Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:6]=2[C:5]([F:19])=[C:4](Cl)[N:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].CCN(C(C)C)C(C)C.O>CC(O)C.CS(C)=O>[C:31]([O:30][C:29]([NH:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@H:22]1[NH:21][C:4]1[N:3]=[C:2]([Cl:1])[C:7]2[C:8](=[O:18])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:6]=2[C:5]=1[F:19])=[O:35])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CC(C)(C)OC(=O)N1Cc2c(F)c(Cl)nc(Cl)c2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a stirred suspension of tert-butyl 4,6-dichloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (12.5 g, 38.9 mmol) in 2-propanol (72 mL) was added a solution of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (10.01 g, 46.7 mmol) in DMSO (12.00 mL) and DIPEA (8.84 mL, 50.6 mmol). The reaction mixture was heated to 90° C. for 16 h at which point it was cooled to 50° C. and water (50 mL) was added dropwise to give a precipitate. The suspension was stirred at 50° C. for 1 h then cooled to RT. The suspension was reheated to 50° C. for 15 min and cooled to RT for two more cycles. The solids were subsequently filtered and washed with isopropanol (20 mL) and dried on a filter to give the title compound (9.538 g, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.76 (br m, 26H), 3.83 (br s, 1H), 4.12 (br s, 1H), 4.72 (s, 2H), 6.71 (d, J=7.58 Hz, 1H), 7.22 (d, J=6.32 Hz, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:25]([CH:27]2[CH2:29][CH2:28]2)[OH:26])=[CH:6][CH:5]=1.[CH3:30]I>CN(C)C=O.[Cl-].[NH4+]>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:25]([CH:27]2[CH2:29][CH2:28]2)[O:26][CH3:30])=[CH:6][CH:5]=1
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
Sodium hydride (60% in oil, 79.6 mg, 1.99 mmol) was added to a stirred solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl] (cyclopropyl)methanol (700 mg, 1.66 mmol) in N,N-dimethylformamide (5.5 mL) at room temperature. After stirring (5 min, methyl iodide (353 mg, 2.49 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (569 mg, 1.30 mmol, 78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Br[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][C:44]([CH3:49])([CH3:48])[CH2:43]1)=O>>[CH3:48][C:44]1([CH3:49])[CH2:45][CH2:46][CH2:47][N:42]([CH2:40][CH2:39][O:37][C:36]2[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:3][C:2]=2[F:1])[CH2:43]1
Reactant: CC1(C)CCCN(C(=O)CBr)C1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCCC(C)(C)C3)c(F)c2)c1
Yield: 50.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-bromo-1-(3,3-dimethylpiperidin-1-yl)ethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (11 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1OS(C(F)(F)F)(=O)=O.[C:27]1([CH3:36])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH3:36]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(COc2cccnc2)cc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1C
Temperature: 80 °C
Yield: 97.1 %

