Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C@H:9]3[C@@H:11]([O:22]COC)[C@H:12]([O:18]COC)[C@@H:13]([CH2:15][O:16][CH3:17])[O:14][C@H:8]3[N:7]([CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:6]=2[CH:33]=1.C(Cl)(Cl)Cl.CO>CO.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C@H:9]3[C@@H:11]([OH:22])[C@H:12]([OH:18])[C@@H:13]([CH2:15][O:16][CH3:17])[O:14][C@H:8]3[N:7]([CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:6]=2[CH:33]=1
Reactant: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](OCOC)[C@H](OCOC)[C@@H](COC)O[C@H]21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](O)[C@H](O)[C@@H](COC)O[C@H]21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.8 %

Procedure:
The compound (26) 63 mg obtained in Example 25 was dissolved in 1 ml of methanol saturated with hydrogen chloride and 3 ml of methanol, and the solution was stirred for 2.5 hours at room temperature. The solution was concentrated under reduced pressure, the resulting residue was poured into 0.5N aqueous sodium hydroxide, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and saturated aqueous sodium chloride successively. The solution was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (manufactured by Fuji Silicia Company), and 47.2 mg (yield 78.5%) of the title compound was obtained from the fraction of chloroform-methanol (19:1).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(N(CC)CC)C.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.[Cu]I>[Cl:1][C:2]1[C:3]([C:25]#[C:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2
Reactant: C#Cc1ccccc1
Reactant: COc1nc2cc(Cl)c(Cl)c(I)c2nc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1nc2cc(Cl)c(Cl)c(C#Cc3ccccc3)c2nc1OC
Yield: 77.1 %

Procedure:
A mixture of 6,7-dichloro-2,3-dimethoxy-5-iodoquinoxaline (Preparation 108, 5.0 g, 13 mmol), phenylacetylene (3.98 g, 39 mmol), bis(triphenylphosphine)palladium(II) chloride (0.913 g, 1.3 mmol) and copper(I) iodide (0.248 g, 1.3 mmol) in triethylamine (100 mL) was heated under reflux for 4 hours. After being cooled, the mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (200 mL) and brine (200 mL). The phases were separated and the aqueous phase extracted with dichloromethane (2×100 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using hexane:dichloromethane (1:0 changing to 1:1, by volume) to afford 6,7-dichloro-2,3-dimethoxy-5-(2-phenylethynyl)quinoxaline (3.60 g, 77%) as a yellow solid, mp 170-172° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:19])[CH:8]=2)[N:3]=1.O.[NH2:21][NH2:22]>>[Cl:19][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:21][NH2:22])[CH:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: Clc1ccc2nc(Cl)cc(-c3ccccc3Cl)c2c1
Reactant: NN
Solvent: O
Product: NNc1cc(-c2ccccc2Cl)c2cc(Cl)ccc2n1

Procedure:
In the manner given in Example 1, 2,6-dichloro-4-(o-chlorophenyl)quinoline is reacted at reflux with hydrazine hydrate to give 6-chloro-4-(o-chlorophenyl)-2-hydrazinoquinoline.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:10][C:9]1[C:8]([O:11][CH3:12])=[CH:7][CH:6]=[C:3]([CH:4]=[O:5])[C:2]=1[Cl:1])(=[O:15])[CH3:14]
Reactant: COc1ccc(C=O)c(Cl)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C=O)c(Cl)c1OC(C)=O
Reaction time: 8 h

Procedure:
26.0 g of 2-chloro-3-hydroxy-p-anisaldehyde are dissolved in 400 ml of acetic anhydride and 5 ml of pyridine. The solution is stirred at 80° for 8 hours, subsequently evaporated, the residue is partitioned between ice-water and methylene chloride, the organic phase is dried over sodium sulfate, evaporated and the residue is recrystallized from methylene chloride/petroleum ether. There is obtained 2-chloro-3-formyl-6-methoxyphenyl acetate of m.p. 48°-50°.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](O)=[CH:5]1)(=O)C.[N+:14]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(O)(=O)C>[N+:14]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CC(=O)n1cc(O)c2ccccc21
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Nc2c[nH]c3ccccc23)cc1

