Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH:10]([N:12]([CH2:17][CH2:18][O:19][CH3:20])[S:13]([CH3:16])(=[O:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:21])[CH:8]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([O:31][CH2:32][CH2:33][CH2:34]Br)[CH3:30]>CCCCCCC.CC(=O)OCC>[CH2:29]([O:31][CH2:32][CH2:33][CH2:34][O:21][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:22])([CH3:1])[CH2:11][CH:10]2[N:12]([CH2:17][CH2:18][O:19][CH3:20])[S:13]([CH3:16])(=[O:15])=[O:14])[CH3:30]
Reactant: COCCN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O
Reactant: CCOCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOCCCOc1ccc2c(c1)C(N(CCOC)S(C)(=O)=O)CC(C)(C)O2

Procedure:
0.5 g (1.5 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-(2-methoxyethyl)methanesulfonamide (Example 16b) was reacted with potassium carbonate and 3-ethoxy-1-bromopropane analogously to Example 1g. After column chromatography on silica gel using n-heptane/EA (5:1), 0.35 g of oily product was obtained.
Reaction SMILES: CN(C=O)C.[Si:6]([O:13][CH2:14][CH2:15][CH2:16][C@H:17]([C@@H:19]1[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@H:33]([CH2:34][CH2:35]2)[C@:31]2([CH3:32])[C@H:26]([CH2:27][C@@H:28]([O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)[CH2:29][CH2:30]2)[CH2:25][C@H:24]3[OH:45])[CH2:21][CH2:20]1)[CH3:18])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH2:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1COCC1>[CH2:46]([O:45][C@@H:24]1[CH2:25][C@@H:26]2[C@:31]([CH3:32])([CH2:30][CH2:29][C@H:28]([O:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][O:40]3)[CH2:27]2)[C@@H:33]2[C@@H:23]1[C@H:22]1[C@:36]([CH3:37])([CH2:35][CH2:34]2)[C@@H:19]([C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][O:13][Si:6]([C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:8])[CH3:7])[CH2:20][CH2:21]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 400 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A flame-dried round-bottom flask with stirring bar was charged with sodium hydride (60% in mineral oil, 28 mg, 0.69 mmol), equipped with a septum and a gas-needle inlet and flushed with argon. The mineral oil was removed by washing (3×) with dry pentane, and the pentane was removed to provide the sodium hydride as a powder. Dry DMF (2.0 ml) was added. A solution of alcohol 2006 (40 mg, 0.069 mmol) in dry THF (2 ml) was added dropwise via syringe. The reaction mixture was stirred overnight and then heated to 400° C. in an oil bath over a 20-minute period. Freshly distilled benzyl bromide (0.165 ml, 1.38 mmol) was added dropwise, and the reaction mixture was stirred at 400° C. for 10 hours. The reaction was allowed to cool to room temperature, and the solvent was removed under reduced pressure. The flask was placed under vacuum overnight to remove any residual DMF. The crude material was purified by flash chromatography (SiO2, hexanes:EtOAc 50:1) giving compound 2007 as a white solid (40 mg, 0.060 mmol, 87%). A gradient of increasing EtOAc concentration provided other components, including the 7α-formate (1 mg, 1%) as well as recovered starting material (3 mg, 8%). Compound 2007:=1H NMR (500 MHz, CDCl3) δ 7.35-7.20 (m, 5 H, benzyl Ar-CH2), 4.73-4.66 (m, 1 H, methine H), 4.535 (d, J=12.0 Hz, 1/2 H, benzyl-CH2) , 4.53 (d, J=12.0 Hz, 1/2 H, benzyl-CH2), 4.26 (d, J=12.2 Hz, 1/2 H, benzyl-CH2), 4.245 (d, J=11.8 Hz, 1/2 H, benzyl-CH2), 3.95-3.85 (m, 1 H, THP CH2O), 3.66-3.52 (m, 3 H, THP CH2O & C-24 H), 3.50-3.45 (m, 1 H, C-3 H), 1.08 (s, 3 H, C-19 H), 0.91 (d, J=6.6 Hz, C-21 H), 0.89 (s, 9H, t-Bu), 0.64 (s, 3 H, C-18 H), 0.04 (s, 6 H, TBDMS CH3); MS (CI/isobutane) m/z 668 (M+1, 6%), 584 (M+1-THP, 18%), 475 (M+1-THPOH, 30%), 457 (M+1-THPOH-HOBn, 58%), 343 (M+1-THP-HOBn-TBDMSOH, 100%), 325 (M+1-THPOH-TBDMSOH-HOBn, 83%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:16]1[C:22](=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH:17]1[CH3:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(P(N(C)C)(N(C)C)=O)C.C([C:38]([O:40][CH3:41])=[O:39])#N>C1COCC1>[CH2:9]([N:16]1[C:22](=[O:23])[CH:21]([C:38]([O:40][CH3:41])=[O:39])[CH2:20][O:19][CH2:18][CH:17]1[CH3:24])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C#N
