Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=[N:14][CH:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])[C:16]#[N:17])(C1C=CC=CC=1)C1C=CC=CC=1.Cl>O1CCCC1>[NH2:14][CH:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])[C:16]#[N:17]
Reactant: COc1ccccc1CC(C#N)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccccc1CC(N)C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 22.5 g 2-(benzhydrylideneamino)-3-(2-methoxyphenyl)propionitrile (66 mmol, crude product from 3.1) in 200 mL tetrahydrofuran was combined with 70 mL 1 M HCl and stirred for 3 hr at room temperature, and the reaction solution was then substantially concentrated on a rotary evaporator. After combination with methylene chloride the organic phase was extracted several times with 6 M HCl; the combined hydrochloric acid phases were made alkaline with 50% NaOH and extracted with methylene chloride, and the organic phase was then dried over Na2SO4 and concentrated. The oily residue (10.4 g) was used without further purification.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:47]1[C:51](=[O:52])[CH2:50][CH2:49][C:48]1=[O:53].C(N(CC)C(C)C)(C)C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C>[CH3:24][O:23][C:18]1[CH:17]=[C:16]([O:25][CH3:26])[CH:15]=[C:14]2[C:19]=1[C:20](=[O:22])[NH:21][C:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([O:4][CH2:3][CH2:2][N:47]3[C:51](=[O:52])[CH2:50][CH2:49][C:48]3=[O:53])=[C:6]([CH3:27])[CH:7]=1)=[N:13]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Reactant: O=C1CCC(=O)N1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4C(=O)CCC4=O)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.50 g, 1.35 mmol) in anhydrous THF (20 mL) were added triphenyl phosphine (0.53 g, 2.02 mmol), pyrrolidine-2,5-dione (0.20 g, 2.02 mmol), and N,N-diisopropylethyl amine (0.44 g, 3.38 mmol). To this stirred solution was added diethylazodicarboxylate (0.35 g, 2.02 mmol). The reaction mixture was stirred at room temperature for 8 hours under nitrogen. Ethyl acetate (400 mL) was added. The organic phase was separated, washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude material was purified by the Simpliflash system (4:96 methanol:CH2Cl2 as eluent) to give the title compound as a white solid. Yield: 0.3 g. (49%). 1H NMR (400 MHz, CDCl3): δ 9.30 (br s, 1H), 7.66 (s, 2H), 6.82 (d, J=2.4 Hz, 1H), 6.46 (d, J=1.6 Hz, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.92 (s, 4H), 2.78 (s, 4H), 2.31 (s, 6H). MS (ES) m/z: 452.51 (M+1) (100%).
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([CH2:10][CH2:11][C:12]3[CH:40]=[CH:39][N:15]4[C:16](=[O:38])[C:17](/[CH:29]=[CH:30]/[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[C:18]([N:20]5[CH2:25][CH2:24]C[CH:22]([O:26]C=O)[CH2:21]5)[N:19]=[C:14]4[CH:13]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C1(C2N=C(CCC3C=CN4C(=O)C(C=O)=C(N5CCOCC5)N=C4C=3)SC=2)CCC1.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH:1]1([C:5]2[N:6]=[C:7]([CH2:10][CH2:11][C:12]3[CH:40]=[CH:39][N:15]4[C:16](=[O:38])[C:17](/[CH:29]=[CH:30]/[C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])=[C:18]([N:20]5[CH2:25][CH2:24][O:26][CH2:22][CH2:21]5)[N:19]=[C:14]4[CH:13]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1c(N2CCCC(OC=O)C2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Agent: O=Cc1c(N2CCOCC2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)OC(=O)/C=C/c1c(N2CCOCC2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Yield: 100 %

Procedure:
Reactions were performed in the same manner as in Example 1, (J) by using 8-[2-(4-cyclobutyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]-pyrimidin-3-carbaldehyde (100 mg, 0.2356 mmol) to obtain 127 mg (100%) of the title compound as a yellow oily substance in a mixture with triphenylphosphine oxide.
Reaction SMILES: O[C:2]1([C:6]2[NH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:15]([N:17]3[CH2:20][CH:19]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[CH2:18]3)=[O:16])=[C:9]([CH3:11])[N:10]=2)[CH2:5][O:4][CH2:3]1.CCN(S(F)(F)[F:39])CC>ClCCl>[F:39][C:2]1([C:6]2[NH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:15]([N:17]3[CH2:20][CH:19]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[CH2:18]3)=[O:16])=[C:9]([CH3:11])[N:10]=2)[CH2:5][O:4][CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2(O)COC2)nc1C
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2(F)COC2)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.5 %

