Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[CH3:14][C:15]([O:19][Si](C)(C)C)([CH3:18])[C:16]#[N:17].[BH4-].[Na+].Cl>C(OCC)C.CO.O>[NH2:17][CH:16]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)[C:15]([CH3:18])([OH:19])[CH3:14]
Reactant: CC(C)(C#N)O[Si](C)(C)C
Reactant: Brc1ccc(SCC2CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CC(C)(O)C(N)c1ccc(SCC2CC2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 53.2 %

Procedure:
To magnesium turnings (888 mg) in diethyl ether (60 mL) was added 1-bromo-4-[(cyclopropylmethyl)thio]benzene (8.4 g). The mixture was heated at reflux for 16 hrs, and then cooled to ambient temperature. A solution of 2-methyl-2-[(trimethylsilyl)oxy]propanenitrile (4.35 g) in diethyl ether (30 mL) was then added and this solution was stirred at ambient temperature for 7 h. Sodium borohydride (1.33 g) in methanol (30 mL) was then slowly added and the solution aged for 2 h Water (25 mL) was added followed by 1N hydrochloric acid (100 mL) and the mixture stirred for 1 h. The organic layer was extracted with a further portion of 1N hydrochloric acid (100 mL) and the acid extracts combined. These were then made basic with 4N sodium hydroxide solution and extracted with dichloromethane (2×100 mL). The organic extracts were dried (MgSO4) and concentrated to give the title compound as a yellow solid (3.7 g). 1H NMR (360 MHz, CDCl3): δ 7.22-7.34 (4H, m), 3.77 (1H, s), 2.85 (2H, d, J=7.0 Hz), 1.21 (3H, s), 1.09-1.03 (1H, m), 1.03 (3H, s), 0.57 (2H, q, J=5.1 Hz), 0.24 (2H, q, J=5.1 Hz); m/z 307 (M-16[NH2])+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)[CH3:11])=[O:8])=[C:4]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)[CH3:11])=[O:8])=[C:4]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(C(C)NC(=O)c2sc(Cl)cc2Cc2cccc(Cl)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(NC(=O)c1sc(Cl)cc1Cc1cccc(Cl)c1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-[1-({[5-chloro-3-(3-chlorobenzyl)-2-thienyl]carbonyl}amino)ethyl]benzoate from Example 1, Step 10 (81.0 mg, 0.181 mmol) and LiOH (0.9 mL, 1M in water) in THF (1.5 mL) and methanol (1.5 mL) was stirred overnight at r.t. and concentrated. The residue was diluted with 1N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the desired product as a white solid. MS (−ESI): m/z 432.0 (M−1)−.
Reaction SMILES: [CH3:1][C@H:2]1[C:7](=O)[CH2:6][C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.[CH3:12]COCC>>[CH3:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:9]([CH3:11])=[CH2:10])[CH2:6][C:7]1=[CH2:12]
Reactant: CCOCC
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C(=O)C1
Product: C=C1CC(C(=C)C)CCC1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
BDAM (2.60 grams) was combined with ether (2 milliliters) and TMAL (1.0 milliliter) as described in Example 4, after which 1.50 grams of (+) dihydrocarvone were added. As in Example 4, a noticeable exotherm was observed. After 3 hours of stirring at room temperature, the reaction mixture was hydrolyzed as in Example 1. After the usual work up and column separation, 1.40 grams of 4-methyl-3-methylene-1-isopropenyl cyclohexane were isolated (95% yield).
