Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[C:20]([O:24][C:25](=[O:31])[N:26]([CH3:30])[CH2:27][CH:28]=O)([CH3:23])([CH3:22])[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:20]([O:24][C:25](=[O:31])[N:26]([CH2:27][CH2:28][N:17]1[CH2:16][CH2:15][N:14]([C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:13][CH:12]=[CH:11][N:10]=2)[CH2:19][CH2:18]1)[CH3:30])([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(CCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
Dissolve 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (2.5 g, 9.7 mmol, 1 eq.) in 1,2 dichloroethane (20 mL). Add methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester (1.77 g, 10.19 mmol, 1.05 eq.). Add sodium triacetoxy-borohydride (3.10 g, 14.6 mmol, 1.5 eq.). Stir at room temperature for 18 hr. Partition the reaction mixture between aqueous saturated NaHCO3 and dichloromethane. Separate the layers. Extract the organic layer with dichloromethane (2×100 mL). Combine the organic layers, dry over anhydrous Na2SO4, filter and concentrate. Purify by normal phase chromatography with 30% EtOAc/hexane—100% EtOAc to afford the title preparation (3.8 g, 97% yield). MS (loop): m/z=416.3 [M+H].
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][CH:7]=1.[CH:15]([NH:17][NH2:18])=O>C(O)CCC>[F:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:15]=[N:17][N:18]=3)[N:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NNC=O
Reactant: Fc1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCCCO
Product: Fc1cccc(-c2ccc3nncn3n2)c1

Procedure:
A mixture of 3.6 g. of 3-chloro-6-(m-fluorophenyl)pyridazine and 2.06 g. of formylhydrazine in 50 ml. of n-butanol is refluxed for 48 hr. and worked up as in Example 35 to give the product as crystals, m.p. 159°-161° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH:18]([NH:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:32][C:31](=O)[CH2:30]2)=[CH:25][CH:24]=1)([CH3:20])[CH3:19]>O1CCCC1>[C:7]([CH:9]=[C:31]1[CH2:32][N:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]([NH:21][CH:18]([CH3:20])[CH3:19])=[O:34])=[CH:24][CH:25]=2)[CH2:30]1)#[N:8]
Reactant: CC(C)NC(=O)c1ccc(N2CC(=O)C2)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1ccc(N2CC(=CC#N)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a cooled (at −6 to 0° C.) solution of 1.0 M potassium tert-butoxide in tetrahydrofuran (7.10 mL, 7.10 mmol) was added dropwise a solution of diethyl cyanomethylphosphonate (1.20 mL, 7.43 mmol, Aldrich: Cat. #D91705) in tetrahydrofuran (10.0 mL) over a period of 10 minutes and at −6 to 0° C. The reaction was warmed and stirred at room temperature for 1 hour. The reaction mixture was re-cooled at −6° C. To the reaction mixture was then added a solution of N-isopropyl-4-(3-oxoazetidin-1-yl)benzamide (1.30 g, 5.60 mmol) in tetrahydrofuran (10.0 mL) over a period of 10 minutes. During this time the temperature of the reaction mixture was between −5 to 0° C. The reaction was allowed to warm to room temperature and was stirred for 3 hours. The reaction mixture was filtered through a pad of silica gel and washed with ethyl acetate. The filtrate was concentrated, and the residue was treated with ether. The precipitates formed were collected by filtration to give 0.60 g desired product. The mother liquid was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (gradient: 30-80%) to afford the desired product (0.21 g). the total product is 0.81 g (57%). LCMS (M+H)+: m/z=256.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:12])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[OH:8].C(O[C:16]([S-])=[S:17])C.[K+].C(O)C>O>[S:17]=[C:16]1[NH:1][C:2]2[CH:3]=[C:4]([CH:9]([CH3:12])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=2[O:8]1
Reactant: CCOC(=S)[S-]
Reactant: CC(C#N)c1ccc(O)c(N)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C#N)c1ccc2oc(=S)[nH]c2c1

