Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C:9](=[O:11])[CH2:8][CH2:7]2.Br[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][C:23]=1[CH3:33]>>[CH3:28][C:27]1[CH:26]=[C:25]([Si:29]([CH3:30])([CH3:32])[CH3:31])[CH:24]=[C:23]([CH3:33])[C:22]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[O:11]
Reactant: Cc1cc([Si](C)(C)C)cc(C)c1Br
Reactant: CC1(C)OB(c2ccc(F)c3c2CCC3=O)OC1(C)C
Product: Cc1cc([Si](C)(C)C)cc(C)c1-c1ccc(F)c2c1CCC2=O

Procedure:
The title compound is prepared from 7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one and (4-bromo-3,5-dimethylphenyl)trimethylsilane following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.89 min; Mass spectrum (ESI+): m/z=327 [M+H]+.
Reaction SMILES: [C:1]([O:10]CC)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:14][C:15]([CH3:17])=[CH2:16].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CC(=O)CC.CCO>[CH3:16][C:15](=[CH2:14])[CH2:17][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: CCOC(=O)c1ccccc1O
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCO
Product: C=C(C)COc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
Under N2, the mixture of ethyl salicylate (4.99 g, 4.40 ml, 30.0 mmol), 3-Bromo-2-methyl-propene (8.10 g, 6.1 ml, 60.00 mmol) and potassium carbonate (5.53 g, 40.0 mmol) in dry 2-Butanone (120 ml) was heated to reflux for 48 h. After the reaction mixture cooled down to 25° C., the suspended inorganic salt was removed by filtration. The concentration of the resulting solution by rotary evaporation yielded pale yellowish syrup, which was then mixed with 2N NaOH (23 ml, 46 mmol) and EtOH (30 ml). After this mixture was stirred for 2 h at 50° C., ethanol was removed at reduced pressure. After the aqueous solution was acidified by 6N HCl to pH 2 at 5° C., the mixture was extracted with Et2O (50 ml×3). The organic phase was combined and washed with water (10 ml×2) respectively. The ether extract was dried with anhydrous sodium sulfate and then concentrated to give 2-(2-Methyl-allyloxy)-benzoic acid as oil (5.26 g, 27.36 mmol). The title compound was then treated with of 1M sodium trimethylsilanolate (24.5 ml, 24.5 mmol) to give sodium 2-(2-methyl-allyloxy)-benzoate (4.18 g) as white powder. 1H-NMR (400 MHz, D2O): 7.36 (m, 2 arom. H); 7.04 (m, 2 arom. H); 5.09, 5.01 (2 d-like, C(CH3)═CH2); 4.57 (d-like, CH2—C(CH3)═CH2); 1.80 C(CH3)═CH2). 13C-NMR (100 MHz, D2O): 176.51 (C═O); 154.32; 141.73; 129.94; 129.76; 127.84; 121.03; 113.98; 112.19; 72.09; 18.57.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([N:6]3[CH2:5][CH:4]([CH2:3][O:2][CH3:1])[O:8][C:7]3=[O:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COCC1CN(c2ccc(C3CCNCC3)cc2)C(=O)O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC1CN(c2ccc(C3CCN(Cc4ccccc4)CC3)cc2)C(=O)O1
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
290.4 mg (1.0 mmol) of (RS)-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-piperidine were dissolved in 5 ml of abs. dimethylformamide and treated with 171.0 mg(1.0 mmol) of benzyl bromide in the presence of 404.8 mg (4.0 mmol) of triethylamine. The reaction mixture was stirred at 600 for 90 minutes. Thereafter, it was evaporated, the residue was partitioned in ethyl acetate and 3N ammonia solution and the organic phase was washed with water, dried over sodium sulfate, filtered and evaporated. The base was dissolved in ethanol, made acid with ethereal hydrochloric acid and distilled repeatedly with toluene. After recrystallization from ethanol/ether there were obtained 291.2 mg of (RS)-1-benzyl-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-piperidine.HCl. M.p.: 175°-177°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([Cl:9])=[C:6](Cl)[N:7]=1.[NH2:14][NH2:15].CO.C(Cl)Cl>C(O)(C)(C)C.CN(C=O)C>[CH3:13][O:12][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH:14][NH2:15])=[C:5]([Cl:9])[N:4]=1)=[O:11]
