine (50 g) in THF. The reaction after chromatography yields a mixture of the mono- and di-adduct. This material is dissolved in pyridine (58 g) and reacted with diethylamine (35 g) at 50° for 3 h. The reaction is concentrated to a residue. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is separated and concentrated. The residue is chromatographed on silica gel, eluting with ethyl acetate/hexane (10/90). The appropriate fractions are pooled and concentrated to give 2,4-bis[diethylamino]-6-chloropyrimidine. This material is dissolved in pyridine (100 g) and reacted with piperazine (40 g) at 100° for 50 h. Following the above workup procedure the title compound is obtained, NMR (CDCl3) 1.15, 2.90, 3.45 and 4.9 δ.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([NH2:13])[CH:5]=1.N1C=CC=CC=1.[Cl:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O.Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([NH:13][S:25]([CH2:24][CH2:23][CH2:22][Cl:21])(=[O:27])=[O:26])[CH:5]=1
Reactant: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)CCCCl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)CCCCl)cc([N+](=O)[O-])c1
Reaction time: 40 h
Yield: 29.8 %

Procedure:
To a solution of 3-amino-5-nitro-benzoic acid methyl ester (D1) (45 g, 229 mmol, 1 equiv) in CH2Cl2 (450 ml) was added pyridine (18.5 ml, 229 mmol, 1 equiv), DMAP (100 mg, 0.8 mmol, catalytic) and 3-chloropropanesulfonyl chloride (28 ml, 230 mmol, 1 equiv). The resulting mixture was stirred for 40 h then diluted with AcOEt. The organic phase was diluted with 2N aqueous HCl solution. The resulting solid was filtered to give 3-(3-chloro-propane-1-sulfonylamino)-5-nitro-benzoic acid methyl ester (23 g, 32%). The filtrate was separated and the organic phase was washed with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with AcOEt and isohexane to give a further 50 g (65%) of 3-(3-chloro-propane-1-sulfonylamino)-5-nitro-benzoic acid methyl ester (D14) as a pale brown solid. [M−H]−=334.9, RT=3.11 min
Reaction SMILES: C([C:3]1[C:4](=[O:16])[NH:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:8]=1)#N>OP(O)(O)=O>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[CH:8]=[CH:3][C:4](=[O:16])[NH:5][CH:6]=2)=[CH:14][CH:13]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c[nH]c1=O
Agent: O=P(O)(O)O
Product: O=c1ccc(-c2ccc(Cl)cc2)c[nH]1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
A mixture of 3-cyano-5-(4-chlorophenyl)-2-pyridinone (4.6 g) and 85% H3PO4 (60 ml) was heated at reflux for 16 hours. The resulting mixture was cooled to room temperature, poured into ice/water and filtered yielding 3.1 g of 5-(4-chlorophenyl)-2-pyridinone as a yellow solid.