Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C>>[OH:30][C:5]1[C:6]([CH2:27][CH2:28][CH3:29])=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]4[N:31]=[N:32][NH:33][N:22]=4)=[CH:19][CH:18]=3)[CH:11]=2)[CH:25]=[CH:26][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2cccc(Nc3ccc(C#N)cc3)c2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCc1c(OCc2cccc(Nc3ccc(-c4nn[nH]n4)cc3)c2)ccc(C(C)=O)c1O
Yield: 28.5 %

Procedure:
Using the general procedure for formation of tetrazole (Et3NHCl method) of Example 1 using 4-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-benzonitrile (380 mg, 0.949 mmol), sodium azide (308 mg, 4.74 mmol), and triethylamine hydrochloride (653 mg, 4.74 mmol) to yield the title product as a white solid (120 mg, 29%): 1H NMR (DMSO-d6) δ 0.785 (t, 3H), 1.44 (sextuplet, 2H), 2.52 (s, 3H), 2.55 (t, 2H), 5.20 (s, 2H), 6.68 (d, 1H), 6.97 (d, 1H), 7.04 (d, 1H), 7.15 (d, 2H), 7.24 (s, 1H), 7.29 (t, 1H), 7.76 (d, 1H), 7.82 (d, 2H), 8.69 (s, 1H), 12.80 (s, 1H); MS (esi negative) m/z (rel intensity) 442 (100).
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:14])=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br>CN(C=O)C>[Cl:1][C:2]1[C:3]([I:14])=[C:4]([C:8]2([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cccc(Cl)c1I
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cccc(Cl)c2I)CCOCC1
Temperature: 25 °C

Procedure:
A mixture of ethyl 2-(3-chloro-2-iodophenyl)acetate (1.3 g, 4.0 mmol) in 6 mL DMF was stirred at room temperature and treated with sodium hydride (0.23 g, 10 mmol). The mixture turned orange, was stirred for 10 minutes, and was treated with 1-bromo-2-(2-bromoethoxy)ethane (1.2 g, 5.2 mmol) in 6 mL DMF dropwise. The mixture was then stirred at room temperature for 2.5 hours. The mixture was carefully quenched with 20 mL H2O and extracted with ether (3×100 mL). The combined organic layers were washed with water (3×50 mL), 20 mL saturated NaCl, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by column eluting with (10-20% EtOAc/hexane) to give the title compound in 0.57 g. MS m/e: (M+H)+ 395.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH:23]=[O:24])[CH2:17][CH2:16]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].B.[Na]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][OH:24])[CH2:17][CH2:16]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:11])([F:12])[F:10]
Reactant: O=CCCC1CCC(CCc2ccc(OC(F)(F)F)c(F)c2)CC1
Agent: B
Agent: [Na]
Solvent: CCO
Product: OCCCC1CCC(CCc2ccc(OC(F)(F)F)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
Ethanol (12 ml) was added to the above 3-(4-(2-(3-fluoro-4-trifluoromethoxyphenyl)ethyl)cyclohexyl)propanal (1.76 g, 5.1 mmol), followed by cooling the mixture down to 0° C. in a nitrogen gas atmosphere, adding to the mixture, sodiumboron hydride (0.19 g, 5.0 mmol) so that the liquid temperature might not exceed 10° C., stirring the mixture at 0° C. for 2 hours, extracting the resulting product with ethyl acetate, washing the organic layer successively with a saturated, aqueous solution of sodium bicarbonate and water, drying over MgSO4, distilling off the solvent, and recrystallizing the residue with heptane, to obtain 3-(4-(2-(3-fluoro-4-trifluoromethoxyphenyl)ethyl)cyclohexyl)propanol (1.52 g, 4.4 mmol). Yield: 86.3%.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH2:13]1)C1C=CC=CC=1>C1C=CC=CC=1>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH:14]1[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: O=C(Cl)Cl
Reactant: COc1ccccc1OC1CCN(Cc2ccccc2)C1
Solvent: c1ccccc1
Product: COc1ccccc1OC1CCN(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a stirred solution of 60 ml of 2 molar phosgene (0.11 mole) in benzene under nitrogen gas was added dropwise a solution of 29.3 g (0.1 mole) of 1-benzyl-3-(2-methoxyphenoxy)pyrrolidine in 100 ml of benzene. The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo to give an oil. The oil was triturated with warm 30/60 petroleum ether and the petroleum ether was decanted to remove benzyl chloride. On the third trituration the oil solidified to give 19.65 g of crude product. The combined petroleum ether decantate, on cooling, yielded an additional 4.8 g, m.p. 80°-81° C. The combined yield was 23.45 g (91.7%). Recrystallization of a 1.25 g sample from 25 ml of 30/60 petroleum ether gave fine white crystals, m.p. 80.5°-82° C. The yield of purified product based on this aliquot was 22.6 g (88%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:10]1([S:16][C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Sc1ccccc1
Reactant: N#Cc1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: N#Cc1cccc(Sc2ccccc2)c1
Yield: 85.7 %

