Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO[S:3]([O-:5])=O.[K+].[OH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH:14][C:15]1S[C:17]2[CH:23]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]([NH:33][CH3:34])=[O:32])[CH:26]=3)[CH:21]=[CH:20][C:18]=2[N:19]=1>O.CO>[OH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH:14][C:15]1[S:3](=[O:5])[C:20]2[CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]([NH:33][CH3:34])=[O:32])[CH:26]=3)[CH:23]=[CH:17][C:18]=2[N:19]=1
Reactant: O=S([O-])OO
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)ccn1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CNC(=O)c1cc(Oc2ccc3c(c2)S(=O)C(N[C@@H]2CCCC[C@H]2O)=N3)ccn1
Reaction time: 23 h

Procedure:
A solution of OXONE® (KHSO5, 380 mg, mmol) in water (4 ml) was added dropwise to a solution of 4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (25 mg, mmol) in methanol (4 ml) at rt. After stirring for 23 hours the suspension is diluted with water (50 ml) and extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with brine, concentrated, and purified by prep HPLC to yield the title compound as white solid. Yield: 2.4 mg. ES/MS m/z 415.1 (MH+), Rt=1.81 min.
Reaction SMILES: C([N:8]([CH:20]1[CH2:26][CH2:25][CH2:24][C:23]2[CH:27]=[C:28]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:29]=[CH:30][C:22]=2[CH2:21]1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:36]([O:35][C:33]([CH2:32][O:31][C:28]1[CH:29]=[CH:30][C:22]2[CH2:21][CH:20]([NH:8][CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:26][CH2:25][CH2:24][C:23]=2[CH:27]=1)=[O:34])[CH3:37]
Reactant: [H][H]
Reactant: CCOC(=O)COc1ccc2c(c1)CCCC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)C2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1ccc2c(c1)CCCC(NC[C@H](O)COc1ccccc1)C2
Yield: 92.2 %

Procedure:
A mixture of (2S)-1-[N-benzyl-(2-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (362 mg) and 10% Pd/C (50% wet, 100 mg) in ethanol (4 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 5 hours and filtered. The filtrate was evaporated in vacuo and the residue was chromatographed (dichloromethane-ethanol) over silica gel (6 g) to afford (2S)-1-[(2-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (274 mg) as a pale yellow oil. The oil (95 mg) and oxalic acid (20 mg) were dissolved in ethanol and the solution was evaporated in vacuo. The residue was powdered from ether to afford (2S)-1-[(2-ethoxycarbonylmethoxy-6,7,8, 9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol oxalate (1;1) (85 mg) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([OH:13])=O)[CH:6]=1)=[O:4].S(Cl)(Cl)=O.Cl.[CH3:19][NH:20][CH3:21].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(Cl)Cl.ClCl.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11](=[O:13])[N:20]([CH3:21])[CH3:19])[CH:6]=1)=[O:4]
Reactant: CNC
Reactant: COC(=O)c1ccnc(C(=O)O)c1
Agent: Cl
Agent: ClCl
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccnc(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
A mixture of compound 26 (73 g, 0.4 mole), thionyl chloride (88 ml, 1.2 mole) in toluene (200 ml) was heated at reflux for 3 hours. The excess thionyl chloride was removed at an atmospheric pressure. Then toluene was removed under reduced pressure. The resulting light green acid chloride 27 was used without further purification. A solution of acid chloride 27 in CH2Cl2 (100 ml) was added to a suspension of dimethylamine hydrochloride (98.6 g, 1.2 mole) and triethylamine (1.3 mole) in CH2 Cl2 (200 ml) at 0° C. dropwise over a period 10 minutes and stirred for 1 hour at room temperature. Water (200 ml) was added to the reaction mixture, water layer was extracted with CH2Cl2. The combined organic layers were washed with 1N NaOH, brine, dried over MgSO4 and concentrated down. The crude solid was purified by silica gel short column chromatography (EtOAc as eluent) to give compound 28 (47 g, 226 mmole, 56%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#N)=[CH:9][CH:8]=1)=[O:6])[CH3:2].C(O)=[O:17]>[Ni]>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:17])=[CH:9][CH:8]=1)[OH:6])[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(C#N)cc1