Reactant: COC(=O)c1nc(Cl)c(Cl)nc1N
Reactant: NN
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Cl)c(NN)nc1N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methyl 3-amino-5,6-dichloro-2-pyrazinecarboxylate (1.10 g, 5 mmol) was dissolved in 20 mL of tert-butyl alcohol and DMF (v/v; 1:1). Anhydrous hydrazine (0.18 mL, 5.5 mmol) and N,N'-diisopropylethyl amine (4.5 mL, 25 mmol) were then added sequentially at 25° C. The resulting mixture was stirred at 25° C. for 12 h. The reaction mixture was then partitioned between EtOAc (100 mL) and sat. NaCl (aq) (100 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to give a brown solid residue. This residue was used in the next-step reaction without further purification: TLC (Rf =0.53; 10% MeOH/CH2Cl2).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4]([OH:6])=[O:5].[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[F:12][C:7]1[C:8]([N+:13]([O-:15])=[O:14])=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(F)ccc(F)c1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1c(F)c(F)cc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
2,3,6-Trifluorobenzoic acid (21.0 g) is added to conc. sulfuric acid (120 ml) under ice-cooling. To the mixture is added dropwise a solution of potassium nitrate (14.5 g) in conc sulfuric acid (30 ml) at below 20° C. After the addition, the mixture is stirred at room temperature for one hour. The reaction mixture is poured into ice water and extracted with diethyl ether. The extract is dried over magnesium sulfate, and then the solvent is distilled off. The residue is recrystallized from dichloromethane-n-hexane to give 2,5,6-trifluoro-3-nitrobenzoic acid (22 g), as colorless prisms, m.p. 98°-99° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:10]2[CH:9]=[C:8]3[N:11]=[C:12]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:23][C:24](=[O:27])[CH2:25][CH3:26])[C:3]1=[O:28].[BH4-].[Na+].Cl>C(Cl)Cl.CO>[OH:27][CH:24]([CH2:25][CH3:26])[CH2:23][N:4]1[C:5]2[CH:6]=[C:7]3[NH:13][C:12]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:11][C:8]3=[CH:9][C:10]=2[C:2]([CH3:1])([CH3:29])[C:3]1=[O:28]
Reactant: CCC(=O)CN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4ccccc4)[nH]c3cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCC(O)CN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4ccccc4)[nH]c3cc21
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To a cooled solution (0° C.) of N-[7,7-dimethyl-6-oxo-5-(2-oxo-butyl)-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl]-benzamide (150 mg) in CH2Cl2 (3.5 ml) and MeOH (1.5 ml) is added NaBH4 (29.1 mg; 0.77 mmol). The mixture is stirred and warmed to RT overnight. After completion hydrochloric acid (5 ml; 1 N) is added and the mixture extracted with EtOAc. The organic phase is washed with brine, dried over MgSO4 and evaporated to dryness to give N-[5-(2-hydroxy-butyl)-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl]-benzamide (67 mg) as a racemic mixture.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[CH:26]([C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1)=[O:27]>C(Cl)Cl.CO>[CH3:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]#[C:8][C:5]3[N:6]=[CH:7][C:2]([C:31]4[CH:32]=[CH:33][C:28]([CH:26]=[O:27])=[CH:29][CH:30]=4)=[CH:3][CH:4]=3)=[CH:11][CH:12]=2)[CH2:20][CH2:21]1
Reactant: O=Cc1ccc(OB(O)O)cc1
Reactant: CC1CCN(CCOc2ccc(C#Cc3ccc(Br)cn3)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CC1CCN(CCOc2ccc(C#Cc3ccc(-c4ccc(C=O)cc4)cn3)cc2)CC1

