Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][N:3]=1.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>C(OCC)(=O)C.O>[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=3)=[CH:4][N:3]=2)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)nc1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(-c2ccc(OCc3ccccc3)cc2)nc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
Palladium chloride (dppf) methylene chloride complex (0.193 g) was added to a mixture of 2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (1.0 g), (4-benzyloxyphenyl)boronic acid (1.08 g), 2M aqueous sodium carbonate solution (4.74 mL) and N,N-dimethylformamide (18.9 mL) under nitrogen atmosphere, and the mixture was stirred at 65° C. under nitrogen atmosphere overnight. To the mixture were added water and ethyl acetate, and then, insoluble material was removed by filtration using Celite. The organic layer was separated, washed with saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=88:12 to 80:20) to obtain 2-[4-(benzyloxy)phenyl]-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (1.038 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[CH:15]1(B(O)O)[CH2:17][CH2:16]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C1(C)C=CC=CC=1.O>[CH:15]1([C:2]2[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)C(=O)Nc1cccc(Br)n1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1cccc(C2CC2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 235.8 %

Procedure:
A mixture of N-(6-bromopyridin-2-yl)pivalamide (2 g, 7.77 mmol), cyclopropylboronic acid (935 mg, 10.88 mmol), potassium phosphate (toluene/water (10/3 mL) taken in screw cap tube was purged with argon for 15 minutes and then added palladium(II)acetate (174 mg, 0.77 mmol), tricyclohexylphosphine (435.7 mg, 1.55 mmol) sequentially, purged argon for another 5 min. The resultant mixture was stirred at 100° C. under closed argon atmosphere. Reaction completed in 14 h, reaction mass was cooled to room temperature, extracted into ethyl acetate, (100 ml) organic portion was washed with water, dried over sodium sulfate and concentrated to afford 4 g of the titled compound. LCMS: m/z=219.0 (M+1).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[O:14]=[CH:15][CH2:16][C@H:17]1[O:22][C:21]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:20][C@@H:19]([CH2:28][C:29]#[N:30])[CH2:18]1.C(OCC)C>CC(C)=O>[C:29]([CH2:28][C@H:19]1[O:20][C:21]2([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[O:22][C@@H:17]([CH2:16][C:15]([OH:3])=[O:14])[CH2:18]1)#[N:30]
Reactant: N#CC[C@H]1C[C@@H](CC=O)OC2(CCCCC2)O1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: N#CC[C@@H]1C[C@H](CC(=O)O)OC2(CCCCC2)O1
Reaction time: 0.25 h

Procedure:
Jones reagent (chromium trioxide-sulfuric acid-water), 4.4 mL (8.85 mmol), is added dropwise to a 0° C. solution of (±)-cis-4-(2-oxoethyl)-1,5-dioxaspiro[5.5]undecane-2-acetonitrile, 3.62 g (12.6 mmol), dissolved in 30 mL of acetone until the orange color is not discharged. After stirring a further 15 minutes, the mixture is poured into 300 mL of diethyl ether and washed with brine until the aqueous washes are colorless. The diethyl ether layer is dried (magnesium sulfate), filtered, and concentrated to provide 3.65 g of (±)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:35]([S:38](Cl)(=[O:40])=[O:39])[CH2:36][CH3:37]>C(#N)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][S:38]([CH2:35][CH2:36][CH3:37])(=[O:40])=[O:39])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of (1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-amine (1a, 18 mg, 50 μmol) in acetonitrile (1 ml) was added triethylamine (100 μl), followed by propane-1-sulfonyl chloride (21 mg, 150 μmol). Stirring was continued overnight. The mixture was then diluted with water (300 μl), and the title compound isolated by preparative HPLC to afford 23 mg (83%) as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[SH:13])([O-])=O.[NH2:14][C:15](N)=S>CN(C)C=O.O>[NH2:14][C:15]1[S:13][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N:1]=1
Reactant: O=[N+]([O-])c1ccc(S)c([N+](=O)[O-])c1
Reactant: NC(N)=S
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2cc([N+](=O)[O-])ccc2s1

Procedure:
A solution of 10 g of 2,4-dinitrothiophenol and 7.6 g of thiourea in 50 ml of dimethylformamide is heated at 120° C. for 3 hours. The mixture is diluted with 300 ml of water, and the solid is filtered off with suction and washed with water. 7.3 g of crude 2-amino-5-nitrobenzothiazole, the identity of which was confirmed by TLC comparison with authentic material, are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:16](Br)([CH3:18])[CH3:17]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)Br
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1C(C)C

