Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7](=O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[S:23]1[CH:27]=[C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=2)[N:25]=[N:24]1.C(N(CC)CC)C>CO>[CH3:1][O:2][C:3]([C:5]1[N:33]([CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:26]3[N:25]=[N:24][S:23][CH:27]=3)=[CH:35][CH:34]=2)[C:7](=[O:6])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: NCc1ccc(-c2csnn2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(-c2csnn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 15 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid methyl ester (359 mg) in methanol (20 ml) were added 4-[1,2,3]thiadiazol-4-ylbenzylamine (956 mg) and triethylamine (1.4 ml) and the mixture was stirred at room temperature for 72 hrs. The solvent was evaporated under reduced pressure, and the residue was partitioned between 1N hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, 4N hydrochloric acid ethyl acetate solution (5 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 10 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1→1/1) to give the title compound (80 mg, 15%).
Reaction SMILES: [NH2:1][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:3]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]([NH:10][CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:2]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:1][C:36]([NH:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:37])=[O:12])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=C=Nc1ccccc1
Reactant: NC(c1ccccc1)C(NC(=O)Nc1ccc([N+](=O)[O-])cc1)c1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)NC(c1ccccc1)C(NC(=O)Nc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [R-(R*,R*)] and [S-(R*,R*)]N-(2-amino-1,2 -diphenylethyl)-N'-(4-nitrophenyl)urea (0.1 g, 0.27 mmol) in dichloromethane (10 mL) is added phenyl isocyanate (0.03 g, 0.27 mmol) in one portion. The resulting mixture is stirred 1 hour at room temperature before filtering off the solid product. The product is suspended in hot diethyl ether, filtered, and dried in vacuo at 114° C. for 4 hours, mp 246°-247° C. IR (KBr): 3355, 1656, 1554, 1498, 1330, 1233, 699 cm-1 ; NMR (DMSO-d6): 5.03 (m, 2H), 6.55-7.37 (m, 17H), 7.59 (d, 2H, J=9.2 Hz), 8.11 (d, 2H, J=9.2 Hz), 8.60 (s, 1H), 9.43 (s, 1H). Analysis calculated for C28H25 5O4.1.0H2O: C, 65.49; H, 5.30; N, 13.64. Found: C, 65.44; H, 5.03; N, 13.77.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[CH:20]=[C:19]([CH:21]([F:23])[F:22])[N:18]=[C:17]([S:24][CH3:25])[N:16]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:15]1[CH:20]=[C:19]([CH:21]([F:23])[F:22])[N:18]=[C:17]([S:24][CH3:25])[N:16]=1)[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1
Reactant: CSc1nc(Cl)cc(C(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nc(C(F)F)cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of (R)-4-((R)-1-tert-butoxyethyl)oxazolidin-2-one (0.100 g, 0.534 mmol) and 4-chloro-6-(difluoromethyl)-2-(methylthio)pyrimidine (0.124 g, 0.587 mmol, 1.10 equiv) in DMF (2.7 mL) was treated with NaH (60%, 0.026 g, 0.64 mmol, 1.20 equiv), then the resulting mixture (yellow) was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (20 mL), washed with saturated aqueous NaCl (2×20 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)oxazolidin-2-one (0.164 g, white solid) in 85% yield. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 6.45 (t, J=54 Hz, 1H), 4.80-4.72 (m, 1H), 4.66 (dd, J=9.4, 3.0 Hz, 1H), 4.49-4.34 (m, 2H), 2.58 (s, 3H), 1.25 (s, 9H), 1.02 (d, J=6.5 Hz, 3H); MS m/z 362.3 (M+H)+; Rt-1.09 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH:20]=[O:21]>C1COCC1>[F:16][C:17]1[CH:18]=[C:19]([CH:20]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:9][CH:10]=2)[OH:21])[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Reactant: O=Cc1cc(F)cc(F)c1
Solvent: C1CCOC1
Product: OC(c1ccc(OC2CCCCO2)cc1)c1cc(F)cc(F)c1
Reaction time: 3 h
Yield: 88.9 %

