Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[C:5](F)=[CH:4][N:3]=1.[CH3:12][NH:13][NH2:14]>C(O)CO.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:13]([CH3:12])[N:14]=[C:8]([CH3:9])[C:6]=2[N:7]=1
Reactant: CC(=O)c1nc(Cl)ncc1F
Reactant: CNN
Solvent: OCCO
Solvent: O
Product: Cc1nn(C)c2cnc(Cl)nc12
Temperature: 25 °C

Procedure:
A solution of 1-(2-chloro-5-fluoropyrimidin-4-yl)ethanone (4.00 g, 22.91 mmol) and methylhydrazine (0.724 mL, 13.75 mmol) in ethylene glycol was heated at 120° C. for 2 h. Reaction mixture was cooled to rt, diluted with H2O and extracted with ethyl acetate (3×). The combined organic layer was washed with H2O (2×), brine, dried (MgSO4), filtered and concentrated. The residue was purified by CombiFlash (0 to 30% EtOAc/Hex) to give the title compound. LCMS-ESI+: calc'd for C7H8ClN4: 183.0 (M+H+); Found: 183.0 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 4.12 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])[C:2]#[CH:3].C(N(CC)CC)C.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>ClCCl>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([N:4]([CH2:1][C:2]#[CH:3])[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])=[O:26]
Reactant: O=C(Cl)c1ccco1
Reactant: C#CCNc1c(C)cccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN(C(=O)c1ccco1)c1c(C)cccc1C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
A mixture of 3.64 g (0.025 mole) of N-(2-propynyl)-2,6-dimethylbenzenamine and 2.52 g (0.025 mole) of triethylamine in 25 ml of dichloromethane is stirred rapidly under nitrogen at room temperature as 3.06 g (0.025 mole) of 2-furoyl chloride, dissolved in 5 ml of dichloromethane, is added at a moderate rate. Upon addition of the 2-furoyl chloride a vigorous exotherm is noted, causing the solvent to reflux for 2 min. The mixture is stirred for 30 min. and then poured into 200 ml of dichloromethane and washed with water (100 ml), 5% HCl (100 ml), water (100 ml) and brine (100 ml). The organic layer is dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to yield a solid. The solid is washed with n-hexane and vacuum dried to yield 3.65 g (0.0144 mole) of N-(2-furoyl)-N-(2-propynyl)-2,6-dimethylbenzenamine.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]([NH:21][C@H:22]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[C:31]([C:32]([OH:34])=[O:33])[C:25]=3[O:24][B:23]2[OH:35])=[O:20])[CH2:14][CH2:13]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][CH2:9][CH2:10][NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]([NH:21][C@H:22]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[C:31]([C:32]([OH:34])=[O:33])[C:25]=3[O:24][B:23]2[OH:35])=[O:20])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (R)-3-(2-(trans-4-(2-(tert-butoxycarbonylamino)ethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (20 mg) in a flask was added 1 mL 4N HCl in dioxane. The resulting reaction mixture was stirred at RT for 2 hr. The solvent was removed in vacuo and the residue was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 390 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[N:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][CH:24]=2)=[N:15]1.Cl[C:35]([F:40])([F:39])C([O-])=O.[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[F:39][CH:35]([F:40])[N:10]1[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][C:3]([N:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]4[N:27]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:26]=[CH:25][CH:24]=4)=[N:15]3)=[C:2]([F:1])[CH:7]=2)[C:9]1=[O:13]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COc1cn(-c2ccc(N3CCNC3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: COc1cn(-c2ccc(N3CCN(C(F)F)C3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Reaction time: 20 h
Yield: 2.3 %

Procedure:
A mixture of 1-[2-fluoro-4-(2-oxoimidazolidin-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (100 mg, 0.22 mmol), sodium chlorodifluoroacetate (40 mg, 0.26 mmol), and 18-crown-6 (12 mg, 0.044 mmol) in acetonitrile (10 mL) was stirred at 90° C. for 20 h. After cooling to room temperature, to the reaction mixture was added silica gel. This mixture was evaporated, and purified by silica gel column chromatography eluting with AcOEt/MeOH (1/0 to 10/1) to give the title compound (2.5 mg, 2.3% yield) as a pale yellow powder: 1H NMR (300 MHz, DMSO-d6): δ ppm 1.11-1.40 (4H, m), 3.61-3.86 (4H, m), 6.96 (1H, d, J=1.9 Hz), 7.01-7.15 (1H, m), 7.16-7.50 (6H, m), 7.71 (1H, dd, J=13.6, 2.3 Hz), 7.79 (1H, d, J=2.3 Hz), 8.47 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 497 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.CN(C=O)C.C([N:25]=[C:26]=[S:27])(=O)C1C=CC=CC=1>C(Cl)Cl.O>[OH:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH2:25])=[S:27])=[N:7][CH:6]=1
Reactant: Nc1ccc(CCCO)cn1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=S)Nc1ccc(CCCO)cn1
Temperature: 25 °C

