Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([C:13]([NH:15][CH2:16][CH2:17]Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][C:22]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([C:13]([NH:15][CH2:16][CH2:17][N:25]2[CH2:26][CH2:27][C:22]([OH:21])([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[CH2:23][CH2:24]2)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: O=C(NCCCl)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1ccc(CC2(O)CCN(CCNC(=O)c3ccc(OCc4ccccc4)cc3)CC2)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 18.7 %

Procedure:
A mixture of 4-benzyloxy-N-(2-chloro-ethyl)-benzamide (2.0 g, 6.9 mmol), 4-hydroxy-4-(4-methyl-benzyl)-piperidine (1.06 g, 5.18 mmol), potassium carbonate (1.43 g, 10.35 mmol) and 2-butanone (40 ml) was stirred for 15 h at 60° C. After the addition of water, the mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica gel, methylene chloride methanol from 95:5 to 9:1) to give 4-benzyloxy-N-[2-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-yl]-ethyl]-benzamide (445 mg, 19%) as a light yellow solid. MS: me/e =459 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[CH:23]=2)=[CH:4][CH:3]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].O.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)=[N:12][N:11]3[C:23]=2[CH:34]2[CH:35]=[CH:36][N:31]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:32]=[CH:33]2)=[CH:4][CH:3]=1
Reactant: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)cn3n2)CC1
Reactant: CCOC(=O)Cl
Reactant: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1C=CC(c2c(-c3ccc(F)cc3)nc3ccc(N4CCN(C)CC4)nn23)C=C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension, cooled to about 0° C., of 3.24 g (10.4 mmol) of 2-(4-fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine in 7.5 mL of pyridine is added dropwise a solution of 5.0 mL (52 mmol) of ethyl chloroformate. After cooling to room temperature, 10 mL (104 mmol) of ethyl chloroformate and 15 mL of pyridine are added in two portions. After 18 hours, the mixture is diluted with 50 mL of dichloromethane and 20 mL (208 mmol) of ethyl chloroformate are added in three portions over 5 hours. 350 mL of water are then added, and the organic phase is separated out and washed twice with water, dried over sodium sulfate and concentrated under reduced pressure to give 4.5 g of a brownish solid. This solid is triturated in diethyl ether to give 3.5 g of beige-colored crystals. The solid is dissolved in dichloromethane and purified by chromatography on a column of silica gel, eluting with a mixture of 10% methanol in dichloromethane, to give 2.95 g of pale yellow crystals after trituration in diethyl ether, filtering through a sinter funnel and drying under vacuum.
Reaction SMILES: Cl.CN.CC(C)(C)C[CH2:7][NH2:8].O=[C:12]1[O:16][C:15]2[CH:17]=[C:18]3[O:44][CH2:43][C:21]4([C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]([CH2:30][C:31]5[O:35][C:34]([C:36]([F:39])([F:38])[F:37])=[C:33]([C:40]([OH:42])=O)[CH:32]=5)[CH2:22]4)[C:19]3=[CH:20][C:14]=2[O:13]1.[O:45]=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC(O)=O>>[CH3:7][NH:8][C:40]([C:33]1[CH:32]=[C:31]([CH2:30][N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]3([C:19]4=[CH:20][C:14]5[O:13][CH2:12][O:16][C:15]=5[CH:17]=[C:18]4[O:44][CH2:43]3)[C:22]2=[O:45])[O:35][C:34]=1[C:36]([F:39])([F:37])[F:38])=[O:42]
Reactant: CC(C)(C)CCN
Reactant: O=C(O)c1cc(CN2CC3(COc4cc5oc(=O)oc5cc43)c3ccccc32)oc1C(F)(F)F
Reactant: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: CN
Agent: Cl
Product: CNC(=O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F

