Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=5)[C:19]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:49][NH2:50]>C1COCC1.C(OCC)(=O)C>[CH3:48][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]=[C:20]([NH:21][C:22]4[C:27]([C:28]([NH:50][CH3:49])=[O:30])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=4)[C:19]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=5)(=[O:37])=[O:38])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4ccc(F)c(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(Nc2nc(Nc3cc4c(cc3OC)CCN4C(=O)CN(C)C)nc3c2ccn3S(=O)(=O)c2ccc(C)cc2)ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,9-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (300 mg, 0.445 mmol) in THF (5 mL) was added methylamine (2 M solution in THF) (2.23 mL, 4.45 mmol). The resulting mixture was let stir at rt for 10 min at which time it was diluted with ethyl acetate and washed with water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure. The residue was purified via chromatography on SiO2 and afforded 6-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluoro-N-methylbenzamide (143 mg, 0.203 mmol) as an off white solid. (ESIMS (M+H)+=705)
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].B(F)(F)F.CCOCC.[CH3:14][O:15][C:16]([C@@H:18]1[CH2:22][CH2:21][CH:20](OC(=O)C)[N:19]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:17]>CCOCC>[CH3:14][O:15][C:16]([C@@H:18]1[CH2:22][CH2:21][C@@H:20]([CH2:1][CH3:2])[N:19]1[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])=[O:17]
Reactant: COC(=O)[C@@H]1CCC(OC(C)=O)N1C(=O)OC(C)(C)C
Reactant: CC[Mg]Cl
Agent: FB(F)F
Solvent: CCOCC
Product: CC[C@@H]1CC[C@@H](C(=O)OC)N1C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of copper bromide-dimethylsulfide complex (2.15 g, 10.4 mmol) in dry Et2O (40 mL), cooled to −40° C., was added dropwise ethyl magnesium chloride (2M in Et2O; 5.22 mL, 10.4 mmol; Aldrich 300330) under an argon atmosphere. After stirring for 45 min, the mixture was cooled to −78° C., followed by dropwise addition of boron trifluoride etherate (1.32 mL, 10.4 mmol) and stirring for 15 min. Then, a solution of (S)-5-acetoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.00 g, 3.48 mmol, prepared as described in Scheme B1) in dry Et2O (10 mL) was added dropwise to result in a black suspension. The reaction mixture was stirred for 15 min and subsequently was allowed to warm up to RT over a period of 1 h. The reaction was quenched by addition of a (1:1)-mixture of a saturated aqueous NH4Cl solution and a concentrated aqueous NH3 solution (10 mL), followed by stirring for 30 min. The organic layer was separated, and the aqueous phase was extracted with Et2O (2×50 mL). The combined organics were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 2:8) to afford the title compound (contained less than 10% of the minor (2S,5S)-diastereoisomer according to 1H-NMR). TLC Rf (EtOAc/c-hexane 1:3)=0.48.
Reaction SMILES: Br[C:2]1(Br)[C:7]2=[N:8][C:9]3[C:14]([C:15](=[O:16])[N:6]2[CH2:5][CH2:4][CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+]>C(O)C>[C:18]1([NH:24][N:25]=[C:2]2[C:7]3=[N:8][C:9]4[C:14]([C:15](=[O:16])[N:6]3[CH2:5][CH2:4][CH2:3]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NNc1ccccc1
Reactant: O=c1c2ccccc2nc2n1CCCC2(Br)Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1c2ccccc2nc2n1CCCC2=NNc1ccccc1
Yield: 81 %