Procedure:
The product was obtained analogously to Example 1.1e starting from 5-bromo-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridine and 4-formylphenylboric acid. Yield: 0.20 g (47% of theoretical); C28H28N2O2 (M=424.534); calc.: molpeak (M+H)+425; found: molpeak (M+H)+: 425; Rf value: 0.40 (silica gel, DCM/MeOH 9:1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]2([N:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.O1CCC2(CC3C(=CC=CC=3)C=N2)CC1>>[O:1]1[CH2:6][CH2:5][C:4]2([NH:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: C1=NC2(CCOCC2)CCc2ccccc21
Agent: C1=NC2(CCOCC2)Cc2ccccc21
Product: c1ccc2c(c1)CCC1(CCOCC1)NC2

Procedure:
Imine 22 (0.430 g, 2.00 mmol) from the previous reaction is reduced according to general procedure D. The product is isolated after an acid/base work-up as described above for the reduction of 21. The resulting white crystals, mp 76-78° C., weigh 0.427 g (98%). 1H NMR(CDCl3) 7.20-7.05(m,4), 3.89(s,2), 3.88-3.75(m,2), 3.70-3.60(m,2), 2.90-2.80(m,2), 1.80-1.55(m,6), 1.23(br s,1); 13C NMR(CDCl3) 142.69, 141.94, 129.21, 127.88, 126.85, 126.00, 63.35, 52.14, 46.70, 40.44, 36.92, 29.34; MS (MW=217.3, CI/CH4, eE=120eV) m/z 218[(M+H)+, base peak], 216, 201, 183, 157, 118, 91.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([O:15]CC)=[O:14])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]([OH:15])=[O:14])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(-c2ccc(C)cc2)cs1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2csc(C(=O)O)n2)cc1
Yield: 71.6 %

Procedure:
To a solution of ethyl 4-(4-methylphenyl)-2-thiazolecarboxylate (300 mg, 1.21 mmol) dissolved in methanol (10 ml) was added 1N-KOH (3.63 ml, 3.63 mmol) and the mixture was allowed to react at 60° C. for 15 minutes. After the solvent was distilled off from the reaction mixture, the residue was dissolved by adding water and acidified (pH=2) with 2N-HCl under ice-cooling. The produced precipitates were filtered with suction, washed with water and recrystallized from methanol-water to afford 190 mg (yield 72%) of the desired 4-(4-methylphenyl)-2-thiazolecarboxylic acid as white solids, m.p. 112°-114° C.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=2[F:24])[CH:8]=1.[CH3:26][N:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28](=[O:33])[CH2:29][C:30](O)=[O:31].C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:30](=[O:31])[CH2:29][C:28]([N:27]([CH3:26])[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:33])=[CH:19][C:18]=2[F:24])[CH:8]=1
Reactant: CN(C)CC/C=C\c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: CN(C(=O)CC(=O)O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)CC/C=C\c1cc2nccc(Oc3ccc(NC(=O)CC(=O)N(C)c4ccccc4)cc3F)c2s1
Reaction time: 6 h
Yield: 34.2 %

Procedure:
A solution of (Z)-4-(2-(4-(dimethylamino)but-1-enyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (235) (69.1 mg, 0.193 mmol), 3-(methyl(phenyl)amino)-3-oxopropanoic acid 31 (46 mg, 0.26 mmol) (scheme 10), and EDC (45 mg, 0.24 mmol) in DMF (2.8 mL) was stirred overnight at room temperature. More 31 (45 mg, 0.26 mmol) and EDC (45 mg, 0.24 mmol) were added and the mixture stirred 6 h more. The mixture was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was redissolved in MeOH and purified twice by preparative HPLC (gradient 40% to 95% MeOH in water, 45 min) giving title compound 231 (35 mg, 0.066 mmol, 34% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.32 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 7.80 (d, J=12.7 Hz, 1H), 7.54 (s, 1H), 7.5-7.3 (m, 7H), 6.78 (d, J=12.2 Hz, 1H), 6.62 (d, J=5.5 Hz, 1H), 5.92 (tt, J=7.2 Hz, J=4.5 Hz, 11.7 Hz, 1H), 3.21 (s, 5H), 2.59 (m, 2H), 2.42 (dd, 6.8 Hz, 7.4 Hz, 2H), 2.16 (s, 6H). MS (m/z): (M+1) 533.1 (100 N.
Reaction SMILES: [Cl-:1].[CH2:2]1[C:10]2[N+:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=O)=[CH:13]1.N1CCCC1>C(O)(C)C>[Cl-:1].[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=[C:2]2[C:10]3[N+:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[CH:13]1
Reactant: c1cc[n+]2c(c1)CCC2
Reactant: Cn1cc(C=O)c2ccccc21
Agent: [Cl-]
Solvent: CC(C)O
Solvent: C1CCNC1
Product: Cn1cc(C=C2CC[n+]3ccccc32)c2ccccc21
Temperature: 80 °C

Procedure:
1.55 g of 2,3-dihydro-1H-indolizinium chloride and 1.59 g of 1-methylindole-3-carboxaldehyde were suspended in 15 ml of isopropanol, in a 50 ml three-necked flask. The reaction mixture was heated at 80° C. and then 820 μl of pyrrolidine were introduced. The reaction mixture was immediately cooled to ambient temperature. The precipitate was filtered off, and washed with 2 times 30 ml of isopropanol before being dried under a strong vacuum in the presence of P2O5, until a constant weight was obtained. 2.59 g of orange powder were recovered. The analyses (NMR) (d6-DMSO) and mass spectrometry ESI+M/Z=261) were in conformity with the expected structure.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1)[OH:4].C(N(CC)CC)C.[OH2:26].Cl>CS(C)=O>[F:18][C:2]([F:1])([F:17])[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1)([OH:26])[OH:4]
Reactant: O=c1nc(-c2cc(C(O)C(F)(F)F)ccn2)[nH]o1
Reactant: O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cc(C(O)(O)C(F)(F)F)ccn2)[nH]o1
Reaction time: 8 h

