Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH2+:5][CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8].[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]=[S:23]>>[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]1[N:5]([CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[CH2:4][CH2:3][S:23]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CCC(CC)[NH2+]CCCl
Agent: [Cl-]
Product: CCC(CC)N1CCSC1=Nc1ccc([N+](=O)[O-])cc1C

Procedure:
3-Pentylamine was converted to N-(2-hydroxyethyl)-N-(3-pentyl)amine according to Method B5a. The amine was reacted with SOCl2 according to Method B7a to give N-(2-chloroethyl)-N-(3-pentyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give to give 2-(2-methyl-4-nitrophenylimino)-3-(3-pentyl)-1,3-thiazolidine.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][C:5]=12.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:11][CH2:10][C:7]2[CH:8]=[CH:9][N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=2)=[O:21])=[CH:15][CH:14]=1
Reactant: NCc1ccn2ccnc2c1
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: ClCCl
Product: O=C(NCc1ccn2ccnc2c1)Nc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
To a solution of imidazo[1,2-a]pyridin-7-ylmethanamine (500 mg, 3.40 mmol) in dichloromethane (17 ml) at room temperature was added 1-bromo-4-isocyanatobenzene (680 mg, 3.40 mmol) as a single portion. The resulting suspension was stirred overnight and then filtered with dichloromethane washes to give the title compound.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:3]1[C:2]([I:1])=[CH:7][N:6]=[C:5]([C:8]([F:11])([F:9])[F:10])[CH:4]=1
Reactant: Cc1cc(C(F)(F)F)ncc1I
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(CBr)c(I)cn1

Procedure:
A mixture of 5-iodo-4-methyl-2-(trifluoromethyl)pyridine (39.1 mg, 0.136 mmol), N-bromosuccinimide (29.1 mg, 0.163 mmol), and benzoyl peroxide (3.3 mg, 0.0136 mmol) in CCl4 (1 mL) was heated at reflux under N2 overnight. Water was added and the mixture was extracted with CH2Cl2 (3×20 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 1-5% EtOAc in hexanes gradient) to afford 4-(bromomethyl)-5-iodo-2-(trifluoromethyl)pyridine. Rf=0.41 (10% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 9.03 (s, 1H); 7.76 (s, 1H); 4.51 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][CH2:4][CH2:5][C:6]([CH:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=[O:7].[C:23]1([C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[CH2:31][Mg:32][Br:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:38]1([C:44]2[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=2[CH2:46]Br)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:23]1([C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[CH2:31][Mg:32][Br:33])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1.[C:44]1([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[CH2:46][C:6]([CH:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)([OH:7])[CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:21])[F:22]
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: O=C(CCCC(F)(F)F)C1CN(Cc2ccccc2)CCO1
Agent: Br[Mg]Cc1ccccc1-c1ccccc1
Product: OC(CCCC(F)(F)F)(Cc1ccccc1-c1ccccc1)C1CN(Cc2ccccc2)CCO1
Yield: 28 %

Procedure:
Compound 67 is prepared from 10 (0.853 g, 2.71 mmol) and 2-phenyl benzyl magnesium bromide (0.25 M solution in diethyl ether, 1.2 eq) following General Procedure 2. 2-Phenylbenzyl magnesium bromide is prepared from commercially available (Aldrich) 2-phenylbenzyl bromide following General Procedure 5. Further 2-phenyl benzyl magnesium bromide is added later (19.2 mL, 4.8 mmol). Purification by automated column chromatography (eluent, EtOAc/cyclohexane 20/80 to 40/60 [v/v]), followed by ion exchange chromatography gives 67 as a viscous oil (369 mg, 28%). MW 483.58; C29H32F3NO2; LCMS: (6 min method) m/z 484 [M+H]+, RT 4.26 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[O:65]([CH2:69][CH2:70]O)[CH2:66][CH2:67][OH:68]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:70][CH2:69][O:65][CH2:66][CH2:67][OH:68])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCOCCO
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)OCCOCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a suspension of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (150 mg, 0.243 mmol) in methylene chloride (8 mL) was added triethylamine (72.0 mg, 0.10 mL, 0.717 mmol) followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (Aldrich, 92 mg, 0.365 mmol). The mixture was stirred at room temperature for 10 min before 2,2′-oxydiethanol (Aldrich, 154 mg, 0.14 mL, 1.45 mmol) was added. This reaction mixture was stirred at room temperature overnight. It was then diluted with methylene chloride and washed with water, brine and concentrated to dryness. The crude material was purified by flash chromatography (eluting with hexane/ethyl acetate, 80/20 to 10/90) to give chiral 2-(2-hydroxyethoxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid (40.8 mg, 23% yield). MS (ES+) m/z calcd. for C35H38Cl2F2N3O6 [(M+H)+]: 704. found: 704.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: O=C(O)c1cc(Cl)ccc1I
Solvent: C1CCOC1
Product: OCc1cc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Borane-dimethylsulfide complex (3.7 mL, 38.9 mmol) was added slowly to a cold (0° C.) solution of 5-chloro-2-iodo-benzoic acid (10 g, 35.4 mmol) in THF (20 mL). The reaction mixture was allowed to warm to rt, stirred for 8 h, quenched by addition of a saturated aqueous solution of ammonium chloride, and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated to provide 9.5 g of the title compound. tR: 4.72 min (HPLC 2); Rf=0.66 (hexane/EtOAc, 7:3).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[CH:18]3[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:20][CH:12]2[CH2:13]4)[CH2:17]3)=[O:9])[CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].Cl>C(Cl)Cl>[CH2:34]([O:33][C:31]([NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[CH:12]3[CH2:13][CH:14]4[CH2:15][CH:16]([CH2:17][CH:18]2[CH2:19]4)[CH2:20]3)=[O:9])[CH2:4]1)=[O:32])[CH3:35]
Reactant: N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A 1.5 dram vial equipped with a flea stirbar was charged with (R)-2-adamantyl 3-aminopyrrolidine-1-carboxylate HCl salt (30 mg, 0.10 mmol), i-Pr2NEt (72 μL, 0.4 mmol) and CH2Cl2 (1 mL). Ethyl chloroformate (15 mL, 0.123 mmol) was added. The mixture was stirred at rt overnight and applied to a 10-mL Chem-Elut cartridge prewetted with 5% aq HCl (6 mL). The cartridge was eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by prep HPLC to afford (R)-(2-adamantyl) 3-(ethoxycarbonylamino)pyrrolidine-1-carboxylate (24 mg, 71%). LC-MS Method 1 tR=1.88 min, m/z=337; 1H NMR (CDCl3) 1.27 (t, 3H), 1.58 (d, 2H), 1.70-2.00 (13H), 2.19 (m, 1H), 3.13 (1H), 3.26 (dd, 1H), 3.59 (m, 2H), 3.70 (m, 1H), 4.17 (d, 1H), 4.29 (1H), 4.78 (1H), 4.82 (s, 1H)
Reaction SMILES: [CH2:1]=O.[NH2:3][C:4]1[C:9]([C:10]2[O:11][C:12]3[C:18]([CH2:19][OH:20])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:8][C:7]([C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:25]=2)=[CH:6][N:5]=1.[Na].N>ClCCl.CO>[NH2:3][C:4]1[C:9]([C:10]2[O:11][C:12]3[C:18]([CH2:19][OH:20])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:8][C:7]([C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:31][CH2:30][N:29]([CH3:1])[CH2:28][CH2:27]3)[CH:25]=2)=[CH:6][N:5]=1