Procedure:
The synthesis of intermediates g started from the commercially available 1-acetyl-3-hydroxyindole a. Condensation of intermediate a with 4-nitroaniline, under refluxing conditions in acetic acid, yielded 3-((4-nitrophenyl)amino)indole (b) (Valezheva et al.; Chem. Heterocycl. Compd. (Engl.Transl.); 14; 1978; 757,759,760; Khim.Geterotsikl.Soedin.; 14; 1978; 939). Deacylation of intermediate b with triethylamine in refluxing methanol and formylation of intermediate c using phosphorus oxychloride in dimetylformamide resulted in intermediate d (Ryabova, S. Yu.; Tugusheva, N. Z.; Alekseeva, L. M.; Granik, V. G.; Pharm. Chem. J. (Engl. Transl.); EN; 30; 7; 1996; 472-477; Khim.Farm.Zh.; RU; 30; 7; 1996; 42-46). Knoevenagel condensation of intermediate d with ethyl cyanoacetate in the presence of a catalytic amount of triethylamine and subsequent intramolecular cyclisation of intermediate e under reflux in 1,2-ethanediol, yielded intermediate f (1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile) (Ryabova, S. Yu.; Alekseeva, L. M.; Granik, B. G.; Chem. Heterocycl. Compd. (Engl.Translat.)36; 3; 2000; 301-306; Khim.Geterotsikl.Soedin.; RU; 3; 2000; 362-367). N-methylation using methyl iodide led to intermediate g (5-methyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile).
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[CH:15][NH:16]3)[CH2:8][CH2:7]1.N>C(O)(=O)C>[CH3:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][NH:16]3)[CH2:10][CH2:11]1
Reactant: CN1CCN(c2cccc3[nH]ccc23)CC1
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCN(c2cccc3c2CCN3)CC1
Temperature: 14 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
429 mg of sodium cyanoborohydride are added in portions to a solution of 490 mg of 4-(4-methylpiperazin-1-yl)-1H-indole, in 17 ml of acetic acid cooled to 14° C. The reaction medium is stirred for 2 hours at ambient temperature and then poured into a water/ice mixture and the pH is brought to neutrality with an aqueous ammonia solution. The mixture is then extracted with dichloromethane and the combined organic phases are dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (95/05), so as to give 395 mg of 4-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indole in the form of a colorless viscous oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([CH2:37][C:38](O)=[O:39])=[CH:36][C:31]=2[O:30][CH2:29]1>>[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([CH2:37][C:38]([NH:27][C@H:24]3[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]4[CH2:17][CH2:18][N:13]([C:9]5[N:10]=[CH:11][CH:12]=[C:7]6[CH2:6][CH2:5][O:4][C:8]=56)[CH2:14][CH2:15]4)[CH2:22][CH2:23]3)=[O:39])=[CH:36][C:31]=2[O:30][CH2:29]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(Cc1ccc2c(c1)OCO2)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (113 mg, 92%), MS (ISP) m/z=493.3 [(M+H)+], mp 187° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 2-(benzo[d][1,3]dioxol-5-yl)-acetic acid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C.[CH3:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>ClCCl>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[CH3:20]
Reactant: Oc1ccc2c(c1Br)CCCC2
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Oc1ccc2c(c1Br)CCCC2
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-5,6,7,8-tetrahydro-2-naphthol (6.81 g) and triethylamine (4.2 ml) in dichloromethane (60 ml) was added 2-methylbenzoyl chloride (4.62 g) dropwise with ice-cooling. The mixture was stirred under ice cooling for 1 hour, after which it was washed with water and dried (MgSO4). The solvent was then distilled off to give 1-bromo-2-(2-methylbenzoyloxy)-5,6,7,8-tetrahydronaphthalene as oil in quantitative yield.
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[C:7]2[OH:15]>C(O)C.[C].[Pd]>[OH:15][C:7]1[C:6]2[C:11](=[CH:2][C:3]([CH3:16])=[CH:4][CH:5]=2)[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=1
Reactant: Cc1ccc2c(O)cc(C(=O)O)cc2c1Br
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(O)cc(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
To a solution of 8-bromo-4-hydroxy-7-methylnaphthalene-2-carboxylic acid (0.45 g) in ethanol (8 mL) was added palladium-carbon (180 mg) in 3 parts, and the mixture was stirred at room temperature for 2 days under a hydrogen atmosphere. The insoluble material was removed by filtering through a Celite pad, and the filtrate was concentrated to give the title compound (0.32 g).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=2)=[O:32])=[O:22])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]([C:25]2[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=2[NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:16][CH:17]=2)=[O:22])=[O:32])=[N:35][CH:36]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccccc1-c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 25 %