Reaction SMILES: [Na].C([C@H:10]([CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:11][CH2:12][P:13]([O:18][CH2:19]C)(=[O:17])[O:14][CH2:15]C)(=O)C1C=CC=CC=1.CC(O)=[O:41]>CO>[CH2:23]([O:22][CH2:21][C@@H:10]([OH:41])[CH2:11][CH2:12][P:13]([O:18][CH3:19])(=[O:17])[O:14][CH3:15])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CCP(=O)(OCC)OCC)C(=O)c1ccccc1
Reactant: CC(=O)O
Agent: [Na]
Solvent: CO
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)CCP(=O)(OC)OC
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To 100 mL of dry MeOH was added 0.18 g (7.83 mmol) of sodium metal. After the sodium metal had completely disappeared, a solution of 3.91 g (7.05 mmol) of benzoyl phosphonate 5 in 10 mL of dry MeOH was added. After the mixture was stirred overnight, the reaction was quenched by addition of 500 μL (8.73 mmol) of AcOH and then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (elution with CHCl3/MeOH 10:1) to provide 2.56 g (86%) of hydroxy phosphonate 6 as a colorless oil; [α]25D −5.20° (c 5.0, C6H6); 1H NMR (CDCl3) δ 0.88 (t, 3H, J=6.8 Hz), 1.26 (br s, 26H), 1.54-1.58 (m, 2H), 1.70-1.90 (m, 4H), 2.78 (br s, 1H), 3.29 (dd, 1H, J=7.1, 9.4 Hz), 3.40-3.48 (m, 3H), 3.74 (d, 6H, J=10.8 Hz), 3.70-3.85 (m, 1H); 13C NMR (CDCl3) δ 14.0, 20.7 (d, J=142.1 Hz), 22.6, 26.0, 26.1 (d, J=4.7 Hz), 29.3, 29.4, 29.5, 29.6, 31.9, 52.3, 69.8 (d, J=14.8 Hz), 71.6, 74.4; MS (electrospray) MH+ m/z calcd for C22H48O5P 423.3, found 423.3.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[I:7]I.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=1>S(=O)(=O)(O)O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:15]=1[I:7]
Reactant: II
Reactant: COC(=O)CCc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Product: COC(=O)CCc1ccc(Cl)c(I)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium metaperiodate (0.240 g, 1.121 mmol) was slowly added to a solution of iodine (0.846 g, 3.33 mmol) in sulfuric acid (21.1 ml). This was stirred at room temperature for 30 minutes. This dark brown iodinating solution was then slowly added to a solution of methyl 3-(4-chlorophenyl)propanoate (1.40 g, 7.05 mmol) in sulfuric acid (7.04 ml) (pre-cooled to 0° C.) taking care not to let the temperature rise above 30° C. This was stirred for 50 min. further, and then the reaction was quenched by pouring onto 100 mL of stirring ice water. This was extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate and purified via column chromatography on a Biotage 40M column eluting with hexanes (1 CV) followed by a gradient of 0-50% ethyl acetate in hexanes to provide the desired product as a clear colorless liquid. 1H NMR (CDCl3, 500 MHz) δ 7.70 (t, J=1.6 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.13 (dd, J=8.2 Hz, 1.8 Hz, 1H), 3.67 (s, 3H), 2.88 (t, J=7.7 Hz, 2H), 2.60 (t, J=7.7 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][OH:11].Br[CH2:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([O:27][CH:28]([CH3:30])[CH3:29])[C:24]([O-:26])=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][O:11][CH2:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([O:27][CH:28]([CH3:30])[CH3:29])[C:24]([OH:26])=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CBr
Reactant: COc1ccc(CO)c(Cl)c1
Product: COc1ccc(COCc2cc(CC(OC(C)C)C(=O)O)ccc2OC)c(Cl)c1

Procedure:
Using (2-chloro-4-methoxyphenyl)methanol and 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(2-chloro-4-methoxybenzyl)oxy]methyl-4-methoxyphenyl)-2-isopropoxy propanoic acid was obtained in the same method as in Example 247).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[N+:27]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[NH2:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Reaction time: 0.75 h
Yield: 84.8 %

Procedure:
To a stirred suspension of 4-(4-allyloxycarbonyl-2-nitro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (20.0 g, 49.33 mmol, 1.0 equiv) and Zn (23.22 g) 0.36 mol, 7.2 equiv) was added a sat. solution of NH4Cl (7.91 g, 0.15 mol, 3.0 equiv) and the reaction mixture heated to reflux. After 45 min, the reaction was cooled, filtered through Celite and concentrated by evaporation under reduced pressure. The filtrate was diluted with water and extracted with dichloromethane (3×200 mL). The combined organic fractions were washed with water, dried over Na2SO4 and concentrated by evaporation under reduced pressure. The brownish solid material was further washed with a mixture of hexane/ethyl acetate (98:2) to yield 15.7 g (85%) of the title product. 1H NMR (400 MHz, DMSO): δ 1.24-1.33 (m, 2H), 1.46 (s, 9H), 1.90-1.94 (m, 2H), 2.88-2.94 (m, 2H), 3.53-3.55 (m, 1H), 3.88-3.95 (m, 2H), 4.68 (d, J=5.2 Hz, 2H), 4.79 (s, 2H), 5.01 (d, J=7.5, 2H), 5.23 (d, J=10.4 Hz, 1H), 5.34 (d, J=17.3 Hz, 1H), 6.00-6.06 (m, 1H), 6.54 (d, J=8.2 Hz, 1H), 7.21 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[CH:6]=[N:5]2.[C:21]([N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>O1CCOCC1.C(OCC)(=O)C>[C:24]([O:23][C:21]([N:28]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH:6]=[N:5]3)[CH:30]=[N:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: Clc1cccc(CNc2cnc3cc(Br)ccc3n2)c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1cc(-c2ccc3nc(NCc4cccc(Cl)c4)cnc3c2)cn1
Temperature: 110 °C

Procedure:
A mixture of (6-Bromo-quinoxalin-2-yl)-(3-chloro-benzyl)-amine (0.4 g, 1 eq., 1.15 mmol), 1-Boc-4-pyrazole boronic acid pinacol ester (0.4 g, 1.2 eq., 1.37 mmol), caesium carbonate (1.5 g, 4.0 eq., 4.6 mmol) and potassium iodide (0.019 g, 0.1 eq., 0.11 mmol) in 1,4-dioxane (22 mL) was degassed at RT under vacuum and then placed under an atmosphere of nitrogen. The process was repeated twice and Fu's catalyst (Bis(tri-tert-butylphosphine)palladium(0)) (0.058 g, 0.1 eq., 0.1 mmol) was added at room temperature. The reaction mixture was heated to 110° C. in a microwave reactor for 180 minutes. After completion of the reaction (confirmed by TLC), the organic mixture was diluted with ethyl acetate (200 mL) and washed with water (75 mL×3) then brine (75 mL). The organic layer was dried and concentrated to afford the crude product.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:16][CH:15]([C:17](O)=[O:18])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:16][CH:15]([C:17]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CCCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyrrolidine (271 μL, 5.50 mmol) was added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.0 g, 4.97 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.18 mL, 12.52 mmol) in DMF (100 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give 3-(pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of 3-(pyrrolidine-1-carbonyl)-azetidine-1-carboxylic acid tert-butyl ester in DCM (15 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a colourless oil (550 mg, 72%). 1H NMR (CD3OD, 400 MHz) δ 3.93-3.65 (m, 5H); 3.43-3.28 (m, 4H) and 2.00-1.81 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[CH3:18][C:19]1[O:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:21][C:20]=1[CH2:30][CH2:31]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:31][CH2:30][C:20]2[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:23][C:19]=2[CH3:18])=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C
Yield: 72.6 %

Procedure:
A mixture of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (4.50 g, 18.9 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester (Japan Tobacco Inc WO 9518125) (8.43 g, 23.6 mmol), and Cs2CO3 (7.68 g, 23.6 mmol) was heated at 55° C. in DMF (45 mL) for 20 h. Additional toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester (2.81 g, 7.86 mmol) and Cs2CO3 (2.56 g, 7.86 mmol) were added, and the mixture was heated at 55° C. in DMF (45 mL) for 6 h. The reaction mixture cooled and partitioned between EtOAc (200 mL) and H2O (100 mL). The organic layer was washed with brine (50 mL). The aqueous layers were extracted further with EtOAc (200 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography using hexanes:ethyl acetate (6:1 to 4:1) to give an oil (5.81 g, 73%): 1H NMR (400 MHz, CDCl3) δ 1.27 (t, 3H, J=7.1 Hz), 1.51 (s, 6H), 2.18 (s, 3H), 2.36 (s, 3H), 2.95 (t, 2H, J=6.6 Hz), 4.17 (t, 2H, J=6.6 Hz), 4.24 (q, 2H, J=7.1 Hz), 6.57 (dd, 1H, J=2.9, 8.8 Hz), 6.65 (d, 1H, J=9.3 Hz), 6.69 (d, 1H, J=2.9 Hz), 7.38-7.45 (m, 3H), 7.98-8.00 (m, 2H); MS (ES) m/e 424.2 [M+1].
