Azzindani/Open_Reaction_Data huggingface dataset:
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]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)=[O:12].[H-].[Na+].[CH3:22]I>O1CCCC1>[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]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)=[O:12]
Reactant: CI
Reactant: COc1ccc(CC(=O)c2ccnc(Cl)c2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)C(=O)c2ccnc(Cl)c2)c(Cl)c1
Temperature: 45 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To a solution of 2-(2-chloro-4-methoxy-phenyl)-1-(2-chloro-pyridin-4-yl)-ethanone (17.1 g, 0.058 mol) in tetrahydrofuran (550 ml) was added sodium hydride (55%-65% dispersion in mineral oil, 2.43 g, 0.063 mol). The mixture was stirred at 45° C. for 3 h and then placed in an ice bath. A solution of methyl iodide (9.01 g, 0.0635 mol) in tetrahydrofuran (50 ml) was added dropwise. The ice bath was removed and the mixture was stirred at 35° C. for 3 h. The mixture was poured in ice water and extracted twice with AcOEt. The organic phases were washed with brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (silica gel, heptane/AcOEt 4:1) to give the title compound (14.7 g) as yellow viscous oil. MS (m/e, ISP neg. ion)=310.3 [M−H−].
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])=[CH:11][C:10]1=[O:22])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[Br:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:23])=[O:2])[C:10](=[O:22])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccccc2Br)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Br)=CC1=O
Temperature: 20 °C
Yield: 103.2 %

Procedure:
To a solution containing (S)-2-[4-(2-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (2.00 g, 0.005 mol) in tetrahydrofuran (40 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 21 mL, 0.011 mol). The mixture was stirred at 20° C. for 2H, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(2-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1.90 g, 99%) as a tan solid.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:25][O:26][CH2:27][C:28](O)=[O:29]>ClCCl>[C:3]1([CH2:2][CH2:1][NH:9][C:28](=[O:29])[CH2:27][O:26][CH3:25])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COCC(=O)O
Reactant: NCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COCC(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
Phenethylamine(11.6 ml, 92.1 mmol) was added dropwise to a solution of dicyclohexylcarbodiimide(19 g, 92.1 mmol), methoxyacetic acid(8.3 g, 92.1 mmol) in dichloromethane(50 ml) at room temperature. After addition was completed, the reaction mixture was stirred for 1 hour at room temperature and the resulting solid was filtered. The filtrate was washed with aqueous hydrochloric acid solution, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford 8.15 g of the titled compound.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)=O)(C)(C)C.[Cl:21][C:22]1[N:27]=[C:26](I)[C:25]([OH:29])=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.CCOC(C)=O.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>[Cl:21][C:22]1[N:27]=[C:26]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:25]([OH:29])=[CH:24][CH:23]=1
Reactant: Oc1ccc(Cl)nc1I
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2c(F)cccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 90 °C
Yield: 72026.3 %

Procedure:
To a solution of (1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid (126 g, 0.45 mol) and 6-chloro-2-iodopyridin-3-ol (96 g, 0.37 mmol) in 1,4-dioxane (1.8 L) and water (0.2 L) were added Pd(PPh3)2Cl2 (13.2 g, 18.6 mmol) and NaHCO3 (94.8 g, 1.13 mol) under nitrogen atmosphere, and the mixture was heated at 90° C. under N2 for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (900 mL), filtered and concentrated. The residue was diluted with H2O (400 mL) and EtOAc (800 mL), and the layer was separated, the aqueous layer was extracted with EtOAc (3*400 mL). The combined organic layers were washed with brine (800 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE:EtOAc=20:1˜3:1) to give 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol (70 g, yield: 70.1%). 1H-NMR (MeOD, 400 MHz) δ 7.36 (s, 1H), 7.23˜7.27 (m, 2H), 7.03˜7.11 (m, 2H), 6.63˜6.68 (m, 1H). MS (M+H)+: 263 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:19][NH2:20])=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[N:17][C:12]([CH3:11])=[N:13][CH:14]=1)[CH:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[O:6]
