Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:15][C@H:14]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]2[F:21])[CH:5]=[N:4][C:3]=1[C:22]([OH:24])=O.[Cl-:25]>O1CCCC1>[C:11]([O:10][C@@H:9]1[C@@H:14]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[O:15][C@@H:7]([N:6]2[C:2]([N:1]=[CH:5][N:6]([CH3:7])[CH3:2])=[C:3]([C:22]([Cl:25])=[O:24])[N:4]=[CH:5]2)[C@@H:8]1[F:21])(=[O:13])[CH3:12]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)O)c2N)[C@H](F)[C@@H]1OC(C)=O
Reactant: [Cl-]
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)Cl)c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Reaction time: 0.5 h

Procedure:
The compound (18) (62 mg) obtained in item (8) above was dissolved in tetrahydrofuran (3 ml), to which was then added N,N-dimethylchloroforminium chloride (90 mg) under ice-cooling and the resulting mixture was stirred at the same temperature as above for 30 minutes to effect both the chlorination and N,N-dimethylaminomethylenation reactions. Thus, compound (19) was produced.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].F[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=1[F:34]>CCOC(C)=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=2[F:34])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-n2ccc(OCc3ccccc3)cc2=O)c(F)c1
Reaction time: 0.08 h
Yield: 116.4 %

Procedure:
To 4-(benzyloxy)pyridin-2(1H)-one (6.12 g, 30.4 mmol) in a 500 mL recovery flask was applied vacuum for 5 minutes then placed under an atmosphere of nitrogen and added DMF (100 mL) to produce a suspension. Added NaH (60% in oil) (1.271 g, 31.8 mmol) over 10 minutes as a slow evolution of gas was observed. By 60 minutes, the tan suspension had become thicker and lighter in color. After 60 minutes added 1,2-difluoro-4-(methylsulfonyl)benzene (5.31 g, 27.6 mmol) and placed the reaction mixture in a 110° C. oil bath under nitrogen for 70 minutes to produce a tan suspension. Added 400 mL of water and 400 mL of EtOAc to the reaction, removed aqueous layer, washed organic layer with 400 mL of brine, dried with MgSO4, filtered and concentrated to give 12 g pale yellow powder. This was purified by flash chromatography (0.75-1.00% MeOH/CH2Cl2) followed by recrystallization from EtOAc to yield 5.39 g (14.4 mmol, 52% yield) of product as a white powder. MS (ESI) 374.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:17])[N:12]([CH:14]([CH3:16])[CH3:15])[N:13]=2)=[N:6][CH:7]=1.[CH3:24][S:25][CH3:26].ClN1C(=O)CCC1=O.C[O-].[Na+]>CO.O>[CH3:24][S:25](=[N:1][C:2]1[N:3]=[C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:17])[N:12]([CH:14]([CH3:16])[CH3:15])[N:13]=2)=[N:6][CH:7]=1)[CH3:26]
Reactant: CSC
Reactant: CC(C)n1nc(-c2ncc(N)nc2-c2ccccc2)ccc1=O
Agent: C[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)n1nc(-c2ncc(N=S(C)C)nc2-c2ccccc2)ccc1=O
Temperature: 22.5 °C
Reaction time: 20 h