Reaction SMILES: [P:1](Cl)(Cl)[O:2][C:3]1[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][C:6]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][C:4]=1[C:17]([CH3:20])([CH3:19])[CH3:18].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30].C(N(CC)CC)C>C(Cl)Cl>[C:17]([C:4]1[CH:5]=[C:6]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[O:2][P:1]1[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(OP(Cl)Cl)c(C(C)(C)C)c1
Reactant: Nc1ccccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C(C)(C)C)c(OP2Nc3ccccc3O2)c(C(C)(C)C)c1
Yield: 26.5 %

Procedure:
Using the general procedure of Example 1, 12.0 g (33 mmol) of 2,4,6-tri-tert-butylphenyl phosphorodichloridite, 3.6 g (33 mmol) of 2-aminophenol, 9.3 ml (66 mmol) of triethylamine and 75 ml of methylene chloride are reacted to give 3.5 g of the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH3:21]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:21])=[O:5]
Reactant: N
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccc(C(F)(F)F)cc1F

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 2-fluoro-4-(trifluoromethyl)benzoic acid (1.5 g), THF (25 mL), oxalyl chloride (0.5 mL) and ammonia gas to afford 1.35 g of the product. 1H NMR (300 MHz, DMSO d6): δ 7.65 (d, J=8.4 Hz, 1H), 7.77-7.84 (m, 3H), 7.96 (br s, 1H); MS (m/z): 208.06 (M+).
Reaction SMILES: [Br:1][C:2]1([Br:20])[C:4]2([CH2:8][C@@H:7]([C:9]([O:11]C)=[O:10])[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]2)[CH2:3]1>C1COCC1.CO.O>[Br:20][C:2]1([Br:1])[C:4]2([CH2:8][C@@H:7]([C:9]([OH:11])=[O:10])[N:6]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:5]2)[CH2:3]1
Reactant: COC(=O)[C@@H]1CC2(CN1C(=O)OC(C)(C)C)CC2(Br)Br
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2(C[C@H]1C(=O)O)CC2(Br)Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of (6S)-5-tert-butyl 6-methyl 1,1-dibromo-5-azaspiro[2.4]heptane-5,6-dicarboxylate (3.05 g, 7.39 mmol) in THF-MeOH-water (35 mL, 14 mL and 14 mL respectively) was added LiOH monohydrate (930 mg, 3 eq). The mixture was stirred at room temperature for 1.5 hr before being evaporated off. The aqueous residue was acidified with 1M HCl, extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and evaporated to give the title compound (quantitative yield) as a light yellow solid. 1H NMR (500 MHz, CDCl3): 10.45 (br s, 1H), 4.65-4.45 (m, 1H), 3.99-3.86 (m, 1H), 3.53-3.31 (m, 1H), 2.87-1.95 (m, 2H), 1.86-1.73 (m, 2H), 1.49, 1.48 and 1.44 (3 s, 9H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:6][C:7]=1Br.C[O-].[Na+].[C:16](O)(=[O:18])C>CO>[Br:1][C:2]1[N:3]=[N:4][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:6][C:7]=1[O:18][CH3:16]
Reactant: FC(F)(F)c1cc(Br)c(Br)nn1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(F)(F)F)nnc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a stirred solution of 3,4-dibromo-6-trifluoromethyl-pyridazine (D5) (1.48 g, 4.85 mmol) in methanol at 0° C., was added a 30% solution of sodium methoxide in methanol (0.8 ml, 4.67 mol). The reaction mixture was stirred at 0° C. for 1 h. After this period, the reaction mixture was neutralized by acetic acid addition and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 3% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. to yield D6 (0.79 g, 64%) as a solid. C6H4BrF3N2O requires 257; Found 258 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8].CCN(CC)CC.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C.CC(OC)(C)C.O>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH2:9][O:10][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:5][N:6]=1
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)OCc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
A mixture of (5,6-dichloro-3-pyridinyl)methanol (2000 mg, 11.23 mmol), Et3N (2.349 ml, 16.85 mmol), and tert-butyldimethylsilyl chloride (1778 mg, 11.80 mmol) in DMF (20 ml) was stirred at room temperature for 4 h. HPLC analyse showed starting material remaining, an excess of tert-butyldimethylsilyl chloride (847 mg, 5.62 mmol) and Et3N (1.174 ml, 8.43 mmol) were added. The mixture reaction was stirred overnight. The crude was diluted with TBME (175 mL) and water. The organic phase was washed with solution sat. NaCl. Combined organics were washed with sat NH4Cl and dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography using Flashmaster II, a 50 g silica gel cartridge, and mixtures of hexane and EtOAc as eluent afforded 2,3-Dichloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)pyridine 2.5 g (72%) of a yellow oil.