Reactant: Cc1ncc(C(CN)C2CCOCC2)cn1
Reactant: O=C(O)c1ccccc1Cl
Product: Cc1ncc(C(CNC(=O)c2ccccc2Cl)C2CCOCC2)cn1

Procedure:
From 2-chlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=360.1, tR (minutes, Method F)=1.97
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]([F:17])([F:16])[F:15])[CH2:12][N:11]2[N:18]=[C:19]([I:24])[C:20]([C:21](O)=[O:22])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:28](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:21]([C:20]1[C:19]([I:24])=[N:18][N:11]2[CH2:12][CH:13]([C:14]([F:17])([F:16])[F:15])[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][C:10]=12)(=[O:22])[NH2:28]
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(=O)O)c(I)nn2CC1C(F)(F)F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(I)nn2CC1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
To a solution of Intermediate 346E (0.12 g, 0.260 mmol) in DMF (1 mL) was added NH4Cl (0.028 g, 0.520 mmol), HATU (0.099 g, 0.260 mmol) and DIPEA (0.136 mL, 0.781 mmol) under nitrogen and the resulting solution was stirred at RT for 16 h. The reaction mixture was poured into water and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 3% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 346F as a white solid (0.07 g, 50%). MS(ES): m/z=460.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[CH:9][CH:8]=[C:7]([S:20]([N:23](CC1C=CC(OC)=CC=1)[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)(=[O:22])=[O:21])[CH:6]=2.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[CH:9][CH:8]=[C:7]([S:20]([NH:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)(=[O:21])=[O:22])[CH:6]=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4OC)c(Br)cnc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COc1ccccc1-c1c(Br)cnc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 3-bromo-N-(4-methoxybenzyl)-4-(2-methoxyphenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (from STEP 1 of EXAMPLE 324, 15 mg, 0.025 mmol) in DCM (1 mL) was treated with TFA (0.5 mL). After 30 min, the mixture was diluted with MeOH, and then concentrated in vacuo. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-5% MeOH/DCM) to give 3-bromo-4-(2-methoxyphenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (11.8 mg, 0.025 mmol, 99% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=13.12 (br. s., 1H), 9.06 (d, J=4.4 Hz, 1H), 8.44 (d, J=1.8 Hz, 1H), 7.85 (dd, J=1.9, 8.9 Hz, 1H), 7.69 (s, 1H), 7.62-7.48 (m, 3H), 7.34-7.22 (m, 2H), 7.14 (dt, J=0.7, 7.4 Hz, 1H), 3.67 (s, 3H). m/z (ESI) 476.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[N:12][C:11]([CH2:14]Br)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][S-:18].[Na+]>CC(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[N:12][C:11]([CH2:14][S:18][CH3:17])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CSCc1cnc(NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of (5-bromomethyl-pyrazin-2-yl)-carbamic acid tert-butyl ester (prepared according to WO 02/070494, 1.03 g, 3.575 mmol) in acetone (11.6 mL) was treated with sodium thiomethoxide (0.33 g, 4.473 mmol). The reaction mixture was stirred at 25° C. for 5 h 15 min. The reaction was then concentrated in vacuo, and the residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was back-extracted with ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 5% ethyl acetate/methylene chloride) afforded (5-methylsulfanylmethyl-pyrazin-2-yl)-carbamic acid tert-butyl ester as a crude white solid (0.45 g, 49%) which was used without further purification.
Reaction SMILES: [K].[C:2]1([CH2:8][C:9]([NH:11][C@@H:12]2[C:44](=[O:45])[N:14]3[C:15]([C:28]([O:30]C(C4C=CC=CC=4)C4C=CC=CC=4)=[S:29])=[C:16]([C:19]4[S:20][CH:21]=[C:22]([CH2:24][C:25]([OH:27])=[O:26])[N:23]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl>[C:2]1([CH2:8][C:9]([NH:11][C@@H:12]2[C:44](=[O:45])[N:14]3[C:15]([C:28]([OH:30])=[S:29])=[C:16]([C:19]4[S:20][CH:21]=[C:22]([CH2:24][C:25]([OH:27])=[O:26])[N:23]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1csc(C2=C(C(=S)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)n1
Agent: [K]
