Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[CH2:6]([O:8]/C=C\[Sn](CCCC)(CCCC)CCCC)[CH3:7].N#N.CO.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH3:47])[C:36]=2[CH:48]=O)=[CH:31][CH:30]=1>C1COCC1>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH3:47])[C:36]=2/[CH:48]=[CH:7]/[CH:6]=[O:8])=[CH:31][CH:30]=1
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Reactant: Cc1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=O
Agent: N#N
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1/C=C/C=O
Temperature: -78 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
n-BuLi (1.6M in hexanes, 1.52 ml, 2.43 mmol) was added to a solution of cis-1-ethoxy-2-(tri-n-butylstannyl)ethylene (1.06 gm, 2.94 mmol) in dry THF (7.5 ml) at -78° C. The mixture was stirred for 11/4 hours, then cooled to -100° C. (liquid N2 /methanol) and treated with a solution of 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxaldehyde (707 mg, 2.43 mmol) in THF (3.0 ml). Forty-five minutes after the addition, the temperature was raised to -78° C. and the mixture was stirred for an additional 50 minutes. The solution was then stirred in an ice bath for 5 minutes and subsequently quenched with H2O (8 ml) and 10% HCl (8 ml). After stirring at room temperature for 1.5 hours, the mixture was made basic with 10% NaOH (10 ml) and extracted twice with Et2O. The combined Et2O layers were washed with H2O and brine, dried (Na2SO4), filtered and stripped to yield a solid. The solid was washed with cold Et2O. The Et2O washings were stripped and triturated with cold hexane to give additional solid, which was pooled with the above solid to give 586 mg (76%) (E)-3-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-2-propenal. Analytically pure material was obtained by recrystallization from hot hexane/EtOAc.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:11]([NH:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NCc1ccccc1
Temperature: 80 °C
Yield: 105.3 %

Procedure:
According to a modification of a procedure by Goker, H. et. al. (II Farmaco 1998, 53, 415-420) a mixture of 1-fluoro-2-nitro-benzene (1067) (1.1 mL, 10.4 mmol) and benzylamine (2.35 mL, 21.5 mmol) in DMF (5 mL) was heated overnight at 80° C. The reaction mixture was concentrated to give an orange solid which was filtered, washed with water and dried to afford benzyl-(2-nitro-phenyl)-amine (1068) (2.5 g, 100%). 1H NMR δ (400 MHz, CDCl3) 8.44 (b, 1H, NH), 8.22-8.19 (dd, 1H), 7.41-7.27 (m, 6H), 6.84-6.81 (dd, 1H), 6.70-6.66 (m, 1H), 4.58-4.57 (d, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].[H-].[Na+].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>CN(C=O)C>[CH3:15][O:14][C:12](=[O:13])[CH2:11][N:3]1[CH2:4][CH2:5][CH2:6][O:1][C:2]1=[O:7]
Reactant: O=C1NCCCO1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1CCCOC1=O
Reaction time: 8 h
Yield: 19.6 %

Procedure:
A solution of 0.20 g (2.0 mmol) of 1,3-oxazinan-2-one from step A above in 2 mL of anhydrous DMF was added to a 10 mL round bottom flask containing 0.13 g (3.2 mmol) of a 60% sodium hydride suspension in mineral oil under an atmosphere of nitrogen. After stirring for 10 min 0.37 g (2.4 mmol) of methyl bromoacetate was added in one portion and the reaction mixture was allowed to stir overnight. The reaction mixture was then quenched with 5 mL of a saturated aqueous ammonium chloride solution and then diluted with 20 mL of water. The resulting suspension was extracted with ethyl acetate (3×10 mL) and the combined organics were washed with water (2×3 mL), brine (1×3 mL) and dried over magnesium sulfate. The mixture was filtered, evaporated and purified by silica gel chromatography eluting with a 5% methanol in ethyl acetate mixture to afford the title compound as a clear oil (0.068 g, 20%). 1HNMR (500 MHz, CDCl3) δ: 4.28 (t, J=5.4 Hz, 2H), 4.03 (s, 2H), 3.70 (s, 3H), 3.36 (t, J=6.2 Hz, 2H), 2.08-2.04 (m, 2H). LC-MS: m/z (ES) 174 (MH)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][C:9]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[CH3:7].C(N(CC)CC)C>ClCCl>[CH2:6]([O:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:13][CH2:12]1)=[O:10])[CH3:7]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(S(C)(=O)=O)CC1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
A solution of methanesulfonyl chloride (28 ml, 0.36 mole) in dichloromethane (50 ml) was added dropwise to a solution of piperidine-4-carboxylic acid ethyl ester (50 grams, 0.32 mole) and triethylamine (53 ml, 0.38 mole) in dichloromethane (350 ml) at 0° C. The reaction mixture was stirred at 0-5° C. for 3 hours. The solution was washed with 2×100 ml water, dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The solid residue was triturated with 100 ml ethyl ether, collected by filtration and dried to give 1-methanesulfonylpiperidine-4-carboxylic acid ethyl ester (68 grams, 90%), m.p. 91-92° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[CH:30][CH:31]=1>>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([C:4]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][C@H:17]4[CH3:21])=[CH:11][C:10]=3[CH:22]=2)=[O:5])[CH:29]=[CH:28][CH:27]=1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Reactant: COc1cccc([Mg]Br)c1
Product: COc1cccc(C(=O)c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1

