Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][Br:6].ClC(Cl)(Cl)C(=N)O[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1CCCCC1.FC(F)(F)S(O)(=O)=O>ClCCl>[Br:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[O:7][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(O)CCCBr
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(CCCBr)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of 1-methyl-4-bromo-1-butanol (9.0 g, 0.05384 mol) and benzyl 2,2,2-trichloroacetimidate (16.3 g,) in a mixture of anhydrous cyclohexane (100 ml) and anhydrous dichloromethane (50 ml) cooled to 0° C., trifluoromethanesulfonic acid (1.0 ml) was added, and the mixture was stirred overnight at room temperature under argon. The mixture was filtered, washed with a saturated solution of NaHCO3 (250 ml) and deionized water (250 ml), and dried with anhydrous Na2SO4. The solvents were removed by distillation under reduced pressure. The crude product (9.2 g) was subjected to vacuum distillation, giving 7.2 g of colorless viscous liquid.
Reaction SMILES: [CH2:1]([O:8][NH:9][CH2:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19](O)=[O:20].C(OC(=O)C)(=O)C>ClCCl>[CH:19]([N:9]([CH2:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=[O:13])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20]
Reactant: O=CO
Reactant: CC(C)CC(CNOCc1ccccc1)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(C)CC(CN(C=O)OCc1ccccc1)C(=O)O

Procedure:
Formylation of 2-(benzyloxyaminomethyl)-4-methylpentanoic acid was carried out in dichloromethane with formic acid/acetic anhydride to give N-formyl-2-(benzyloxyaminomethyl)-4-methylpentanoic acid. Coupling with a compound of formula (J): To N-formyl-2-(benzyloxyamino-methyl)-4-methylpentanoic acid (175 mg) and (J) (230 mg) in 5% pyridine/dichloromethane (30 mL) was added 4-dimethylaminopyridine (DMPA) (200 mg) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI) at room temperature. The reaction mixture was stirred for 8 h and then concentrated, partitioned between 30 mL of ethyl acetate and 30 mL of 20% HCl. The organic portion was washed with water (20 mL), 5% NaHCO3 (20 mL) and brine, dried over MgSO4 and concentrated. Purification on silica gel, eluting with 50% ethyl acetate/hexane gave the product as a mixture of two isomers. Hydrogenolysis in methanol over 10% Pd/C afforded (2RS, 10S)-2-[N-formyl, N-hydroxyaminomethyl]-4-methyl-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19)13(18),14,6-tetraen-10-yl]pentamide, as a mixture of 2 isomers, MS 455 (M-H)+, (Compound 6).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([OH:15])[C:8]=2[C:7]=1[CH3:16])=[O:5].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O>CN(C=O)C>[CH3:3][C:4]([C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH2:21][C@H:22]3[O:24][CH2:23]3)[C:8]=2[C:7]=1[CH3:16])=[O:5]
Reactant: CC(=O)c1oc2cccc(O)c2c1C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1oc2cccc(OC[C@@H]3CO3)c2c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
To a suspension (60 ml) of sodium hydride (1.4 g) in DMF was added dropwise a solution (30 ml) of 4-hydroxy-3-methylbenzo(b)furan-2-yl methyl ketone (6.1 g) in DMF under ice-cooling and the mixture was stirred at room temperature for 30 min. To this reaction mixture was added dropwise under ice-cooling a solution (30 ml) of (S)-glycidyl nosylate (9.1 g) in DMF, and the mixture was stirred for 2 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.1 g) as pale-yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.BrN1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:43][CH:42]=1.N1C=CC=CC=1>ClCCl.CN(C)C=O>[C:44]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:43]=[CH:42][C:41]([NH:40][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([OH:1])[CH:3]=2)=[CH:46][CH:45]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: COc1ccc(C(=O)O)cc1O
