Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:4]1=[O:18].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C([O-])(O)=O.[Na+]>ClCCl>[O:18]=[C:4]1[CH:3]([CH2:2][O:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:7][CH2:6][N:5]1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1C(CO)CCN1c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCN(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 113.6 %

Procedure:
A mixture of 3-hydroxymethyl-1-(3-trifluoromethyl-phenyl)-pyrrolidin-2-one obtained in step 3 (0.17 g, 0.6 mmol), dichloromethane (8 ml) and triethyl amine (0.085 g, 0.84 mol) was cooled to 0° C. and stirred for 15 min at that temperature. Methane sulfonyl chloride (0.090 g, 0.78 mmol) was added to the mixture over a period of 5 min and the reaction mixture was stirred for 1.5 hrs at 10-15° C. To this reaction mixture saturated NaHCO3 solution (10 ml) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with saturated brine solution, dried over Na2SO4 and evaporated to obtain methanesulfonic acid 2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl ester as a brown oil (0.23 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[O:20][CH2:21][CH2:22][NH2:23].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:13])=[CH:4][C:3]=1[O:20][CH2:21][CH2:22][NH:23][C:31](=[O:33])[CH3:32]
Reactant: NCCOc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1F
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCOc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.6 %

Procedure:
2-{[6-Fluoro-1-(phenylsulfonyl)-1H-indol-5-yl]oxy}ethanamine (Intermediate 29, 2.0 g 6.0 mmol) in DCM (100 mL) was treated with triethylamine (2.5 mL, 18 mmol) and 4-dimethylaminopyridine (0.37 g, 3.0 mmol). The solution was cooled to 0° C. and treated with acetyl chloride (0.85 mL, 12 mmol). The mixture was stirred at room temperature for 1.5 hours and washed with saturated aqueous NaHCO3 (40 mL) and 0.5 M HCl (40 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (2.0 g). MS m/z 377 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH2:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(O)(=[O:23])C.ClC1C=CC=C(C(OO)=O)C=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH2:20])=[O:19])[C:11]3=[N+:12]([O-:23])[CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CC(=O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Product: NC(=O)Cn1c(-c2ccc(Cl)cc2)nc2ccc[n+]([O-])c21
Temperature: 60 °C
Yield: 52 %

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide (1.84 g, 0.0064 mole), glacial acetic acid, and m-chloroperbenzoic acid (4.4 g, 0.0256 mole) was heated at 60° C. for a total of 4 hours. The reaction mixture was diluted with water and the organic acid which precipitated was filtered. The aqueous filtrate was neutralized for peroxides with 10% sodium sulfite. The aqueous solution was evaporated to dryness and the residue was treated with methylene chloride/saturated sodium bicarbonate. The insoluble precipitate was filtered, washed with methylene chloride and water, and dried at 50° C. under high vacuum overnight to give 1.0 g (52%) of title compound, mp. 272°-75° C. with decomposition.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Cl[C:32]1[CH:33]=[CH:34][C:35]2[N:36]([N:38]=[C:39]([CH3:41])[N:40]=2)[N:37]=1>O1CCCC1>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([N:38]=[C:39]([CH3:41])[N:40]=4)[N:37]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: Cc1nc2ccc(Cl)nn2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
4-(Diphenylmethoxy)-1-piperidinepropanol (743 mg) was dissolved in dried tetrahydrofuran (17 ml), followed by addition of sodium t-butoxide (241 mg). The mixture was heated to 60° C. and stirred for 30 minutes. After the mixture was cooled, 6-chloro-2-methyl[1,2,4]triazolo[1,5-b]pyridazine (384 mg) was added thereto, followed by reflux under heating for 21 hours. After the mixture was cooled, ice-water was added thereto, followed by extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of ethyl acetate, methanol and triethylamine (50:5:1). Fractions containing the objective compound were collected. The resulting crystals were washed with ethyl ether and dried to yield the title compound (700 mg).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]([F:22])([F:21])[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[N:13]=1.[Br:23][CH2:24][CH2:25]Br>C(#N)C>[Br:23][CH2:24][CH2:25][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[N:13]=[C:9]([C:8]([F:7])([F:21])[F:22])[S:10][CH:11]=1
Reactant: BrCCBr
Reactant: Oc1ccccc1-c1csc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: FC(F)(F)c1nc(-c2ccccc2OCCBr)cs1
Temperature: 70 °C