Procedure:
The product from Example 71E and 3-methoxyphenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.42 (d, 3H), 1.72 (m, 1H), 2.10 (m, 2H), 2.35 (m, 1H), 3.30 (m, 4H), 3.55 (m, 1H), 3.80 (m, 2H), 3.83 (s, 3H), 6.83 (s, 1H), 7.2 (m, 1H), 7.30 (m, 2H), 7.45 (m, 1H), 7.60 (m, 2H), 7.80 (dd, 1H), 8.02 (d, 1H); MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]([CH2:20][C:21]([O:23][CH2:24][CH:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH3:29])=[O:22])#[N:19].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[C:14]([C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:12]=1[OH:13])[CH:8]=[C:20]([C:18]#[N:19])[C:21]([O:23][CH2:24][CH:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH3:29])=[O:22])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCCCC(CC)COC(=O)CC#N
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCCCC(CC)COC(=O)C(C#N)=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
28.1 g of 3,5-di-tertiary-butyl-4-hydroxybenzaldehyde were dissolved in 60 ml of toluene. 21.7 g of 2-ethylhexyl cyanoacetate, 0.27 g of piperidine and 0.67 g of acetic acid were added. The mixture was heated to reflux, and about 2 g of water were removed azeotropically. The clear solution was washed, dried and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:8][Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC[Si](Cl)(CC)CC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)Oc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A 500 ml flask was charged with 3-bromophenol (A) (25 g, 144 mmol), THF (200 ml) and triethylamine (14.67 g, 145 mmol). The flask was cooled to 0° C. in an ice bath, and chlorotriethylsilane (21.8 g, 144 mmol) was added dropwise. The mixture was allowed to stir at room temperature to completion over 2 h. The hydrochloride salt was then filtered. Removal of solvents followed by flash chromatography afforded 3-bromo-O-triethylsilylphenol (J) as a clear liquid (30.4 g, 73%).
Reaction SMILES: [OH:1][CH:2]([C@H:4]1[CH2:8][CH2:7][N:6]([C:9](OC(C)(C)C)=O)[CH2:5]1)[CH3:3].Cl.CCN(C(C)C)C(C)C.ClC1[C:36]2[C:31](=[N:32][CH:33]=[CH:34][N:35]=2)[CH:30]=[C:29]([Cl:37])[N:28]=1>C1COCC1>[Cl:37][C:29]1[N:28]=[C:9]([N:6]2[CH2:7][CH2:8][CH:4]([C@@H:2]([OH:1])[CH3:3])[CH2:5]2)[C:36]2[C:31](=[N:32][CH:33]=[CH:34][N:35]=2)[CH:30]=1
Reactant: CC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Clc1cc2nccnc2c(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](O)C1CCN(c2nc(Cl)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-butyl 3-(1-hydroxyethyl)pyrrolidine-1-carboxylate was treated with HCl solution (in EtOAc, 5 mL) at room temperature for 2 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in anhydrous THF (10 mL). To the resulted THF solution, DIPEA (570 mg, 4.4 mmol) and 5,7-dichloropyrido[4,3-b]pyrazine (400 mg, 2.0 mmol) were added, and the reaction was stirred at room temperature overnight. The volatiles were removed under reduced pressure, and the residue was dissolved in ethyl acetate, washed with brine and dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to afford the title compound. MS (m/z): 279 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[CH2:31][CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([NH2:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:40][CH2:41][C:42](Cl)=[O:43]>C(Cl)Cl.O>[Cl:40][CH2:41][C:42]([NH:20][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[CH2:13][CH2:12][N:11]3[C:7]4[C:6](=[O:32])[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:31][CH2:30][CH2:29][CH2:28][C:8]=4[C:9]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[C:10]3[C:19]=2[CH:18]=1)=[O:43]
Reactant: COc1cc2c(cc1N)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1NC(=O)CCl)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reaction time: 0.25 h

