Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].C(N(CC)C(C)C)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.[NH2:62][C:63]1([C:66]([NH:68][CH3:69])=[O:67])[CH2:65][CH2:64]1>CN(C=O)C.O>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:62][C:63]2([C:66](=[O:67])[NH:68][CH3:69])[CH2:65][CH2:64]2)=[O:19])[CH:8]=1)=[O:5]
Reactant: CNC(=O)C1(N)CC1
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)c(Cl)cc2Cl)n(-c2ccccc2)n1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)C1(NC(=O)c2cc(NC(=O)c3cc(-c4ncccc4F)c(Cl)cc3Cl)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.1 %

Procedure:
To a solution of 5-(2,4-dichloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 107, 961 mg, 2.04 mmol) in DMF (20 mL), were added N,N-diisopropylethylamine (0.8 mL, 5.5 mmol) and TPTU (848 mg, 2.85 mmol) and the mixture stirred at room temperature for 5 minutes. 1-Amino-N-methylcyclopropanecarboxamide (PCT Int. Appl., 2008051547) (300 mg, 2.65 mmol) was then added and the mixture stirred for 30 minutes. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous brine solution, dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography over silica gel, eluting with EtOAc to afford the title compound as a white solid (916 mg, 79%). Crystallisation by vapour diffusion using methanol as the solvent and acetonitrile as the anti-solvent also afforded the title compound as crystalline colourless needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[N:21]=[CH:22][CH:23]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:33]1[CH:34]=[CH:35][N:31]([C:28]2[CH:27]=[CH:26][C:25]([CH2:24][N:20]3[N:21]=[CH:22][CH:23]=[N:19]3)=[CH:30][CH:29]=2)[C:32]1=[O:36])[CH3:12]
Reactant: O=c1[nH]ccn1-c1ccc(Cn2nccn2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](n1ccn(-c2ccc(Cn3nccn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 1-[4-(2H-1,2,3-triazol-2-ylmethyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-1,2,3-triazol-2-ylmethyl)phenyl]-2(1H,3H)-imidazolone (Compound 20).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.C(N(CC)CC)C.[C:21](C(CC(N)=O)C(N)=O)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CN(C=O)C>[C:25]1([CH2:24][O:23][C:21]([NH:1][CH2:2][CH:3]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]2)=[O:22])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NC(=O)CC(C(N)=O)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(CNC(=O)OCc2ccccc2)C1
Reaction time: 18 h
Yield: 64 %

Procedure:
To a solution of 1,1-dimethylethyl 3-(aminomethyl)-1-azetidinecarboxylate (5.0 g, 26.84 mmole) in DMF (40 mL) was added triethylamine (4.9 mL, 34.9 mmole) and Cbz-succinamide (8.7 g, 34.9 mmole). After 18 hours, the reaction solution was concentrated under vacuum and redissolved in EtOAc (250 mL). The organic solution was washed with H2O (2×150 mL), brine (100 mL) and dried over Na2SO4 and concentrated. The remaining residue was purified on silica (hexanes/EtOAc, 1:1) to give the title compound (5.5 g, 64%) as a light yellow oil: LC-MS (ES) m/e 321 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1>O1CCCC1>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[OH:16])[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [Li]c1cccs1
Reactant: O=CC1CCN(CCc2ccccc2)CC1
Solvent: C1CCOC1
Product: OC(c1cccs1)C1CCN(CCc2ccccc2)CC1
Temperature: -78 °C

Procedure:
Dissolve 1-(2-phenylethyl)-4-piperidinecarboxaldehyde (10.0 g, 46.02 mmol) in anhydrous tetrahydrofuran (300 mL), place under an argon atmosphere and cool to -78° C. Add, by dropwise addition, a solution of 2-lithiothiophene (46.02 mL of a 1M solution in tetrahydrofuran, 46.02 mmol) and stir for 3 hours at -78° C. Quench with saturated ammonium chloride, separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (ethyl acetate) and recrystallize (cyclohexane) to give the title compound as a white solid; mp 123°-125° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][C@@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: C[C@H](NC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.090 mmol), L-alanine (1061 mg, 11.9 mmol) and NaOMe solution (18 mL, 9 mmol, 0.5 M in MeOH) was refluxed for 48 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated to give a crude solid. The solid was dissolved in saturated NaHCO3 and washed with ether. 4 M HCl was added to the aqueous layer until pH was about 1, and the resulting precipitate was isolated by filtration to give 25 mg of the title compound as an off-white solid. MS: (+) m/z 393.25 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(OC)C=CC=CC=1.[CH:13]1[C:22]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][C:14]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:69]CC2C=CC=CC=2)=[C:28]([C@@H:30]2[O:59][C@H:58]([CH2:60][O:61]CC3C=CC=CC=3)[C@@H:49]([O:50]CC3C=CC=CC=3)[C@H:40]([O:41]CC3C=CC=CC=3)[C@H:31]2[O:32]CC2C=CC=CC=2)[CH:29]=1.O>C(Cl)Cl>[CH:13]1[C:22]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][C:14]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:69])=[C:28]([C@@H:30]2[O:59][C@H:58]([CH2:60][OH:61])[C@@H:49]([OH:50])[C@H:40]([OH:41])[C@H:31]2[OH:32])[CH:29]=1
Reactant: c1ccc(COC[C@H]2O[C@@H](c3cc(Cc4cc5cccccc-5c4)ccc3OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: COc1ccccc1
Product: OC[C@H]1O[C@@H](c2cc(Cc3cc4cccccc-4c3)ccc2O)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
Aluminum chloride (0.12 g) and anisole (4.0 ml) were added to a solution of (1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-(benzyloxy)phenyl]-2,3,4,6-tetra-O-benzyl-D-glucitol (0.07 g) in methylene chloride (5 ml) and the mixture was stirred at room temperature for two hours. The reaction mixture was poured into ice-cooled water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-hydroxyphenyl]-D-glucitol (0.01 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[CH:11](O)[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@@H:14]1[CH2:26][OH:27].C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[CH:11]1[O:27][CH2:26][C@H:14]2[CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:17][CH2:18][N:13]2[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc(F)c(C#N)c2Cl)[C@@H](CO)C1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN2CC(c3ccc(F)c(C#N)c3Cl)OC[C@H]2C1
Temperature: 100 °C

Procedure:
(3R)-tert-butyl 4-(2-(2-chloro-3-cyano-4-fluorophenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (15.6 g, 37.3 mmol) and cyanomethylene tri-n-butyl phosphorane (16.4 g, 67.8 mmol) were dissolved in benzene (90 mL), degassed and heated at 100° C. for 16 h. The reaction mixture was concentrated and chromatographed through a 330 g ISCO Redi-sep column and eluted with 35% EtOAc/hexane to yield the title compound (cis-trans diastereomers mixture). LC-MS (IE, m/z): 396 [M+1]+; The cis-trans diastereomers were separated by SFC-HPLC using the following condition: Chiralpak AD 21×250 mm, 20% IPA, 50 ml/min, ˜85 mg/mL in 1:1 MeOH/MeCN, 100 bar, 220 nm, 35° C. 31A: 1H-NMR (600 MHz, CDCl3) δ ppm 7.826 (dd, J=8.7, 6.5 Hz, 1H), 7.184 (t, J=8.4 Hz, 1H), 4.975 (dd, J=9.6, 1.9 Hz, 1H), 3.989 (b, 2H), 3.953 (dd, J=5.7, 3.2 Hz, 1H) 3.484 (t, J=10.85 Hz, 1H), 3.015 (dd, J=11.4, 2.2 Hz, 2H), 2.733 (d, J=10.3 Hz, 1H), 2.52 (b, 1H), 2.18-2.26 (m, 2H), 1.981 (t, J=10.85 Hz, 1H), 1.474 (s, 9H). 31B: 1H-NMR (600 MHz, CDCl3) δ ppm 8.331 (s, 1H), 7.163 (t, J=8.35 Hz, 1H), 5.038 (t, J=3.7 Hz, 1H), 3.738-3.947 (b, 2H), 3.649 (d, J=10.9 Hz, 1H) 3.371 (s, 1H), 3.02 (dd, J=12, 4.1 Hz, 2H), 2.843 (dd, J=12, 3.8 Hz, 1H), 2.784 (d, J=9.4 Hz, 2H), 2.556 (b, 2H), 1.471 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][C:17]#[N:18])[C:4]=2[N:3]=1.N1CCOCC1.Cl.C(Cl)(Cl)Cl>C1COCC1.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][C:17]#[N:18])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CC#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: N#CCn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Reaction time: 2 h
