Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C([Li:21])CCC>C1(C)C=CC=CC=1>[C:12]([C:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[O:16][Li:21])([CH3:15])([CH3:14])[CH3:13]
Reactant: [Li]CCCC
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: [Li]Oc1c(C(C)(C)C)cc(C)cc1C(C)(C)C
Yield: 95 %

Procedure:
Both 10 mmol (2.2 g) of monocyclopentadienyl titanium chloride(CpTiCl3) and 100 ml of toluene were added to a 200 ml Schlenk reactor in the inert atmosphere. Then, 10 mmol of 2,6-di-t-butyl 4-methyl phenoxy lithium, so obtained from the reaction between 2,6-di-t-butyl 4-methyl phenol and n-butyl lithium, was slowly added to the mixture. The reactional solution was stirred at room temperature and stood for 1 hour. After 1 hour, some portions of the mixture we collected ad were analyzed by 1H-NMR spectroscopy to ascertain the reaction results.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH:19]1[CH:23]=[C:22]([NH2:24])[CH:21]=[N:20]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:24][C:22]3[CH:23]=[N:19][NH:20][CH:21]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: Nc1cn[nH]c1
Reactant: Clc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Clc1cccc(Cl)c1-c1nc2ccnc(Nc3cn[nH]c3)c2s1
Temperature: 25 °C
Yield: 19.5 %

Procedure:
To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17 mmol), 1H-pyrazol-4-amine (0.018 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2CO3 (0.11 g, 0.34 mmol) in dioxane (3.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature the solid was removed via filtration. The filtrate was concentrated under reduced pressure and the residue was purified with reverse phase column chromatography eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a white solid (12 mg, 20% yield). 1H NMR (500 MHz, CH3OH-d4): δ 8.27 (d, J=5.5 Hz, 1H), 8.12 (br, 1H), 7.74 (br, 1H), 7.64-7.58 (m, 3H), 7.41-7.40 (d, J=5.5 Hz, 1H). LCMS (Method A): RT=4.94 min, m/z: 362.0 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[C:4](I)[CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>[Cu]I.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[C:4]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:3]=1
Reactant: CC(C#N)c1ccc(Cl)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CC(C#N)c1ccc(Cl)cc1C#C[Si](C)(C)C

