Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:12]([F:13])=[C:11]([F:14])[C:7]([C:8](O)=[O:9])=[C:6]([F:15])[C:5]=1[F:16].S(Cl)([Cl:19])=O>>[CH3:1][O:2][CH2:3][C:4]1[C:12]([F:13])=[C:11]([F:14])[C:7]([C:8]([Cl:19])=[O:9])=[C:6]([F:15])[C:5]=1[F:16]
Reactant: COCc1c(F)c(F)c(C(=O)O)c(F)c1F
Reactant: O=S(Cl)Cl
Product: COCc1c(F)c(F)c(C(=O)Cl)c(F)c1F
Reaction time: 3 h

Procedure:
4-(Methoxymethyl)-2,3,5,6-tetrafluorobenzoic acid [5.0 g prepared by a process similar to that described in European Patent Application No. 54360] was dissolved in thionyl chloride (50 cm3) and heated to the reflux temperature with stirring for 3 hours. The excess thionyl chloride was evaporated under reduced pressure to yield 4-(methoxymethyl)-2,3,5,6-tetrafluorobenzoyl chloride (ca 5 g) as a pale yellow liquid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[C:21]1([C:29](OCC)=[O:30])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22]1.[Cl-].[NH4+]>CCOCC>[CH2:27]([O:26][C:24]([C:21]1([C:29](=[O:30])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:23][CH2:22]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Reactant: CC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CCOC(=O)C1(C(=O)CC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
A solution of n-butyllithium (2.5M in hexane, 40 ml) was added dropwise with stirring to a cooled solution of diisopropylamine (10.1 g) in anhydrous ether (100 ml) in an atmosphere of nitrogen, whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 0.5 hour and a solution of t-butyl acetate (11.6 g) in anhydrous ether (20 ml) was added dropwise, whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 1 hour and a solution of diethyl cyclopropane-1,1-dicarboxylate (18.6 g) in anhydrous ether (20 ml) was added dropwise whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 0.5 hour and the temperature was allowed to rise to room temperature. A saturated solution of ammonium chloride (150 ml) was added cautiously and the layers were separated. The organic extract was washed with water (2×50 ml) hydrochloric acid (2M, 2×50 ml) and water (2×50 ml). The solution was dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give t-butyl 3-(1-ethoxycarbonylcyclopropyl)-3-oxopropionate (11.66 g) as a clear oil bp 89°-90° C./0.5 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[C:32]([F:35])([F:34])[F:33]>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:8]2[C:9]3[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)(=[O:29])=[O:30])=[CH:24][C:23]=1[C:32]([F:35])([F:33])[F:34]
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: O=S(=O)(Cl)c1ccc(F)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccc(F)c(C(F)(F)F)c2)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 4-fluoro-3-(trifluoromethyl)benzenesulphonyl chloride (29 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (3 mg, 8%) as a white solid. MS (ESI+) for C19H18F4N2O3S m/z 431 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1.[NH2:22][C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.O1CCOCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C@@H:13]([NH:12][C:4]2[N:3]=[C:2]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH3:14])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(Cl)nc1N[C@@H](C)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Nc2cnccn2)nc1N[C@@H](C)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
2.83 g of methyl (S)-6-chloro-2-[1-(4-fluorophenyl)ethylamino]nicotinate, 870 mg of 2-aminopyrazine, 1.06 g of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 4.09 g of tripotassium phosphate and 475 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 15 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 3.14 g of the objective compound as orange powder.
Reaction SMILES: C(#N)C.[C:4]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)(=[O:6])[CH3:5].[CH2:12]([O:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]([CH:21]=[CH:22][CH2:23][Br:24])=[CH:19][CH:18]=1)=[O:16])[CH3:13]>C(OCC)C>[Br-:24].[C:4]([N+:7]1[CH:11]=[CH:10][N:9]([CH2:23][CH:22]=[CH:21][C:20]2[CH:25]=[CH:26][C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[CH:18][CH:19]=2)[CH:8]=1)(=[O:6])[CH3:5]
Reactant: CC(=O)n1ccnc1
Reactant: CCOC(=O)c1ccc(C=CCBr)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)c1ccc(C=CCn2cc[n+](C(C)=O)c2)cc1
Product: [Br-]
Temperature: 60 °C
Yield: 95.3 %

Procedure:
To 10 ml of dry acetonitrile were added 3.3 g of 1-acetylimidazole and 8.04 g of 4-ethoxycarbonylcinnamyl bromide, and the mixture was heated for 3 hours at 60° C. under stirring. After cooling, to the reaction mixture was added an adequate amount of dry diethyl ether and the resulting powder was collected by filtration and dried to obtain 10.8 g of 1-acetyl-3-(4-ethoxycarbonylcinnamyl)-imidazolium bromide. (colorless hygroscopic amorphous).
