Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11].[CH2:17](Cl)[C:18]#[C:19][CH2:20]C.O>C1COCC1>[CH3:11][C:10]([CH3:2])([CH2:12][C:17]#[C:18][CH2:19][CH3:20])[C:9]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCC#CCCl
Reactant: CCOC(=O)C(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC#CCC(C)(C)C(=O)OCC
Temperature: -78 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of LDA (146 ml, 291 mmol, 2M in THF) at −78° C. under nitrogen was added a solution of ethyl isobutyrate (33.9 g, 291 mmol) in dry THF (100 ml) and the mixture was stirred at −78° C. for 2 hours. To the mixture was added 2-pentynyl chloride (25 g, 243 mmol) slowly over a period of 20 min. The reaction mixture was slowly warmed to RT over a period of 12 hours. Water (200 ml) was added and the product was extracted with Et2O (2×200 ml). The combined organic layers were washed with water, brine and dried (MgSO4). The solvent was removed under vacuum and the residue was purified by flash chromatography on silica (pet. ether/EtOAc 9/1) to afford the titled compound as a colorless liquid (29 g, 66%). TLC: Pet ether/EtOAc (8/2): Rf=0.75. 1H-NMR (CDCl3:300 MHz) δ 1.11 (3H, t), 1.24 (6H, s), 2.15 (2H, m), 2.38 (2H, s), 4.14 (2H, m).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C.CCOC(C)=O>[C:14]1([S:20]([N:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=3[CH:3]=[CH:2]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=Cc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1

Procedure:
1H-Indole-4-carbaldehyde (24.8 g, 0.17 mol) was dissolved in dry DMF (500 ml), cooled in ice-bath and NaH (7.5 g (60% suspension in oil), 0.19 mol, 1.1 eq.) was added. After stirring for a few minutes, the cold bath was removed and the r×n mixture was stirred at room temperature for 40 min. under Ar. The insoluble NaH clumps were brought in solution by means of sonication for a few minutes. The mixture was cooled in ice-bath and benzenesulfonyl chloride (23.9 ml, 0.188 mol, 1.1 e.q.) was added dropwise over 3 min. The reaction mixture was stirred at room temperature for 1 hour, then poured slowly into a mixture of water (1 L) and EtOAc (200 ml). The aqueous phase was extracted with EtOAc (5×100 ml), the organic phase was washed with brine (200 ml), dried over Na2SO4 and evaporated. The residue was purified on silica flash column using petroleum ether/EtOAc (1:1) giving the product as a colorless crystalline solid. Yield: 45.5 g. MS m/z 286 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12](OC(OCC)OCC)C>>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][CH:12]=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: CCOC(OCC)OCC
Product: Fc1ccc(-c2nnco2)cc1
Yield: 57 %