Procedure:
The mixture of the compound of (2-{[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]carbonylamino}-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide example 12 (0.5 mmol) in trifluoroacetic acid (5 ml) was stirred at r.t. for 5 hrs. After the evaporation of solvent, the crude residue was purified by RP—HPLC to give N-(5-chloro(2-pyridyl))(5-chloro-2-{[4-(2-sulfamoylphenyl)-phenyl]carbonylamino}phenyl)-carboxamide as a white powder (68 mg, 25%). MS found for C25H18Cl2N4O4S
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:12]=[C:13]([CH:22]=O)[NH:14][C:15]=3C3C=CN=CC=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:22][C:13]2[NH:14][C:15]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[C:2](=[O:1])[CH2:3][CH2:4]4)[N:12]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=Cc1nc(-c2ccc3c(c2)CCC3=O)c(-c2ccncc2)[nH]1
Reactant: C1CCNCC1
Product: O=C1CCc2cc(-c3nc(CN4CCCCC4)[nH]c3-c3ccccn3)ccc21
Yield: 44 %

Procedure:
The title compound (0.11 g, 44%) was prepared from the product of Step 2 and piperidine as described in Example 6; MS(AP+) m/e 373 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[C:22]([NH:25][CH2:26][CH:27]1[O:32][CH2:31][CH2:30][NH:29][CH2:28]1)(=[O:24])[CH3:23].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:29]2[CH2:30][CH2:31][O:32][CH:27]([CH2:26][NH:25][C:22](=[O:24])[CH3:23])[CH2:28]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(=O)NCC1CNCCO1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(=O)NCC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1
Yield: 49.2 %

