Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:2]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=[O:7])[CH:6]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:28]1([Mg]Br)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[OH:15][C:14]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:2]2[N:1]=[CH:6][C:5](=[O:7])[NH:4][C:3]=2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]1=2
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Reactant: Br[Mg]c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1cnc2c([nH]1)-c1ccccc1C2(O)c1ccccc1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
9H-Indeno[1,2-b]pyrazine-3,9(4H)-dione (2 g) was dissolved in dry THF (50 ml). Triethylamine (1.6 ml) was added and trimethylsilyl chloride (1.4 ml) dissolved in THF (10 ml) was added dropwise at room temperature. The mixture was stirred overnight and the precipitate filtered off. Phenylmagnesium bromide (20 mmol) in THF (10 ml) was subsequently added dropwise under nitrogen, and the resulting mixture stirred at room temperature for 3 days. Subsequent evaporation followed by addition of water and addition of HCl (1N) to slightly acidic solution resulted in precipitation of yellow crystals (2.7 g). The precipitate was purified on silica gel column using methylene chloride/methanol (9/1) as eluent resulting in 1.2 g pure title compound. M.p.>270° C. The MS showed the molecular ion 276. 1H-NMR (DMSO-d6, δ): 6.39 (s, 1H), 7.15-7.5 (m, 8H), 7.82 (s+m, 2H), 12.6 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:6](=[O:12])[NH:5][C:4](=[O:13])[CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:20])(=O)=O>O>[NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:6](=[O:12])[N:5]([CH3:20])[C:4](=[O:13])[CH:3]=1
Reactant: C=C(C)Cn1c(N)cc(=O)[nH]c1=O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)Cn1c(N)cc(=O)n(C)c1=O
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Methallylamine (211 g, 2.97 mol) is added to a solution of concentrated hydrochloric acid (250 ml) in water (1.91), followed by portionwise addition of potassium cyanate (240 g, 2.97 mol). The reaction is then heated for 2 hours at 80° C., prior to cooling and evaporation to afford (2-methyl-allyl)-urea (244.5 g), mp 114-115° C. The urea (268 g, 2.35 mol) is added to a solution of cyanoacetic acid (220 g, 2.59 mol) in acetic anhydride (536 ml) and the reaction is heated at 70° C. for 1 hour, cooled to 0° C. and diluted with ether. The resultant solid is collected by filtration, washed with ether, suspended in water (2.21) and heated to 75° C. 2M aqueous sodium hydroxide solution is then added portionwise over 30 min to maintain pH between 8 and 9.5. The reaction is cooled to room temperature, treated with acetic acid (12 ml), further cooled to 10° C. and the resultant solid is collected by filtration, washed with cold water and dried to afford 6-amino-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 267-269° C. The uracil (253 g, 1.40 mol) is added to a solution of sodium hydroxide (123 g, 3.07 mol) in water (2.5 l) and allowed to exotherm then cooled to 20° C. Dimethyl sulfate (196 ml, 2.06 mol) is added portionwise over 1 hour. After standing overnight, the reaction is cooled to 5° C. and the solid collected by filtration to give 6-amino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 162-163° C. The methyluracil (165 g, 0.85 mol) is suspended in water (1.55 l) and concentrated hydrochloric acid (72 ml). A solution of sodium nitrite (58.4 g, 0.85 mol) in water (117 ml) is then added dropwise over 30 minutes and the reaction is stirred at 20° C. for 3 hours. The solid is collected by filtration, washed successively with water, methanol and ether to afford 6-amino-3-methyl-1-(2-methyl-allyl)-5-nitroso-1H-pyrimidine-2,4-dione, mp 213° C. (dec). The nitrosouracil (190 g, 0.85 mol) is suspended in water (950 ml), heated to 85° C. and sodium dithionite (85%, 347.2 g, 1.69 mol) is added portionwise. After cooling to room temperature, the solid is collected by filtration to afford 5,6-diamino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 152-153° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[CH3:9][NH2:10].C(O)C>>[CH3:9][NH:10][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1
Reactant: CN
Reactant: ClCCn1cccc1
Solvent: CCO
Product: CNCCn1cccc1
Temperature: 90 °C
Yield: 88 %

