Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1>C1COCC1.CCOC(C)=O>[CH:11]([C@@H:4]1[C:3]([O:2][CH3:1])=[N:8][C@@H:7]([C@H:25]([C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=2)[OH:26])[C:6]([O:9][CH3:10])=[N:5]1)([CH3:13])[CH3:12]
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@@H](O)c1ccc(C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 22.1 %

Procedure:
To a mixture of (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (5.2 mL, 29 mmol) (commercially available from 3B Scientific Corporation Product List (Order Number 3B3-054672)) and THF (50 mL) at −78° C. was added n-butyllithium (2.5 M solution in hexane, 12 mL, 31 mmol). The mixture was stirred for 15 minutes. The colorless solution turned light brown. A solution of 4-(trifluoromethyl)benzaldehyde (5.1 mL, 38 mmol) (commercially available from 3B Scientific Corporation Product List (Order Number 3B4-3644)) in THF (50 mL) was added dropwise through a dropping funnel at −78° C. The mixture was stirred for 1 hour. The reaction mixture was diluted with EtOAc and washed with a mixed solution of aqueous Na2HPO4 and KH2PO4 solution (pH=8). The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was separated into two isomers by silica gel chromatography: 0-2%-10% CH3CN—CH2Cl2. The product was obtained as light yellow oil (2.3 g, 22%). LCMS (API-ES) m/z: 359 (M+H+).
Reaction SMILES: CC([C:5]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[C:25]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)=[C:6]([CH3:10])[C:7]([O-:9])=[O:8])(C)C.C(O)(C(F)(F)F)=O>>[C:25]1(=[C:17]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:14]2[CH:15]=[CH:16][C:11](/[CH:5]=[C:6](\[CH3:10])/[C:7]([OH:9])=[O:8])=[CH:12][CH:13]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(C(=O)[O-])=C(c1ccc(C(=C2CCCCCCC2)c2ccc(O)cc2)cc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C/C(=C\c1ccc(C(=C2CCCCCCC2)c2ccc(O)cc2)cc1)C(=O)O
Yield: 92.4 %

Procedure:
The general hydrolysis procedure described for 195 was followed. (1,1-dimethylethyl (2E/2Z)-3-{4-[cyclooctylidene(4-hydroxyphenyl)methyl]phenyl}-2-methyl-2-propenoate (214) (0.200 g, 0.46 mmol) was treated with TFA to afford 0.160 g (92%) of the title compound 215 as a mixture of E and Z (˜65:35) isomers. The pure E isomer was isolated by HPLC to afford the title compound 214 as a white solid. 1H NMR (300 MHz, CD3OD): δ 7.67 (s, 1H), 7.38 (br d, J=6.0 Hz, 2H), 7.22 (br, d, J=6.6 Hz, 2H), 7.00 (br d, J=6.6 Hz, 2H), 6.72 (br d, J=6.3 Hz, 2H), 2.31 (br s, 4H), 2.10 (s, 3H), 1.70 (br s, 2H), 1.58 (br s, 8H). LCMS (ESI): m/z 375 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.[C:12]1(=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[NH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:13]2[C:14](=[O:21])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]2=[O:22])=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCc1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1c2ccccc2C(=O)N1CCCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To 3-(4-bromophenyl)propan-1-ol (4.70 g, 21.9 mmol), isoindoline-1,3-dione (3.54 g, 24.04 mmol) and triphenylphosphine (6.88 g, 26.2 mmol) in a 500 mL round-bottomed flask equipped with a stir bar, nitrogen, and addition funnel cooled in an ice water bath was added diisopropyl azodicarboxylate (5.10 mL, 26.2 mmol). The reaction was allowed to warm to room temperature over the weekend. The reaction mixture was adsorbed onto Celite®. Purification by flash column chromatography using 5-20% ethyl acetate/hexanes as eluent provided a solid which was dried overnight at 50° C. at about 25 in. Hg providing the title compound as a white solid (6.51 g, 87%): mp 88-90° C.; 1H NMR (400 MHz, CDCl3) δ 7.86-7.79 (m, 2H), 7.71 (dd, J=5.5, 3.0 Hz, 2H), 7.38-7.32 (m, 2H), 7.11-7.04 (m, 2H), 3.73 (t, J=7.1 Hz, 2H), 2.68-2.59 (m, 2H), 2.07-1.96 (m, 2H); ESIMS m/z 346 ([M+2]+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[O:18].[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][N:42]=1.C(=O)(O)[O-].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([C:44]1[CH:43]=[N:42][C:41]([O:40][CH3:39])=[CH:46][CH:45]=1)=[CH:23][CH:22]=2)=[O:18]
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3cc(Br)ccc32)cc1
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(c2)cc(C(=O)c2cnn(-c4ccc5[nH]c(C)nc5c4)c2N)n3S(=O)(=O)c2ccc(C)cc2)cn1