Procedure:
Into a 50-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(1-(3-(2-(3-hydroxyoxetan-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile (compound 192, 200 mg, 0.47 mmol) in dichloromethane (5 mL). This was followed by the addition of a solution of DAST (76.2 μL, 0.58 mmol) in dichloromethane (1 mL) dropwise at −78° C. The resulting solution was stirred for 1 h at room temperature, then quenched by the addition of 2 mL of sodium bicarbonate (sat.). The resulting solution was diluted with 60 mL of EtOAc and additional water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate as eluent. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, WATER WITH 0.05% TFA and MeCN (18.0% MeCN up to 28.0% in 9 min, up to 100.0% in 2 min, down to 18.0% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in 15.1 mg (8%) of the title compound as a white solid. m/z (ES+) 431 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[CH2:29]([O:31][C:32](=[O:35])[CH2:33]Br)[CH3:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:29]([O:31][C:32](=[O:35])[CH2:33][O:1][CH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1)[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(CO)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)COCc1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Temperature: 80 °C
Yield: 27.6 %

Procedure:
A mixture of 6-hydroxymethyl-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile (Example 3B) (36 mg, 0.097 mmol), bromo-acetic acid ethyl ester (24 mg, 0.146 mmol) and K2CO3 (67 mg, 0.48 mmol) in DMF (0.6 ml) was heated at 80° C. for 45 min, then diluted with CHCl3 (50 ml), washed with H2O (2×20 ml), dried with Na2SO4. Concentrated in vacuo and purified by prep. TLC to give the title compound (12.2 mg, 28%) (50% EtOAc—hexanes). It has a retention time of 6.62 min (standard LCl method, 8 min run). MS Found: (M+H)+=457.1
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1.[CH3:14][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[CH:17][CH:16]=1>O1CCCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:21](=[NH:22])[C:20]2[C:15]([CH3:14])=[CH:16][CH:17]=[N:18][CH:19]=2)=[N:11][CH:12]=1
Reactant: Cc1ccncc1C#N
Reactant: Nc1ccc(F)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccncc1C(=N)Nc1ccc(F)cn1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6 M, 3.33 mL, 0.00534 mol) was added slowly for a period of 5 min at a temperature of at −78° C. to a solution of 5-fluoro-pyridin-2-ylamine (0.3 g, 0.00267 mol) in anhydrous tetrahydrofuran (20 mL). Then the temperature raised to −40° C. and the reaction mixture was stirred for 15 min. The reaction mixture was cooled to −78° C. and 4-methyl-nicotinonitrile (0.316 g, 0.00267 mol) in tetrahydrofuran (5 mL) was added. The temperature was raised to RT and stirred for 18 h. The reaction mixture quenched with a saturated aqueous ammonium chloride solution (25 mL) and then extracted with ethyl acetate (2×50 mL). The combined organic layer were dried over sodium sulphate and concentrated under vacuum to afford the crude product, N-(5-fluoro-pyridin-2-yl)-4-methyl-nicotinamidine, which was used without further purification in the next step. MS (M+1): 231.1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH:14]1([C:17](O)=[O:18])[CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH:14]1([C:17]([NH:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[O:18])[CH2:16][CH2:15]1
Reactant: O=C(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)C2CC2)C1
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a mixture of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (500 mg, 2.68 mmol) in CH2Cl2 (101 mL) was added cyclopropanecarboxylic acid (276 μL, 3.48 mmol), followed by the addition of HATU (1.3 g, 3.48 mmol) and triethylamine (725 μL, 5.2 mmol). The reaction was complete after stirring for 1 h. After quenching with water, the aqueous layer was extracted twice with CH2Cl2, and the combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude material was purified via silica gel chromatography 0-20% EtOAc/CH2Cl2 to afford (R)-tert-butyl 3-(cyclopropanecarboxamido)pyrrolidine-1-carboxylate (500 mg, 73%). LC/MS: m/z 255.3 (M+H)+ at 2.33 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][C:15]1[C:25]([C:26](=[O:34])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])=[CH:24][C:18]2[CH2:19][CH:20]([CH2:22][OH:23])[O:21][C:17]=2[C:16]=1[Cl:35]>CC(C)=O>[Cl:14][C:15]1[C:25]([C:26](=[O:34])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])=[CH:24][C:18]2[CH2:19][CH:20]([C:22]([OH:3])=[O:23])[O:21][C:17]=2[C:16]=1[Cl:35]
Reactant: O=C(c1ccccc1F)c1cc2c(c(Cl)c1Cl)OC(CO)C2
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(c1ccccc1F)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2