Reactant: CC1COCCC(=O)N1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1COCC(C)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of lithium diisopropylamide in THF (0.101 M, 100 mL, 10.1 mmol, 1.30 equiv) freshly prepared at −78° C. was added via cannula to a solution of 4-benzyl-3-methyl-1,4-oxazepan-5-one (4-3, 1.71 g, 7.80 mmol, 1 equiv) in THF (100 mL) at −78° C. and the resulting mixture was stirred for 20 min. HMPA (1.36 mL, 7.80 mmol, 1.00 equiv) was added followed by methyl cyanoformate (1.24 mL, 15.6 mmol, 2.00 equiv). The resulting mixture was warmed to 0° C., stirred for 20 min, and then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (20% EtOAc in hexanes initially, grading to 100% EtOAc) to give methyl 4-benzyl-3-methyl-5-oxo-1,4-oxazepane-6-carboxylate (4-4) as a mixture of diastereomers (colorless oil). LRMS m/z (M+H) 278.2 found, 278.1 required.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>>[C:12]1(=[O:17])[N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12
Reactant: Nc1cccc2cccnc12
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1c1cccc2cccnc12

Procedure:
Referring to the above equations, the starting 8-aminoquinoline I was treated with phthalic anhydride to give the 8-phthalimidoquinoline II. This was necessary to provide protection for the 8-amino group during peroxidation and introduction of the 2-chloro group. Thus compound II was treated with MCPBA, followed by chromatography over basic alumina to afford the 1-oxide III. Intermediate III was treated directly (preferred procedure) with phosphorus oxychloride to afford the 2-chloro derivative V. However, it was discovered also that treatment of the reaction mixture from the oxidation step with a combination of basic and neutral alumina gave the 2-quinolone IV which was converted also with phosphorus oxychloride to give the 2-chloro derivative V, albeit in lower yield.
Reaction SMILES: C1(C2C(=O)[C:11]34[CH2:18][CH2:17][O:16][C:12]3=[N:13][CH:14]=[N:15][C:10]4=CC=2)C=CC=CC=1.P(Cl)(Cl)([Cl:23])=O.[CH:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Cl:23][C:10]1[C:11]2[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:17][O:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1C(c2ccccc2)=CC=C2N=CN=C3OCCC123
Reactant: c1ccccc1
Product: Clc1ncnc2occ(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 100 mL round bottom flask was placed 5-phenylfuro[2,3-d]benzopyrimidin-4 (3H)-one (1.12 g, 5.3 mmol) and benzene (75 mL). The flask was equipped with a stir bar, reflux condenser, and Dean-Stark trap, and the reaction was allowed to reflux with stirring for 1 hour azeotropically removing the water formed. The reaction was cooled to room temperature. Phosphorus oxychloride was added (2.43 g, 15.9 mmol) dropwise, the flask equipped with a reflux condenser and the reaction was heated at reflux for 20 hours with stirring.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:24])=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][C:6]1[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[N:13]([CH:14]=1)[CH:12]=[CH:11][CH:10]=[CH:9]2.N1C=CC=CC=1.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(N(CC)CC)C>C(Cl)Cl.Cl>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:32]([C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:6]=2[CH2:5][C:4]2[CH:21]=[CH:22][CH:23]=[C:2]([F:1])[C:3]=2[CH3:24])=[O:34])[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: Cc1c(F)cccc1Cc1cn2ccccc2c1-c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1.33 h
Yield: 76.8 %

Procedure:
The compound of step 3 (0.635 g, 2.01 mmol) was dissolved in DCM (5 ml) under argon and cooled at 0° C. Pyridine (0.16 ml, 2.01 mmol) and triphosgene (0.598 g, 2.01 mmol) were added, and the mixture was stirred at room temperature for 80 min. The mixture was then added dropwise to a solution of 1-tert-butoxycarbonyl-piperazine (1.50 g, 8.05 mmol) and triethylamine (1.12 ml, 8.05 mmol) in DCM (15 ml) cooled to 0° C. After stirring at room temperature overnight, the mixture was diluted with 1 N hydrochloric acid and extracted with DCM. The extracts were washed with a saturated solution of sodium hydrogencarbonate and twice washed with saturated solution of sodium chloride. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography with DCM/MOH (from 100:0 to 98:2) and subsequent silica gel chromatography with cyclohexane/EA (from 100:0 to 70:30) to give 0.815 g of 4-[2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizin-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester as a light pink powder. For removal of the tert-butoxycarbonyl group and conversion into the hydrochloride, 0.689 g of the obtained product were dissolved in DCM (10 ml), the solution cooled to 0° C. and saturated with gaseous hydrogen chloride. After stirring for 1 h at 0° C., the mixture was evaporated to dryness. The residue was triturated with diethyl ether, filtered, washed with diethyl ether and dried under reduced pressure to give 0.53 g of the title compound in the form of [2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizin-3-yl]-piperazin-1-yl-methanone hydrochloride as an off-white powder with the following characteristics:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[C:25]([Br:29])=[C:26]([Br:28])[S:27][C:21]=2[N:20]=[C:19]1[CH:30]([NH:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH2:31][CH3:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[C:25]([Br:29])=[C:26]([Br:28])[S:27][C:21]=2[N:20]=[C:19]1[CH:30]([N:33]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:31][CH3:32])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC(NCCN(C)C)c1nc2sc(Br)c(Br)c2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(c1nc2sc(Br)c(Br)c2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (19 mg, 0.085 mmol, 1 equiv) in dichloromethane (1 mL) was added to a solution of 3-benzyl-5,6-dibromo-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one (2-7, 45 mg, 0.085 mmol, 1 equiv) and N,N-diisopropylethylamine (11 mg, 0.085 mmol, 1 equiv) in dichloromethane (5 mL), and the resulting reaction mixture was stirred under ambient conditions for 1 h. The reaction mixture was washed with saturated aqueous NaHCO3 solution, then brine, and dried (MgSO4) and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide N-[1-(3-benzyl-5,6-dibromo-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide (2-9) as a colorless foam. MS(M+1)=708.9
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].[OH-].[K+:12]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O-:10])=[CH:6][CH:5]=1)[CH3:2].[K+:12]
Reactant: CCOc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Product: CCOc1ccc([O-])cc1

Procedure:
In a 50-ml flask at ambient temperature 4-ethoxy-phenol (Aldrich) (1492 mg, 10.8 mmoles) was stirred with 2.0 M aqueous KOH (5.50 ml) to form potassium 4-ethoxyphenolate. Methyl 4-chloro-3,5-dinitrobenzoate (Ullmann, 1909, Annalen der Chemie 366:92-93; commercial source: Spectrum Chemical Company, Gardena, Calif.; 2606 mg, 10.0 mmoles) was added, the mixture heated to reflux for 1 hour and chilled in an ice-bath, whereupon a rubbery mass of product deposited. Cold aqueous 1.0 M KOH (20 ml) was added, and 35 upon continued chilling the product solidified. The yellow-orange solid was broken-up, collected on a suction filter, rinsed with water and dried. The material (3.08 g) was crystallized from hot 95% ethanol (50 ml) to give 2.56 g (70.6% yield) of methyl 3,5-dinitro-4-(4′-ethoxyphenoxy)benzoate. Melting point: 101-103° C.