Procedure:
10.8 g. (0.03 mole) 6,6-Dibromo-6,7,8,9-tetrahydro-11-oxo-11H-pyrido[2,1-b]quinazoline and 13.0 g. (0.12 mole] of phenyl hydrazine are heated in 120 ml ethanol for 4 hours. The precipitated crystals are filtered after cooling. When evaporating the mother liquor further crystals are precipitating, which are filtered and washed with some alcohol. The combined filtered product is suspended in 150 ml. of water containing 8.4 g. (0.06 mole) of sodium acetate whereafter it is filtered and washed with water. 8.4 g. (81%) of 6-phenylhydrazono-6,7,8,9-tetrahydro-11-oxo-11H-pyrido[2,1-b]quinazoline are obtained which after recrystallization from isopropanol melts at 177°-179° C. and which does not give a degression of melting point when admixed with the product according to Example 16.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([Cl:10])[CH:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][S:19]([CH3:18])(=[O:21])=[O:20])=[C:4]([Cl:10])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(Br)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(Br)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-chlorobenzyl alcohol (3.56 g) and anhydrous triethylamine (3 ml) in anhydrous dichloromethane (36 ml) was added dropwise methanesulfonyl chloride (1.4 ml) under a nitrogen flow under ice-cooling. The mixture was stirred for 1 hr and the reaction mixture was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The filtrate was concentrated to give 4-bromo-2-chloro-1-(methanesulfonyloxymethyl)benzene as a pale-brown solid (4.77 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14](=[O:28])[C:13](=[CH2:29])[CH2:12]1>CO>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:21][CH:22]=2)[C:14](=[O:28])[CH:13]([CH3:29])[CH2:12]1
Reactant: C=C1CC(c2c(OC)cccc2OC)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Solvent: CO
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of rac-(S*)-5-(2,6-dimethoxyphenyl)-3-methylene-1-(4-(trifluoromethoxy)-benzyl)pyrrolidin-2-one (310 mg; 0.76 mmol), and 10% Pd(C) (62 mg; 20% in mass) in anh. MeOH (3 ml) was stirred at rt, under hydrogen atmosphere (1 atm), for 60 h. Filtration over a pad of celite, concentration to dryness under reduced pressure, and subsequent purification by FC (DCM/MeOH=30/1) afforded rac-(3S*,5S*)-5-(2,6-dimethoxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)-benzyl)pyrrolidin-2-one as an orange oil. LC-MS (conditions A): tR=0.94 min.; [M+H]+: 410.27 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.Br[CH:10]1[C:15](=O)[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]1>C1(C)C=CC=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][N:3]2[C:10]3[CH2:11][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:14][C:15]=3[N:1]=[C:2]2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Reactant: Nc1cc(Br)ccn1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2nc3cc(Br)ccn3c2C1
Temperature: 105 °C
Yield: 31.9 %

Procedure:
2-Amino-4-bromopyridine (786 mg, 4.55 mmol) and tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (1.39 g, 5.00 mmol) were combined in toluene (20 mL) and heated at 105° C. for 16 h. The mixture was concentrated and purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 30 min at 40 mL/min) to provide the title compound (512 mg, 32%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.93 (s, 1H), 7.46 (d, J=9.1 Hz, 1H), 7.22 (d, J=9.1 Hz, 1H), 4.69 (br s, 2H), 3.85 (br s, 2H), 2.93 (br s, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH3:13])[C:7]=2[C:6](=[O:14])[NH:5][C:4]1=[O:15])[CH3:2].Cl[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22]>>[CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH3:13])[C:7]=2[C:6](=[O:14])[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])[C:4]1=[O:15])[CH3:2]
Reactant: CCn1cnc2c1c(=O)[nH]c(=O)n2CC
Reactant: CC(C)(O)CCCCCl
Product: CCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2CC

Procedure:
This compound was obtained according to the method described in Example 1 starting from 3,7-diethylxanthine and 1-chloro-5-hydroxy-5-methylhexane and recrystallizing the final product from diisopropylether.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH:7]2[OH:12]
Reactant: O=C1CCCc2c(F)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCCc2c(F)cccc21
Reaction time: 1.5 h

