Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:17][O:16][C:15](=[O:18])[C@H:14]([CH2:19][C:20](O)=[O:21])[C@@H:13]([O:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C@H:12]([CH3:29])[O:11][C:10]1=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].B>C1COCC1>[C:24]([O:23][C@@H:13]1[C@@H:14]([CH2:19][CH2:20][OH:21])[C:15](=[O:18])[O:16][CH2:17][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:10](=[O:30])[O:11][C@H:12]1[CH3:29])(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CC(=O)O
Agent: B
Solvent: C1CCOC1
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCO
Temperature: 22 °C
Reaction time: 1.5 h
Yield: 71.2 %

Procedure:
To a solution of 2-((3S,7R,8R,9S)-3-(tert-butoxycarbonylamino)-8-(isobutyryloxy)-9-methyl-2,6-dioxo-1,5-dioxonan-7-yl)acetic acid (2.0 g, 4.64 mmol) in THF (15 mL) was added borane (1.0 M in THF, 5.56 mL, 5.56 mmol) at 0° C. After 15 min the ice bath was removed and the reaction was allowed to warm to room temperature (about 22° C.). After an additional 1.5 h, the reaction was quenched with EtOAc (10 mL) and washed successively with 0.5 N HCl (10 mL) and sat'd aqueous NaHCO3 (10 mL). The phases were separated and the organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (1.38 g, 72%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 5.40-5.19 (m, 2H), 5.07 (t, J=9.9 Hz, 1H), 4.95-4.75 (m, 2H), 3.74-3.52 (m, 3H), 2.83-2.68 (m, 1H), 2.61 (dt, J=13.9, 7.0 Hz, 1H), 2.07-1.90 (m, 1H), 1.70-1.52 (m, 1H), 1.44 (s, 9H), 1.27 (d, J=6.3 Hz, 3H), 1.20 (d, J=7.0 Hz, 6H); ESIMS m/z 440.3 ([M+Na]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1>>[N:8]1([C:6]2[N:5]=[C:4]3[CH2:13][CH2:14][CH2:15][C:3]3=[C:2]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=3)[CH:7]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Clc1cc(N2CCCC2)nc2c1CCC2
Product: CCOC(=O)Cc1ccc(Nc2cc(N3CCCC3)nc3c2CCC3)cc1
Yield: 91.2 %

Procedure:
Following general procedure B1, 4-chloro-2-(pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.068 g, 0.30 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.080 g, 0.45 mmol) to afford the title compound (0.100 g, 90%) as a brown oil. MW=365.47. APCI MS m/z 366 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:12].[H-].[Na+].[CH3:22]I>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:22])[C:11]([C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:12]
Reactant: COc1ccc(CC(=O)c2cnc(C)cn2)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C(=O)c2cnc(C)cn2)c(Cl)c1
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A solution of 2-(2-chloro-4-methoxy-phenyl)-1-(5-methyl-pyrazin-2-yl)-ethanone (370 mg, 1.3 mmol) in DMF (5 mL) was added slowly over 30 min to a suspension of NaH (50% in mineral oil, 96 mg, 1.9 mmol) in DMF (2 mL). After 30 min, methyl iodide (199 mg, 1.4 mmol) was added slowly, and the mixture was stirred for 2d at r.t. The reaction mixture was taken up in ethyl acetate, and washed (water, then brine). The organic layer was separated, dried (Na2SO4), and the solvent was evaporated to give a residue, which was purified by column chromatography (silica gel, heptane:ethyl acetate=100:0-80:20) to give the title compound (290 mg, 75%). 1H NMR (300 MHz, CDCl3) δ 9.08 (1H, s), 8.45 (1H, s), 7.11 (1H, d), 6.92 (1H, d), 6.73 (1H, dd), 5.53 (1H, q), 3.75 (3H, s), 2.61 (3H, s), 1.49 (3H, d); MS (m/e)=291.0 [MH+].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]1[CH2:14][S:11](=[O:13])(=[O:12])[O:10][CH2:9]1>C(O)(C)C.CCOCC>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:8][CH2:14][S:11]([OH:13])(=[O:12])=[O:10])[CH2:4][CH2:3]1
Reactant: O=S1(=O)CCCO1
Reactant: CN1CCNCC1
Solvent: CCOCC
Solvent: CC(C)O
Product: CN1CCN(CCCS(=O)(=O)O)CC1
Reaction time: 8 h