Reactant: O=CO
Agent: [Ni]
Product: CCOC(=O)C(O)c1ccc(C=O)cc1

Procedure:
A mixture of (4-cyano-phenyl)-oxo-acetic acid ethyl ester 0.41 g, 2.0 mmol) in 25 mL of 90% formic acid and a large excess of Raney nickel (50% slurry in water) was refluxed for 1 hr. The solid was filtered off and the liquid was concentrated. The crude material was purified by silica gel chromatography (5˜100% ethyl acetate/hexane) to give 0.35 g of (4-formyl-phenyl)-hydroxy-acetic acid ethyl ester as an oil.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].B1C2CCCC1CCC2.C(CN)O>O1CCCC1>[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)COc2ccc(C(=O)OC)cc21
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Solvent: NCCO
Product: CCCCN1CCOc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of methyl 4-butyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (800 mg) and 9-BBN (1.6 g) in tetrahydrofuran (13 mL) was refluxed for 1.5 h. The mixture was cooled to room temperature, ethanolamine (0.4 mL) was added, and the resulting solution was concentrated under reduced pressure. The residue was washed with hexanes, filtered, and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (silica, 25% ethyl acetate/hexanes) afforded 607 mg of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 7.21, 7.16, 6.75, 4.24-4.21, 3.78, 3.34-3.24, 1.55-1.47, 1.38-1.30, 0.95-0.90.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[N:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:8]=2[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[N:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:8]=2[C:9]([OH:11])=[O:10])=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1Oc1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(F)(F)F)cnc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
A mixture of methyl 2-(4-fluorophenoxy)-5-(trifluoromethyl)nicotinate (step 2, 32 mg, 0.10 mmol) and 4.0 M lithium hydroxide aqueous solution (1.0 mL, 4.0 mmol) in a mixture of tetrahydrofuran (2 mL) and dioxane (10 mL) was stirred for 3 h at room temperature. The pH value was adjusted to 4.0 by the addition of 2 N hydrochloric acid. The mixture was diluted with water (100 mL) and extracted with dichloromethane (20 mL×3). The combined organic extracts were washed with brine (50 mL), dried (sodium sulfate), and concentrated to afford 29 mg (99%) of the title compound: MS (ESI) m/z 256 (M−45)−.—
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:18][C:17]([CH3:28])([CH3:27])[C:16]=3[CH:29]=2)=[O:10])=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([OH:24])=[O:23])[CH2:18][C:17]([CH3:28])([CH3:27])[C:16]=3[CH:29]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC1CC(C)(C)c2cc(NC(=O)c3ccc(C=NN)cc3)ccc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(CC(=O)O)Oc2ccc(NC(=O)c3ccc(C=NN)cc3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.3 g (0.67 mmol) of the ester from Example 79 were suspended in 10 ml ethanol followed by addition of 1 ml aqueous 2 N sodium hydroxide. It was stirred at room temperature for 4 hours. The mixture was filtered, the filtrate concentrated to dryness under reduced pressure, and the residue was dissolved in water. It was then neutralized with diluted acetic acid, and the precipitate of the compound (336) was filtered with suction, washed thoroughly with water, and dried in vacuo at 50° C. Yield: 0.2 g (78%) of a yellow crystalline solid, m.p. 248-250° C.
Reaction SMILES: N1CCCC([C:7]2[O:8][C:9]3[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)C1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.CN(C)CC(O)=O>C.[Cl-].[Cl-]>[O:8]1[C:9]2[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=[CH:7]1