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(-c3ccccc3)cc2)cc1O
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-hydroxy-4-methoxybenzoic acid (0.5 g, 3 mmol) in dichloromethane and dimethylformamide was cooled to −20° C., and N-bromosuccinimide (0.57 g, 3.2 mmol) and triphenylphosphine (0.8 g, 3.1 mmol) were added in one portion. The mixture was stirred at −20° C. for 10 min, and treated with a solution of 4-aminobiphenyl (0.5 g, 3 mmol) and dry pyridine (0.3 g, 3.8 mmol) in dichloromethane (5 mL). The mixture was allowed to warm to RT, stirred 20 h, concentrated in vacuo, and the residue was stirred in 5% methanol/dichloromethane (40 mL) and filtered. The filtrate was concentrated in vacuo, chromatographed (silica gel, 5% methanol/dichloromethane), and fractions containing the product were pooled, concentrated in vacuo, and dissolved in dichloromethane from which the title compound precipitated (0.11 g): MS(ES) m/e 320 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[CH3:22][O:23][C:24]1[CH:35]=[CH:34][C:27]([CH2:28][CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:31]1[CH2:32][CH2:33][CH:29]([CH2:28][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:35][CH:34]=2)[CH2:30]1)=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: COc1ccc(CC2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: COc1ccc(CC2CCN(C(=O)c3cnoc3-c3ccccc3Cl)C2)cc1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(4-methoxybenzyl)pyrrolidine oxalate (16.9 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (8.1 mg). Calcd for C22H21ClN2O3: 396.1241, found 396.1235.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[N:11]2[CH2:12][CH2:13][CH2:14][NH:15][C:10]2=[C:9]([CH2:16][CH2:17][C:18]([NH2:20])=O)[CH:8]=1.[F-].[K+].O>O1CCCC1>[N:7]1[N:11]2[CH2:12][CH2:13][CH2:14][NH:15][C:10]2=[C:9]([CH2:16][CH2:17][CH2:18][NH2:20])[CH:8]=1
Reactant: NC(=O)CCc1cnn2c1NCCC2
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: NCCCc1cnn2c1NCCC2
Yield: 75.4 %

Procedure:
To a suspension of lithium aluminum hydride (7.6 g) in tetrahydrofuran (300 ml) was added 3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)propionamide (10 g) at room temperature. The mixture was stirred under reflux for 2 days. After cooling on an ice bath, potassium fluoride (34 g) and water (10 ml) were added to the reaction mixture. The insoluble materials were removed by filtration. To the filtrate were added 10% aqueous sodium carbonate solution (100 ml) and di-tert-butyl dicarbonate (20.0 g). The mixture was stirred at room temperature for 1 hour. After evaporation of the solvent in vacuo, the residue was dissolved in chloroform. The solution was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. To the oily residue were added methanol (100 ml) and 4 mol/l hydrogen chloride solution in dioxane (50 ml), and the mixture was stirred under reflux for 30 minutes. The reaction mixture was concentrated in vacuo to give crude 3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)propylamine (7.0 g) as an oil. This product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]([OH:24])([CH2:22][CH3:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)OCC2C=CC=CC=2)=[CH:7][CH:6]=1)[CH3:2]>[C].[Pd].O1CCCC1>[NH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:24])([CH2:1][CH3:2])[CH2:22][CH3:23])=[CH:10][CH:9]=1
Reactant: CCC(O)(CC)Cc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC(O)(CC)Cc1ccc(N)cc1
Yield: 94.4 %

Procedure:
A mixture of benzyl 4-(2-ethyl-2-hydroxybutyl)phenylcarbamate (6.30 g), 10% palladium carbon (5.0 g) and tetrahydrofuran (150 mL) was subjected to catalytic reduction under a hydrogen atmosphere at atmospheric pressure. The catalyst was removed by filtration, and the filtrate was concentrated to give 3-(4-aminobenzyl)-3-pentanol as colorless crystals (3.51 g, yield 95%). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 85-86° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:20][O:19][C:18]4[CH:21]=[C:22]5[C:26](=[CH:27][C:17]3=4)[CH2:25][CH2:24][O:23]5)[C:9]2=[O:28])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(COC4=CC5CCOC=5C=C34)C2=O)C=CC=CC=1>>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([CH2:20][O:19][C:18]3[CH:21]=[C:22]4[C:26](=[CH:27][C:17]2=3)[CH2:25][CH2:24][O:23]4)[C:9]1=[O:28]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCC3
Product: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 1.49, and making non-critical variations using 1′-(diphenylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one, the title compound was obtained (68%): mp 208-210° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.39-6.76 (m, 4H), 6.45 (s, 1H), 6.35 (s, 1H), 4.68 (ABq, 2H), 4.45 (t, 2H), 2.92 (t, 2H); MS (ES+) m/z 280.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.[C:14]([C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([CH3:18])[CH3:17])#[N:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH:13][C:23](=[O:24])[C:22]3[CH:21]=[CH:20][C:19]([C:16]([C:14]#[N:15])([CH3:17])[CH3:18])=[CH:27][CH:26]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1cnc2ccc(Br)cc2n1
Reactant: CC(C)(C#N)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1ccc(C(=O)NNc2cnc3ccc(Br)cc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
To a solution of 7-bromo-2-hydrazinylquinoxaline (1.5 g, 0.063 mol) and 4-(2-cyanopropan-2-yl) benzoic acid (1.1 g, 0.063 mol) in DMF (5 mL) was added HATU (2.4 g, 0.063 mol) and DIEA (1.2 g, 0.095 mol). The reaction mixture was then stirred at r.t. overnight. The solution was diluted with water (5 mL), and the solid was collected on a filter to give N′-(7-bromoquinoxalin-2-yl)-4-(2-cyanopropan-2-yl)benzohydrazide as a yellow solid (2.2 g, yield 85.0%). MS (m/z): 412 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:23]=[C:22]([CH:24]3[CH2:26][CH2:25]3)[C:21]3[CH:20]([N:27]([CH:29]4[CH2:31][CH2:30]4)[CH3:28])[CH2:19][CH2:18][C:17]([CH3:33])([CH3:32])[C:16]=3[CH:15]=2)=[CH:8][CH:7]=1)[CH3:5].[OH-].[Li+].[Cl-].[NH4+]>CO.O1CCCC1>[CH:24]1([C:22]2[C:21]3[CH:20]([N:27]([CH:29]4[CH2:30][CH2:31]4)[CH3:28])[CH2:19][CH2:18][C:17]([CH3:32])([CH3:33])[C:16]=3[CH:15]=[C:14]([C:13]#[C:12][C:9]3[CH:8]=[CH:7][C:6]([CH:4]([CH3:5])[C:3]([OH:34])=[O:2])=[CH:11][CH:10]=3)[CH:23]=2)[CH2:26][CH2:25]1
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
A solution of 2-{4-[4-cyclopropyl-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-propionic acid methyl ester (Intermediate 165, 0.075 g, 0.16 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was treated with 2M lithium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at ambient temperature for 5 h. The reaction mixture was neutralized with ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title product as a yellow solid (0.07 g, 96%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[N:7]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C@H:22]([CH2:30][N:31]([CH3:33])[CH3:32])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=1)=[O:5])C.O.[OH-].[Li+].O>O1CCCC1.Cl>[CH3:32][N:31]([CH2:30][C@@H:22]([NH:21][CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:7]1[CH:6]([C:4]([OH:5])=[O:3])[CH2:10][CH2:9][S:8]1(=[O:12])=[O:11])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH3:33]