Reaction SMILES: Cl.[N:2]1([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:17][C:18]1[CH:19]=[CH:20][C:21]([N+:28]([O-:30])=[O:29])=[C:22]([CH2:24][C:25](O)=[O:26])[CH:23]=1>>[S:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([N:2]2[CH2:7][CH2:6][N:5]([C:25](=[O:26])[CH2:24][C:22]3[CH:23]=[C:18]([F:17])[CH:19]=[CH:20][C:21]=3[N+:28]([O-:30])=[O:29])[CH2:4][CH2:3]2)=[N:9]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C(O)Cc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Product: O=C(Cc1cc(F)ccc1[N+](=O)[O-])N1CCN(c2nsc3ccccc23)CC1
Yield: 50 %

Procedure:
1-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-2-(5-fluoro-2-nitro-phenyl)-ethanone was prepared according to the general method as outlined in Preparation 12 starting from 3-piperazin-1-yl-benzoisothiazole hydrochloride (1.31 g, 5.1 mmol) and (5-fluoro-2-nitro-phenyl)-acetic acid (800 mg, 4.3 mmol). The product was isolated via column chromatography to afford 870 mg of an off white foam. Yield 50%; mp 72° C.; MS (APCI): 401 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6](Cl)=[O:7])[CH:2]([CH3:4])[CH3:3].C[O:10][C:11]([C:13]1[CH:14]=[C:15]([CH3:39])[C:16]2[O:22][C:21]3[C:23]([Cl:35])=[CH:24][C:25]([NH:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:26][C:20]=3[CH2:19][S:18](=[O:37])(=[O:36])[C:17]=2[CH:38]=1)=[O:12].C(N(CC)CC)C.O>C(Cl)Cl>[Cl:35][C:23]1[C:21]2[O:22][C:16]3[C:15]([CH3:39])=[CH:14][C:13]([C:11]([OH:12])=[O:10])=[CH:38][C:17]=3[S:18](=[O:37])(=[O:36])[CH2:19][C:20]=2[CH:26]=[C:25]([N:27]([C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:7])[CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:24]=1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCCC3)cc(Cl)c1O2
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCN3CCCC3)C(=O)OCC(C)C)cc1CS2(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isobutylchloroformate (0.17 mL, 1.33 mmol) was added to a solution of Example 72k (0.40 g, 0.88 mmol) in dry CH2Cl2 (15 mL). Triethylamine (0.23 ml, 1.67 mmol) was added and the reaction mixture was stirred at 0° C. for 1 h. It was brought to room temperature, treated with water and extracted with chloroform. The organic layer was washed with water, brine, dried, concentrated and crystallised using ethyl acetate to obtain the title compound as a white solid. Yield: 0.280 g, (58%). 1H NMR (DMSO-d6): δ 0.80 (d, 6H, 2CH3), 1.70-1.80 (m, 5H, 2CH2, CH), 2.50-2.89 (m, 11H, 4CH2, CH3), 3.90 (d, 2H, CH2), 5.19 (s, 2H, CH2), 7.55 (s, 1H, Ar), 7.75 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.20 (s, 1H, Ar). MS: m/e (EI+) 565 (M+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:25][CH2:26][CH2:27][CH2:28]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C>CN(C)C=O>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][N:22]([CH2:28][CH2:27][CH2:26][F:25])[CH2:21]3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCCF)cc1
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2ccc([C@@H]3CCNC3)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc([C@@H]3CCN(CCCF)C3)cc2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
0.215 g of 4-isopropyl-N-[4-((S)-pyrrolidin-3-yl)-phenyl]-benzenesulfonamide (0.0.62 mmol) and 0.16 g of toluene-4-sulfonic acid 3-fluoro-propyl ester (0.69 mmol) were dissolved in 5 ml of dimethylformamide, 0.43 ml of triethylamine added and the reaction stirred for 1 h at 50° C. Additional toluene-4-sulfonic acid 3-fluoro-propyl ester and triethylamine were added to drive the reaction to completion. After stirring at room temperature for 15 h, the solvent was evaporated, the residue re-dissolved in dichloromethane, and the organic layer washed with 1 N aqueous sodium