Procedure:
Jones reagent [J. Chem. Soc., 2555 (1953)] (84 ml.) was added dropwise to a stirred, cooled solution of 6,7-dichloro-2,3-dihydro-5-(2-fluorobenzoyl)-2-hydroxymethylbenzofuran (43 g., 0.126 mole) in acetone (700 ml.) at such a rate that the internal temperature did not exceed 25° C. The resultant mixture was stirred for 18 hours at 25° C. The insoluble chromium salts were separated by decantation and washed with acetone. The washings were combined with the filtrate, and the resultant solution was concentrated to 1/5 the original volume and then poured into H2O. This mixture was extracted with methylene chloride and the organic extract was washed several times with aqueous NaCl. The methylene chloride solution was then extracted with 0.5N KOH. Upon standing the aqueous extract deposited the potassium carboxylate salt as a crystalline solid. The solid was dissolved in warm water, acidified with 6N HCl and the resulting solution extracted with ethyl acetate. Drying and evaporation furnished 38 g. of carboxylic acid, m.p. 180°-181° C. This material was used without additional purification for the next step.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:18]=[CH:17][C:8](/[CH:9]=[N:10]/[S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])=[C:7]([F:19])[CH:6]=1)([F:4])[CH3:3].[CH3:20][Mg]Br>C(Cl)Cl>[F:1][C:2]([C:5]1[CH:18]=[CH:17][C:8]([C@@H:9]([NH:10][S:11]([C:13]([CH3:14])([CH3:15])[CH3:16])=[O:12])[CH3:20])=[C:7]([F:19])[CH:6]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1ccc(/C=N/[S@](=O)C(C)(C)C)c(F)c1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: C[C@H](NS(=O)C(C)(C)C)c1ccc(C(C)(F)F)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (R,E)-N-(4-(1,1-difluoroethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (497 mg, 1.706 mmol) in DCM (9.59 mL) was added methylmagnesium bromide (3M in diethylether; 1.20 mL) at 0° C. The reaction mixture was allowed to stir for 1 hr at 0° C., gradually allowed to warm to room temperature and stirred for 1 hr at room temperature. The mixture was cooled to 0° C., additional methylmagnesium bromide (3M in diethylether; 0.5 mL) was added and stirring was continued for 30 min at 0° C. The reaction mixture was carefully quenched with saturated aqueous ammonium chloride solution (6 mL) and diluted with water (20 mL). The separated aqueous phase was extracted with DCM (30 mL). The combined organic layers were washed with brine (50 mL), concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 24 g, heptane/ethyl acetate] providing N—((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (349 mg) as a white solid. LCMS m/z 308.2 (M+H)+, Rt 0.91 min.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:12]=2[CH:13]=1>N1C=CC=CC=1>[CH3:6][N:7]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:25][CH:26]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([NH:18][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][C:12]=2[CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCc1ccc(N)cc1)Cc1cc2cc(N)ccc2o1
Solvent: c1ccncc1
Product: CN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1cc2cc(NS(C)(=O)=O)ccc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulphonyl chloride (0.76 g, 6.6 mmole) was added dropwise to a solution of N-methyl-N-(5-aminobenzofur-2-ylmethyl)-4-aminophenethylamine (see Preparation 3--0.9 g, 3.0 mmole) in pyridine (25 ml) and the mixture was stirred at room temperature for 18 hours. The solvent was then evaporated and the residue diluted with aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were dried (MgSO4) and evaporated, and the residue was purified by chromatography on silica eluting with ethyl acetate. The product-containing fractions were combined, evaporated and the resulting solid was recrystallised from ethyl acetate/methanol to give the title compound, yield 0.35 g, m.p. 177°-179°.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][O:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](F)(F)F)=[CH:20][C:19]=3[N+:28]([O-:30])=[O:29])[CH:14]=[CH:15][CH:16]=2)=[N:6][CH:5]=[N:4]1)C.C(C(OCC1NC=CN=1)C1C=C(N)C=CC=1)C>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][O:9][CH2:8][C:7]3[N:3]([CH3:1])[N:4]=[CH:5][N:6]=3)[CH:12]=2)=[C:19]([N+:28]([O-:30])=[O:29])[CH:20]=1
Reactant: CCn1ncnc1COCc1cccc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1
Agent: CCC(OCc1ncc[nH]1)c1cccc(N)c1
Product: Cc1ccc(Nc2cccc(COCc3ncnn3C)c2)c([N+](=O)[O-])c1
Yield: 78 %

