Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:18][C@@H:17]([C:19]2[CH:30]=[CH:29][C:22]3[O:23][C:24]([CH3:28])([CH3:27])[O:25][CH2:26][C:21]=3[CH:20]=2)[O:16][C:15]1=[O:31].P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:27][C:24]1([CH3:28])[O:23][C:22]2[CH:29]=[CH:30][C:19]([C@H:17]3[O:16][C:15](=[O:31])[N:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:3][CH2:2][CH2:1][OH:4])[CH2:18]3)=[CH:20][C:21]=2[CH2:26][O:25]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCBr)C(=O)O3)ccc2O1
Reactant: OCCO
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Reaction time: 0.25 h

Procedure:
A solution of ethylene glycol (5.00 ml) in DMF (40 ml) under nitrogen at 0° was treated portionwise with sodium hydride (60% dispersion in mineral oil, 1.292 g) and the mixture was stirred at 0° for 15 min. A solution of (5R)-3-(6-bromohexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (7.40 g) in DMF (10 ml) was added. The mixture was stirred at 0° for 0.5 h then at 20° for 3 h. Phosphate buffer solution (pH 6.5, 40 ml) and water (160 ml) were added and the mixture was extracted with EtOAc (2×100 ml). The combined extracts were washed with water (2×150 ml), brine (50 ml) and were dried (Na2SO4). The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel. Elution with MeOH-EtOAc (1:9) gave the title compound (4.10 g). LCMS RT=2.90 min, ES+ve 394 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[CH:14]=[N:15][C:16]([I:17])=[C:10]2[CH:9]1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:30]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([Cl:30])=[N:15][C:16]([I:17])=[C:10]2[CH:9]1[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCn2cnc(I)c2C1CCc1ccc(C(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2c(Cl)nc(I)c2C1CCc1ccc(C(F)(F)F)cc1
Temperature: 70 °C

Procedure:
To a solution of 1-iodo-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.000 g; 1.918 mmol) in chloroform (30 ml) was added N-chlorosuccinimide (307 mg; 2.298 mmol; 1.2 eq.), and the resulting mixture was heated to reflux (70° C.) for 2 h30. Additional N-chlorosuccinimide (120 mg; 0.898 mmol; 0.46 eq.) was then added and the resulting mixture was additionally refluxed for 2 h30. The reaction mixture was allowed to cool to rt, diluted with DCM (50 ml), and washed with brine (80 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/EA=1/1) afforded the expected product 3-chloro-1-iodo-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (475 mg; 45%). LC-MS: tR=1.13 min.; [M+H]+=556.24 g/mol.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6](=[O:21])[CH2:7][C:8]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([CH:19]=O)[CH:12]=[N:13]2.[BH3-]C#N.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1.CO.O>[CH3:4][O:5][C:6](=[O:21])[CH2:7][C:8]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([CH2:19][N:2]([CH3:3])[CH3:1])[CH:12]=[N:13]2
Reactant: CNC
Reactant: COC(=O)Cc1c(Cl)ccc2ncc(C=O)nc12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1c(Cl)ccc2ncc(CN(C)C)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.3 %