hydroxide. The aqueous phase was extracted twice with dichloromethane, the organic layers combined, dried over magnesium sulfate, filtered and the solvent evaporated. The crude product was purified via silica gel chromatography (chromabond column) using dichloromethane/methanol 0-3%. Fractions containing the product were collected and the solvent evaporated to yield 0.115 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C@H:13]3[CH2:16][C@H:15]([O:17][CH3:18])[CH2:14]3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([CH:13]3[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]3)[C:6]=2[CH:19]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CO[C@H]1C[C@H](n2c([C@H](C)N)nc3ccc(F)cc32)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC1CC(n2c([C@H](C)Nc3ncnc4[nH]cnc34)nc3ccc(F)cc32)C1
Temperature: 90 °C
Yield: 32.3 %

Procedure:
To a solution of (S)-1-[6-fluoro-1-(trans-3-methoxycyclobutyl)-1Hbenzoimidazol-2-yl]ethylamine (79 mg, 0.3 mmol) in IPA (1 mL) was added 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (72 mg, 0.3 mmol) and DIPEA (0.26 mL, 1.5 mmol) and the reaction mixture heated at 90° C. for 16 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford 397 as a white solid (37 mg, 32%). 1H NMR δ (DMSO-d6): 12.82 (1H, s), 8.25 (1H, s), 8.14 (1H, s), 7.92 (1H, s), 7.67-7.57 (2H, m), 7.05 (1H, td, J=9.30, 2.38 Hz), 5.86 (1H, s), 5.44-5.33 (1H, m), 4.17 (1H, t, J=6.72 Hz), 3.12 (3H, s), 3.07-2.96 (1H, m), 2.88-2.86 (1H, m), 2.56-2.45 (1H, m), 2.27-2.18 (1H, m), 1.65 (3H, d, J=6.69 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.Cl.[Cl:17][C:18]1[C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1>O1CCCC1>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:24]([C:23]1[C:18]([Cl:17])=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:25]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1ccccc1O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
As described in J. Med. Chem., 37, 519 (1994), a solution of 1.09 g of 2-aminophenol in 15 ml of tetrahydrofuran is added dropwise to a mixture of 2.1 g of triethylamine and 2.33 g of 2-chloropyridine-3-carbonyl chloride hydrochloride in 10 ml of tetrahydrofuran. The mixture is stirred at room temperature for one hour under argon and then refluxed for one hour. The solvent is removed under vacuum and the residue triturated with water: The solid is filtered off and washed with water to give 1.02 g of solid. Recrystallization from 2-propanol gives crystals, m.p. 145°-146° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:2]2[S:6][C:5]3=[N:7][CH:8]=[CH:9][N:4]3[N:3]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: Brc1nn2ccnc2s1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nn3ccnc3s2)cc1OC
Temperature: 110 °C
Yield: 12.2 %

Procedure:
A solution of 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole (0.5 g, 2.5 mmol, 1 eq), 3,4-dimethoxyphenylboronic acid (0.683 g, 3.7 mmol, 1.5 eq), dioxane (12.5 mL) and Na2CO3 (2M aq. solution, 3.8 mL) was degassed for 20 minutes at room temperature. Pd(Ph3P)2Cl2 was added and the reaction heated at 110° C. for 2 h in an argon atmosphere. The reaction mixture was diluted with EtOAc and washed with water. The combined organic layers were dried (Na2SO4), filtered and concentrated, and the residue was purified by column chromatography (SiO2, cyclohexane/20-100% ethylacetate). The product was further purified by triturating with Et2O, filtered off and dried affording the desired product (0.080 g). 1H NMR (300 MHz, DMSO) δ/ppm 8.18 (d, J=1.4, 1H), 7.47 (m, 2H), 7.33 (d, J=1.4, 1H), 7.15 (d, J=8.3, 1H), 3.86 (s, 3H), 3.75 (s, 3H). The filtrate was concentrated, redissolved in DCM and purified by flash-chromatography (SiO2, DCM/1% MeOH) to afford the desired product (0.65 g, containing some Ph3PO) that was used as such in the next step.