Procedure:
The general procedure in example 39 was followed. 3-Iodobenzonitrile (229 mg, 1.0 mmol), thiophenol (103 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3-cyanophenyl phenyl sulfide (181 mg, 86% yield) as colorless liquid. Column chromatography solvent (hexane/ethyl acetate=25/1). Rf=0.4 (hexane/ethyl acetate=20/1). 1H NMR (CDCl3, 300 MHz) δ 7.30-7.45 (m, 9 H). 13C NMR (CDCl3, 75 MHz) δ 140.2, 133.6, 132.9, 132.3, 131.7, 130.0, 129.7, 129.6, 129.1, 118.5, 113.5. MS (EI) m/z (relative intensity) 211 (30), 185 (20), 134 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=[O:13])[CH2:7][CH2:6]2.N1CC[CH2:16][CH2:15]1.CO.C(I)C>C1(C)C=CC=CC=1>[CH2:15]([CH:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:13])[CH3:16]
Reactant: COc1ccc2c(c1)CCC(=O)C2
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Solvent: CCI
Solvent: CO
Product: CCC1C(=O)CCc2cc(OC)ccc21
Temperature: 25 °C

Procedure:
A solution of 6-methoxy-2-tetralone (120.55 grams, 0.684 mol) and pyrrolidine (61 mL, 0.685 mol) in toluene (1.7 L) was heated to reflux using a Dean-Stark trap apparatus for 3 hours. After removal of the azeotroped water, the reaction mixture was cooled to room temperature and concentrated to a solid. To this solid was added methanol (1.2 L) and ethyl iodide (121 mL, 1.51 mol). The resulting solution was heated at reflux overnight and then concentrated under vacuum to remove methanol. A solution of acetic acid (120 mL), sodium acetate (120 g) in water (240 mL) was added to the residue and the resultant mixture was heated at reflux for 2 hours. After cooling, the mixture was extracted several times with diethyl ether. The combined organic layers were washed twice with aqueous 1M HCl, twice with aqueous 1M NaOH and once with brine. After drying over magnesium sulfate, the solvent was evaporated to afford the title compound as an oil, 121.8 grams. Mass spectrum: m/e 204.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:4][C@H:3]1[C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1.O.[N+:12]([CH:15]([CH:18]=O)[CH:16]=O)([O-:14])=[O:13].[Na].O>CC(O)=O>[CH3:1][C@H:2]1[CH2:4][C@H:3]1[C:5]1[C:9]2[C:8](=[N:10][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:18]=2)[NH:7][N:6]=1
Reactant: C[C@H]1C[C@H]1c1cc(N)[nH]n1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: C[C@H]1C[C@H]1c1n[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 25 °C
Yield: 35.6 %

