Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C=C[C@@H]1[C@@H]2C[C@H]([C@@H](O)C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.N1C=CC=CC=1.[CH3:36][NH:37][C:38]([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:50]([C:52]3[N:53]=[CH:54][N:55]([C:57]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)[C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[CH:56]=3)=[O:51])[CH:46]=2)[CH:41]=1)=[O:39]>C1COCC1.C(OCC)(=O)C.Cl>[OH:51][C@@:50]([C:45]1[CH:44]=[CH:43][C:42]2[C:47](=[CH:48][CH:49]=[C:40]([C:38]([NH:37][CH3:36])=[O:39])[CH:41]=2)[CH:46]=1)([C:52]1[N:53]=[CH:54][N:55]([C:57]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)([C:70]2[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=2)[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH:56]=1)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C[C@](O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
Under argon atmosphere, a solution of 8.44 mL (76.5 mmol) of ethyl bromoacetate in 35 mL of THF was added to a solution of 5 g of Rieke-Zn in 105 mL of THF at 19˜21° C. over 20 minutes. The mixture was stirred at 20˜25° C. for 20 minutes, and allowed to stand for 3 hours and 30 minutes. 1.26 g (4.3 mmol, 1.25 eq) of (+)-cinchonine was added to 30 mL of the above Reformatsky reagent at 8° C. 1.1 mL (13.8 mmol, 4 eq) of pyridine was added dropwise at 5˜7° C. The mixture was stirred at 4˜7° C. for 15 minutes, and a solution of 1.79 g (3.4 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 15 mL of THF was added dropwise at −8˜−6° C. The mixture was stirred at −10˜−8° C. for 2 hours and 30 minutes. 10 mL of 1N hydrochloric acid was added dropwise, and the mixture was warmed to 0° C. After diluted with 50 mL of ethyl acetate, 10 mL of 1N hydrochloric acid was added, and the layers were separated. The organic layer was washed successively with 20 mL of 1N hydrochloric acid two times, 20 mL of water, 20 mL of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution. After concentrated under reduced pressure, 4 mL of ethyl acetate and 2 mL of IPE were added to the concentration residue. Crystals were filtered, and washed with 2 mL of ethyl acetate three times. Vacuum drying (40° C.) to a constant weight afforded 1.41 g of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphty}-3-(1-trityl-1H-imidazol-4-yl)propanoate(yield 68%, enantiomer excess 63.1% ee).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:13][C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH4+].[Cl-]>C1COCC1>[C:9]([O:13][C:14]([C:16]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To a stirring solution of LDA (11 mL, 22 mmol, 2 M in THF) in THF (40 mL) under nitrogen is added drop wise at −75° C. a THF solution (10 mL) of the title A compound, cyclopropanecarboxylic acid tert-butyl ester (2.85 g, 20 mmol). The resulting mixture is stirred for 5 h at −75° C. before the addition of a THF solution (10 mL) of benzylbromide (3.8 mL, 32 mmol). The reaction mixture is allowed to reach room temperature overnight and poured into a saturated NH4Cl aqueous solution. The aqueous layer is extracted twice with EtOAc and the combined organic extracts are dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (hexane/EtOAc 97/3) to afford the title compound: TLC, Rf (hexane/AcOEt 95/5)=0.47; MS 249.9 [M+18].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17](OC)=[C:18](OC)[CH:19]=3)[CH:14]2[CH3:27])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].B.[ClH:29]>C1COCC1>[ClH:29].[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]2[CH3:27])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc2c(cc1OC)C(C)N(C(=O)Cc1ccc([N+](=O)[O-])cc1)CC2
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC1c2ccccc2CCN1CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(4-Nitrophenylacetyl)-1,2,3,4-tetrahydro-6,7- dimethoxy-1-methylisoquinoline (62.9 g, 0.17 m) was added portionwise to 500 ml of 1 M borane in THF which was diluted with 500 ml THF and maintained under nitrogen. The mixture was stirred at ambient temperature for 1 hr, then heated to reflux for 4 hr. The mixture was then cooled in an ice bath and treated carefully with 20% HCl (250 ml). The mixture was refluxed for 1 hr, cooled and then the solvents evaporated on an aspirator. Water (1 liter) was added and the solution basified to pH 11 with 50% NaOH, then extracted with CHCl3 (3×300 ml). The extracts were dried over MgSO4 and evaporated to an oily residue. The residue was dissolved in 300 ml of 1:1 methanol:isopropanol and treated with HCl gas until acidic. Upon cooling, a yellow solid was obtained which was collected by filtration and air dried to give 66.4 g (100+%) N-(4-nitrophenethyl)-1,2,3,4-tetrahydro-1-methylisoquinoline hydrochloride. The product was slightly wet with isopropanol.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:32]1[CH:33]=[C:34]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:35]=[CH:36][CH:37]=1>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:36]2[CH:37]=[CH:32][CH:33]=[C:34]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:35]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cccc(-c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc2)c1
