Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Al+3:22].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Al+3].[OH:34][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:44]=1[N:43]=[CH:42][CH:41]=[CH:40]2.[OH-].[Na+]>O>[CH:37]1[CH:36]=[C:35]([O-:34])[C:44]2[N:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH:38]=1.[CH:37]1[CH:36]=[C:35]([O-:34])[C:44]2[N:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH:38]=1.[CH:37]1[CH:36]=[C:35]([O-:34])[C:44]2[N:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH:38]=1.[Al+3:22]
Reactant: Oc1cccc2cccnc12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Na+]
Solvent: O
Product: [O-]c1cccc2cccnc12
Yield: 197.6 %

Procedure:
To 93 g of water were added 25 g of aluminum sulfate hexadecahydrate and 35 g of 99% pure 8-hydroxyquinoline and the mixture was neutralized by dropwise addition of 29 g of a 33% solution of sodium hydroxide with stirring and allowed to react. The solid formed was collected by filtration, washed with water and dried to give 36 g of Alq3.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15](O)=[O:16])=[C:10]2[CH:9]=[C:8]([CH2:19][CH3:20])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:57][CH2:58][C:59]([NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:63])[CH2:60][CH2:61][CH3:62]>O1CCCC1>[C:67]([O:66][C:65](=[O:71])[NH:64][C:59]([CH3:63])([CH2:60][CH2:61][CH3:62])[CH2:58][NH:57][C:15]([C:14]1[C:13]([CH3:18])=[N:12][N:11]2[C:6]([O:5][CH2:4][C:3]3[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:2]=3[F:1])=[CH:7][C:8]([CH2:19][CH3:20])=[CH:9][C:10]=12)=[O:16])([CH3:70])([CH3:69])[CH3:68]
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Reactant: CCc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(CC)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 19 %

Procedure:
A solution of 280 mg (0.19 mmol, 23% purity) of 7-[(2,6-difluorobenzyl)oxy]-5-ethyl-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (Example 168A) in 4 ml of tetrahydrofuran was admixed with 43 mg (0.22 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS: 25952-53-8) and 30 mg (0.22 mmol) of 1-hydroxy-7-azabenzotriazole (CAS: 39968-33-7). The solution was stirred at room temperature for 20 minutes. The reaction mixture was admixed with 0.097 ml (0.56 mmol) of N,N-diisopropylethylamine and 48 mg (0.22 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester (Example 152A). The mixture was stirred at room temperature for a further 24 hours, and the reaction mixture was then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was removed and concentrated under reduced pressure. The residue was purified by preparative HPLC chromatography (Method 21), which gave 19 mg (19% yield, 95% purity) of product.
Reaction SMILES: C([C@H:3]([S:7]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-])=[O:5])C.[CH3:42][NH:43][CH2:44][CH2:45][OH:46]>>[CH3:34][N:33]1[C:29]([C:27]([NH:26][C:22]2[CH:21]=[C:20]([C:19]#[C:18][C:16]3[CH:15]=[N:14][CH:13]=[C:12]([CH:17]=3)[C:10]([N:9]=[S@@:7]([CH2:3][C:4]([N:43]([CH2:44][CH2:45][OH:46])[CH3:42])=[O:5])(=[O:8])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:11])[CH:25]=[CH:24][CH:23]=2)=[O:28])=[CH:30][C:31]([CH3:35])=[N:32]1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1
Reactant: CNCCO
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=[S@](=O)(CC(=O)N(C)CCO)c4ccccc4)c3)c2)n(C)n1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate and 2-methylaminoethanol were reacted to give the title compound.
