Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.O>[Cl:26][C:21]1[CH:20]=[C:19]([NH:18][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:32]4[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)[CH:3]=3)[N:8]=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:6]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: COc1ccc(B(O)O)cn1
Reactant: Fc1ccc(Nc2nc(-c3cccnc3)nc3ccc(Br)cc23)cc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3nc(-c4cccnc4)nc(Nc4ccc(F)c(Cl)c4)c3c2)cn1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
A 2.0 dram reaction vial was charged with 6-bromo-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (synthesized as described in Scheme 1 and 4, substituting 5-bromo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and 3-chloro-4-fluoroaniline for 2-aminobenzamide) (100 mg, 0.233 mmol, 1.0 equiv), 6-methoxypyridin-3-ylboronic acid (44.5 mg, 0.291 mmol, 1.25 equiv), Pd(APhos)2Cl2 (6.6 mg, 0.0093 mmol, 4 mol %) and potassium phosphate monohydrate (69 mg, 0.70 mmol, 3.0 equiv). The mixture was suspended in dioxane/water (9:1, 4 mL), and the reaction was heated at 90° C. for 14 h. The reaction mixture was cooled to room temperature, diluted with water (15 mL) and the resultant precipitate was collected by filtration. The crude product was purified by stirring in methanol for 30 min at 60° C. to give the desired product as a pale yellow solid (58 mg, 54%) LCMS m/z=458.1 (M+1) (Method C) (retention time=2.56 min). 1H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.53 (s, 1H), 8.82 (s, 1H), 8.70 (dd, J=16.9, 5.4 Hz, 3H), 8.25 (d, J=8.6 Hz, 3H), 8.01-7.87 (m, 2H), 7.57 (dd, J=11.2, 6.0 Hz, 2H), 7.03 (d, J=8.6 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16]([O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)[CH3:17].C(OCC)(=O)C>C1(C)C=CC=CC=1.CO.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>[CH2:16]([O:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:17]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)cc1F
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
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1cccc(-c2ccc(N)c(F)c2)c1
Temperature: 80 °C
Yield: 95.9 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (3.2 g, 17.05 mmol), 2M K2CO3 (24 ml, 48.00 mmol), Pd(PPh3)4 (1.2 g, 1.02 mmol) in toluene (120 ml) under nitrogen atmosphere was added dropwise a solution of the 3-ethoxyphenylboronic acid (4.25 g, 25.61 mmol) in 31 ml of MeOH. The mixture was heated to 80° C. overnight and then cooled to room temperature. Ethyl acetate was added and washed twice with a K2CO3 aqueous solution. The organic layer was washed with brine, dried over magnesium sulphate, filtered and the solvent evaporated under vacuum. The residue obtained was purified by flash chromatography eluting with Hexane/AcOEt (from 10/1 to 8/1). The solid obtained was recrystallized in hexane to yield 3.78 g of the desired compound as a white solid. Yield=72%
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CCCCC1>O>[C:1]1([CH:7]([CH3:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: NC=O
Solvent: C1CCCCC1
Product: CC(CO)c1ccccc1

Procedure:
(1st step). 1,340 parts of 2-phenylpropanal, 450 parts of formamide, 95 parts of p-toluenesulfonic acid and 420 parts by volume of cyclohexane are refluxed for 41/2 hours at 95°-98° C. in a stirred apparatus equipped with a reflux condenser and water separator; 144 parts of water are separated off. The reaction mixture is subjected to fractional distillation. The distillate is extracted with 500 parts by volume of ether. Distillation of the ether extract under reduced pressure gives 118 parts of unconverted 2-phenylpropanol, whilst crystallization of the extraction residue and the distillation residue gives 947 parts of N-(2-phenyl-prop-1-enyl)-formamide, corresponding to a yield of 64.5% of theory, based on 2-phenylpropanol converted.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1B(O)O.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:14]([N+:24]([O-:26])=[O:25])[CH:13]=1.[C:27](=O)([O-])[O-].[K+].[K+]>O.C1COCC1.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>[CH3:27][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][C:14]=1[N+:24]([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cc(Br)ccc1-c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1-c1ccc(-c2ccccc2)cc1[N+](=O)[O-]