Procedure:
3-(cis-2-Methylcyclopropyl)-1H-pyrazol-5-amine (0.0742 g, 0.541 mmol) and sodium nitromalonaldehyde hydrate (0.0892 g, 0.568 mmol) were heated in AcOH at 90° C. overnight. Water was added, and the precipitate was collected by filtration. This solid was taken up in water as a slurry and heated to reflux for two days. The solution was cooled to room temperature, and the resulting crystals were collected by filtration. The mother liquor was extracted with DCM (3×), dried over Na2SO4 and concentrated to a solid, which was combined with the crystals to provide 3-(cis-2-methylcyclopropyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (42 mg, 65%) as a solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:10]([CH:12]2[C:16](=O)[CH2:15][N:14]([CH3:18])[C:13]2=[O:19])[CH:11]=1.O.Cl>ClC1C=CC=CC=1.CCCCCC>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:16]3[CH2:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[C:10]=2[CH:11]=1
Reactant: CN1CC(=O)C(c2cc(Cl)ccc2Oc2ccccc2)C1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: CN1CC2=C(C1=O)c1cc(Cl)ccc1Oc1ccccc12
Temperature: 98 °C
Reaction time: 1 h

Procedure:
Anhydrous aluminium chloride (5 g) was added to a reaction mixture containing 3-(5-chloro-2-phenoxyphenyl)-1-methylpyrrolidine-2,4-dione (1 g) in monochlorobenzene (1 mL) at ambient temperature. The reaction mixture was stirred at about 98° C. for about 1 hour, then cooled to ambient temperature. A mixture of water and concentrated hydrochloric acid (50 mL:5 mL) was added slowly. The contents were stirred for about 30 minutes. Hexane (50 mL) was added. The contents were stirred for about 1 hour, filtered, washed with hexane (15 mL) and dried in air at about 30° C. for about 15 hours to obtain 11-chloro-2-methyl-2,3-dihydro-1H-dibenzo [2,3:6,7] oxepino [4,5-c]pyrrol-1-one.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]I.[Cl:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[CH:17]=2)[CH:12]=[N:11]1.[S:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:37]=[C:36]3[C:32]([CH:33]=[N:34][NH:35]3)=[CH:31][CH:30]=2)=[CH:25]1.[H-].[Na+]>CN(C=O)C>[Cl:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[CH:17]=2)[CH:12]=[N:11]1.[Cl:1][CH2:2][CH2:3][CH2:4][N:34]1[CH:33]=[C:32]2[C:36]([CH:37]=[C:29]([C:26]3[CH:27]=[CH:28][S:24][CH:25]=3)[CH:30]=[CH:31]2)=[N:35]1
Reactant: c1cc(-c2ccc3cn[nH]c3c2)cs1
Reactant: ClCCCI
Agent: ClCCCn1ncc2ccc(-c3ccsc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCCn1cc2ccc(-c3ccsc3)cc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28 %

Procedure:
1-(3-chloropropyl)-6-(3-thienyl)-1H-indazole 1-chloro-3-iodopropane (0.14 mL, 1.3 mmol) was added to a DMF (3 mL) solution of 6-(3-thienyl)-1H-indazole (88.4 mg, 0.44 mmol) and sodium hydride (60%, 72 mg, 1.8 mmol) that had been allowed to stir for 5 min at room temperature under argon. The reaction mixture was allowed to stir at room temperature overnight before quenching with brine (20 mL) and partitioning into ethyl acetate (100 mL), and drying over anhydrous sodium sulfate. The solvent was removed in vacuo and flash chromatography (silica gel, 10-20% ethyl acetate in hexane) yielded 1-(3-chloropropyl)-6-(3-thienyl)-1H-indazole (76.6 mg, 63%) as well as the side product 2-(3-chloropropyl)-6-(3-thienyl)-2H-indazole (33.9 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:24][C:25](=[O:37])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)([C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[C:45]([C:48](OCC)=O)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:24][C:25](=[O:37])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([C:33]([F:34])([F:36])[F:35])[CH:27]=2)([C:16]2[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([O:22][CH2:45][CH3:48])[CH:21]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)I
Reactant: O=C(N[C@@](Cc1ccccc1)(c1cc(O)cc(F)c1)c1ccc(Cl)cn1)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc(F)cc([C@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2ccc(Cl)cn2)c1
Temperature: 60 °C
Yield: 7.4 %