Procedure:
A mixture of 1 g of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.15 g of 2-acetylaminomethylmorpholine, 1 g of triethylamine and10 ml of pyridine was heated under reflux for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, and ethyl acetate was added to the residue. The resulting crystals were collected byfiltration, and suspended in 20 ml of water. The suspension was extracted with chloroform, and the extract was dried and concentrated. Recrystallization of the residue from ethanol gave 720 mg of 5-amino-7-(2-acetylaminomethylmorpholino)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 228°-229° C.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@@H:6]([OH:19])[CH2:5]1.[C:20]([O:24][C:25]([N:27]([CH2:40][CH:41]1[CH2:43][CH2:42]1)[CH2:28][C@H:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:29]([C:30]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:31])[CH2:28][N:27]([CH2:40][CH:41]2[CH2:42][CH2:43]2)[C:25](=[O:26])[O:24][C:20]([CH3:23])([CH3:21])[CH3:22])=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)[C@H](CN(CC4CC4)C(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
(5R,7S)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.0444 g, 0.1445 mmol) and (S)-3-(tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chlorophenyl)propanoic acid (0.05114 g, 0.1445 mmol) were combined in methylene chloride (1.25 mL). They were then treated with diisopropylethylamine (0.07552 ml, 0.4336 mmol), followed by HBTU (0.05495 g, 0.1445 mmol). The reaction was stirred at ambient temperature for 16 hours. The reaction was quenched with 10% Na2CO3, diluted with methylene chloride and separated. The aqueous portion was washed with methylene chloride (2×), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The material was chromatographed on SiO2 (Biotage 12M) and eluted with 4% MeOH/MC. The material was concentrated in vacuo to give tert-butyl (S)-2-(4-chlorophenyl)-3-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(cyclopropylmethyl)carbamate as a white solid (67.4 mg, 82%). LCMS (APCI+) [M+H]+ 570.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][NH:11][C:12]2([C:17]([O:19]C)=O)[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH2:23]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[CH3:24].CC(O)=O.[BH3-]C#N.[Na+]>CO>[F:8][C:6]1[CH:5]=[C:4]([CH:9]2[N:28]([CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:29])[C:17](=[O:19])[C:12]3([CH2:13][CH2:14][CH2:15][CH2:16]3)[NH:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C1(NCC(=O)c2cc(F)cc(F)c2)CCCC1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CN1C(=O)C2(CCCC2)NCC1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of methyl 1-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}cyclopentanecarboxylate from Step A (10.0 g, 33.6 mmol), glycine ethyl ester hydrochloride (46.9 g, 336 mmol), and AcOH (5.78 mL, 101 mmol) in MeOH (300 mL) was stirred at ambient temperature for 10 min. NaCNBH3 (2.54 g, 40.4 mmol) was added and the pH of the mixture was checked and adjusted to pH ˜5 as necessary by addition of AcOH. The reaction mixture was heated to 50° C. for 18 h then allowed to cool. The reaction mixture was carefully quenched with saturated aqueous NaHCO3 (250 mL) and then extracted with CH2Cl2 (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=353 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([C:15](=[O:17])[CH3:16])[C@@H:10]([CH3:18])[CH2:9]1)=O)(C)(C)C.[ClH:19].CCOCC>C(Cl)Cl>[ClH:19].[CH3:14][C@@H:12]1[CH2:13][NH:8][CH2:9][C@H:10]([CH3:18])[N:11]1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)N1[C@H](C)CN(C(=O)OC(C)(C)C)C[C@@H]1C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)N1[C@H](C)CNC[C@@H]1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(3S,5R)-4-Acetyl-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (450 mg, 1.75 mmol) was dissolved in DCM (10 ml) and acidified with HCl/Et2O. The mixture was stirred at room temperature for two days. The resulting solid was filtered to give 190 mg of 1-((2R,6S)-2,6-dimethyl-piperazin-1-yl)ethanone hydrochloride. The mother liquors were treated with HCl/Et2O for 4 h and the resulting solid was filtered to give additional 43 mg of the title compound as hydrochloric salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21].[CH3:23][O:24][C:25](=[O:29])[CH:26](Br)[CH3:27]>>[CH3:23][O:24][C:25](=[O:29])[CH:26]([O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9](=[O:12])[NH:10]2)[CH3:27]
Reactant: Cc1c(Cc2ccc(Cl)cc2)c(=O)[nH]c2c(Cl)ccc(O)c12
Reactant: COC(=O)C(C)Br
Product: COC(=O)C(C)Oc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(Cl)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 34d using 8-chloro-3-(4-chlorobenzyl)-5-hydroxy-4-methyl-1H-quinolin-2-one and 2-bromopropionic acid methyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:12]([O:16][C:17]([N:19]1[C:24]([CH3:26])([CH3:25])[CH2:23][CH2:22]OS1(=O)=O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([NH:19][C:24]([CH3:25])([CH3:26])[CH2:23][CH2:22][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)CCOS1(=O)=O
Product: CC(C)(CCn1ccc2cc(C=O)ccc21)NC(=O)OC(C)(C)C