Procedure:
The title compound, MS: m/e=260.6 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and isopropylbromide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[C:12]([NH2:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:24]#[C:25]Br.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)[C:25]([NH2:24])=[N:23][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: Nc1ccc(OCc2ccccc2)nc1Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nc2ccc(OCc3ccccc3)nc2n1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 6-(benzyloxy)-N2-(4-bromophenyl)pyridine-2,3-diamine (3.86 g, 10.4 mmol) in H2O was added cyanogen bromide (1.44 g, 13.5 mmol) and TFA (200 μL). The reaction mixture was stirred at room temperature for 2.5 h, added 2 M aqueous Na2CO3 and extracted with DCM. The organic extract was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography to give 5-(benzyloxy)-3-(4-bromophenyl)-3H-imidazo[4,5-b]pyridin-2-amine intermediate. The benzyl group was removed in a similar manner as the one described in Example 1.102 to give the title compound. LCMS m/z=305.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.22 (broad s, 2H), 6.29 (d, J=8.2 Hz, 1H), 7.39-7.46 (m, 3H), 7.77 (m, 2H), 9.96 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[OH:16].[Cl-].[NH4+]>C1COCC1.O.C(=O)([O-])[O-].[Na+].[Na+].[Fe]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:17])=[C:8]([OH:16])[CH:9]=1
Reactant: CN(C)CCCOc1ccc([N+](=O)[O-])cc1O
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc(N)cc1O
Yield: 24 %

Procedure:
2-(3-(Dimethylamino)propoxy)-5-nitrophenol (220 mg 0.92 mmol), ammonium chloride (232 mg, 4.34 mmol) and powdered iron (242 mg, 4.33 mmol) were suspended in THF (5 ml) and water (10 ml) and the mixture was stirred at 70° C. overnight. The reaction mixture was diluted with water, neutralised to pH=6 with sodium carbonate and extracted with ethyl acetate (×3). The organic phase was washed successively with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 75 mg (24% yield, 61% purity) of the title compound were obtained and used in the next synthetic step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)[CH3:2].[OH:21][C:22]1[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:23]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:36][C:34]2[CH:33]=[CH:32][C:23]([C:24](=[O:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:22]([OH:21])[CH:35]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Product: CCOC(=O)C(Cc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)c(O)c2)cc1)OC

Procedure:
A mixture of (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Step A and 2,4-dihydroxybenzophenone were allowed to react under the Standard Procedure I to get to title compound.
Reaction SMILES: N1C=CN=C1.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21])=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1H-imidazole (1.06 g, 15.6 mmol) and 2-(4-bromophenyl)ethanol (2.19 g, 10.9 mmol) in THF (20 mL) at room temperature was added tert-butylchlorodimethylsilane (1.81 g, 12.0 mmol). The reaction mixture was stirred at room temperature for 2 h and diluted with hexanes. The organic phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated to give (4-bromophenethoxy)(tert-butyl)dimethylsilane 65 which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[C:17]=2[O:24]C)[CH:5]=[CH:4][C:3]=1[C:26](=[O:28])[CH3:27].B(Br)(Br)Br>C(Cl)Cl>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:17]=2[OH:24])[CH:5]=[CH:4][C:3]=1[C:26](=[O:28])[CH3:27]
Reactant: CCCc1c(OCCCCc2cccc(OC)c2OC)ccc(C(C)=O)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCc1c(OCCCCc2cccc(O)c2O)ccc(C(C)=O)c1O
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To 5.02 g of 1-[2-hydroxy-4-[4-(2,3-dimethoxyphenyl)butoxy]-3-propylphenyl]ethanone in 300 mL of methylene chloride stirred and cooled at -70° was added 39 mL of 1M boron tribromide in methylene chloride. The reaction mixture was stirred at -70° for 30 minutes and kept at -20° for 5.5 hours. Workup as in Example 32 and recrystallization from acetone-hexane gave 3.81 g (82% yield), mp 103°-105° of 1-[2-hydroxy-4-[4-(2,3-dihydroxyphenyl)butoxy]-3-propylphenyl]ethanone.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:18]([C:26]3([C:29]([O:31]C)=[O:30])[CH2:28][CH2:27]3)[O:17][N:16]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[OH-].[Na+]>O1CCCC1.O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:18]([C:26]3([C:29]([OH:31])=[O:30])[CH2:28][CH2:27]3)[O:17][N:16]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)C1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(c2onc(-c3ccc(O)cc3)c2-c2ccccc2)CC1
Temperature: 60 °C
Yield: 78.9 %