Reaction SMILES: [Cl:1][C:2]([CH3:16])([CH2:13][CH2:14][CH3:15])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([Cl:11])=[C:7](Cl)[CH:6]=[N:5]1.[CH2:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1)[CH3:18].[OH-].[K+]>CN(C)C=O>[Cl:11][C:8]1[C:9](=[O:10])[N:4]([CH2:3][C:2]([Cl:1])([CH3:16])[CH2:13][CH2:14][CH3:15])[N:5]=[CH:6][C:7]=1[O:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=1
Reactant: CCc1ccc(CO)cc1
Reactant: CCCC(C)(Cl)Cn1ncc(Cl)c(Cl)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCC(C)(Cl)Cn1ncc(OCc2ccc(CC)cc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
In 20 ml of N,N-dimethylformamide were added 1.2 g of 2-(2-chloro-2-methylpentyl)-4,5-dichloro-3(2H)-pyridazinone and 0.64 g of 4-ethylbenzyl alcohol, and thereto was added 0.31 g of powdery potassium hydroxide under ice-cooling and stirred for one day at room temperature. Then, the procedures in Preparation Example 2 were repeated to give 600 mg of the intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([NH:30][C:31](OC(C)(C)C)=[O:32])[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:39]1([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][C@H:40]1C(O)=O.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([NH:30][C:31]([C@@H:40]2[CH2:41][C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:48][N:39]2[C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[O:32])[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Temperature: 25 °C

Procedure:
To a round-bottomed flask equipped with stirring was added N-[(1R)-1-[(3,4-dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]-(tert-butoxy)carboxamide (Step a) (0.455 g, 0.8 mmol) and a saturated soln of anhydrous HCl in EtOAc (20 mL). The reaction mixture was stirred at RT for 1 h then concentrated in vacuo to provide a solid. The solid was dissolved in DMF (10 mL), stirred at 0° C. and treated with Boc-L-TicOH (Advanced ChemTech) (0.25 g, 0.9 mmol), HOAT (Aldrich) (0.122 g, 0.9 mmol), TEA (Aldrich) (0.188 mL, 1.35 mmol) then EDC (Advanced ChemTech) (0.26 g, 1.35 mmol). The reaction mixture was warmed to RT over 2 h, then stirred at RT for 12 h. The reaction mixture was diluted with EtOAc (70 mL), washed with satd NaHCO3, (50 mL), satd NaCl (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (1:1 EtOAc:hexane then 100% EtOAc) provided the title compound as a white foam (0.54 g). MS (ESI, pos. ion) m/z: 729 (M+1); MS (ESI, neg. ion) m/z: 727 (M−1). Calc'd for C36H42Cl2N4O6S: 728.22.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH:25]=[C:26](Br)Br)[N:22]=[N:21]4)[O:16][C:15]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1.[CH2:32]([Sn](CCCC)(CCCC)CCCC)[CH:33]=C.COC1C=CC(P(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)=CC=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C.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]>[O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([C:25]#[C:26][CH:32]=[CH2:33])[N:22]=[N:21]4)[O:16][C:15]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1O[C@@H](Cn2cc(C=C(Br)Br)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Agent: [Pd]
Agent: COc1ccc(P(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CC#Cc1cn(C[C@H]2CN(c3ccc(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)nn1
Temperature: 80 °C
Yield: 13.9 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2,2-dibromoethenyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (Example 25) (0.3 g, 0.52 mmol), allyl tributyl tin (160 μl, 0.55 mmol) and tris(4-methoxyphenyl)phosphine (28 mg, 0.08 mmol) were dissolved in DMF (2.5 ml). Diisopropylethyl amine (136 μl, 0.78 mmol) was added, the reaction mixture was flushed with argon and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) was added. The mixture was heated to 80° C. for 10 hours under argon. It was diluted with ethyl acetate, washed with phosphate buffer (pH 7), saturated aqueous potassium fluoride solution and with water and dried over sodium sulfate. Chromatography on silica gel with chloroform/methanol (15:1) gave 32 mg (14%) of the title compound as a colourless solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][N:7]([CH3:10])[CH:8]=O.[NH:11]1[C:20](=O)[C:19]2[NH:18][CH:17]=[N:16][C:15]=2[N:14]=[C:12]1[NH2:13].O.C(=O)([O-])O.[Na+]>>[CH3:6][N:7]([CH:8]=[N:13][C:12]1[N:14]=[C:15]2[C:19]([NH:18][CH:17]=[N:16]2)=[C:20]([Cl:3])[N:11]=1)[CH3:10]