Reaction SMILES: C(O)=O.Cl[S:5]([N:8]=C=O)(=[O:7])=[O:6].[CH3:11][C@@:12]12[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]1[C@H:24]1[C@@H:15]([C:16]3[CH:17]=[CH:18][C:19]([OH:30])=[CH:20][C:21]=3[CH2:22][CH2:23]1)[CH2:14][CH2:13]2>ClCCl.CN(C)C(=O)C>[S:5](=[O:6])(=[O:7])([O:30][C:19]1[CH:18]=[CH:17][C:16]2[C@@H:15]3[C@H:24]([C@H:25]4[C@@:12]([CH2:13][CH2:14]3)([CH3:11])[C:28](=[O:29])[CH2:27][CH2:26]4)[CH2:23][CH2:22][C:21]=2[CH:20]=1)[NH2:8]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Solvent: ClCCl
Solvent: O=CO
Solvent: CC(=O)N(C)C
Product: C[C@]12CC[C@@H]3c4ccc(OS(N)(=O)=O)cc4CC[C@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of formic acid (284.92 mmol) and N,N-dimethyl acetamide (3.03 mmol) was added to a stirred solution of chlorosulfonyl isocyanate (277.47 mmol) in dichloromethane (87.5 ml) at 42° C. within a period of 3.5 hours. The mixture was heated to reflux for 15 minutes and cooled to ambient temperature. The resulting mixture was added to a stirred solution of estrone (184.93 mmol) in N,N-dimethyl acetamide (625 ml) at ambient temperature within a period of 20 minutes. The mixture was stirred at ambient temperature for 17 hours, and then poured onto water (1875 ml). After a while a white precipitate was formed. The suspension was stirred at ambient temperature for another 2 hours, and filtered. The crystals were washed twice with water (250 ml), and used without further drying and purification in the next step (Procedure II). Yield: 87.8 g (wet material) white crystals, purity (HPLC): 99.12%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:22]([O:26][C:27]([NH:29][CH2:30][C:31](=[CH2:35])[C:32](O)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:22]([O:26][C:27]([NH:29][CH2:30][C:31](=[CH2:35])[C:32]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: C=C(CNC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C(CNC(=O)OC(C)(C)C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (300 mg, 1.06 mmol), 2-((tert-butoxycarbonylamino)methyl)acrylic acid (321 mg, 1.60 mmol), HATU (606 mg, 1.59 mmol) and DIPEA (371 μL, 2.13 mmol) in DMF (5.0 mL) was stirred at room temperature for 3 hours. The resulting mixture was diluted with ethyl acetate (15 mL) and washed with saturated aqueous bicarbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier to give ethyl 4-(3-(2-((tert-butoxycarbonylamino)methyl)acrylamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C24H28N5O5 [M+H]+: 466, found 466.
Reaction SMILES: Cl[O-].[Na+].[OH-].[Na+].[F:6][C:7]1([F:30])[O:29][C:10]2=[CH:11][C:12]3[NH:16][C:15]([S:17][CH2:18][C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([CH3:27])=[CH:21][N:20]=4)=[N:14][C:13]=3[CH:28]=[C:9]2[O:8]1.S([O-])([O-])(=[O:33])=S.[Na+].[Na+].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>C(OCC)(=O)C>[F:30][C:7]1([F:6])[O:29][C:10]2=[CH:11][C:12]3[NH:16][C:15]([S:17]([CH2:18][C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([CH3:27])=[CH:21][N:20]=4)=[O:33])=[N:14][C:13]=3[CH:28]=[C:9]2[O:8]1
Reactant: O=S([O-])([O-])=S
Reactant: COc1cc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)ncc1C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(CS(=O)c2nc3cc4c(cc3[nH]2)OC(F)(F)O4)ncc1C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
