Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1.CCN(C(C)C)C(C)C.[CH3:42][N:43]([CH3:48])[S:44](Cl)(=[O:46])=[O:45].O>C(Cl)Cl>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:44]([N:43]([CH3:48])[CH3:42])(=[O:46])=[O:45])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)N(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
A solution of 224 mg (0.5 mmol) of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 2) and 130 mg (1 mmol) of DIPEA in 10 mL of CH2Cl2 was treated with 150 mg (1 mmol) of dimethylsulfamoyl chloride and the mixture was stirred at room temperature overnight. Water was added, and the organic layer was separated and dried. Chromatography on silica, eluting with CH2Cl2/EtOAc (9:1), gave 217 mg (78% yield) of 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N,N-dimethyl-1-piperazinesulfonamide: mp (MeOH) 286-288° C.; 1H NMR (CDCl3) δ 7.86 (dd, J=8.4, 0.7 Hz, 1H), 7.44 (t, JHF=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 4.05 (s, 3H), 3.96 (m, 4H), 3.89 (m, 4H), 3.78 (m, 4H), 3.34 (m, 4H), 2.87 (s, 6H); Anal. Calcd. for C22H29F2N9O4S: C, 47.7; H, 5.3; N, 22.8. Found: C, 47.95; H, 5.3; N, 22.9%.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH:21]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:39][CH2:40][C:41](Cl)=O>ClCCCl>[Si:32]([O:31][CH:21]([CH2:20][N:19]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=[C:41]1[CH2:40][Cl:39])[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCC(CNc1c(N)cnc2ccccc12)O[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(Cn1c(CCl)nc2cnc3ccccc3c21)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
Triethylamine (46.2 g, 456 mmol) was added to a solution of tert-butyl 3-[(3-aminoquinolin-4-yl)amino]-2-{[tert-butyl(dimethyl)silyl]oxy}propylcarbamate (101.9 g, 228.1 mmol) in 1,2-dichloroethane (600 mL). A solution of chloroacetyl chloride (28.3 g, 251 mmol) in 1,2-dichloroethane was added dropwise, and the reaction was stirred overnight at ambient temperature. The reaction mixture was filtered to remove a solid, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting sequentially with 95.5:0.5 and 95:5 dichloromethane:methanol), and the purified product was dried overnight under high vacuum to provide 71.93 g of tert-butyl 2-{[tert-butyl(dimethyl)silyl]oxy}-3-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl.O=S(Cl)[Cl:13]>O1CCOCC1>[ClH:13].[Cl:1][CH2:3][C:4]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=S(Cl)Cl
Reactant: NC1(CO)CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(CCl)CCCC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 100.3 %

Procedure:
To a solution of 1-hydroxymethylcyclopentanamine HCl salt (Method B1c; 20 g, 0.17 mol) in anh. p-dioxane (65 mL) was added HCl (4M in p-dioxane; 65 mL, 0.26 mol). The resulting solution was stirred for 20 min. at room temp., then SOCl2 (22.7 g, 0.19 mol) was added dropwise. The reaction mixture was heated at 80° C. for 2 d, cooled to room temp., and concentrated under reduced pressure to give 1-chloromethylcyclopentanamine HCl salt (29 g, 100%): CI-MS m/z 171 ((M+H)+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)c1ccc(Br)cc1
Product: CCC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
To fuming nitric acid (200 ml), 1-(4-bromophenyl)-1-propanone (40 g) was added while keeping the inside temperature of the mixture at 5 to 10° C. The reaction solution was stirred at that temperature for 30 minutes and then poured into ice. The precipitate was collected by filtration, washed with distilled water, and recrystallized from methanol to obtain the title compound (18 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]([CH2:13][C:14]3[C:15](=[O:22])[NH:16][C:17]([CH3:21])=[CH:18][C:19]=3[CH3:20])[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[CH:4][C:3]=1[O:24]C.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]([CH2:13][C:14]3[C:15](=[O:22])[NH:16][C:17]([CH3:21])=[CH:18][C:19]=3[CH3:20])[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:24]
Reactant: COc1ccc2c(c1Cl)C(=O)N(Cc1c(C)cc(C)[nH]c1=O)CCO2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(C)c(CN2CCOc3ccc(O)c(Cl)c3C2=O)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a 0° C. solution of 6-chloro-4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-methoxy-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (124c, 500 mg, 1.38 mmol) in anhydrous DCM (10 mL) was added slowly a solution of BBr3 (1 M in DCM, 4.00 mL, 4.00 mmol). The reaction mixture was stirred at 0° C. for 3 hours, then quenched with water, and further diluted with water to 100 mL. The resulting mixture was extracted with DCM (3×100 mL). The combined organic phases were dried over sodium sulfate, and concentrated under vacuum to give 6-chloro-4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-hydroxy-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (124d, 456 mg, 95% yield) as a solid.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14](S(C4C=CC=CC=4)(=O)=O)[C:15]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4cccc(F)n4)ccnc3n2S(=O)(=O)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4cccc(F)n4)ccnc3[nH]2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of Example 309D (3.0 g, 5.61 mmol) in 1,4-dioxane (50 mL) was treated with a solution of sodium hydroxide (0.673 g, 16.83 mmol) in water (10 mL). The resulting mixture was stirred at 80° C. overnight. Most solvent was evaporated. The solids were filtered, washed with water/ethyl acetate/ether, and vacuum oven-dried to give the title compound. MS (ESI+) m/z 395.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([CH:26]2[O:28][CH2:27]2)=[CH:24][CH:23]=1>CO>[CH2:1]([N:8]([CH2:27][CH:26]([OH:28])[C:25]1[CH:29]=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2CO2)cc1
Reactant: COc1ccc(CCNCc2ccccc2)cc1OC
Solvent: CO
Product: COc1ccc(CCN(Cc2ccccc2)CC(O)c2ccc(Cl)cc2)cc1OC