Procedure:
To a solution of 365 mg of 20b and 160 ul of triethylamine in 1 ml of CH2Cl2 was added at 0° C. 90 ul of chloroacetylchloride in ½ ml of CH2Cl2. The reaction was stirred for 15 min, and then diluted with water and extracted with ethyl acetate. The extract was washed several times with water, and then dried and concentrated. The residue was treated with diethylether, to provide, after decantation of the supernatant and drying 390 mg of light grey solid 22a; Rf (heptane/ethyl acetate) 0.50 (Rf 20b: 0.60). NMR (CDCl3) δ 8.73 (bs, 1, NH), 7.42, 7.18, and 6.96 (3×m, 3, thienyl-H), 6.72 and 8.12 (2×s, 2, Ar—H), 4.62 and 3.88 (2×bm, 2, CH2), 4.08 (s, 2, CH2Cl), 3.87 (s, 3, OCH3), 3.90 and 3.50 (2×bm, 2, CH2), 2.90+3.10 (2×b.m, 2, CH2), 2.52 (b.m, 2, CH2), 1.60-2.0 (b.m, 4, 2×CH2), 1.57 (s, 9, tertC4H9).
Reaction SMILES: NC1C(C=[N:11][NH:12][C:13](=[O:26])[C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=2)=NC(Cl)=C(Cl)N=1.[N+](C1C=C(C=C([N+]([O-])=O)C=1)C(Cl)=O)([O-])=O.NN>>[N+:20]([C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([N+:23]([O-:25])=[O:24])[CH:17]=1)[C:13]([NH:12][NH2:11])=[O:26])([O-:22])=[O:21]
Reactant: Nc1nc(Cl)c(Cl)nc1C=NNC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: NN
Agent: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Product: NNC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1

Procedure:
3,5-Dinitrobenzoic acid 2-[(3-amino-5,6-dichloropyrazinyl)methylene]hydrazide by the reaction of 3,5-dinitrobenzoyl chloride with hydrazine to form 3,5-dinitrobenzoylhydrazine, followed by the reaction of the latter with 3-amino-5,6-dichloropyrazinaldehyde.
Reaction SMILES: [CH3:1][C:2]([C@@:4]1([OH:29])[CH2:27][C@H:26]([OH:28])[C:7]2=[C:8]([OH:25])[C:9]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]=4[O:23][CH3:24])[C:13](=[O:14])[C:10]=3[C:11]([OH:12])=[C:6]2[CH2:5]1)=[O:3].FC(F)(F)C([NH:34][C@@H:35]1[CH2:40][C@H:39]([CH3:41])[O:38][CH:37]([Cl:42])[CH2:36]1)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)C.[OH-].[Na+]>[CH3:41][C@H:39]1[O:38][C@H:37]([O:28][C@@H:26]2[C:7]3[C:6](=[C:11]([OH:12])[C:10]4[C:13](=[O:14])[C:15]5[CH:16]=[CH:17][CH:18]=[C:19]([O:23][CH3:24])[C:20]=5[C:21](=[O:22])[C:9]=4[C:8]=3[OH:25])[CH2:5][C@@:4]([OH:29])([C:2]([CH3:1])=[O:3])[CH2:27]2)[CH2:36][C@@H:35]([NH2:34])[CH2:40]1.[ClH:42]
Reactant: C[C@H]1C[C@@H](NC(=O)C(F)(F)F)CC(Cl)O1
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O[C@@H]1C[C@@H](N)C[C@@H](C)O1
Product: Cl
Reaction time: 2 h

