Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].CN(C)C=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.Cl.[CH2:44]([NH:46][C:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[N:57]=[C:58]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][C@@H:67]3[CH3:72])[C:59]3[CH2:65][NH:64][CH2:63][CH2:62][C:60]=3[N:61]=2)=[CH:52][CH:51]=1)=[O:48])[CH3:45]>>[C:1]([CH2:3][C:4]([N:64]1[CH2:63][CH2:62][C:60]2[N:61]=[C:56]([C:53]3[CH:52]=[CH:51][C:50]([NH:49][C:47]([NH:46][CH2:44][CH3:45])=[O:48])=[CH:55][CH:54]=3)[N:57]=[C:58]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][C@@H:67]3[CH3:72])[C:59]=2[CH2:65]1)=[O:6])#[N:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)CC#N)CC3)cc1
Temperature: 40 °C
Reaction time: 96 h

Procedure:
Cyanoacetic acid (0.0300 g, 0.000353 mol) in dry N,N-Dimethylformamide (1.60 mL, 0.0207 mol) was added 1-Hydroxybenzotriazole (0.0488 g, 0.000361 mol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0721 g, 0.000376 mol) then followed by N,N-Diisopropylethylamine (0.161 mL, 0.000924 mol) and then (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea hydrochloride (0.1000 g, 0.0002310 mol). The reaction mixture heated at 40° C. and was stirred for 4 days. The reaction mixture was concentrated, chromatographed through silica gel again (12 g, 0-10% MeOH in dichloromethane), and purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.69 (s, 1H), 8.18 (d, J=8.8, 2H), 7.48 (d, J=8.8, 2H), 6.18 (t, J=5.6, 1H), 4.65 (d, J=15.7, 1H), 4.51-4.38 (m, 1H), 4.26-4.14 (m, 2H), 3.96-3.84 (m, 2H), 3.80-3.56 (m, 5H), 3.44 (dd, J=19.8, 12.6, 2H), 3.15-3.07 (m, 2H), 3.02-2.94 (m, 1H), 2.84 (s, 1H), 1.25 (t, J=5.4, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+464.2 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:21]=[CH:20][C:9]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:8][CH:7]=1)([OH:3])=[O:2].[OH:22]O.Cl>[OH-].[Na+]>[C:1]([CH2:4][CH2:5][C:6]1[CH:21]=[CH:20][C:9]([CH:10]2[O:22][CH:11]2[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)([OH:3])=[O:2]
Reactant: O=C(O)CCc1ccc(C=CC(=O)c2ccccc2)cc1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1ccc(C2OC2C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a suspension of 5.6 g of 4-(2-carboxyethyl)benzalacetophenone and 20 ml of 1 N sodium hydroxide solution was added 4 ml of 30% hydrogen peroxide at room temperature. The mixture was cooled in an ice-bath and 15 ml of 0.5 N sodium hydroxide solution was added dropwise over a few min. with stirring. The reaction mixture was stirred at room temperature for 3 hrs. and then the pH was adjusted from 9.4 to 4.5 by the addition of 1 N hydrochloric acid. After about 1/2 hr., the precipitate was collected. The precipitate was dissolved in 200 ml of ethyl acetate, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated. The residue was dissolved in 100 ml of boiling ethyl acetate. About 50 ml of the solvent was evaporated and 50 ml of ether was added. The solution was concentrated to about 25 ml and after standing at room temperature for 17 hrs., the solid was collected, washed with 1:4-ethyl acetate-ether followed by ether and dried under vacuum at 60°-65° C. to give 3.3 g (55%) of 3-[4-(2-carboxyethyl)phenyl]-1-phenyl-2,3-epoxy-1-propanone as colorless crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:15][N:16]([CH3:20])[C:17](=[S:19])[S-:18].C[NH2+]C>C(=S)=S>[CH3:15][N:16]([CH3:20])[C:17](=[S:18])[S:19][CH:8]([CH2:9][N+:10]([O-:12])=[O:11])[C:7]1[CH:13]=[CH:14][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(C)c1ccc(C=C[N+](=O)[O-])cc1
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: S=C=S
Product: CC(C)c1ccc(C(C[N+](=O)[O-])SC(=S)N(C)C)cc1