Reactant: CCOC(=O)C1CCS(=O)(=O)N1Cc1cccc(CN[C@@H](Cc2ccccc2)CN(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C[C@H](Cc1ccccc1)NCc1cccc(CN2C(C(=O)O)CCS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (360 mg, approx. 0.67 mmol) in tetrahydrofuran (4 mL) was added lithium hydroxide hydrate (57.4 mg, 1.37 mmol) followed by water (1 mL). It was stirred at room temperature for 2 h. To the stirred solution was added ˜15 drops 1N hydrochloric acid to bring the pH to 4.5. The sample was concentrated to dryness and dried over phosphorus pentoxide overnight. The crude 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (350 mg, ca 80% pure) (LiCl present) was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([N:20]1[C:28]3[C:23](=[CH:24][CH:25]=[C:26](I)[CH:27]=3)[C:22]([CH3:31])([CH3:30])[CH2:21]1)=[C:5]([CH3:19])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[N:7]2.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([N:20]1[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:27]=3)[C:22]([CH3:31])([CH3:30])[CH2:21]1)=[C:5]([CH3:19])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[N:7]2
Reactant: C1COCCN1
Reactant: Cc1c(-c2ccccc2F)nc2cccc(Cl)c2c1N1CC(C)(C)c2ccc(I)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2F)nc2cccc(Cl)c2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Prepared according to procedure N using 5-chloro-2-(2-fluorophenyl)-4-(6-iodo-3,3-dimethylindolin-1-yl)-3-methylquinoline (14.4 mg, 0.027 mmol) (described herein), morpholine (5 μL, 0.05 mmol), Pd2dba3 (3.64 mg, 4.0 μmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (3.79 mg, 8.0 μmol), and sodium tert-butoxide (7.65 mg, 0.080 mmol) in toluene (1.0 mL). The reaction mixture was stirred at 100° C. for 1 h. Purification afforded 5-chloro-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-2-(2-fluorophenyl)-3-methylquinoline as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.12 (1H, dd, J=6.5, 3.1 Hz), 7.55-7.69 (3H, m), 7.41-7.52 (1H, m), 7.30-7.38 (1H, m), 7.14-7.23 (1H, m), 7.04 (1H, d, J=8.0 Hz), 6.25 (1H, d), 5.59 (1H, d), 3.98-4.08 (1H, m), 3.76 (4H, br. s.), 3.54 (1H, d, J=1.8 Hz), 3.01 (4H, br. s.), 2.12-2.25 (3H, m), 1.47-1.55 (3H, m), 1.42 (3H, s). Mass Spectrum (ESI) m/e=502 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:30][Si](C)(C)C>CC(CC)=O>[ClH:30].[CH3:29][N:2]([CH3:1])[C:3]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCCCc2ccccc2)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexylidene)-N-(4-phenyl-butyl)acetamide (292 mg, 0.747 mmol) was dissolved in ethyl methyl ketone (5 ml), and chlorotrimethylsilane (0.14 ml, 1.12 mmol) was added. After 1.5 h the hydrochloride was isolated as a colourless solid in a yield of 69% (221 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.[NH2:44][C:45]1[CH:50]=[CH:49][C:48](Br)=[CH:47][N:46]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:44][C:45]1[N:46]=[CH:47][C:48]([C:32]2[CH:33]=[CH:34][C:29]([C:9]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:16](=[O:17])[C:15]4[N:14]=[CH:13][N:12]([C:18]5[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=5)[C:11]=4[N:10]=3)=[CH:30][CH:31]=2)=[CH:49][CH:50]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(ncn4-c4cccc(NS(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)nc5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of N-(3-{1-(4-chloro-phenyl)-6-oxo-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,6-dihydro-purin-9-yl}-phenyl)-methane sulfonamide (prepared as described in example 26, 0.700 g, 1.13 mmol) in N,N-dimethylformamide (15 mL) is degassed with argon for 0.5 h. Then 2-amino-5-bromopyridine (0.290 g, 1.69 mmol), cesium carbonate (0.740 g, 2.26 mmol), Pd(dppf)2Cl2 (0.040 g, 0.056 mmol) is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 3 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by preparative HPLC to afford N-{3-[2-[4-(6-amino-pyridin-3-yl)-phenyl]-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-phenyl}-methane sulfonamide, as a yellow solid. 1H NMR (CD3OD, 400 MHz) δ 8.51 (s, 1H), 8.22 (m, 1H), 8.12 (d, 1H), 7.93 (d, 1H), 7.55 (m, 6H), 7.37 (m, 2H), 7.34 (m, 2H), 7.32 (d, 1H), 7.10 (d, 1H), 3.0 (s, 3H); LC-MS calculated for C29H22ClN7O3S (M+H+) 584.1, found 583.9.