Procedure:
To a solution consisting of 1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropanecarboxylic acid methyl ester (Example 1, Compound D, 10 g) in tetrahydrofuran (100 mL) is added a 50 wt % sodium hydroxide in water solution (10 mL). The mixture is heated to 60° C. for 18 hours. The reaction mixture is concentrated under reduced pressure and partitioned between diethyl ether and water. The aqueous layer is washed with diethyl ether and acidified to pH 5 with concentrated aqueous hydrochloric acid. The aqueous phase is extracted with ethyl acetate. The combined extracts are washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the title compound (5.64 g); MS (APCI+) m/z 322 (MH+.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH2:18][C:19]([NH:21][CH3:22])=O)=[CH:10][N:11]2[CH3:17].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Al+3].[Cl-].[Cl-].[Cl-].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH2:18][CH2:19][NH:21][CH3:22])=[CH:10][N:11]2[CH3:17]
Reactant: CNC(=O)Cc1cn(C)c2ccc(F)c(OCc3cccc(Cl)c3)c12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CNCCc1cn(C)c2ccc(F)c(OCc3cccc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
A solution of 33-7 (50 mg, 0.139 mmol) in THF (10 mL) was added dropwise into the solution of lithium aluminum hydride (19 mg, 0.417 mmol) and AlCl3 (41 mg, 0.381 mmol) in THF (10 mL). The mixture was stirred at room temperature for 1 h. Na2SO4.10 H2O was added to quench the reaction. The solid was filtered off and washed with ethyl acetate (20 mL). The organic solvent was washed with brine (3×30 mL), dried over MgSO4, filtered and evaporated. The resulting residue was purified by preparative HPLC (acid condition, water/CH3CN, 30-35% CH3CN in 7.5 min, RT=6.5 min) to give 33-8 (11 mg, 23%) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.80-8.60 (brs, 1H), 7.47 (s, 1H), 7.34 (s, 2H), 7.28 (s, 1H), 7.02-6.99 (m, 1H), 6.92-6.89 (m, 2H), 5.25 (s, 2H), 3.66 (s, 3H), 3.13-3.05 (m, 4H), 2.45 (s, 3H). LRMS: calc and found: 347.1 [M+1].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][CH2:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:35][S:36]([CH2:39][C:40](O)=[O:41])(=[O:38])=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][CH2:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[C:40](=[O:41])[CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNCc1ccc(CC(=O)OC)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1ccc(CC(=O)OC)cc1)C(=O)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
To a solution of the product from example 1 (221 mg) in DCM (10 mL) was added 2-(methylsulfonyl)acetic acid (66.4 mg) followed by TEA (0.201 mL) and HATU (201 mg). The reaction mixture was stirred at rt for 16 h then the solvents were evaporated. The crude product was purified by RPHPLC to afford the title compound (120 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH3:16])[O:8][C:6]=2[CH:7]=1.[OH:17][CH2:18][C@@H:19]([N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34])[CH2:20][CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:22][CH:21]([CH3:23])[CH2:20][C@H:19]([N:24]1[C:25](=[O:34])[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]1=[O:33])[CH2:18][O:17][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH3:16])[O:8][C:6]=2[CH:7]=1
Reactant: CC(C)C[C@@H](CO)N1C(=O)c2ccccc2C1=O
Reactant: CC1Oc2cc(Br)ccc2-c2ccncc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](COc1ccc2c(c1)OC(C)c1cnccc1-2)N1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 64 %