Procedure:
Similarly, 5.42 g. (0.02 mol) of N-benzyl-3,4-dimethoxyphenethylamine and 4.64 g. (0.03 mol) of p-chlorostyrene oxide are reacted in methanol to give N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-chlorophenyl) ethylamine. The hydrochloride of this ethylamine is dissolved in methanol and hydrogenated with 0.5 g. of 10% palladium-on-carbon in 10 ml. of ethyl acetate at room temperature and 60 psi. for about 90 minutes. The filtered reaction mixture is evaporated in vacuo to yield N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-chlorophenyl)ethylamine hydrochloride, m.p. 167°-171° C.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CN(C)C=O>[CH2:25]([N:27]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCNCC
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)cc2C1=O
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A suspension of 1.5 g (0.0043 mol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 15 ml of dimethylformamide was treated with 1.6 g (0.022 mol) of diethylamine. After stirring at room temperature for 16 hrs. the solution obtained was freed completely from the solvents. The residue was chromatographed over silica gel with dichloromethane/methanol 9:1 as the eluent. There were obtained 1.33 g (81%) of 3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 172°-174°.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]2[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)=[N:9][N:10]=[C:5]2[C:4](=[O:17])[N:3]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][N:6]2[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)=[N:9][N:10]=[C:5]2[C:4](=[O:17])[NH:3]1
Reactant: C[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a solution of (S)-tert-butyl 6-methyl-8-oxo-3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (0.4 g, 1.2 mmol) in DCM (12 mL) was added trifluoroacetic acid (2.5 mL, 31.7 mmol) and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated and EtOAc (10 mL) was added. The resulting precipitate was collected via filtration and dried to provide the desired compound (267 mg, 64%). MS (ESI): mass calcd. for C10H10N6O, 230.2; m/z found, 231.1 [M+H]+. 1H NMR (400 MHz, DMSO) δ 9.44 (d, J=1.4 Hz, 1H), 8.85-8.81 (m, 2H), 8.69 (s, 1H), 4.92 (m, 1H), 4.31-4.23 (m, 1H), 4.10-3.96 (m, 1H), 1.24 (d, J=6.6 Hz, 3H).
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][C:12]([OH:18])([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)C1C=CC=CC=1>[Pd].CCO>[NH2:8][CH:9]1[CH2:14][CH2:13][C:12]([OH:18])([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1
Reactant: O=C(O)C1(O)CCC(NCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: NC1CCC(O)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.7 %