A mixture of 8 ml commercially available sodium hypochlorite solution (about 15% of active chlorine) and 5 ml of 10% strength sodium hydroxide solution is added dropwise to a suspension of 1.5 g of 2,2-difluoro-6-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-5H-[1,3-]-dioxolo[4,5-f]benzimidazole in 60 ml of ethyl acetate at 0° C. in the course of 20 min., and stirring is continued at 0° C. for 15 min. 0.5 ml of 10% strength sodium thiosulfate solution and 1.3 g of ammonium sulfate are added, the organic phase is separated off and washed with water, the solution is concentrated in vacuo at 30° C. and the residue is crystallized from ethyl acetate. 1.2 g (74%) of the title compound of m.p. 175°-176° C. (decomposition) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][C:8]([OH:12])([CH3:11])[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].CO.C(N(CC)CC)C.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][C:8]([OH:12])([CH3:11])[CH2:7][N:6]1[S:43]([C:40]1[CH:39]=[CH:38][C:37]([O:36][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:42][CH:41]=1)(=[O:45])=[O:44])=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)C1CCC(C)(O)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(C)(O)CN1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To a mixture of 5-hydroxy-5-methyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.08 g) and 5 mL of methanol was added 10 drops of 12 M aqueous HCl. After stirring for 1 hour, the mixture was concentrated in vacuo, and the residue was dissolved in 1 mL of DMF. After cooling to 0° C., the mixture was treated with triethylamine (0.11 mL, 0.80 mmol) and 4-benzyloxy-benzenesulfonyl chloride (0.11 g, 0.40 mmol). After stirring for 2 h at room temperature, the mixture was diluted with ethyl acetate, washed 2× with 1M HCl, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by radial chromatography (2:1 hexane-ethyl acetate, 2 mm silica gel plate) affording 0.047 g of 1-(4-benzyloxy-benzenesulfonyl)-5-hydroxy-5-methyl-piperidine-2-carboxylic acid methyl ester as a colorless solid.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([CH:2]1[CH2:3][CH2:4][O:5][C:1]1=[O:6])=[O:13]
Reactant: O=C1CCCO1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)C2CCOC2=O)c1
Reaction time: 1 h
Yield: 35.9 %

Procedure:
A solution of γ-butyrolactone (2 g, 23.3 mmol) in dehydrated tetrahydrofuran (250 ml) was cooled to −78° C. under a nitrogen atmosphere, and dehydrated tetrahydrofuran solution of 3-methoxybenzoyl chloride (4.17 g, 24.5 mmol) was added, followed by slow addition of lithium hexamethyldisilazide (LHMDS, 1M tetrahydrofuran solution, 46.6 ml, 46.6 mmol). After stirring for 1 hour, saturated sodium hydrogencarbonate aqueous solution (50 ml) was added at −78° C. followed by quenching. After extraction with ethyl acetate (200 ml), the organic layer was washed with brine (2×200 ml), dried over sodium sulfate, and subsequently the solvent was removed under reduced pressure, to obtain a crude product as a yellow oil. The crude was purified by silica gel column chromatography (hexane/ethyl acetate=50/50), to obtain the desired compound as a yellow solid (1.84 g, 36%).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].O.S(=O)(=O)(O)O.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[CH2:17][CH2:16][CH2:15]2>C(Cl)(Cl)Cl>[F:11][C:12]1[CH:21]=[CH:20][C:19]2[NH:1][C:18](=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCc2cc(F)ccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1CCCc2cc(F)ccc2N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 11.6 %

Procedure:
Sodium azide 1.1 g (16.92 mmol) was added to a mixture of 6.0 mL of chloroform and 1.1 mL of water at 0° C. Concentrated sulfuric acid (0.44 mL) was added dropwise and the mixture stirred at 0° C. for two hours then filtered. The chloroform layer containing hydrazoic acid was added to a solution of 1.3 g (7.92 mmol) of 6-fluoro-1-tetralone (prepared by the method of Allinger and Jones, J. Org. Chem., 27, 70-76 (1962)) in 4.8 mL of chloroform. Additional sulfuric acid (2.16 mL) was added dropwise with stirring while maintaining the temperature below 40° C. The mixture was stirred at 40° C. for two hours then at room temperature for 16 hours. The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was added to ice; the resulting recipitate was extracted with methylene chloride (5x). The combined extracts were washed with brine, dried over magnesium sulfate and filtered through a silica plug. Solvents were removed under vacuum to afford 162 mg (0.92 mmol, 11%) of the product. 