Procedure:
As in Example 17, reaction of p-isopropyl-β-nitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave p-isopropyl-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 119° - 120° C. after recrystallization without heating from acetone-methanol solution.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.CN1C[CH2:24][CH2:23][C:22]1=O.C(N(CC)CC)C.C([Sn](CCCC)(CCCC)/C=C/C)CCC>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]1([C@@H:12]([N:8]2[C:6]3=[N:7][C:2](/[CH:22]=[CH:23]/[CH3:24])=[CH:3][N:4]=[C:5]3[N:10]=[C:9]2[OH:11])[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN1CCCC1=O
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C/C=C/[Sn](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C/C=C/c1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Temperature: 120 °C
Yield: 54 %

Procedure:
A thick-walled microwave bottle equipped with a stirbar was charged with (S)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), and (Ph3P)4Pd (0.12 equiv). The bottle was covered with a sheet of Parafilm and purged with nitrogen for 5 min, and N-methylpyrrolidone (14 volume equivalents), triethyl amine (2.0 equiv), and (E)-tributyl(prop-1-enyl)stannane (3.0 equiv) were added by syringe. The resulting mixture was immediately fitted with a septum and cap and heated to 120° C. in a microwave for 20 min. The reaction was then diluted with EtOAc, washed four times with saturated aq. NaHCO3 and once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse-phase preparative HPLC provided the title compound (54%) as a foam. LCMS m/z (APCI)=281.1 (M+H).
Reaction SMILES: [CH2:1]([O+](CC)CC)[CH3:2].[F:8][B-:9]([F:12])([F:11])[F:10].[NH:13]1[CH2:17][CH2:16][NH:15][C:14]1=[CH:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>C(Cl)Cl>[CH2:1]([O:20][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:18][C:14]1[NH:13][CH2:17][CH2:16][N:15]=1)[CH3:2].[F:8][B-:9]([F:12])([F:11])[F:10]
Reactant: CC[O+](CC)CC
Reactant: O=C(C=C1NCCN1)c1ccccc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=CC1=NCCN1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
20 g (0.105 mole) of triethyloxonium-tetrafluoroborate is dissolved in 200 ml of methylene chloride. To the solution is added 18.8 g (0.1 mole) of crystalline 2-(2--imidazolidinylidene)-acetophenone [m.p. 211°-212°, see J. Klosa, Arch. Pharmaz. 286, 397 (1953)]. After the slightly exothermic reaction has subsided, the reaction mixture, a clear yellow solution, is stirred for 16 hours at room temperature; it is subsequently concentrated to dryness in the rotary evaporator; and the crystallising residue is suspended in 300 ml of ethyl acetate. The suspension is cooled to 5°, and the crystals are filtered off with suction to obtain 2-(2-ethoxy-2-phenyl-ethenyl)-2-imidazoline-tetrafluoroborate, m.p. 151°-152°. After drying at 60° in vacuo, the product is further employed without additional purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Br:7])[S:5][CH:6]=1.[Cl:8][CH2:9][C:10](Cl)=[O:11].N1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(Cl)Cl>[Br:7][C:4]1[S:5][CH:6]=[C:2]([NH:1][C:10](=[O:11])[CH2:9][Cl:8])[N:3]=1
Reactant: Nc1csc(Br)n1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)Nc1csc(Br)n1
Yield: 29.7 %

Procedure:
The starting material was prepared as follows. 4-Amino-2-bromothiazole (15.6 g) and chloroacetyl chloride (7.6 g) were suspended in methylene chloride (100 ml) with stirring and treated with pyridine (16 ml) over 15 min., maintaining reaction temperature at 0° C. with an ice bath. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours, then poured onto 20% aqueous sodium acetate (500 ml) and stirred for 30 minutes. The mixture was separated and the organic layer washed with 2N hydrochloric acid, water, sodium carbonate solution and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo and the residue recrystallised twice from carbon tetrachloride to give 2-bromo-4-chloroacetamidothiazole (5.1 g). m.p. 146°-8° C. (Found: C, 24.1; H, 1.7; N, 11.2. C5H4ClBrN2OS requires C, 23.5; H, 1.6; N, 11.0%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:14])=[O:13])[C:2](=[O:4])[CH3:3].[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:3][C:2]1([CH2:1][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12]([NH2:15])(=[O:14])=[O:13])[O:18][CH2:17][CH2:16][O:4]1
Reactant: CC(=O)COc1ccccc1S(N)(=O)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1(COc2ccccc2S(N)(=O)=O)OCCO1