Procedure:
A mixture of dioxane (0.6 ml), [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[5-bromo-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone (60 mg, 0.102 mmol), dichlorobis(triphenylphosphine)palladium (II) (14 mg, 0.020 mmol), 2-methoxy-5-pyridine boronic acid (39 mg, 0.255 mmol), and an aqueous solution of 2 M sodium bicarbonate (0.255 mL, 0.51 mmol) was stirred at 140° C. for six minutes in a microwave reactor. The reaction mixture was filtered through Celite, and washed with ethyl acetate and then with methanol. The filtrate was dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentration was performed. The residue obtained was purified by amino gel chromatography (dichloromethane/methanol=99/1 to 92/8). Thus, [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[5-(6-methoxy-pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone was obtained as a pale yellow solid (54 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20]O)[O:17][C:16]2=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([S:13][CH3:14])[N:10]=[N:9]1.[CH3:23][C:24]1[N:25]=[N:26][NH:27][N:28]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CO>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][N:26]3[N:27]=[N:28][C:24]([CH3:23])=[N:25]3)[O:17][C:16]2=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([S:13][CH3:14])[N:10]=[N:9]1
Reactant: Cc1nn[nH]n1
Reactant: CSc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)nn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: ClCCl
Solvent: CO
Product: CSc1cn(-c2ccc(N3C[C@H](Cn4nnc(C)n4)OC3=O)cc2F)nn1
Yield: 47.8 %

Procedure:
(5R)-3-{3-Fluoro-4-[4-(methylthio)-1H-1,2,3-triazol-1-yl]phenyl}-5-(hydroxymethyl)-oxazolidin-2-one (Intermediate 48) (1.10 g, 3.39 mmol), 5-methyl-2H-tetrazole (0.347 g, 4.09 mmol), polystyrene-triphenylphosphine (phosphine loading 1.51 mmol/g, 3.79 g, 5.72 mmol) and diisopropyl azodicarboxylate (0.856 g, 4.11 mmol) were reacted as described for Example 29 to afford the title product (0.632 g) after chromatography on silica gel with 5% methanol in dichloromethane. The regioisomeric product (5R)-3-{3-Fluoro-4-[4-(methylthio)-1H-1,2,3-triazol-1-yl]phenyl}-5-[(5-methyl-1H-tetrazol-1-yl)methyl]-1,3-oxazolidin-2-one was also isolated (0.369 g).
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.[Br:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1O.[OH-].[Na+].N>O>[Br:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:13][C:14]=1[O:6][CH3:7]
Reactant: Oc1ccc(-c2ccccc2)cc1Br
Reactant: COS(=O)(=O)OC
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2ccccc2)cc1Br
Reaction time: 2 h

Procedure:
Dimethylsulfate (10.3 mL, 109 mmol) was added to a mixture of 3-bromo-[1,1′-biphenyl]-4-ol and sodium hydroxide (8 g, 201 mmol) in water (12.4 mL) at 0° C. After stirring for 2 hours at reflux, ammonia (1.2 mL) was added to the mixture. The solid was filtered and washed with water. The product, 3-bromo-4-methoxy-1,1′-biphenyl, was crystallized from heptane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)=[C:4]([F:18])[CH:3]=1.[O:19]1[CH2:23][CH2:22]OC1=O.CN1C=CN=C1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:22][CH2:23][OH:19])[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)=[C:4]([F:18])[CH:3]=1
Reactant: CCOC(=O)c1c[nH]c(-c2ccc(Br)cc2F)n1
Reactant: O=C1OCCO1
Agent: Cn1ccnc1
Product: CCOC(=O)c1cn(CCO)c(-c2ccc(Br)cc2F)n1