Procedure:
A stirred solution of 4-fluorobenzohydrazide (4.2 g, 27.2 mmol) in triethylorthoformate (27 mL) was heated at 140° C. for 5 h. The reaction was evaporated under reduced pressure. The crude was purified by silica gel column chromatography (100-200 mesh; using 12% ethyl acetate in hexane) to afford 2-(4-fluorophenyl)-1,3,4-oxadiazole [Polshettiwar, Tetrahedron Letters, 49:879-883 (2008)] as off-white solid (2.5 g, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 8.08 (dd, 2H), 7.19 (dd, 2H); LC-MS m/z calculated for [M+H]+165.04. found 165.00.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:20])[C:7](=[O:19])[CH2:8][CH2:9][O:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][CH3:18])[CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)=[O:32].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][C:31](=[O:32])[N:17]([C@H:14]2[CH2:13][CH2:12][C@H:11]([O:10][CH2:9][CH2:8][C:7](=[O:19])[N:6]([CH2:5][CH2:4][CH2:3][OH:2])[CH3:20])[CH2:16][CH2:15]2)[CH3:18])=[CH:35][CH:36]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CN[C@H]1CC[C@H](OCCC(=O)N(C)CCCO)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCO)C(=O)CCO[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 158 mg (0.5 mmol) of trans-N-(3-hydroxy-propyl)-N-methyl-3-(4-methylamino-cyclohexyloxy)-propionamide-hydrochloride in 3 mL of CH2Cl2 were added 0.43 mL (2.6 mmol, 5 eq) of N,N-diisopropylethylamine followed by 0.08 mL (0.56 mmol, 1.1 eq) of 4-chlorophenyl chloroformate. The mixture was stirred at RT for 1 h, and the solution was added to a mixture of NaHCO3 solution and CH2Cl2. The phases were separated and the inorganic phase was extracted with CH2Cl2. The organic phase was washed with 1M KHSO4. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. Column chromatography on silica gel with a gradient of CH2Cl2:MeOH 98:2 to 95:5 yielded 105 mg (48%) of trans-(4-{2-[(3-hydroxy-propyl)-methyl-carbamoyl]-ethoxy}-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester as colorless oil, MS: 427 (MH+,1Cl).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1)(=[O:12])=[O:11].[H-].[Na+].Br[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH2:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:14]=1)(=[O:11])=[O:12]
Reactant: BrCc1ccncc1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cccc(CO)c2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cccc(COCc3ccncc3)c2)c(C)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
N-(2,4-dimethylphenyl)-3-(hydroxymethyl)-N-isobutylbenzenesulfonamide (50 mg, 0.144 mmol) and Sodium hydride (60% in Mineral Oil) (6.33 mg, 0.158 mmol) were dissolved in N,N-Dimethylformamide (DMF) (3 mL). To this solution was added 4-(bromomethyl)pyridine (24.75 mg, 0.144 mmol), and the reaction heated to 60° C. and left to stir for 30 min. The reaction solution concentrated on the Biotage V10 and then extracted the crude product to the organic phase of an aqueous work up between ethyl acetate (15 mL) and water (15 mL). The organic phase was separated (hydrophobic frit) and then concentrated in vacuo. The sample was dissolved in 1:1 MeOH:DMSO 1 mL and purified by mass directed autoprep on Sunfire C18 column using acetonitrile:water with a formic acid modifier. The solvent was evaporated in vacuo. The crude product was run through an NH2 SPE column (1 g) eluting with methanol, to remove the formic acid. The product was then dried under a stream of nitrogen on a Radleys blow down unit, to give the final product, 13.5 mg.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][N:7]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)=[N:8]1>CN(C=O)C.O>[N:1]([CH2:6][N:7]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)=[N:8]1)=[N+:2]=[N-:3]
Reactant: ClCn1cc(Cl)c(-c2cc(Cl)cc(Cl)c2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCn1cc(Cl)c(-c2cc(Cl)cc(Cl)c2)n1
Reaction time: 12 h
Yield: 85.9 %

Procedure:
0.70 g (0.010 mol) of sodium azide is added, at room temperature, to a solution of 1.85 g (0.005 mol) of 1-chloromethyl-4-chloro-3-(3,5-dichlorophenyl)pyrazole in 25 ml of DMF. The reaction mixture is stirred for 12 h, diluted with 100 ml of H2O and extracted with ether. After drying the organic phase and concentration under vacuum, the residue is triturated with 20 ml of heptane, filtered and dried. We obtain 1.30 g of 1-azidomethyl-4-chloro-3-(3,5-dichlorophenyl)pyrazole, melting at 74° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:18]2[CH2:19][CH2:20][CH:15]([F:14])[CH2:16][CH2:17]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: FC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CCC(F)CC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.1 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (1 g, 5.84 mmol), 4-fluoropiperidine hydrochloride (0.97 g, 6.42 mmol) and 4 Å molecular sieves (10 g) in DCE (50 mL). The reaction mixture was stirred for 4 h at room temperature. Sodium triacetoxyborohydride (2.48 g, 11.68 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, gradient 0:100 to 100:0) then (Si—PPC, MeOH:DCM, 0:100 to 5:95) to give 3-(4-Fluoropiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil (0.59 g, 39%). 1H NMR (CDCl3, 400 MHz) δ 4.80-4.58 (m, 1 H); 3.97-3.89 (m, 2 H); 3.85-3.76 (m, 2 H); 3.08 (t, J=6.4 Hz, 1 H); 2.50-2.28 (m, 4 H); 1.99-1.82 (m, 4 H); 1.48-1.38 (m, 9 H).
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(CC1C(=O)C=C(C)CC1)(OCC)=O>C1COCC1>[C:24]([CH2:23][CH:10]1[C:9](=[O:13])[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)([O:26][CH2:27][CH3:28])=[O:25]
Reactant: O=C1C=C(c2ccccc2)CCC1
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: CCOC(=O)CC1CCC(C)=CC1=O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCC(c2ccccc2)=CC1=O
Yield: 86.8 %