Yield: 24.9 %

Procedure:
A solution of [8-chloro-2,6-dioxo-7-(2-propen-1-yl)-1,2,6,7-tetrahydro-3H-purin-3-yl]acetonitrile (0.084 g, 0.32 mmol) in THF (5 ml) was degassed by the successive application of vacuum and nitrogen pressure to the reaction mixture. The solution was subsequently treated with morpholine (0.3 ml, 3.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.03 mmol). After 2 hours, the mixture was treated with 2M aqueous hydrochloric acid (3 ml) and chloroform (5 ml). The mixture was separated and the organic phase evaporated. The product was purified from the residue using mass-directed HPLC, to afford the title compound as a white solid (0.018 g, 25%). NMR δH (400 MHz, d6-DMSO) 4.95 (s, 2H), 11.49 (s, 1H), 14.63 (br. s, 1H); m/z 226 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1B1OC(C)(C)C(C)(C)O1.Br[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[N:22]([C@@H:28]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:29][OH:30])[CH2:21]2.C(N(CC)C(C)C)(C)C.O1CCOCC1.O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[N:22]([C@@H:28]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:29][OH:30])[CH2:21]2
Reactant: O=C1c2ccc(Br)cc2CN1[C@H](CO)Cc1cccc(F)c1
Reactant: Cn1ncc(Cl)c1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: Cn1ncc(Cl)c1-c1ccc2c(c1)CN([C@H](CO)Cc1cccc(F)c1)C2=O
Yield: 66.6 %

Procedure:
A mixture of 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (177.0 mg, 0.7297 mmol), bis(tri-t-butylphosphine)palladium (31.1 mg, 0.0608 mmol), 5-bromo-2-[(1S)-1-(3-fluorobenzyl)-2-hydroxyethyl]isoindolin-1-one (220.0 mg, 0.6081 mmol) and N,N-diisopropylethylamine (0.318 mL, 1.82 mmol) in 1,4-dioxane (3 mL, 40 mmol) and water (150 μL, 8.3 mmol) was microwaved at 110° C. for 15 minutes. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash chromatography eluting with EtOAc/hexane (30-100%) to give 0.162 g (67% yield) of the desired product as yellowish solid. LC/MS found: 399.9 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([CH2:14][O:15][Si](C)(C)C(C)(C)C)[N:3]1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.F.N1C=CC=CC=1.P(=O)(O)(O)O>C1COCC1.N1C=CC=CC=1>[OH:15][CH2:14][C@H:4]1[N:3]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:2](=[O:1])[C@H:5]1[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: F
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
N-{(3S,4S)-2-oxo-1-(phenylmethoxy)-4-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]azetidin-3-yl}(tert-butoxy)carboxamide (2.80 g, 6.41 mmol) was dissolved in THF (50 mL) and pyridine (5 mL). Pyridine-hydrofluoride complex (4.0 mL, 2.6 eq of pyridine, 24 eq of HF) was added at −20° C. After 10 min, the mixture was warmed up at room temperature and stirred for 3.5 h. Phosphoric acid buffer (0.025 M, KH2PO4/Na2HPO4; ratio 1/1, 400 mL) was added and the resulting solution was extracted with ethyl acetate (3×100 mL). The organic phase was dried over Na2SO4 and the solvent was evaporated in vacuo. 2.04 g of the desired product was obtained and used for the next step.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[C:8]([OH:26])([CH3:25])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.[NH3:27].CO>C1COCC1>[OH:26][C:8]1([CH3:25])[C:7]2[S:6][C:5]([C:3]([NH2:27])=[O:2])=[N:14][C:13]=2[C:12]2[CH:15]=[C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])[CH:17]=[CH:18][C:11]=2[O:10][CH2:9]1