Procedure:
To a solution of 4-(3-pyridyloxymethyl)-2-(trifluoromethanesulfonyloxy)benzoic acid methyl ester (216 mg, 0.55 mmol), prepared as in Example 203C, in 4 mL of DMF at 25° C. was added PdCl2(PPh3)2 (38 mg, 0.055 mmol, 10 mol %) followed by 2-tolyl boronic acid (113 mg, 0.83 mmol) and Cs2CO3 (270 mg, 0.83 mmol) and the reaction was heated to 80° C. for 12 hours. The reaction was then cooled to ambient temperature, taken up in 50 mL ethyl acetate, and washed with H2O (5×10 mL). The organic phase was dried over Na2SO4, filtered and evaporated to an oil. Purification by radial chromatography using a gradient of 25% ethyl acetate-hexanes to 75% ethyl acetate-hexanes gave 4-(3-pyridyloxymethyl)-2-(2-methylphenyl)benzoic acid methyl ester (178 mg, 97%) as an oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[O:9][C@H:8]([O:10][C@H:11]2[C@H:16]([OH:17])[C@H:15]([N:18]([C:20]([CH2:22][NH2:23])=[O:21])[CH3:19])[C@@H:14]([O:24][CH3:25])[CH2:13][C@H:12]2[NH2:26])[C@H:7]([NH2:27])[CH2:6][CH2:5]1.CNC[C@H]1[O:36][C@H:35]([O:37][C@H]2[C@H](O)[C@H](N(C(CN)=O)C)[C@@H](OC)C[C@@H]2N)[C@H](N)CC1>>[CH3:1][NH:2][CH2:3][C@H:4]1[O:9][C@H:8]([O:10][C@H:11]2[C@H:16]([OH:17])[C@H:15]([N:18]([C:20]([CH2:22][NH2:23])=[O:21])[CH3:19])[C@@H:14]([O:24][CH3:25])[CH2:13][C@H:12]2[NH2:26])[C@H:7]([NH2:27])[CH2:6][CH2:5]1.[C:35](=[O:37])([O-:9])[O-:36]
Reactant: CNC[C@@H]1CC[C@@H](N)[C@@H](O[C@H]2[C@H](O)[C@H](N(C)C(=O)CN)[C@@H](OC)C[C@@H]2N)O1
Agent: CNC[C@@H]1CC[C@@H](N)[C@@H](O[C@H]2[C@H](O)[C@H](N(C)C(=O)CN)[C@@H](OC)C[C@H]2N)O1
Product: O=C([O-])[O-]

Procedure:
Istamycin B is very similar to istamycin A in its properties, and istamycin B is also a basic compound. Istamycin B isolated as a carbonate thereof is in the form of a colorless powder which has no definite melting point, decomposes at 112°-124° C. and gives a specific optical rotation [α]D25 =+165° (c 0.4, water) and of which the elemental analysis is coincident with the theoretical values of the molecular formula C17H35N5O5.1/2H2CO3 (C 49.99%, H 8.63%, N 16.65%, O 24.73%). This molecular formula has been confirmed by high-resolution mass-spectrometry (Found: m/e 389.2625; Calcd. for C17H35N5O5 : m/e 389.2635). The infra-red absorption spectrum of istamycin B hemicarbonate pelleted in potassium bromide is shown in FIG. 2 of the attached drawings. The ultraviolet absorption spectrum of the istamycin B hemi-carbonate in water shows only end absorption. In the proton (1H) nuclear magnetic resonance absorption spectrum (external standard: TMS, pD 5.4) of istamycin B hemi-carbonate in deutero-water, there are shown characteristic signals at δ 3.26 (s, N--CH3), 3.59 (s, N--CH3), 3.95 (s, O--CH3), 4.57 (s, CH2) and 5.96 (d, J=3.5 Hz, CH). Like istamycin A, istamycin B is soluble in water and methanol but sparingly soluble or insoluble in ethanol and other common organic solvents, and it is positive to the ninhydrin reaction and to the Rydon-Smith reaction. As stated hereinbefore, istamycin B is separable from istamycin A by thin layer chromatography on cellulose.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([N:60]4[CH2:65][CH2:64][O:63][CH2:62][CH2:61]4)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)N5CCOCC5)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.2 %

Procedure:
To a solution of {2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (65 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), and morpholine (49 mg), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (102 mg, yield 60%) as a pale-yellow amorphous solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:9](=[O:29])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:8]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:9](=[O:29])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)O)cc1
Reaction time: 8 h
Yield: 35.3 %