Procedure:
1-(2-Chloroethyl)pyrrole (2.0 g, 15.43 mmol) was combined with a solution of 33% methylamine in ethanol (7.3 mL of 33% w/v, 77.15 mmol). The mixture was heated at 90° C. for 16 h before it was concentrated under reduced pressure to provide N-methyl-2-pyrrol-1-yl-ethanamine (2.19 g, 88%) which was used directly in next reaction. ESI-MS m/z calc. 124.1, found 125.3 (M+1)+; Retention time: 0.22 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 6.73-6.68 (m, 2H), 6.22-6.14 (m, 2H), 4.05 (t, J=5.9 Hz, 2H), 2.94 (t, J=5.9 Hz, 2H), 2.45 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7].[CH3:16][N:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH2:18]>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]([OH:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][CH2:2][NH:18][N:17]([CH3:16])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1
Reactant: CN(N)c1ccccc1
Reactant: C=CCC(O)(CCCl)c1ccc(F)cc1
Product: C=CCC(O)(CCNN(C)c1ccccc1)c1ccc(F)cc1
Temperature: 140 °C
Yield: 7.2 %

Procedure:
1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (20 mg, 0.088 mmol) and 1-methyl-1-phenylhydrazine (640 mg, 5.26 mmol) were combined and heated in a microwave for 10 min at 120° C. and for 20 min at 140° C. The crude mixture was purified by chromatography on a silica gel cartridge eluted with an EtOAc/hexanes gradient followed by preparative HPLC to afford 3-(4-fluorophenyl)-1-(2-methyl-2-phenylhydrazinyl)hex-5-en-3-ol (2 mg). LC-MS Method 1 m/z=315 (M+1).
Reaction SMILES: N12CCCN=C1CCCCC2.CS(O[CH:17]1[CH2:23][CH:22]2[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:19]([CH2:20][CH2:21]2)[CH:18]1[C:32]([O:34][CH3:35])=[O:33])(=O)=O>CN(C=O)C>[CH:19]12[N:24]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH:22]([CH2:21][CH2:20]1)[CH2:23][CH:17]=[C:18]2[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)C1C(OS(C)(=O)=O)CC2CCC1N2C(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)C1=CCC2CCC1N2C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 64 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (8.05 g, 53 mmol) was added into a solution of 8-tert-butyl 2-methyl 3-(methylsulfonyloxy)-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate (5.29 mmol) in DMF at room temperature and the reaction solution was heated at 100° C. for 16 h. The resulting solution was concentrated and purified using flash chromatography (0-60% ethyl acetate in hexane) to give the titled compound (905 mg, yield 64% for three steps).
Reaction SMILES: [C@@H:1]1(N2C3N=CN=C(O)C=3N=C2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[F:19][C:20]1[C:21](=[O:27])[NH:22][C:23](=[O:26])[NH:24][CH:25]=1>C([O-])(=O)C.[NH4+]>[F:19][C:20]1[C:21](=[O:27])[NH:22][C:23](=[O:26])[N:24]([CH:25]=1)[C@@H:1]1[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reaction time: 5 h
Yield: 30 %