Procedure:
3-(6-Amino-pyridin-3-yl)-propan-1-ol (7-3), 2.83 g (19.5 mmol) was stirred in 15 mL of anhydrous CH2Cl2 under Ar. Anhydrous DMF, 5 mL was added and the solution became homogeneous. Benzoylisothiocyanate (2.62 mL, 19.5 mmol) was added and after 2 h the reaction was concentrated in vacuo. To the residue was added 60 mL 1 M NaOH, and 120 mL THF and the resulting mixture was heated to reflux. After 2 h reaction was cooled to RT, and diluted with water (pH 9). The aqueous phase was extracted three times with EtOAc. The combined organic phases was dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (gradient: CH2Cl2 to 95:5 CH2Cl2/MeOH) to afford the pure titled compound. 1H NMR (DMSO-d6) δ 10.57 (bs, 1H), 10.43 (bs, 1H), 8.80 (bs, 1H), 8.05 (d, 1H, J=2.3 Hz), 7.62 (dd, 1H, J=2.4, 8.6 Hz), 7.10 (d, 1H, J=8.7 Hz), 4.48 (t, 1H, J=3.0 Hz), 3.41 (m, 2H), 2.59 (t, 2H, J=6.9 Hz), 1.68 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[H-].[Na+].[SH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[CH3:18][O:17][C:15]([C:14]1[S:13][C:3]2[C:2]([Br:1])=[CH:9][CH:8]=[CH:7][C:4]=2[CH:5]=1)=[O:16]
Reactant: O=Cc1cccc(Br)c1F
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2cccc(Br)c2s1