Procedure:
Methyl 2-[(4-{2-[benzyl(hexyl)amino]-2-oxoethyl}phenoxy)methyl]benzoate (70 mg, 0.148 mmol) in THF (2 ml) was cooled in an ice-bath. Lithium hydroxide (7.08 mg, 0.296 mmol) in water (1 ml) was dropped in. The cooling-bath was then removed and the mixture was stirred overnight. HPLC showed that the reaction was not complete. More lithium hydroxide (0.2M, 0.5 ml) was added. The reaction mixture was stirred for 4 days more. It was then evaporated in vacuum to remove THF. The residue was acidified with 1% hydrochloric acid, pH=3-4, and extracted with ethyl acetate. The organic phase was dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, MeOH/DCM (1:99, and then 2:98) as eluant gave 24 mg the desired product, yield 35%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:14](I)[CH3:15]>CN(C=O)C>[CH2:14]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:15]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 1H-indole-5-carbonitrile (2.0 g, 14.1 mmol) in DMF (30 mL) was added NaH (60% suspension in mineral oil, 0.81 g, 20.3 mmol, 1.4 eq) at 0° C. The mixture was stirred at 0° C. for 30 min before EtI (1.35 mL, 16.9 mmol, 1.2 eq) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with H2O then extracted by Et2O (3×40 mL). The combined organic layers were washed with H2O (50 mL) then dried over Na2SO4. The solvent was removed to afford crude product (2.57 g, ca. 14.1 mmol) which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:20][C:21](=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=O)[CH2:2]CCCCCCCCCCCCCCCC.C(O)C[OH:42].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:21]([O:20][CH2:1][CH2:2][OH:42])(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCC
Reactant: OCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OCCO
Reaction time: 1.5 h
Yield: 39.2 %

Procedure:
A solution of stearic anhydride (1.14 g, 2.06 mmol) in dichloromethane (30 mL) was cannulated into a stirred solution of ethylene glycol (1.10 mL, 19.7 mmol), DMAP (22 mg, 0.18 mmol) and triethylamine (0.300 mL, 2.16 mmol) in dichloromethane (20 mL). After stirring for 90 min. the reaction was quenched with the addition of H2O (100 mL). After separation of the phases the aqueous fraction was re-extracted with dichloromethane (2×50 mL) and the combined organic extract was washed with brine (70 mL). After drying (MgSO4) and filtration the solvent was removed at reduced pressure to give the crude product that was purified by chromatography on silica gel. Gradient elution with ethyl acetate/petroleum ether (10:90→30:70) afforded the title compound 48 (265 mg, 0.807 mmol, 39%) as an oil; 1H NMR (300 MHz, CDCl3) δ 4.25-4.20 (m, 2H), 3.83-3.78 (m, 2H), 2.38 (t, 2H, J 7.5 Hz), 2.00-1.97 (m, 1H), 1.62-1.55 (m, 2H), 1.35-1.20 (m, 28H), 0.87-0.81 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 174.6, 66.3, 61.7, 34.6, 32.3, 30.1, 29.8, 29.7, 29.6, 29.5, 25.3, 23.1, 14.5; HRMS-ESI (+ve) (Found: m/z 346.3323 (MNH4+). C20H44NO3 requires m/z 346.3316).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[NH2:14].[N:15]([O-])=O.[Na+].[ClH:19]>O>[ClH:19].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[NH:14][NH2:15]
Reactant: Nc1cc(-c2ccccc2)ccc1Br
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(-c2ccccc2)ccc1Br
Temperature: 0 °C

Procedure:
To 4 g of 4-bromo-[1,1'-biphenyl]-3-amine were added 25 ml of water and 50 ml of concentrated HCl with stirring. The solution was cooled to 0° C. A solution of 1.1 g of sodium nitrite in 6 ml of water was then added dropwise while maintaining a temperature of 0° C. After this addition, the mixture was stirred at 0° C. for one hour. A solution of 20 g of stannous chloride in 20 ml of concentrated HCl cooled to -20 C. was added to the reaction mixture and again the mixture was stirred for one hour.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][S:10](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:14]1(C)C=CC=CC=1.S(OC)(OC)(=O)=O>O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[N:8]([CH3:14])[CH2:9][S:10](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: O=S1C=Nc2c(Cl)cccc21
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CN1CS(=O)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
4-chlorobenzothiazolone (9.28 g, 0.05 mole) was dissolved in a solution of sodium hydroxide (3.19 g, 0.075 mole) in water (220 ml), and benzyltriethylammonium chloride (0.34 g, 0.0015 mole) and toluene (80 ml) were added thereto. Dimethyl sulfate (9.40 g, 0.075 mole) was added dropwise thereto at room temperature, and the mixture was stirred at room temperature for 4 hours, followed by phase-separation. The toluene layer was washed once with water, and the solvent was removed under reduced pressure to obtain 8.97 g of 4-chloro-N-methylbenzothiazolone as pale yellow crystals. Yield 90.3%, purity 96.7%, m.p. 129°-131° C.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[O:7])=[C:4](O)[CH:3]=1.[H-].[Na+]>>[CH2:6]([O:7][C:5]1([CH:17]=[C:18]([Cl:19])[C:2]([NH2:1])=[CH:3][CH2:4]1)[C:6]([NH:8][CH:9]1[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH2:10]1)=[O:7])[CH:5]=[CH2:4]
Reactant: Nc1cc(O)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Agent: [H-]
Agent: [Na+]
Product: C=CCOC1(C(=O)NC2CN3CCC2CC3)C=C(Cl)C(N)=CC1
Yield: 90.7 %