Procedure:
2-(4-Chloro-2-iodophenyl)propanenitrile (0.620 g, 2.13 mmol), (trimethylsilyl)acetylene (0.451 mL, 3.19 mmol), copper(I) iodide (0.0144 mL, 0.425 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.149 g, 0.213 mmol), and TEA (20 mL) were stirred at 70° C. for 3 hours. The reaction was monitored by LC-MS. The solution was filtered through a plug of Celite, and the filtrate was concentrated under vacuum. The residue was purified by silica flash chromatography, 0-15% EtOAc/hexanes. MS m/e=262 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH2:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C:16]1=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:16]2[CH2:15][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: O=C1Cc2ccccc2C1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC1Cc2ccccc2C1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 2-indanone.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1I>CCCCCC.O1CCCC1.CCOCC.[Cl-].[Zn+2].[Cl-]>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:18]2[C:17]([C:16]([O:15][CH3:14])=[O:24])=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccccc1I
Reactant: Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
A 1.6M solution of butyllithium in hexane (24.0 ml) was added dropwise to a stirred solution of 4-bromotoluene (6.0 g) in dry tetrahydrofuran (THF) (50 ml) at -78° C. under an atmosphere of argon. The temperature was maintained at -78° C. for 20 minutes and then a 1M solution of anhydrous zinc chloride in ether (38.6 ml) was added. The solution was kept at -78° C. for 15 minutes, and then tetrakis (triphenylphosphine)palladium (60 mg) in THF (5 ml) was added, followed by methyl-2-iodobenzoate (6.1 g) in THF (10 ml). The solution was allowed to reach ambient temperature over 1 hour, then heated under reflux for 5 hours. The solvent was removed by evaporation and the residue was dissolved in chloroform (150 ml). The solution was washed with a solution of ethylene diaminetetracetic acid (10 g) in water (100 ml) and the aqueous layer was re-extracted with chloroform (100 ml). The combined organic extracts were dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:9 v/v) to give methyl 4'-methylbiphenyl-2-carboxylate (B) as a colourless oil (4.4 g); NMR: 2.4(s,3H), 3.65(s,3H), 7.2(s,4H), 7.35(m,3H), 7.5(m,1H), 7.8(d,1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].F[P-](F)(F)(F)(F)F.[NH2:30][N+:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.CN(CCN(C)C)C.II.Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl.CN1CCCC1=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)=[C:36]3[N:31]([N:32]=[CH:33][CH:34]=[CH:35]3)[N:30]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)Cc2ccc(S(C)(=O)=O)cc2)cc1
Reactant: N[n+]1ccccn1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCOc1ccc(-c2nn3ncccc3c2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
Titanium tetrachloride (26 mL) was added to a stirred suspension of 1-(4-ethoxyphenyl)-2-(4-methanesulfonyl-phenyl)-ethanone (75.0 g), N-amino-pyridazinium hexafluorophosphate (59.6 g) in DCM (1125 mL) at about 20° C. N-Methyl-pyrrolidinone (23 mL) was added and TMEDA (50 mL) was added over a period of about 4 hours and the reaction mixture heated at 40° C. for 4.5 hours. The reaction mixture was stirred at about 20° C. for about 2 hours and further TMEDA (93 mL) was added over about 15 minutes. The mixture was stirred for about 18 hours and iodine (63 g) was added. After about a further 5 hours, IMS (55 mL) was added, followed by 3.3M hydrochloric acid (1125 mL) and the layers were separated. The organic extract was further washed with 3.3M hydrochloric acid (375 mL), aqueous sodium carbonate solution (20% w/v, 375 mL), aqueous sodium thiosulfate solution (20% w/v, 2×375 mL) and aqueous sodium chloride solution (3% w/v, 2×375 mL). The organic extract was then concentrated by distillation to a residual volume of about 450 mL and iso-octane (about 187 mL) was added at about 38° C. The resultant slurry was cooled to about 0-5° C. and filtered. The crude product was washed with DCM/iso-octane (1:1, 2×150 mL) and iso-octane (400 mL), dried, and then dissolved in acetone (1200 mL). This solution was heated to about 50° C. and treated with charcoal (19 g) for about 1 hour before filtering. The charcoal was washed with hot acetone (750 mL) and the combined filtrates and washings were concentrated by distillation to a residual volume of about 825 mL. Further acetone (375 ml) was added to the concentrate, which was concentrated again to a residual volume of about 825 mL. Maintaining the temperature at about 50° C., water (450 mL) was added over about 1 hour, causing the product to crystallise. After cooling the slurry to about 0-5° C. the product was isolated by filtration, washed with chilled acetone/water (1:1, 2×150 mL), and dried in vacuo at 65° C. to give the title compound as a pale yellow crystalline solid (63.6 g, 68.6%), spectroscopically identical to the product of Example 7.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)[N:3]=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>>[N+:20]([C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([C:4]1[N:3]=[C:2]([NH:23][C@H:24]3[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]3)[N:10]=[C:9]3[C:5]=1[N:6]=[CH:7][NH:8]3)[CH2:12][CH2:13]2)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2c1nc(Cl)nc2[nH]cnc12
Reactant: N[C@H]1CC[C@H](N)CC1
Product: N[C@H]1CC[C@H](Nc2nc(N3CCc4cc([N+](=O)[O-])ccc43)c3nc[nH]c3n2)CC1
Temperature: 140 °C

