Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([OH:18])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.C1C(=O)N([Br:26])C(=O)C1.O>C(#N)C>[Br:26][C:14]1[C:15]2[C:10](=[CH:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)=[CH:17][CH:16]=2)[CH:11]=[CH:12][C:13]=1[OH:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccc(-c2ccc3cc(O)ccc3c2)cc1
Solvent: CC#N
Solvent: O
Product: Oc1ccc(-c2ccc3c(Br)c(O)ccc3c2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of 6-(4-hydroxyphenyl)-2-naphthol (4.02 g, 17.0 mmol) in acetonitrile (150 mL) at 0° C. was added NBS (3.03 g, 17.0 mmol). The reaction was stirred at 0° C. for 3 hr and then poured into water (200 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered, evaporation of the solvent, and purification by silica column chromatography (20% ethyl acetate—hexanes) yielded 5.33 g (100%) of the title compound as a tan solid. The title compound was further purified by reverse phase HPLC to yield a white solid: mp 208-210° C.; 1H NMR (DMSO-d6): δ 6.89 (2H, d, J=8.47 Hz), 7.28 (1H, d, J=8.80 Hz), 7.63 (2H, d, J=8.50 Hz), 7.85 (2H, d, J=8.84 Hz), 8.02-8.06 (2H, m), 9.60 (1H, s), 10.54 (1H, s); MS (ESI) m/z 313/315 (M−H)−.
Reaction SMILES: COC1C=CC(C[S:8][C:9]2[C:14](=[O:15])[N:13]3[C:16]4([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[NH:17][C:18](=[O:19])[C:12]3=[C:11]([CH3:25])[CH:10]=2)=CC=1.CS(O)(=O)=O.O>C(Cl)(Cl)Cl>[SH:8][C:9]1[C:14](=[O:15])[N:13]2[C:16]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:17][C:18](=[O:19])[C:12]2=[C:11]([CH3:25])[CH:10]=1
Reactant: COc1ccc(CSc2cc(C)c3n(c2=O)C2(CCCCC2)NC3=O)cc1
Agent: CS(=O)(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(S)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 6′-((4-methoxybenzyl)thio)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (3, 3.3 g, 8.58 mmol) in chloroform (40 mL) is added methanesulfonic acid (3 mL, 46.23 mmol). The reaction is stirred at 50° C. overnight. The resulting mixture is cooled to room temperature, poured into water and extracted with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated. The crude is purified via column chromatography to afford 6′-mercapto-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (4).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([NH:18][NH2:19])=[N:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>ClCCl>[C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([NH:18][NH:19][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[N:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)C(=O)Cl
Reactant: NNc1ccc(-c2ocnc2-c2ccccc2)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)NNc1ccc(-c2ocnc2-c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-Phenyl-oxazol-5-yl)-pyridin-2-yl-hydrazine (2.5 g, 9.9 mmol), and N,N-diisopropylethylamine (8.6 mL, 50 mmol) in dichloromethane (8 mL) at 0° C. was added dropwise isobutyryl chloride (1.04 mL, 9.9 mmol); the mixture was stirred at 0° C. for 2 hours. The reaction was quenched with water and extracted with dichloromethane (3×). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to a dark sticky solid. The residue was purified by flash chromatography (eluting with ethyl acetate/hexanes 3:1) to give the title compound as a yellow solid.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].O1CCCC1.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22]I)=[O:16])([CH3:13])([CH3:12])[CH3:11].[NH4+].[Cl-]>C(OCC)C.[Cu]I>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][CH:1]=[CH2:2])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CI
Reactant: C=C[Mg]Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -36 °C
Reaction time: 6 h

Procedure:
Under a nitrogen atmosphere, a solution of vinylmagnesium bromide, 1.0 M in tetrahydrofuran (2.0 mL, 2.0 mmol) was slowly added to a suspension of copper(I) iodide (244.9 mg, 1.28 mmol) in dry diethyl ether (10 mL) at −78° C. Upon completion of the addition, the mixture was warmed to −36° C. for 5 min and was then cooled to −78° C. A solution of (2S)-N-(tert-butoxycarbonyl)-2-(iodomethyl)pyrrolidine (200.0 mg, 0.64 mmol) in dry diethyl ether (5 mL) was added over a period of 10 min. The reaction mixture was warmed to −36° C. and was stirred at −36° C. for 6 h. The resulting dark mixture was treated with saturated aqueous NH4Cl solution (5 mL) and was stirred while warming to ambient temperature. The reaction mixture was extracted with diethyl ether (4×10 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated under vacuum to yield a pale-yellow oil (200 mg). The product was purified by column chromatography, eluting with hexane:ethyl acetate (1:1). Fractions containing the product were combined and concentrated under vacuum to afford 100 mg (73.6%) of an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[Cl:37][C:38]1[CH:39]=[C:40]2[C:48](=[CH:49][CH:50]=1)[N:47](C)[C:46]1C=CC(C(=O)C)=CC2=1.[OH-].[K+]>C(O)C>[Cl:37][C:38]1[CH:50]=[C:49]2[C:48](=[CH:40][CH:39]=1)[N:47]([CH3:46])[C:3]1[CH:4]=[CH:5][C:6]([C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)=[CH:7][C:2]2=1
Reactant: CC(=O)c1ccc2c(c1)c1cc(Cl)ccc1n2C
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c2ccc(Cl)cc2c2cc(-c3ccc4cc(-c5nc6cc(C(=O)O)ccc6n5C5CCCCC5)ccc4n3)ccc21
Yield: 12 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(6-chloro-9-methyl-9H-carbazol-3-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (18 mg, 12% yield). MS: 585.21 (M+H+); HPLC Procedure A, retention time=16.25 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8].[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>C(Cl)Cl.CCN(C(C)C)C(C)C>[Br:1][C:2]1[C:3]([N:16]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:22](=[O:25])[CH:23]=[CH2:24])=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8]
Reactant: C=CC(=O)Cl
Reactant: Cc1nc(-n2c(C)ccc2C)nc(NN2CCCC2)c1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N(c1nc(-n2c(C)ccc2C)nc(C)c1Br)N1CCCC1
Reaction time: 1 h

Procedure:
To a reaction solution of 5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methyl-N-(pyrrolidin-1-yl)pyrimidin-4-amine (3.14 g, 8.97 mmol) in anhyrous methylene chloride (120 ml) and hunig's base (4.68 ml) was added slowly a solution of acryloyl chloride (0.80 ml, 9.86 mmol) in methylene chloride (30 ml) dropwise at R.T. After stirring at R.T for 60 mins, the reaction mixture was concentrated under reduced pressure and the residue was purified by 120 g column eluted with 40% ethyl acetate:hexane to give the titled product weighted 3.5 g a white solid 97%
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][C@@H:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][C@@H:17]2[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.IC.[CH2:37](OCC)C>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][C@@H:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][C@@H:17]2[N:25]([CH3:37])[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(OCc2ccccc2)cc1
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1Cc2ccccc2[C@H]1Oc1ccc(OCc2ccccc2)cc1

Procedure:
The title compound was prepared in a similar manner to Preparation 19 from sodium hydride (80% disp. in oil, 83 mg, 2.76 mmol) in dry N,N-dimethylformamide (5 ml), (±)cis-1-(4-benzyloxy phenoxy)-2-tert-butoxycarbonylaminoindane (1 g, 2.3 mmol) in N,N-dimethylformamide (5 ml) and iodomethane (175 μl, 2.76 mmol). Column chromatography on silica gel eluting with a gradient of 10-15% diethyl ether in hexanes afforded the title compound (968 mg) as a