Procedure:
1.7 g (1.49 mmol) of Pd(PPh3)4 are added to a well-stirred, degassed suspension of 25 g (183.8 mmol) of o-tolylboronic acid, 51.1 g (183.8 mmol) of 4-bromo-2-nitrobiphenyl and 66.5 g (212.7 mmol) of potassium carbonate in a mixture of 250 ml of water and 250 ml of THF, and the mixture is heated under reflux for 17 h. After cooling, the organic phase is separated off, washed three times with 200 ml of water and once with 200 ml of saturated, aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in a rotary evaporator. The grey residue is recrystallised from hexane. The deposited crystals are filtered off with suction, washed with a little MeOH and dried in vacuo; yield: 50.5 g, 95% of theory; purity: 99.5% according to HPLC.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.[CH:28]1C=C[C:31]2[N:36]([OH:37])N=[N:34][C:32]=2[CH:33]=1.CC1ON=CC=1N>CN(C)C=O.O>[CH3:28][C:33]1[O:37][N:36]=[CH:31][C:32]=1[NH:34][C:11](=[O:13])[C:10]1[CH:14]=[C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:16]=[CH:17][C:9]=1[O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: Cc1oncc1N
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: Cc1oncc1NC(=O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[(phenylmethyl)oxy]-5-(4-pyridinyl)benzoic acid (may be prepared as described in Description 79; 100 mg, 0.30 mmol), EDC (115 mg, 0.60 mmol), and HOBT (92 mg, 0.60 mmol) in dimethylformamide (2 ml) was stirred in air at room temperature for 1 h, then 5-methyl-4-isoxazolamine (may be prepared as described in Description 93; 100 mg, 1.02 mmol) was added in one charge. The reaction mixture was stirred at 25° C. overnight. The solution was heated at 35° C. for 7 hours, then diluted with water (30 ml) and extracted with ethyl acetate (80 ml×3). The organic phase was washed with brine (60 ml×2), dried over anhydrous MgSO4, and concentrated. The residue was purified by chromatography (silica gel, 20 g, eluent: dichloromethane/methanol=60:1, 600 ml). The crude product was washed with methanol (2 ml×2), filtered, and dried in vacuum to yield the title compound. 23 mg.
Reaction SMILES: C[C@]1(O)[C@@H]2C(=[C:12]([OH:30])[C@:13]3([OH:29])[C:20](=[O:21])[C:19](C(N)=O)=[C:18]([OH:25])[C@@H:17](N(C)C)[C@@H]3C2)C(=O)C2C(O)=CC=CC1=2.NCC(O)=[O:36].[Na+].[Cl-].[OH-:40].[Na+].[N+](C1C=C([N+]([O-])=O)C=C(C(O)=O)C=1O)([O-])=O>>[O:40]=[CH:17][C@@H:18]([C@H:19]([C@@H:20]([C@@H:13]([CH2:12][OH:30])[OH:29])[OH:21])[OH:36])[OH:25]
Reactant: NCC(=O)O
Reactant: [OH-]
Reactant: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)cccc4[C@@](C)(O)[C@H]3C[C@@H]12
Agent: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Agent: [Cl-]
Agent: [Na+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 37 °C
Reaction time: 8 h

Procedure:
One ml of a culture of strain HB101(pPU100) which had been cultured overnight using 5 ml of an LB medium (containing tetracycline) was inoculated into 100 ml of an LB medium (containing tetracycline), followed by shaking culture at 37° C. for 24 hours. Subsequently, the cells collected through centrifugal separation were suspended in Tris-HCl buffer (pH 8.0) and the cells were disrupted by sonication. The cell debris was removed by centrifugal separation, and the supernatant was used as a cell-free extract. Similarly, a control cell-free extract was prepared using strain HB100(pBR322). Pullulanase activity of these extracts was measured. The pullulanase activity was measured by first causing a reaction in a reaction mixture containing 40 mM glycine—NaCl—NaOH buffer (pH 10) and pullulan (final concentration=0.25%) at 40° C. for 30 minutes, and the resultant reducing sugar was quantitatively determined by the 3,5-dinitrosalicylic acid (DNS) method (Miller, G. L., et al., Anal. Biochem., 2, 127 (1960)). The amount of enzyme which produces a quantity per minute of reducing sugar equivalent to 1 μmol of glucose is taken as 1 unit. As a result, pullulanase activity was detected in a cell-free extract of strain HB101(pPU100). Further, when the optimum working pH of the produced pullulanase was measured, it was found that the pullulanase was in fact an alkaline pullulanase having the optimum working pH of pH 9.5. For the measurement of enzymatic activity, the following buffers (each at 40 mM) were used:
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[CH2:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[N:10]1[C:11]2[CH:2]([NH:1][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([CH2:27][NH:28][S:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)(=[O:30])=[O:31])=[CH:38][CH:39]=3)[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: NC1CCCc2cccnc21
Reactant: O=S(=O)(NCc1ccc(CCl)cc1)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCc1ccc(CNC2CCCc3cccnc32)cc1)c1ccccn1

Procedure:
Reaction of 8-amino-5,6,7,8-tetrahydroquinoline (200 mg, 1.35 mmol), N,N-diisopropylethylamine (157 uL, 0.90 mmol) and pyridine-2-sulfonic acid 4-chloromethyl-benzylamide (266 mg, 0.90 mmol) for 3 h at 50° C. followed by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 98:1:1) gave AMD9426 (150 mg, 41%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.68-1.79 (m, 2H), 1.97-2.03 (m, 1H), 2.12-2.20 (m, 1H), 2.69-2.84 (m, 3H), 3.77-3.81 (m, 2H), 3.92 (d, 1H, J=12.0 Hz), 4.20 (br s, 2H), 7.05 (dd, 1H, J=7.5, 4.8 Hz), 7.15 (d, 2H, J=7.8 Hz), 7.25 (d, 2H, J=7.8 Hz), 7.36 (d, 1H, J=7.5 Hz), 7.39-7.44 (m, 1H), 7.82 (ddd, 1H, J=7.8, 7.8, 1.5 Hz), 7.92 (d, 1H, J=7.8 Hz), 8.36 (d, 1H, J=3.9 Hz), 8.59 (d, 1H, J=4.2 Hz); 13C NMR (75.5 MHz, CDCl3) δ 20.09, 28.94, 29.23, 47.80, 51.75, 57.87, 122.25, 122.63, 126.94, 128.45 (2C), 128.88 (2C), 132.88, 135.25, 137.30, 138.35, 147.68, 147.15, 150.34, 157.75, 157.95. ES-MS m/z 409 (M+H). Anal. Calcd. for C22H24N4O2SO.0.2H2O.0.3CH2Cl2: C, 61.21; H, 5.76; N, 12.80; S, 7.33; O, 0.804. Found: C, 60.82; H, 5.73; N, 12.42; S, 7.30; O, 8.14.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[H-].[Na+].[CH3:19]I.[ClH:21]>C1COCC1.CCO>[ClH:21].[CH3:19][O:16][CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCC1CCNCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
N-Boc-4-(2-hydroxy-ethyl)-piperidine (5 g, 21.8 mmol) in THF (25 ml) was added to a suspension of NaH (1.47 g, 43.7 mmol) in THF (75 ml) at 0° C. under N2. The reaction was stirred for 1 hour at 0° C. and MeI (2.72 ml, 43.7 mmol) added slowly. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (100 ml) and extracted with DCM (3×100 ml). The combined DCM layers were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo. The crude reaction (7.5 g) was treated with 3M HCl solution in EtOH (150 ml) for 12 hours. The reaction was concentrated in vacuo and azeotroped with toluene (2×150 ml) to give 4-(2-methoxy-ethyl)-piperidine hydrochloride (3.5 g, 89%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>C(O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([N:15]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCCCBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCCCC2)CC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Trans-4-tert-butoxycarbonylamino-aminocyclohexane (1 g) and potassium carbonate (1.3 g) were suspended in ethanol (20 mL), and then 1,5-dibromopentane (1.07 g) was added thereto. The reaction solution was stirred at 80° C. for 48 hours. After the reaction solution was cooled to room temperature, the solvent was concentrated under reduced pressure. The residue was dissolved in water (50 mL). The aqueous layer was extracted twice with dichloromethane (50 mL). The combined organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After removing the anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate: 10%-saturated aqueous ammonia-methanol=1:0→10:1) to obtain the title compound (492 mg) having the following physical properties.