Procedure:
Dimethylamine (5.6 M solution in EtOH, 1.0 ml, 5.6 mmol, 1.5 equiv) was added to a solution of (6-chloro-3-formyl-quinoxalin-5-yl)-acetic acid methyl ester (966 mg, 3.65 mmol) in anhydrous THF (23 ml). The reaction mixture was stirred at room temperature for 18 hours. A solution of NaCNBH3 (275 mg, 4.37 mmol, 1.2 equiv) in methanol (6 ml) was added, immediately followed by the addition of acetic acid (1.10 g, 18.25 mmol, 5.0 equiv). After 5 minutes at room temperature, TLC analysis indicated complete conversion. The reaction mixture was diluted with water, adjusted to pH=8 with concentrated aqueous NaHCO3 solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of CH2Cl2/MeOH 99:1 to 90:10) to afford the title compound (303 mg, 28%) as a colorless solid and the regioisomeric (6-chloro-2-dimethylaminomethyl-quinoxalin-5-yl)-acetic acid methyl ester (48 mg, 5%). Data for (6-chloro-3-dimethylaminomethyl-quinoxalin-5-yl)-acetic acid methyl ester: 1H NMR (400 MHz, CDCl3): δ=9.13 (s, 1H), 8.02 (d, J=9.0 Hz, 1H). 7.81 (d, J=9.0 Hz, 1H), 4.52 (s, 2H), 4.39 (s, 2H), 3.68 (s, 3H), 2.80 (s, 6H). MS (ES+): 294.2 (M+H)+. Data for (6-chloro-2-dimethylaminomethyl-quinoxalin-5-yl)-acetic acid methyl ester: 1H NMR (400 MHz, CDCl3): δ=9.30 (s, 1H), 7.98 (d, J=9.0 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 4.49 (s, 2H), 3.82 (s, 2H), 3.71 (s, 3H), 2.34 (s, 6H). MS (ES+): 294.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[I-].[OH:9][C:10]1[C:11]([CH2:16][N+](C)(C)C)=[N:12][CH:13]=[CH:14][CH:15]=1>CS(C)=O.O>[O:9]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:16][CH2:4]1
Reactant: C[S+](C)C
Reactant: C[N+](C)(C)Cc1ncccc1O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: c1cnc2c(c1)OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
To a suspension of 60% sodium hydride (11.4 g, 286 mmol) in DMSO (170 mL) was added trimethylsulfonium iodide (29.9 g, 136 mmol), and the mixture was stirred at room temperature for 30 min. A solution of (3-hydroxypyridin-2-yl)-N,N,N-trimethylmethanaminium iodide (40.0 g, 136 mmol) in DMSO (130 mL) was added dropwise thereto, and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. 1M Hydrochloric acid was added to the extract, and the mixture was extracted with water. The extract was basified with 1M aqueous sodium hydroxide solution and extracted again with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→50/50) to give the title compound (7.77 g, yield 47%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][C:13]([N:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]4)=[N:12][N:11]3[C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]3[N:33](S(C4C=CC=CC=4)(=O)=O)[CH:34]=[CH:35][C:28]=23)=[CH:4][CH:3]=1.O1CCCC1.CO.[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][C:13]([N:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]4)=[N:12][N:11]3[C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]3[NH:33][CH:34]=[CH:35][C:28]=23)=[CH:6][CH:7]=1
Reactant: Cc1cc(N2CCN(CCO)CC2)nn2c(-c3ccnc4c3ccn4S(=O)(=O)c3ccccc3)c(-c3ccc(F)cc3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N2CCN(CCO)CC2)nn2c(-c3ccnc4[nH]ccc34)c(-c3ccc(F)cc3)nc12
Temperature: 50 °C
Yield: 64.8 %

