Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[N:9][CH:8]=[N:7][CH:6]=1.[CH2:11]([O:18][C:19]([N:21]1[CH:26]([CH3:27])[CH2:25][N:24]([CH2:28][C:29]2[CH:34]=C[C:32](C#N)=[C:31](N)[CH:30]=2)[C:23](=[O:38])[C@@H:22]1[CH3:39])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C>C(O)C>[CH2:11]([O:18][C:19]([N:21]1[CH:26]([CH3:27])[CH2:25][N:24]([CH2:28][C:29]2[CH:34]=[C:6]3[C:32]([C:10]([NH2:5])=[N:9][CH:8]=[N:7]3)=[CH:31][CH:30]=2)[C:23](=[O:38])[C@@H:22]1[CH3:39])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ncncn1
Reactant: CC1CN(Cc2ccc(C#N)c(N)c2)C(=O)[C@H](C)N1C(=O)OCc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1C(=O)OCc1ccccc1
Yield: 85.1 %

Procedure:
Glacial acetic acid (0.9 ml, 15.54 mmol) and 1,3,5-triazine (840 mg, 10.36 mmol) is added to a solution of (2S,6RS)-4-(3-amino-4-cyano-benzyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (2.03 g, 5.18 mmol) in ethanol. The resulting mixture is heated to reflux overnight. Replaced the ethanol with ethyl acetate and washed with saturated sodium bicarbonate (5 mL). The ethyl acetate layer is dried with magnesium sulfate, filtered and condensed. The resulting residue is purified by flash colunm (SiO2, 20% methanol/methylene chloride) to give the product (2S,6RS)-4-(4-amino-quinazolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (1.85 g, 85%) as a yellow solid. C23H25N5O3 MS m/z: 420.
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][C:37]([O:39]CC)=[O:38])=[CH:32][C:31]=3[Cl:42])[CH:19]=2)=[C:8]([Cl:43])[CH:7]=1)C.[OH-].[Na+]>C1COCC1.C(O)C>[C:37]([CH2:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:28]/[CH:27]=[CH:26]/[C:25]#[C:24][C:20]2[CH:19]=[C:18]([C:17]#[C:16]/[CH:15]=[CH:14]/[CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:44])=[O:3])=[CH:7][C:8]=3[Cl:43])[CH:23]=[CH:22][CH:21]=2)=[C:31]([Cl:42])[CH:32]=1)([OH:39])=[O:38]
Reactant: CCOC(=O)Cc1ccc(OC/C=C/C#Cc2cccc(C#C/C=C/COc3ccc(CC(=O)OCC)cc3Cl)c2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cc1ccc(OC/C=C/C#Cc2cccc(C#C/C=C/COc3ccc(CC(=O)O)cc3Cl)c2)c(Cl)c1

Procedure:
To a solution of (E)(E) [3-chloro-4-(5-{3-[5-(2-chloro-4-ethoxycarbonylmethyl-phenoxy)-pent-3-en-1-ynyl]-phenyl}-pent-2-en-4-ynyloxy)-phenyl]-acetic acid ethyl ester (example 7) (180 mg 0.28 mmol) in THF (3 mL) and ethanol (3 mL) was added 1N sodium hydroxide (1.5 mL).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][CH:20]=[CH:19]4)=[CH:12][CH:11]=1)[CH2:2]2.[CH2:25]=O.[CH3:27][NH:28][CH3:29]>O1CCOCC1.CC(O)=O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][CH:20]=[C:19]4[CH2:27][N:28]([CH3:25])[CH3:29])=[CH:12][CH:11]=1)[CH2:2]2
Reactant: C=O
Reactant: CNC
Reactant: c1cc2cc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)ccc2[nH]1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CN(C)Cc1c[nH]c2ccc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)cc12