Reaction SMILES: ClCCCl.[N:5]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:16][C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[N+]=[N-]>C(Cl)Cl.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]2[C:17]3[N:16]=[C:15]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=4)[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]=3[NH:5][C:23]=2[CH:22]=1)([O-:26])=[O:25]
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc(-c2ccc([N+](=O)[O-])cc2)c1N=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCCCCCCC(=O)O
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc([N+](=O)[O-])ccc12
Temperature: 80 °C
Yield: 41.9 %

Procedure:
1,2-Dichloroethane (10 mL) was added to a mixture of methyl 3-azido-2-(4-nitrophenyl)-6-(3-(trifluoromethyl)phenyl)isonicotinate (1.0 g, 2.3 mmol), rhodium octanoate dimer (0.125 g, 0.161 mmol) and crushed 4A° molecular sieves (1.0 g). The reaction was heated at 80° C. for 20 hr. The crude mixture was diluted with DCM and silica gel chromatography (step gradient elution with DCM containing 0 to 20% MeOH) afforded methyl 7-nitro-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (400 mg, 0.963 mmol, 43% yield). MS (ESI) m/z 416.09 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.24 (1H, br s), 8.42-8.72 (5H, m), 8.16 (1H, dd, J=8.55, 1.83 Hz), 7.82 (2H, ddd, J=15.11, 7.78, 7.63 Hz), 4.10 (3H, s).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[S:11][C:10]([C:12]([O:14]C)=[O:13])=[CH:9][CH:8]=1)=O.[NH2:17][C:18]([NH2:20])=[S:19].[CH3:21]C(C)([O-])C.[K+].C1COCC1.IC>COC(O)C>[CH3:21][S:19][C:18]1[N:20]=[C:5]([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=2)[CH:4]=[CH:3][N:17]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc(C(=O)/C=C/N(C)C)s1
Reactant: NC(N)=S
Agent: COC(C)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nccc(-c2ccc(C(=O)O)s2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 48 %

Procedure:
A mixture of (E)-methyl 5-(3-(dimethylamino)acryloyl)thiophene-2-carboxylate (1.2 g, 5.02 mmol) and thiourea (0.38 g, 5.02 mmol) in methoxyethanol (20 mL) was treated slowly with 1.0 M potassium tert-butoxide in THF (5 mL, 5.02 mmol) at rt. The resulting mixture refluxed for 6 h. After cooling to rt, iodomethane (1.4 g, 10.04 mmol) was added and the mixture was stirred at rt for 15 h. The solvent was removed under vacuum and water (150 mL) was added to the residue. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuo and the solid was treated with methanol (10 mL) and filtered. The solid was suspended in 2.5 M sodium hydroxide (100 mL), stirred at rt for 24 h and extracted with ethyl acetate (50 mL). The aqueous layer was acidified with hydrochloric acid (6 N) and acetic acid to pH 5 and then extracted with ethyl acetate (3×70 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the solid treated with methanol (10 mL) and filtered to give the title compound (0.58 g, 48%). MS (M+H)+ 253.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11]CC)[CH3:10]>C(OC(=O)C)(=O)C>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: CCOCC
Reactant: Cc1ccnc(N)c1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C)ccn1
Temperature: 25 °C
Yield: 95 %

Procedure:
2-Amino4-methylpyridine (99.0 g, 91.5 mmol) in acetic anhydride (250 mL) was warmed to 70° C. for two h. The mixture was cooled to room temperature and diethyl ether (100 mL) added. The product crystallized as white needle crystals. Filtering and drying in vacuo afforded N-(4-methyl-pyridin-2-yl)-acetamide (130 g, 95%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]([OH:15])[CH2:13][CH2:12][C@@H:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]([O:15][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:13][CH2:12][C@@H:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC[C@H](OS(C)(=O)=O)[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