Procedure:
A solution of 5-fluoro-3,4-dihydronaphthalen-1(2H)-one (1.26 mmol) in MeOH (4 mL) at 0° C. was quickly charged with a solution of sodium borohydride (3.23 mmol, 2.5 eq) in MeOH (2 mL). The reaction was stirred for 1.5 h from 0° C. to ambient temperature. The reaction was quenched with water and extracted with ether. All organic layers were combined and dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was dissolved in minimal CH2Cl2 and was purified by chromatography on silica gel [0.5″×10″ glass column, eluting with neat CH2Cl2→5:1 CH2Cl2:EtOAc]. Fractions containing product were combined and concentrated in vacuo, giving the title material as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ=1.73 (d, J=6.8 Hz, 1H), 1.75-1.90 (m, 2H), 1.91-2.10 (m, 2H), 2.61-2.86 (m, 2H), 4.67-4.83 (m, 1H), 6.90 (ddd, J=8.5, 8.5, 2.8 Hz, 1H), 7.06 (dd, J=8.5, 5.7 Hz, 1H), 7.17 (dd, J=9.6, 2.8 Hz, 1H). MS (ES+): m/z 149.02 (100) [MH+−OH]. HPLC: tR=2.96 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][C:26]#[CH:27])[CH3:23]>CCCCCCC.CCOC(C)=O>[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][C:26]#[C:27][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])[CH3:23]
Reactant: C#CCN(CC)CC
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCN(CC)CC#Cc1ccccc1NC(C)=O

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and diethyl-prop-2-ynyl-amine following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 8:2; yield (73 mg, 60%); 1H NMR δ (CDCl3): 8.47 (d, J=8.52 Hz, 1H), 7.93 (br s, 1H), 7.36 (dm, 1H), 7.31-7.23 (m, 1H), 7.02 (t, J=7.24 Hz, 1H), 3.54 (s, 2H), 2.62 (q, J=7.13 Hz, 4H), 2.21 (s, 3H), 1.11 (t, J=7.11 Hz, 6H); LCMS m/z: 244.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:23]=[CH:22][C:11]2[C:12](=[O:21])[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[O:15][C:10]=2[CH:9]=1.[C:24](=[O:27])([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[O:21]=[C:12]1[C:11]2[CH:22]=[CH:23][C:24]([O:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]3[CH:23]=[CH:22][C:11]4[C:12](=[O:21])[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[O:15][C:10]=4[CH:9]=3)=[CH:9][C:10]=2[O:15][CH:14]=[CH:13]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(=O)c2ccc(OCCCCCBr)cc2o1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1cc(=O)c2ccc(OCCCCCOc3ccc4c(=O)ccoc4c3)cc2o1

Procedure:
A mixture of 4.6 parts of 7-(5-bromopentyloxy)4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester, 2 parts of ethyl 7-hydroxychromone-2-carboxylate,1.8 parts of potassium carbonate, a few potassium iodide crystals and 80 parts by volume of dry acetone was refluxed on a steam bath for 20 hr. The cooled mixture was filtered and the filtrate evaporated down to give an oil which when treated with petroleum ether (40-60° ), solidified to give 4.0 parts of crude product. Crystallisation from ethanol gave 2.9 parts of 7-[5-(4-oxo-4H-1-benzopyran-7-yloxy)pentyloxy]-4-oxo-4H-1-benzopyran-2-carboxylic acid; ethyl ester, m.p. 113°-116° .
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]>>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure M, 1-(6-bromo-4-((trans-4-(dimethylamino)cyclohexyl)amino)quinolin-3-yl)propan-1-one (125 mg, 0.31 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (93 mg, 0.34 mmol) to afford the desired product (81 mg, 56%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 10.56 (d, J=8.0 Hz, 1H), 8.97 (s, 1H), 8.34 (d, J=2.1 Hz, 1H), 8.04 (dd, J=8.7, 1.9 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.65-7.58 (m, 2H), 4.18-4.12 (m, 1H), 3.13 (q, J=7.2 Hz, 2H), 2.39-2.32 (m, 1H), 2.27-2.19 (m, 8H), 1.93-1.86 (m, 2H), 1.56-1.39 (m, 4H), 1.12 (t, J=7.2 Hz, 3H). ESI MS m/z 470 [C26H29ClFN3O2+H]+; HPLC>99% (AUC), tR=7.97 min.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:18]=[C:17]([NH2:19])[C:16]([O:20][CH3:21])=[C:15]([NH2:22])[N:14]=2)=[N:6]1.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C=O)C>[NH2:19][C:17]1[N:18]=[C:13]([C:7]2[C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[N:5]([CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[F:1])[N:6]=2)[N:14]=[C:15]([NH:22][C:34](=[O:36])[CH3:35])[C:16]=1[O:20][CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(N)nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(N)nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1NC(C)=O
Temperature: 100 °C