Procedure:
4-(2-Tetrahydro-2H-pyranoxy)phenylmagnesium bromide (0.5 M in THF, 35 mL, 17.5 mmol) was added to a solution of 3,5-difluorobenzaldehyde (1.95 g, 13.7 mmol) in THF (50 mL) slowly via syringe at −78° C. The reaction mixture was stirred at this temperature for 3 hours and then quenched with saturated NH4Cl (aqueous). The mixture was extracted with EtOAc (60 mL×2), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a colorless oil (3.9 g) as product M6.1, which was used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].ClCCl.[C:14]12(O)[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.S(=O)(=O)(O)O>O>[C:14]12([C:7]3[C:8]([OH:10])=[CH:9][C:2]([OH:1])=[C:3]([CH:6]=3)[CH:4]=[O:5])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: O=Cc1ccc(O)cc1O
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: O=Cc1cc(C23CC4CC(CC(C4)C2)C3)c(O)cc1O
Temperature: 25 °C

Procedure:
40 g (0.29 mol) of 2,4-dihydroxybenzaldehyde, 600 ml of dichloromethane and 46.4 g (0.34 mol) of 1-adamantanol were introduced into a round-bottomed flask and 24 ml of concentrated sulfuric acid were added. The reaction medium was stirred at room temperature for twelve hours and was then poured into water. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with dichloromethane. 50.8 g (64%) of the expected aldehyde, having a melting point of 259°-61° C., were recovered.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH:12]=[CH2:13])=[C:7]([O:14][CH3:15])[CH:6]=[CH:5]2.C([Li])CCC.[NH:21]1[CH:25]=[C:24]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[N:23]=[CH:22]1.[Cl-].[NH4+]>C1COCC1.CCCCCC.O>[CH2:12]([C:8]1[C:7]([O:14][CH3:15])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([C:26]([C:24]1[N:23]=[CH:22][NH:21][CH:25]=1)([OH:30])[CH:27]([CH3:29])[CH3:28])=[CH:3]2)[CH3:13]
Reactant: C=Cc1c(OC)ccc2cc(Br)ccc12
Reactant: CC(C)C(=O)c1c[nH]cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1c(OC)ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc12
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
6-Bromo-1-ethenyl-2-methoxynaphthalene (1.20 g) was dissolved in THF (12 ml). To the solution was added dropwise a solution of n-butyllithium in hexane (1.6M: 3.4 ml) at −70° C., and the mixture was stirred for 30 min. A solution of 1-(1H-imidazol-4-yl)-2-methyl-1-propanone (1.73 g) in THF (10 ml) was stirred for 40 min, and the temperature of the mixture was elevated to room temperature. To the reaction mixture were added an aqueous solution of ammonium chloride (10 ml) and water (10 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried and concentrated. The residue was crystallized from ethyl acetate to give the titled compound (1.28 g) as a colorless powder. Mother liquor was purified by silica gel column chromatography (eluent, hexane-ethyl acetate=1:1) followed by recrystallization from ethyl acetate-diisopropyl ether to give the titled compound (0.23 g).
Reaction SMILES: FC(F)(F)C(O)=O.C([NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[N:39][O:40][CH3:41])[C:17]([NH:19][C@@H:20]2[C:37](=[O:38])[N:22]3[C:23]([C:34]([O-:36])=[O:35])=[C:24]([CH2:27][N+:28]4[N:29]([CH3:33])[CH:30]=[CH:31][CH:32]=4)[CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1)=O.Cl.C(OCC)C>CO>[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[N:39][O:40][CH3:41])[C:17]([NH:19][C@@H:20]2[C:37](=[O:38])[N:22]3[C:23]([C:34]([O-:36])=[O:35])=[C:24]([CH2:27][N+:28]4[N:29]([CH3:33])[CH:30]=[CH:31][CH:32]=4)[CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cccn3C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: CO
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cccn3C)CS[C@H]12)c1csc(N)n1
Reaction time: 2 h
Yield: 37.5 %