Procedure:
The reaction of 3-phenyl-2-cyclohexen-1-one (3.0 g, 17.4 mmoles) in 10 ml of THF with lithium diisopropylamide (19.2 mmoles) followed by ethyl bromoacetate (3.5 g, 20.9 mmoles) in 10 ml of THF, at -78° C. under argon, was conducted in a similar manner to the synthesis of 6-(carbethoxymethyl)-3-methyl-2-cyclohexen-1-one described in Example II. A yield of 3.90 g (87%) of 6-(carbethoxymethyl)-3-phenyl-2-cyclohexen-1-one was obtained.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH2:16])[C:5]2[N:6]([N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:7]=1.[CH2:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:18][CH2:19][C:20]#[CH:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:5]2[C:4]([NH2:16])=[N:3][C:2]([C:21]#[C:20][CH2:19][CH2:18][CH2:17][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][N:6]2[N:8]=1
Reactant: C#CCCCc1ccccc1
Reactant: Nc1nc(Br)cn2nc(-c3ccco3)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nc(C#CCCCc2ccccc2)cn2nc(-c3ccco3)nc12
Yield: 40.8 %

Procedure:
A solution of 6-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine (56 mg, 0.2 mmol; see Examples 1 and 2 above), pent-4-ynyl-benzene (44 mg, 0.3 mmol), Pd(PPh3)4 (26 mg, 0.03 mmol), CuI (4 mg, 0.03 mmol), PPh3 (8 mg, 0.03 mmol), and TEA (11 μL, 2.5 mmol) in DMF (5 mL) was heated (at around 105° C.) under N2 for 2 hours. The reaction was diluted with EtOAc (15 mL) and washed with brine (3×10 mL) and dried with MgSO4. The solvent was removed and the reaction purified by HPLC (C18, H2O:MeCN gradient) to afford the product as a brown solid (28 mg,). 1H NMR (400 MHz, DMSO-d6) δ 1.85 (quin, J=7.5 Hz, 2H) 2.44 (t, J 7.1 Hz, 2H), 2.74 (t, J=7.8 Hz, 2H), 6.72 (dd, J=3.4, 1.8 Hz, 1H), 7.14 (dd, J=3.5, 0.8 Hz, 1H), 7.2-7.30 (br m, 5H), 7.92 (dd, J=1.7, 0.8 Hz, 1H), 8.35 (s, 1H). MS: m/z 344 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1>>[CH3:28][N:25]1[C:26]2[CH:27]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=4)=[CH:10][C:11]3=[O:15])[CH:20]=[CH:21][C:22]=2[C:23]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]1=2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 59 %

Procedure:
4-(6-(Trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (131 mg, 0.54 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 0.54 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (167 mg, 59%) as a green solid: 1H NMR (300 MHz, CDCl3) δ 8.99 (d, J=2.0 Hz, 1H), 8.10 (dd, J=8.1, 1.8 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.60-7.54 (m, 2H), 7.32 (d, J=1.9 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 6.49 (dd, J=7.1, 2.0 Hz, 1H), 4.66 (s, 2H), 3.85 (br m, 2H), 3.65 (s, 3H), 2.84 (s, 2H), 1.50 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:28])=[CH:14][CH:13]=1)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[CH3:42]
Reactant: CCOC(=O)CBr
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN(CCC)CCCCN(CC(=O)OCC)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (28.58 g) obtained in Example 23-4 was dissolved in anhydrous DMF (560 ml) and added with triethylamine (20.35 ml) and ethyl bromoacetate (12.14 ml) and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in ethyl acetate and washed with water, followed by drying with magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (21.265 g) as a colorless oily substance.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:32][CH3:33])=O)C1C=CC=CC=1.C(OCC)(=O)C>[Pd].CO>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:32][CH3:33]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)oc1CC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)oc1CC
Yield: 107.1 %