Procedure:
50 mg of 2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5-methoxy pyrimidine-4,6-diamine 1-6-1 were suspended in 0.7 mL DMF. After addition of 14 mg of triethylamine (0.14 mmol, 1.0 eq.) and 14 mg of acetic anhydride (0.14 mmol, 1.0 eq.), the resulting reaction mixture was heated for three h at 100° C. For completition of reaction further 4 mg of triethylamine (0.04 mmol, 0.3 eq.) and 4 mg of acetic anhydride (0.04 mmol, 0.3 eq.) were added and the mixture was heated over night at 100° C. After cooling and dilution with water, the crude product was extracted with DCM and was purified by flash chromatography yielding 25 mg (0.063 mmol, 45%) of analytically pure target compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C[O-].[Na+]>CO>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[N:3][CH:4]=1
Reactant: Clc1ncnc2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1ccc2ncncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 298.8 %

Procedure:
To a solution of the quinazoline 3 (0.14 g, 0.36 mmol) in MeOH (3 mL) was added NaOMe (1.44 mL, 0.72 mmol) at RT. The reaction was stirred overnight at RT. The reaction mixture was concentrated using rotavap (25° C.), then the residue was taken up with water (75 mL) and washed with EtOAc (3×50 mL). The aqueous phase was dried with lyophilizer to give final product 4 (0.14 g, 98% yield) as solid. LC/MS (10-99%) M/Z 406.0 retention time 3.32 min.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:16](Br)(Br)[C:15](=[O:19])[N:14]([CH3:20])[C:11]2=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:23])C>[Zn]>[C:1]([C:8]1[CH:9]=[C:10]2[CH2:16][C:15](=[O:19])[N:14]([CH3:20])[C:11]2=[N:12][CH:13]=1)(=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CN1C(=O)C(Br)(Br)c2cc(Cc3ccccc3)cnc21
Agent: [Zn]
Product: CN1C(=O)Cc2cc(C(=O)c3ccccc3)cnc21
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Add a spatula tip of zinc to a solution of 40 mg of the compound of Step 2 in acetic acid. After 30 minutes' stirring, concentrate to dryness under reduced pressure, take up in water and extract with dichloromethane. The crude product obtained by concentrating to dryness is purified by chromatography on a silica column (eluant: petroleum ether/ethyl acetate, 6/4). The title product is obtained in the form of an oil in a yield of 60%. ##STR63##
Reaction SMILES: C(OC([NH:8][C:9]([NH:23][CH2:24][CH3:25])=[N:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=2)[CH2:12]1)=O)(C)(C)C.[ClH:26]>C(O)C.O1CCOCC1>[ClH:26].[ClH:26].[CH2:24]([NH:23][C:9]([NH:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=2)[CH2:12]1)=[NH:8])[CH3:25]
Reactant: CCNC(=NC1CCN(c2cc(C)ccn2)C1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCNC(=N)NC1CCN(c2cc(C)ccn2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of N-(tert-butoxycarbonyl)-N′-ethyl-N″-(1-(4-methylpyridin-2-yl)pyrrolidin-3-yl)guanidine (200 mg) in ethanol (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 3 ml), and the mixture was stirred at ambient temperature for 6 hours. The solvent was evaporated under reduced pressure. To the residue was added 10% ethanol in ethyl acetate (50 ml), and the resultant precipitate was collected by filtration and dried under reduced pressure to give N-ethyl-N′-(1-(4-methylpyridin-2-yl)pyrrolidin-3-yl)guanidine dihydrochloride (120 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[P:21](Cl)([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cn2ccnc2)cc1
Reactant: CCOP(=O)(Cl)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1nccn1Cc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 1-benzylimidazole (1.1 mmol) in THF was treated with LDA (1.1 mmol) at −78° C. for 1 h, and followed by addition of diethyl chlorophosphate (2 mmol), and stirred for 2 h. Extraction and chromatography gave 1-benzyl-2-diethylphosphonoimidazole as a yellow oil. TLC: Rf=0.35, 80% EtOAc-hexane.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[C:8](O)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:5].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:19]=[CH:18][C:3]=1[C:4]1[O:5][C:8]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=[CH:16][C:7]=2[N:6]=1
Reactant: COC(=O)c1cccc(NC(=O)c2ccc(-c3ccccn3)cc2F)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2nc(-c3ccc(-c4ccccn4)cc3F)oc12
Temperature: 118 °C
Reaction time: 48 h
Yield: 37.8 %