Procedure:
To a solution of compound 18a (1.0 g, 4.9 mmol) in anhydrous NMP (10 ml) was added triethylamine (0.68 ml, 4.9 mmol) and compound 17a (0.68 ml, 4.91 mmol) and the resultant mixture was stirred at 100° C. over night. The cooled reaction mixture was poured into ice-water and the precipitate was filtered off, re-dissolved in dichloromethane, dried over magnesium sulphate and concentrated in vacuo. This concentrate was triturated in a mixture of diethyl ether and petroleum ether to afford 19a as a brownish solid (1.2 g, 62%). The following compounds were prepared in analogy herewith: [3-(2-Ethyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-(2-nitro-4-trifluoromethylphenyl)-amine (19b) from 17a and 18b. Yield: 78% (4-Methyl-2-nitro-phenyl)-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-amine (19c) from 17b and 18a. Yield: 20% 1-{4-[3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenylamino]-3-nitro-phenyl}-ethanone (19d) from 17c and 18a. Yield: 74%
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:14]1=[O:24].Br[C:26]1[CH:27]=[N:28][C:29]([CH2:32][CH3:33])=[N:30][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:32]([C:29]1[N:30]=[CH:31][C:26]([N:21]2[CH2:22][CH2:23][CH:18]([N:15]3[CH2:16][CH2:17][C@H:13]([NH:12][C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=4[F:1])[C:14]3=[O:24])[CH2:19][CH2:20]2)=[CH:27][N:28]=1)[CH3:33]
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Reactant: CCc1ncc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCc1ncc(N2CCC(N3CC[C@H](Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)cn1
Temperature: 110 °C
Reaction time: 8 h
Yield: 4.1 %

Procedure:
A mixture of (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (Preparation E; 0.20 g, 0.56 mmol), 5-bromo-2-ethylpyrimidine (0.13 g, 0.68 mmol), Binap-rac (0.035 g, 0.056 mmol), Pd(OAc)2 (0.013 g, 0.056 mmol), and Cs2CO3 (0.92 g, 2.8 mmol) were combined in degassed toluene (6 mL) and stirred in a sealed tube at 110° C. overnight. The solution was cooled, quenched with water, extracted with EtOAc, dried over MgSO4, and concentrated. Flash chromatography (2% MeOH in EtOAc) of the crude material, followed by trituration of the crude product with 9:1 hexanes:DCM gave a white solid that was filtered and dried. The material was characterized as (S)-1-(1-(2-ethylpyrimidin-5-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.010 g, 0.023 mmol, 4% yield). 1H NMR (400 MHz, CDCl3) δ 1.20 (t, 3H), 1.61-1.92 (m, 5H), 2.47 (q, 2H), 2.60-2.70 (m, 1H), 2.90-3.03 (m, 2H), 3.03 (s, 3H), 3.30-3.47 (m, 2H), 4.10-4.17 (m, 1H), 4.25-4.38 (m, 1H), 4.83-4.92 (m, 2H), 5.10 (s, 1H), 6.80 (t, 1H), 7.55 (d, 1H), 7.60 (d, 1H), 7.70 (s, 2H). Optical purity was not determined.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=3)[C:15]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)=CC=1)([O-])=O.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH2:42][CH2:43][CH2:44][NH2:45])[CH:36]=1>O1CCCC1>[CH3:25][O:24][C:18]1[CH:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14](/[CH:13]=[CH:12]/[C:11]([NH:45][CH2:44][CH2:43][CH2:42][CH2:41][C:37]3[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=3)=[O:10])=[C:15]2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)=[CH:20][CH:19]=1
Reactant: COc1cccc(-c2c(/C=C/C(=O)Oc3ccc([N+](=O)[O-])cc3)ccc3ccc(OC)cc23)c1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: COc1cccc(-c2c(/C=C/C(=O)NCCCCc3cccnc3)ccc3ccc(OC)cc23)c1
Yield: 67.5 %