Procedure:
To 2 ml of dimethyl sulfoxide were added 0.3 g of 3-[4-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl]-1,2,4-oxadiazol-5-one and 0.48 ml of triethylamine, and 1 ml of a solution of 0.55 g of sulfur-trioxide-pyridine complex in dimethyl sulfoxide was added dropwise. After stirring for 8 hours, 0.17 g of sulfur-trioxide-pyridine complex was added, and the mixture was further stirred for 7 hours. To the reaction solution were added water and 10% HCl, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.18 g of 3-{4-[2,2,2-trifluoro-1,1-dihydroxyethyl]pyridin-2-yl}-1,2,4-oxadiazol-5-one (present compound (58)).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccco1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccco2)C1
Yield: 78.6 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-furanboronic acid (102 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (150 mg, 78.5%) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]2[O:7][C:8]([CH3:19])([CH3:18])[C@@H:9]([OH:17])[C@H:10]([NH:11][C:12](=[N:14][C:15]#[N:16])[CH3:13])[C:5]=2[CH:4]=1)#[N:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[C:1]([C:3]1[CH:21]=[CH:20][C:6]2[O:7][C:8]([CH3:18])([CH3:19])[C@@H:9]([O:17][S:23]([CH3:22])(=[O:25])=[O:24])[C@H:10]([NH:11][C:12](=[N:14][C:15]#[N:16])[CH3:13])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Solvent: c1ccncc1
Product: CC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1OS(C)(=O)=O
Temperature: 0 °C

Procedure:
17.25 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-[(N-cyano-acetimidoyl)amino]-2H-benzo[b]pyran-3-ol was dissolved in 130 ml of pyridine, and 9.0 of methanesulfonyl chloride was added under stirring and cooling with ice. The mixture was reacted for 4 hours. The reaction mixture was poured into ice water, whereby a solid precipitated. This solid was collected by filtration and recrystallized from ethanol to obtain 28.5 g of 6-cyano-3,4-dihydro-3-methanesulfonyloxy-2,2-dimethyl-trans-4-[(N-cyano-acetimidoyl)amino]-2H-benzo[b]pyran in the form of crystals.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:8]1[C:9](O)=[C:10]([N+:15]([O-:17])=[O:16])[C:11](=[O:14])[NH:12][CH:13]=1)[CH3:7]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Cl:3][C:9]1[C:8]([CH2:6][CH3:7])=[CH:13][NH:12][C:11](=[O:14])[C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1c[nH]c(=O)c([N+](=O)[O-])c1O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: CCc1c[nH]c(=O)c([N+](=O)[O-])c1Cl
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
Phosphorus oxychloride (6.7 ml, 39.1 mmoles) was added to a solution of compound 5b (3.00 g, 16.3 mmoles) and benzyltriethylammonium chloride (14.90 g, 65.2 mmoles) in acetonitrile (60 ml). The mixture obtained was agitated at 40° C. for 30 minutes and heated under reflux for 1 hour. After evaporation of the solvent, 60 ml of water was added and the mixture agitated at ambient temperature for 3 hours. The yellow precipitate was collected, washed with cyclohexane (3×6 ml) and dried to give compound 6b (2.4 g, 74%) in the form of pale yellow crystals: NMR-1H (DMSO-d6) δ 13.19 (1H, s, NH-1), 7.73 (1H, s, H-6), 2.56 (2H, q, L=7.5 Hz, CH2CH3), 1.16 (3H, t, J=7.5 Hz, CH2CH3 ).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=1[F:22])([CH3:14])[CH3:13])[CH2:2]2.[CH3:24][CH:25]([CH3:30])[CH2:26]B(O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:22][C:16]1[CH:17]=[CH:18][C:19]([CH2:24][CH:25]([CH3:30])[CH3:26])=[CH:20][C:15]=1[C:12]([NH:11][C:10](=[O:23])[O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)([CH3:14])[CH3:13]
Reactant: CC(C)CB(O)O
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cc(Br)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)Cc1ccc(F)c(C(C)(C)NC(=O)OC2CN3CCC2CC3)c1
Yield: 32.7 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(5-bromo-2-fluorophenyl)propan-2-yl]carbamate (120 mg, 0.312 mmol), 2-methylpropylboronic acid (79.4 mg, 0.779 mmol) and palladium (II) acetate gave the title as a white solid compound (37 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 7.08 (dd, J=2.0, 8.2 Hz, 1H), 6.95 (d, J=4.9 Hz, 1H), 6.93-6.85 (m, 1H), 5.23 (s, 1H), 4.72-4.52 (m, 1H), 3.20-2.47 (m, 6H), 2.41 (d, J=7.1 Hz, 2H), 1.89-1.76 (m, 1H), 2.02-1.26 (m, 5H), 1.70 (d, J=7.6 Hz, 6H), 0.88 (d, J=6.6 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ 160.4, 158.0, 137.1, 137.1, 129.2, 129.1, 128.1, 116.2, 116.0, 71.2, 55.8, 54.2, 47.6, 46.7, 45.1, 30.5, 29.9, 28.6, 27.0, 25.6, 24.8, 22.5, 19.8, 19.5 ppm. Purity: 95.0% UPLCMS (210 nm); retention time 1.02 min; (M+1) 363.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34]CC)=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH3:3].[OH-].[Na+]>CO>[CH2:1]([S:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH3:3]
Reactant: CCCSc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 89 %