Procedure:
The product of Example 9B (150 mg, 0.47 mmol) was treated with HCHO (Aldrich, 37%, 76 mg, 0.94 mmol) and dimethylamine (Aldrich, 42 mg, 0.94 mmol) in dioxane/HOAc (v. 1:1, 5 mL) at ambient temperature for 16 hours. It was then concentrated and the title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 μm, 30×100 mm. Eluting Solvent, MeCN/H2O (NH4HCO3, 0.1 M, pH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (80 mg, 45%). 1H NMR (MeOH-D4, 300 MHz) 1.59-1.75 (m, 1H), 1.77-1.99 (m, 2H), 2.07-2.23 (m, 1H), 2.36-2.44 (m, 1H), 2.60-2.69 (m, 6H), 2.91-3.13 (m, 5H), 3.52-3.65 (m, 1H), 4.22 (s, 2H), 5.32-5.40 (m, 1H), 7.30 (d, J=9.5 Hz, 1H), 7.49 (s, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.81 (dd, J=8.5, 1.7 Hz, 1H), 8.15 (d, J=9.5 Hz, 1H), 8.29 (s, 1H) ppm. MS (DCI/NH3) m/z 378(M+H)+.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][C:32]3[CH:41]=[C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:39]([O:47][CH:48]([CH3:50])[CH3:49])=[CH:38][C:33]=3[C:34]=2[C:35]([NH2:37])=O)=[CH:26][CH:25]=1>C1COCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][C:32]3[CH:41]=[C:40]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[C:39]([O:47][CH:48]([CH3:49])[CH3:50])=[CH:38][C:33]=3[C:34]=2[C:35](=[S:10])[NH2:37])=[CH:26][CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)Oc1cc2c(C(N)=O)c(-c3ccc(F)cc3)oc2cc1NS(C)(=O)=O
Solvent: C1CCOC1
Product: CC(C)Oc1cc2c(C(N)=S)c(-c3ccc(F)cc3)oc2cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 169.6 %

Procedure:
The reaction was run in two batches and combined for workup. In the first batch, Lawesson's reagent (27 mg, 0.067 mmol) was added to a solution of 2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxamide (35 mg, 0.086 mmol) in THF (1.2 mL). The reaction was stirred at r.t. for 2 h, at which point additional Lawesson's reagent (8 mg, 0.020 mmol) was added. In the second batch, Lawesson's reagent (129 mg, 0.32 mmol) was added to a solution of 2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxamide (125 mg, 0.31 mmol) in THF (3 mL) was stirred at r.t. for 1.5 h. The two batches were then combined and partitioned between EtOAc (50 mL) and water (10 mL). The organic phase was washed with sat'd NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated to give a yellow oil. The residue was purified by silica gel chromatography (Biotage 25+S silica gel cartridge, gradient elution: 20% to 80% EtOAc/hexanes over 20 column volumes, fraction collection at λ=320 nm) to give 48 mg (29% yield) of the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.76-7.87 (m, 2H) 7.71 (d, J=5.86 Hz, 2H) 7.53 (br. s., 1H) 7.13-7.23 (m, 2H) 6.97 (s, 1H) 6.90 (br. s., 1H) 4.74 (dt, J=12.08, 6.04 Hz, 1H) 2.93 (s, 3H) 1.40 (d, J=6.22 Hz, 6H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=5% CH3CN/95% H2O/0.1% NH4OAc, solvent B=95% CH3CN/5% H2O/0.1% NH4OAc, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=5 ml/min, column: XBridge C18 5 μm 4.6×50 mm; HPLC Rt=1.39 min, (ES+) m/z (MH+)=423.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Cl-].[Br:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][C:26]=1[F:27])[CH:18]=[N+:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.BrC1C=C(C=CC=1F)C=O.N1CCCC1>>[Br:14][C:15]1[CH:16]=[C:17]([CH:18]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:12]=[CH:11][CH:10]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Fc1ccc(C=[N+]2CCCC2)cc1Br
Reactant: Fc1ccc(-n2cccc2)cc1
Agent: O=Cc1ccc(F)c(Br)c1
Agent: [Cl-]
Solvent: C1CCNC1
Product: Fc1ccc(-n2cccc2C(c2ccc(F)c(Br)c2)N2CCCC2)cc1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-(4-fluoro-phenyl)-1H-pyrrole and 1-(3-bromo-4-fluoro-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 4 from 3-bromo-4-fluorobenzaldehyde and pyrrolidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:13][O:12][CH2:11]1)=[O:8])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:13][O:12][CH2:11]1)=[O:8]
Reactant: O=C(NC1COC1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)NC2COC2)c1
Reaction time: 0.33 h
Yield: 92.5 %