colourless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@H:19]([C:28]([N:30]([CH2:40][C:41]1[C:42]2[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=2[S:44][CH:45]=1)[C@@H:31]([CH3:39])[CH:32]([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[S:44]1[CH:45]=[C:41]([CH2:40][N:30]([C@@H:31]([CH3:39])[CH:32]([O:33][CH2:34][CH3:35])[O:36][CH2:37][CH3:38])[C:28](=[O:29])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:12]([CH3:13])[NH:11][C:9](=[O:10])[NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C:42]2[CH:49]=[CH:48][CH:47]=[CH:46][C:43]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 77 mg (0.32 mmol) was coupled with (S)-tert-butyl 3-amino-4-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-4-oxobutanoate (Compound IV-18) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:41]([NH:44][CH2:45][CH2:46][CH2:47][NH2:48])([CH3:43])[CH3:42]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:48][CH2:47][CH2:46][CH2:45][NH:44][CH:41]([CH3:43])[CH3:42])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)NCCCN
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)NCCCNC(=O)[C@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and N-isopropyl-1,3-propanediamine (34 mg) according to Method B to give the title compound (26 mg). 1H-NMR (400 MHz, CD3OD) d 7.46 (d, J=2.2 Hz, 1H), 7.36 (dd, J=2.2 Hz, J=6.2 Hz, 1H), 7.29-7.20 (m, 5H), 7.08 (d, J=8.4 Hz, 1H), 4.68 (s, 2H), 4.44 (dd, J=5.7 Hz, J=9.9 Hz, 1H), 4.30 (dd, J=5.5 Hz, J=9.2 Hz, 1H), 3.27 (m, 2H), 3.06 (m, 2H), 2.89 (dd, J=10.1 Hz, J=13.0 Hz, 1H), 2.80 (m, 2H), 2.65 (m, 2H), 1.30 (dd, J=2.9 Hz, J=6.6 Hz); IR (KBr) cm−1; HRMS m/z 628.3082 (calc. of monoisotopic mass for C32H44N4O9 gives 628.3108).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH2:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(OC(=O)C)C>[CH3:23][C:22]([NH:20][CH2:19][C@@H:17]1[O:16][C:15](=[O:21])[N:14]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)=[C:2]([F:1])[CH:3]=2)[CH2:18]1)=[O:24]
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (10 gm) and ethylacetate (100 ml), acetic anhydride (10 ml) is slowly added at ambient temperature, then stirred at ambient temperature for 1 hour. The separated solid is filtered and dried under reduced pressure at 50° C. to give 9.5 gm of linezolid form III.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[NH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:29]=[C:25]([C:24]([F:23])([F:34])[F:35])[N:26]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[N:27]=1
Reactant: FC(F)(F)c1cc(C(F)(F)F)[nH]n1
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(CO)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(Cn3nc(C(F)(F)F)cc3C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.9 %

Procedure:
(R)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (50 mg, 0.19 mmol) was dissolved in DCM (5 mL) and cooled to 0° C. before thionyl chloride (110 mg, 0.93 mmol) was added. The reaction mixture was stirred at room temperature for 1 h before being concentrated to dryness. The whole was dissolved in DMF (3 mL) to this was added 3,5-bis(trifluoromethyl)-1H-pyrazole (38 mg 0.19 mmol) followed by potassium carbonate (51 mg, 0.37 mmol). The reaction mixture was heated to 60° C. for 2 h before being quenched with water (2 mL) and the organics extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Purification by preparative acidic HPLC gave (R)—N-(5-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (1.7 mg, 3.7 μmol, 2.0%). MS (ESI): m/z [M+H]+ 456.1
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:12])=[N+:7]([O-])[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].C([O-])([O-])=[O:14].[K+].[K+]>CC(OC(C)=O)=O.CO>[CH2:1]([C:5]1[C:6]([CH2:12][OH:14])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1c(CC(C)C)ccc[n+]1[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CC(C)Cc1cccnc1CO
Temperature: 100 °C
Reaction time: 16 h

Procedure:
3-Isobutyl-2-methyl-pyridine-1-oxide (821 mg, 4.97 mmol) was dissolved in Ac2O (10 mL) and stirred at 100° C. for 16 hours. The Ac2O was removed under reduced pressure and the resulting brown oil was quenched with saturated NaHCO3 (30 mL) and extracted with CH2Cl2 (6×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to yield a brown oil. Purification was avoided at this step due to the identical Rf values of the two products formed. The brown oil was dissolved in MeOH (20 mL) and powdered K2CO3 (2.05 g) was added. The mixture was stirred at room temperature for 2.5 hours. The solid was removed via suction filtration and the filtrate was concentrated in vacuo to give a brown oil. Purification via column chromatography on silica gel (CH2Cl2:MeOH, 95:5, v/v) afforded (3-isobutyl-pyridin-2-yl)-methanol as a yellow oil (383 mg, 78%, 2-steps). 1H NMR (CDCl3) δ 0.93 (d, 6H, J=6.0 Hz), 1.86 (m, 1H), 2.38 (d, 2H, J=6.0 Hz), 4.73 (s, 2H), 4.90 (br s, 1H), 7.18 (dd, 1H, J=9.0, 3.0 Hz), 7.45 (d, 1H, J=9.0), 8.41 (d, 1H, J=6.0 Hz).
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[S:7][C:6]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:4])=[O:3].[NH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>C(Cl)(Cl)Cl>[CH3:23][O:22][C:20]([CH2:19][NH:18][S:2]([C:5]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[S:7][C:6]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:4])=[O:3])=[O:21]
Reactant: COC(=O)c1sc(C(F)(F)F)cc1S(=O)(=O)Cl
Reactant: COC(=O)CN
Solvent: ClC(Cl)Cl
Product: COC(=O)CNS(=O)(=O)c1cc(C(F)(F)F)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
103.8 g of methyl 3-chlorosulfonyl-5-trifluoromethyl-thiophene-2-carboxylate are dissolved in 600 ml of chloroform, 68.05 g of freshly distilled methyl glycinate are added dropwise thereto in a manner such that the temperature does not exceed 30°, the mixture is stirred at room temperature for an additional 0.5 hour and then extracted three times with 200 ml of 1N hydrochloric acid each time. The organic phase is dried over sodium sulfate and evaporated. The oily residue is stirred with 175 ml of diisopropyl ether, and there is obtained methyl 3-[(methoxycarbonylmethyl)sulfamoyl]-5-trifluoromethyl-thiophene-2-carboxylate in the form of colorless crystals which are removed by filtration under suction and washed with diisopropyl ether. The product melts at 76°-78° after recrystallization from diisopropyl ether.
Reaction SMILES: C[Zn]C.Cl[C:5]1[CH:10]=[C:9]([C:11]#[C:12][C:13]2[CH:14]=[N:15][N:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][C:19]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[N:18][C:17]=23)[CH:8]=[CH:7][N:6]=1.[CH3:36]COC(C)=O>C1COCC1.C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:36][C:5]1[CH:10]=[C:9]([C:11]#[C:12][C:13]2[CH:14]=[N:15][N:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][C:19]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[N:18][C:17]=23)[CH:8]=[CH:7][N:6]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccnc(Cl)c4)c3n2)cc1
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Zn]C
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)ccn1
Yield: 26 %

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (710 mg, 2.0 mmol) and 2-chloro-4-iodopyridine [CAS 153034-86-7; commercially available] (479 mg, 2.0 mmol) according to general procedure II to produce the intermediate 3-(2-chloro-pyridin-4-ylethynyl)-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (569 mg, 61%) as a yellow solid. MS (ISP) 467 [(M+H)+] and 469 [(M+2+H)+]; mp 200° C. This material was transformed to the title compound as follows: In a dried flask under argon, dimethylzinc-solution (2M in toluene, 0.16 mL, 0.33 mmol) was added to a solution of the above prepared 3-(2-chloro-pyridin-4-ylethynyl)-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (233 mg, 0.50 mmol) and Pd(PPh3)4 (17 mg, 3 mol %) in THF (1.7 mL) at 23° C. The reaction mixture was warmed up slowly and refluxed for 2 h. The reaction mixture was poured in sat. NaHCO3-sol., shaken with EtOAc and filtered through Celite. The organic layer was extracted twice with 1N HCl, the combined aqueous layer were made alkaline with 32% NaOH-sol., extracted with EtOAc, the organic washed with sat. NaCl-sol., dried over Na2SO4 and evaporated. The obtained crude product was purified by MPLC with heptane/EtOAc, followed by trituration with ether to give the title 3-(2-methyl-pyridin-4-ylethynyl)-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (59 mg, 26%) as a yellow solid. MS (ISP) 447 [(M+H)+]; mp 206° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][OH:10].