Procedure:
Cesium carbonate (266 mg, 0.816 mmol) was added to a solution of 2-[2-(trifluoromethyl)-1,3-thiazol-4-yl]phenol (C4) (100 mg, 0.408 mmol) and 1,2-dibromoethane (0.35 mL, 4.1 mmol) in acetonitrile (33 mL), and the mixture was heated at 70° C. for 18 hours. After cooling to room temperature, the reaction was partitioned between dichloromethane and water; the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 10% to 30% ethyl acetate in heptane) afforded the title compound. Yield: 115 mg, 0.327 mmol, 80%. 1H NMR (400 MHz, CDCl3) δ 3.78 (br dd, J=5.5, 5.5 Hz, 2H), 4.48 (dd, J=5.7, 5.5 Hz, 2H), 6.97 (br d, J=8.4 Hz, 1H), 7.13 (ddd, J=7.7, 7.4, 1.1 Hz, 1H), 7.35 (ddd, J=8.3, 7.3, 1.8 Hz, 1H), 8.31 (dd, J=7.8, 1.8 Hz, 1H), 8.37 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].Cl.C(N(CC)CC)C.Cl>CN1CCCC1=O>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]2[NH:12][N:11]=[N:10][N:2]=2)=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Oc1ccc(-c2nnn[nH]2)cc1
Temperature: 140 °C
Yield: 78.6 %

Procedure:
A mixture of 4-cyanophenol (4.8 g, 40 mmol), sodium azide (7.8 g, 120 mmol) and triethylamine hydrochloride (8.24 g, 60 mmol) in 1-methyl-2-pyrrolidinone (40 ml) was stirred and heated in an oil bath at 140° C. for five hours. The cooled solution was acidified with 2M hydrochloric acid (200 ml) and extracted with ethyl acetate (3×100 ml). The combined ethyl acetate extracts were washed with water (3×100 ml), dried over anhydrous magnesium sulphate, filtered and evaporated to a fawn solid which was crystallised from 50% v/v ethyl acetate in isohexane to give the title compound (5.1 g.) NMR d (d6-DMSO) 6.95 (2H,d), 7.85 (2H,d), 10.13 (1H,br); MS[MH]+ 163
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:39][CH3:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH3:12][N:11]1[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:6]2[N:21]=[C:2]([NH:22][C:23]3[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]4)=[O:28])=[CH:25][C:24]=3[O:39][CH3:40])[N:3]=[CH:4][C:5]1=2
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CC1CN(C2CCOCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCOCC1)CC(C)C(=O)N2C
Yield: 56.1 %

Procedure:
A solution of 0.050 g (0.00016 mole) of (rac)-2-chloro-5,7-dimethyl-9-(tetrahydropyran-4-yl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-45), 0.042 g (0.00016 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.047 g (0.00024 mole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated and the residue diluted with dichloromethane, washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (100:0-75:25) to give 0.0483 g of (rac)-4-(5,7-dimethyl-6-oxo-9-(tetrahydro-pyran-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-45) as a white powder. HRMS (ES+) m/z Calcd for C28H39N7O4+H [(M+H)+]: 538.3137. Found: 538.3136.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=2[O:32][CH3:33])=[CH:11][C:10]=1[C:34](O)=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][NH2:57])=[CH:51][CH:50]=1>CN(C=O)C.O>[CH2:56]([NH:57][C:34]([C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[C:27]([CH:29]([CH3:30])[CH3:31])[CH:26]=[CH:25][C:24]=2[O:32][CH3:33])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:35])[CH2:55][C:52]1[CH:53]=[CH:54][CH:49]=[CH:50][CH:51]=1
Reactant: COc1ccc(C(C)C)cc1-c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: NCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C)cc1-c1cc(C(=O)NCCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 94 %