Procedure:
A mixture of 4.58 g of 2-(2-propanon-1-yloxy)phenylsulfonamide, 2 ml of ethylene glycol, 0.02 g of p-toluenesulfonic acid and 30 ml of toluene is heated for 7 hours to reflux while simultaneously separating the water of reaction. The cooled solution is taken up in 80 ml of ethyl acetate and the organic phase is washed with saturated sodium bicarbonate solution and water, dried and concentrated, affording 5 g of 2-(2-methyl-1,3-dioxolan-2-yl-methoxy)phenylsulfonamide in the form of a yellow viscous oil which can be further used without purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].Cl.[NH2:12][OH:13].CC(C)([O-])C.[K+].O>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[NH:12][OH:13])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=N)NO)ccc1Br
Reaction time: 0.5 h
Yield: 309.2 %

Procedure:
A solution of 4-bromo-3-methylbenzonitrile (20.0 g) in methanol (100 ml) was treated with hydroxylamine hydrochloride (4×2.08 g) and potassium t-butoxide (4×3.25 g) over 6 hours and the resulting mixture heated at reflux for 18 h. After cooling, the reaction mixture was poured into water (800 ml), the suspension stirred for 30 min, and the white solid filtered off and dried in vacuo to give the title compound (21.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][C@@H:19]([C:21]2[CH:32]=[CH:31][C:24]3[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=3[CH:22]=2)[O:18][C:17]1=[O:33].[C:37]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:42]=[CH:41][C:40]([N:43]=[C:44]=[O:45])=[CH:39][CH:38]=1.C(O)(C)C>ClCCl>[C:37]1([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:38]=[CH:39][C:40]([NH:43][C:44]([NH:1][C:2]2[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][C@@H:19]([C:21]4[CH:32]=[CH:31][C:24]5[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=5[CH:22]=4)[O:18][C:17]3=[O:33])[CH:3]=2)=[O:45])=[CH:41][CH:42]=1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5ccc(-c6ccccc6)cc5)c4)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 19 h
Yield: 42.3 %

Procedure:
A solution of (5R)-3-(6-{2-[(3-aminobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.202 g) in dichloromethane (4 ml) was treated with 4-biphenylyl isocyanate (0.126 g) and the mixture stirred under nitrogen at 20° C. for 19 h. Isopropanol (15 ml) was added to quench excess isocyanate, and the mixture stirred for 2 h. The solvents were removed in vacuo to give a residue which was purified by Biotage. Elution with 6:4 EtOAc/cyclohexane followed by solvent evaporation in vacuo gave the title compound (0.119 g). LCMS RT=4.09 min, ES+ve 694 (MH)+.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([O:10]C)=[C:6]([CH2:8][CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>[Cu](I)I>[CH2:8]([C:6]1[C:5](=[O:10])[NH:4][C:3]([CH3:12])=[C:2]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH:7]=1)[CH3:9]
Reactant: c1nc[nH]n1
Reactant: CCc1cc(Br)c(C)nc1OC
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cc(-n2cncn2)c(C)[nH]c1=O
Temperature: 180 °C
Yield: 18.9 %

Procedure:
Into a microwave vial is added 3-bromo-5-ethyl-6-methoxy-2-methyl-pyridine (400 mg, 1.74 mmol), potassium carbonate (360 mg, 2.61 mmol), copper iodide (50 mg, 0.263 mmol) and 1,2,4-triazole (240 mg, 3.47 mmol). The vial is flushed with N2 before anhydrous dimethylformamide (5 mL) is added and then sealed. The reaction is heated in the CEM Discover microwave at 180° C. for 40 minutes. LC/MS shows the reaction is incomplete. Further 1,2,4-triazole (120 mg) and copper iodide (30 mg) are added, the reaction flushed with N2 and is re-microwaved to 180° C. Initially the pressure limit of 20 bar is reached and the process is aborted. The residual pressure is released and the reaction is re-microwaved to 180° C. for 40 min with a maximum pressure of 9-11 bar attained. LC/MS shows the reaction to be complete. The reaction is diluted and extracted with 11 portions of dichloromethane. The combined extracts are then dried over magnesium sulfate and evaporated to give a dark oil. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (19:1). Clean fractions containing the product are combined, the solvent evaporated, and the residue is further purified by flash chromatography on a 5-gram silica gel cartridge by elution with heptane:ethyl acetate (19:1) then dichloromethane:heptane (1:1, increasing to 1:0). Clean fractions containing the product are combined and evaporated to give an orange residue. The product is triturated with ether/heptane to give 3-ethyl-6-methyl-5-(1,2,4-triazol-1-yl)-1H-pyridin-2-one as an orange powder (67 mg, 19% yield). This material (57 mg) is suspended in dichloromethane (2 mL) and treated with ethereal hydrochloric acid (2.0 M, 0.444 mL). The mixture is stirred for 1.5 h and then evaporated to give 3-ethyl-6-methyl-5-1,2,4-triazol-1-yl-1H-pyridin-2-one hydrochloride (70 mg) as a cream-orange solid. LC/MS: RT: 1.79 min, MS: m/e=205 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([I:17])[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1NC.C[CH2:26][N:27](C(C)C)C(C)C>CN(C=O)C.O>[O:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH2:26][NH:27][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([I:17])[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN[C@@H]1CCCO1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ncnc2oc(I)c(-c3ccccc3)c12
Solvent: CN(C)C=O
Solvent: O
Product: Ic1oc2ncnc(NC[C@@H]3CCCO3)c2c1-c1ccccc1