Procedure:
A solution of 1.5 g of daunomycinone in 150 ml of anhydrous methylene dichloride containing 0.75 g of 2,3,4,6-tetradeoxy-3-trifluoroacetamido-L-threo-hexopyranosyl chloride (II), was vigorously stirred in the presence of 10 g of molecular sieve (4 A Merck) and 0.77 g of AgSO3CF3 in 20 ml of anhydrous diethyl ether. After two hours at room temperature, the reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate and the organic phase, after being separated, was evaporated under vacuum to obtain a residue. The thus obtained residue was dissolved in 50 ml of 0.1 N aqueous sodium hydroxide, and after 30 minutes at 0° C the solution was adjusted to pH 3.5 and repeatedly extracted with chloroform to eliminate the unreacted aglycone. Then the solution was ajusted to pH 8.3 and extracted with chloroform until the chloroform extracts were no longer colored. The chloroform extracts were combined, dried over anhydrous sodium sulphate and concentrated to a small volume and thereafter acidified to pH 4.5 with 0.1 N methanolic hydrogen chloride. The addition of excess diethyl ether yielded 4'-deoxydaunomycin as the hydrochloride; m.p. 160°-164° C (dec). A sample of the product was subjected to thin layer chromatography (TLC) on Merck Kieselgel F254 plates using a chloroform-methanol-water (150 : 42 : 6 v/v) solvent system. The Rf of the compound was 0.47; [α]D20 = +296° (c = 0.05 CH3OH).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:48][O:49][CH3:50])[C:27]([NH:29][C@@H:30]2[C:37](=[O:38])[N:36]3[C@@H:31]2[CH2:32][S:33][C:34]([CH2:46][Cl:47])=[C:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[N:25]=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.[C:51]1([P:57]([C:64]2C=[CH:68][CH:67]=[CH:66][CH:65]=2)[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.O1CCC[CH2:71]1>>[Cl-:47].[C:2]1([C:1]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:48]/[O:49][CH3:50])/[C:27]([NH:29][C@@H:30]3[C:37](=[O:38])[N:36]4[C@@H:31]3[CH2:32][S:33][C:34]([C:46]3[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=3[P+:57]([CH3:71])([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[C:35]4[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(CCl)SC[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C1CCOC1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(c3ccccc3[P+](C)(c3ccccc3)c3ccccc3)SC[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: [Cl-]
Temperature: 20 °C
Reaction time: 26 h

Procedure:
2.182 g of 1,1-dimethylethyl (6S,7S) 7-[-2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-3-chloromethyl-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate, prepared as in Step G of reference Example B and 1.679 g of triphenyl phosphine were dissolved in 24 ml of tetrahydrofuran, and 14.1 g of silica were added. The tetrahydrofuran was distilled off under reduced pressure over 2 hours and the remainder was cooled, stirred for 26 hours at 20° C. then chromatographed over silica (eluent, dichloromethane-methanol, 9/11) to obtain 1.89 g of (6S,7S) 7-[(2-triphenylmethylaminothiazol-4-yl)-2-(Z)-methoxyimino-acetamido]-2-[(1,1-dimethylethyl)-oxycarbonyl]-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-3-yl-methyl-triphenyl-phosphonium chloride.
Reaction SMILES: [Na].[CH2:2]([OH:4])[CH3:3].Cl[C:6]1[CH:7]=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1.CS(C)=O>O>[Cl:12][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([O:4][CH2:2][CH3:3])[CH:11]=1
Reactant: Clc1cncc(Cl)c1
Reactant: CCO
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cncc(Cl)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sodium (8.1 g, 338 mmol) was added to ethanol (200 ml). After complete reaction, the excess of ethanol was evaporated. 3,5-Dichloropyridine (40.0 g, 270 mmol) and dimethyl sulfoxide (300 ml) were added to the crude mixture. The mixture was stirred at 70° C. for 1 h. Water (500 ml) was added, followed by extraction twice with ethyl acetate (300 ml). The product was isolated in quantitative yield.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([S:23]([CH:25]5[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]5)=[O:24])[C:20]([CH3:22])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:34]=2)=[N:7][C:6]([CH3:35])=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:37].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([S:23]([CH:25]5[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]5)(=[O:37])=[O:24])[C:20]([CH3:22])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:34]=2)=[N:7][C:6]([CH3:35])=[N:5]1)([CH3:2])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)C)CC4)c(C)cc2OCC3)n(C(C)C)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)(=O)C4CCN(C(C)C)CC4)c(C)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
To an ice-cooled solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidine-4-sulfinyl)-8-methyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene 225 (30 mg, 0.061 mmol) in DCM (3 mL) was added TFA (24 μL, 0.306 mmol) followed by a solution of m-CPBA (14 mg, 0.0796 mmol) in DCM (1 mL). The resulting mixture was stirred for 3 h at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 20-50% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH. The basic fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient 3-15% MeOH in DCM) affording 243 as a white solid (14 mg, 44%). LCMS: RT 2.83 min [M+H]+ 513.1. 1H NMR (CD3OD, 400 MHz): δ 9.08 (1H, s), 7.76 (1H, s), 7.10 (1H, s), 5.93-5.80 (1H, m), 4.63-4.53 (4H, m), 3.21-3.10 (1H, m), 3.00 (2H, bd, J=11.56 Hz), 2.77-2.67 (1H, m), 2.64 (3H, s), 2.37 (3H, s), 2.24 (2H, t, J=12.17 Hz), 1.97 (2H, d, J=12.67 Hz), 1.87-1.74 (2H, m), 1.56 (6H, d, J=6.65 Hz), 1.04 (6H, d, J=6.56 Hz)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14][CH2:15][Mg+].[Br-]>C1COCC1.CN1C(=O)CCC1.CCOCC.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH2:14]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)[CH3:15]
Reactant: COC(=O)c1ccc(Cl)cc1OC
Reactant: CC[Mg+]
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCc1ccc(C(=O)OC)c(OC)c1
Yield: 50 %