Procedure:
To a suspension of 6-(5-amino-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (1.01 g) was added dimethyl sulfide (0.263 ml) and N-chlorosuccinimide (435 mg) under −5° C. The mixture was stirred at −5° C. for 30 minutes and at 20-25° C. for 20 hours. A solution of 28% sodium methoxide in MeOH (1.13 ml) was added to the mixture and the solution was stirred at the same temperature for an hour. After addition of water (10 ml), the organic layer was collected, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of MeOH and EtOAc (1:99 v/v) to give 6-{5-[(dimethyl-lambda˜4˜-sulfanylidene)amino]-3-phenyl-2-pyrazinyl}-2-isopropyl-3(2H)-pyridazinone as a solid (0.80 g).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:13][C:14]([F:25])([F:26])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])=[CH:19][CH:20]=1
Reactant: NCCCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1CCCc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (1.13 g, 4.9 mmol), 3-(4-trifluoromethyl-phenyl)-propylamine (1 g, 4.9 mmol), and K2CO3 (1.13 g, 8.17 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(4-trifluoromethyl-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.314 g, 20%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.02 (m, 2H), 2.76 (t, 2H), 3.69 (t, 2H), 4.36 (s, 2H), 7.29-7.56 (m, 7H), 7.83 (d, 1H). GC-MS: m/z 319 (M)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1)=[O:2].[CH:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CCCCCCC.CCOC(C)=O>[C:20]([C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=1)#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C#CCCCCC
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C=O)cc2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC#Cc1ccc(C=O)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-formyl-phenyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (60 mg, 70%); 1H NMR δ (CDCl3): 10.02 (s, 1H), 7.8 (d, J=8.65 Hz, 2H), 7.53 (d, J=8.62 Hz, 2H), 2.45 (t, J=7.22 Hz, 2H), 1.62 (p, J=7.11 Hz, 2H), 1.48-1.3 (m, 4H), 0.93 (t, J=7.20 Hz, 3H); LCMS m/z: 200
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([NH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][N:26]=1)[C:22]#[N:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([NH:18][C:19]1[CH:20]=[C:21]([C:22]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:23]=2)[CH:24]=[CH:25][N:26]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCNc1cc(C#N)ccn1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCNc1cc(-c2nc(=O)c3ccccc3s2)ccn1
Yield: 18.1 %

Procedure:
Methyl thiosalicylate (0.44 g, 2.6 mmol) and 2-(hexylamino)isonicotinonitrile (0.26 g, 1.3 mmol) were dissolved in toluene (2.0 ml), and triethylamine (0.40 ml, 2.9 mmol) was added thereto. The reaction mixture was refluxed for 14 hrs, subjected to a silica gel (50 g) chromatography, eluted with hexane-ethyl acetate (2:1, v/v) and recrystallized from ethanol to give the titled compound (0.08 g, 18%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[NH:13][C:14]([CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>P(Cl)(Cl)(Cl)=O>[CH:16]1([C:14]2[NH:13][C:3]3[C:4](=[O:12])[N:5]([CH2:9][CH2:10][CH3:11])[C:6]([Cl:22])=[N:7][C:2]=3[N:1]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCCn1c(=O)[nH]c(N)c(NC(=O)C2CCCC2)c1=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCn1c(Cl)nc2nc(C3CCCC3)[nH]c2c1=O

Procedure:
To a suspension of cyclopentanecarboxylic acid (6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (0.40 g, crude) obtained from step 1 in phosphorus oxychloride (25 ml) was added phosphorus pentachloride (0.10 g) and the resulting reaction mixture was refluxed overnight. Phosphorus oxychloride was evaporated under reduced pressure. The residue was slowly quenched with water. Ethyl acetate was added and the organic layer was separated and washed thoroughly with water followed by brine. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by preparative TLC using dichloromethane, methanol (9:1) as the solvent system to give 0.075 g (19% over two steps) of the product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:15][NH:16][NH2:17]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:17][NH:16][CH3:15])[CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CNN
Reactant: CS(=O)(=O)CC(=O)c1ccc(F)cc1
Solvent: CCO
Product: CNN=C(CS(C)(=O)=O)c1ccc(F)cc1
Yield: 31.9 %