Procedure:
To a solution of (S)-N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-hydroxyphenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (32 mg, 0.06 mmol, prepared as described in Procedure 14) in DMF (0.5 mL) was added Cs2CO3 (39 mg, 0.12) and ICF2CO2Et (28 mg, 0.12 mmol). The mixture was heated at 60° C. for 3 days. NaHCO3 was added. It was extracted with CH2Cl2. The organic layer was washed with 10% citric acid, brine, dried over MgSO4, concentrated and the crude mixture was purified by preparative HPLC (phenominex C18 column, 21×100 mm, 5 μ) using MeOH/H2O (0.1% TFA) to give two products, (S)-N-(1-(5-chloropyridin-2-yl)-1-(3-ethoxy-5-fluorophenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (2.5 mg, 7% yield) as a pale yellow solid, LCMS: 4.38 min [M+1] 561.44 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 1.33-1.40 (m, J=6.88, Hz, 3 H), 3.61 (d, J=12.88 Hz, 1 H), 3.93-4.00 (m, 2 H), 4.54 (d, J=12.88 Hz, 1 H), 6.49-6.56 (m, 3 H), 6.76 (dt, J=9.85, 1.89 Hz, 1 H), 6.84 (s, 1 H), 7.02 (t, J=7.45 Hz, 2 H), 7.11 (t, J=7.33 Hz, 1 H), 7.22-7.31 (m, 3 H), 7.70 (dd, J=8.59, 2.27 Hz, 1 H), 7.85-7.90 (m, 1 H), 8.03 (dd, J=6.82, 2.02 Hz, 1 H), 8.32 (d, J=2.53 Hz, 1 H), 9.11 (s, 1 H), and (S)-N-(1-(5-chloropyridin-2-yl)-1-(3-(difluoromethoxy)-5-fluorophenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (3 mg, 7% yield) as a pale yellow foam, LCMS: 4.28 min [M+1] 583.32 (4 min gradient, MeOH/H2O 0.1% TFA); 1 H NMR (400 MHz, CDCl3) δ ppm 3.61 (d, J=12.88 Hz, 1 H), 4.54 (d, J=12.88 Hz, 1 H), 6.51 (m, 3 H), 6.76-6.83 (m, 1 H), 7.00-7.08 (m, 4 H), 7.13 (t, J=7.45 Hz, 1 H), 7.20-7.29 (m, 2 H), 7.74 (dd, J=8.59, 2.27 Hz, 1 H), 7.87 (ddd, J=8.46, 4.67, 2.27 Hz, 1 H), 8.02 (dd, J=6.69, 1.89 Hz, 1 H), 8.35 (d, J=2.27 Hz, 1 H), 9.11 (s, 1 H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:24]([C:28]1[CH:29]=[CH:30][C:31]([O:48][CH3:49])=[C:32]([CH:47]=1)[CH2:33][N:34]1[C:42]2[C:37](=[CH:38][C:39]([Cl:43])=[CH:40][CH:41]=2)[CH:36]=[C:35]1[C:44](O)=[O:45])([CH3:27])([CH3:26])[CH3:25].[NH2:50][CH2:51][C:52]([CH3:56])([CH3:55])[CH2:53][OH:54]>C(Cl)Cl.O>[OH:54][CH2:53][C:52]([CH3:56])([CH3:55])[CH2:51][NH:50][C:44]([C:35]1[N:34]([CH2:33][C:32]2[CH:47]=[C:28]([C:24]([CH3:27])([CH3:25])[CH3:26])[CH:29]=[CH:30][C:31]=2[O:48][CH3:49])[C:42]2[C:37]([CH:36]=1)=[CH:38][C:39]([Cl:43])=[CH:40][CH:41]=2)=[O:45]
Reactant: COc1ccc(C(C)(C)C)cc1Cn1c(C(=O)O)cc2cc(Cl)ccc21
Reactant: CC(C)(CN)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(C)(C)C)cc1Cn1c(C(=O)NCC(C)(C)CO)cc2cc(Cl)ccc21
Reaction time: 0.17 h
Yield: 36.5 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g, 0.57 mmol) followed by 1-hydroxybenzotriazole hydrate (0.08 g, 0.59 mmol) were added to a solution of 1-(5-tert-butyl-2-methoxybenzyl)-5-chloro-1H-indole-2-carboxylic acid (0.20 g, 0.54 mmol) in DCM (10.0 ml) and after stirring for 10 min, 3-amino-2,2-dimethylpropan-1-ol (67 mg, 0.65 mmol) was added. After stirring for 17.5 h, water (10 ml) was added, the layers separated, the organic washed with water (3×15 ml) and dried with magnesium sulfate. Purification was achieved by chromatography on silica using DCM:methanol (3:1) as eluent. Crystallisation of the crude afforded the title compound as a white solid (90 mg, 36%).
Reaction SMILES: [O:1]=[C:2]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].Cl.[NH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:34][CH3:35])=[C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=1.C(N(CC)CC)C>ClCCl>[CH3:33][S:30]([NH:29][C:27]1[CH:28]=[C:23]([CH2:22][CH2:21][NH:20][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:1])[CH:24]=[CH:25][C:26]=1[O:34][CH3:35])(=[O:32])=[O:31]
Reactant: COc1ccc(CCN)cc1NS(C)(=O)=O
Reactant: O=C(O)CCCCC(=O)NCCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)CCCCC(=O)NCCc2ccccc2)cc1NS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
N,N'-carbonyldiimidazole (3.25 g, 0.02 moles) was added in portions under nitrogen to a suspension of 6-oxo-6-(2-phenylethylamino)hexanoic acid (4.98 g, 0.02 moles) in dry dichloromethane (100 ml). The mixture was stirred for 30 mins, the product from step (b) (5.6 g, 0.02 moles) and triethylamine (2.8 ml, 2.02 g, 0.02 moles) were added, and stirring continued for a further 4 hr. The precipitate was collected and the filtrate washed with dilute hydrochloric acid and aqueous sodium bicarbonate solution and evaporated. The residue and the original precipitate were combined and recrystallised from methanol giving the sub-title compound (6.6 g) as white needles mp 193°-195°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>O1CCCC1>[OH:15][CH2:14][C:11]1([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2cccnc2)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)(c2cccnc2)CC1
Temperature: 0 °C