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1csc(C2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a mixture of benzhydryl 7β-(2-phenylacetamido)-3-(4-carboxymethylthiazol-2-yl)thio-3-cephem-4-carboxylate potassium salt (1.10 g), anisole (1.10 ml) and dichloromethane (3.30 ml) was added trifluoroacetic acid (2.20 ml) at 15° C. After stirring at room temperature for 1 hour, the solution was poured into diisopropyl ether. The resulting precipitate was collected by filtration, added to a mixture of tetrahydrofuran and water and adjusted to pH 7.2 with an aqueous sodium bicarbonate. The separated aqueous solution was adjusted to pH 3.0 with 1N-hydrochloric acid and extracted with tetrahydrofuran. The tetrahydrofuran solution was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. Ethyl acetate was added to the residue and the resulting crystal was collected by filtration to give 7β-(2-phenylacetamido)-3-(4-carboxymethylthiazol-2-yl)thio-3-cephem-4-carboxylic acid (595 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:11]=[C:6]2[C:7](=[O:8])[O:9][CH2:12][C:5]2=[N:4][CH:3]=1
Reactant: COC(=O)c1cc(Cl)c[n+]([O-])c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCc2ncc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.9 %

Procedure:
A mixture of crude methyl 5-chloro-2-methylnicotinate 1-oxide (Organic letters, 2001, J, 209, 2.29 mmol) and trifluoroacetic acid (453 μL, 3.21 mmol) in dichloromethane (20 mL) was stirred at room temperature for 2 days and heated at 45° C. for 1 hour. The mixture was partitioned between sat. aqueous sodium hydrogen carbonate (50 mL) and ethyl acetate (50 mL). The organic layer was washed with brine (50 mL), dried (sodium sulfate), and evaporated. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1/1) to afford 225 mg of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[C:27]1([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([N:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)N(c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 70.1 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (1.73 g, 0.0137 mole) was added dropwise, slowly, to a stirred and chilled (10° C.) solution of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.7 g, 0.013 mole) in anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 60° C. for 4 hr under nitrogen, cooled and added dropwise to a stirred and chilled (10° C.) solution of diphenylamine (2.37 g, 0.014 mole) and triethylamine (1.42 g, 0.014 mole) in anhydrous dimethylformamide (75 ml). The reaction mixture was stirred at room temperature overnight and then poured into water (400 ml). The mixture was extracted with ethyl acetate (2×75 ml). The aqueous layer was saturated with sodium chloride and extracted again with ethyl acetate (75 ml). The combined organic layers were washed with 5% potassium hydroxide solution (2×50 ml), water (50 ml) and saturated sodium chloride solution (50 ml). The combined layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4.0 g of an oil (70%). The oil was crystallized from isopropyl ether-isopropyl alcohol to give 2.2 g (39%) of a white solid, mp. 176°-178° C.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]#[C:14][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])([OH:9])[CH2:5][CH2:4]1.[NH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1I.C(=O)([O-])[O-].[Na+].[Na+]>O=O.C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-2](Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:28][N:2]([CH3:1])[C:3]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]2[C:31]3[CH:32]=[N:33][CH:34]=[CH:35][C:30]=3[NH:29][C:14]=2[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])([OH:9])[CH2:5][CH2:4]1
Reactant: Nc1ccncc1I
Reactant: CC[Si](C#CCCCC1(O)CCC(c2ccccc2)(N(C)C)CC1)(CC)CC
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-2](Cl)c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: O=O
Product: CC[Si](CC)(CC)c1[nH]c2ccncc2c1CCCC1(O)CCC(c2ccccc2)(N(C)C)CC1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A suspension of 4-dimethylamino-4-phenyl-1-(5-triethylsilanyl-pent-4-inyl)cyclohexanol (741 mg, 1.85 mmol), 4-amino-3-iodopyridine (488 mg, 2.22 mmol), [1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)palladium(II)-chloride (PEPPSI, 251 mg, 0.37 mmol) and sodium carbonate (980 mg, 9.25 mmol) in oxygen-free N,N-dimethylformamide (10 mL) was stirred for 20 h at 100° C. The reaction mixture was then concentrated to low volume in a vacuum, the residue repeatedly taken up in toluol (10 mL) and each time concentrated to low volume again in a vacuum, this residue was taken up in ethyl acetate (30 mL) and water (30 mL) and the organic phase washed with water (2×15 mL) and sodium thiosulphate solution (2×25 mL), dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product was purified by means of flash chromatography (38 g, 20×2.5 cm) with ethyl acetate/methanol (4:1).