Procedure:
Following the procedure as described in EXAMPLE 12.49 and making non-critical variations using methylamine hydrochloride to replace 3,3-dimethylbutylamine, 5-[(2-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxylic acid to replace (2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetic acid, N-methyl-5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxamide was obtained (96%) as a colorless solid: mp 202-203° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) 7.31-7.27 (m, 2H), 7.19-7.17 (m, 1H), 7.10-7.05 (m, 1H), 6.95-6.92 (m, 1H), 6.62 (s, 1H), 6.49 (s, 1H), 6.09 (s, 1H), 5.94 (br s, 1H), 5.85-5.84 (m, 2H), 5.03-4.85 (m, 3H), 4.67-4.64 (m, 1H), 2.92 (d, J=3.0 Hz, 3H); MS (ES+) m/z 487.3 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][N:24]=1)[C:19](Cl)=[O:20].Cl.CCCCCC.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][N:24]=[C:16]([Cl:15])[CH:17]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: CS(=O)(=O)c1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(S(=O)(=O)NC(=O)c2ccnc(Cl)c2)cc1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
2.3 g (0.01 mol) of 4-methylsulfonylbenzenesulfonamide were dissolved in 20 ml of pyridine, and added dropwise by 1.7 g (0.01 mol) of 2-chloroisonicotinoyl chloride at room temperature, followed by agitation for 2 hrs. at the same temperature. After acidified by adding aqueous hydrochloric acid, the precipitate was extracted by ethyl acetate. The organic layer obtained was dried and then concentrated to precipitate crude crystals, which were recrystallized by n-hexane/ethyl acetate to 2.8 g (yield: 74.7%) of N-(4-methylsulfonylphenylsulfonyl)-2-chloroisonicotinamide as white crystals.
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([CH3:13])[CH:11]([NH2:14])[CH:10]([CH3:15])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)Cl>[C:16]1([CH:9]2[CH:10]([CH3:15])[CH:11]([NH:14][C:29](=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:12]([CH3:13])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:8]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC1C(c2ccccc2)NC(c2ccccc2)C(C)C1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)NC1C(C)C(c2ccccc2)NC(c2ccccc2)C1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
To a stirred 0° C. solution of 12.7 g (45.3 mmol) of 2,6-diphenyl-3,5-dimethyl-4-aminopiperidine and 5.1 g (50 mmol) of triethylamine in 150 ml of methylene chloride is added dropwise a solution of 9.9 g (45.3 mmol) of lauroyl chloride. After stirring for 30 minutes at 0° C., the reaction mixture is washed with water (2×200 ml) followed by a saturated aqueous sodium bicarbonate solution (300 ml). The organic phase is separated, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting solid is recrystallized from ethanol to give 15.4 g (73% yield) of the title compound as a white solid melting at 112°-114° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([CH3:13])=[N:7]2.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>CS(C)=O>[Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([CH3:13])=[N:7]2
Reactant: Cc1nc2ccc(F)c(Br)c2[nH]c1=O
Reactant: CC(C)(C)N
Solvent: CS(C)=O
Product: Cc1nc2ccc(F)c(Br)c2nc1NC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A glass reaction vessel was charged with 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline (600) (9.705 g, 35.2 mmol) in DMSO (58.7 mL). Then tert-butylamine (Alfa Aesar; Ward Hill, Mass.) (18.51 mL, 176 mmol) was added into the mixture. The vial was sealed, then placed into a pre-heated (100° C.) oil bath and stirred 2 h. The vessel was removed from the heat source and cooled to RT. The mixture was poured into water (1100 mL) sat undisturbed 30 min, then stirred. The precipitate was collected by filtration (through a medium fritted-funnel) and the solids were washed with water. The solids were dried in a reduced-pressure oven overnight, to provide 8-bromo-N-(tert-butyl)-7-fluoro-3-methylquinoxalin-2-amine (286a) (8.27 g, 75% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (dd, J=9.00, 5.87 Hz, 1H) 7.33 (t, J=8.80 Hz, 1H) 6.30 (s, 1H) 2.54 (s, 3H) 1.59 (s, 9H). m/z (ESI, +ve) 311.9 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([I:10])[CH:3]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[CH:13]=[CH:12]1>C(O)(=O)C>[O:15]=[C:14]1[CH:13]=[CH:12][C:11](=[O:16])[N:1]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([I:10])[CH:3]=1
Reactant: N#Cc1ccc(N)cc1I
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: N#Cc1ccc(N2C(=O)C=CC2=O)cc1I
Temperature: 25 °C
Yield: 90.5 %