Procedure:
To a solution of trifluoroacetic acid salt of 7β-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer, 2.2 g) in methanol (11 ml) was added conc. hydrochloric acid (0.78 ml) at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was added to diethyl ether (300 ml), and the precipitates were collected by filtration. The precipitates were dissolved in water (20 ml) and the solution was adjusted to pH 5 with saturated aqueous solution of sodium bicarbonate. The solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" and eluted with 15% aqueous solution of isopropyl alcohol The fractions containing the object compound were collected and evaporated in vacuo to remove isopropyl alcohol. The solution was lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer, 0.78 g).
Reaction SMILES: C([O-])(=O)C.[K+].Br[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].N#N.[CH3:17][O:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][O:24][CH2:25][C:26]2[CH:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[CH:21][CH:20]=1>O.[Pd](Cl)Cl.CC(N(C)C)=O>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][O:24][CH2:25][C:26]2[C:30]([C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[C:9]#[N:10])=[C:29]([CH3:31])[O:28][N:27]=2)=[CH:32][CH:33]=1
Reactant: COc1ccc(COCc2cc(C)on2)cc1
Reactant: N#Cc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(COCc2noc(C)c2-c2ccccc2C#N)cc1
Temperature: 130 °C

Procedure:
To a resealable vial was added potassium acetate (112 mg, 1.143 mmol), palladium(II) chloride (0.507 mg, 2.86 μmol), and 2-bromobenzonitrile (104 mg, 0.572 mmol). The vial was sealed and evacuated and purged with N2 (3×) before addition of DMA (4 mL) and 3-((4-methoxybenzyloxy)methyl)-5-methylisoxazole (200 mg, 0.857 mmol). The vial was heated to 130° C. overnight. The reaction was cooled to room temperature and diluted with water. The aqueous was extracted with EtOAc and the combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford 2-(3-((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)benzonitrile. LC/MS m/z 335 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH3:16].[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([N+:17]([O-:19])=[O:18])[C:3]=1[O:15][CH3:16]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc2c(Cl)c(OC)ccc2o1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2c(Cl)c(OC)c([N+](=O)[O-])cc2o1
Temperature: 0 °C
Yield: 91 %

Procedure:
Methyl 4-chloro-5-methoxybenzofuran-2-carboxylate was dissolved in conc. sulphuric acid (58 mL) with stirring in an ice bath then conc. nitric acid was added dropwise, maintaining the temperature below 5° C. The reaction was then stirred at room temperature for 2.5 h. The reaction was added to ice water (500 mL) over 2 h. The resulting solid was filtered and washed with water until neutral. The solid was dried to afford methyl 4-chloro-5-methoxy-6-nitrobenzofuran-2-carboxylate (6.3 g, 91%), which was taken through to the next step with no further purification.
Reaction SMILES: [C:1]([NH:8][C@H:9]1[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[CH2:12][NH:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)(O)[O-].[Na+].C1COCC1.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>CCOC(C)=O.O>[C:4]([O:3][C:1]([NH:8][C@H:9]1[CH2:14][C@@H:13]([C:15]([F:17])([F:16])[F:18])[CH2:12][N:11]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:10]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C(F)(F)F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To a round bottom flask containing cis-3-(Boc-amino)-5-(trifluoromethyl)piperidine (Molbridge, 10.00 g, 37.27 mmol) and sodium bicarbonate (18.8 g, 224 mmol), THF (200 mL) was added, followed by water (200 mL). Benzyl chloroformate (20.1, g, 112 mmol) was then added dropwise over a period of 30 min. via a syringe pump. The mixture was stirred at room temperature for 2 h. The mixture was then diluted with EtOAc and water. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (340 g, 15% EtOAc in hexanes) to give a white foamy solid which was subjected to chiral HPLC separation (Phenomenex Lux Cellulose C-1, 5 μm, 21.2×250 mm column, eluting with 15% EtOH in hexanes, at flow rate of 18 mL/min., with a loading of 100 mg in 1000 μL at 220 nm wavelength) to give the sub-title compound (retention time: 9.1 min.) as a white foamy solid (6.51 g, 43%). LCMS calc. for C19H25F3N2NaO4 (M+Na)+: m/z=425.2. found: 425.2. The sub-title compound is assigned as the (3S,5R) isomer. The alternative (3R,5S) isomer can be obtained from the same separation.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:28](=O)[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:28](=[O:27])[C:23]5=[CH:22][C:21]([F:20])=[CH:31][CH:30]=[C:24]5[C:25]4=[O:26])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Solvent: ClCCl
Product: O=C1c2ccc(F)cc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirred mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.63 g, 0.01 mole) and 4-fluorophthalic anhydride (1.83 g, 0.011 mole) in dichloromethane (100 ml) is stirred at room temperature for 4 hours. The solvent is then removed under reduced pressure and the residual solids are purified by flash chromatography. The product is further purified by recrystallization to afford N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-fluorophthalimide.
Reaction SMILES: Br[CH:2]1[CH2:10][CH2:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]1=[O:11].[Li+].[Br-]>CN(C=O)C>[S:6]1[CH:7]=[CH:8][C:4]2[C:3]([OH:11])=[CH:2][CH:10]=[CH:9][C:5]1=2
Reactant: O=C1c2ccsc2CCC1Br
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Oc1cccc2sccc12
Temperature: 25 °C