Reactant: NC(=O)c1cccc2nc(C3CCCNC3)oc12
Agent: C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)CC(=O)O
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc2ncoc12
Temperature: 25 °C
Yield: 7 %

Procedure:
A mixture of 2-(piperidin-3-yl)benzo[d]oxazole-7-carboxamide (160 mg, 1.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (82.4 mg, 0.61 mmol), 1-hydroxybenzotriazole (82 mg, 0.61 mmol), triethyl amine (117 mg, 0.61 mmol), 2-(dimethylamino)acetic acid (83 mg, 0.61 mmol) were added in 50 ml dichloride methane and stirred at room temperature over night. The mixture was evaporated under reduced pressure and purified by pre-HPLC. 13 mg 2-(1-(2-dimethylamino)acetyl)piperidin-3-yl)benzo[d]oxazole-7-carboxamide was obtained. Yield 7%. 1H-NMR (400 MHz, CD3OD): δ 1.52-1.65 (m, 1H), 1.77-1.85 (m, 1H), 2.15-2.31 (m, 8H), 2.20-2.28 (m, 2H), 3.31-3.39 (m, 2H), 3.75-3.90 (m, 2H), 4.42-4.36 (m, 1H), 7.44-7.47 (m, 1H), 7.81-7.88 (m, 2H). LC-MS (ESI) m/z: 331 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1([CH3:16])[CH3:15].[C:18](OC(=O)C)(=[O:20])C>C(O)=O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]([CH:18]=[O:20])[CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1([CH3:15])[CH3:16]
Reactant: COC(=O)CNC1c2ccccc2CC1(C)C
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COC(=O)CN(C=O)C1c2ccccc2CC1(C)C
Reaction time: 18.5 h

Procedure:
936 g of N-(2,2-dimethyl-indan-1-yl)glycine methyl ester are added dropwise with cooling to 5° C. to 1817 ml of formic acid. Additionally 664 ml of acetic anhydride are added, and the mixture is kept at room temperature for 18.5 hours. Destillation under vacuum affords 1015 g of N-formyl-N-(2,2-dimethyl-indan-1-yl)glycine methyl ester.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 1-benzhydryl-azetidin-3-ol (50 g, 0.208 mol) in dry pyridine (500 mL) was cooled to 5° C. Methane sulfonyl chloride (16.2 mL, 0.208 mol) was added over 30 minutes. The mixture was slowly (12 hours) brought to ambient temperature and stirring was continued for additional 2 hours. The solvent was removed in vacuo at 40° to 50° C. The residue was redissolved in methylene chloride, washed with water (2×), and dried. The crude material was triturated with a solution of t-butylmethylether/petroleum ether (15:85), to produce the purified product as crystals. (53 g, 80% yield). M.Pt.: 85°-87° C. MS
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][NH:18][C:17](=[O:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][C:29]([Cl:35])=[CH:30][CH:31]=2)[N:26]=1>CN(C=O)C.O>[Cl:35][C:29]1[CH:28]=[C:27]2[C:32]([CH:33]=[CH:34][C:25]([CH2:24][N:18]3[CH2:19][CH:15]([C:9]4[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[CH:8]=4)[CH2:16][C:17]3=[O:20])=[N:26]2)=[CH:31][CH:30]=1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC1CCCC1
Reactant: ClCc1ccc2ccc(Cl)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2CC(=O)N(Cc3ccc4ccc(Cl)cc4n3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[3-Cyclopentyloxy-4-methoxyphenyl]-2-pyrrolidinone (1.00 g, 3.63 mmol, 1.0 eq) was added to a room temperature suspension of (145 mg, 3.63 mmol, 1.0 eq) NaH (60% oil dispersion) in 30 ml of anhydrous DMF. After stirring at room temperature for 1 hour, (0.77 g, 3.63 mmol, 1.0 eq) 2-chloromethyl-7-chloroquinoline was added, and the reaction mixture was allowed to stir at room temperature for 60 hours. The reaction mixture was then diluted with 250 mL H2O and extracted with ethyl acetate. The ethyl acetate extract was washed twice with H2O, once with brine, dried over Na2SO4 and concentrated to yield a yellow oil. Silica gel chromatography eluting with 5% CH3OH/CH2Cl2 followed by recrystallization from ethyl acetate-hexane yielded 0.61 g, 37%, of white crystals. M.P.: 106°-107° C. Elemental Analysis Calc'd for C26H27N2O3Cl: Calc'd: C, 69.15; H, 6.03; N, 6.21. Found: C, 69.22; H, 5.75; N, 615.