Procedure:
Compound 489C (3.97 g, 16.3 mmol) and maleic anhydride (2.41 g, 24.4 mmol) were refluxed in glacial acetic acid (15 mL) for 5 h. The reaction was cooled to 25° C. and then poured onto ice (100 mL). The resulting precipitate was isolated by filtration and washed with water (2×25 mL) and dried under vacuum to yield 4,78 g (90%) of compound 489D as a tan solid. HPLC: 82% at 2.68 min (retention time) C Shimadzu VP-ODS column, 4.6×50 mm, eluting with 10–90% aqueous methanol over 4 min containing 0.1% trifluoroacetic acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 325.04 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:13](=[O:22])[CH:12]=[C:11]3[C:23]2[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34]>CN(C=O)C.C(NCC)C.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:13](=[O:22])[CH:12]=[C:11]3[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])[CH:24]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(I)c1)cc(=O)n2CC1CC1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1cccc(-c2cc(=O)n(CC3CC3)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
A solution of 6-(4-chloro-benzoyl)-1-cyclopropylmethyl4-(3-iodo-phenyl)-1H-quinolin-2-one (4.0 g, 7.41 mmol) in DMF/diethylamine (1:1, 80 mL) was treated with palladium (II) bis(triphenyl)phosphine chloride (0.26 9, 0.37 mmol), trimethylsilylacetylene (1.09 g, 11.1 mmol), and copper (1) iodide (0.21 g, 1.09 mmol). The reaction mixture was stirred at room temperature for 3 hours, concentrated in vacuo, poured into H2O (450 mL), and filtered to give a crude brown foam. Purification by flash column chromatography (silica, ether:petroleum ether 1:1) gave 6-(4-Chlorobenzoyi)-1-cyclopropylmethyl4-(3-trimethylsilanylethynyl-phenyl)-1 H-quinolin-2-one (3.47 g, 92%) as a yellow solid.
Reaction SMILES: C([O:5][C:6](=[O:48])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[C:20](=[O:34])[N:19]2[CH3:35])=[CH:11][C:10]=1[CH2:36][N:37]1[C:45](=[O:46])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]1=[O:47])(C)(C)C>C(Cl)Cl>[O:47]=[C:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45](=[O:46])[N:37]1[CH2:36][C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[C:20](=[O:34])[N:19]2[CH3:35])[CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][C:6]([OH:48])=[O:5]
Reactant: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CN2C(=O)c3ccccc3C2=O)c1
Solvent: ClCCl
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CCC(=O)O)c(CN2C(=O)c3ccccc3C2=O)c1
Yield: 50.9 %

Procedure:
A solution of the ester obtained in Step A (70 mg, 0.10 mmol) in trifluoroacetic (1 ml) and methylene chloride (2 ml) is stirred at 23° C. for 7 hours. Concentration of the reaction mixture gave an oil which is partitioned between ethyl acetate (20 ml) and water (25 ml). The ethyl acetate layer is washed with water (15 ml), brine (20 ml), dried (Na2SO4), and concentrated to an oil which is purified by chromatography on a Biotage silica cartridge (gradient elution, 100% methylene chloride to 10:1 methylene chloride:methanol) to produce an oil (31 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:13]([O:28][CH3:29])[CH:12]=3)=[CH:9][N:8]([CH:30]3[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[C:13]([O:28][CH3:29])[CH:12]=3)=[CH:9][N:8]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)[CH2:32][CH2:31]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(-c2cn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(-c2cn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Reaction time: 20 h