Procedure:
A mixture of 2-(3-amino-4-hydroxyphenyl)propionitrile (4.86 g.), potassium ethylxanthate (5.3 g.), ethanol (30 ml.) and water (5.0 ml.) was heated under reflux for four hours. The mixture was filtered, diluted with water (15 ml.), acidified with acetic acid and then diluted with more water. The resulting brown precipitate was filtered off and recrystallised from aqueous ethanol to give 2-(2-thioxo-2,3-dihydrobenzoxazol-5-yl) propionitrile, m.p. 173°-6° C. Dry chlorine was passed into a suspension of the thione (8.0 g.) in freshly dried and distilled chloroform (200 ml.). After 20 hours, most of the solid had dissolved and the mixture was filtered. The filtrate was washed with water (100 ml.), 1N sodium hydroxide (50 ml.) and water (3 × 100 ml.) The dried (Na2SO4) organic solution was evaporated to yield 2-[2-chloro-5-benzoxazolyl]propionitrile as a brown oil which was shown to be a single compound by thin layer chromatography. The oil distilled at 128°-134° C./0.3 mm.Hg.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[CH:17]=[CH:16][C:11]([NH:12]C(=O)C)=[N:10][C:8]1=[O:9])=[N+:2]=[N-:3].N>CO>[N:1]([CH2:4][CH2:5][CH2:6][N:7]1[CH:17]=[CH:16][C:11]([NH2:12])=[N:10][C:8]1=[O:9])=[N+:2]=[N-:3]
Reactant: CC(=O)Nc1ccn(CCCN=[N+]=[N-])c(=O)n1
Agent: N
Solvent: CO
Product: [N-]=[N+]=NCCCn1ccc(N)nc1=O

Procedure:
A mixture of 1-(3-azidopropyl)-N4-acetylcytosine was reacted with 7N ammonia solution in methanol at room temperature for 2 days to give 1-(3-azidopropyl)cytosine as a white solid.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH:19]=[C:18]([C:21]2[N:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1.CO>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH:17]=[C:18]([C:21]2[N:26]=[CH:25][C:24]([C:27]([O:29][CH3:1])=[O:28])=[CH:23][N:22]=2)[CH2:19][CH2:20]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ncc(C(=O)O)cn2)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(C2=CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
(Trimethylsilyl)diazomethane, 2M in hexanes (4.19 ml, 8.38 mmol) was added dropwise to 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid (1.28 g, 4.19 mmol) in toluene (12 ml) and methanol (3.00 ml) at 25° C. over a period of 2 mins under nitrogen. The resulting solution was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with the dropwise addition of acetic acid until bubbling ceased, then the reaction mixture was diluted with EtOAc (100 mL) and water (100 mL). The organic layer was removed and the aqueous further extracted with EtOAc (2×50 mL). The combined organics were washed with sodium hydrogen carbonate solution (100 mL), water (100 mL), brine (100 mL) and dried over MgSO4, filtered and evaporated to afford methyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate (1.182 g, 88%) as a yellow solid. This was used directly with no further purification.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][N:4]=[C:5]([NH2:27])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)[N:8]=1.O.NN>C(O)C>[F:29][C:2]([F:1])([F:28])[CH2:3][N:4]=[C:5]([NH2:27])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][NH2:16])[N:8]=1
Reactant: NC(=NCC(F)(F)F)Nc1ccnc(SCCN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Yield: 60.1 %