Reaction SMILES: [C:1]([O:5][C:6]1[C:11]([OH:12])=[C:10]([F:13])[N:9]=[C:8]([F:14])[C:7]=1[F:15])([CH3:4])([CH3:3])[CH3:2].[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]1[C:11]([O:12][CH3:16])=[C:10]([F:13])[N:9]=[C:8]([F:14])[C:7]=1[F:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1c(O)c(F)nc(F)c1F
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(F)nc(F)c(F)c1OC(C)(C)C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
To a solution of 237 mg (1.07 mmol) of 4-t-butoxy-2,3,6-trifluoro-5-hydroxypyridine, from step 275a above, in 3 mL of anhydrous THF was added 335 mg (1.277 mmol) of triphenyl phosphine and 0.060 mL (1.48 mmol) of methanol. To this solution was added 0.200 mL (1.270 mmol) of DEAD dropwise at room temperature. The reaction was complete in 10 min, so the solvents were removed under vacuum and the residue was purified by flash chromatography on silica gel, eluting with 1:16 ethyl acetate:hexane to give 215.6 mg of the title product as a colorless liquid after removal of the solvent.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.C1C2C(=CC=CC=2)C=CC=1[Mg]Br.N#N.C[C:29]1[CH:30]=[C:31]([CH:45]=[CH:46][C:47]=1C)/[CH:32]=[C:33]1\CC[C:36]2NC(C(OC)=O)=[CH:39][C:40]\1=2>C1COCC1.[Pd].CCOCC>[CH:39]1[C:30]2[C:31](=[CH:45][CH:46]=[CH:47][CH:29]=2)[CH:32]=[CH:33][C:40]=1[CH2:36][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)CC/C2=C\c1ccc(C)c(C)c1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Agent: [Pd]
Agent: Br[Mg]c1ccc2ccccc2c1
Agent: N#N
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc2ccccc2c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (1.00 g, 5.58 mmol) was reacted with 2-naphthalenylmagnesium bromide (55 mL, 21 mmol) according to General Procedure 3. In this example, the 2-naphthalenylmagnesium bromide was first placed in a separate flask and the Et2O was blown off with N2. The residue was then dissolved in 50 mL THF, and added to the 4-oxo solution over 20 min via cannulae. The resulting exo-olefin ((E)-methyl 4-(naphthalen-2-ylmethylene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was converted to the title compound by hydrogenation according to General Procedure 6 (with 10% Pd/C). The crude product was used in the next step without further purification. 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.16 (ddt, J=12.27, 8.77, 6.00, 6.00 Hz, 1H) 2.51-2.62 (m, 1H) 2.62-2.78 (m, 2H) 2.97 (d, J=7.61 Hz, 2H) 3.37-3.46 (m, 1H) 3.67-3.69 (m, 3 H) 6.27 (d, J=1.71 Hz, 1H) 7.40-7.52 (m, 3H) 7.73 (s, 1H) 7.81-7.91 (m, 3H) 10.47 (br. s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([O:17]S(C3C=CC(C)=CC=3)(=O)=O)[CH:16]=[C:12]2[C:11]([CH3:28])=[N:10][N:9]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:17])[CH:16]=[C:12]2[C:11]([CH3:28])=[N:10][N:9]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc3c(C)nnc(-c4ccccc4F)n3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc(-c2ccccc2F)n2nc(O)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
To a stirred solution of toluene-4-sulfonic acid 7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (3.39 g, 8.51 mmol) in 1,4-dioxane (150 ml) and water (30 ml) was added 4 N aqueous NaOH (10.64 ml, 42.6 mmol) and the mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo to about 30 ml, and the aqueous residue was diluted with water (150 ml) and washed with ethyl acetate (50 ml). The remaining aqueous layer was acidified to pH 5 with 5 N aqueous HCl (4 ml) and the resulting precipitate was collected by filtration, washed with water and dried at 60° C. under vacuum to leave 1.98 g (95%) of the title compound as a cream solid: 1H NMR (360 MHz, DMSO-d6) δ 2.68 (3H, s), 6.38 (1H, s), 7.41-7.47 (2H, m), 7.66-7.77 (2H, m); MS (ES+) m/e 245 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[O:16][CH:17]([CH3:19])[CH3:18].[Li+].[OH-].Cl>C1COCC1>[CH:17]([O:16][C:7]1[CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:4][C:3]([OH:20])=[O:2])([CH3:19])[CH3:18]
Reactant: COC(=O)C=Cc1ccc(C(F)(F)F)cc1OC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C(F)(F)F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
To a suspension of 3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (15 mg, 0.052 mmol) in THF (1 ml) was added a solution of 0.5 N-LiOH (0.2 ml), and the resulting mixture was stirred for 3 hours at room temperature. The reaction mixture was acidified with 1N HCl to pH 1˜2. The mixture solution was extracted three times with methylene chloride, and the combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give 3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylic acid (14 mg, 98%). To a suspension of 3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylic acid (14 mg, 0.051 mmol) and N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HCl salt (17.2 mg, 0.060 mmol) in DMF (2 mL) was added N-methylmorpholine (0.007 ml, 0.060 mmol). The mixture was stirred for 5 minutes, to which were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (26 mg, 0.132 mmol). The mixture was stirred for 12 hours at room temperature, and then diluted with EtOAc (4 mL). The organic layer was washed with 1N HCl, water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography (Hex/EtOAc=1/1) to give the title compound (24 mg, 79%).