1H NMR (300MHz, CDCl3): 2.21 (m,2H), 2.32 (t,7Hz,2H), 2.7 (t,7Hz,2H), 6.93 (m,3H), 7.8 (br s,1H). FAB-MS: calculated for C10H10FNO 179; found 180 (M+H,100%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCC[CH2:8]1.[C:12]([C:16]1([OH:24])[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH2:17]1)([O:14][CH3:15])=O.[OH-].[Na+].OCC1(O)C2CCN(CC2)C1.C(=O)C.B(F)(F)F.[OH-].[K+]>O1CCCC1.C(Cl)Cl.O.C(OCC)(=O)C>[CH3:8][CH:15]1[O:24][C:16]2([CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17]2)[CH2:12][O:14]1
Reactant: COC(=O)C1(O)CN2CCC1CC2
Reactant: C1CCOC1
Agent: CC=O
Agent: FB(F)F
Agent: OCC1(O)CN2CCC1CC2
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC1OCC2(CN3CCC2CC3)O1
Temperature: 0 °C

Procedure:
To a stirred suspension of 17.5 g. lithium aluminum hydride in 100 ml dry tetrahydrofuran there was added during 1 hour a solution of 3-carbomethoxy-3-quinuclidinol tetrahydrofuran, 50 g in 100 ml. This was prepared according to Grob. Helv. Chim. Acta, 37, 1689 (1954). The reaction mixture was refluxed during 41/2 hours, treated with 20 ml ethyl acetate under nitrogen, then with water (17 ml) then with 15% aqueous sodium hydroxide (17 ml.), and again with water, 51 ml. The resulting mixture was filtered and the filtrate was evaporated under reduced pressure, leaving as residue a syrup, 35 g., comprising 3-hydroxymethyl-3-quinuclidinol. A quantity of 5 g. of this syrup was treated with 20 ml. acetaldehyde and 20 ml. of methylene chloride. The resulting emulsion was cooled to 0° C and treated under agitation with 20 ml boron trifluoride ethereate for 1 hour. The resulting mixture was then poured on water containing an excess of potassium hydroxide and stirred until a complete decomposition of boron trifluoride had taken place. The mixture was extracted with ether and the extract was subjected to evaporation under reduced pressure. The residue consisted of crude 2-methyl spiro (1,3-dioxolane-4,3') quinuclidine, B.P.=68°-72° at 0.2 mm-Hg , Rf on neutral alumina (ethyl acetate) = 0.6; M+ - 183. This product consists of a mixture of the two isomers wherein the methyl group is in one case in the cis-position (70%), the other in the trans-position (30%) respective to the nitrogen of the ring. The mixture was resolved into the two isomers by column chromatography on neutral alumina with ethyl acetate. The hydrochlorides of these were prepared by treatment of the two substances in dry acetone with gaseous hydrogen chloride, M.P. (cis-isomer) 233.8° (dec.); of the mixture : 234.2° (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Yield: 95.8 %

Procedure:
4-(5-Bromopyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.01 g), 4-fluorophenylboronic acid (0.45 g), tetrakis(triphenylphosphine)palladium(0) (0.12 g) and potassium phosphate (1.25 g) were dissolved in a mixture of 1,2-dimethoxyethane (40 ml) and water (10 ml), degassed and heated to reflux under nitrogen. After 16 h. the reaction was cooled, reduced in vacuo, dissolved in diethyl ether (100 ml) and washed with water (3×20 ml), saturated brine (20 ml), dried (Na2SO4) and evaporated. The black residue was then chromatographed on silica, with 2% methanol/dichloromethane to provide the title compound as a pale yellow solid (1.01 g, 96%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24]>>[OH:24][CH2:23][C:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:26])[CH3:25]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 2-amino-2-methyl-1-propanol (CAN 124-68-5) as starting materials, MS (EI): m/e=356.2 [M+H]+.