Procedure:
4-(Benzylamino)-1-hydroxycyclohexanecarboxylic acid (0.44 g, 1.765 mmol) and 10% palladium on carbon (0.282 g, 0.265 mmol) were charged into a round bottom flask under nitrogen atmosphere. To this was added EtOH (8.82 mL), and the mixture was stirred under an atmosphere of hydrogen at RT for 72 hours. The mixture was diluted with EtOH (10 mL) and filtered through Celite® brand filter aid, rinsing with DCM (10 mL), EtOH (10 mL), and MeOH (10 mL). The filtrate was concentrated under reduced pressure to afford 4-amino-1-hydroxycyclohexanecarboxylic acid as a yellow solid (0.28 g, 100% yield). MS m/z=160.2 [M+H]. Calc'd for C7H13NO3: 159.1.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[F:23])[C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:24])[CH:7]=1.[Br:30]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>>[Br:30][C:7]1[C:8](=[O:24])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[F:23])[C:16]([O:18][CH3:19])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoate (7.3 g, 18 mmol) and N-methyl-2-pyrrolidine (20 mL). N-Bromo succinimide (3.5 g, 19.8 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. The mixture poured into saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2SO4, and concentrated in vacuo. The residue was triturated with diethyl ether and filtered to give the title compound as a white powder (3.49 g). 1H NMR (400 MHz, CD3OD) δ 8.16 (qd, J=3, 6.8 and 15.6 Hz, 1H), 7.84 (d, J=2.12 Hz, 1H), 7.64 (q, J=8.4 and 14.8 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.04 (m, 2H), 6.60 (s, 1H), 5.34 (s, 2H), 3.87 (s, 3H), 2.00 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ−111.51 (1 F), −115.98 (1 F), −117.43 (1 F) ppm. ES-HRMS m/z 494.0387(M+H calcd for C22H19BrF2NO5 requires 494.0409). Step 2 Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[N:16]O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].Cl>C(O)CCCC>[CH2:1]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([NH2:16])[CH2:10]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ON=C1CC2CCC(C1)N2Cc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCCCCO
Product: NC1CC2CCC(C1)N2Cc1ccccc1
Temperature: 5 °C
Yield: 36.4 %

Procedure:
To a solution of oxime 99 (7.65 g, 33 mmol) in 1-pentanol (130 mL) at 120° C., was added sodium metal (7.6 g, 0.33 mol, 10.0 equiv) portionwise over 2 h. The mixture was stirred and heated under reflux conditions for 5 h, then was cooled to 5° C. The reaction mixture was slowly acidified with 6M HCl to a pH of 2 then was further extracted with 6M HCl (3×100 mL). The aqueous layer was gradually made basic by the addition of 5M NaOH to a pH of 10. The resulting aqueous solution was extracted with EtOAc (3×100 mL) and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Purification of the crude material via column chromatography (5-10% MeOH/CH2Cl2) afforded pure 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine 100 as a solid (2.60 g, 36%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:20])=[C:7]([C:11]([I:19])=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[C:13]=1[I:14])[C:8](Cl)=[O:9])(=[O:3])[CH3:2].Cl.[CH2:22]([O:24][C:25](=[O:35])[C@H:26]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH2:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:35])[C@H:26]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH:27][C:8](=[O:9])[C:7]1[C:6]([I:20])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:13]([I:14])=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[C:11]=1[I:19])[CH3:23]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)Cl)c1I
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I

Procedure:
Following the procedure of example 13, 60 g (75%) of the product was synthesized from 63.2 g (0.1 Mol) 3,5-diacetamido-2,4,6-triiodobenzoyl chloride and 33.5 g (0.15 Mol) L-phenylalanine ethyl ester hydrochloride.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)[NH:6][C:5]2=O.F[P-](F)(F)(F)(F)F.[N:26]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:30]2C=CC=CC=2N=N1.N12CCCN=C1CCCCC2.CN.C1COCC1>O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)[N:6]=[C:5]2[NH:26][CH3:30]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=c1[nH]c(-c2cnccn2)nc2ccc(I)cc12
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CNc1nc(-c2cnccn2)nc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
In a 100 mL round-bottomed flask was added 6-iodo-2-(pyrazin-2-yl)quinazolin-4(3H)-one (0.500 g, 1.428 mmol), BOP (0.821 g, 1.857 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.426 ml, 2.86 mmol) in DMT (10 mL) to give a colorless solution. Methylamine, 2M in THF (2.142 ml, 4.28 mmol) was added and stirred at room temperature overnight. The reaction mixture was diluted with water (50 mL) and then a precipitate formed. The resulting solid was collected by filtration and dried to give 0.515 g of 6-iodo-N-methyl-2-(pyrazin-2-yl)quinazolin-4-amine as a pale brown solid in a 99% yield. LCMS m/z=364 (M+1) (Method D) (retention time=1.25 min). 1H NMR (300 MHz, DMSO) δ 9.60 (s, 1H), 8.89-8.65 (m, 3H), 8.65-8.48 (m, 1H), 8.06 (d, J=8.7 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 3.11 (d, J=4.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][CH2:40][NH2:41]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: CN(C)CCCN
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCCN(C)C)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 77.5 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (30 mg, 0.06 mmol) in DCM (5 mL) was added N,N-dimethyl-1,3-propanediamine (0.036 mL, 0.30 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (25 mg, 77%). LC-MS m/z 552 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 3H), 1.58 (m, 2H), 1.66 (m, 2H), 2.16 (m, 2H), 2.18 (s, 6H), 2.30 (s, 3H), 3.06 (m, 2H), 3.37 (m, 2H), 4.10 (s, 2H), 7.17 (t, 2H), 7.45 (d, 1H), 7.53 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: C(OC1C=CC(Br)=CC=1CCNC1C=CC(C(OCC)=O)=CC=1)C1C=CC=CC=1.[CH2:30]([O:37][C:38]1[CH:58]=[CH:57][C:56]([Br:59])=[CH:55][C:39]=1[CH2:40][CH2:41][N:42]([C:44]1[CH:54]=[CH:53][C:47]([C:48]([O:50]CC)=[O:49])=[CH:46][CH:45]=1)[CH3:43])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CI>>[CH2:30]([O:37][C:38]1[CH:58]=[CH:57][C:56]([Br:59])=[CH:55][C:39]=1[CH2:40][CH2:41][N:42]([C:44]1[CH:45]=[CH:46][C:47]([C:48]([OH:50])=[O:49])=[CH:53][CH:54]=1)[CH3:43])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1ccc(N(C)CCc2cc(Br)ccc2OCc2ccccc2)cc1
Agent: CCOC(=O)c1ccc(NCCc2cc(Br)ccc2OCc2ccccc2)cc1
Solvent: CI
Product: CN(CCc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)O)cc1