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:35]2[CH2:46][CH2:45][N:44]3[C:37](=[CH:38][C:39]4[CH2:40][C:41]([CH3:48])([CH3:47])[CH2:42][C:43]=43)[C:36]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:32]=[C:22]3[CH2:23][N:24]([CH:27]([CH3:31])[CH2:28][O:29][CH3:30])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[OH:4][CH2:5][C:6]1[C:7]([N:35]2[CH2:46][CH2:45][N:44]3[C:43]4[CH2:42][C:41]([CH3:48])([CH3:47])[CH2:40][C:39]=4[CH:38]=[C:37]3[C:36]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:32]=[C:22]3[CH2:23][N:24]([C@H:27]([CH3:31])[CH2:28][O:29][CH3:30])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[CH:13]=1
Reactant: COCC(C)N1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)cc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: COC[C@@H](C)N1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a solution of 300d (200 mg, 0.30 mmol) in THF/i-propanol/water (6/3/3 mL) was added lithium hydroxide (36 mg, 1.5 mmol). The mixture was stirred at 30° C. for 1 h and concentrated under reduced pressure. The residue was partition between ethyl acetate (15 mL) and (10 mL). The water phase was extracted with ethyl acetate (3×10 mL). The combined organic layer was dried, filtered, and concentrated under reduced pressure. Prep-HPLC and chiral resolution afforded the two enantiomers: 300 (35 mg, 18.6%) as white solid; and 303 (28 mg, 15%) as white solid. MS-ESI: [M+H]+ 627.4. 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J=5.0 Hz, 1H), 7.92 (d, J=2.5 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.41 (s, 1H), 7.35 (d, J=5.0 Hz, 1H), 6.85 (s, 1H), 5.72 (s, 1H), 5.05-5.03 (m, 1H), 4.67-4.45 (m, 1H), 4.52-4.50 (m, 1H), 4.35-4.31 (m, 1H), 4.18-4.16 (m, 2H), 4.09-4.07 (m, 2H), 3.87-3.85 (m, 3H), 3.71 (s, 3H), 3.56-3.52 (m, 1H), 3.45-3.43 (m, 1H), 3.38 (s, 3H), 3.11-3.08 (m, 3H), 2.60-2.58 (m, 2H), 2.53 (s, 2H), 1.29 (s, 6H), 1.17 (d, J=6.0 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C@@H:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[CH2:2]1.Cl[C:18]1[N:19]([CH3:31])[C:20](=[O:30])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:23]=1.C(N(CC)CC)C>O1CCCC1>[CH3:31][N:19]1[C:20](=[O:30])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:23]=[C:18]1[N:1]1[CH2:6][CH2:5][O:4][C@@H:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=2)[CH2:2]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: CC(=O)Nc1ccc([C@H]2CNCCO2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc([C@H]2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCO2)cc1
Yield: 58 %

Procedure:
A solution of N-(4-((2S)-morpholin-2-yl)phenyl)acetamide (2.63 g, 11.9 mmol), 2-chloro-1-methyl-6-oxo-4-(pyridin-4-yl)-1,6-dihydropyrimidine (2.60 g, 11.9 mmol), and triethylamine (3.60 g, 35.7 mmol) in tetrahydrofuran (100 ml) was stirred at 95° C. for one hour. The solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography on silica gel (chloroform-methanol, 10:1) to afford N-(4-((2S)-4-(1-Methyl-6-oxo-4-(pyridin-4-yl)-1,6-dihydropyrimidin-2-yl)morpholin-2-yl)phenyl)acetamide (2.8 g, 58%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5](CC2C=CC(OC)=CC=2)[C:4](=[O:25])[C:3]=1[C:26]#[N:27].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[NH:5][C:4](=[O:25])[C:3]=1[C:26]#[N:27]