Procedure:
4,6-Bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-carboxylic acid (965 mg, 2 mmol) was dissolved in DMF (anhydrous, 10 ml), and CDI (324 mg, 2 mmol) was added and the resulting solution was stirred at r.t for 2 h. 2-Phenethylamine (267 mg, 2.2 mmol) solution in DMF (5 ml) was added and the resulting solution was stirred at r.t. until the reaction was complete. The reaction was diluted with water (50 ml), extracted with dichloromethane (50 ml×3), and the combined organics were washed thoroughly with water to remove DMF and dried over sodium sulfate. After filtration and concentration, the residue was purified by flash chromatography on silica gel to give 4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-carboxylic acid phenethyl-amide (1101 mg, 94%). M.p.: 138-140° C.; 400 MHz 1H NMR (CDCl3) δ: 8.17 (s, 1H), 7.87 (t, J=5.6 Hz, 1H), 7.40-7.36 (m, 3H), 7.32-7.11 (m, 14H), 6.87 (d, J=8.0 Hz, 1H), 6.54 (s, 1H), 5.03 (s, 2H), 5.00 (s, 2H), 3.72 (s, 3H), 3.64 (q, J=6.4 Hz, 2H), 2.92-2.81 (m, 1H), 2.75 (t, J=7.2 Hz, 2H), 1.23 (d, J=7.2 Hz, 6H); LCMS: 586 [M+H].
Reaction SMILES: [C:1](=[O:18])(ON1C(=O)CCC1=O)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[N+:20]([C:23]1[CH:24]=[C:25]([C@@H:29]([NH2:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[N+:20]([C:23]1[CH:24]=[C:25]([C@@H:29]([NH:31][C:1](=[O:18])[O:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:30])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: C[C@H](N)c1cccc([N+](=O)[O-])c1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)OCc1ccccc1)c1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 118.4 %

Procedure:
Benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.36 g, 5.5 mmol) was added to a solution of (S)-1-(3-nitrophenyl)ethanamine HCl (1 g, 4.95 mmol) in CH2Cl2 (70 mL) and DIEA (2.2 mL, 12.4 mmol) and the reaction mixture was stirred for 1 h. The mixture was diluted with CH2Cl2 (100 mL), washed with NaHCO3, brine, dried over Na2SO4 and concentrated in vacuo to yield 59A (1.76 g, 99%) as a white solid. MS (ESI) m/z 323.02 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:18])([CH3:17])[CH2:9][C@:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)=[C:4]([CH3:19])[CH:3]=1.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:27][CH2:19][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:8]([CH3:17])([CH3:18])[CH2:9][C@:10]1([C:13]([F:16])([F:14])[F:15])[CH2:12][O:11]1
Reactant: Cc1cc(F)ccc1C(C)(C)C[C@]1(C(F)(F)F)CO1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C[C@]1(C(F)(F)F)CO1)c1ccc(F)cc1CBr
Temperature: 80 °C
Yield: 105.6 %

Procedure:
To a solution of 17.7 g (R)-2-[2-(4-fluoro-2-methylphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (0.064 mol) in 250 mL of CCl4 was added 14.8 g (0.083 mol) of NBS followed by 1.5 g (0.006 mol) benzoyl peroxide and heated to 80° C. for 2 hours. The mixture was cooled to room temperature, diluted with 1800 mL of hexanes, filtered through a pad of CELITE® filter aid, and concentrated in vacuo. The crude mixture was chromatographed on silica gel using 0-5% ethyl acetate/hexanes to afford 24 g (69%) (R)-2-[2-(2-bromomethyl-4-fluorophenyl)-2-methylpropyl]-2-trifluoromethyloxirane.
Reaction SMILES: [CH3:1][C:2]1([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:19]#[N:20])[CH:16]=3)[C:11]2=[O:21])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9].[ClH:22]>CC(O)C.O.O=[Pt]=O>[ClH:22].[NH2:20][CH2:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:21])[N:10]([C:2]1([CH3:1])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9])[CH2:18]2
Reactant: CC1(N2Cc3cc(C#N)ccc3C2=O)CCC(=O)NC1=O
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC1(N2Cc3cc(CN)ccc3C2=O)CCC(=O)NC1=O
Yield: 92 %