Reaction SMILES: [C:1]([CH2:4][C:5](=O)[CH3:6])(=O)[CH3:2].[CH2:8]([NH:10][C:11]([NH2:13])=[O:12])[CH3:9].C(O)C.S(=O)(=O)(O)O>CCOCC>[CH2:8]([N:10]1[C:1]([CH3:2])=[CH:4][C:5]([CH3:6])=[N:13][C:11]1=[O:12])[CH3:9]
Reactant: CC(=O)CC(C)=O
Reactant: CCNC(N)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOCC
Product: CCn1c(C)cc(C)nc1=O
Reaction time: 240 h

Procedure:
Acetylacetone (9.0 g., 0.09 moles) and ethylurea (7.13 g., 0.081 moles) are dissolved in 30 ml. ethanol. The solution is cooled in an ice-water bath while 30 g. of cold concentrated sulfuric acid is added. The resulting yellow solution is stored at room temperature for 10 days and diluted with a large volume of ether. The ether-ethanol mixture is decanted from the thick syrupy residue which is washed with additional fresh ether. The residue is made basic with 2.5 N sodium hydroxide and extracted throughly with methylene chloride. The organic extracts are dried over sodium sulfate, treated with charcoal, filtered, and evaporated under vacuum affording 1-ethyl-4,6-dimethyl-2(1H)-pyrimidinone as a tan solid (7.6 g., 62%).
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.O[C:28]1([C:49]2[C:57]([OH:58])=[CH:56][C:52]3[O:53][CH2:54][O:55][C:51]=3[CH:50]=2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([CH2:37][C:38]2[CH:39]=[C:40]([CH:45]=[CH:46][CH:47]=2)[C:41]([O:43][CH3:44])=[O:42])[C:29]1=[O:48]>>[OH:58][C:57]1[C:49]([CH:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH2:37][C:38]3[CH:39]=[C:40]([CH:45]=[CH:46][CH:47]=3)[C:41]([O:43][CH3:44])=[O:42])[C:29]2=[O:48])=[CH:50][C:51]2[O:55][CH2:54][O:53][C:52]=2[CH:56]=1
Reactant: COC(=O)c1cccc(CN2C(=O)C(O)(c3cc4c(cc3O)OCO4)c3ccccc32)c1
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: COC(=O)c1cccc(CN2C(=O)C(c3cc4c(cc3O)OCO4)c3ccccc32)c1

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with methyl 3-{[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate, the title compound was obtained (98%): MS (ES+) m/z 418.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[N:15]1[CH:16]=[CH:17][C:12]([NH:11][S:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:9])=[O:8])=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: Nc1ccncc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccncc1)c1ccc(Br)s1
Temperature: 50 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
A mixture of 5-bromo-thiophene-2sulphonyl chloride (1.31 g, 5.0 mmol), 4-dimethylamino-pyridine (0.61 g, 5.0 mmol) and 4-amino-pyridine (0.71 g, 7.5 mmol) in pyridine (20 ml) was stirred at 50° C. for 16 h. THE reaction mixture was evaporated and diluted with dichloromethane/MeOH/NH4OH 80:10:1. The formed precipitate was collected by filtration to yield the title compound (1.53 g, 96%) as an off-white solid, which was used without further purification. MS (ISN) 317.0 [(M−H)−], mp 310° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:13][CH3:14])([O:11][CH3:12])[CH3:10].C([Li])(C)(C)C.[F:20][C:21]([F:37])([F:36])[C:22]1[CH:35]=[CH:34][C:25]([CH:26]=[N:27][S@@:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29])=[CH:24][CH:23]=1.O>C1COCC1>[CH3:12][O:11][C:9]([O:13][CH3:14])([CH3:10])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:26]([C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:36])([F:37])[F:20])=[CH:35][CH:34]=1)[NH:27][S@@:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29]
Reactant: CC(C)(C)[S@@](=O)N=Cc1ccc(C(F)(F)F)cc1
Reactant: COC(C)(Cc1ccccc1Br)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(C)(Cc1ccccc1C(N[S@](=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Bromo-2-(2,2-dimethoxypropyl)benzene (4.00 g, 15.43 mmol) was dissolved in 150 mL THF and tert-butyllithium (18.160 mL, 30.871 mmol) was added dropwise at −78° C. After addition a solution of (R)—N-(4-(trifluoromethyl)-benzylidene)-2-methylpropane-2-sulfinamide (8.5608 g, 30.871 mmol) in THF (10 mL) was added and stirring was continued for 10 min in the cold. The reaction was hydrolyzed with 50 mL water and the mixture was warmed to RT. TLC showed a 1:1 mixture of the 2 diastereomers. No attempt was undertaken to separate the isomers. Glass column chromatography provided the title compound as a mixture of diastereomers. MS (ESI, positive ion) m/z: 412.0 (M+1; hydrolysis of the dimethyl acetal to the corresponding ketone).