Reaction SMILES: [C:1]([N:20]1[N:24]=[N:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=NN=N1.C([Li])CCC.[Li].C[Mg]Cl.I[C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1>C1COCC1.[Ni].[Cl-].[Zn+2].[Cl-].Cl[Ni](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.[Zn]>[C:1]([N:20]1[N:24]=[N:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:46]2[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=2)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Reactant: Cc1ccc(I)cc1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Ni]
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
(2-Trityltetrazol-5-yl)benzene (25.0 g) was dissolved in dry THF (250 mL) and the solution of the tetrazole was cooled to -20° C. and n-butyllithium (28.3 mL, 2.5M in hexanes) was added. The mixture was gradually warmed to -10° C. over 1 hour and then aged at this temperature for an additional 30 minutes. A 1.4M THF solution of zinc chloride (51.3 mL) was then added to the aryllithium reagent prepared above while maintaining the lithium reagent solution at ≤0° C. In another flask an activated nickel catalyst solution was prepared as follows. To a solution of (PPh3)2NiCl2 (2.5 g) in THF (35 mL) at 0° C. was added methylmagnesium chloride (2.5 mL, 3M in THF) followed by p-iodotoluene (17.5 g). The catalyst solution was warmed to 20° C. and the solution of the zinc reagent was added at a rate that maintained the reaction temperature between 20° to 25° C. Ten hours after the addition of the zinc reagent to the reaction was complete, the reaction mixture was cooled to 0° C., 8.0 g of SuperCel (filter aid) was added, followed by the addition of concentrated ammonium hydroxide (15 mL) over 30 minutes. The heterogeneous solution was aged at 0° C. for 1 hour and filtered. The filter cake was washed with THF (50 mL). The filtrate was washed with a mixture of saturated NaCl (80 mL) and saturated NaHCO3 (30 mL) and the layers separated. The THF layer was dried with anhydrous Na2CO3 (30 g) and filtered. The volume of the filtrate was reduced to 150 mL and cyclohexane (300 mL) was added. The THF was further distilled in vacuo while the temperature of the mixture was maintained at 40° to 45° C. Cyclohexane was added periodically to maintain the volume at 200 mL. When the amount of THF dropped to ≤3 percent, the distillation was stopped and the mixture was cooled to room temperature. Hexanes (150 mL) was then added and the mixture further aged at 0° C. for 1 hour. The product was collected and washed with hexanes (100 mL). The yield was 28.8 g (94%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([CH:33]2[CH2:35][CH2:34]2)=[CH:29][N:28]=1>>[CH:33]1([C:30]2[CH:29]=[N:28][C:27]([N:23]3[CH2:24][CH2:25][CH:20]([C@@H:18]4[O:17][C:14]5=[CH:15][N:16]=[C:11]([C:8]6[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=6)[CH:12]=[C:13]5[CH2:19]4)[CH2:21][CH2:22]3)=[N:32][CH:31]=2)[CH2:35][CH2:34]1
Reactant: Clc1ncc(C2CC2)cn1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(c4ncc(C5CC5)cn4)CC2)C3)CC1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-cyclopropyl-pyrimidine following a procedure analogous to that described for Example 79. LC (method 10): tR=1.61 min; Mass spectrum (ESI+): m/z=482 [M+H]+.