Procedure:
To a solution of methyl 4-chloro-2-methoxybenzoate (example 18d) (4.16 g, 20.8 mmol) in THF (120 mL) and NMP (12 mL) was added under inert atmosphere Iron(III) acetylacetonate (398 mg, 1.17 mmol) giving a red color. Then EtMgBr (29 ml of 1M solution in ether) was added dropwise under vigorous stirring. The mixture turned dark brown and then violet and then was stirred for 15 more min. The reaction was diluted with ether and quenched upon the addition of aq. HCl (1M, 50 mL). The crude product was extracted with ether and the combined organic layers were successively washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (Eluent: 30% EtOAc in hexanes) to give methyl 4-ethyl-2-methoxybenzoate (2.01 g, 50%) as an oil. 1H NMR (300 MHz, dMSO): δ 1.20-1.22 (t, 3H), 2.65-2.7 (dd, 2H), 3.9 (s, 3H), 6.8 (s, 1H), 6.97 (m, 1H), 7.7 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]=O)=[CH:18][CH:17]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[N:26]1([CH2:24][CH2:23][CH2:22][C:19]2[CH:18]=[CH:17][C:16]([C:14]3[CH:13]=[N:12][C:11]4[N:10]([N:9]=[CH:8][C:7]=4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:15]=3)=[CH:21][CH:20]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C1COCCN1
Reactant: O=CCCc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: c1ccc(-c2cnn3cc(-c4ccc(CCCN5CCOCC5)cc4)cnc23)cc1

Procedure:
A solution of 3-[4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl]propanal (2-5, 150 mg, 0.458 mmol, 1 equiv), morpholine (0.048 mL, 0.55 mmol, 1.2 equiv), acetic acid (0.026 mL, 0.55 mmol, 1.0 equiv), and sodium triacetoxyboro-hydride (116 mg, 0.547 mmol, 1.20 equiv) in dichloroethane (8 mL) was stirred in the presence of 4 angstrom molecular sieves for 15 minutes. The reaction mixture was partitioned between saturated sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (50% hexane in chloroform saturated with ammonia gas, grading to 100% chloroform saturated with ammonia gas) to give 6-[4-(3-morpholin-4-ylpropyl)phenyl]-3-phenylpyrazolo[1,5-a]pyrimidine (2-6) as a yellow solid (mp=147-149° C.). 1H NMR (400 MHz, CDCl3) δ8.82 (s, 2H), 8.45 (s, 1H), 8.06 (br d, 2H, J=7.8 Hz), 7.53 (d, 2H, J=8.2 Hz), 7.47 (t, 2H, J=7.8 Hz), 7.35 (d, 2H, J=8.2 Hz), 7.29 (t, 1H, J=7.8 Hz), 3.73 (m, 4H), 2.73 (t, 2H, J=7.5 Hz), 2.46 (m, 4H), 2.40 (t, 2H, J=7.2 Hz), 1.87 (pentet, 2H, J=7.7 Hz).
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][C:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=[C:11]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:10]=12>C1C=CC=CC=1.C(N(CC)CC)C>[ClH:1].[ClH:1].[CH2:6]([O:5][C:3](=[O:4])[CH2:2][N:21]1[CH2:22][CH2:23][C:10]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]=2[CH3:8])[CH2:19][CH2:20]1)[CH3:7]
Reactant: CCOC(=O)CCl
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)CN1CCc2nc3ccccc3c(C)c2CC1
Product: Cl

Procedure:
15 ml (141 millimols) of ethyl chloroacetate were added dropwise to a boiling solution of 30 gm (141 millimols) of 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline in 200 ml of benzene and 20 ml of triethylamine. After filtering off the precipitated triethylamine hydrochloride, the solvent was distilled off, and the residual base was converted into the dihydrochloride in ethanol with ethanolic hydrochloric acid.