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)-guanidino]-2-(2-phthalimidoethylthio)pyrimidine (0.6 g.) ethanol (20 ml.) and 99% hydrazine hydrate (0.5 ml.) was heated under reflux for 1 hour and then evaporated to dryness. The residue was stirred with N hydrochloric acid and the mixture filtered. The filtrate was basified with 17 N NaOH and the mixture extracted three times with ether. The combined ether extracts were dried and then evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-aminoethylthio)pyrimidine (0.25 g.) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([NH:12][O:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:39][CH2:40][CH2:41][CH2:42][CH2:43]Br>CN(C=O)C.CCOC(C)=O>[Br:39][CH2:40][CH2:41][CH2:42][CH2:43][N:12]([O:13][C:14]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:10](=[O:11])[CH2:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: BrCCCCBr
Reactant: O=C(CSc1ccc(F)cc1)NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CSc1ccc(F)cc1)N(CCCCBr)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
To a solution of 2-(4-fluoro-phenylsulfanyl)-N-trityloxy-acetamide (132.1 mg, 0.228 mmol) from step C and Cs2CO3 (125.6 mg, 0.385 mmol) in anhydrous DMF (3 mL) was added 1,4-dibromo-butane (0.2 ml, 364.8 mg) in one portion and the resulting solution was warmed to 60° C. After TLC indicated the completion of the reaction (<30 min), the reaction mixture was diluted with EtOAc and washed sequentially with water and saturated NaCl solution. The organic phase was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude material, which was then used in next step without further purification.
Reaction SMILES: [C:1]([O:18][CH2:19][CH:20]([CH2:22][OH:23])[OH:21])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[C:48](O)(=O)[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]/[CH:56]=[CH:57]\[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65]>ClCCl>[CH2:48]([O:23][CH2:22][CH:20]([CH2:19][O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[OH:21])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]/[CH:56]=[CH:57]\[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(O)CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCOCC(O)COC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 23 %

Procedure:
Glycerol palmitate (example 2b) (5.516 g, 0.017 mol) was dissolved in dichloromethane (500 ml) and dicyclohexylcarbodiimide (5.165 g, 0.025 mol), dimethylaminopyridine (3.058 g, 0.025 mol) and oleic acid (4.714 g, 0.017 mol) were then added. The reaction mixture was stirred at room temperature for 24 hours. The dicyclohexylurea precipitate was filtered, washed with dichloromethane and the filtrate was evaporated under vacuum. The residue obtained was purified by silica gel chromatography (eluent:CH2Cl2) to give the desired compound as a white solid (yield: 23%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[CH:20]=[CH:19][C:18]([CH:21]5[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]5)=[N:17]4)[CH:14]=3)[N:9](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:8]=2)=[CH:3][CH:2]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[CH:20]=[CH:19][C:18]([CH:21]5[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]5)=[N:17]4)[CH:14]=3)[NH:9][N:8]=2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccn(-c3ccc4c(c3)c(-c3ccncc3)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCCC(c2ccn(-c3ccc4[nH]nc(-c5ccncc5)c4c3)n2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 135 %

Procedure:
To tert-butyl 3-(1-(3-(pyridin-4-yl)-1-trityl-1H-indazol-5-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (140 mg, 0.2 mmol) in DCM (5 mL) were added triethylsilane (40 mg, 0.34 mmol) and trifluoroacetic acid (1 mL), the reaction mixture was stirred at room temperature for 3 h. After concentration, crude mixture was column purified with mixture of methanol, dichloromethane and ammonia to give tert-butyl 3-(1-(3-(pyridin-4-yl)-1H-indazol-5-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (120 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)=[CH:11][CH:10]=1.[CH2:31](I)[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:30][C:20]1[CH:21]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:23]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[N:17][N:18]([CH2:31][CH3:32])[N:19]=2)=[CH:11][CH:10]=1
Reactant: CCI
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(-c3nn[nH]n3)cc2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1nnc(-c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)n1

Procedure:
100 mg of 5-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-2H-tetrazole, 48 mg of ethyl iodide and 141 mg of potassium carbonate are stirred for 4 hours at 50° C. in 3 ml of dimethylformamide. The reaction mixture is poured onto water and extracted with ethyl acetate. Concentration of the organic phase and purification over silica gel yield 5-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-2-ethyl-2H-tetrazole (compound 1.4).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[C:26]([CH2:28][CH3:29])[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])=[CH:14][C:13]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[C:30]([N:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:24]=[CH:25][C:26]([CH2:28][CH3:29])=[CH:27][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]([F:23])[CH:14]=1)[CH2:19][CH2:20][CH2:21][NH2:22])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccc(Oc2ccc(NCCCN)cc2F)c(OCc2ccccc2)c1
Solvent: ClCCl
Product: CCc1ccc(Oc2ccc(N(CCCN)C(C)=O)cc2F)c(OCc2ccccc2)c1