Reactant: C=O
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cccc(CO)c2o1
Agent: N
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(n2cc(-c3cnc(N)c(-c4nc5cccc(CO)c5o4)c3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
37% Aqueous formaldehyde (0.015 ml) at 0° C., was added to a stirred solution [2-[2-amino-5-[1-(4-piperidyl)pyrazol-4-yl]-3-pyridyl]-1,3-benzoxazol-7-yl]methanol (46 mg) dissolved in dichloromethane (2 ml) and methanol (2 ml) over a period of 5 minutes. The resulting solution was stirred at 0° C. for 10 minutes. Sodium triacetoxyhydroborate (30.0 mg) was added at 0° C. to the mixture and stirred at 0° C. for 1 hour. A solution 7N of ammonia in methanol (20 ml) was added to the mixture and adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 4 to 8% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness and the product was recrystallized from acetonitrile to afford [2-[2-amino-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]-3-pyridyl]-1,3-benzoxazol-7-yl]methanol (37.0 mg) as a solid. NMR Spectrum: (CDCl3) 2.05-2.29 (m, 6H), 2.36 (s, 3H), 2.98-3.08 (m, 2H), 4.12-4.23 (m, 1H), 5.09 (s, 2H), 6.88 (bs, 2H), 7.37 (dd, 1H), 7.43 (d, 1H), 7.66 (d, 1H), 7.67 (s, 1H), 7.74 (s, 1H), 8.30 (d, 1H), 8.32 (d, 1H); Mass spectrum: M+H+ 405;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:26])([CH3:25])[CH2:17][CH2:18][N:19]3[CH:22]([CH3:24])[CH3:23])=[CH:14][C:13]=2[CH3:27])=[CH:7][CH:6]=1)[CH3:2].C=O.[C:31]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:25])([CH3:26])[CH2:17][CH2:18][N:19]3[CH:22]([CH3:23])[CH3:24])=[CH:14][C:13]=2[CH3:27])[CH3:31])=[CH:9][CH:10]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CCN3C(C)C)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)c1ccc(N(C)c2cc3c(cc2C)C(C)(C)CCN3C(C)C)cc1
Yield: 30.6 %

Procedure:
A solution of 4-(1-isopropyl-4,4,6-trimethyl-1,2,3,4-tetrahydroquinolin-7-ylamino)-benzoic acid ethyl ester (Compound 46, 30 mg, 0.0788 mmol), formaldehyde (23.66 mg, 0.788 mmol), sodium cyanoborohydride (3.9 mg, 0.788 mmol), acetic acid (0.125 mL), and acetonitrile (1 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel chromatography (5% ethyl acetate in hexane, Rf=0.27) to give the title compound(9.5 mg, 31%) as a white solid:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[CH:20](Br)([CH3:22])[CH3:21].O>CN(C=O)C>[CH:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1)([CH3:22])[CH3:21]
Reactant: CC(C)Br
Reactant: O=C1CCCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)C(=O)CCCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a suspension of 2-hydroxy-6,7,8,9-Tetrahydro-5H-benzocyclohepten-9-one (9.69 g, 56.3 mmol) and potassium carbonate (23.3 g, 0.17 mol) in DMF (60 ml) was added dropwise, under ice-cooling, isopropyl bromide (34.6 g, 0.28 mol). The reaction mixture was stirred for one hour at 100° C., which was poured into water, followed by extraction of the organic substance with ethyl acetate. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=9:1) to give the above-titled compound (11.4 g, yield 93%, oil).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH:8]1[O:13][CH:5]2[CH:6]=[CH:7]1.C1C[O:17][CH2:16]C1>CO>[F:12][C:11]1[CH:10]=[C:9]2[C:4](=[CH:3][C:2]=1[F:1])[C@H:5]([OH:13])[C@@H:6]([O:17][CH3:16])[CH:7]=[CH:8]2
Reactant: Fc1cc2c(cc1F)C1C=CC2O1
Reactant: C1CCOC1
Solvent: CO
Product: CO[C@H]1C=Cc2cc(F)c(F)cc2[C@@H]1O
Yield: 88 %

Procedure:
To a flame dried round bottom flask, [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), (S)-(R)-PPF-PtBu2 (5.4 mg, 0.010 mmol) and 24 (72 mg, 0.40 mmol) were added followed by addition of THF (1.0 mL) and methanol (1.0 mL). The mixture was heated to reflux for 1 hour. The solvents were then removed in vacuo. The resulting solid was purified by flash chromatography (20% ethyl acetate in hexanes) to give 27 as a white crystalline solid (74.9 mg, 88%). The ee was determined to be 96.4% using HPLC analysis on a CHIRALCEL OD column, λ=486 nm. Retention times in 4% isopropanol in hexanes were 8.9 min and 10.1 min (major). Rf=0.27 on silica gel (30% ethyl acetate:hexanes); mp 129-131° (Et2O); [α]25D=+134.4° (c=9.3, CHCl3); IR (KBr, cm−1) 3269 (br), 2937 (w), 1597 (m), 1503 (s), 1306 (s), 1103 (s), 893 (s); 1H NMR (400 MHz, CDCl3) δ7.40 (1H, ddd, JH-F=10.8, 7.8 Hz, JH-H=0.6 Hz), 6.85 (1H, dd, JH-F=10.9, 7.8 Hz), 6.31 (1H, dd, J=10.0, 2.0 Hz), 6.05 (1H, dd, J=10.0, 2.0 Hz), 4.79 (1H, d, J=11.0 Hz), 4.05 (1H, ddd, J=11.0, 2.0, 2.0 Hz), 3.49 (3H, s), 2.94 (1H, d, J=2.2 Hz); 13C NMR (400 MHz, CDCl3) δ151.0 (d, JH-F=12.5 Hz), 148.5 (dd, JH-F=12.5,2.9 Hz), 133.2 (dd, JH-F=5.2, 3.6 Hz), 128.9 (dd, JH-F=6.6, 4.4 Hz), 128.0 (d, JH-F=2.2 Hz), 126.5 (dd, JH-F=2.2, 1.5 Hz), 115.1 (d, JH-F=18.3 Hz), 114.8 (d, JH-F=19.8 Hz), 82.3, 72.0, 57.0. HRMS calcd for C11H10O2F2 (M+): 212.0649. Found: 212.0658.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=O.CN(C)CCN>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([NH:26][CH2:27][CH2:28][N:24]([CH3:25])[CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: C[C@@H](C(=O)NCCN(C)C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) in tetrahydrofuran (100 ml) was stirred at room temperature for two hours with nitrogen bubbling through it. A solution of N,N-dimethylethylenediamine (4.41 g, 0.050 mole) in tetrahydrofuran (5.5 ml) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The solvents were removed under reduced pressure and the solid was triturated in water (100 ml). The solid was collected by filtration, rinsed once with water, twice with 5% potassium hydroxide solution and twice with water. The solid was recrystallized from hot isopropyl ether to give 1.99 g (32%) of a solid. A 0.5-g sample was dried under high vacuum to give 0.49 g of title compound, mp 130°-133° C.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)=O)[CH2:3][CH2:2]1.O.NN.[OH-].[K+]>C(O)CO>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:4][CH:1]2[CH2:2][CH2:3]2)=[CH:7][CH:8]=1
Reactant: O=C(c1ccc(Br)cc1)C1CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Brc1ccc(CC2CC2)cc1
Yield: 49.2 %

Procedure:
4-Bromophenyl cyclopropyl ketone (5.63 g), hydrazine monohydrate (2.5 ml) and potassium hydroxide (3.33 g) were added to ethylene glycol (25 ml) and the mixture heated to reflux for 1 hour. The reaction mixture was cooled and partitioned between water (20 ml) and ethyl acetate (30 ml) and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (30 ml) and the combined organic phases were washed with 2M hydrochloric acid (15 ml) and water (15 ml) then dried (MgSO4) and evaporated. The residue was purified by chromatography on a Mega Bond Elut column, eluting with hexane to give 1-bromo-4-(cyclopropylmethyl)benzene (2.6 g); 1H NMR (CDCl3): 0.2 (m, 2 H), 0.55 (m, 2 H), 2.50 (d, 2 H), 7.14 (d, 2 H), 7.41 (d, 2 H); mass spectrum (EI+) 210 (M.)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(N(CC)CC)C.C1(C2C=CC=CC=2)C=CC=CC=1.[B]1OC(C)(C)C(C)(C)O1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].Cl[C:50]1[C:51]2[CH:61]=[CH:60][C:59](=[O:62])[N:58]([C:63]3[C:68]([F:69])=[CH:67][CH:66]=[CH:65][C:64]=3[F:70])[C:52]=2[N:53]=[C:54]([S:56][CH3:57])[N:55]=1>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].O>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([C:50]2[C:51]3[CH:61]=[CH:60][C:59](=[O:62])[N:58]([C:63]4[C:68]([F:69])=[CH:67][CH:66]=[CH:65][C:64]=4[F:70])[C:52]=3[N:53]=[C:54]([S:56][CH3:57])[N:55]=2)[CH:3]=1