Procedure:
Prepared analogously to Component V(a) by alkylation of indole-5-carbaldehyde with N-tert-butoxycarbonyl-4,4-dimethyl-[1,2,3]oxathiazinane-2,2-dioxide (Component XI).
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH:11](=[O:18])C1C=CC=CC=1>>[O:18]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][CH2:11]1
Reactant: O=C(CO)c1ccccc1
Reactant: O=Cc1ccccc1
Product: O=C1CCOc2ccccc21

Procedure:
2-Hydroxyacetophenone compounds of structure XXXXI are treated with benzaldehyde compounds of structure XXXXII under suitable conditions to provide chroman-4-one compounds of structure XXXXIII. In some embodiments, 2-hydroxyacetophenone compounds of structure XXXXI are treated with benzaldehyde compounds of structure XXXXII, pyrrolidine, and methanol, with heating to about 50° C. for about 2 days to provide chroman-4-one compounds of structure XXXXIII. Chroman-4-one compounds of structure XXXXIII are then reacted tris(dibenzylideneacetone)dipalladium(0), tri-tert-butylphosphonium tetrafluoroborate, potassium bicarbonate, a suitable arylbromide, and 1,4-dioxane/water (4:1,) at about 110° C. to provide chroman-4-one compounds of structure XXXXIV. Chroman-4-one compounds of structure XXXXIV are then treated with methyl magnesium chloride in tetrahydrofuran at about 0° C., followed by 80% AcOH/H2O with warming to about 90° C. to provide compounds of structure XXXXV.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)=O.[CH3:19][O:20]CCO.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:19][O:20][CH2:2][CH2:3][NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1
Reactant: COCCO
Reactant: CCOC(=O)c1ccc(NC(=O)C(F)(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NCCOC)cc1
Reaction time: 4 h
Yield: 31.1 %

Procedure:
To a solution of ethyl 4-(2,2,2-trifluoro-acetylamino)-benzoate (1.58 g, 6.05 mmol, CASRN 24568-14-7) in dry THF was added 2-methoxyethanol (1.192 mL, 15.12 mmol), diisopropyl azodicarboxylate (2.94 mL, 15.12 mmol) and P (3.97 g, 15.12 mmol) and the resulting solution stirred for 4 h. The reaction mixture was concentrated, dissolved in EtOAc, washed sequentially with water and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with 50% EtOAc/hexane to afford 0.42 g of ethyl 4-(2-methoxy-ethylamino)-benzoate (338).
Reaction SMILES: [K].[Cl:2][C:3]1[C:13]([Cl:14])=[C:12]([Cl:15])[C:11]([Cl:16])=[C:5]2[C:6]([NH:8][C:9](=[O:10])[C:4]=12)=[O:7].[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([N:8]1[C:9](=[O:10])[C:4]2=[C:3]([Cl:2])[C:13]([Cl:14])=[C:12]([Cl:15])[C:11]([Cl:16])=[C:5]2[C:6]1=[O:7])=[O:21]
Reactant: O=C1NC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [K]
Solvent: C1COCCO1
Product: O=C(c1ccc(Cl)cc1Cl)N1C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C

Procedure:
The potassium salt of 3,4,5,6-tetrachlorophthalimide (0.10 mole) and dioxane (1200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,4-Dichlorobenzoyl chloride (0.10 mole) is then added dropwise, with stirring, to the reaction mixture at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is stripped of solvent to yield the desired product N-(2,4-dichlorobenzoyl)-3,4,5,6-tetrachlorophthalimide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:23][NH2:24]>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:24][CH3:23])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: FC(F)(F)Oc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CN
Solvent: CO
Product: CNc1nc(Cl)nc2c1CCC2c1ccc(OC(F)(F)F)cc1
Yield: 111.7 %

Procedure:
A solution of 2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg, 0.573 mmol), and methanamine (0.286 mL, 0.573 mmol) in MeOH (5 mL) was stirred at rt for 1 h. The solvent was removed in vacuum to afford crude 2-chloro-N-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (220 mg, 0.640 mmol, 112% yield). LC-MS (M+H)+=343.9.