Procedure:
Using 27.8 g (137.1 mmol) of 3-bromo-2-fluorobenzaldehyde, 8.2 g (205.7 mmol) of sodium hydride (60% pure) and 16.0 g (150.9 mmol) of methyl mercaptoacetate, 20.57 g of a mixture of the title compound and the corresponding acid (about 1:1) are obtained.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[S:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][C:27]1[N:28]=[C:29]([CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[S:30][CH:31]=1.[I-].[K+]>CC(=O)CC>[F:43][C:40]([F:41])([F:42])[C:37]1[CH:38]=[CH:39][C:34](/[CH:33]=[CH:32]/[C:29]2[S:30][CH:31]=[C:27]([CH2:26][O:18][C:15]3[CH:16]=[CH:17][C:12]([C:9]4[S:10][CH:11]=[C:7]([CH2:6][N:1]5[CH:5]=[CH:4][N:3]=[N:2]5)[N:8]=4)=[CH:13][CH:14]=3)[N:28]=2)=[CH:35][CH:36]=1
Reactant: Oc1ccc(-c2nc(Cn3ccnn3)cs2)cc1
Reactant: FC(F)(F)c1ccc(C=Cc2nc(CCl)cs2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(-c4nc(Cn5ccnn5)cs4)cc3)cs2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
A mixture of 0.129 g (0.50 mmol) 4-(4-[1,2,3]triazol-1-ylmethyl-thiazol-2-yl)-phenol and 0.10 g (0.30 mmol) cesium carbonate in 10 ml butanone was stirred at 60° C. for 30 min, then 0.153 g (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-thiazole and 0.083 g (0.50 mmol) potassium iodide were added and stirring at 60° C. continued over night. After evaporation, 15 ml water was added and the mixture extracted with two portions of 15 ml ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide and water, dried over sodium sulfate and evaporated to give 174 mg raw material which was purified on silica. Elution with ethyl acetate/heptane 5:1 yielded 86 mg white crystals (33%) of 1-[2-(4-{2-[2-((E)-4-trifluoromethyl-phenyl)-vinyl]-thiazol-4-ylmethoxy}-phenyl)-thiazol-4-ylmethyl]-1H-[1,2,3]triazole melting at 146-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:39][C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[N:45][CH:46]=2)[N:41]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:39][C:40]4[CH:49]=[CH:48][C:47]5[C:42](=[CH:43][CH:44]=[N:45][CH:46]=5)[N:41]=4)=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=1
Reactant: ClCc1ccc2cnccc2n1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4cnccc4n3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate (EP 419,049, Mar. 27, 1991, Example 1, Step C) (350 mg) in acetonitrile (5 mL) were added Cs2CO3 (489 mg) and 80% pure halide (180 mg) from Step 1. The mixture was stirred at room temperature for 18 hr. then the mixture was poured into 25% aq. NH4OAc (50 mL), extracted with ethyl acetate (2×50 mL), washed with brine (50 mL), dried (MgSO4), and evaporated to dryness. Chromatography of the residue on flash silica gel using ethyl acetate:toluene (2:3) as eluant gave the title compound as a white solid; m.p. 152°-155° C.
Reaction SMILES: Br[CH:2]1[C:6]2[C:7]([Cl:14])=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[O:4][C:3]1([CH3:16])[CH3:15].C(N(CC)CC)C.CS(C)=[O:26]>F[B-](F)(F)F.[Ag+]>[Cl:14][C:7]1[C:6]2[C:2](=[O:26])[C:3]([CH3:16])([CH3:15])[O:4][C:5]=2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=1
Reactant: CS(C)=O
Reactant: CC1(C)Oc2c([N+](=O)[O-])ccc(Cl)c2C1Br
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: CC1(C)Oc2c([N+](=O)[O-])ccc(Cl)c2C1=O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 15.0 g (0.0489 mole) of 3-bromo-4-chloro-2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran in 100 mL of dimethyl sulfoxide was added slowly to a mixture of 9.73 g (0.050 mole) of silver tetrafluoroborate in 100 mL of dimethyl sulfoxide. Upon completion of addition, 5.0 g (0.050 mole) of triethylamine was added to the reaction mixture, and stirring was continued for approximately 16 hours at ambient temperature. At the conclusion of this period the reaction mixture was heated at 60° C. for one hour and then cooled to ambient temperature. The mixture was filtered, and the filtrate was poured into 200 mL of water. This mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure, leaving a residue. This residue was passed through a column of silica gel, yielding 5.35 g of 4-chloro-2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran-3-one as a solid residue, m.p. 167°-168° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH:5]([O:7][CH3:8])[CH2:4][C@H:3]1[OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:1][C@@H:2]1[CH2:6][CH:5]([O:7][CH3:8])[CH2:4][C@H:3]1[O:9][S:18]([CH3:17])(=[O:20])=[O:19])(=[O:20])=[O:19]
Reactant: COC1C[C@@H](O)[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1C[C@@H](OS(C)(=O)=O)[C@H](OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1.33 h

Procedure:
(1R*,2R*)-1,2-Dihydroxy-4-methoxycyclopentane (1.21 g) and triethylamine (7.66 ml) were dissolved in dichloromethane (20 ml), and methanesulfonyl chloride (2.13 ml) was added dropwise over 20 minutes at −78° C. After completion of drop addition, the mixture was warmed to 0° C. and stirred for 80 minutes to obtain crude (1R*,2R*)-1,2-bis(methanesulfonyloxy)-4-methoxy-cyclopentane. This product was dissolved in N,N-dimethylformamide (20 ml), and sodium azide (3.57 g) was added. The mixture was stirred at 65° C. for 22 hours. Sodium azide (3.57 g) was additionally added to stir the mixture at 70° C. for 2 days. The reaction mixture was allowed to cool, and water and diethyl ether was added to separate an organic layer. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate 2:1) to obtain the title compound (584 mg) as a colorless liquid.
Reaction SMILES: [CH:1](=[C:8]1[NH:12][C:11](=[O:13])[C:10]([N:14]=[O:15])=[C:9]1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH2:18]([NH:25][C:9]1[C:8](=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:12][C:11](=[O:13])[C:10]=1[N:14]=[O:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: COC1=C(N=O)C(=O)NC1=Cc1ccccc1
Solvent: CO
Product: O=NC1=C(NCc2ccccc2)C(=Cc2ccccc2)NC1=O
Yield: 60 %