Procedure:
5-Bromo-6,7-dihydro-5H-benzo[b]thiophen-4-one (199, 77% pure, 8.7 g, 28.9 mmol), LiBr (5.7 g, 65.1 mmol) and Li2CO3 (4.3 g, 57.8 mmol) are placed under argon in 300 ml of DMF and refluxed for 3 h. The reaction mixture is allowed to cool down to room temperature and evaporated under high vacuum. After addition of ice water and cold 2M aqueous HCl solution the mixture is extracted with diethyl ether. The organic layers are extracted with 2M NaOH and the combined aqueous layers are acidified with concentrated HCl. The product is extracted twice with ethyl acetate and the organic layers are washed with saturated NaCl solution, dried over Na2SO4 and evaporated under reduced pressure.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH2:8])=[CH:6][CH:5]=[N:4]1)[CH3:2].[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19]OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]>>[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19][NH:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]
Reactant: CCn1nccc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccnn1CC)C(=O)OCC
Temperature: 120 °C
Yield: 87.1 %

Procedure:
To 2-ethyl-2H-pyrazol-3-ylamine (5.6 g, 0.050 mol) was added 2-ethoxymethylene-malonic acid diethyl ester (10.1 mL, 0.050 mol) and the mixture was heated at 120° C. for 4 hours. After cooling down to RT, the crude mixture was purified by column chromatography (SiO2, EtOAc/Heptane 1/1) to give 12.25 g (86%) of the title compound as a yellow oil. ES-MS m/e: 282.4 (M+H−).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].Cl.O[C@H:30]1CCCNC1>>[Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:30][CH2:25][C@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@H]1CCCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 12.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35) and (S)-3-hydroxypiperidine hydrochloride to afford a brown oil. UPLC-MS (condition 1) tR=3.36 min, m/z=460.0-462.0, m/z=458.0-460.1; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.28-1.41 (m, 1H) 1.49-1.63 (m, 1H) 1.75-1.84 (m, 1H) 1.90-1.97 (m, 1H) 2.73 (dd, J=12.10, 9.17 Hz, 1H) 2.87-2.96 (m, 1H) 3.59-3.68 (m, 1H) 3.75 (d, J=12.72 Hz, 1H) 3.87-3.95 (m, 1H) 4.88 (s, 1H) 7.36 (d, J=8.80 Hz, 2H) 7.82-7.88 (m, 2H) 8.42 (d, J=1.96 Hz, 1H) 8.76 (d, J=1.96 Hz, 1H) 10.37 (s, 1H).
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[N:17]=[C:16]2[S:18][CH:19]=[CH:20][C:15]2=[CH:14][C:13]=1[C:21]([OH:23])=[O:22])=O)([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[OH-].[Na+].OS(O)(=O)=O>O>[CH:5]([C:4]1([CH3:8])[C:1](=[O:3])[NH:2][C:10]([C:12]2[N:17]=[C:16]3[S:18][CH:19]=[CH:20][C:15]3=[CH:14][C:13]=2[C:21]([OH:23])=[O:22])=[N:9]1)([CH3:7])[CH3:6]
Reactant: CC(C)C(C)(NC(=O)c1nc2sccc2cc1C(=O)O)C(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C1(C)N=C(c2nc3sccc3cc2C(=O)O)NC1=O
Temperature: 80 °C