Procedure:
N-methyl piperizine (4.68 g) was dissolved in isopropanol (25 ml) and treated with 1,3-propanesultone (5.7 g) with cooling to maintain the temperature of the reaction below 50° C. The reaction mixture was allowed to stand at room temperature overnight, then diluted with ether and the white solid filtered. On standing, the white solid became a sticky semi-solid (7.1 g). Mass spec MH+ (found)=223 MH+ (calc)=223.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)[C:5](=[O:20])[N:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)[C:3]1=[O:32].Cl.N1C=CC=CC=1.O>C(Cl)Cl>[CH3:1][C:2]1([CH3:33])[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)[C:5](=[O:20])[N:4]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]([F:30])([F:31])[F:29])=[CH:25][CH:26]=2)[C:3]1=[O:32]
Reactant: COc1ccc2c(CN3C(=O)N(c4ccc(OC(F)(F)F)cc4)C(=O)C3(C)C)ccnc2c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1ccnc2cc(O)ccc12
Temperature: 220 °C
Yield: 9.9 %

Procedure:
A mixture of 0.89 g of 5,5-dimethyl-1-(7-methoxyquinolin-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione and 5.5 g of pyridine hydrochloride is heated at a temperature in the region of 220° C. for 4 hours. After cooling, 200 ml of water and 100 ml of CH2Cl2 are added. After separation of the phases by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated under reduced pressure. The solid obtained is purified by flash chromatography (SiO2, EtOAc/CH2Cl2 40/60 by volume as eluent, Ar). The fractions containing the product are concentrated under reduced pressure. 85 mg of 5,5-dimethyl-1-(7-hydroxyquinoline-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione are thus obtained, the characteristics of which product are as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]([NH2:14])([CH3:13])[CH3:12].C(P(O)(=O)O)CC.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][CH:11]([CH3:13])[CH3:12])=[O:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CC(C)N
Agent: CCCP(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)NC(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 7.7 %