Procedure:
To a 50 ml volume three-necked flask, 1-(4-fluorophenyl)-2-methylsulfonylethan-1-one (7-2-3) (5.0 g), methylhydrazine (14-a) (1.2 g), and ethanol (17.1 ml) were added under a nitrogen atmosphere, and heated to reflux for 4 hours. After the mixture was cooled, the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure. To the residue was added hot hexane to be dissolved. The mixture was left to cool. Then, the precipitated crystals were collected by filtration, washed, and dried under reduced pressure. The crystal was purified by recrystallization (methanol) to give 1.8 g of 1-[1-(4-fluorophenyl)-2-methylsulfonylethylidene]-2-methylhydrazine (5-2-4).
Reaction SMILES: [O:1]=[C:2]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[CH2:11][C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:37][CH2:38][S:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=1>C(#N)C.O>[F:46][C:42]1[CH:41]=[C:40]([S:39][CH2:38][CH2:37][N:8]2[CH2:9][CH2:10][C@@H:5]([CH2:4][CH2:3][C:2](=[O:1])[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]=[CH:18][CH:17]=3)[C@@H:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:7]2)[CH:45]=[CH:44][CH:43]=1
Reactant: COC(=O)C[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Reactant: Fc1cccc(SCCCl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C[C@H]1CN(CCSc2cccc(F)c2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Yield: 103.1 %

Procedure:
2.26 g of methyl(3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate, dissolved beforehand in 50 cm3 of acetonitrile, were added dropwise, with stirring and at a temperature in the region of 20° C., followed by 6.91 g of potassium carbonate and 2 g of potassium iodide, to a solution of 4 g of 1-[(2-chloroethyl)thio]-3-fluorobenzene in 50 cm3 of acetonitrile. The mixture was heated for 18 hours at a temperature in the region of 70° C. After a further addition of 0.3 g of potassium iodide and additional heating at a temperature in the region of 70° C. for 4 hours, the reaction mass was cooled to approximately 20° C., 200 cm3 of water were added and extraction was carried out with 2 times 150 cm3 of ethyl acetate. The combined extracts were washed with 300 cm3 of water, dried over magnesium sulfate, filtered, and evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μ; diameter 5.2 cm; silica volume 950 cm3), elution was carried out with a dichloromethane/methanol (99/1 by volume) mixture, and approximately 6-cm3 fractions were collected. Fractions 24 to 36 were combined and concentrated under the above conditions. 3.3 g of methyl (3R,4R)-1-[2-(3-fluorophenylthio)ethyl]-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate were obtained in the form of an oil with a yellow color.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:17]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[Cs+]>CN(C=O)C>[C:11]1([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([CH2:2][O:21][C:18](=[O:20])[CH3:19])=[CH:17][C:7]=3[N:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccc2oc(-c3ccccc3)nc2c1
Reactant: CC(=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc2oc(-c3ccccc3)nc2c1
Yield: 101.2 %

Procedure:
5-Bromomethyl-2-phenylbenzoxazole 56 (1.0 g, 3.4 mmol) and cesium acetate (1.33 g, 6.94 mmol) were stirred together in DMF(25 ml) under an atmosphere of N2 overnight. The DMF was evaporated under high vacuum and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The ethyl acetate layer was separated then washed and dried. Evaporation of the solvent yielded 920 mg of acetic acid 2-phenylbenzoxazol-5-ylmethyl ester 57.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:13]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:6]=[C:5]([OH:20])[C:4]=1[OH:21].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+]>CC(C)=O.O>[Cl:2][C:3]1[C:13]2[CH2:12][CH2:11][N:10]([C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:25][CH:26]=3)[CH2:9][CH:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:6]=[C:5]([OH:20])[C:4]=1[OH:21]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Oc1cc2c(c(Cl)c1O)CCNCC2c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1ccc(C(F)(F)F)cc1)N1CCc2c(cc(O)c(O)c2Cl)C(c2ccccc2)C1