Reactant: Cc1ccc(N)cc1I
Reactant: CSc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)O[B]OC1(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1nc(-c2cc(N)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 3-iodo-4-methylaniline (110.0 mg, 0.47 mmol) in dioxane (1.0 mL) was added (under argon) triethylamine (0.26 mL, 1.86 mmol), palladium diacetate (5.2 mg, 0.023 mmol), 2-(dicyclophexyl phosphino) biphenyl (33.0 mg, 0.093 mmol), and pinacolborane (0.20 mL, 1.40 mmol). The mixture was stirred at about 80° C. for about 1 hour, cooled to room temperature (rt), and added with water (0.2 mL), barium hydroxide octahydrate (440.0 mg, 1.40 mmol) and 4-chloro-8-(2,6-difluorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (180.0 mg, 0.47 mmol). The mixture was heated at about 100° C. under stirring for about 1 hour, cooled to room temperature, filtered through celite, and diluted with brine (5.0 mL). The mixture was then extracted with CH2Cl2 (3×10 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. Purification via the CombiFlash system then afforded the title compound (155.0 mg, 75%): LC-MS m/z 411 (M+H)+, 2.60 min (ret. time).
Reaction SMILES: [CH2:1]([NH:9][C:10]1[CH:11]=[C:12]([C:22]([OH:24])=[O:23])[C:13]([C:19]([OH:21])=[O:20])=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:25](NC1C=C(C(O)=O)C(C(O)=O)=C(C(O)=O)C=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]C.C(NC1C=C(C(O)=O)C(C(O)=O)=C(C(O)=O)C=1)CCCCCCCCC.C(NC1C=C(C(O)=O)C(C(O)=O)=C(C(O)=O)C=1)CCCCCCCCCC.CC(NC1C=C(C(O)=O)C(C(O)=O)=C(C(O)=O)C=1)CCCCCCCCCC.C(NC1C=C(C(O)=O)C(C(O)=O)=C(C(O)=O)C=1)CCCCCCCCCCC.C(NC1C=C(C(O)=O)C(C(O)=O)=C(C(O)=O)C=1)CCCCCCCCCCCC.C(NC1C=C(C(O)=O)C(C(O)=O)=C(C(O)=O)C=1)CCCCCCCCCCCCC.C(NC1C=C(C(O)=O)C(C(O)=O)=C(C(O)=O)C=1)CCCCCCCCCCCCCC.CC(C)CCCCCCCCCCCCCNC1C=C(C(O)=O)C(C(O)=O)=C(C(O)=O)C=1.C(NC1C=C(C(O)=O)C(C(O)=O)=C(C(O)=O)C=1)CCCCCCCCCCCCCCCC.C(NC1C=C(C(O)=O)C(C(O)=O)=C(C(O)=O)C=1)CCCCCCCCCCCCCCCCC.C(NC1C=C(C(O)=O)C(C(O)=O)=C(C(O)=O)C=1)CCCCCCCCCCCCCCCCCC>>[CH2:1]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[C:12]([C:22]([OH:24])=[O:23])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCNc1cc(C(=O)O)c(C(=O)O)c(C(=O)O)c1
Reactant: CCCCCCCCNc1cc(C(=O)O)c(C(=O)O)c(C(=O)O)c1
Agent: CC(C)CCCCCCCCCCCCCNc1cc(C(=O)O)c(C(=O)O)c(C(=O)O)c1
Agent: CCCCCCCCCCC(C)Nc1cc(C(=O)O)c(C(=O)O)c(C(=O)O)c1
Agent: CCCCCCCCCCCCCCCCCCCNc1cc(C(=O)O)c(C(=O)O)c(C(=O)O)c1
Product: CCCCCCCCCCCCCCCCNc1cc(C(=O)O)c(C(=O)O)c(C(=O)O)c1

Procedure:
Similarly, the 5-alkylamino-1,2,3-benzenetricarboxylic acid triphenyl esters described in Example 5 give, respectively, 5-octylamino-1,2,3-benzenetricarboxylic acid, 5-nonylamino-1,2,3-benzenetricarboxylic acid, 5-decylamino-1,2,3-benzenetricarboxylic acid, 5-undecylamino-1,2,3-benzenetricarboxylic acid, 5-(1-methylundecyl)amino-1,2,3-benzenetricarboxylic acid, 5-dodecylamino-1,2,3-benzenetricarboxylic acid, 5-tridecylamino-1,2,3-benzenetricarboxylic acid, 5-tetradecylamino-1,2,3-benzenetricarboxylic acid, 5-pentadecylamino-1,2,3-benzenetricarboxylic acid, 5-(14-methylpentadecyl)amino-1,2,3-benzenetricarboxylic acid, 5-heptadecylamino-1,2,3-benzenetricarboxylic acid, 5-octadecylamino-1,2,3-benzenetricarboxylic acid, and 5-nonadecylamino-1,2,3-benzenetricarboxylic acid.