After ethyl (1R*,3S*,4S*)-3-tert-butoxycarbonylamino-4-hydroxycyclohexane-1-carboxylate (16 g) and triethylamine (38 ml) were dissolved in dichloromethane (150 ml), and the solution was cooled to −78° C., methanesulfonyl chloride (13 ml) was added dropwise at the same temperature. After stirring for 15 minutes at the same temperature, the mixture was heated to 0° C. and stirred for 30 minutes and then 2 hours at room temperature. After 0.1N hydrochloric acid was added, and the mixture was diluted with dichloromethane, the resultant organic layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude ethyl (1R*,3S*,4S*)-3-tert-butoxycarbonylamino-4-methanesulfonyloxycyclohexane-1-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][Br:13])=[C:6]([F:14])[C:5]=1[F:15])[CH3:2].[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Br-:13].[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][P+:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:6]([F:14])[C:5]=1[F:15])[CH3:2]
Reactant: CCOc1ccc(CCCBr)c(F)c1F
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOc1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c1F
Product: [Br-]
Temperature: 25 °C
Yield: 78.9 %

Procedure:
3-(4-Ethoxy-2,3-difluorophenyl)bromopropane (s22) (11.5 g), toluene (100 ml) and triphenylphosphine (21.6 g) were placed in a reaction vessel under an atmosphere of nitrogen, and the mixture was heated to reflux for 5 hours. After the reaction mixture had been cooled to 25° C., the deposits were filtered, and the unreacted material was removed by washing with toluene three times. The resulting colorless solids were dried to give 3-(4-ethoxy-2,3-difluorophenyl)propyltriphenylphosphonium bromide (s23) (17.6 g). The yield based on the compound (s22) was 78.9%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O>C1(C)C=CC=CC=1>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9])=[O:7]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: NCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCCCN
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A mixture of 5.05 gm (43.1 mmole) of 5-aminopentanoic acid, 23.3 gm (86.1 mmole) of stearyl alcohol, and 12.0 gm (63.1 mmole) of p-toluenesulfonic acid monohydrate in 200 ml of toluene was heated at reflux, using a Dean-Stark trap to remove water. After 90 minutes, the solution was allowed to cool to 0° C., giving a heavy gelatinous precipitate. The crude ester was collected, washed thoroughly with toluene, triturated with diethyl ether, and dried in vacuo to give 21.1 gm (38.8 mmole) of fluffy white octadecyl 5-aminopentanoate as the tosylate salt. The ester was sufficiently pure according to nmr spectroscopy (in (CD3)2SO) for subsequent use without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[F:14].[C:18]([O:22][C:23]([N:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>C(COC)OC.O>[F:14][C:13]1[CH:12]=[CH:11][C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:8]=1[C:26]1[N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
1.1 g of tetrakis-triphenylphosphine palladium and 4.2 g of sodium carbonate were added to a solution of 4.3 g of 3-bromo-4-fluoro-nitrobenzene and 5.0 g of 1-(t-butoxycarbonyl)pyrrole-2-boronic acid in a mixture of 130 ml of dimethoxyethane and 22 ml of water, and the reaction liquid was heated overnight under reflux. Aqueous saturated sodium bicarbonate was added to the reaction liquid, and this was extracted with ethyl acetate. The organic layer was washed with water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=20/1) to obtain the entitled compound as a yellow oily substance.