Reactant: COC(=O)c1nc2c(s1)C(C)(O)COc1ccc(C#CC(C)(C)O)cc1-2
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(C)(O)CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (312 mg, 0.84 mmol) in THF (8 mL) at room temperature, NH3/CH3OH (self-made, 8 mL) was added. The mixture was stirred at room temperature for 3 h, and then concentrated to give a residue which was purified by flash column chromatography (silica gel, EtOAc in hexane from 0 to 50%) to give 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as an off-white solid (212 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 8.57 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 7.90 (s, 1H), 7.31 (dd, J1=8.3 Hz, J2=2.1 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.26 (s, 1H), 5.46 (s, 1H), 4.21 (d, J=11.7 Hz, 1H), 4.01 (d, J=11.8 Hz, 1H), 1.57 (s, 3H), 1.49 (s, 6H); LC-MS (ESI & APCI): 359.2 (M+1).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1>[C:1]1([C:7]#[C:8][C:9]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC#Cc1ccccc1
Solvent: Cc1ccccc1
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
In a dry 25 mL Schlenk-tube, which has been flooded with argon, [Mo(≡N)(OSiPh3)3)(bipy)] (109.2 mg, 0.10 mmol), MnCl2 (12.6 mg, 0.10 mmol) and molecular sieve 5 Å (1.0 g) was suspended in dry toluene (5 mL) and the mixture was heated to 80° C. After 30 min, 1-phenyl-1-propine (116.2 mg, 1.00 mmol) was added, the reaction mixture was stirred for 3 h at 80° C. and was filtered after cooling over a short silica gel column. The filtrate was concentrated and the residue was purified by means of column chromatography (hexane). 88.2 mg of tolane (99%) were isolated as a white solid, the spectroscopic and analytical data were identical to those of a commercial sample. M.p.=59-61° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[Cl:28]N1C(=O)CCC1=O>O1CCCC1.CCOCC>[Cl:28][C:15]1[N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[C:11]2[CH:12]=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2nn3ccccc3c2-c2ccncc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccncc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a stirred solution of 2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridine (100 mg, 0.346 mmol) in 4 ml of tetrahydrofuran at −78° C. under N2 was added 2.5 M n-butyllithium in hexanes (22 μl, 2 eq). The mixture was stirred at −78° C. for 30 min and N-chlorosuccinimide (2.2 eqv) was then added. The mixture was allowed to warm to room temperature after 30 min and was stirred at room temperature for 1 hr. The mixture was diluted with ether and washed with 1N hydrochloric acid solution. The aqueous layer was basified with 1N sodium hydroxide solution and extracted thoroughly with ether. The combined organic layers were dried on anhydrous magnesium sulfate, filtered and evaporated. Purification by chromatography yielded 7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridine (71%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Cc1ccnc(Br)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2cc(C)ccn2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 85.8 %

Procedure:
To a suspension of 2-bromo-4-methylpyridine (1.60 g), 4-methoxyphenylboronic acid (1.84g) and tetrakis(triphenylphosphine)-palladium (537 mg) in 1,2-dimethoxyethane (40 ml) was added 2M aqueous solution of sodium carbonate (12.1 ml). The mixture was stirred at 80° C. for 24 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 75 g, 20% ethyl acetate in n-hexane) to give 4-(4-methylpyridin-2-yl)anisole (1.59 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:11]=1[C:12](O)=[O:13])([CH3:9])[CH3:8].O.Cl>O1CCCC1.C(OCC)C>[CH:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:10]([CH:7]([CH3:9])[CH3:8])[C:11]=1[CH2:12][OH:13])([CH3:21])[CH3:20]