Reaction SMILES: O=[C:2]([C:9]1[CH:13]=[CH:12][O:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14]1(C=C[CH:19]=[C:17](O)[CH:16]=1)[OH:15].O.C1COCC1>[Cl-].[Na+].O.CCOC(C)=O>[O:11]1[CH:12]=[CH:13][C:9]([C:2]2[C:19]3[C:7](=[CH:8][C:14]([OH:15])=[CH:16][CH:17]=3)[O:6][C:4](=[O:5])[CH:3]=2)=[CH:10]1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)c1ccoc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1cc(-c2ccoc2)c2ccc(O)cc2o1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 3-oxo-3-(3-furyl)propionate (Aldrich; 3.17 g) and resorcinol (3.83 g) was treated with polyphosphoric acid (15 g) and heated to 110° C. under nitrogen. After 2 hr., the tarry mixture was cooled, then H2O and THF were added until a solution was obtained. Brine and EtOAc were added, the organic layer was removed and washed twice with brine. Chromatography of the residue, after concentration, using hexane/EtOAc 2:1 followed by swishing the product with ether afforded the title compound as a solid, m.p. 229-232° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=2[C:6]2[C:7](=[O:20])[NH:8][C:9]([NH:13]C(=O)C(C)(C)C)=[N:10][C:11]=2[CH:12]=1.[C:25](O)(=[O:27])C>C[O-].[Na+]>[NH2:13][C:9]1[NH:8][C:7](=[O:20])[C:6]2[C:5]3[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=3[C:3]([CH2:2][O:27][CH3:25])=[CH:12][C:11]=2[N:10]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)C(=O)Nc1nc2cc(CBr)c3ccccc3c2c(=O)[nH]1
Agent: C[O-]
Agent: [Na+]
Product: COCc1cc2nc(N)[nH]c(=O)c2c2ccccc12
Temperature: 650 °C

Procedure:
A solution of N-(6-(bromomethyl)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.28 g, 0.72 mmole) in 0.3 M sodium methoxide (25 ml) was stirred and heated at 650° C. under a nitrogen atmosphere for 4 hours. After cooling, the mixture was acidified to pH 6 with glacial acetic acid, and then all solvent was removed under reduced pressure. The residue was triturated with water (20 ml), then filtered, washed with water and acetone, and dried to give 3-amino-6-(methoxymethyl)benzo[f]quinazolin-1(2H)-one as an off-white solid. (0.12 g, 58%) 1H NMR (DMSO-d6, 200 MHz) d 3.39 (s, 3H, OCH3); 4.85 (s, 2H, CH2); 6.54 (br s, 2H, NH2); 7.33 (s, 1H, Ar); 7.44 (dt, J=6.9, 1.4 Hz, 1H, Ar); 7.59 (dt, J=6.9, 1.4 Hz, 1H, Ar); 7.96 (dd, J=8.2, 1.0 Hz, 1H, Ar); 9.69 (d, J=8 Hz, 1H, Ar); 11.11 (br s, 1H, NH); 11.91 (br s, <1H, pyr-NH+). Anal. Calculated for C14H13N3O2.1/2HOAc.1/10H2O: C, 62.75; H, 5.34; N, 14.64. Found C, 62.74; H, 5.31; N, 14.64.