Procedure:
6-[(1-Carbamoyl-1,2-dimethylpropyl)carbamoyl]thieno[2,3-b]pyridine-5-carboxylic acid (17.35 g, 0.052 mol) is added to water (225 mL) containing sodium hydroxide (10.35 g, 0.26 mol). The resulting basic solution is heated at 80° C. for two hours and 45 minutes, cooled in an ice-water bath and acidified with 6N H2SO4. The product 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)thieno[2,3-b]pyridine-5-carboxylic acid is filtered off, washed with water and air dried yielding 1.54 g, 70.3%, mp 221°-223° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([C:18]2[CH2:19][CH2:20][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:22][CH:23]=2)[CH:3]=1.[NH2:28][C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[C:4]([C:18]3[CH2:19][CH2:20][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:22][CH:23]=3)[CH:3]=[C:2]([NH:28][C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1cc(C2=CCN(S(C)(=O)=O)CC2)cc(Cl)n1)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(C2=CCN(S(C)(=O)=O)CC2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
115 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]pyridine-2-amine, 40 mg of 2-aminopyrazine, 53 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 40 mg of sodium t-butoxide and 26 mg of tris(dibenzylideneacetone) dipalladium were added in turn to 5 ml of degassed toluene, and the mixture was stirred at 100° C. for 5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 89 mg of the objective compound as pale brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:43])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[CH3:42])=[C:31]([Cl:44])[CH:30]=2)=[C:6]([NH:8][C:9](=[O:27])[O:10][CH2:11][O:12][C:13](=[O:26])[CH2:14][CH2:15][C:16]([O:18]CC2C=CC=CC=2)=[O:17])[CH:7]=1>O1CCCC1.[Pd]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:43])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[CH3:42])=[C:31]([Cl:44])[CH:30]=2)=[C:6]([NH:8][C:9](=[O:27])[O:10][CH2:11][O:12][C:13](=[O:26])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:7]=1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2NC(=O)OCOC(=O)CCC(=O)OCc2ccccc2)cc1Cl
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2NC(=O)OCOC(=O)CCC(=O)O)cc1Cl

Procedure:
1-(3-(Benzyloxycarbonyl)propanoyloxy)methyl N-[5-bromo-2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]carbamate (Compound 212) (580 mg, 0.9 mmol) was dissolved in tetrahydrofurane (50 ml), 10% Pd on carbon (200 mg) was added, and the reaction mixture was hydrogenated (1 atm) under vigorously shaken until no more starting material remained, as seen on TLC. The reaction mixture was purified by chromatography using a mixture of methanol/chloroform 1:9 to give the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[F:9][C:10]([F:36])([F:35])[C:11]([CH2:30][NH:31][CH2:32][CH2:33][CH3:34])([OH:29])[CH2:12][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:32]([N:31]([CH2:30][C:11]([OH:29])([CH2:12][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]([F:36])([F:35])[F:9])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8])[CH2:33][CH3:34]
Reactant: O=C(O)c1ccsc1
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccsc1

Procedure:
Prepared similarly to Example 1 from 3-thiophenecarboxylic acid and 1,1,1-trifluoro-3-[(1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.