Procedure:
To a stirred solution of 8-bromo-5-methyl-5H-chromeno[3,4-c]pyridine (200 mg, 0.724 mmol) in toluene (4 mL), were added (S)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (537 mg, 2.173 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1′,1′-biphenyl]-2-yl)phosphine (185 mg, 0.435 mmol), cesium carbonate (354 mg, 1.086 mmol) and palladium (II) acetate (48.8 mg, 0.217 mmol). Nitrogen was bubbled through the reaction mixture for 10 min and the mixture was heated at 80° C. 12 h. The reaction mixture was cooled to room temperature and filtered through celite and residue rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified via prep TLC (60% ethyl acetate in pet ether) to afford 2-((2S)-4-methyl-1-(5-methyl-5H-chromeno[3,4-c]pyridin-8-yloxy)pentan-2-yl)isoindoline-1,3-dione (205 mg, 0.463 mmol, 64% yield). LCMS (ESI) m/e 443.2 [(M+H)+, calcd for C27H27N2O4 443.2]; LC/MS retention time (Method C): tR=2.27 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[N:15]1([CH2:21][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CN(C)C(=O)C.O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:29][CH:28]=1)=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S([O-])O
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1
Temperature: 150 °C

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (150 mg, 0.76 mmol) and 4-morpholin-4-ylmethyl benzaldehyde (156 mg, 0.76 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (150 mg, 0.84 mmol) and p-TSA (174 mg, 0.91 mmol) were added and the reaction mixture was heated at 150° C. for 5 h. The reaction mixture was cooled to room temperature, water was added and the mixture was neutralized with NaHCO3. The solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography to give 5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one, which was converted to the hydrochloride salt (165 mg, 51%). Selected data: MS (ES) m/z: 382.07; MP 206-208° C. (at decomposition).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:33](=[O:34])[N:6]2[C:7]([C:20]([O:22]CC3C=CC([N+]([O-])=O)=CC=3)=[O:21])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[C:12]=3[CH3:19])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].P([O-])([O-])([O-])=O.C(NCC1N=CN2C(C3C[C@@H]4[C@@H]([C@H](O)C)C(=O)N4C=3C([O-])=O)=CSC=12)=O.[Na+]>C1COCC1.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:33](=[O:34])[N:6]2[C:7]([C:20]([OH:22])=[O:21])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[C:12]=3[CH3:19])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: Cc1c(C2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)sc2cncn12
Agent: [Pd]
Agent: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3csc4c(CNC=O)ncn34)C[C@H]12
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: Cc1c(C2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)sc2cncn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To a solution of 157.3 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate in 3 ml of THF and 3 ml of {fraction (1/15)} M phosphate buffer (pH 6.8) was added 0.24 g of 100 Pd-C. The reactor was purged with hydrogen, the reaction mixture was stirred at room temperature for 1 hour. The catalyst was collected by filtration, and washed with 50 ml of water. The filtrate was diluted with 20 ml of ethyl acetate, separated, and the organic layer was further washed with water. The combined aqueous layer was concentrated under reduced pressure to a volume of about 30 ml. The residual concentrate was purified by column chromatography on DIAION HP-20. The fraction containing the aimed product was lyophilized to give 63.5 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O.O.NN>C1COCC1.C(O)C.[Ni]>[N:8]1([CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:16]=[CH:15][CH:14]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cccc(CN2CCOCC2)c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 117.3 %

Procedure:
To a solution of 4-(3-nitrobenzyl)morpholine (2.0 g; 9.0 mmol) in THF/ethanol mixture (1:1) (50 mL) was added a catalytical amount of Raney-Nickel and hydrazine hydrate (36.0 mmol) and the mixture was stirred at ambient temperature for 15 minutes, then filtered through a Celite-pad and the filtrate was evaporated to provide pure 3-(morpholin-4-yl)methylphenylamine (2.03 g, 98%), which was used in further reactions without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.I[CH2:10][CH2:11][OH:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:10][CH2:11][OH:12])[CH:7]=1
Reactant: OCCI
Reactant: O=c1ccc(Br)c[nH]1
Product: O=c1ccc(Br)cn1CCO

Procedure:
5-Bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one was prepared from 5-bromopyridin-2(1H)-one and 2-iodoethanol following a procedure analogous to that described in Example 20 Step 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]#[N:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1>[Fe]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([C:13]#[N:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1C#N
Agent: [Fe]
Product: COc1cc2c(Oc3ccc(N)cc3)ccnc2cc1C#N
Yield: 68.5 %

Procedure:
6-Methoxy-4-(4-nitrophenoxy)quinoline-7-carbonitrile (290 mg) was subjected to iron reduction by the same method as in Production Example 10 to obtain the title compound (180 mg).