Procedure:
A solution of 164 (550 mg, 1.54 mmol), (S)-tetrahydrofuran-2-yl-methylamine (190 μL, 1.85 mmol), and DIEA (401 μL, 2.3 mmol) in DMF (4 mL) was heated to 100° C. for 1 h. The reaction mixture was diluted with water, the precipitated solid was filtered and dried.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][C@H:14]([C:16]2([NH:19]C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[C@@H:13]([O:27][CH3:28])[CH2:12]1)=O)C1C=CC=CC=1.[NH2:29][C:30]1[C:39]([F:40])=[C:38](F)[C:37](C)=[C:36]2[C:31]=1[C:32](=[O:50])[C:33]([C:47]([OH:49])=[O:48])=[CH:34][N:35]2[C@@H:43]1[CH2:45][C@@H:44]1[F:46].C(N(CC)CC)C>C(O)C.[C].[Pd]>[NH2:29][C:30]1[C:39]([F:40])=[C:9]([N:11]2[CH2:15][C@H:14]([C:16]3([NH2:19])[CH2:17][CH2:18]3)[C@@H:13]([O:27][CH3:28])[CH2:12]2)[C:37]([CH3:38])=[C:36]2[C:31]=1[C:32](=[O:50])[C:33]([C:47]([OH:49])=[O:48])=[CH:34][N:35]2[C@@H:43]1[CH2:45][C@@H:44]1[F:46]
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C1(NC(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CO[C@H]1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn([C@@H]4C[C@@H]4F)c3c2C)C[C@@H]1C1(N)CC1
Reaction time: 4 h
Yield: 15.9 %

Procedure:
1-Benzyloxycarbonyl-4-(R)-(1-tert-butoxycarbonylaminocyclopropyl)-3-(R)-methoxypyrrolidine (550 mg, 1.41 mmol) was dissolved in ethanol (40 ml), and the solution was mixed with a 5% palladium-carbon catalyst (water content, 55.6%; 550 mg) and stirred for 4 hours under a pressured hydrogen atmosphere (4.5 kg/cm2). The catalyst was removed by celite filtration (methanol washing), and the filtrate was concentrated under reduced pressure. The thus obtained residue was dissolved in dimethyl sulfoxide (5 ml), and the solution was mixed with 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (249.8 mg, 0.80 mmol) and triethylamine (3 ml) and stirred for 2 days in an oil bath of 120° C. under a nitrogen atmosphere. After cooling, dimethyl sulfoxide was evaporated under reduced pressure, the thus obtained residue was dissolved in chloroform (100 ml) and washed with a 10% citric acid aqueous solution (50 ml×2) and saturated brine (100 ml) in that order and then the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. To the thus obtained residue, which was cooled in an ice bath, was added dropwise concentrated hydrochloric acid (10 ml), followed by 1 hour of stirring at room temperature. After adding water (20 ml) to the reaction solution, the aqueous solution was washed with dichloromethane (50 ml×3), adjusted to pH 11 with sodium hydroxide aqueous solution and then washed with dichloromethane (50 ml×2). This was adjusted to pH 7.4 with concentrated hydrochloric acid and extracted with chloroform (150 ml×3). The organic layers were combined, dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to preparative silica gel thin layer chromatography (development with the bottom layer of a mixture of chloroform:methanol:water=7:3:1), and the resulting crude product was purified by recrystallizing from ethanol-diisopropyl ether and then dried under a reduced pressure to obtain 57 mg (16%) of the title compound as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[S:12][CH:13]=[C:14]([CH3:17])[C:15]=3[CH3:16])=[C:6]2[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([O:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[S:12][CH:13]=[C:14]([CH3:17])[C:15]=3[CH3:16])=[C:6]2[N:5]=[CH:4][N:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: Cc1csc(-c2cnn3c(O)ncnc23)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ncnc2c(-c3scc(C)c3C)cnn12
Reaction time: 0.17 h