[K].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[OH:10][CH2:9][C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[O:5][CH2:4][CH2:3][CH2:2][N:19]1[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25]
Reactant: OCc1cccc(OCCCCl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CO)c1
Yield: 76.9 %

Procedure:
m-(3-Chloropropyloxy)benzyl alcohol (14 g), phthalimide potassium salt (13 g) and tetra-n-butyl ammonium hydrogen sulfate (2 g) were suspended in 200 g of acetonitrile. The suspension was refluxed for 18 hours. After cooling, the insoluble matter was removed by filtration, and the filtrate was concentrated. The concentrate was taken into ethyl acetate, washed with a 1N aqueous solution of sodium hydroxide and water, and then dried. The solvent was evaporated, and the residue was recrystallized from ethanol to give 16.7 g (yield 76.9%) of N-[3-(3-hydroxymethylphenoxy)propyl]phthalimide.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C@H:5]1[C:10](=O)[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][C:7](=O)[NH:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:12]([N:9]1[CH2:8][CH2:7][NH:6][C@@H:5]([CH2:4][CH2:3][OH:2])[CH2:10]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC[C@H]1CN(Cc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a 0° C. solution of (S)-(4-benzyl-3,6-dioxopiperazin-2-yl)acetic acid methyl ester (31.9 g, 0.12 mol) in tetrahydrofuran (1 L), add lithium aluminum hydride via slow cannulation (350 mL of a commercial 1.0 M solution in tetrahydrofuran). Stir at room temperature overnight, quench by successive careful addition of 13.3 mL of water, 13.3 mL of 15% aqueous sodium hydroxyde, and 39.9 mL of water, all the while with vigourous stirring to ensure formation of a fine precipitate. Filter through a fritted funnel, washing the solids well with tetrahydrofuran and dichloromethane. Concentrate in vacuo to provide 26.5 g of an oily residue, apply directly to a silica gel column. Elute with a 5% mixture of 7N ammonia-methanol in dichloromethane, to obtain the desired product as an orange oil which solidifies under vacuum. Take up the solid in acetonitrile and sonicate for a few minutes. Filter the resulting precipitate to obtain 7.5 g (25%) of the title compound as an off-white crystalline solid, mp 78.9-80.4° C. Concentrate the mother liquor to obtain 6.8 g (23%) of slightly less pure material as an amorphous solid: mass spectrum (ES): m/e 221.3 (M+1); specific Rotation: −7.84.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].S(=O)(=O)(O)O.[C:17](=O)([O-])[O-].[Na+].[Na+]>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Br)c(O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Br)c(O)c1
Temperature: 0 °C
Yield: 89 %

Procedure:
To a solution of 4-bromo-3-hydroxybenzoic acid (30 mmol) in methanol (100 mL) was added concentrated sulfuric acid (2.6 mL). The solution was heated at reflux for 5 hours, cooled to 0° C., and then brought to pH 7 by adding saturated aqueous sodium carbonate. The solution was evaporated to one-third the original volume. Water was added and the product was extracted into ethyl acetate. The organic extracts were washed with water and brine and dried over anhydrous sodium sulfate. Evaporation gave 6.15 g (89%) of the product as a white solid, m.p. 130-132° C.