Procedure:
To a stirred solution of 3-Nitro-N-(oxetan-3-yl)benzamide (0.06 g, 0.270 mmol) in methanol (5 ml) was added Pd/C (2.87 mg) and the reaction mixture was stirred under hydrogen atmosphere for 20 min. The reaction mixture was diluted with methanol (10 ml) and the mixture was filtered through celite, and the filtrate was concentrated under vacuum to afford the title compound (48 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[CH2:13][CH2:12][S:11]3)=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:23]1([C:22]([N:16]2[CH:21]=[CH:20][CH:19]([C:15]3[N:14]4[C:10]([S:11][CH2:12][CH2:13]4)=[N:9][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:18]=[CH:17]2)=[O:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccncc1
Reactant: Fc1ccc(-c2cn3c(n2)SCC3)cc1
Solvent: ClCCl
Product: O=C(c1ccccc1)N1C=CC(c2c(-c3ccc(F)cc3)nc3n2CCS3)C=C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
6-(4-Fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole (45.0 g, 0.204 mol) and 55 ml (0.68 mol) of pyridine were dissolved in 500 ml of methylene chloride. To this cooled (ice water bath) solution (10°) was added 91.3 g (0.65 mol) of benzoyl chloride in 100 ml of methylene chloride under a nitrogen atmosphere. During the addition, the reaction pot temperature was not allowed to rise past 10°. After the addition, the desired product precipitated from solution. The addition of the benzoyl chloride solution was continued. The resulting suspension was stirred at ambient temperature for 15 minutes, then heated to reflux for 15 minutes. Thin-layer chromatography (ethyl acetate/hexane/methanol, 15:1:0.1) showed the presence of some starting material. An additional 20 ml of pyridine followed by benzoyl chloride (28 g, 0.2 mol) were added at room temperature. The suspension was stirred for an additional 0.5 hour. Analysis did not detect starting material at this time. The reaction suspension was filtered. The collected solid was washed with petroleum ether. The solid was vacuum dried to yield 66.8 g (81%) of 5-(N-phenylcarbonyl-1,4-dihydro-4-pyridyl)-6-(4-fluorophenyl)-2,3-dihydroimidazo-[2,1-b]thiazole; m.p. 188°-189°.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([C:18]#N)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1.C([O:31]CC)C>ClC1C=CC=CC=1>[CH:1]([N:14]1[CH2:17][CH:16]([C:18]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)=[O:31])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: Clc1ccccc1
Product: O=C(c1ccc(Cl)cc1)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of 1-Benzhydryl-azetidine-3-carbonitrile (23.6 g, 95 mmol) in chlorobenzene (250 ml) under nitrogen is treated with a 1.0 M solution of 4-chlorophenylmagnesium bromide in diethylether (100 ml, 100 mmol) over one hour, ensuring the temperature does not exceed 30° C. The stirred reaction mixture is heated to 60° C. for 1 hour, then cooled back to ambient temperature and quenched with a saturated aqueous solution of ammonium chloride (250 ml). The organic phase is washed with brine, dried over magnesium sulphate, and evaporated to a yellow oil. The oil is dissolved in methanol (300 ml), treated with concentrated hydrochloric acid (25 ml), and stirred at ambient temperature for 18 hours. The solvent is evaporated and the residue partitioned between ethylacetate (250 ml) and saturated sodium bicarbonate solution (250 ml). The aqueous phase is extracted with more ethylacetate and the combined organic phases, treated with magnesium sulphate and charcoal, filtered and evaporated to afford (1-Benzhydryl-azetidin-3-yl)-(4-chloro-phenyl)-methanone. [MH]+ 361.99
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35]OS(C)(=O)=O)=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].Cl.[CH3:42][NH:43][CH3:44].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:42][N:43]([CH2:35][C:3]1[C:2]([F:1])=[C:26]([NH:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:32])[CH3:31])[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:22])[CH3:20])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]=1[F:34])[CH3:44]
Reactant: CNC
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(COS(C)(=O)=O)c(F)c3o2)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)Cc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.8 %