Procedure:
A solution of ethyl 2-propylthio-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.25 g) in methanol (5 ml) containing 1N-NaOH (1.5 ml) was heated under reflux for 2 hours. After removal of the solvent, the aqueous residue was adjusted to about pH 3-4 with 1N-HCl to give crystals. The crystals were collected by filtration. Recrystallization from ethyl acetate-hexane gave colorless crystals (0.21 g, 91%), m.p. 222-223° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([CH:37]2[CH2:39][CH2:38]2)[CH:34]=[CH:33][C:4]=1[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:32]=[CH:31][C:13]([O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH:19]([C:25]([O:27]CC)=[O:26])[CH2:20][CH2:21][O:22]3)=[CH:17][C:16]=2[Cl:30])=[CH:12][CH:11]=1)=[O:9].[OH-].[Na+]>C1COCC1.C(O)C.CCOC(C)=O.Cl>[Cl:30][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:15]=1[O:14][C:13]1[CH:31]=[CH:32][C:10]([C:8](=[O:9])[NH:7][CH2:6][CH2:5][C:4]3[CH:33]=[CH:34][C:35]([CH:37]4[CH2:39][CH2:38]4)=[CH:36][C:3]=3[O:2][CH3:1])=[CH:11][CH:12]=1)[O:22][CH2:21][CH2:20][CH:19]2[C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C5CC5)cc4OC)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C2CC2)ccc1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a stirred solution of ethyl 7-(4-(2-methoxy-4-cyclopropylphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (0.07 g; 0.133 mmol) in a mixture of 1.2 mL THF and 0.6 mL ethanol at ambient temperature was added 0.53 mL of 1M aqueous NaOH. The resulting slightly cloudy mixture was vigorously stirred at ambient temperature. After 1 hour the reaction mixture was diluted with 6 mL EtOAc and 3 mL of 1M aqueous HCl, then transferred to a separatory funnel. After shaking, the organic layer was washed with 2 mL brine, then dried over sodium sulfate and evaporated to give 62 mg of 6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid as a colorless oil. MS (apci, pos) m/z=523.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([N:17]3[CH2:22][CH2:21][CH2:20][CH:19]([CH3:23])[CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[NH2:14][C:12]1[C:11]([N:17]2[CH2:22][CH2:21][CH2:20][CH:19]([CH3:23])[CH2:18]2)=[CH:10][C:8]2[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6][C:7]=2[CH:13]=1
Reactant: CC1CCCN(c2cc3nc(C(C)(C)C)sc3cc2[N+](=O)[O-])C1
Agent: [Ni]
Solvent: CO
Product: CC1CCCN(c2cc3nc(C(C)(C)C)sc3cc2N)C1

Procedure:
A solution of 1.7 g of 2-tert-butyl-5-[3-methylpiperidin-1-yl]-6-nitrobenzothiazole in 50 ml of methanol is hydrogenated in presence of 0.5 g of raney nickel at room temperature. After removing the catalyst the solution is concentrated and the solid filtered to give 6-amino-2-tert-butyl-5-[3-methylpiperidin-1-yl]benzothiazole melting at 108°-112°.