Procedure:
Ethyl 4-[N-(2-benzyloxy-5-bromophenethyl)amino]benzoate was converted to ethyl 4-[N-(2-benzyloxy-5-bromophenethyl)-N-methylamino]benzoate using a similar method to that described in Example 41(D) except methyl iodide was used in place of iodoethane.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([Cl:10])=[C:8]([F:11])[CH:7]=[CH:6][C:5]=1[Cl:12])=[O:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O>[Cl:10][C:9]1[C:8]([F:11])=[CH:7][CH:6]=[C:5]([Cl:12])[C:4]=1[CH:2]([OH:3])[CH3:1]
Reactant: CC(=O)c1c(Cl)ccc(F)c1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
2,6-Dichloro-3-fluoroacetophenone (15 g, 0.072 mol) was stirred in THF (150 mL, 0.5M) at 0° C. using an ice bath for 10 min. Lithium aluminum hydride (2.75 g, 0.072 mol) was slowly added. The reaction was stirred at ambient temperature for 3 hr. The reaction was cooled in ice bath, and water (3 mL) was added drop wisely followed by adding 15% NaOH (3 mL) slowly. The mixture was stirred at ambient temperature for 30 min. 15% NaOH (9 mL), MgSO4 were added and the mixture filtered to remove solids. The solids were washed with THF (50 mL) and the filtrate was concentrated to give 1-(2,6-dichloro-3-fluoro-phenyl)-ethanol (14.8 gm, 95% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 1.45 (d, 3H), 5.42 (m, 2H), 7.32 (m, 1H), 7.42 (m, 1H).
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:9](O)=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.CN.[CH3:22][N:23](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[C:15]([O:14][C:12](=[O:13])[NH:1][C@@H:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[C:9](=[O:10])[NH:23][CH3:22])([CH3:18])([CH3:17])[CH3:16]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Yield: 76 %

Procedure:
Boc-Chg-OH (387 mg, 1.50 mmol) was coupled to methylamine hydrochloride (111 mg, 1.65 mmol) using the same HATU coupling conditions as in the synthesis of compound 7. The crude product was extracted with EtOAc, washed with brine and concentrated. Purification by flash column chromatography (EtOAc) provided the title compound (307 mg, 76%) as a colorless solid.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].C(C1C=CC(C(C)C(O)=O)=CC=1)=O>CO.[Pt]=O>[CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: O=[Pt]
Agent: CC(C(=O)O)c1ccc(C=O)cc1
Solvent: CO
Product: O=Cc1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 253 mg (1.44 mmol) of 4-formylcinnamic acid and 32.61 mg of platinum oxide in 10 mL of methanol is stirred overnight at room temperature under an atmosphere of hydrogen supplied by a balloon. The mixture is filtered through celite and concentrated in vacuo. The residue is dissolved in 0.1N sodium hydroxide solution and washed with ether. The aqueous layer is then acidified and the product is extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is removed in vacuo to afford an inseparable mixture of 4-formylphenylpropanoic acid and other reduction products. The mixture is utilized in the next reaction without characterization or further purification.