Procedure:
4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-hydroxybenzamide (444 mg) was added to a suspension of sodium hydride (66 mg of a 60% oil emulsion, washed with pentane) in DMF (10 mL). When the evolution of hydrogen ceased, the solution was treated with allyl bromide (195 mg) for 1 hour. The solution was diluted with ethyl acetate and the volume of solvent mixture consisting of acetonitrile, methanol and ammonium hydroxide in the ratio of 100:15:0.5, and flash chromatographed over silica gel eluting with the same solvent system. The appropriate fractions were combined and concentrated. The solid obtained was collected by filtration and dried under vacuum to yield 0.230 g (46%) of the title compound, m.p. 220° C.
Reaction SMILES: CS(O[CH2:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=2)[CH:8]=1)(=O)=O.[N:20]1([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28]#[N:29])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[F:17][C:16]([F:19])([F:18])[C:12]1[CH:13]=[C:14]2[S:15][C:7]([CH2:6][N:23]3[CH2:22][CH2:21][N:20]([C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]#[N:29])[CH2:25][CH2:24]3)=[CH:8][C:9]2=[N:10][CH:11]=1
Reactant: CS(=O)(=O)OCc1cc2ncc(C(F)(F)F)cc2s1
Reactant: N#Cc1ccccc1N1CCNCC1
Product: N#Cc1ccccc1N1CCN(Cc2cc3ncc(C(F)(F)F)cc3s2)CC1

Procedure:
The solution from Example 25C (2 mL) and 2-(1-piperazinyl)benzonitrile (187 mg) were processed as described in Example 25D to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.81 (4H, t, J=4.8 Hz), 3.29 (4H, J=4.8 Hz), 4.00 (s, 2H), 7.03 (2H, m), 7.50 (2H, m), 7.59 (dd, 1H, J=7.5,1.5 Hz), 8.39 (1H, m), 8.86 (1H, m). MS (DCI/NH3) m/z 403.1 (M+H)+. Anal. Calcd for C20H17N4F3S: C, 59.69; H, 4.26; N, 13.92. Found: C, 59.53; H, 4.12; N, 14.22.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH3:12][CH2:13][C:14]1([C:23]2C=[CH:27][CH:26]=[CH:25][CH:24]=2)C(=O)NC(=O)NC1=O.BrCCCCCCCC.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN1C=CN=C1CC1N(C)C=CN=1.Cl>C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni].CN(C)C(=O)C>[CH2:12]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:13][CH2:14][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCC1(c2ccccc2)C(=O)NC(=O)NC1=O
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Agent: Cl
Solvent: CCCCCCCCBr
Solvent: CC(=O)N(C)C
Solvent: C1=CCCC=CCC1
Product: CCCCCCCCc1ccc(OC)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
In an argon atmosphere, 0.4 mmol (61 mg) of p-methoxyphenylboronic acid, 0.3 nunol (57 mg) of 1-bromooctane, 0.45 mmol (95 mg) of potassium phosphate, 0.015 mmol (2.6 mg) of bis(N-methylimidazole-2-yl)methane, and 0.015 mmol (4.1 mg) of bis(1,5-cyclooctadiene)nickel were mixed with 1 ml of N,N-dimethylacetamide. The resulting mixture was heated to 80° C. and then held at the same temperature for 2 hours under stirring. After the reaction was completed, the reaction mixture was allowed to stand at room temperature. After 10 ml of 1 N hydrochloric acid was added to dissolve potassium phosphate, the reaction mixture was transferred to a separating funnel and extracted with ethyl acetate. The extracted organic layer was washed with a saturated sodium chloride solution. The 4-octylanisole was obtained in a yield of 87% as shown in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH:6]=C.[O:23]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[C:4]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH:6]=[O:23]
Reactant: C=CCC(NC(=O)OC(C)(C)C)(C(=O)OC)c1ccccc1
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(CC=O)(NC(=O)OC(C)(C)C)c1ccccc1
Yield: 35.8 %