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:6])[CH2:3][OH:4].[F:12][C:13]1[N:18]=[C:17](F)[C:16]([F:20])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:8]([O:7][C@@H:5]([CH3:6])[C@H:2]([NH:1][C:15]1[C:16]([F:20])=[CH:17][N:18]=[C:13]([F:12])[N:14]=1)[CH2:3][OH:4])([CH3:10])([CH3:9])[CH3:11]
Reactant: Fc1ncc(F)c(F)n1
Reactant: C[C@H](OC(C)(C)C)[C@H](N)CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](OC(C)(C)C)[C@@H](CO)Nc1nc(F)ncc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a round bottom flask containing (2R,3S)-2-amino-3-(tert-butoxy)butan-1-ol (1.25 g, 7.75 mmol) and a stir bar was added acetonitrile (50 mL) followed by the addition of 2,4,5-trifluoropyrimidine (1.04 g, 7.75 mmol) and DIEA (4.1 mL, 23.3 mmol). The resulting reaction mixture allowed to stir 1 hr at room temperature. The volatiles were then removed. Reaction mixture was then partitioned between EtOAc and water. Aqueous layer extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a viscous yellow oil of (2R,3S)-3-(tert-butoxy)-2-((2,5-difluoropyrimidin-4-yl)amino)butan-1-ol (1.56 g, 5.67 mmol, 73% yield). 1H NMR (400 MHz, CDCl3) δ 1.15 (s, 9H) 1.32 (d, J=6.26 Hz, 3H) 3.45 (br. s., 1H) 3.67 (d, J=11.35 Hz, 1H) 3.85-3.92 (m, 1H) 4.27 (d, J=11.74 Hz, 1H) 6.29 (d, J=5.48 Hz, 1H) 7.87 (d, J=2.35 Hz, 1H). LCMS m/z 276.4 (M+H)+, Rt 0.71 min.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.I[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([C:28]2[CH:37]=[C:36]([CH3:38])[C:31]3[O:32][CH2:33][CH2:34][O:35][C:30]=3[CH:29]=2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:38][C:36]1[C:31]2[O:32][CH2:33][CH2:34][O:35][C:30]=2[CH:29]=[C:28]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:21]=2)=[O:27])[CH:37]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(I)ncn2)cc2c1OCCO2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64 mg (0.22 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 84 mg (0.22 mmol) (6-iodo-pyrimidin-4-yl)-(8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone and 0.15 mL (0.88 mmol) DIPEA were combined in 2.5 mL DMF and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was mixed with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C[O:11][C:12]1[CH:17]=CC=C[C:13]=1C=CC(=O)C>>[C:2]1([CH3:1])[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:12](=[O:11])[CH3:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: COc1ccccc1C=CC(C)=O
Product: CC(=O)C=Cc1ccc(C)cc1

Procedure:
The title compound was prepared from 4-methyl-benzaldehyde (6.0 g, 50.0 mmol), following the procedure describing the synthesis of 4-(2-methoxy-phenyl)-but-3-en-2-one (example 1/a stage 1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN1CCCC1=O>[N:17]1([C:2]2[N:7]=[CH:6][C:5]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[N:9]=3)=[CH:4][CH:3]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: Clc1ccc(-c2nc3ccccc3[nH]2)cn1
Solvent: CN1CCCC1=O
Product: c1ccc2[nH]c(-c3ccc(N4CCNCC4)nc3)nc2c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of 2-(6-chloropyridin-3-yl)-1H-benzoimidazole (0.468 g, 2.040 mmol) and piperazine (0.516 g, 6.000 mmol) in 1-methyl-2-pyrrolidone was heated to 140° C. with stirring for 2 hours. The solvent was removed in vacuo. The residue was diluted with water (100 mL) and stirred for 15 minutes. A white precipitate was formed which was collected by filtration and dried to afford the title compound in 93% yield (0.529 g, 1.900 mmol).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:13])[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CNC
Product: CN(C)c1c([N+](=O)[O-])cnn1C
Yield: 100 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and dimethylamine gave N,N,1-trimethyl-4-nitro-1H-pyrazol-5-amine as a yellow solid (210 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 3.75 (s, 3H), 2.90 (s, 6H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH:6]([CH3:11])[CH2:7][CH2:8][C:9]#[N:10].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH:6]([CH3:11])[CH2:7][CH2:8][C:9]1[NH:17][N:16]=[N:15][N:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(CCC#N)Oc1cccc(O)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CCc1nnn[nH]1)Oc1cccc(O)c1

Procedure:
A mixture of 5.9 g of 4-(3-hydroxyphenoxy)valeronitrile, 6.13 g of sodium azide and 5.0 g of ammonium chloride is heated with 30 ml of dry dimethylformamide at 140° C. for 20 hours. The reaction mixture is poured into ice, basified with 1N sodium hyroxide and extracted 2 times with warm ethyl acetate. The aqueous fraction is acidified with acetic acid. The product is filtered and washed with water to give crude product. Crystallization from ethyl acetate gives pure product which is used directly in the next step.