Procedure:
Ethyl 2-(4-bromo-2-fluorophenyl)-1H-imidazole-4-carboxylate 26 and 1,3-dioxolan-2-one and N-methylimidazole were reacted to give 27.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1.S([O-])([O-])(=O)=O.[Mg+2]>C1CCCCC1>[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:9]1
Reactant: C1CCNCC1
Reactant: CC1CCCC(=O)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCCCC1
Product: CC1CCCC(N2CCCCC2)C1
Reaction time: 6 h
Yield: 76.7 %

Procedure:
A three neck 500 mL flask was charged with 20 g (0.23 mole) of piperidine, 53 g (0.47 mole) of 3-methylcyclohexanone and 200 mL of anhydrous cyclohexane. To the resulting solution, 84 g (0.70 mole) of anhydrous magnesium sulfate was added and the mixture was mechanically stirred and heated at reflux (the reaction was monitored by NMR) for 192 hours. The reaction mixture was then filtered through a fritted glass funnel. The filtrate (containing the enamine product, excess 3-methylcyclohexanone and cyclohexane) was transferred to a hydrogenation vessel. To this mixture, 3 g of 10% Pd on activated carbon was added and the vessel affixed to a hydrogenation Parr shaker at 65 psi of hydrogen. The mixture was left on the Parr shaker for 6 hours at room temperature. The mixture was then filtered through a bed of Celite® in a fitted glass filtering funnel. The filtrate was transferred to a round bottom flask and concentrated under reduced pressure on a rotary evaporator. The obtained residue, which contained 1-(3-methylcyclohexyl)piperidine and excess 3-methylcyclohexanone, was treated with 120 mL of 3M aqueous HCl solution. The mixture was stirred in an ice-water bath for 20 minutes. Then, the mixture was transferred to a reparatory funnel and extracted with 200 mL of diethyl ether. The ether layer, containing the excess 3-methylcyclohexanone, was separated from aqueous layer containing the amine in the form of its onium hydrochloride salt. The ether layer was dried over MgSO4, filtered and concentrated under reduced pressure on a rotary evaporator to recover 31 g of the excess 3-methylcyclohexanone. The aqueous layer was treated with 50 wt. % aqueous NaOH solution in an ice bath until a pH of about 11 was reached. This solution was then extracted with 300 mL of diethyl ether. The ether layer was dried over MgSO4, filtered and concentrated under reduced pressure on a rotary evaporator to give 32 g of 1-(3-methylcyclohexyl)piperidine as a yellow oil. The product was confirmed by 1H-NMR and 13C-NMR analysis. Some piperidine was also present in the oil as an impurity.
Reaction SMILES: I[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH2:13])[N:3]=1.[CH2:14]([SH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].Cl>>[CH2:14]([S:21][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH2:13])[N:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: SCc1ccccc1
Reactant: CCn1cnc2c(N)nc(I)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1cnc2c(N)nc(SCc3ccccc3)nc21

Procedure:
A mixture of 2-iodo-9-ethyl-9H-purin-6-ylamine (0.2 g, 0.69 mmol), 3 mL of benzyl mercaptan, and solid sodium hydroxide (200 mg, 5.0 mmol) was heated in a steel bomb at 100° C. for 24 hours. The reaction mixture was neutralized with 1N HCl and partitioned between water and chloroform. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo, and the residue chromatographed on a silica gel column, eluting with a mixture of chloroform/methanol (97:3), to give 2-benzylthio-9-ethyl-9H-purin-6-ylamine, a compound of formula (4), as a chromatographically pure solid.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([F:18])[CH:4]=1)#[N:2].[NH2:19][OH:20]>CCO>[NH2:2][C:1](=[N:19][OH:20])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([F:18])[CH:4]=1
Reactant: CCOC(=O)CCCOc1ccc(C#N)cc1F
Reactant: NO
Solvent: CCO
Product: CCOC(=O)CCCOc1ccc(C(N)=NO)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Ethyl 4-(4-cyano-2-fluorophenoxy)butanoate (3.50 g; 13.93 mmol; 1 eq.) was dissolved in EtOH (70 mL). Hydroxylamine (2.05 mL; 69.65 mmol; 5 eq.) was added in one portion. The reaction mixture was stirred at RT for 12 hours. The reaction mixture was concentrated under vacuum affording the title compound as a white solid. (3.82 g, 96%). 1H NMR (DMSO-d6, 300 MHz) δ 9.59 (br s, 1H), 7.49-7.43 (m, 2H), 7.18-7.12 (m, 1H), 5.80 (br s, 2H), 4.11-4.02 (m, 4H), 2.46-2.43 (m, 2H), 2.03-1.94 (quint., J=6.97 Hz, 2H), 1.20-1.15 (t, J=7.11 Hz, 3H). LC/MS (Method B): 285.1 (M+H)+. HPLC (Method A) Rt 2.67 min (Purity: 99.1%).
Reaction SMILES: Br[C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])=[CH:18][CH:17]=2)=[C:4]([O:32][CH3:33])[CH:3]=1.[CH3:34]B1OB(C)OB(C)O1>>[CH3:33][O:32][C:4]1[CH:3]=[C:2]([CH3:34])[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]=1[C:16]1[CH:17]=[CH:18][C:19]([CH:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])=[CH:20][CH:21]=1
Reactant: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Reactant: CB1OB(C)OB(C)O1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Yield: 71.7 %