Reactant: COc1ccc(Cn2c(=O)c(C#N)c(Cl)c3cc(OC)c(OC)cc32)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2[nH]c(=O)c(C#N)c(Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.6 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-1-(4-methoxybenzyl)2-oxo-1,2-dihydroquinoline-3-carbonitrile (300 mg), trifluoroacetic acid (5 ml), anisole (2 ml) and trifluoromethanesulfonic acid (1 ml) was stirred at room temperature for 1 day. After concentoration, the residue was cooled to 0° C. and ethyl acetate was added. The pH was adjusted to about 9 by adding 5% sodium carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate. The concentrated residue was purified with silica gel column chromatography to obtain the target compound (125 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([Cl:14])[N:5]=[C:4]([S:15][CH3:16])[N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)[N:3]=[C:4]([S:15][CH3:16])[N:5]=1
Reactant: CSc1nc(Cl)c(-c2ccccc2)c(Cl)n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CSc1nc(Cl)c(-c2ccccc2)c(-c2ccc(Cl)cc2)n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 35.1 %

Procedure:
To a mixture of 4,6-dichloro-2-(methylthio)-5-phenylpyrimidine (2.71 g, 10.0 mmol), 4-chlorophenylboronic acid (1.72 g, 11.0 mmol) and tetrakis(triphenylphosphine)palladium (578 mg, 0.50 mmol) in toluene (25 mL) at room temperature under argon was added aqueous Na2CO3 solution (2 M, 10 mL, 20.0 mmol). The resulting reaction mixture was stirred at 100° C. under argon for 6 h, after which time analysis by HPLC/MS indicated that the reaction was complete. After cooling the reaction mixture to room temperature, water (50 mL) was added. The resulting mixture was extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NaCl, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to obtain 1.22 g of the title compound as a white solid. HPLC/MS: retention time=4.32 min, [M+H]30 =347.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O-]CC.[Na+].Cl>C(O)C>[C:12]1([C:7]2[C:6]([C:4]([OH:3])=[O:5])=[C:10](/[CH:11]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:9][N:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1c(-c2ccccc2)noc1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1c(-c2ccccc2)noc1/C=C/c1ccccc1
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
To a solution of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid ethyl ester (2.28 g, 10 mmol) and benzaldehyde (1.01 mL, 10 mmol) in ethanol (15 mL) was added sodium ethoxide (0.74 g, 11 mmol) and the reaction mixture was heated under reflux for 10 min. Aqueous hydrochloric acid (1 M, 12 mL) was then added and after stirring for 15 min the precipitate was filtered and dried to afford the title compound as a light brown solid (2.0 g, 71%). MS: m/e=292.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]1[C:7](=[CH:8][C:9](=[O:17])[CH:10]=[CH:11]1)[S:6]2.Cl.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]1[C:7](=[CH:8][C:9](=[O:17])[C:10]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[CH:11]1)[S:6]2
Reactant: CN1CCNCC1
Reactant: COc1ccc2nc3ccc(=O)cc-3sc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2nc3cc(N4CCN(C)CC4)c(=O)cc-3sc2c1
Temperature: 100 °C

Procedure:
A mixture of 7-methoxy-3H-phenothiazin-3-one (1.2 g) and N-methyl piperazine HCl (3.4 g) in DMF (20 ml) was heated at 100° C. for 3 hours. Then NaIO4 (1 g) was added and the reaction mixture was heated at 100° C. for 1 hour. Ice-water was added to the reaction mixture followed by ethyl acetate. The aqueous layer was decanted, filtered and the filtrate basified with K2CO3 and extracted with ethyl acetate. The organic layer was evaporated to dryness, the resulting residue was dissolved in CH2Cl2, dried and evaporated to dryness to afford the crude final product (1.2 g) which was purified by chromatography on silica gel column eluting with 10% MEOH/CH2Cl2 to give the title compound, m.p. 208°-209°.