Procedure:
A mixture of 2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (1.20 g, 4.00 mmol) and PtO2 (0.4 g) in 5-6 N HCl in iPrOH was hydrogenated (55 psi, rt) for 24 h. The resulting mixture was diluted with water (30 mL) and filtered through celite. The celite was washed with water (30 mL) and the combined filtrates were concentrated in vacuo. The residue was triturated in acetonitrile (50 mL) and the product was isolated by filtration and dried in vacuo providing 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-3-methyl-piperidine-2,6-dione hydrochloride (1.2 g, 92% yield); 1H NMR (DMSO-d6) δ 1.70 (s, 3H), 1.87-1.93 (m, 1H), 2.55-2.82 (m, 3H), 4.14 (s, 2H), 4.66 (d, J=17.7 Hz, 1H), 4.75 (d, J=17.7 Hz, 1H), 7.61-7.74 (m, 3H), 8.60 (br, 3H), 10.88 (s, 1H).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH:4][CH3:5].[NH2-].[Li+].[CH3:8][O:9][C:10]([CH3:16])([O:12]CC#C)[CH3:11].BrCC>CCCCCC>[CH3:8][O:9][C:10]([CH3:16])([O:12][CH2:1][C:2]#[C:3][CH2:4][CH3:5])[CH3:11]
Reactant: C#CCOC(C)(C)OC
Reactant: C=CC=CC
Agent: [Li+]
Agent: [NH2-]
Solvent: CCCCCC
Solvent: CCBr
Product: CCC#CCOC(C)(C)OC
Reaction time: 1 h
Yield: 101.9 %

Procedure:
0.89 g (127 mmol) of granulated lithium were added within 20 minutes to 100 ml (4 mol) of liquid ammonia at −37° C. The mixture was stirred until no more lithium floated (after approximately 15 minutes). A dark cyan solution of lithium in liquid ammonia was obtained. 6.34 g (92 mmol) of piperylene (=1,3-pentadiene) were added portion wise within 30 minutes. The end of the formation of lithium amide could be recognized by the discoloration of the reaction mixture. 10.1 g (71 mmol) of 3-(1-methoxy-1-methyl-ethoxy)-propyne (89.7% GC) were added with a dropping funnel to the reaction mixture at −37° C. within 30 minutes. The reaction mixture was held at −37° C. for about 1 hour. 14.0 g (126 mmol) of bromoethane were added with a dropping funnel to the reaction mixture within 30 minutes. The reaction mixture was subsequently stirred for 1 hour. 100 ml of n-hexane were added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 1.5 hours. 50 ml of water were added to the reaction mixture at 22° C., and the mixture was vigorously stirred until all salt was dissolved. The water layer was extracted once with 50 ml of n-hexane. The organic layer was dried over 5 g of anhydrous sodium sulfate. The solution was concentrated under reduced pressure (40° C., 60 mbar) and the crude product was analyzed by GC. 11.3 g of crude 1-(1-methoxy-1-methyl-ethoxy)-pent-2-yne were obtained with a purity of 87.5% (yield 85.3% based on 3-(1-methoxy-1-methyl-ethoxy)-propyne).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[C:13]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)([O:15][CH2:16][CH3:17])=[O:14].O>C1COCC1>[C:13]([N:18]1[CH2:19][CH2:20][C:21]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)([OH:24])[CH2:22][CH2:23]1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Brc1cccnc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(O)(c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
To a flask of THF (200 mL) at −78° C. was added n-butyllithium (24.0 mL, 2.5 M), and the resulting mixture was stirred for 10 min. 3-bromopyridine (5.40 mL, 56.0 mmol) was added to this solution and the resulting mixture was stirred for 30 min. A solution of 1-carbethoxy-4-piperidone (7.24 mL, 48.0 mmol) in THF (20 mL) was cannula to the above anion slowly. The reaction mixture was stirred for 2 hours while warmed to room temperature gradually. Water (100 mL) was added and the mixture was concentrated. Extracted with EtOAc (3×100 mL), the organic extract was dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel with EtOAc and 5% MeOH in EtOAc to give 7.26 g of 1-carbethoxy-4-(3-pyridyl)-4-hydroxyl-piperidine.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][CH:22]=[N:21][C:20]=2[C:24]#[N:25])=[CH:15][CH:14]=1.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[Cl:28][C:22]1[O:23][C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:26])[F:27])=[CH:18][CH:17]=2)=[C:20]([C:24]#[N:25])[N:21]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: N#Cc1ncoc1-c1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1nc(Cl)oc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
LiHMDS (1.0 M in THF, 4.5 mL, 4.5 mmol) was added dropwise to a solution of Example 56C (0.980 g, 4.11 mmol) in THF (13 mL) at −78° C. After 30 min solid hexachloroethane (0.974 g, 4.11 mmol) was added in one portion. The reaction was allowed to warm to room temperature while stirring overnight during which a solid formed. The mixture was diluted with hexanes and water, and filtered. The filtrate was diluted with EtOAc, and the phases separated. The organic phase was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was dissolved in toluene, loaded on silica gel, and eluted with 1 column length of hexanes and then 0% to 30% EtOAc:hexanes to afford 0.51 g (46%) of the title compound as a yellow milky oil. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=8.2, 2H), 7.81 (d, J=8.3, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[Cl-].[NH4+].CCN(C(C)C)C(C)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CO.[Zn]>[NH2:8][C:7]1[C:2]([F:1])=[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:4]=[CH:5][C:6]=1[NH:9][C:33](=[O:34])[O:35][CH2:36][CH3:37]
Reactant: CCOC(=O)Cl
Reactant: Nc1c([N+](=O)[O-])ccc(NCc2ccc(F)cc2)c1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)Nc1ccc(NCc2ccc(F)cc2)c(F)c1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.2 %