Procedure:
800 mg (1.37 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methanesulfonyloxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 120 (1) was dissolved in 10 mL of dimethylformamide, 558 mg (6.85 mmol) of dimethylamine hydrochloride and 945 mg (6.85 mmol) of potassium carbonate were added and the mixture was stirred at room temperature for 45 minutes. Water was added to the reaction solution and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 727 mg of 7-dimethylaminomethyl-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 100%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[C:3]=1[NH:11][CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:16]=[CH:15][C:14]=1[F:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])=[C:4]([CH3:10])[C:3]=1[NH:11][CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:16]=[CH:15][C:14]=1[F:26]
Reactant: Cc1cc(O)c(C)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCC(=O)OC(C)C)c(C)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a solution of 4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-2,5-dimethyl-phenol (220 mg, 0.62 mmol, 1.0 eq) in DMF (6 mL) was added Cs2CO3 (301 mg, 0.92 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 30 min, then isopropyl bromoacetate (134 mg, 0.74 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 1 h. TLC showed the starting material was not consumed. A further portion of Cs2CO3 (300 mg, 0.92 mmol, 1.5 eq) was added and the reaction stirred for 1 h, then a further portion of isopropyl bromoacetate (134 mg, 0.74 mmol, 1.2 eq) was added and the reaction stirred for 4 h. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 50:1 to 20:1) to give the title compound as a colorless oil (225 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.Cl[C:23]1[CH:33]=[C:27]2[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=1)[CH2:20][O:21][C:23]1[CH:33]=[C:27]2[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2ccc(C(F)(F)F)cc2)c(F)c1
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3ccc(C(F)(F)F)cc3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3,5-difluoro-4-(4-(trifluoromethyl)phenoxy)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:13](=[O:32])[CH2:14][C:15]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:18]=3[S:17](=[O:31])(=[O:30])[N:16]=2)[C@H:10]2[CH2:38][C@@H:7]1[CH2:8][CH2:9]2)=O)C.[O-]CC.[Na+].Cl>C(O)C>[CH:35]1([CH2:34][CH2:33][N:12]2[C:13](=[O:32])[C:14]([C:15]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][C:18]=4[S:17](=[O:30])(=[O:31])[N:16]=3)=[C:4]([OH:3])[C@H:6]3[C@@H:11]2[C@H:10]2[CH2:38][C@@H:7]3[CH2:8][CH2:9]2)[CH2:36][CH2:37]1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC1CC1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(CCC3CC3)C1=O)N2
Temperature: 25 °C
Reaction time: 23 h
Yield: 22.9 %

Procedure:
To a solution of the crude (1S,2R,3S,4R)-3-{(2-cyclopropyl-ethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester in absolute ethanol (11 mL) was added a 21 wt. % solution of sodium ethoxide in ethanol (2.4 mL, 7.41 mmol). After shaking at 25° C. for 23 h, additional 21 wt. % solution of sodium ethoxide in ethanol (1.0 mL, 3.09 mmol) was added. After shaking at 25° C. for 6 h, additional 21 wt. % solution of sodium ethoxide in ethanol (1.0 mL, 3.09 mmol) was added and the mixture was shaken for another 24 h. The mixture was then acidified with 1.0M aqueous hydrochloric acid solution (22 mL) and was extracted with ethyl acetate (3×60 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min @30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, N-{3-[(1R,2S,7R,8S)-3-(2-cyclopropyl-ethyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (160.7 mg, 0.309 mmol, 22.9% over two steps), as a solid. 1H NMR (400 MHz, CDCl3) δ: 0.09-0.15 (2H, m), 0.49-0.54 (2H, m), 0.64-0.73 (1H, m), 1.27-1.31 (2H, m), 1.48-1.78 (6H, m), 2.55-2.56 (1H, m), 2.74-2.80 (1H, m), 2.85 (1H, d, J=9.2 Hz), 3.06 (3H, s), 3.10-3.17 (1H, m), 3.57 (1H, d, J=9.2 Hz), 3.80-3.87 (1H, m), 6.99 (1H, s), 7.22-7.25 (1H, m), 7.62-7.68 (2H, m). LC-MS (ESI) calcd for C23H28N4O6S2 520.15, found 521.4 [M+H+].
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH3:13])[CH:6]=1)=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][N:16]=1>C(#N)C>[BrH:1].[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][N:16]3[CH:2]=2)=[CH:6][C:7]=1[O:12][CH3:13]
Reactant: COc1cc(C(=O)CBr)ccc1O
Reactant: Nc1ccc(I)cn1
Solvent: CC#N
Product: Br
Product: COc1cc(-c2cn3cc(I)ccc3n2)ccc1O