Procedure:
To a solution of 300 mg (2.17 mmol) of 6-aminonicotinic acid in 50 mL of chloroform were added 370 μL (4.34 mmol) of isopropylamine, 4 mL of anhydrous propanephosphonic acid (25 wt % solution in ethyl acetate) and 1.4 mL (10 mmol) of triethylamine, and the mixture was stirred for 6 hours at room temperature. Then, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1 to 5/1) to give 30 mg (8%) of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.C1COCC1.[C:20]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:21]C([O-])=O.[K+].[Cl-].[Mg+2].[Cl-]>C(Cl)(=O)C(Cl)=O.CN(C=O)C.C(#N)C.C(N(CC)CC)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:10](=[O:12])[CH2:21][C:20]([O:26][CH2:27][CH3:28])=[O:25])=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(-c2ccco2)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)c1ccc(-c2ccco2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The acid from Step 1 was converted to the acid chloride by refluxing in a mixture of oxalyl chloride (1.3 ml), THF (20 ml) and several drops of DMF. Small portions of oxalyl chloride were added until the reaction was homogeneous. Reflux continued for 0.5 hours, then the solvent was removed in vacuo to give the crude acid chloride. Meanwhile, potassium ethyl malonate (2.7 g) was reacted with anhydrous magnesium chloride (1.9 g) and triethylamine (2.21 ml) in dry acetonitrile (50 ml) at room temperature for 3 hours. Triethylamine (1 ml) was added, followed by addition of a solution of the acid chloride in acetonitrile. The mixture was then stirred overnight at room temperature, then concentrated to dryness. The residue was partitioned between toluene and 10% aqueous HCl. The organic layer was washed with 10% HCl and water, dried and was then concentrated to give crude ethyl 3-(4-(2-furyl)phenyl)-3-oxopropanoate as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:19]1[N:26]=[CH:25][CH:24]=[C:23]([I:27])[C:20]=1[CH:21]=[O:22].[NH4+].[Cl-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:19]1[C:20]([CH:21]=[O:22])=[C:23]([I:27])[CH:24]=[CH:25][N:26]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1c(I)ccnc1F
Reactant: CC(C)(C)c1ccc2c(=O)[nH]ncc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc2c(=O)n(-c3nccc(I)c3C=O)ncc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a 100 mL round-bottomed flask, 6-tert-butylphthalazin-1(2H)-one (700 mg, 3.46 mmol, Eq: 1.00) was combined with THF (30 ml) to give a colorless solution. Sodium hydride (152 mg, 3.81 mmol, Eq: 1.1) was added. The reaction mixture was stirred at ambient temperature for 15 min. A solution of 2-fluoro-4-iodonicotinaldehyde (956 mg, 3.81 mmol, Eq: 1.1) in 10 mL THF was the added to the reaction mixture and it was stirred at ambient temperature for 3.5 h. The reaction was not complete. An additional 50 mg NaH was added. The reaction was stirred for an additional 1.5 h, before addition of saturated NH4Cl. The reaction mixture was poured into 100 mL H2O and extracted with dichloromethane (5×50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 10% to 60% EtOAc in hexanes) to afford slightly impure product. The product was triturated with EtOAc to afford the desired product as a cream solid. The combined filtrate and washes from the trituration were concentrated, re-purified by flash chromatography (silica gel, 80 g, 10% to 60% EtOAc in hexanes) and trituration with EtOAc to afford additional product as a cream solid. The two batches of product were combined to afford 320 mg of the desired product. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9 H) 7.74 (d, J=1.89 Hz, 1 H) 7.89 (dd, J=8.50, 1.70 Hz, 1 H) 8.02 (d, J=5.29 Hz, 1 H) 8.28-8.44 (m, 3 H) 9.92 (s, 1 H) (M+H)+=434 m/e.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)([CH3:5])[CH:3]=O.N1CCCC1.[Si](Cl)(C)(C)C.[NH2:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([CH2:53][C@@H:54]3[CH2:58][CH2:57][CH2:56][N:55]3[C:59](=[O:63])[CH2:60][C:61]#[N:62])[N:37]=[C:38]([C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[CH:41][C:40]=3[F:52])[C:31]=12>C(Cl)Cl.O>[NH2:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([CH2:53][C@@H:54]3[CH2:58][CH2:57][CH2:56][N:55]3[C:59](=[O:63])[C:60]([C:61]#[N:62])=[CH:3][C:2]([N:6]3[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]3)([CH3:1])[CH3:5])[N:37]=[C:38]([C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)=[CH:41][C:40]=3[F:52])[C:31]=12
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)C=O)CC1
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCN(C(C)(C)C=C(C#N)C(=O)N2CCC[C@H]2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl 4-(1,1-dimethyl-2-oxo-ethyl)piperazine-1-carboxylate (326.2 mg, 1.27 mmol) in DCM (6 mL), was added pyrrolidine (0.17 mL, 2.04 mmol). The reaction mixture was cooled to 0° C., followed by the addition TMS-Cl (0.13 mL, 1.02 mmol). The ice bath was removed and the mixture stirred for 10 min before adding 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (120 mg, 0.250 mol). The mixture was stirred for 4 h at room temperature, at which point TLC and LC-MS showed the reaction was finished. To the mixture was added 30 ml water, the layers separated and the aq. layer was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent removed in vacuo. The residue was dissolved in minimum CH2Cl2, loaded on a silica gel column and purified by MeOH/CH2Cl2(1/4):EtOAc 20-30% gradient to get pure product tert-butyl 4-[4-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-cyano-1,1-dimethyl-4-oxo-but-2-enyl]piperazine-1-carboxylate as light yellow oil
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:10]([Mg]Br)#[CH:11]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[C:10]#[CH:11])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(O)c1cccc(Br)n1
Temperature: -78 °C