Procedure:
An assay mixture containing 2 g (wet weight) of Bacillus stearothermophilus cells, 5 mM 2′-deoxyinosine and 5 mM 5-fluorouracil was made in 10 ml of 50 mM ammonium acetate buffer (pH 5.5). The conversions were run at 55° C. for 5 hour. The reaction mixture was centrifuged and then filtered using an Amicon Ultrafiltration device (YM-3 membrane) and the products were separated and analyzed by HPLC (C-18 column) in 5% methanol and 5 mM phosphate buffer at pH 4.6 using a flow rate of 0.5 ml/min. Blanks were run to check the authenticity of the reaction. No undesirable side reactions were detected. 5-fluoro-2′-deoxyuridine was obtained in 30% yield (62% conversion).
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: Clc1ccc(CCBr)cc1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc(Cl)cc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.6 g--see Preparation 8), 4-chlorophenethyl bromide (0.46 g), anhydrous potassium carbonate (0.6 g) and acetonitrile (20 ml) was heated under reflux for 1.25 hours. The mixture was partitioned between 10% aqueous potassium carbonate (10 ml) and dichloromethane (30 ml), the layers were separated, and the aqueous layer was extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to Rive a foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.43 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:34])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NC(=O)C2(CC(c3ccccc3F)Oc3ccc(Br)cc32)N1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1ccccc1F)Oc1ccc(Br)cc12
Yield: 69.1 %

Procedure:
A suspension of 6-bromo-2-(2-fluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (250 mg, 0.64 mmol) and Lawesson's Reagent (259 mg, 0.64 mmol) in dry 1,4-dioxane (20 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(2-fluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (180 mg, 67%).
Reaction SMILES: C1(C)C=CC=CC=1.[C:8](OC(=O)C)([CH3:11])([CH3:10])[CH3:9].CS(O)(=O)=O.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([CH3:31])[CH:30]=1)[NH:27][N:26]=[CH:25]2>O>[Br:21][C:22]1[CH:30]=[C:29]([CH3:31])[C:28]2[C:24](=[CH:25][N:26]([C:8]([CH3:9])([CH3:10])[CH3:11])[N:27]=2)[CH:23]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: Cc1cc(Br)cc2cn[nH]c12
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(Br)cc2cn(C(C)(C)C)nc12
Temperature: 80 °C
Reaction time: 28 h

Procedure:
Toluene (150 mL), acetic acid tert-butyl ester (360 mL), and methanesulfonic acid (22 mL) were added to 5-bromo-7-methyl-1H-indazole (35.9 g), and the reaction solution was stirred at 80° C. for 28 hours. The reaction solution was cooled to room temperature, water (500 mL) was added, and extracted with toluene (500 mL) and 200 mL toluene. After separation, the organic layer was washed with water twice. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. Hexane was added to the resultant residue and the insolubles were separated by filtration. The solvent was evaporated from the filtrate under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 5-bromo-2-(tert-butyl)-7-methyl-2H-indazole as a light red oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[NH2:8].[Cl-].Cl[C:19](=[N+:21]([CH2:24][CH3:25])[CH2:22][CH3:23])Cl>>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[N:1][C:2]=2[CH:3]=1)#[N:12]
Reactant: CC[N+](CC)=C(Cl)Cl
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Agent: [Cl-]
Product: CCN(CC)c1nc2cc(-c3ccccc3C#N)ccc2[nH]1

Procedure:
2-(3,4-Diaminophenyl)benzonitrile (4.78 mmoles, 1.0 g) was reacted as described in Example 31 with (dichloromethylene) diethylammonium chloride (1.435 mmoles, 2.73 g prepared following the procedure described in Angew, Chem, Int. Ed. 12:806 (1973)) to yield 0.91 g of 5-(2-cyanophenyl)-2-diethylamino-1H-benzimidazole.
Reaction SMILES: [CH3:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:9])=[N:6][C:7]=1[Cl:8].[NH3:11]>C(COC)OC>[NH2:11][C:3]1[C:2]([CH3:1])=[C:7]([Cl:8])[N:6]=[C:5]([Cl:9])[N:4]=1
Reactant: Cc1c(Cl)nc(Cl)nc1Cl
Reactant: N
Solvent: COCCOC
Product: Cc1c(N)nc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
39.5 g (0.2 mol) of 5-methyl-2,4,6-trichloropyrimidine are dissolved in 250 ml of dimethoxyethane, and ammonia gas is then introduced at room temperature until the solution is saturated. A white suspension is formed, which is stirred for 12 hours at room temperature; it is subsequently concentrated in a rotary evaporator, and 200 ml of water are added to the residue. The formed suspension is filtered and the precipitate is dried. The mother liquor is concentrated to half the volume, filtered, and the precipitate is dried. There are thus obtained 26.4 g of crude product, which is recrystallised from acetonitrile/water (5:1); m.p. 193°-194° C. (yield=75% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[C:11]([OH:15])(=[O:14])[CH:12]=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][O:10][CH:12]2[C:11]([OH:15])=[O:14]
Reactant: O=CC(=O)O
Reactant: OCCc1ccccc1Br
Product: O=C(O)C1OCCc2c(Br)cccc21