Procedure:
Added to a solution of 0.22 g (0.36 mmol) of 2-{4-[2-(4-fluorophenyl)-8-methyl-3-{1-[phenylsulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol in 5 ml of a mixture of tetrahydrofuran and methanol (1/1), is 0.12 ml (0.72 mmol) of a 6N aqueous solution of sodium hydroxide. The mixture is heated at 50° C. for 1 hour, then poured into 20 ml of water. The product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The yellowish residue obtained is then purified by chromatography on a silica gel column (40 g) by eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5) in order to give 0.110 g of 2-{4-[2-(4-fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol after crystallization in 10 ml of acetonitrile, filtration and drying.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:28]2[C:33]([CH3:34])=[CH:32][C:31]([O:35][CH2:36][C:37]([CH3:42])([CH3:41])[CH2:38][O:39][CH3:40])=[CH:30][C:29]=2[CH3:43])=[C:8]2[C:12]=1[C@H:11]([O:13][C:14]1[CH:27]=[CH:26][C:17]3[C@H:18]([CH2:21][C:22]([O:24]C)=[O:23])[CH2:19][O:20][C:16]=3[CH:15]=1)[CH2:10][CH2:9]2.Cl>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:28]2[C:33]([CH3:34])=[CH:32][C:31]([O:35][CH2:36][C:37]([CH3:41])([CH3:42])[CH2:38][O:39][CH3:40])=[CH:30][C:29]=2[CH3:43])=[C:8]2[C:12]=1[C@H:11]([O:13][C:14]1[CH:27]=[CH:26][C:17]3[C@H:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][O:20][C:16]=3[CH:15]=1)[CH2:10][CH2:9]2
Reactant: COCC(C)(C)COc1cc(C)c(-c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)OC)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCC(C)(C)COc1cc(C)c(-c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1 M aqueous NaOH solution (450 μL) is added to a solution of methyl 2-((S)-6-((R)-7-fluoro-4-(4-(3-methoxy-2,2-dimethylpropoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (82 mg) in methanol (2 mL). The mixture is stirred at room temperature for 12 hours. 1 N Hydrochloric acid (450 μL) is added and the residue is purified by HPLC on reversed phase to give the title compound. Yield: 39 mg; LC (method 8): tR=0.97 min; Mass spectrum (ESI+): m/z=549 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][N:11]([CH2:13][CH2:14][NH:15][C:16](=O)[CH3:17])[C:12]=3[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH2:7][C:8]3[CH:9]=[C:10]4[C:16]([CH3:17])=[N:15][CH2:14][CH2:13][N:11]4[C:12]=3[C:4]=2[CH:3]=1
Reactant: CC(=O)NCCn1ccc2c1-c1cc(Cl)ccc1CC2
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CC1=NCCn2c1cc1c2-c2cc(Cl)ccc2CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
N-[2-(8-Chloro-4,5-dihydro-1H-benzo[g]indol-1-yl)-ethyl]acetamide (2.9 g) was treated with 20 ml of phosphorus oxychloride under argon and the mixture was stirred at 100° C. for 30 minutes. The cooled mixture was poured on to 1500 g of ice-water and treated with 100 ml of 2N sodium hydroxide solution and 150 ml of 28% sodium hydroxide solution. The mixture was extracted once with 250 ml of methylene chloride and twice with 150 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue (2.7 g) was dissolved in a 20-fold amount of ethanol and treated while hot with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 3.2 g (83%) of 2-chloro-5,6,10,11-tetrahydro-8-methylbenzo[g]pyrazino[1,2-a]indole fumarate (1:1); m.pt.: 172°-174° C. (dec.).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].[Cl:29][CH:30]([CH3:34])[C:31](Cl)=[O:32].[OH-].[Na+]>O1CCCC1.O>[Si:9]([O:8][C@H:6]1[CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:3]([CH2:2][NH:1][C:31](=[O:32])[CH:30]([Cl:29])[CH3:34])[CH2:7]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(Cl)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(Cl)C(=O)NC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of (2S,4R)-2-aminomethyl-4-(t-butyldimethylsilyloxy)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (15 g) in a mixture of tetrahydrofuran (100 ml) and water (50 ml) was added dropwise 2-chloropropionylchloride (4.27 ml) with stirring under ice-cooling, keeping the pH 9-10 with 4N sodium hydroxide. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was evaporated in vacuo to remove the organic layer. The resulting residue was extracted twice with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give (2S,4R)-4-(t-butyldimethylsilyloxy)-2-(2-chloropropionyl)aminomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (18.36 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C[C:22]([N:24](C)C)=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[Zn]>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:3][C:2]([C:22]#[N:24])=[CH:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(-c2ncc(Cl)cc2-c2ccccc2)cc1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(-c2ncc(C#N)cc2-c2ccccc2)cc1
Temperature: 150 °C