Procedure:
First, 2-bromo-4′-hydroxy-3′-methoxyacetophenone and 2-amino-5-iodopyridine are dissolved in an inactive solvent such as acetonitrile, and are allowed to react with each other at a reflux temperature for 2 to 6 hours to produce 2-(4′-hydroxy-3′-methoxyphenyl)-6-iodoimidazo[1,2-a]pyridine hydrobromide salt as white precipitates. The solvent used in this instance may be acetonitrile or another solvent that is usually employed in a similar reaction, for example, methanol and acetone. The reaction temperature may be a temperature allowing refluxing, for example, 110° C. when the solvent is acetonitrile. The amount of the solvent to be used may be an amount sufficient to effect the reaction, however, it should be noted that if the solvent is too much, it will become difficult to obtain precipitates of reaction products. For example, when 2-bromo-4′-hydroxy-3′-methoxyacetophenone in an amount corresponding to 2 mmol is used for the reaction, the amount of a solvent to be used can be about 15 to 30 mL.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][F:20].[H][H]>CO.N1C2C(=CC=CC=2)C=CC=1.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][F:20]
Reactant: FCCCCCCCCC#CCCOC1CCCCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: FCCCCCCCC/C=C\CCOC1CCCCO1
Yield: 98.1 %

Procedure:
A solution of 12-fluoro-3-dodecyn-1-yl tetrahydropyranyl ether (0.5262 g, 1.85 mmol) (prepared as in Example 3 above) in methanol (10 mL) containing about 4 drops of quinoline is hydrogenated at room temperature over 5% palladium on barium sulfate (25 mg). The mixture is kept at about 762 psi of hydrogen until 41.5 ml (1.85 mmol) of hydrogen has been absorbed. The catalyst is then filtered off and the solvent removed in vacuo. The residue is purified by flash chromatography using hexane/ethyl acetate (9:1, v/v) to give 12-fluoro-(Z)-3-dodecen-1-yl tetrahydropyranyl ether (0.52 g, 99%) as a clear oil: Rf=0.65, hexane/ethyl acetate (7:3, v/v); IR (film) ν3025 (C=CH); and 1H-NMR δ1.20-1.80 (m, 18H), 2.05 (m,2H), 2.35 (br q, J=4 Hz, 2H), 3.60 (m, 4H), 4.41(dt, J=48 Hz, 2H), 4.56 (br s, 1H), 5.41 (m, 2H).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:12]2)=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:4]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11]3([O:15][CH2:16][CH2:17][O:18]3)[CH2:12]2)=[CH:7][CH:6]=1)#[CH:3]
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)CC1(CC2)OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2c(c1)CC1(CC2)OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A solution of 3', 4'dihydro-7'[2-(trimethylsilyl)ethynyl]spiro[1,3-dioxolane-2,2'(1'H)-naphthalene](1.45 g, 5.02 mmol ) and suspended K2CO3 (0.50 g) in methanol (20 ml) was stirred at room temperature for 30 minutes. The solution was then filtered and concentrated in vacuo. The residue was absorbed onto silica gel (2 g) and purified by chromatography on silica gel (1 hg) eluting with diethyl ether:hexane (1:9) to give 7'-ethynyl-3', 4'-dihydrospiro[1,3-dioxolane-2,2'(1'H)-naphthalene] as a solid (0.85 g). 1H NMR (CDCl3, 200 MHz) δ: 1.94 (t, J=7 Hz, 2H, CH2), 2.95 (s, 2H, CH2), 2.98 (t, J=7 Hz, 2H, CH2), 3.01 (s, 1H, ethynyl H), 4.02 (s, 4H, OCH2CH20), 7.07 (d, J=8 Hz, 1H, Ar), 7.19 (s, 1H, Ar), 7.24 (d, J=8 Hz, 1H, Ar).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]O>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([O:1][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])[CH:3]=3)[N:8]=[CH:7][N:6]=2)=[CH:17][CH:18]=1
Reactant: COCCOCCO
Reactant: COc1ccc(CNc2ncnc3cc(OC)c(O)cc23)cc1
Product: COCCOCCOc1cc2c(NCc3ccc(OC)cc3)ncnc2cc1OC

Procedure:
6-Hydroxy-4-(4-methoxybenzylamino)-7-methoxyquinazoline was reacted with 2-(2-methoxyethoxy)ethanol using an analogous procedure to that described in the second last paragraph of Note [1] immediately above that is concerned with the preparation of starting materials. There was thus obtained (4-(4-methoxybenzylamino)-7-methoxy-6-[2-(2-methoxyethoxy)ethoxy]quinazoline; NMR Spectrum: (CDCl3) 3.51 (m, 2H), 3.68 (m, 2H), 3.82 (s, 3H), 3.88 (m, 2H), 3.96 (s, 3H), 4.26 (m, 2H), 4.76 (d, 2H), 5.87 (t, 1H), 6.89 (d, 2H), 7.13 (s, 1H), 7.19 (s, 1H), 7.34 (d, 2H), 8.59 (s, 1H); Mass Spectrum: M+H+ 414.