Procedure:
A solution of 2-(2-bromophenyl)ethanol (40 g, 0.2 mol) and glyoxylic acid (16 g, 0.22 mol) in 100 mL of trifluoacetic acid was refluxed overnight. The solvent was concentrated. Water and ammonium hydroxide was added to the residue to adjust the pH of the solution over 7. The solution was extracted with diethyl ether, and the aqueous layer was adjusted to about 3 with 1M HCl, and then the solution was extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was without purification to give 5-bromo-3,4-dihydro-1H-isochromene-1-carboxylic acid. 1H-NMR (400 MHz, CDCl3) δ 7.52 (d, J=7.6 Hz, 1H), 7.12 (t, J=7.8 Hz, 2 H), 5.33 (s, 1H), 4.27˜4.33 (m, 1H), 3.99˜4.06 (m, 1H), 2.87˜2.89 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=[C:2]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: C1CCNC1
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCO
Product: COc1nc(N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 98.1 %

Procedure:
4.79 g (0.021 mol) of 6-chloro-2-methoxy-3-nitropyridine, 40 ml of ethanol and 3.5 ml (0.042 mol) of pyrrolidine are charged to a fully equipped round-bottomed flask. The mixture is brought to reflux for 1 hour with stirring and then the mixture is cooled to ambient temperature. The product which crystallizes is filtered off and then washed with diisopropyl ether. After drying, 4.6 g of yellow powder are obtained, Yd: 96%.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:23]([OH:25])=[O:24])[C:10]([S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([CH3:12])[CH3:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][S:13][C:10]([CH3:12])([CH3:11])[C@H:9]([C:23]([OH:25])=[O:24])[NH2:8])=[CH:20][CH:19]=1
Reactant: COc1ccc(CSC(C)(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CSC(C)(C)[C@@H](N)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The N-t-butoxycarbonyl-S-(4-methoxybenzyl)-D-penicillamine (5.0 g, 13.5 mmol) is dissolved in 40 mL of methylene chloride and cooled to 0° C. in an ice bath. Trifluoroacetic acid (18.5 g, 162 mmol) is added next, and the resulting mixture is stirred at 0° C. for 1 hour. The reaction mixture is warmed to room temperature and stirred until the starting material disappeared by TLC and mass spec (3 h.). The trifluoroacetic acid and methylene chloride are evaporated under reduced pressure to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44]O)[CH2:39][CH2:38]1>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:44][CH2:43][N:40]3[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][F:34])[CH2:38][CH2:39]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: OCCN1CCN(CCF)CC1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OCCN1CCN(CCF)CC1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 67.6 %