Procedure:
To a solution of N1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine (60 mg, 0.15 mmol) in 10 ml of dry dichloromethane, cooled to 0° C., was added acetic anhydride (20 mg, 0.19 mmol) taken in 0.5 ml of dichloromethane dropwise.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15]2)=[C:11]([Cl:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:15]2[CH3:26])=[C:11]([Cl:23])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCOC(=O)c1cc2c(Cl)cc(OCc3ccccc3)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)cc(OCc3ccccc3)cc2n1C
Temperature: 25 °C

Procedure:
After 3.70 g (11.2 mmol) of ethyl 6-benzyloxy-4-chloro-2-indolecarboxylate was added to a suspension of 0.45 g (11.2 mmol) of 60% sodium hydride in 70 ml of dimethylformamide, the mixture was stirred at room temperature. After the mixture became an almost transparent solution, a solution of 3.18 g (22.4 mmol) of methyl iodide in 10 ml of dimethylformamide was dropwise added to the transparent solution at room temperature followed by stirring for 5 hours at the same temperature. The reaction solution was poured onto ice water. The resulting mixture was then extracted three times with ethyl acetate and the combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was isolated and purified by silica gel column chromatography to give 3.72 (96.4%) of ethyl 6-benzyloxy-4-chloro-1-methyl-2-indolecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][C:6](=[O:16])[CH2:7][NH:8]C(OC(C)(C)C)=O.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][C:6](=[O:16])[CH2:7][NH2:8]
Reactant: COC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNC(=O)CN

Procedure:
N-tert-butoxycarbonyl glycyl glycine methyl ester 19 (9.20 g, 37.4 mmol) was dissolved in a 50% (v/v) solution of TFA in CH2Cl2 (120 mL) at room temperature. The reaction mixture was stirred for 1 h 30 min before the solvent and bulk of excess TFA were evaporated. The residue was washed with Et2O (3×50 mL) and CH2Cl2 (50 mL) and dried affording the title compound as a slightly reddish viscous liquid in quantitative yield and with spectral characteristics in accordance with literature data.9; δH (300 MHz; d6-DMSO) 8.91 (1H, t, J 6, NH), 8.20 (3H, br s, NH3+), 3.96 (2H, d, J 6, CαH2(Gly2)), 3.67-3.59 (5H, m, CαH2(Gly1)/OCH3); 13C-NMR (75 MHz, d6-DMSO): δC 169.9, 166.7, 158.7 (q, JCF 33), 116.4 (q, JCF 294), 54.9, 51.8, 40.6; m/z (ESI) 147.0769 (M+; C5H11N2O3 requires 147.0769)
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:21])([F:20])[C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH:11]1[CH3:19])=[O:9]>>[F:21][C:7]([F:6])([F:20])[C:8]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:16][CH:17]=2)[CH2:12][CH:11]1[CH3:19])=[O:9]
Reactant: CC1Cc2ccccc2N1C(=O)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: CC1Cc2cc(S(=O)(=O)Cl)ccc2N1C(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 1 h
Yield: 7587.5 %

Procedure:
Chlorosulfonic acid (25 ml, 0.37 mmol) was cooled down to 0° C. in a three necked flask equipped with a thermometer. N-trifluoroacetyl-2-methyl-indoline (17 g, 74.23 mmol) was added thereto in several portions. After the resulting mixture was stirred at 60° C. for 1 hour, the reaction mixture was slowly poured into 200 ml of ice water. The precipitate thus formed was collected by filtration and dried to afford 9.2 g of the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:25]=[CH:26][C:27]=1[F:28])[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1.C(N(CC)CC)C>C(Cl)Cl>[F:28][C:27]1[CH:26]=[CH:25][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:8][C:7]=1[NH:6][C:2]([O:4][CH3:5])=[O:3]
Reactant: COC(=O)Cl
Reactant: COc1cc2ncnc(Nc3ccc(F)c(N)c3)c2cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cc(Nc2ncnc3cc(OC)c(OC)cc23)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.4 %