Procedure:
56 g of product obtained in stage 1 above are mixed with 140 g of trans-1,4-diaminocyclohexane, and the mixture is then heated at 140° C. for approximately 55 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 85-15-1.5 mixture for eluent. 19.7 g of product are recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:12][C:13](O)=[O:14])[CH3:11])=[C:4]([N+:16]([O-])=O)[CH:3]=1.[H][H].C1(N=C=NC2CCCCC2)CCCCC1>CO.[Pt]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][CH2:9][N:10]([CH3:11])[CH2:12][C:13](=[O:14])[NH:16][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: CN(CCc1ccc(Cl)cc1[N+](=O)[O-])CC(=O)O
Agent: [Pt]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: CN1CCc2ccc(Cl)cc2NC(=O)C1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
{[2-(4-Chloro-2-nitro-phenyl)-ethyl]-methyl-amino}-acetic acid (18.5 g, approximately 0.068 mole, not quite pure) in methanol (250 mL) containing platinum on sulfided carbon (5 wt. %, 12.0 g) was hydrogenated at room temperature and a hydrogen pressure of 50 psi overnight. The catalyst was removed by filtration through Celite and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in pyridine (2 L) and the solution was cooled to 0° C., and 1,3-dicyclohexylcarbodiimide (30.0 g, 0.145 mol) was added. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 48 hours. The solvent was removed and the residue was slurried with 10% hydrochloric acid and filtered. The filtrate was extracted with ether, the aqueous phase was made basic with sodium carbonate and then extracted with dichloromethane. The extract was dried over sodium sulfate and evaporated in vacuo. Purification by flash column chromatography (silica gel, methylene chloride) provided 5.1 g of the title compound as a white solid. 1H NMR (CDCl3): 7.55 δ (broad s, 1H); 7.18 δ (d, 1H); 7.10 δ (d, 1H); 7.00 δ (s, 1H); 3.18 δ (s, 2H); 2.80 δ (broad s, 4H); 2.40 δ (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[N:9]([CH3:21])[C:10](=[O:20])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)[N:13]=2)[CH2:6][CH2:5][N:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH2:3]1.[Cl-].[OH:31][NH3+:32].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:31][NH:32][C:26](=[NH:27])[C:25]1[CH:28]=[CH:29][C:22]([N:4]2[CH2:5][CH2:6][N:7]([C:8]3[N:9]([CH3:21])[C:10](=[O:20])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][N:15]=4)[N:13]=3)[C@H:2]([CH3:1])[CH2:3]2)=[CH:23][CH:24]=1
Reactant: C[C@@H]1CN(c2ccc(C#N)cc2)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@@H]1CN(c2ccc(C(=N)NO)cc2)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-[(3R)-3-methyl-4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-piperazin-1-yl]-benzonitrile (1.50 mg, 3.87 mmol) in ethanol (8.0 ml) and water (4.0 ml) was added hydroxylammonium chloride (807 mg, 11.6 mmol) and sodium carbonate (2.05 g, 19.4 mmol), and the reaction mixture was stirred for 2 hours under reflux. The solution was partitioned between water and chloroform, and the organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting solid was used for next reaction without further purification.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH:16]([NH2:18])[CH3:17])[CH2:10][CH2:9][CH:8]([S:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].C(N(CC)CC)C>ClCCl>[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22]([NH:18][CH:16]([C:5]1([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:6][CH2:7][CH:8]([S:11][CH2:12][CH:13]2[CH2:14][CH2:15]2)[CH2:9][CH2:10]1)[CH3:17])=[O:23]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CC(N)C1(CC2CC2)CCC(SCC2CC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)c1ccc(Cl)cc1Cl)C1(CC2CC2)CCC(SCC2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1-{1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)thio]cyclohexyl}ethyl)amine (0.1 g; 0.3745 mmol), 2,4-dichlorobenzoyl chloride (0.1174 g; 0.56175 mmol) and triethylamine (0.0567 g; 0.56175 mmol) were dissolved in dichloromethane and stirred for one hour at room temperature. The reaction was evaporated and partitioned between ethyl acetate and saturated bicarbonate solution. The organic layer was dried and evaporated and the residue was purified by silica chromatography using ethyl acetate hexanes to yield 2,4-dichloro-N-(1-{1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)thio]cyclohexyl}ethyl) benzamide. (130 mg, 79%)
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]([CH:18]([CH3:20])[CH3:19])[C:13]=2[CH:14]=[C:15](Br)[CH:16]=1)=[O:7].Cl>CN1C(=O)CCC1.O.[Cu]I>[CH3:4][O:5][C:6]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]([CH:18]([CH3:20])[CH3:19])[C:13]=2[CH:14]=[C:15]([O:2][CH3:1])[CH:16]=1)=[O:7]
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Reactant: C[O-]
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cc(OC)cc2c1ccn2C(C)C
Temperature: 120 °C
Yield: 168.5 %