Temperature: 90 °C
Yield: 31.9 %

Procedure:
[4-(Dibenzylamino)phenyl]boronic acid (UK Patent Application No. GB 2276161 (1994)) (400 mL, 1.26 mmol) was stirred in 5 mL dry toluene and potassium carbonate was added followed by ethyl (3-bromophenyl)acetate (338 mg, 1.39 mmol) as a solution in toluene (1 mL). The reaction vessel was evacuated and refilled with nitrogen (5 times). Pd(PPh3)4 (73 mg, 0.06 mmol) was added as a solution in toluene (1 mL) and the vessel was deoxygenated as before. The reaction mixture was heated at 90° C. for 16 h then cooled and filtered through diatomaceous earth. Volatile material was removed by evaporation, the residue was adsorbed onto silica and purified by chromatography eluting with 10-50% EtOAc/isohexane to give the title compound (175 mg, 32%) as a gum; 1H NMR δ 1.18 (t, 3H), 3.67 (s, 2H), 4.07 (q, 2H), 4.76 (s, 4H), 6.76 (d, 2H), 7.11 (d, 2H), 7.44-7.20 (m, 14H); MS m/e MH+ 436.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O1CCCC1.[Na].[CH2:24]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30]Br)[CH3:25]>C(O)C>[CH2:24]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][S:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[CH:16][CH:15]=1)[CH3:25]
Reactant: Sc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CCOC(=O)CCCBr
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCCSc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 50 °C

Procedure:
A solution of 5 g of the crude 4-(1-adamantyl)-thiophenol obtained above, in 25 ml of absolute ethanol and 25 ml of absolute tetrahydrofurane is added dropwise to a solution of 500 mg of sodium in 20 ml of absolute ethanol whilst stirring in a dry nitrogen atmosphere, and 2.9 ml of 4-bromobutyric acid ethyl ester are then added under the same conditions. After completion of the addition, the mixture is heated to 50° C for 14 hours. It is then evaporated to dryness in vacuo and the evaporation residue is partitioned between 3 times 100 ml of methylene chloride and 100 ml of 2 N hydrochloric acid. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Chromatography of the evaporation residue on 240 g of silica gel, with benzene as the eluant, yields chromatographically pure 4-[4-(1-adamantyl)-phenylthio]-butyric acid ethyl ester in the form of a yellow-brown oil (IR spectrum: C=0 band at 1,740 cm-1 (in CH2Cl2)).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:32]([O:33][CH3:34])=[CH:31][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:8]=2[CH:7]=1)[N:15]=[CH:14][C:13]([C:18]#[N:19])=[C:12]3[NH:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([Cl:29])=[CH:23][C:22]=1[Cl:30].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[I-].[Na+]>COCCOC>[Cl:30][C:22]1[CH:23]=[C:24]([Cl:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=1[NH:20][C:12]1[C:11]2[C:16](=[CH:17][C:8]3[CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:32]([O:33][CH3:34])=[CH:31][C:9]=3[CH:10]=2)[N:15]=[CH:14][C:13]=1[C:18]#[N:19]
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCN5CCOCC5)c(OC)cc4cc23)c(Cl)cc1Cl

Procedure:
Following procedure 1 of Example 149, a mixture of 0.105 g (0.20 mmol) of 8-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.3 mL of morpholine and 0.01 g of sodium iodide in 10 mL of 1,2-dimethoxyethane is heated under reflux for 7 hours. The resulting solid is purified by silica gel chromatography, utilizing a 98:2 to 94:6 gradient of methylene chloride/methanol to give 0.089 g of 4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxy-8-(3-morpholin-4-yl-propoxy)benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 205–208° C.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[C:26]2[C:21](=[CH:22][N:23]=[CH:24][CH:25]=2)[S:20][CH:19]=1>>[S:20]1[C:21]2=[CH:22][N:23]=[CH:24][CH:25]=[C:26]2[C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)=[CH:19]1
Reactant: Nc1csc2cnccc12
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Product: c1ccc2c(c1)C[C@H]1CSC(=Nc3csc4cnccc34)N1C2
Yield: 68.2 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (10.1 g) and 3-aminothieno[2,3-c]pyridine (6.4 g) as the starting materials, (S)-3-[(thieno[2,3-c]pyrid-3-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (6.4 g) is obtained in the form of white crystals, m.p.=180° C.