Reaction SMILES: [C:1]([S:4][C:5]1[S:9][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[N:7][CH:6]=1)(=O)[CH3:2].CC(C)([O-])C.[K+].BrCC1[O:23][C:24]([CH3:28])=[C:25]([CH3:27])[N:26]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:27][C:25]1[N:26]=[C:2]([CH2:1][S:4][C:5]2[S:9][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[N:7][CH:6]=2)[O:23][C:24]=1[CH3:28]
Reactant: Cc1nc(CBr)oc1C
Reactant: CC(=O)Nc1ncc(SC(C)=O)s1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(SCc2nc(C)c(C)o2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
N-[5-(Acetylthio)-2-thiazolyl]acetamide (0.050 g, 0.23 mmol) was dissolved in dry THF (10 ml) and here potassiumtert-butoxide (1.0 M solution in THF, 0.25 ml, 0.25 mmol) was added to the mixture. The reaction mixture was stirred at rt for 15 min., and 2-(bromomethyl)-4,5-dimethyloxazole (0.064 g, 0.34 mmol) was added to this mixture. The reaction mixture was stirred at rt for 3 h and saturated aqueous NaHCO3 solution (20 mL) was added to the mixture. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layers was concentrated. The residue was purified by flash column chromatography (SiO2 ; methanol:dichloromethane/1:20) to afford N-[5-[[(4,5-dimethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide (15 mg, 23%) as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[C:19]([Cl:26])[CH:18]=1>ClCCl.CCCCCC>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:15][NH:14][C:12](=[O:13])[CH2:11][C@@H:8]2[CH2:9][CH2:10][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:7]2)=[O:25])=[C:19]([Cl:26])[CH:18]=1
Reactant: O=C=Nc1ccc(Br)cc1Cl
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1Cl
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (700 mg, 3.31 mmol) in dry dichloromethane (15 mL) was added 4-bromo-2-chloro-1-isocyanatobenzene (770 mg, 3.31 mmol). The reaction was stirred overnight, diluted with hexane (15 mL), and the precipitate collected and washed with hexane to provide the title compound (1.3 g, 2.93 mmol, 88% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.85 (br. s, 1H), 8.82 (br. s, 1H), 8.50-8.23 (m, 1H), 8.05 (dd, J=5.3, 8.8 Hz, 1H), 7.72 (d, J=1.8 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 3.81 (dd, J=7.6, 9.9 Hz, 0.5H), 3.77-3.39 (m, 2H), 3.31-3.13 (m, 1H), 2.94 (d, J=19.5 Hz, 0.5H), 2.64-2.54 (m, 0.5H), 2.47-2.39 (m, 0.5H), 2.28 (dd, J=7.3, 16.7 Hz, 2H), 2.17-1.88 (m, 1H), 1.80-1.47 (m, 2H), 0.81-0.61 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:20][C:21](=[CH2:23])[CH3:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)OC(C)(C)C)c(Cl)c1
Temperature: -78 °C

Procedure:
To 24.9 g of 2-chloro-4-(methoxycarbonyl)benzoic acid and 2 mL of Sulfuric Acid in 350 mL of DCM was added isobutylene gas at −78° C. until the solvent was saturated and capped off securely. Let go several days at room temperature and re-cool to −78° C. before removing cap. Concentrate solvent, extract with Ethyl Acetate and bicarbonate, dry with Magnesium Sulfate, filter and concentrate to give 31.4 g of 1-tert-butyl 4-methyl 2-chloroterephthalate. 3.35 g of 1-tert-butyl 4-methyl 2-chloroterephthalate was hydrolyzed via Procedure M. 2.5 g of 4-(tert-butoxycarbonyl)-3-chlorobenzoic acid was was cooled to 0° C. in 25 mL of THF before a solution of 19.5 mL of 1M BH3-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at ˜50% complete by TLC. The reaction is re-cooled to 0° C. and another 19.5 mL of BH3-THF is added dropwise before the ice bath is removed. Upon completion, the reaction is re-cooled to 0° C. and quenched with 3N HCl dropwise. The aqueous layer was extracted two times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 564 mg of tert-butyl 2-chloro-4-(hydroxymethyl)benzoate was cooled to 0° C. in 5 mL of DCM before adding 665 mg of Triphenylphosphine and 417 mg of NBS. Reaction was concentrated and directly purified via ISCO Combi-Flash to give pure tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 147 mg of tert-butyl 4-(bromomethyl)-2-chlorobenzoate was reacted with 2,2,2-trifluoroethanamine in DMSO via Procedure P. 141 mg of tert-butyl 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoate was treated with 4N HCl in Dioxane at 45° C. and concentrated to give 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 75 mg of 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to give pure 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2,2,2-trifluoroethylamino)methyl)benzamide. MS (Q1) 454.6 (M)+.