Procedure:
6-Bromo-2-pyridine carboxaldehyde (3.00 g, 16.13 mmol) was dissolved in THF (50 mL) and cooled to −78° C. Ethynylmagnesium bromide (0.5 M in THF, 45.2 mL, 22.58 mmol) was added, and the reaction was allowed to warm to room temperature over 2 h. It was then quenched with saturated NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (50% EtOAc/hexanes) afforded the title compound as a yellow solid.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][S:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:13]S(O)(=O)=O.O>CC(O)=O>[C:1]1([C:7]2[NH:11][C:10](=[O:13])[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CSCC(=O)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(-c2ccccc2)cs1

Procedure:
To a solution of 1-phenyl-2-thiocyanato-ethanone (20 g, 113 mmol) in HOAc (100 mL) was added 50% aqueous H2SO4 (20 mL). The mixture was refluxed for 10 min. The mixture was poured into water. The solid formed was collected by filtration to give crude 4-phenyl-3H-thiazol-2-one (20 g) which was used for the next step without further purification.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CI.[C:13](=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:13][S:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1nc2ccccc2o1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.9 %

Procedure:
Method A, Part A. A solution of 2-mercapto-1H-benzoxazole (5.85 g, 38.7 mmol), methyl iodide (2.70 mL, 43.4 mmol), and potassium carbonate (7.39 g, 53.5 mmol) in tetrahydrofuran (100 mL) was heated to reflux for 18 hours. After stirring at room temperature for an additional 24 hours, the solution was poured into (2×150 mL). The extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford sufficiently pure 2-methylthio-1-H-benzoxazole (6.27 g, 37.9 mmol, 98%) as a pale yellow oil. This material was dissolved in methylene chloride (100 mL), cooled to 0° C., and treated with a solution of m-chloroperben-zoic acid (7.20 g, 41.7 mmol) in methylene chloride (40 mL). Sodium bicarbonate (about 10 g) was added, and the mixture was stirred for 18 hours. This mixture was diluted slightly with methylene chloride, then washed with aqueous sodium carbonate solution (1M, 2×150 mL) and water (150 mL). The aqueous phases were back-extracted in sequence with methylene chloride (150 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to afford the product, 2-methylsulfonyl-1H-benzoxazole (7.04 g, 35.7 mmol, 94%), as a waxy solid. 1H NMR (CDCl3): 8.03-7.40 (4H, m); 3.22 (3H, s).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][Cl:6])[CH3:2].Cl.[CH2:10]([N:12]([CH2:16][CH3:17])[CH2:13][CH2:14][Cl:15])[CH3:11].[OH:18][C:19]1[CH:31]=[CH:30][C:29]2[C:28]3[C:23](=[CH:24][C:25]([OH:32])=[CH:26][CH:27]=3)[CH2:22][C:21]=2[CH:20]=1.C[O-].[Na+]>C1(C)C=CC=CC=1>[ClH:6].[ClH:15].[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][O:18][C:19]1[CH:31]=[CH:30][C:29]2[C:28]3[C:23](=[CH:24][C:25]([O:32][CH2:14][CH2:13][N:12]([CH2:10][CH3:11])[CH2:16][CH3:17])=[CH:26][CH:27]=3)[CH2:22][C:21]=2[CH:20]=1)[CH3:2]
Reactant: CCN(CC)CCCl
Reactant: Oc1ccc2c(c1)Cc1cc(O)ccc1-2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN(CC)CCOc1ccc2c(c1)Cc1cc(OCCN(CC)CC)ccc1-2
Reaction time: 3 h