Reactant: CN(C)C=O
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)C=Nc1nc(Cl)c2[nH]cnc2n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
115.0 g (0.75 mol) of phosphorus oxychloride was added to 263.1 g (3.6 mol) of N,N-dimethylformamide, and 45.3 g (0.3 mol) of guanine (manufactured by Sumika Fine Chemicals Co., Ltd.) was then added, followed by stirring at 100° C. for 5 hours. After cooling, the reaction mixture was added to 1500 ml of water containing 315.0 g (3.75 mol) of sodium hydrogen carbonate. The precipitating crystal was collected by filtration and washed with 500 ml of water to yield a crystal of 2-dimethylaminomethyleneamino-6-chloropurine, whose properties are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[CH3:22])=[CH:7][N:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]2)=[O:4].I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(=O)C.[K+].O>CN1C(=O)CCC1.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[CH3:22])=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]2)=[O:4]
Reactant: COC(=O)c1c(Cc2cccc(F)c2C)cn2ccccc12
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c(Cc2cccc(F)c2C)c(-c2ccccc2)n2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.4 %

Procedure:
The compound of step 2 (1.79 g, 6.02 mmol), iodo-benzene (1.47 g, 7.22 mmol), potassium acetate (1.18 g, 12.03 mmol) and bis(triphenylphosphine)palladium(II) chloride (844 mg, 1.20 mmol) in NMP were heated at 100° C. for 10 min under argon. Then water (844 mg, 36.10 mmol) was added and heating continued for 12 h. The mixture was cooled to room temperature, diluted with DCM and washed with water. The organic phase was dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (HEP/EA) to give 729 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[Br:17]Br.O>ClCCl.[Fe]>[Br:17][C:7]1[C:2]([OH:1])=[C:3]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=[C:5]([CH3:8])[CH:6]=1
Reactant: BrBr
Reactant: Cc1ccc(O)c(C(=O)c2ccccc2)c1
Agent: [Fe]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Br)c(O)c(C(=O)c2ccccc2)c1
Reaction time: 0.33 h
Yield: 86.2 %

Procedure:
To a solution of 116 g (0.55 mol) of 25 in 200 mL of dry dichloromethane, 1.5 g of iron turnings was added, and then a solution of 41.4 mL (136 g, 0.83 mol) of bromine in 500 mL of dichloromethane was added dropwise with vigorous stirring for 20 min. This mixture was refluxed for 30 min, and then 1200 mL of water was added. The organic layer was separated, and the aqueous layer was extracted with 2×300 mL of dichloromethane. The combined organic extract was washed by saturated aqueous Na2SO3, dried over K2CO3, and then evaporated to dryness. Drying the residue in vacuum gave 138 g (86%) of the title product (bp 165-172° C./1 mm).
Reaction SMILES: C(Cl)CCl.Cl.[O:6]=[C:7]1[NH:16][C:15]2[N:14]=[CH:13][C:12](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:11][C:10]=2[CH2:9][CH2:8]1.CNC[C:25]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:27]2[CH2:34][CH2:35][CH2:36][C:26]=12.C1C=CC2N(O)N=NC=2C=1.C[CH2:48][N:49](CC)[CH2:50]C>CN(C=O)C.O>[CH2:36]1[C:26]2[N:27]([CH:28]=[CH:29][C:30]3[C:25]=2[C:33]([CH2:48][N:49]([CH3:50])[C:19](=[O:21])/[CH:18]=[CH:17]/[C:12]2[CH:13]=[N:14][C:15]4[NH:16][C:7](=[O:6])[CH2:8][CH2:9][C:10]=4[CH:11]=2)=[CH:32][CH:31]=3)[CH2:34][CH2:35]1
Reactant: CCN(CC)CC
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccc2ccn3c(c1-2)CCC3)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reaction time: 8 h
Yield: 25 %

Procedure:
EDC (0.192 g, 1.0 mmole) was added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt (0.254 g, 1.0 mmole), 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene (0.2 g, 1.0 mmole), HOBt.H2O (0.135 g, 1.0 mmole), and Et3N (0.15 mL, 1.1 mmole) in DMF (20 mL) at RT. The reaction was stirred overnight, then was poured into H2O (50 mL) and extracted with CH2Cl2 (2×30 mL). The combined extracts were washed with brine and dried (MgSO4). Flash chromatography on silica gel (5% MeOH/CH2Cl2) gave the title compound (0.1 g, 25%) a yellow solid: MS (ES) m/e 401 (M+H)+.