Procedure:
Methyl chloroformate (0.048 ml) was added to a suspension of 4-(3-amino-4-fluoroanilino)-6,7-dimethoxyquinazoline (161 mg) and triethylamine (0.14 ml) in dry methylene chloride (3.5 ml) and the resulting mixture was stirred at ambient temperature for 18 hours. Methylene chloride (100 ml) was added and the mixture washed with water and brine, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified by silica column chromatography, eluting with 3% methanol in methylene chloride to yield the title compound as a solid (16 mg, 8.4%); NMR: 3.66 (s, 3H), 3.92 (s, 3H), 3.96 (s, 3H), 7.16 (s, 1H), 7.22 (t, 1H), 7.57 (m, 1H), 7.82 (s, 1H), 8.01 (m, 1H), 8.42 (s, 1H), 9.34 (s, 1H), 9.47 (s, 1H); m/s: M+H+ 373.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[P:6]([O-:23])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[P:6]([Cl:4])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:23]
Reactant: O=S(=O)(Cl)Cl
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Reaction time: 1.25 h

Procedure:
A solution of sulphuryl chloride (3.48 g) in toluene (25 ml) was added to a stirred solution of dibenzyl phosphite (6.08 ml) in toluene (75 ml) under nitrogen. The mixture was stirred for 75 min. under nitrogen, washed with 8% sodium bicarbonate solution (75 ml) and the organic layer separated and dried over anhydrous sodium sulphate. After filtration the filtrate was evaporated and dried to give dibenzyl chlorophosphate (7.75 g) as a colourless oil. Potassium carbonate (1.81 g) was added to a solution of 5-hydroxy-1,4-naphthalenedione (2.18 g) in acetonitrile (300 ml) with stirring at room temperature. Freshly prepared dibenzyl chlorophosphate (7.75 g, see above) in acetonitrile (50 ml) was added and the mixture stirred for 20 h. Potassium carbonate (907 mg) was then added and a further quantity (907 mg) of potassium carbonate added after another 24 h. The mixture was evaporated to dryness and dried in vacuo to give an oil. The oil was subjected to column chromatography (silica, 500 g, 70-230 mesh) eluting with dichloromethane:acetone (96:4). Fractions (250 ml) were collected and fractions 4-12 combined and the solvent evaporated. After drying in vacuo the title compound (3.18 g) was obtained as an orange solid; δ(CDCl3) 5.28 (OCH2), 7.38 (Ph).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6]C2CCCCO2)=[CH:4][C:3]=1[CH:15]([O:17]C1CCCCO1)[CH3:16].[Li]CCCC.[B:29](OC(C)C)(OC(C)C)[O:30]C(C)C.Cl>C1COCC1>[CH3:16][CH:15]1[O:17][B:29]([OH:30])[C:2]2[CH:14]=[CH:13][C:5]([OH:6])=[CH:4][C:3]1=2
Reactant: CC(OC1CCCCO1)c1cc(OC2CCCCO2)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1OB(O)c2ccc(O)cc21
Temperature: -78 °C
Reaction time: 21 h
Yield: 81.5 %

Procedure:
A solution of 2-(4-bromo-3-(1-(tetrahydro-2H-pyran-2-yloxy)ethyl)phenoxy)tetrahydro-2H-pyran (4.38 g, 11.3 mmol) in anhydrous THF (11 mL) was made before cooling the reaction mixture on a −78° C. bath. Reaction mixture was then treated, drop-wise, with n-BuLi (8.48 mL, 13.6 mmol) and allowed to stir for 1 hr before (i-PrO)3B (3.9 mL, 17 mmol) was added via syringe. After the addition of (i-PrO)3B, the reaction mixture was warmed to room temperature and allowed to stir for 21 hr. Cyclization of the bicyclic ring was done in situ by the addition of 7 mL of 6 M HCl. The mixture was stirred for 3 h before quenching the reaction with equal volume of concentrated NH4Cl(aq) and EtOAc (1:1, 20 mL). The layers were separated and the aqueous layer was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash give 3-methylbenzo[c][1,2]oxaborole-1,5(3H)-diol (1.51 g, 81%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.32 (d, J=5.1 Hz, 3H), 5.03-5.08 (m, 2H), 6.68 (s, 1H), 6.71 (dd, J=6.0, 1.5 Hz, 1H), 7.45 (d, J=6.0 Hz, 1H), 8.57 (s, 1H), 9.71 (s, 1H).