Procedure:
Methyl 3-(2-fluoro-4-(pyridin-2-yl)benzamido)-2-hydroxybenzoate (1.40 g, 3.8 mmol) and 4-methylbenzenesulfonic acid (1.82 g, 9.6 mmol) were added to toluene (50 mL) and the mixture was stirred at 118° C. for 2 days. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20/1 to 10/1). 500 mg of methyl 2-(2-fluoro-4-(pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxylate was obtained as a solid; yield 38%. LC-MS (ESI) m/z: 349 (M+1)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:11][C:12]1[N:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH:8]([CH3:10])[CH3:9].[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1F)[C:23]#[N:24]>CS(C)=O.O>[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:18][C:15]1[CH:16]=[N:17][C:12]([O:11][CH2:7][CH:8]([CH3:10])[CH3:9])=[CH:13][CH:14]=1)[C:23]#[N:24]
Reactant: CC(C)COc1ccc(O)cn1
Reactant: N#Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)COc1ccc(Oc2ccc(C#N)cc2Br)cn1
Temperature: 80 °C
Yield: 97.5 %

Procedure:
Potassium carbonate (0.622, 4.50 mmol) and 6-isobutoxypyridin-3-ol (Preparation 7, 0.251 g, 1.50 mmol) were added to a solution of 3-bromo-4-fluorobenzonitrile (0.300 g, 1.50 mmol) in DMSO (7 mL). The reaction was heated at 80° C. for a total of 4 hours and then allowed to cool to room temperature. The mixture was diluted with water (50 mL) and extracted with DCM (3×30 mL). The combined organics were washed with brine (2×50 mL), filtered and concentrated in vacuo to yield the title compound as a solid (0.508 g).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH2:6]([O:8][C:9](=[O:25])[C:10]1[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[C:12]([C:13]([N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[O:14])[CH:11]=1)[CH3:7]>C1COCC1>[CH2:6]([O:8][C:9](=[O:25])[C:10]1[CH:22]=[C:21]([CH:23]([CH:1]2[CH2:3][CH2:2]2)[OH:24])[CH:20]=[C:12]([C:13]([N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[O:14])[CH:11]=1)[CH3:7]
Reactant: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(O)C2CC2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 37.4 %

Procedure:
Add cyclopropyl magnesium bromide (0.8 M in THF, 1.3 mL, 1.02 mmol) dropwise to a solution of 5-formyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (283 mg, 1.02 mmol) in THF (5 mL) at −10° C. After stirring at 0° C. for 1.5 h, quench the mixture with 5% aqueous ammonium chloride solution while maintaining the temperature below 5° C. Extract with ethyl acetate (3×30 mL), dry (sodium sulfate) concentrate and purify (silica gel chromatography, eluting with ethyl acetate and hexanes) to give the title compound (122 mg, 38%).
Reaction SMILES: O=[C:2]([NH:9][C:10](=[O:15])[C:11]([O:13]C)=[O:12])[CH2:3][C:4]([F:8])=[C:5]([F:7])[F:6].[OH-].[Na+]>CO.O>[F:8][C:4](=[C:5]([F:6])[F:7])[CH2:3][CH2:2][NH:9][C:10](=[O:15])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(=O)NC(=O)CC(F)=C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)NCCC(F)=C(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
A solution of Compound 142 (3.16 g, 0.015 mole) in methanol (25 mL) is treated with a solution of NaOH (0.8 g, 0.02 mole) in water (5 mL). The solution is stirred at room temperature for 30 min and concentrated. The residue is dissolved in water (20 mL) and extracted with dichloromethane (2×30 mL). The aqueous layer is acidified with conc. HCl and extracted with ethyl acetate. The organic layer is dried and evaporated to give 0.75 g of the title compound as a white solid, a 25% yield. m.p. 95°-100° C.