Procedure:
The same operation as in Example (95b) was performed using butyl cis(±)-2-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (110b) (0.5 g, 1.09 mmol), 10% Pd/C (0.2 g), ethyl acetate (3 mL) and methanol (3 mL), to obtain 0.38 g of the title compound as a yellow oily substance (100%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:11]=[C:12]([CH:33]=[CH:34][CH:35]=1)[CH2:13][NH:14][C:15](=[O:32])[CH2:16][O:17][CH2:18][C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])=[O:20]>>[Cl:31][C:28]1[CH:29]=[CH:30][C:22]([NH:21][C:19](=[O:20])[CH2:18][O:17][CH2:16][C:15](=[O:32])[NH:14][CH2:13][C:12]2[CH:11]=[CH:10][CH:35]=[C:34]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:33]=2)=[C:23]([CH:27]=1)[C:24]([OH:26])=[O:25]
Reactant: OB(O)c1cccs1
Reactant: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)NCc1cccc(Br)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)NCc1cccc(-c2cccs2)c1

Procedure:
Using the same method as in Example 19-(ii), 2-thiopheneboronic acid was reacted with the 2-[((2-[(3-bromobenzyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester obtained in Example 72-(i) to give 5-chloro-2-([(2-oxo-2-([3-(thiophen-2-yl)benzyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 67%).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[C:11]2[CH:16]3[CH2:17][CH2:18][N+:13]([CH2:19][CH:20](O)[CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])([CH2:14][CH2:15]3)[CH2:12]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=[O:33]>>[OH-:23].[C:22]([CH2:21][CH2:20][CH:19]([N+:13]12[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]1)[C:11](=[CH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=1)[CH2:12]2)[OH:33])([OH:24])=[O:23]
Reactant: CC(C)(C)OC(=O)CC(O)C[N+]12CCC(CC1)C(=CCc1ccc(Cl)cc1)C2
Reactant: O=C(O)C(F)(F)F
Agent: [Cl-]
Product: O=C(O)CCC(O)[N+]12CCC(CC1)C(=CCc1ccc(Cl)cc1)C2
Product: [OH-]

Procedure:
Stir 4.42 g (0.01 mole) of 3-[2-(4-chlorophenyl)ethylidene]-1-[3-((1,1-dimethylethoxy)carbonyl)-2-hydroxypropyl]-1-azoniabicyclo[2.2.2]octane chloride in 25 ml of trifluoroacetic acid. Follow the progress of the reaction by thin-layer chromatography on silica gel. When the reaction is complete (ca. 3-5 hr) remove the solvent in vacuo. Dissolve the residue in methanol/water. Stir the aqueous methanol solution with sufficient anion exchange resin (Biorad AG-1-X8, hydroxide form) to bring the pH of the solution to pH=9. Remove the resin by filtration and evaporate the solvent in vacuo at room temperature to provide the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1([CH2:6][C:7](OC)=[O:8])[CH2:5][CH2:4]1.O.[OH-].[Na+].[ClH:15]>O1CCCC1.O1CCOCC1>[ClH:15].[CH3:1][N:2]([CH3:11])[C:3]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4]1
Reactant: COC(=O)CC1(N(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C1(CCO)CC1
Temperature: 5 °C