Procedure:
A mixture of 5-Chloro-2-(4-methylphenyl)-3-phenylpyridine (0.320 g, 1.144 mmol), zinc cyanide (0.081 g, 0.687 mmol), Pd2(dba)3 (0.063 g, 0.069 mmol), dppf (0.076 g, 0.137 mmol) and zinc (0.018 g, 0.275 mmol) in DMA (5 mL) was degassed (3×pump/N2) and heated to 150° C. for 20 hr. The reaction was then cooled to rt, concentrated, partitioned between EtOAc and water, and extracted 3× with EtOAc. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. Purfied by silica gel chromatography (0-20% EtOAc in Hexanes) to give the titled compound. 1H-NMR (500 MHz, CDCl3) δ 8.92 (d, 1H, J=2.0 Hz), 7.95 (d, 1H, J=2.2 Hz), 7.34-7.33 (m, 3H), 7.28-7.26 (1,2H), 7.20-7.18 (m, 2H), 7.07 (d, 2H, J=8.1 Hz), 2.33 (s, 3H) LRMS m/z (M+H) Calcd: 271.0, found: 271.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][C@H:35]1[O:40][C@@H:39]([CH3:41])[CH2:38][NH:37][CH2:36]1>>[CH3:41][C@H:39]1[O:40][C@@H:35]([CH3:34])[CH2:36][N:37]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:38]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4C[C@@H](C)O[C@@H](C)C4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and cis-2,6-dimethylmorpholine. ES-MS m/e (%):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O>C(Cl)Cl>[Br:35][CH2:14][CH2:13][CH2:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1ccc(C(F)(F)F)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CCCBr)c(Cl)c1
Reaction time: 16 h
Yield: 89 %

Procedure:
Compound 71-2 (2.48 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (3.00 g) and N-bromosuccinimide (2.03 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 16 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.79 g) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:7]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30])[CH:23]=[CH:22]2>>[ClH:18].[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:35]3[CH2:34][CH2:33][N:32]([S:29]([C:24]4[CH:23]=[CH:22][C:21]5[C:26](=[CH:27][CH:28]=[C:19]([Cl:18])[CH:20]=5)[CH:25]=4)(=[O:31])=[O:30])[CH2:37][CH2:36]3)=[O:14])=[CH:15][CH:16]=2)[N:7]=1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: Nc1nc(-c2ccc(C(=O)O)cc2)c[nH]1
Agent: Cl
Product: Nc1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)c[nH]1

Procedure:
In the same manner as in Example A-4, a reaction was conducted using 4-[2-aminoimidazol-4-yl]benzoic acid hydrochloride and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2[C:37]([C:42]3[CH:47]=[CH:46]C=C(F)C=3)=[N:38]OC=2C)=NC=1>>[CH:42]1([CH2:37][NH:38][C:3](=[O:24])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])=[N:6][CH:5]=2)[CH2:47][CH2:46]1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccnc3)noc2C)nc1
Product: Cc1onc(-c2cccnc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 67 %

Procedure:
As described for example 90, 6-(5-methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (130 mg, 0.4 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, was converted to the title compound (98 mg, 67%) which was obtained as a light yellow solid. MS: m/e=365.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:13][C:12]([C:14]([O:16]CC)=[O:15])=[CH:11][C:10](=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.[ClH:20]>>[Cl:20][C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[C:8]1[O:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][C:10](=[O:19])[CH:9]=1
Reactant: Cl
Reactant: CCOC(=O)c1cc(=O)cc(-c2ccc(Cl)cc2)o1
Product: O=C(O)c1cc(=O)cc(-c2ccccc2Cl)o1