Procedure:
Following General Procedure J, tert-butyl 1-(4-(6-bromo-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethylcarbamate (32 mg, 0.060 mmol) was reacted with trimethylboroxine (8 mg, 0.060 mmol) to afford the desired product (20 mg, 61%) as a grey solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][N:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:28])=O>>[CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([C:23]([Cl:28])=[O:25])=[CH:19][N:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCc1ccc(-c2ncc(C(=O)O)cn2)cc1
Product: CCCCCCCCCCc1ccc(-c2ncc(C(=O)Cl)cn2)cc1

Procedure:
2-(4-n-Decylphenyl)pyrimidine-5-yl-carboxylic acid (1.5 g) was heated together with excess thionyl chloride for 4 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 2-(4-n-decylphenyl)pyrimidine-5-yl-carboxylic acid chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:16]1([Mg]Br)[CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[CH:16]1([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Br[Mg]C1CCCC1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC(CNS(C)(=O)=O)c1ccc(C2CCCC2)cc1
Yield: 13 %

Procedure:
Condition 1: The product of Example 1, 0.50 g (1.71 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml) under an atmosphere of nitrogen. To this was added tetrakis-(triphenylphosphine)palladium(0) (0.099 g, 0.086 mmol) followed by cyclopentyl magnesium bromide (2 M in diethyl ether, 2.14 ml, 4.28 mmol). The solution was heated to reflux for 16 hours. Upon cooling the reaction was partitioned between water and diethyl ether. The aqueous layer was back extracted with diethyl ether twice and the organic fractions combined. The organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. Chromatography (Sio2, 30% ethyl acetate/hexanes) gave the title compound 0.06 g (13%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10].Cl.[CH3:13][NH:14][OH:15].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([CH:7]=[N+:14]([CH3:13])[O-:15])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10]
Reactant: Cn1c(C=O)cnc1[N+](=O)[O-]
Reactant: CNO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cn1c(C=[N+](C)[O-])cnc1[N+](=O)[O-]

Procedure:
A mixture of 0.250 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde, 0.150 g. of N-methylhydroxylamine hydrochloride and 0.150 g. of sodium bicarbonate is refluxed in 80 ml. of anhydrous ethanol for 2 hours and after filtration is concentrated to small volume. The title compound crystallizes on cooling. Yield: 0.24 g, m.p. 208°-209° C.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](=[O:15])[CH2:13]Br)=[CH:10][CH:9]=1.O>CO>[C:1]([O:4][CH2:13][C:12]([C:11]1[CH:16]=[CH:17][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1)=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)COC(C)=O)cc1
Yield: 64.5 %

Procedure:
To a solution of 63 g potassium acetate in 750 ml of methanol, 92.9 g of 4-methoxyphenacyl bromide was dropped in. The resulting solution was refluxed for 4 hours, then cooled and poured into water. The aqueous layer was extracted with ether, then the combined organic phases were washed with water, dried, and evaporated to dryness. The resulting solid was recrystallized from methanol to yield 54.5 g crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.Br.Br[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[N:13]([CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Reactant: BrCc1ccncc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccncc1
Reaction time: 0.17 h