Procedure:
To a solution of 92% pure N1-{4-[4-amino-7-(4-oxocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-3-phenylpropanamide (1.0 g, 2.1 mmol), N-methylpiperazine (0.63 g, 6.3 mmol), acetic acid (0.38 g, 6.3 mmol) in dichloroethane (100 mL) was added sodium triacetoxyborohydride (0.67 g, 3.15 mmol) portionwise under nitrogen. The solution was stirred for 20 hr and then quenched by the addition of saturated aqueous sodium bicarbonate solution (50 mL). The aqueous layer was extracted with dichloromethane (3×50 mL), dried (sodium sulphate), filtered and evaporated to leave a sludge which was purified by flash silica gel column chromatography using dichloromethane to 50% MeOH/dichloromethane in 10% increments. F84-96 were combined and evaporated to leave cis-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)-3-phenylpropanamide (0.26 g) as a cream foamy glass. HPLC: (5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) tr=12.65 min, 95.2%.1H NMR (d6 DMSO, 400 MHz): 9.17(1H, s), 8.14(1H, s), 8.05(1H, d), 7.28(5H, m), 7.18(1H, m), 7.10(1H, s), 6.99(1H, d), 6.11(2H, bs), 4.67(1H, m), 3.88(3H, s), 2.90(2H, m), 2.73(2H, m), 2.50(7H, m), 2.28(3H, s), 2.06(3H, m), 1.71(2H, m), 1.55(2H, m). F121-138 were combined and evaporated to leave trans-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)-3-phenylpropanamide (0.11 g) as a white solid. HPLC: (5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) tr=12.61 min, 96.2%. 1H NMR (d6 DMSO, 400 MHz): 9.16(1H, s), 8.13 (1H, s), 8.04(1H, d), 7.44(1H, s), 7.29 (4H, m), 7.18(1H, m), 7.09(1H, s), 6.97 (1H, d), 6.11(2H bs), 4.53(1H, m), 3.88 (3H, s), 2.93(2H, m), 2.71(2H, m), 2.50 (4H, m), 2.30(5H, m), 2.14(3H, s), 1.89(6H, m), 1.46(2H, m).
Reaction SMILES: C([O-])C.[CH3:4][O:5][C:6]1[C:7]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[C:8]2[C:13](=[C:14]([N:16]3[C:20](=[O:21])[C:19]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]4[C:17]3=[O:26])[CH:15]=1)[N+:12]([O-])=[CH:11][CH:10]=[C:9]2[CH3:28].O=P(Cl)(Cl)[Cl:42].[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:42][C:11]1[CH:10]=[C:9]([CH3:28])[C:8]2[C:13](=[C:14]([N:16]3[C:17](=[O:26])[C:18]4=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]4[C:20]3=[O:21])[CH:15]=[C:6]([O:5][CH3:4])[C:7]=2[O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:37])[F:39])[CH:31]=2)[N:12]=1
Reactant: COc1cc(N2C(=O)c3ccccc3C2=O)c2c(c(C)cc[n+]2[O-])c1Oc1cccc(C(F)(F)F)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc(N2C(=O)c3ccccc3C2=O)c2nc(Cl)cc(C)c2c1Oc1cccc(C(F)(F)F)c1

Procedure:
From 6-methoxy-4-methyl-8-phthalimido-5-(3-trifluoromethylphenoxy)quinoline-1-oxide Ethanolate (III): A solution of 6-methoxy-4-methyl-8-phthalimido-5-(3-trifluoromethylphenoxy)quinoline-1-oxide ethanolate (32.7g, 60.5 mmol) in CHCl3 (500 mL) was treated with POCl3 (55 mL, 92 g, 602 mmol) over 15 min. The solution was refluxed 2 hours, cooled, poured onto ice (1500 mL) and the pH was adjusted to 12 with 20% NaOH (700 g). The separated aqueous layer was extracted with CHCl3 (2×200 mL). The extract was washed with H2O (2×200 mL), saturated NaHCO3 (20 mL), dried (MgSO4) and evaporated in vacuo to a white solid. Recrystallization from ethanol gave 23.2 g (75%) of 1st crop title compound, mp 227°-229° C. Further recrystallizations did not change the melting point.
Reaction SMILES: [I:1][C:2]#[C:3][CH2:4][O:5][C:6]1[C:10]([C:11]#[N:12])=[C:9](S(C)(=O)=O)[S:8][N:7]=1.[CH3:17][NH:18][CH3:19].O>C(COC)OC>[I:1][C:2]#[C:3][CH2:4][O:5][C:6]1[C:10]([C:11]#[N:12])=[C:9]([N:18]([CH3:19])[CH3:17])[S:8][N:7]=1
Reactant: CNC
Reactant: CS(=O)(=O)c1snc(OCC#CI)c1C#N
Solvent: O
Solvent: COCCOC
Product: CN(C)c1snc(OCC#CI)c1C#N