Procedure:
Freshly prepared sodium methoxide (500 mg in 5 mL methanol) was added to a stirred suspension of 6-bromo-1-isopropyl-1H-indole-4-carboxylic acid methyl ester (500 mg, 1.68 mmol) and CuI (480 mg, 2.53 mmol) in NMP (8 mL) and then heated at 120° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and acidified with 1N HCl. The reaction mixture was filtered through Celite and washed with EtOAc (5 mL). Separated the EtOAc layer from filtrate, dried over anhydrous Na2SO4 and concentrated under reduced pressure to furnish the crude 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid (700 mg), which was used in the next stage without further purification. 1H NMR (400 MHz, DMSO-d6): δ 1.44 (d, J=6.4 Hz, 6H), 3.84 (s, 3H), 4.80-4.76 (m, 1H), 6.87 (d, 1H), 7.33 (t, J=3.2 Hz, 2H), 7.49 (d, J=3.2 Hz, 1H), 12.65 (bs, 1H). LCMS (ES+): m/z=234.11 [M+H].
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[C:24]([C:27]1[S:28][CH:29]=[C:30](B(O)O)[CH:31]=1)([OH:26])=[O:25].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O.ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:23][C:9]1[N:8]=[CH:7][C:6]2[C:2]([C:30]3[CH:31]=[C:27]([C:24]([OH:26])=[O:25])[S:28][CH:29]=3)=[CH:3][O:4][C:5]=2[C:10]=1[O:11][C@@H:12]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=1[Cl:22])[CH3:13]
Reactant: O=C(O)c1cc(B(O)O)cs1
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C[C@@H](Oc1c(N)ncc2c(-c3csc(C(=O)O)c3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 90 °C

Procedure:
3-Bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine (180.0 mg, 0.4285 mmol), 2-carboxythiophene-4-boronic acid (147 mg, 0.857 mmol), potassium carbonate (178 mg, 1.28 mmol), 1,4-dioxane (4.2 mL, 54 mmol), H2O (1.2 mL, 67 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (20 mg, 0.02 mmol) were mixed and heated in a microwave reactor at 90° C. for 20 minutes. The crude was passed through Thiol-SPE to remove palladium. MS (ES+): m/z 467.02/469.02 (100/70) [MH+]. HPLC: tR=0.85 min (HPLC-ACQUITY, Analytical). 1H NMR (400 MHz, DMSO-d6): δ=1.84 (d, J=6.8 Hz, 3H), 5.63 (s, 2H), 6.26 (q, J=6.8 Hz, 1H), 7.45 (t, J=8.7 Hz, 1H), 7.53 (dd, J=9.0, 4.9 Hz, 1H), 7.76 (br. s., 1H), 7.94 (br. s., 1H), 8.20 (s, 1H), 8.40 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)c(Cl)cc1F
Yield: 70.7 %