Reactant: CC(C)c1cccc(C(C)C)c1C(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)c1cccc(C(C)C)c1CO
Yield: 39.6 %

Procedure:
To a suspension of 1.35 g (35.6 mmol) of lithium aluminum hydride in 60 ml of dry tetrahydrofuran was added 3.71 g (18 mmol) of 2, 6-diisopropylbenzoic acid, and the resultant mixture was refluxed with heating for 16 hours. After cooling, 80 ml of water was portionwise added to the mixture, which was mixed with 90 ml of ethyl ether. The mixture was strongly acidified with conc. hydrochloric acid. The aqueous layer was separated and shaken with ethyl ether. The organic layers were combined, washed with aqueous sodium hydroxide and then saturated saline, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo to give 1.37 g of 2, 6-diisopropylbenzyl alcohol as white solid.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].Cl.[C@@H:10]1([C:21]2[CH:30]=[C:29]3[C:24]([CH:25]=[C:26]([C:32](O)=[O:33])[C:27](=[O:31])[O:28]3)=[CH:23][CH:22]=2)[O:18][C@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]1[OH:12].C(N=C=NCCCN(C)C)C.[NH4+].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>O.C(N)(N)CCCCC>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH:8][C:32]([C:26]1[C:27](=[O:31])[O:28][C:29]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[C:21]([C@@H:10]1[O:18][C@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]1[OH:12])[CH:30]=2)=[O:33]
Reactant: NCCCCCCN
Reactant: O=C(O)c1cc2ccc([C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)cc2oc1=O
Agent: CCCCCC(N)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Product: NCCCCCCNC(=O)c1cc2ccc([C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)cc2oc1=O
Temperature: 4 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
1,6-Hexanediamine (1.76 g, 15 mmoles) was dissolved in 20 ml of distilled water and the pH was adjusted to 9 with concentrated hydrochloric acid. 7-β-galactosylcoumarin-3-carboxylic acid (1.83 g, 5 mmoles) [Burd et al, Clin. Chem. 23:1402(1977)] was dissolved in the hexanediamine solution and the pH was further adjusted to 5±0.5. This solution was cooled to 4° C. in an ice bath. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.16 g, 6.15 mmoles) [Pierce Chemical Co., Rockford, Ill.] was added to the cooled solution and the pH was maintained at 5±0.5 manually. The reaction was allowed to proceed at 4° C. for two hours and then two more hours at room temperature. At the end of four hours, 80 ml water and 0.6 g (3.2 mmoles) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide were added to the reaction solution and the pH was maintained at 5. The solution was stirred continuously overnight at room temperature. Then it was diluted to 6 L with distilled water and applied onto a column (5×40 cm) of CM-Sepharose CL in the ammonium form [Pharmacia Fine Chemicals, Piscataway, N.J⟧ The column was washed successively with 3 L distilled water, 1 L of 1 mM ammonium bicarbonate and 2 L of 2 mM ammonium bicarbonate. The chromatogram was developed with a linear gradient generated with 4 L of 2 mM and 4 L of 300 mM ammonium bicarbonate and 10 ml fractions were collected. The absorbance of the eluate was monitored at 280 nm and selected fractions were examined by thin layer chromatography on silica gel 60 plates using a 0.5 M triethylammonium bicarbonate; pH 7.8: ethanol (3:7) solvent. The fractions eluted between 70 to 90 mM ammonium bicarbonate showed several fluorescent spots when viewed under long wavelength UV light and one spot, Rf =0.24, gave a positive reaction with ninhydrin. These fractions were pooled and evaporated to dryness. The residue was dissolved in water and evaporated to dryness several times to remove the residual ammonium bicarbonate. The yield was less than 10% .