Procedure:
As in Example 114, (E)-3-[7-methoxy-1-(3-methoxyphenyl)-2-naphthalenyl]-2-propenoic acid 4-nitrophenyl ester (1.2 g) was reacted with 3-pyridinebutanamine (0.46 g) in tetrahydrofuran (12 mL) for 2 hours at room temperature. The crude product, isolated in the usual manner was purified by using HPLC (ethyl acetate) and then was crystallized from diethyl ether to yield 0.83 g of (E)-3-[7-methoxy-1-(3-methoxyphenyl)-2-naphthalenyl]-N-[4-(3-pyridinyl)butyl]-2-propenamide, mp 108.5°-110° C. Anal. Calcd for C30H30N2O3O.15 H2O: C, 76.78; H, 6.51; N, 5.97; H2O, 0.57 Found: C, 76.68; H, 6.51; N, 6.04; H2O, 0.57
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]([CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCC>[Br:14][CH2:13][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Cl:1])[C:11]=1[Cl:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(Cl)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCC
Product: COC(=O)c1ccc(CBr)c(Cl)c1Cl
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 40 g (0.183 mol) of methyl 2,3-dichloro-4-methylbenzoate, 34.17 g (0.192 mol) of N-bromosuccinimide, 0.4 g (0.0017 mol) of benzoylperoxide, and 640 mL of carbon tetrachloride was stirred at room temperature while being irradiated with a 150 watt flood lamp for 2.5 hours. Concentration of the filtered reaction mixture under vacuum gave 54 g of material which on trituration with pentane followed by storage of the slurry at 5° C. for 18 hours gave 34.6 g (63.5%) of product; mp 57°-61° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[CH:31][C:32]([O:34][Si](C(C)(C)C)(C)C)=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:42])[CH2:15][CH2:14][CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[CH:31][C:32]([OH:34])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:42])[CH2:15][CH2:14][CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3cc(O[Si](C)(C)C(C)(C)C)ccc3[nH]2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3cc(O)ccc3[nH]2)o1
Yield: 50.6 %

Procedure:
9-{5-[5-(tert-Butyl-dimethyl-silanyloxy)-1H-benzimidazol-2-ylsulfanyl]-furan-2-yl}-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester (376 mg, 0.62 mmol) is treated with tetra-N-butylammonium fluoride (162 mg 0.62 mmol) in tetrahydrofuran (5 ml) for 5 hours at room temperature. The reaction mixture is then concentrated under reduced pressure and the residue is purified on a silicagel column (40 g) eluted with a mixture of dichloromethane and methanol (9/1, v/v). The fractions containing the expected product are concentrated under reduced pressure and the residue is washed with acetonitrile (20 ml), pentane (20 ml), diisopropylether (20 ml) and dried under vacuum to yield 154 mg of 9-[5-(5-hydroxy-1H-benzoimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester as a light yellow powder. Yield=50%. Analytical LC/MS (method C): m/z=489 (negative ion mode [M−H]−), m/z=491 (positive ion mode [M+H]+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[CH:3][N:2]=1.[CH:21]1([S:27][C:28]2[C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=[C:30]([C:36]([F:39])([F:38])[F:37])[N:29]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>CS(C)=O.O>[CH:21]1([S:27][C:28]2[C:33]([CH2:34][NH:35][C:12]([NH:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=[N:2][CH:3]=3)=[O:20])=[CH:32][CH:31]=[C:30]([C:36]([F:38])([F:39])[F:37])[N:29]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C(Nc1cncc2ccccc12)Oc1ccccc1
Reactant: NCc1ccc(C(F)(F)F)nc1SC1CCCCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCc1ccc(C(F)(F)F)nc1SC1CCCCC1)Nc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 13.4 %

Procedure:
Phenyl isoquinolin-4-ylcarbamate (68 mg, 0.26 mmol) and (2-(cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yl)methanamine (78 mg, 0.27 mmol) were dissolved in dimethyl sulfoxide. Then triethylamine (0.08 mL, 0.52 mmol) was added to it. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give 1-((2-(cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(isoquinolin-4-yl)urea (example compound 19) (16 mg, 14%).