Procedure:
10.2 g of the compound obtained in Step 3 dissolved in 200 ml of tetrahydrofuran are slowly added to a solution of 5 g of AlLiH4 in 300 ml of tetrahydrofuran. After refluxing for 2 hours, the reaction mixture is cooled to 5° C. and 10.7 ml of water, 10.7 ml of 4N sodium hydroxide and then 32.1 ml of water are added. After filtering and concentrating under reduced pressure, chromatography over silica gel (dichloromethane/methanol: 95/5) allows the expected product to be isolated, which is converted into its hydrochloride form by the action of a solution of hydrochloric acid in dioxane.
Reaction SMILES: [CH:1]1([CH2:4][P:5](Cl)(Cl)=[O:6])[CH2:3][CH2:2]1.[CH:9]([Mg]Br)=[CH2:10].[Cl-].[NH4+].[CH2:15]1COC[CH2:16]1>>[CH:1]1([CH2:4][P:5](=[O:6])([CH:9]=[CH2:10])[CH:15]=[CH2:16])[CH2:3][CH2:2]1
Reactant: O=P(Cl)(Cl)CC1CC1
Reactant: C=C[Mg]Br
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: C=CP(=O)(C=C)CC1CC1
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
Cyclopropylmethyl-phosphonic dichloride (8.43 g, 48.7 mmol) was dissolved in dry THF (70 mL), placed under a nitrogen atmosphere, and chilled to −70° C. To this stirred solution was added dropwise vinyl magnesium bromide in THF (122 mL, 1 M). The resulting solution was stirred for 90 minutes at −70° C. An aqueous solution of ammonium chloride (500 mL, 2 M) was chilled to 0° C. and stirred rapidly while the cold reaction mixture was added. The product was extracted into dichloromethane and washed with saturated aqueous sodium bicarbonate and then with water. The organic phase was dried with sodium sulfate, filtered, and concentrated by rotary evaporation to yield 3.56 g of (cyclopropylmethyl)-divinyl-phosphine oxide (22.8 mmol, 47%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 6.44-6.14 (m, 6H); 1.84-1.78 (d of d, 2H) 0.98-0.86 (m, 1H); 0.66-0.60 (m, 2H); 0.25-0.19 (m, 2H); ESMS (m/z): (M+1)+ found, 157; (M−1)− found, 155.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([N:20]3[CH2:25][CH2:24][Si:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]3)=[C:15]([F:28])[CH:14]=2)[CH2:8]1)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+].O>CN(C=O)C>[N:29]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([N:20]3[CH2:21][CH2:22][Si:23]([CH3:26])([CH3:27])[CH2:24][CH2:25]3)=[C:15]([F:28])[CH:14]=2)[CH2:8]1)=[N+:30]=[N-:31]
Reactant: C[Si]1(C)CCN(c2c(F)cc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si]1(C)CCN(c2c(F)cc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To the Mesyl compound 18a (320 mg, 0.74 mmol) in DMF, NaN3 (63 mg, 0.97 mmol) is added and stirred at 60° C. for 2 h. Water (5 mL) is added and extracted with DCM (2×5 mL), dried and concentrated. The crude (300 mg) is used for further steps without purification.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:9].[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17]
Reactant: Clc1ccccc1Br
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Mg]
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Yield: 64 %

Procedure:
Following the procedure outlined in Example 1, 1.3 g (52 mmol) of magnesium turnings, 10.0 g (52 mmol) of 1-bromo-2-chlorobenzene and 9.4 g (52 mmol) benzophenone gave 9.81 g (64%) of (2-Chlorophenyl) diphenyl methanol (Compound T3), mp: 91° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:7]([CH:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:27])=[CH:5]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:15])=[O:14])=[C:7]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:27])=[CH:5]2
Reactant: CCOC(=O)C(O)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(6-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (2.19 g, 4.65 mmol) in anhydrous dichloromethane (50 mL) at 0° C. was added Dess-Martin Periodinane (2.76 g, 6.51 mmol) portion-wise over 5 minutes. The reaction mixture was stirred at 0° C. for 1 hour and quenched with sodium thiosulfate solution and saturated sodium bicarbonate solution and stirred for 30 minutes. The mixture was diluted with ethyl ether and washed with saturated sodium bicarbonate solution (3×), brine and dried (MgSO4), filtered, concentrated to give a yellow oil with a white precipitate. The mixture was suspended in diethyl ether, washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give the desired compound.