Procedure:
4-Chloro-7-hydroxy-6-methoxyquinazoline (146 mg, 0.69 mmol), (prepared as described for the starting material in Example 4), was suspended in dichloromethane (7.5 ml). Triphenylphosphine (254 mg, 0.97 mmol) and 2-[4-(2-fluoroethyl)piperazin-1-yl]ethanol (134 mg, 0.76 mmol) were added. Diisopropyl azadicarboxylate (165 μl, 0.83 mmol) was then added dropwise. The reaction mixture was stirred for 2.25 hours at ambient temperature and then loaded directly onto a silica column and eluted with methylene chloride/methanol (92/8) to give 4-chloro-7-{2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy}-6-methoxyquinazoline (172 mg, 67%).
Reaction SMILES: [C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:8][CH:9]2[N:12]([CH:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])O)[C:11](=[O:25])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S(Cl)([Cl:46])=O>O1CCCC1>[C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:8][CH:9]2[N:12]([CH:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[Cl:46])[C:11](=[O:25])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(OCc1ccccc1)C(O)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C(Cl)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a solution of 4-(triphenylmethylthio)-1-(benzyloxycarbonylhydroxymethyl)azetidin-2-one (1.0 g) and pyridine (240 μl) in tetrahydrofuran (THF) (15 ml) at 0° C. under nitrogen was added slowly thionyl chloride (180 μl ). After 15 minutes the precipitate was collected by filtration and the filtrate evaporated. The residue was rapidly eluted through a short plug of silica gel using a 15 to 30% ethyl acetate/hexane solvent gradient to afford 4-(triphenylmethylthio)-1-(benzyloxycarbonylchloromethyl)azetidin-2-one (900 mg) as a 4:3 mixture of diastereomers.
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=[NH:4].[H-].[Na+].[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][C:20](OCC)=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].O>CN(C)C=O>[CH:5]1([C:3]2[N:4]=[C:20]([CH2:19][CH2:18][NH:17][C:15](=[O:16])[O:14][C:10]([CH3:13])([CH3:12])[CH3:11])[O:1][N:2]=2)[CH2:7][CH2:6]1
Reactant: N=C(NO)C1CC1
Reactant: CCOC(=O)CCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1nc(C2CC2)no1
Temperature: 50 °C
Reaction time: 0.1 h

Procedure:
3.10 g (30.96 mmol) N-hydroxy-cyclopropanecarboxamidine are placed in 10 ml dimethylformamide and molecular sieve. 1.32 g (34.06 mmol) sodium hydride (60% in mineral oil) are added. The mixture is stirred for 0.1 hours at 50° C., then 7.40 g (34.06 mmol) ethyl 3-tert-butoxycarbonylamino-propionate in 20 ml dimethylformamide are added. The reaction mixture is stirred for 3 hours at 50° C. After cooling 15 ml of water are added, the mixture is suction filtered through Celite. The 2 phases of the filtrate are separated, the aqueous phase is extracted with ethyl acetate, the combined organic phase is evaporated down. The residue is purified by chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][NH:20][CH:21]=3)[CH:15]=2)[CH:11]=[CH:10]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[OH:53][C:54]([C:57]1[CH:58]=[C:59]([CH:63]=[C:64]([S:66]([F:71])([F:70])([F:69])([F:68])[F:67])[CH:65]=1)[C:60](O)=[O:61])([CH3:56])[CH3:55].N>CN(C=O)C>[OH:53][C:54]([C:57]1[CH:58]=[C:59]([CH:63]=[C:64]([S:66]([F:71])([F:67])([F:68])([F:69])[F:70])[CH:65]=1)[C:60]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][NH:20][CH:21]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:61])([CH3:55])[CH3:56]
Reactant: CC(C)(O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(NC(=O)c2cc(C(C)(C)O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound from Example 7A (2.63 g, 9.45 mmol) was dissolved in 55 ml of DMF. HATU (7.91 g, 20.8 mmol) and N-methylmorpholine (8.31 ml, 75.6 mmol) were added, and the mixture was stirred at RT for 30 min. The mixture was then cooled to −5° C. and the compound from Example 19A (5.79 g, 18.9 mmol) was added. The mixture was stirred for a further 45 min, concentrated aqueous ammonia solution was then added and the mixture was stirred for another 15 min. The mixture was then extracted with ethyl acetate, and the organic extract was washed with conc. sodium chloride solution, dried over sodium sulphate and concentrated. The crude product was purified by preparative HPLC [column: Waters Sunfire C-18.5 μm, 250 mm×20 mm; ternary gradient water/acetonitrile/1% TFA in water: 0-6.7 min 45:50:5, ramp, 6.9-9.0 min 0:95:5]. This gave 3.86 g (72% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])=[CH:34][CH:33]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(Cl)cc2)CC1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 4-chlorphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (69%).