Reaction SMILES: COC1C=C([C:15]([C:43]#[N:44])([CH2:21][CH2:22][C:23]([C:41]#[N:42])([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)C(OCC)=O)C(OCC)=O)C=C(SC)C=1OCCC.[OH-].[K+]>C(O)C>[CH3:40][O:39][C:31]1[CH:30]=[C:29]([CH:23]([C:41]#[N:42])[CH2:22][CH2:21][CH2:15][C:43]#[N:44])[CH:34]=[C:33]([O:35][CH3:36])[C:32]=1[O:37][CH3:38]
Reactant: CCCOc1c(OC)cc(C(C#N)(CCC(C#N)(C(=O)OCC)c2cc(OC)c(OC)c(OC)c2)C(=O)OCC)cc1SC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C(C#N)CCCC#N)cc(OC)c1OC
Temperature: 95 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of diethyl 2-(3-methoxy-5-(methylthio)-4-propoxyphenyl)-2,5-dicyano-5-(3,4,5-trimethoxyphenyl)-1,6-hexanedioate (12.0 g, 0.019 mol) in ethanol (250 ml) was added potassium hydroxide (4.4 g, 0.079 mol). The reaction was heated to 95° C. for 20 minutes, then filtered, and the filtrate concentrated. Methanol (300 ml) was added to the residue, and the solution was stirred at room temperature overnight. The reaction was filtered and the precipitate dried to yield 2-(3-methoxy-5-methylthio)-4-propoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1,6-hexanedinitrile in a 66% yield. (m.p. 131°-132.5° C.). NMR (CDCl3): δ 1.04 (t, 3H, term CH3), 1.80 (m, 2H, OCH2CH2CH3), 2.18 (m, 2H, CH2 from ##STR30## 2.44 (m+s, SCH3 --CH2 from ##STR31## 3.90 (m, 14H, --OCH3 +OCH2CH2CH3), 6.64+6.72 (s, 2H, ArH), 6.71, 6.77, 6.81, 6.83 (d,d, 2H, ArH).
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3]1.[CH2:10]=[C:11]([CH3:13])[CH3:12].C(=O)(O)[O-].[Na+]>ClCCl>[O:1]=[C:2]1[O:6][CH:5]([C:7]([O:9][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:8])[CH2:4][CH2:3]1
Reactant: C=C(C)C
Reactant: O=C1CCC(C(=O)O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(=O)O1
Temperature: -60 °C
Reaction time: 8 h

Procedure:
To a solution of 5.0 g 5-oxo-2-tetrahydrofurancarboxylic acid in 100 ml dichloromethane 0.3 ml concentrated sulfuric acid and then an excess amount of isobutene (about 50 ml) were added, while maintaining the solution at -60° C. The reaction mixture was kept standing in a tightly seald flask at room temperature overnight, and thereafter it was poured into a cooled saturated aqueous solution of sodium bicarbonate, and the dichloromethane layer was separated. After washing with water and drying (over Na2SO4), the dichloromethane layer was concentrated to yield t-butyl 5-oxo-2- tetrahydrofurancarboxylate in the form of a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:19]([O:21][C:22](=[O:34])[CH2:23][CH2:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1)[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:16]1([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:4]3[CH:3]=[C:2]([C:28]4[CH:29]=[N:30][C:25]([CH2:24][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:34])=[N:26][CH:27]=4)[CH:7]=[C:6]([CH3:8])[CH:5]=3)[N:15]=2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)CCc1ncc(B(O)O)cn1
Reactant: Cc1cc(Br)cc(Nc2nccc(C3CC3)n2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)CCc1ncc(-c2cc(C)cc(Nc3nccc(C4CC4)n3)c2)cn1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
PdCl2(dppf)-CH2Cl2 adduct (0.012 g, 0.015 mmol), N-(3-bromo-5-methylphenyl)-4-cyclopropylpyrimidin-2-amine (0.036 g, 0.120 mmol), [2-(3-ethoxy-3-oxopropyl)pyrimidin-5-yl]boronic acid (0.022 g, 0.1 mmol), and sodium carbonate (100 μL, 0.200 mmol) were suspended in dioxane (750 uL) and heated to 100° C. for 14 hours. Si-dimercaptotriazine (0.185 g, 0.1 mmol) was added to the reaction mixture. The vessel was sealed and allowed to stir at room temperature for 4 hours. The mixture was filtered, washing with DMSO (1 mL) and concentrated under reduced pressure at 40° C. The residue, dissolved in 2 mL of DMSO, was purified by mass triggered reverse phase HPLC to afford ethyl 3-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-2-yl)propanoate. MS ESI calcd. For C23H26N5O2 [M+H]+ 404. found 404. 1H NMR (600 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.92 (s, 2H), 8.24 (d, J=5.0 Hz, 1H), 7.96 (s, 1H), 7.55 (s, 1H), 7.10 (s, 1H), 6.78 (d, J=5.1 Hz, 1H), 4.01 (q, J=7.1 Hz, 2H), 3.18 (t, J=7.0 Hz, 2H), 2.82 (t, J=7.0 Hz, 2H), 2.31 (s, 3H), 1.99 (m, 1H), 1.12 (t, J=7.1 Hz, 3H), 1.06-0.96 (m, 4H).