Procedure:
A flask was charged with 1-(tert-butoxycarbonyl)-4-(pyridin-3-yl)piperidine-4-carboxylic acid (4.0 g, 13.06 mmol) and tetrahydrofuran (25 mL). The reaction was placed under N2. To the flask was added Borane/THF (26.1 mL of 1M soln, 26.1 mmol) and set to reflux for 2 hours. The reaction was cooled to 0° C. and quenched with MeOH (100 mL). The solution was then conc. in vacuo. The residue was purified via column chromatography (5% MeOH/95% CH2Cl2) to yield 3.2 g (84%). Mass Spec.: 293.26 (MH)+. LC: tr=1.65 min HPLC Method 1. 1H-NMR (CD3OD, 400 MHz) δ 8.56 (s, 1H), 8.45 (d, 1H), 8.10 (d, 1H), 7.59 (m, 1H), 3.67 (m, 2H), 3.56 (s, 2H), 3.11 (t, 2H), 2.11 (d, 2H), 1.85 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:19])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:20]N1C(=O)CCC1=O>O1CCOCC1>[NH2:1][C:2]1[C:7]2[C:8](=[O:19])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[O:11][C:6]=2[C:5]([Cl:20])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(-c2cc(=O)c3c(N)cccc3o2)cc1
Solvent: C1COCCO1
Product: Nc1ccc(-c2cc(=O)c3c(N)ccc(Cl)c3o2)cc1
Yield: 11.7 %