Procedure:
A solution of 2-diethylaminoethyl chloride [obtained from 12.9 g (0.075 mole) of 2-diethylaminoethyl chloride hydrochloride] in 100 ml of toluene (dried over molecular sieves) is added to a mixture of 4.9 g (0.025 mole) of 2,7-dihydroxyfluorene and 2.7 g (0.05 mole) of sodium methoxide in 200 ml of toluene (dried over molecular sieves). This mixture is refluxed with stirring for three hours. Upon cooling the mixture is filtered to remove the precipitated sodium chloride. The toluene solution is washed three times with water, then once with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. This mixture is filtered and the filtrate acidified to Congo Red with ethereal hydrogen chloride. The solid which precipitates is filtered, dissolved in butanone with enough methanol added to effect solution, decolorized with charcoal, and the product obtained at 80°C under vacuum, 2,7-bis(2-diethylaminoethoxy)fluorene dihydrochloride. M.P. 213°-216°C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[S:29][C:28]2=[N:30][CH:31]=[C:32]([C:33](O)=[O:34])[N:27]2[CH:26]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[N:27]3[C:28]([S:29][C:25]([CH3:24])=[CH:26]3)=[N:30][CH:31]=2)=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1cn2c(C(=O)O)cnc2s1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnc3sc(C)cn23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.86 min; [M+H]+=491.9.
Reaction SMILES: [Cl:1][CH:2]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.C(O)=O>ClC1C=CC=CC=1>[Cl:1][CH:2]([CH:8]([OH:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCC(=O)C(Cl)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: Clc1ccccc1
Product: CCCC(O)C(Cl)C(=O)OCC
Reaction time: 3 h

Procedure:
Ethyl 2-chloro-3-oxohexanoate (194 mg), chlorobenzene (3 ml), RuCl[(S,S)-TsDPEN](p-cymene) complex (1 mol %) and triethylamine (5 equivalents) were mixed, and formic acid (3 equivalents) was gradually added thereto. The reaction was carried out at 40° C. for 3 hours. The reaction mixture was analyzed. As a result, the conversion ratio was 100%, and the isomer ratio of (2S,3R):(2S,3S):(2R,3R):(2R,3S) is 63.7:24.9:4.1:7.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[C@H:9]([NH2:19])[CH2:8][C@@H:7]1[CH3:20])=[O:5])[CH3:2].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH:26]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCCl.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[C@H:9]([NH:19][CH2:26][C:25]2[CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=[C:23]([C:22]([F:21])([F:35])[F:36])[CH:24]=2)[CH2:8][C@@H:7]1[CH3:20])=[O:5])[CH3:2]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)N1c2cc(O)c(OC)cc2[C@H](N)C[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)N1c2cc(O)c(OC)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.5 %

Procedure:
To a stirred suspension of cis-4-amino-7-hydroxy-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (4.49 g, 16.0 mmol) in 1,2-dichloroethane (100 mL) was added 3,5-bis(trifluoromethyl)benzaldehyde (2.6 mL, 16.0 mmol), followed by acetic acid (0.9 mL, 16.0 mmol). After 45 min, sodium triacetoxyborohydride (5.1 g, 24.0 mmol) was added, and the reaction was stirred at room temperature overnight. Water (75 mL) and ethyl acetate (75 mL) were added to the mixture which was then made basic to pH 10 with solid potassium carbonate. The mixture was then extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 8.17 g of crude product. Purification by silica gel chromatography using 0-30% ethyl acetate/hexanes as eluent afforded 4.90 g of the title compound (60%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[I-].[K+].Br[CH2:9][CH2:10][CH2:11][C:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20]Br)=[O:13]>C(OC(=O)C)(=O)C.CCOC(C)=O>[C:1]([O:4][CH2:9][CH2:10][CH2:11][C:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][O:4][C:1](=[O:3])[CH3:2])=[O:13])(=[O:3])[CH3:2]
Reactant: O=C(CCCBr)CCCC(=O)CCCBr
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCCC(=O)CCCC(=O)CCCOC(C)=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.3 %

Procedure:
A solution of 20.6 g potassium acetate and 3.49 g potassium iodide in 306 ml acetic anhydride was stirred and the product (VII) of Ex. 1 added. The reaction mixture was refluxed with stirring for 12-16 hrs, then cooled to 25° C. and diluted with 100 ml EtOAc. The reaction mixture was filtered, and the filtrate concentrated in vacuo. Ethyl acetate (400 ml) was added and the resultant solution was washed with 2×200 ml of 50% aq. NaHCl3. The organic layer was isolated, dried (MgSO4 an.), filtered and concentrated in vacuo. Purification by flash chromatography yielded product (VIII) in 66.3% yield as a viscous light yellow oil (93% pure).