Procedure:
The solution of compound 12 (30.5 g, 0.1 mol) in CH2Cl2 (300 mL) at −78° C. was bubbled with O3 until the solution turned gray-blue. Then PPh3 (40 g, 0.15 mol) was added slowly to quench the reaction. After concentration, the residue was purified by column chromatography on silica gel (PE: EA=10:1) to give compound 13 (11 g, 35.8%). 1H NMR (400 MHz, CDCl3) δ 1.37 (s, 9 H), 3.57-3.61 (d, 1 H, J=18 Hz), 3.71 (s, 3H), 3.98-4.12 (m, 1 H), 6.16 (bs, 1 H), 7.31-7.43 (m, 5 H), 9.74 (s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[S:7][C:6]([C:8]([NH2:10])=[NH:9])=[CH:5][CH:4]=1.O=[C:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17](OCC)=[O:18].C[O-].[Na+]>C(O)C>[Cl:2][C:3]1[S:7][C:6]([C:8]2[NH:10][C:17](=[O:18])[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[N:9]=2)=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccc(Cl)s1
Reactant: CCOC(=O)C1CCCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(-c2ccc(Cl)s2)nc2c1CCC2
Temperature: 25 °C
Yield: 71 %

Procedure:
A 50-mL round bottomed flask was charged with 5-chlorothiophene-2-carboxamidine HCl salt (400 mg, ˜2 mmol, 1 eq.), ethyl 2-oxocyclopentanecarboxylate (320 mg, 2 mmol, 1 eq.), and ethanol (10 ml). To the mixture was added sodium methoxide (25 w % in methanol, 540 mg, 2.5 mmol, 1.25 eq.). The resulting mixture was stirred under reflux for 20 hr. After cooling to room temperature, the mixture was evaporated under reduced pressure to dryness and the residue was treated with 1N HCl (6 ml). Solid was collected by filtration and washed water followed by ether. The product thus obtained was forwarded to the next step without any further purification (360 mg, 71% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])[O:9]CC)=[C:4]([CH3:21])[C:3]=1[CH3:22].[I-].[Na+:24]>CC(CC)=O>[Na+:24].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:9])[O-:12])=[C:4]([CH3:21])[C:3]=1[CH3:22]
Reactant: CCOP(=O)(C(=O)c1ccccc1)c1ccc(C)c(C)c1C
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: Cc1ccc(P(=O)([O-])C(=O)c2ccccc2)c(C)c1C
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
644 g of ethyl trimethylbenzoylphenylphosphinate (Lucirin® TPO-L, BASF AG) were initially introduced in 3000 ml of ethyl methyl ketone, and 1.1 equivalents (285 g) of sodium iodide were added to the solution. After 15 minutes, the homogeneous solution was heated to 65° C. and stirred for 24 hours. The yellow precipitate was filtered off with suction and washed with 2×500 ml of petroleum ether. The filter cake was dried at 60° C. under reduced pressure. 530 g (85% of theory) of pale-yellow powder were isolated.