Reaction SMILES: ClCC([NH:5][C:6]1([CH3:14])[CH2:11][CH:10]([CH3:12])[O:9][CH:8]([CH3:13])[CH2:7]1)=O.NC(N)=S>C(O)C.C(O)(=O)C>[CH3:13][CH:8]1[CH2:7][C:6]([NH2:5])([CH3:14])[CH2:11][CH:10]([CH3:12])[O:9]1
Reactant: CC1CC(C)(NC(=O)CCl)CC(C)O1
Agent: NC(N)=S
Solvent: CCO
Solvent: CC(=O)O
Product: CC1CC(C)(N)CC(C)O1

Procedure:
To a solution of 2-chloro-N-(2,4,6-trimethyltetrahydro-2H-pyran-4-yl) acetamide obtained in Example 9-3 (1.85 g) in ethanol/acetic acid (5/1, 15 mL), was added thiourea (705 mg) at room temperature. The reaction mixture was heated at reflux for 2 hrs.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C:2]1=[O:5].[C:6]([O-:9])(=[O:8])[CH3:7].[Na+].C(O)(=O)C.C(OO)(=O)C>C(OCC)(=O)C.O.O.O.[Os](Cl)(Cl)Cl.O>[C:6]([O:9][CH:4]1[NH:1][C:2](=[O:5])[CH2:3]1)(=[O:8])[CH3:7]
Reactant: O=C1CCN1
Reactant: CC(=O)[O-]
Agent: Cl[Os](Cl)Cl
Agent: CC(=O)OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC1CC(=O)N1
Yield: 78.6 %

Procedure:
To a mixture of 200 mg (2.8 mmole) of azetidin-2-one, 230 mg (2.8 mmole) of anhydrous sodium acetate, 2 ml of acetic acid, and 17 mg (2 mole % based on the amount of azetidin-2-one) of osmium trichloride trihydrate was added dropwise, with stirring, 1.56 g (6.2 mmole) of a 30% peracetic acid solution in ethyl acetate at room temperature over a period of 2 hours or more. The reaction mixture was poured into 50 ml of water and extracted with n-hexane. The extract was separated and purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1 by volume). Thus, 280 mg (2.2 mmole, percent yield: 78%) of 4-acetoxyazetidin-2-one in a colorless oily state was obtained.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:3].[CH:10]1[C:16]([NH2:17])=[N:15][C:13](=[O:14])[N:12]([C@@H:18]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:20]([OH:25])[C:19]2([F:27])[F:26])[CH:11]=1.Cl>>[F:27][C:19]1([F:26])[C@H:20]([OH:25])[C@@H:21]([CH2:23][OH:24])[O:22][C@H:18]1[N:12]1[CH:11]=[CH:10][C:16]([NH:17][C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:3])=[N:15][C:13]1=[O:14]
Reactant: CCCCCOC(=O)Cl
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Agent: Cl
Product: CCCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Yield: 95 %

Procedure:
Using Method A and pentyl chloroformate, gemcitabine hydrochloride was converted to 29 (white solid, 95% yield): 1H NMR (200 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.23-8.27 (d, 1H), 7.11-7.15 (d, 1H), 6.34-6.37 (d, 1H), 6.16-6.24 (t, 1H), 5.34 (s, 1H), 4.11-4.18 (t, 3H), 3.82-3.94 (m, 2H), 3.57-3.72 (m, 1H), 1.61-1.68 (t, 2H), 1.34-1.38 (t, 4H), 0.88-0.95 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[C:15]([NH:16][C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:21])=[CH:6][CH:5]=[CH:4][N:3]=1.S(O[CH:27]([CH2:31][C:32]#[CH:33])[C:28](=O)[CH3:29])(C)(=O)=O>CO.C(Cl)(Cl)Cl>[CH3:21][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][C:17]([O:19][CH3:20])=[O:18])[C:10]=1[CH2:9][NH:8][C:7]1[C:2]2[N:3]([C:27]([CH2:31][C:32]#[CH:33])=[C:28]([CH3:29])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: C#CCC(OS(C)(=O)=O)C(C)=O
Reactant: COC(=O)Nc1cccc(C)c1CNc1cccnc1N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(=O)OC)cccn12
Yield: 55.7 %

Procedure:
A mixture of 2-amino-3-(2-methyl-6-methoxycarbonylaminobenzylamino)pyridine (180 mg) and 3-mesyloxy-5-hexyn-2-one (120 mg) in methanol (0.36 ml) and chloroform (0.36 ml) was refluxed for 20 hours. After cooling, chloroform was added to the mixture and the resultant mixture was washed with an aqueous solution of sodium carbonate and water. The solvent was evaporated under reduced pressure and the residue was subjected to column chromatography on silica gel (4 g), eluting with chloroform to give an oily product. The residue was triturated with diethyl ether to give 8-(2-methyl-6-methoxycarbonylaminobenzylamino)-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (127 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH:13](O)[CH3:14])[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:13][CH2:14][Cl:18])[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCCN(Cc1ccc(Cl)nc1)C(C)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCN(CCCl)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 1.0 gram (0.0044 mole) of 2 {[(6-chloro(3-pyridyl))methyl]propylamino}ethan-1-ol in two mL of chloroform was cooled to 0° C., and 2 mL (excess) of thionyl chloride was added dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature, and then it was heated to reflux where it was stirred for one hour. After this time the reaction mixture was concentrated and made basic with aqueous 10% sodium hydroxide. The mixture was then extracted multiple times with ethyl acetate. The combined extracts were then dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding about 1.0 gram of the subject compound.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][C:6]3([CH2:13][N:14]4[CH:18]=[CH:17][CH:16]=[N:15]4)[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([O:19][CH2:20][CH2:21][OH:22])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:23]([Li])CCC.IC>O1CCCC1>[CH3:11][C:8]12[CH2:7][C:6]3([CH2:13][N:14]4[C:18]([CH3:23])=[CH:17][CH:16]=[N:15]4)[CH2:12][C:2]([CH3:1])([CH2:3][C:4]([O:19][CH2:20][CH2:21][OH:22])([CH2:5]3)[CH2:10]1)[CH2:9]2
Reactant: [Li]CCCC
Reactant: CC12CC3(C)CC(Cn4cccn4)(C1)CC(OCCO)(C2)C3
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccnn1CC12CC3(C)CC(C)(C1)CC(OCCO)(C3)C2
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a cold (−78° C.) solution of the 2-{[3,5-dimethyl-7-(1H-pyrazol-1-ylmethyl)tricyclo[3.3.1.13,7]dec-1-yl]oxy}ethanol (3.69 g) in tetrahydrofuran (50 mL) was added n-butyllithium (20 mL, 2.5 M in hexane) under nitrogen. The mixture was stirred at −78° C. for 1.5 hours. Iodomethane (10 mL) was added by syringe, and the mixture was stirred for an additional 3 hours. The reaction mixture was then quenched by the addition of aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried with sodium sulfate, filtered and concentrated. The residue was purified by normal phase chromatography to give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[CH2:8][CH2:9][CH:10]([NH:16][C:17](=[O:19])[CH3:18])[CH2:11][C:12]=3[NH:13]2)=[CH:5][CH:4]=1.C(Cl)Cl.B(Br)(Br)Br>CO>[OH:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[CH2:8][CH2:9][CH:10]([NH:16][C:17](=[O:19])[CH3:18])[CH2:11][C:12]=3[NH:13]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c3c([nH]c2c1)CC(NC(C)=O)CC3
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NC1CCc2c([nH]c3cc(O)ccc23)C1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of 25.8 g (0.1 mol) of N-(1,3,4,9-tetrahydro-7-methoxy-2H-carbazol-2-yl)acetamide in 2 l. of CH2Cl2 was stirred at -50° to -60° C. under N2 while adding 101 g (0.4 mol) of BBr3 dropwise during 15-30 min. Stirring was continued for 30 min at -55° C. and then 3 hr at room temperature. After cooling to -40° C., 600 ml of MeOH was cautiously added dropwise during 45 min. The reaction mixture was allowed to warm to room temperature (ca. 1 hr) and then evaporated. The residue was dissolved in one l. of 1 N KOH, filtered from insolubles, and the cold filtrate was acidified (pH 3) with conc. HCl. The precipitate was filtered, washed with H2O, and recrystallized from i-PrOH to give the title compound, mp 245°-246°.