Procedure:
A mixture of ethyl 6-(4-chlorophenyl)-4-oxo-4H-pyran-2-carboxylate (3.9 g) and concentrated hydrochloric acid (40 ml) was heated under reflux for 2 hours. The reactant dissolved on warming and a solid began to precipitate. Water (40 ml) was added to the cooled mixture and the resulting buff solid yielded the title product as off-white needles (mp 241°-246° C. with decomposition).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](Cl)(=[O:5])=[O:4].C(=O)=O.[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].C(N(CC)CC)C>C(Cl)Cl.CCOCC.CC(O)C>[F:12][C:13]([F:17])([F:16])[CH2:14][O:15][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: OCC(F)(F)F
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)O
Product: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of trifluoromethanesulfonyl chloride (640 μL, 6 mmol) in CH2Cl2 (5 mL) was cooled under argon to -78° C. (IPA:dry ice bath). 2,2,2-Trifluoroethanol was added (365 μL, 5 mmol) and triethylamine (834 μL, 6 mmol) was added dropwise. The reaction was stirred for 1.5 hours then warmed to 0° C. for 1 hour. Anhydrous ether (20 mL) was added and the mixture was stirred at 0° C. for 30 minutes. The solids were filtered off and the solvent was removed under reduced pressure with the flask maintained at 0° C. This afforded the 2,2,2-trifluoroethyltriflate as a yellow oil which was used immediately.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[C:42]([CH3:43])=[C:41]([CH3:44])[N:40]([CH3:45])[C:39](=[O:46])[CH:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[C:42]([CH3:43])=[C:41]([CH3:44])[N:40]([CH3:45])[C:39](=[O:46])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1c(Br)cc(=O)n(C)c1C
Product: Cc1c(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(=O)n(C)c1C

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-1,5,6-trimethylpyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.187 min, m/z=489.2; 1H NMR (CDCl3) 1.10 (s, 3H), 1.15 (s, 3H), 1.32 (m, 3H), 1.52 (m, 3H), 1.72 (s, 1H), 2.18 (m, 3H), 2.19 (m, 1H), 2.42 (m, 4H), 2.86 (m, 1H), 4.12 (m, 2H), 5.66 (m, 1H), 6.16 (s, 1H), 6.53 (s, 1H), 6.98 (m, 2H), 7.23-7.34 (m, 7H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].OS(O)(=O)=O.[CH3:21]O>C(OCC)(=O)C>[CH3:21][O:14][C:13](=[O:15])[CH2:12][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: O=C(O)Cc1cc2cccnc2cc1F
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc2cccnc2cc1F
Yield: 98 %

Procedure:
To a solution of (7-fluoro-quinolin-6-yl)-acetic acid (13.4 g, 65.36 mmol) in methanol (140 mL) was added conc.H2SO4 (3.5 mL, 68.63 mmol). The reaction mixture was concentrated to give a brown residue, which was diluted with 100 ml of ethyl acetate, washed with sat. aq. NaHCO3 and brine, then the organic layer was dried over anhydrous Na2SO4, and concentrated to give (7-fluoro-quinolin-6-yl)-acetic acid methyl ester as yellow solid (14.0 g, yield: 98%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[O:2]2>[Pd].CO>[OH:2][C@@H:1]1[CH2:6][CH2:5][C@H:4]([NH:3][C:8](=[O:9])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1OC2C=CC1C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C1
Temperature: 60 °C
Reaction time: 48 h
Yield: 79.6 %

Procedure:
A mixture of tert-butyl 2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (8.0 g, 40.56 mmol, 1.00 equiv) and palladium on carbon (0.5 g) catalyst in methanol (100 mL) was stirred under an atmosphere of hydrogen atmosphere at 60° C. for 48 h. The reaction mixture was cooled to room temperature and the catalyst was removed by filtration. The catalyst was washed with 3×10 mL of MeOH. The combined filtrate and washings was concentrated under vacuum to give 6.5 g (80%) of tert-butyl N-[(1S,3R)-3-hydroxycyclopentyl]carbamate as a white solid. 1HNMR (400 MHz, D2O, ppm) δ 4.72 (1H, s), 4.55 (1H, s), 1.92-1.87 (3H, m), 1.76-1.60 (3H, m), 1.50 (9H, s).