Procedure:
A solution of 0.74 g (0.002 mole) of 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, 0.55 g (0.0025 mole) of p-trifluoromethyl benzoylchloride, 0.17 g (0.002 mole) of sodium bicarbonate and 40 ml of 1:1 acetone-water solution was stirred overnight under nitrogen. The mixture was evaporated to dryness. The residue was extracted with ethylacetate. The extracted material was purified over a silica gel column using methanol-ethyl acetate to give 6-chloro-7,8-dihydroxy-1-phenyl-3-(p-trifluoromethylbenzoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 243°-245° (dec.).
Reaction SMILES: O1CCCC1.B.[CH3:7][C:8]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=O.[ClH:21]>O1CCCC1>[ClH:21].[CH3:7][C:8]1[C:16]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:14]=[CH:13][C:9]=1[CH2:10][NH2:12]
Reactant: Cc1c(C(N)=O)cccc1C(F)(F)F
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(CN)cccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Borane tetrahydrofuran (1M, 39.4 ml, 39.4 mmol) was added to a solution of 2-methyl-3-trifluoromethyl benzamide (2 g, 9.85 mmol) in tetrahydrofuran (75 ml) and stirred at 70° C. for 5 hrs. LCMS showed incomplete reaction so heating at 70° C. under argon was continued overnight and then for a further 5 hrs following this. The reaction mixture was treated with 2N aqueous hydrogen chloride and stirred at 100° C. for 4 hrs and then left to cool over the weekend. The mixture was reduced to dryness undervacuum and then partitioned between dichloromethane and 2N aqueous sodium hydroxide. The organic layer was separated using a hydrophobic frit and reduced to give a residue which was purified by flash silica column chromatography (eluting with 0-5% 2N ammonia/methanol in dichloromethane). The solvent was evaporated and the residue taken up in diethyl ether and treated with 1M ethereal hydrogen chloride. The solid that precipitated was collected by filtration and this was then triturated with dichloromethane and after filtration 2-Methyl-3-(trifluoromethyl)phenyl]methyl}amine hydrochloride (1.4 g) was obtained as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[ClH:18].[N:19]1(C(=N)N)[CH:23]=[N:22]C=N1>CN(C)C=O.CCOCC>[ClH:18].[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([C:23](=[NH:19])[NH2:22])[CH2:5]1
Reactant: CC1CNCC(C)O1
Reactant: N=C(N)n1cncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1CN(C(=N)N)CC(C)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
A mixture of 2,6-dimethylmorpholine (6.16 ml, 50.0 mmol) (Fluka, a 2.5:1 mixture of cis:trans isomers), diisopropylethylamine (8.73 ml, 50.0 mmol) and 1H-1,2,4-triazole-1-carboximidamide hydrochloride (6.11 g, 55 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 24 hours. The suspension was diluted with ether (50 ml) and the reaction mixture was stirred at room temperature for 10 minutes. The ether layer was decanted off. Ether (50 ml) was added and the process repeated twice. The solid was collected, washed with ether and dried to give the title compound as a colourless solid (7.1 g, 73%) as a 2.3:1 mixture of cis:trans isomers. LC/MS [M+H]+=158.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][C:8](=[O:17])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[CH3:18].[OH-].[Na+:20]>CO>[CH3:1][N:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][C:8](=[O:17])[C:4]([C:5]([O-:7])=[O:6])=[C:3]1[CH3:18].[Na+:20]
Reactant: Cc1c(C(=O)O)c(=O)cc(-c2ccccc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)[O-])c(=O)cc(-c2ccccc2)n1C
Yield: 349.7 %