Procedure:
A solution of 0.11 g (0.5 mmol) 5-benzylidene-4-methoxy-3-nitroso-1,5-dihydropyrrol-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in methanol was boiled under reflux with 0.25 ml (0.25 mmol) benzylamine for two minutes. The compound 4-benzylamino-5-benzylidene-3-nitroso-1,5-dihydropyrrol-2-one was obtained as red-violet crystals in a yield of 60% after recrystallization from methanol. The compound decomposes at 220° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1([CH3:32])[CH2:18][CH2:17][N:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:16]1[CH2:17][CH2:18][C:13]([CH3:32])([CH3:12])[CH2:14][CH2:15]1)[C:22]1[CH:23]=[N:24][C:25]([C:28]([F:30])([F:31])[F:29])=[N:26][CH:27]=1)=[O:6]
Reactant: CC1(C)CCN(C(CN)c2cnc(C(F)(F)F)nc2)CC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: CC1(C)CCN(C(CNC(=O)c2cccc(Cl)c2Cl)c2cnc(C(F)(F)F)nc2)CC1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4,4-dimethylpiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:13])([F:12])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10]O)=[N:8][CH:9]=1.O=S(Cl)[Cl:16]>>[Cl:16][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([F:13])([F:12])[F:2])=[CH:9][N:8]=1.[ClH:1].[Cl:16][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([F:13])([F:12])[F:2])=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(C(F)(F)F)cn1
Agent: Cl
Product: FC(F)(F)c1ccc(CCl)nc1
Reaction time: 0.17 h

Procedure:
The mixture of (5-(trifluoromethyl)pyridin-2-yl)methanol HCl salt (293 mg, 1.4 mmol) and SOCl2 (1.5 ml) was stirred for 10 min. After this time, the solution was concentrated under reduced pressure to give the title compound, 2-(chloromethyl)-5-(trifluoromethyl)pyridine HCl salt.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]2[CH:19]=[N:20][CH:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1)(O)=O.S(N)([NH2:25])(=O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>S1(CCCC1)(=O)=O>[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]2[CH:19]=[N:20][CH:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1)#[N:25]
Reactant: O=C(O)CCCCCc1cccc2cncn12
Reactant: NS(N)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: N#CCCCCCc1cccc2cncn12
Temperature: 0 °C

Procedure:
Thionyl chloride (11.42 g) is added slowly at room temperature to a suspension of 5-(5-carboxypentyl)imidazo[1,5-a]pyridine (21.0 g) and sulfamide (10.5 g) in 90 ml of sulfolane. The mixture is heated at 120° until gas evolution ceases and solid p-toluenesulfonic acid monohydrate (1.71 g) is added carefully. After heating an additional 3 hours at 120°, the reaction mixture is cooled, poured onto 200 g of ice and acidified with 130 ml of 1N hydrochloric acid. The aqueous phase is sequentially extracted with ethyl acetate (3×100 ml), made basic with solid sodium bicarbonate and reextracted with ethyl acetate (3×125 ml). The organic extracts are washed with 0.5N sodium hydroxide (5×50 ml), dried over sodium sulfate and evaporated to yield an oil which is chromatographed on 60 g of silica gel with ethyl acetate to yield 5-(5-cyanopentyl)-imidazo[1,5-a]pyridine as an oil.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:11]([O:12]C(=O)C)[CH:10]=[CH:9][CH2:8][O:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:3][CH2:4][CH:6]1[CH:11]([OH:12])[CH:10]=[CH:9][CH2:8][O:7]1
Reactant: CCOC(=O)[C@@H]1OCC=C[C@H]1OC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1OCC=CC1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of trans-3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (56 mg, 0.26 mmol) in THF (5 ml) was added LiAlH4 (62 mg, 1.64 mmol). The resulting solution was stirred at ambient temperature for 15 min and quenched by addition of H2O (10 ml). The solution was diluted with EtOAc (50 ml×2), washed with brine (50 ml), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography with 20% EtOAc-hexane (Rf=0.25 in EtOAc) to give 2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol as a colorless liquid
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10])=[N+:2]=[N-:3].[CH3:11][O:12][CH2:13][C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17].C([Sn](CCCC)(CCCC)C#CC)CCC>>[F:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N:1]1[C:14]([CH2:13][O:12][CH3:11])=[C:15]([Si:16]([CH3:19])([CH3:18])[CH3:17])[N:3]=[N:2]1
Reactant: [N-]=[N+]=Nc1ccccc1F
Reactant: COCC#C[Si](C)(C)C
Agent: CC#C[Sn](CCCC)(CCCC)CCCC
Product: COCc1c([Si](C)(C)C)nnn1-c1ccccc1F

Procedure:
A reaction was carried out by the method mentioned in Example 8-2 except that 1-azido-2-fluorobenzene was used in place of 1-azido-2-chlorobenzene used in Example 1-2 and that (3-methoxy-1-propynyl)-trimethylsilane prepared in the above 1) was used in place of tributyl (1-propynyl)tin used in Example 8-2 to give the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])([O-])=O.[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>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:2]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(OC)ccc1Br
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(OC)ccc1-c1cccs1
Reaction time: 8 h
Yield: 51.3 %