Procedure:
3.6 Grams of 3-(3-iodo-2-propynyloxy)-4-cyano-5-methylsulfonylisothiazole was dissolved in 30 ml of dimethoxyethane, 1.5 g of dimethylamine (as 50% aqueous solution) was added at room temperature with stirring, and then the reaction solution was stirred at 50° C. for 2 hours. Water was added to precipitate crystals, which were then collected by filtration, washed with water, dried and recrystallized from ethyl acetate. Thus, 2.2 g of white crystals having a melting point of 171° to 172° C. was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:10][C@@H:9]1[C@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:12][Cl:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([Mg]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1COCC1.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Si:15]([O:14][C@@H:11]([C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:10][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12][Cl:13])([C:18]([CH3:21])([CH3:19])[CH3:20])([CH3:16])[CH3:17]
Reactant: Cl[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]1[C@@H](CCl)O[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](CCl)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a magnetically stirred solution of N-t-butyloxycarbonyl-2(R)-(1(S)-t-butyldimetylsilyloxy-2-chloroethyl)aziridine (36.0 mg, 0.107 mmol) in toluene was added copper bromide dimethyl sulfide complex (11.0 mg, 0.054 mmol) at rt under N2. The reaction mixture was cooled to −78° C. then treated with a 2 M solution of PhMgCl in THF (0.54 mL, 1.072 mmol). The resulting mixture was warmed to −20° C. and stirred overnight. The reaction mixture was treated with sat NH4Cl (4 mL) and extracted with EtOAc(5 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, concentrated and column-chromatographed (3% EtAc in n-Hex) to provide 2(S)-t-butyldimetylsilyloxy-3(R)-(t-butyloxycarbonyl)amino-1-chloro-4-phenylbutane (33.5 mg) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:36]([O:37][CH3:38])=[CH:35][C:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])[CH2:28][CH2:29][C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[C:36]([O:37][CH3:38])=[CH:35][C:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]([OH:33])([CH3:34])[CH3:32])[CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(C)O)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(CC(C)(C)O)CC2
Yield: 64 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2-methyl-propan-2-ol. Product isolated as a white foam (68 mg, 64%). MS (ESI+): 527 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.20 (s, 1H), 7.90 (s, 1H), 7.42 (s, 1H), 6.65 (s, 1H), 6.57 (d, J=9 Hz, 1H), 6.33 (s, 2H), 5.63 (br s, 1H), 5.32 (br s, 1H), 4.46 (t, 1H), 3.88 (s, 3H), 3.09 (s, 1H), 2.88-2.82 (m, 10H), 2.54-2.49 (m, 3H), 2.28 (d, J=9 Hz, 1H), 1.22 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][NH:4][N:3]=1.[ClH:8].[C:9](=[NH:15])(OCC)[CH2:10][CH3:11]>C(#N)C>[ClH:8].[CH3:7][C:6]1[C:2]([NH:1][C:9](=[NH:15])[CH2:10][CH3:11])=[N:3][NH:4][CH:5]=1
Reactant: Cc1c[nH]nc1N
Reactant: CCOC(=N)CC
Agent: Cl
Solvent: CC#N
Product: CCC(=N)Nc1n[nH]cc1C
Reaction time: 1 h

Procedure:
A 8.06 g portion of 3-amino-4-methyl-1H-pyrazole was dissolved in 30 ml of acetonitrile and, with cooling on an ice bath, 12.9 g of ethyl propionimidate hydrochloride was added to the solution. The resulting mixture was stirred for 1 hour at the same temperature and then overnight at room temperature. After removing insoluble materials by filtration, the resulting filtrate was concentrated under a reduced pressure, and the thus obtained residue was subjected to silica gel column chromatography. Elution with methanol-chloroform (1:9-3:7, v/v) gave 8.40 g of N-(4-methyl-1H-pyrazol-3-yl)propionamidine hydrochloride.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[CH2:21]([O:28][P:29]([CH2:38][C@H:39]([OH:49])[CH2:40][NH:41][C:42](=[O:48])[C@@H:43]([NH2:47])[CH:44]([CH3:46])[CH3:45])([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][P:29]([CH2:38][C@H:39]([OH:49])[CH2:40][NH:41][C:42](=[O:48])[C@@H:43]([NH:47][C:7](=[O:9])[C@@H:2]([NH:1][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:3][CH:4]([CH3:5])[CH3:6])[CH:44]([CH3:46])[CH3:45])([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)[C@H](N)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1)C(C)C

Procedure:
The title compound was prepared substantially in a similar manner as Step 1 of Example 10 using N—Z-Leu-OH and [(R)-3-((S)-2-amino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride as the starting materials. The title compound was purified by SiO2 chromatography using 0-4% MeOH/CH2Cl2 as the eluent. 1H NMR (CD3OD, 300 MHz): δ 7.34 (m, 10H), 5.50 (m, 4H), 4.19 (m, 2H), 4.01-3.94 (m, 1H), 3.30 (m, 2H), 2.15 (m, 1H), 1.92 (m, 2H), 1.77-1.64 (m, 8H), 1.50 (m, 2H), 1.40-1.12 (m, 4H), 1.11-0.97 (m, 14H). 31P NMR (CD3OD, 300 MHz): δ 60.56, 59.87. LCMS m/z: [M+H]+=672.