Procedure:
15 g (0.01617 mol) of 1,2-dimethyl-6-phenyl-4-oxonicotinic acid is suspended in 200 ml of methanol and to it there is added 2.71 g (0.0678 mol) of sodium hydroxide pellets. The solution formed is concentrated in vacuo to afford 15 g (92% yield) of product.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=2)[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:38](Cl)(=[O:44])[O:39][CH2:40][CH2:41][O:42][CH3:43]>C1COCC1>[C:1]1([CH2:7][C:8]([NH:9][C:38](=[O:44])[O:39][CH2:40][CH2:41][O:42][CH3:43])([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:29])([F:30])[F:31])[CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCOC(=O)Cl
Reactant: NC(Cc1ccccc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCCOC(=O)NC(Cc1ccccc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To a solution of 2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethanamine (20 mg, 0.045 mmol) in THF (6 mL) was added 1M K2CO3 (20 mg in 0.1 mL), followed by 2-methoxyethyl carbonochloridate (0.106 mL, 0.91 mmol). The resulting mixture was stirred at rt for 16 h. The crude product was purified by prep HPLC (phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford 2-methoxyethyl 2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethylcarbamate (Example 283) as white lyophillate (12 mg, 51% yield). LCMS: RT=4.19 min [M+H] 544.2 (4 min Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm.
Reaction SMILES: C(S[C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:29])=[CH:14][N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:16]2=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(Cl)Cl.C(O)(=O)C.[S:37]([Cl:41])(Cl)(=[O:39])=[O:38]>O>[Cl:29][C:13]1[C:12]2[C:17](=[CH:18][C:9]([S:37]([Cl:41])(=[O:39])=[O:38])=[CH:10][CH:11]=2)[C:16](=[O:19])[N:15]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH:14]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc(Cn2cc(Cl)c3ccc(SCc4ccccc4)cc3c2=O)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cn2cc(Cl)c3ccc(S(=O)(=O)Cl)cc3c2=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.6 %

Procedure:
A round bottomed flask cooled to 0° C., was charged 7-(benzylthio)-4-chloro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one (0.400 g, 0.948 mmol), DCM (9.03 ml), Acetic Acid (0.226 ml), and Water (0.226 ml). After stirring for 5 minutes at 0° C., sulfuryl chloride (0.077 ml, 0.948 mmol) was added and stirring was continued for an additional 1 hour at 0° C. The reaction was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 0.342 g of 4-chloro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-7-sulfonyl chloride. m/z (ESI) 399.2 (M+H)+.
Reaction SMILES: C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.Cl.CO[C:17]1[CH:39]=[CH:38][C:20]([C:21]([NH:34][CH2:35][CH2:36][NH2:37])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:18]=1.COC1C=CC(C(NCCN)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>C(Cl)Cl.CO>[C:21]([NH:34][CH2:35][CH2:36][NH2:37])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:20]1[CH:38]=[CH:39][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(C(NCCN)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(C(NCCN)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: ClCCl
Solvent: CO
Product: NCCNC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
C21H22N2 (288.42); RF=0.21 (DCM/MeOH 5:1, v/v); spot stains with ninhydrin spray or with HCl vapour); N-(4-monomethoxytrityl)ethylenediamine; C22H24N2O (332.45); RF=0.21 (DCM/MeOH 5:1, v/v); spot stains with ninhydrin spray or with HCl vapour); N-(4,4′-dimethoxytrityl)ethylenediamine; C23H26N2O2 (362.48); RF=0.22 (DCM/MeOH 5:1, v/v); spot stains with ninhydrin spray or with HCl vapour).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[O:23])=[CH:17][CH:16]=3)[N:12]=[C:11]([N:31]3[CH2:36][CH2:35][CH:34]([NH:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[CH2:33][CH2:32]3)[N:10]=1)[CH2:2]2.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>ClCCl>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)=[O:23])=[CH:19][CH:20]=3)[N:12]=[C:11]([N:31]3[CH2:36][CH2:35][CH:34]([NH:37][CH2:38][C:39]([OH:41])=[O:40])[CH2:33][CH2:32]3)[N:10]=1)[CH2:2]2.[C:48]([OH:50])([C:47]([F:52])([F:51])[F:46])=[O:49]
Reactant: CC(C)(C)OC(=O)CNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
Tert-butyl 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate (28 mg) in dichloromethane (3 mL) was treated with trifluoroacetic acid (1 mL) and then concentrated to dryness to give the title compound as its TFA salt.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)[CH3:2].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:18]=2)=[O:8])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: CCc1ccc(C(=O)Nc2ccc(C(=O)CCC(=O)O)cc2)cc1
Yield: 28.3 %

Procedure:
In a manner similar to that described in Example 3, 4-ethyl-benzoyl chloride (0.057 g, 0.00034 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.023 g of 4-[4-(4-ethyl-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+326.