Procedure:
To a stirred solution of compound 3 (0.800 g, 2.86 mmol, 1.00 equiv) in methanol (7.2 mL) was added zinc powder (0.930 g, 14.3 mmol, 5.00 equiv) followed by ammonium chloride solution (0.760 g, 14.3 mmol, 5.00 equiv) dropwise. After being stirred at RT for 5 h, DIPEA (0.460 g, 3.58 mmol, 1.25 equiv) and ethyl chloroformate (0.310 g, 2.87 mmol, 1.00 equiv) were added to reaction mixture at 10° C. and the stirring was continued for another 3 h at RT. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (24 mL) and stirred for 1 h to give the solid. The obtained solid was filtered, dissolved in EtOAc (15 mL) and again filtered the un-dissolved solid. The filtrate was evaporated and recrystallized using n-hexane to afford compound 1A (0.250 g, 27.0%) as brown solid. TLC: 50% EtOAc/Hexane (Rf: 0.20) 1H NMR (500 MHz, CDCl3): δ 7.31 (t, J=7.5 Hz, 2H), 7.02 (t, J=6.8 Hz, 2H), 6.75 (d, J=6.8 Hz, 1H), 6.07 (t, J=6.8 Hz, 1H), 4.31 (s, 2H), 4.22-4.18 (m, 3H), 3.84 (br s, 2H, Exc), 1.29 (t, J=5.6 Hz, 3H); UPLC purity: 91.0%; LC-MS: m/z=322 (M+-1) at RT 3.37 (82.8%)
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].Br[C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[N:31][CH:32]=1>O1CCCC1>[CH2:33]([C:30]1[CH:29]=[CH:28][C:27]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:32][N:31]=1)[CH3:34]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CCc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CC)nc1
Temperature: -78 °C

Procedure:
n-Butyllithium (2 ml, 1.6M in hexanes, 3.22 mmol) was added dropwise to an ice-cooled solution of diisopropylamine (0.45 ml, 3.22 mmol) in tetrahydrofuran (6 ml) under a nitrogen atmosphere, and the solution stirred for an hour. Tri-n-butyltin hydride (0.79 ml, 2.96 mmol) was added and the solution stirred for a further 2 hours, and then cooled to −78° C. A solution of 5-bromo-2-ethylpyridine (WO 97/01552) (500 mg, 2.69 mmol) in tetrahydrofuran (4 ml) was then added dropwise, and once addition was complete, the reaction was allowed to warm to room temperature, and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane and aqueous ammonium chloride solution. The layers were separated, the organic phase dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (100:0 to 90:10) to afford the tide compound, (210 mg, 19%) as a yellow oil.