Procedure:
Sodium hydride (13 mg, 0.32 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (20 mg, 0.1 mmol, from Example 2, Step 5) in DMF (3.0 mL). After stirring for 10 minutes, a solution of 4-(bromomethyl)pyridine hydrobromide (0.027 g, 0.11 mmol, Aldrich) in DMF (0.8 mL) was added. The mixture was stirred for 45 minutes and then quenched by the addition of water, diluted to 5 mL with MeCN, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (1.0 mg, 3%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1I.C1(C)C=CC=CC=1.[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])#[CH:23]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[C:23]#[C:22][Si:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1ccc(F)c(I)c1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C(F)(F)F
Temperature: 60 °C
Yield: 81 %

Procedure:
A 20 mL vial was charged with 4-fluoro-3-iodo-2-(trifluoromethyl)benzonitrile, (0.315 g, 1.00 mmol), Pd(PPh3)2Cl2 (0.014 g, 0.020 mmol) and CuI (0.0076 g, 0.040 mmol), and sealed with a rubber septum. Anhyd PhMe (5 mL) and DIPA (0.210 mL, 1.500 mmol) were added via syringe and the mixture was degassed 10 min by sparging with N2 while immersed in an ultrasonic bath. Ethynyltrimethylsilane (0.155 mL, 1.100 mmol) was added dropwise via syringe and the septum was replaced by a PTFE-faced crimp top. The mixture was stirred in a heating block at 60° C. Upon cooling the mixture was diluted with EtOAc and filtered through Celite. The filtrate was washed (satd NH4Cl, water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording 4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile (0.231 g, 81% yield) as a light orange oil: 1H NMR (400 MHz, CDCl3) δ 7.75 (ddd, J=8.7, 5.0, 0.6 Hz, 1H), 7.39 (ddd, J=8.6, 7.8, 0.5 Hz, 1H), 0.28 (s, 9H); MS (GCMS EI) m/z 285 ([M]+, 15%), 270 ([M-CH3]+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=1.[F:21][C:22]([F:46])([F:45])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43]Br)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26]>>[F:21][C:22]([F:45])([F:46])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43][N:15]2[CH2:16][CH2:17][N:12]([C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:5][C:4]4[CH:18]=[CH:19][CH:20]=[C:2]([Cl:1])[CH:3]=4)[N:11]=3)[CH2:13][CH2:14]2)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Clc1cccc(Oc2cccc(N3CCNCC3)n2)c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cccc(Oc4cccc(Cl)c4)n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-[6-(3-chloro-phenoxy)-pyridin-2-yl]-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9]O)[S:7][CH:8]=1)([CH3:3])[CH3:2].S(Cl)([Cl:13])=O>ClCCl>[Cl:13][CH2:9][C:6]1[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1csc(CO)n1
Solvent: ClCCl
Product: CC(C)c1csc(CCl)n1
Reaction time: 0.33 h

Procedure:
(4-Isopropyl-1,3-thiazol-2-yl)methanol (10 g, 63.6011 mmol) dissolved in dichloromethane (60 ml) was added with thionyl chloride (7 ml, 95.40 mmol) under ice cooling, and then the reaction solution was returned to room temperature and stirred for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was subjected to azeotropy with toluene and then diluted with diethyl ether, and further neutralized with saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated brine, then dried over magnesium sulfate and concentrated under reduced pressure. The title compound was obtained as the residue without purification (11 g, 100%).
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[Cl:11][S:12]([C:8]1[CH:9]=[N:10][C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:14])=[O:13]
Reactant: O=C(O)c1cccnc1O
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1cc(S(=O)(=O)Cl)cnc1O
Temperature: 160 °C
Yield: 44 %

Procedure:
2-Hydroxynicotinic acid (10.0 g, 71.8 mmol) was dissolved in 25 ml of chlorosulfonic acid and heated to 160° C. overnight. After cooling the reaction was slowly poured into ice and stirred in an ice bath until a white precipitate formed. The solid was filtered off and dried under vacuum to afford 7.55 g of 5-(chlorosulfonyl)-2-hydroxynicotinic acid (44% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.9 (dd, J=2.5, 0.7 Hz, 1H) 8.4 (dd, J=2.6, 0.7 Hz, 1H).