Procedure:
2.0 g (7.93 mmol) of 5-amino-2-(4-aminophenyl)-4H-1-benzopyran-4-one (EP-A-374789) was dissolved in 50 ml of dioxane, 1.59 g (11.9 mmol) of N-chlorosuccinimide was added and the mixture was stirred under heating at reflux for 5 hours. The reaction solution was extracted with ethyl acetate, and the extract was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform: acetone=4:1) to give 0.61 g (27%) of crude product. Further recrystallization from chloroform/methanol afforded 266 mg (12%) of Compound 2.
Reaction SMILES: Cl.[C:2]1([C@:8]23[CH2:16][NH:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:36]1[N:41]=[C:40]([CH:42]([CH3:44])[CH3:43])[C:39]([F:45])=[CH:38][N:37]=1>O1CCOCC1.O.C(=O)(O)[O-].[Na+]>[F:45][C:39]1[C:40]([CH:42]([CH3:44])[CH3:43])=[N:41][C:36]([N:15]2[CH2:14][C@@H:13]3[C@@:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)([N:9]=[C:10]([NH:17][C:18](=[O:25])[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[S:11][CH2:12]3)[CH2:16]2)=[N:37][CH:38]=1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3)CNC[C@H]2CS1)c1ccccc1
Reactant: CC(C)c1nc(Cl)ncc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)c1nc(N2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccccc3)C2)ncc1F
Yield: 3090.6 %

Procedure:
A solution of N-[(4aR,7aS)-7a-phenyl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide hydrochloride (285 mg, 7.62 μmol), diisopropylethylamine (798 μL, 4.57 mmol) and 2-chloro-5-fluoro-4-isopropyl-pyrimidine (0.798 g, 4.57 mmol) in 1,4-dioxane (15 mL) is heated to 100° C. for eight hours under nitrogen. The reaction mixture is cooled and diluted with water and aqueous saturated sodium bicarbonate. The mixture is extracted with ethyl acetate (3×). The combined organic layers are dried over sodium sulfate and the solvent is removed under vacuum. The crude product is purified over silica gel eluting with a 5% to 100% ethyl acetate in hexanes gradient, to give the title compound (112 mg, 31%). ES/MS (m/e): 476 (M+H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[CH:12]=[C:13]([C@@H:19]2[CH2:28][C@H:27](O)[CH2:26][C@@H:25]3[N:20]2[C:21](=[O:45])/[C:22](=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([N:37]4[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]4)=[C:33]([O:43][CH3:44])[CH:32]=2)/[CH2:23][CH2:24]3)[CH:14]=[C:15]([F:18])[C:16]=1[F:17].O.C(OCC)(=O)C>ClCCl>[F:7][C@H:27]1[CH2:26][C@@H:25]2[N:20]([C:21](=[O:45])/[C:22](=[CH:30]/[C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]4)=[C:33]([O:43][CH3:44])[CH:32]=3)/[CH2:23][CH2:24]2)[C@H:19]([C:13]2[CH:14]=[C:15]([F:18])[C:16]([F:17])=[C:11]([F:10])[CH:12]=2)[CH2:28]1
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1cc(/C=C2\CC[C@@H]3C[C@@H](O)C[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1cc(/C=C2\CC[C@@H]3C[C@H](F)C[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Reaction time: 2 h

Procedure:
Diethylaminosulfur trifluoride (13.2 μL) was added to a solution of (E)-(6S,8R,9aR)-6-(3,4,5-trifluorophenyl)-8-hydroxy-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]octahydroquinolizin-4-one that is an optically active compound obtained above with a retention time of 4.8 minutes (10 mg) in dichloromethane (2.0 mL) under ice-cooling, and the reaction solution was stirred for two hours. Crushed ice, water, and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 5.9 mg of the title optically active compound. The property values of the optically active compound are as follows.
Reaction SMILES: [C:1]12[C:8]3=[CH:9][CH:10]=[CH:11][CH:12]=[C:7]3[C:6](=[O:13])[O:5][C:3](=[O:4])[C:2]1=[CH:14][CH:15]=[CH:16][CH:17]=2.C[OH:19]>>[C:1]1([C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]([OH:5])=[O:13])[C:2](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:3]([OH:19])=[O:4]
Reactant: O=c1oc(=O)c2ccccc2c2ccccc12
Reactant: CO
Product: O=C(O)c1ccccc1-c1ccccc1C(=O)O

Procedure:
Diphenic anhydride (10 g, 0.045 mol) was dissolved in 30 ml of methanol and refluxed overnight. Removal of the solvent and drying the product under vacuum afforded 11.8 g of diphenic acid momo-methyl ester.