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:23])[CH2:4][C@H:5]([NH2:22])[C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:10][CH:11]=1.[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30](F)=[N:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>N#N>[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([NH:22][C@H:5]([C:6]2[CH:7]=[N:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:10][CH:11]=2)[CH2:4][CH:3]([CH3:23])[CH3:2])=[N:29][CH:28]=1
Reactant: COC(=O)c1ccc(F)nc1
Reactant: CC(C)C[C@H](N)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: Cl
Agent: N#N
Agent: O=C([O-])[O-]
Product: COC(=O)c1ccc(N[C@@H](CC(C)C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)nc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 94.5 %

Procedure:
(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamine hydrochloride (31.33 g, 90.60 mmol) was combined with 6-fluoro-nicotinic acid methyl ester (16.9 g, 109 mmol) and K2CO3 (37.6 g, 272 mmol, 325 mesh) in a 500 mL N2-purged round bottom. Anhydrous dimethylformamide (115 mL) was added. The reaction was heated to 100° C. as a suspension. At 35 min another 3.00 g of 6-fluoro-nicotinic acid methyl ester was added. At 20 h, the reaction was placed in an ice bath and when the internal temperature was below room temperature sat. NH4Cl (500 mL) was added. This was stirred for a couple minutes in the bath and then the bath was removed and stirred at room temperature. Ethyl acetate (600 mL) and a small amount of water were added and the layers separated. The aqueous was extracted with ethyl acetate (150 mL) and the combined organics were washed with additional sat. NH4Cl (125 mL). The aqueous was back extracted with ethyl acetate (50 mL). The combined organics were dried over MgSO4. Purification was done by silica gel flash chromatography (ethyl acetate/heptane) to give impure 6-{(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]butylamino}-nicotinic acid methyl ester (38.07 g) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.85 (s, 2H) 8.69 (d, J=1.6 Hz, 1H) 8.55 (d, J=8.2 Hz, 2H) 8.01 (dd, J=8.8, 2.1 Hz, 1H) 7.74 (d, J=8.4 Hz, 2H) 6.39 (d, J=8.8 Hz, 1H) 5.01 (q, J=6.9 Hz, 1H) 3.86 (s, 3H) 1.85-1.98 (m, 1H) 1.70-1.82 (m, 2H) 1.05 (d, J=6.2 Hz, 3H) 1.01 (d, J=6.0 Hz, 3H); MS (M+1): 445.3.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:8]([C:9]2[C:14]([CH2:15][Br:16])=[CH:13][C:12]([O:17]C)=[CH:11][C:10]=2[O:19]C)=[C:7]([O:21]C)[CH:6]=[C:5]([O:23]C)[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:23])[CH:6]=[C:7]([OH:21])[C:8]=1[C:9]1[C:10]([OH:19])=[CH:11][C:12]([OH:17])=[CH:13][C:14]=1[CH2:15][Br:16]
Reactant: COc1cc(CBr)c(-c2c(CBr)cc(OC)cc2OC)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(O)c(-c2c(O)cc(O)cc2CBr)c(CBr)c1
Reaction time: 48 h

Procedure:
6,6′-bis-bromomethyl-2,4,2′,4′-tetramethoxy-biphenyl (685 mg) was dissolved in DCM (3.0 mL), and 1M BBr3 in DCM (16.4 mL) was slowly added. After stirring for 2 days, the mixture was poured on to ice and concentrated. The crude material was used for the next step without a further purification.
Reaction SMILES: [CH3:1][C@@:2]1([C:8]([OH:10])=O)[CH2:6][O:5][C:4](=[O:7])[O:3]1.C(Cl)(=O)C([Cl:14])=O.CN(C=O)C>ClCCl>[CH3:1][C@@:2]1([C:8]([Cl:14])=[O:10])[CH2:6][O:5][C:4](=[O:7])[O:3]1
Reactant: C[C@@]1(C(=O)O)COC(=O)O1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@]1(C(=O)Cl)COC(=O)O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound prepared in Example 184 (330 mg) in dichloromethane (11 mL) were added oxalyl chloride (290 μL) and DMF (0.1 mL) and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated in vacuum condition to give the title compound (2.0 g) having the following physical data as a coarse product. This compound was used for the next reaction without being purified.