Procedure:
To a mixture of 4-hydroxy-8-(3-methyl-4-methylthiophenyl)pyrazolo[1,5-a]-1,3,5-triazine (0.100 g), triethylamine (0.1 ml) and methylene chloride (10 ml) is added dropwise acetyl chloride (0.1 ml) at room temperature. After reacting for 10 minutes, to the reaction mixture is added methylene chloride (90 ml). The mixture is washed with water (20 ml×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.110 g).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([C:19]2[O:20][C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[C:23]=2[CH3:24])(O)[CH2:15]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([SiH](CC)CC)C.FC(F)(F)C(O)=O.B(F)(F)F.CCOCC>ClCCl>[CH:1]([N:14]1[CH2:17][CH:16]([C:19]2[O:20][C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[C:23]=2[CH3:24])[CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)oc2ccccc12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2CN(C(c3ccccc3)c3ccccc3)C2)oc2ccccc12
Temperature: 25 °C
Reaction time: 23 h
Yield: 62.8 %

Procedure:
To a cooled (0° C.) solution of 1-benzhydryl-3-(3-methylbenzofuran-2-yl)azetidin-3-ol (406 mg, 1.099 mmol) in dichloromethane (50 mL) were added triethylsilane (1.775 mL, 10.99 mmol) and trifluoroacetic acid (1.630 mL, 22.01 mmol). The reaction mixture was warmed to rt and stirred for 23 h. After 18 h, boron trifluoride etherate (0.6 mL, 4.73 mmol) was added and the reaction was allowed to stir for an additional 5 h. The reaction mixture was partitioned between sat. NaHCO3 and DCM. The layers were separated, the organic layer was washed with sat. NaHCO3 and brine, dried on Na2SO4 and concentrated. The residue was purified by flash chromatography (heptane/EtOAc, 0%→30%), yielding the title product (244 mg, 63%) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1>C(N(CC)CC)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][N:25]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cccc(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with 4-(m-methoxyphenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(m-methoxyphenyl)-4-(p-nitrobenzyl)piperazine.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(O)C.C(O)(C)C>[I:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(I)c2c(c1)CCN2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCO
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(I)c2[nH]ccc2c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
A solution of 7-iodo-5-nitro-2,3-dihydro-1H-indole II (15 g, 51.7 mmol) in ethanol (1200 mL) and isopropanol (20 mL) at 25° C. was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (13.6 g, 59.9 mmol). The resulting solution was warmed to 65° C. and air was bubbled through for 1 h. An additional 0.57 equivalents of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (6.8 g, 29.9 mmol) was added and the reaction was stirred at 65° C. for another 2 h before being concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 toluene/ethyl acetate) afforded 7-iodo-5-nitro-1H-indole III (13.07 g, 79%) as a yellow solid: 1H NMR (DMSO-d6, 300 MHz) δ 11.82 (broad s, 1H), 8.59 (d, J=1.83 Hz, 1H), 8.30 (d, J=1.83 Hz, 1H), 7.61 (t, J=2.93 Hz, 1H), 6.90 (dd, J1=1.83 Hz, J2=3.30 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([CH2:9][OH:10])[NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:17][CH:18](Br)[CH3:19].C(OCC)(=O)C>CN(C=O)C.O>[Br:17][CH2:18][CH2:19][N:6]1[C:7]([CH2:9][OH:10])=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: CC(Br)Br
Reactant: O=[N+]([O-])c1cc(CO)[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 49.8 %

Procedure:
A mixture of 296a (345 mg, 2.41 mmol), and cesium carbonate (965 mg, 2.96 mmol) in DMF (5 mL) was cooled to 0° C. using an ice/acetone bath and dibromoethane (4.48 g, 24.1 mmol) was added portion-wise (no exotherm). The reaction was stirred at 0° C. for 1 h and room temperature for 4 h. After this time ethyl acetate (20 mL) and water (15 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (2×10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to afford the crude product, which was purified by silica-gel column chromatography eluting with 6:1 petroleum ether/ethyl acetate to afford 296b (300 mg, 50%). MS-ESI: [M+H]+ 250