Procedure:
To a solution of 10.8 g (0.053 mole) of 2-chloro-4-fluoro-5-nitrobenzaldehyde in 100 ml of tetrahydrofuran was added 0.50 g (0.013 mole) of sodium borohydride portionwise. The reaction mixture was stirred for one hour after which dilute hydrochloric acid was added to destroy unreacted sodium borohydride. To this mixture was added 200 ml of methylene chloride, and the phases were separated. The organic phase was washed three times with water, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated from the filtrate under reduced pressure, leaving a residue weighing 10.7 g. This residue was combined with 1.67 g of a similar residue another run of the same reaction. The combined residues were passed through a silica gel column, eluting with ethyl acetate/heptane (1/4) to yield 7.7 g of 2-chloro-4-fluoro-5-nitrobenzyl alcohol as a yellow solid.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.[C:13]1(B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:13]1([C:2]2[CH:3]=[N:4][N:5]([CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)[CH:6]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: Ic1cnn(C2CCCCO2)c1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C1=C(c2cnn(C3CCCCO3)c2)CCCC1
Yield: 38.1 %

Procedure:
A solution of 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (J. Org. Chem. 2007, 72, 3589-3591; 2.00 g, 7.19 mmol), 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.50 g, 7.21 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (300 mg, 0.41 mmol) and potassium carbonate (3.00 g, 21.7 mmol) in DMF (13 mL) was stirred at 90° C. for 3 hours under microwave irradiation. After allowing to cool, water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was washed twice with water (100 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with column chromatography (hexane/ethyl acetate=9:1) to yield the title compound (637 mg, 38%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11]>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1cccnc1
Product: COC(=O)C(=O)Nc1cccnc1

Procedure:
In a manner similar to that described in Referential Example 242, 3-aminopyridine was condensed with methyl 2-chloro-2-oxoacetate to form methyl 2-[(pyridin-3-yl)amino]-2-oxoacetate. In a manner similar to that described in Example 271, the title compound was obtained from the thus-condensed ester product and the compound obtained in Referential Example 310.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=O)[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1
Reactant: COc1ccc(CNCC(=O)Nc2c(Cl)cccc2Cl)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(CNCCNc2c(Cl)cccc2Cl)cc1OC

Procedure:
In a manner similar to Preparation 2, react N-(2,6-dichlorophenyl)-2-[[(3,4-dimethoxyphenyl)methyl]amino]acetamide with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[Na].[C:10]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([NH:17][NH2:18])=O)#[N:11]>CO>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[NH:2][C:15]([C:14]2[CH:19]=[CH:20][CH:21]=[C:12]([C:10]#[N:11])[CH:13]=2)=[N:17][N:18]=1
Reactant: N#Cc1cccc(C(=O)NN)c1
Reactant: N#Cc1ccccn1
Agent: [Na]
Solvent: CO
Product: N#Cc1cccc(-c2nnc(-c3ccccn3)[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
A solution of 2-cyanopyridine (0.18 mL, 1.86 mmol) in methanol (5 mL) was treated with sodium metal (12.8 mg, 0.56 mmol) a stirred at ambient temperature for 1 hour. The reaction mixture was then treated with a solution of 3-cyanobenzhyrazide (0.30 g, 1.86 mmol) in methanol (5 mL) and heated at reflux for 3 hours. The reaction mixture was then concentrated in vacuo. The resulting yellow solid was dissolved in toluene (2 mL) and heated overnight at 175° C. The reaction mixture was concentrated in vacuo. Silica gel chromatography using 2% methanol in dichloromethane afforded 0.12 g (26%) of 2-(2-pyridyl)-5-(3-cyanophenyl)-1,3,4-triazole.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[C:14]1([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:25][N:24]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(-c2ccccc2)cn1
Solvent: ClCCl
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(-c2ccccc2)cn1
Temperature: 25 °C

Procedure:
2,6-Dichlorobenzoyl isocyanate (1.5 grams) in a small amount of dichloromethane was added to a solution of 5-phenyl-2-pyridylamine (1.0 gram) in 15 ml dichloromethane. After refluxing for about 5 minutes a precipitate formed. Following this, the reaction mixture was stirred at room temperature, cooled, and then the precipitate was filtered and recrystallized from ethanol, yield 1.8 grams. The identity of the final product was confirmed by NMR, m.p. 221°-231° C.