Procedure:
To a degassed solution of methyl 2-bromo-5-methoxybenzoate 8 (0.25 g, 1.020 mmol), 2-thiophene boronic acid 9 (0.170 g, 1.326 mmol), tri-o-tolylphosphine (0.093 g, 0.306 mmol), and K2CO3 (0.423 g, 3.06 mmol) in DME (3 mL) and water (1 mL) was added Pd(Ph3P)4 (0.077 g, 0.066 mmol) and the reaction mixture was placed in a preheated oil bath at 85° C. and stirred overnight. The next morning the reaction was complete by HPLC therefore it was solvent evaporated, diluted with DCM, washed with water, brine, dried over MgSO4, filtered and solvent evaporated to provide compound 10 (0.13 g, 52% yield) as a colorless oil after purification by Biotage (0 to 10% EtOAc in Hexane). LRMS (ESI): (calc.) 248.05 (found) 249.1 (MH)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:37])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:20][N:21]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[C:22]([NH:24][CH3:25])=[O:23])=O)=[CH:11][CH:10]=1)[CH3:7])=[O:5])[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:5])[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]2[N:24]([CH3:25])[C:22](=[O:23])[N:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=3)[N:20]=2)=[CH:11][CH:10]=1)([CH3:37])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)NN(Cc2ccc(C(C)(C)C)cc2)C(=O)NC)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCc2nn(Cc3ccc(C(C)(C)C)cc3)c(=O)n2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(4-t-butyl phenylmethyl)-4-methylsemicarbazide (0.93 g, 1.82 mmol) was dissolved in ethyl acetate (10 mL). Camphorsulfonic acid (0.46 g, 1.98 mmol) was added in one portion and the solution was heated to reflux and stirred for 1 h. The solution was cooled to rt and washed with sat'd aq. NaHCO3 (2×8 mL), 1N HCl (2×8 mL) and sat'd aq. NaCl (8 mL)). The organic phase was dried (MgSO4), filtered and concentrated to afford the title compound as clear, colorless oil (0.84 g, 93.6%): 1H NMR (DMSO-d6) δ 7.30 (d, 2H, J=8 Hz), 7.15 (d, 2H, J=8 Hz), 7.05 (d, 2H, J=8 Hz), 6.68 (d, 2H, J=8 Hz), 4.77 (s, 2H), 4.13 (q, 2H, J=7 Hz), 3.69 (s, 3H), 2.53 (t, 2H, J=8 Hz), 2.47 (t, 2H, J=8 Hz), 1.81 (quint, 2H, J=7 Hz), 1.47 (s, 6H), 1.22 (s, 9H), 1.14 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ 174.0, 154.1, 153.8, 150.4, 147.1, 135.6, 135.0, 129.8, 128.0, 125.9, 119.5, 79.2, 61.6, 48.3, 34.9, 34.1, 31.8, 27.7, 27.6, 25.7, 25.1, 14.6; IR *(CHCl3) 2967, 1695, 1509, 1475, 1232 cm−1; Anal. Calcd. for C29H39N3O4: C, 70.56; H, 7.96; N, 8.51. Found: C, 70.28; H, 7.85; N, 8.43.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([N:13]3[CH2:16][C:15](=O)[CH2:14]3)=[O:12])[S:8][C:7]=2[CH:18]=1.[C:21]([NH:28][CH2:29][CH2:30][NH2:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:24]([O:23][C:21](=[O:22])[NH:28][CH2:29][CH2:30][NH:31][CH:15]1[CH2:16][N:13]([C:11]([C:9]2[S:8][C:7]3[CH:18]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:4]=[CH:5][C:6]=3[CH:10]=2)=[O:12])[CH2:14]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C1CN(C(=O)c2cc3ccc(C(F)(F)F)cc3s2)C1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCNC1CN(C(=O)c2cc3ccc(C(F)(F)F)cc3s2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
To a mixture of 1e (62 mg, 0.207 mmol), N-Boc-ethylenediamine 1f (100 mg, 0.62 mmol), and acetic acid (0.3 mL) in 1,2-dichloroethane (3 mL) was added Na(OAc)3BH (53 mg, 0.25 mmol). The reaction mixture was stirred at room temperature overnight, and was then quenched with aq. NaHCO3. The resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 4% MeOH/CH2Cl2) gave intermediate 1g as colorless oil (30 mg).