Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N:9]([CH2:12][C:13]([Cl:15])=[CH2:14])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.O.[NH4+]=[S:20]>C(C(C)=O)C(C)C>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([N:9]([CH2:12][C:13]([Cl:15])=[CH2:14])[C:10]([NH2:11])=[S:20])[CH:6]=[CH:7][CH:8]=1
Reactant: C=C(Cl)CN(C#N)c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C=C(Cl)CN(C(N)=S)c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 90 %

Procedure:
The N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide (2.61 g) was dissolved in methyl isobutyl ketone (13.01 g), to which ammonium sulfide solution, yellow (8.12 g) having an S content of 6% was added dropwise at room temperature with stirring. The mixture was heated to 50° C. and stirred at the same temperature for 9 hours. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, which afforded 2.67 g of N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea as a solid (90% yield in appearance). The percentage area of gas chromatography was 85%.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([CH2:11][S:12]([CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[C:18]([Cl:23])[C:17]=2[Cl:24])(=[O:14])=[O:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:24][C:17]1[C:18]([Cl:23])=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:15]1[S:12](=[O:14])(=[O:13])[CH2:11][C:10]2[N:9]=[CH:8][CH:7]=[N:6][C:5]=2[C:3]=1[OH:4]
Reactant: COC(=O)c1nccnc1CS(=O)(=O)Cc1c(F)ccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S1(=O)Cc2nccnc2C(O)=C1c1c(F)ccc(Cl)c1Cl
Temperature: 100 °C

Procedure:
A mixture of 3-(2,3-dichloro-6-fluoro-phenylmethanesulfonylmethyl)-pyrazine-2-carboxylic acid methyl ester (0.261 g) and potassium carbonate (0.182 g) in N,N-dimethylformamide (6 ml) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with water and washed with diethyl ether. The aqueous layer was acidified with aqueous hydrochloric acid (2M) and the resulting precipitate isolated by filtration. The precipitate was washed with water and diethyl ether and dried to give Compound No. C1 of Table C (0.106 g). MH+=361, RT=1.35 min.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.CS(O[CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:17]3[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 70 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
A mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.73 g, 0.0028 mol), tert-butyl 3-[(methylsulfonyl)oxy]-1-azetanecarboxylate (1.05 g, 0.0042 mol) and cesium carbonate (1.4 g, 0.0042 mol) in N,N-dimethylformamide (25 mL) were stirred at 70° C. under an atmosphere of nitrogen for 16 hours. The mixture was cooled to room temperature. Additional tert-butyl 3-[(methylsulfonyl)oxy]-1-azetanecarboxylate (0.35 g, 0.0014 mol) and cesium carbonate (0.46 g, 0.0014 mol) were added to the mixture. The mixture was stirred at 70° C. under an atmosphere of nitrogen for 16 hours. The solvent was removed under the reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with dichloromethane (3×70 mL). The combined organic extracts were washed with water, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure. The residue was triturated with dichloromethane (2×3 mL) to give tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-azetanecarboxylate (0.57 g, 0.0014 mol). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 9.4 min. MS: MH+ 417
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:17](OC([O-])=O)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CC#N>[C:20]([O:19][C:17]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: OCCC1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 93.6 %

Procedure:
Amine preparation: To a solution of 4-piperidine ethanol (540 mg) in MeCN (8 mL) was added triethylamine (0.70 mL) followed by tert-butyl dicarbonate (1.00 g). The mixture was stirred at room temperature for 22 h and partitioned between 0.5 M hydrochloric acid and ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and the solvent evaporated to give 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (897 mg). This was dissolved in THF (14 mL) and sodium hydride added (172 mg; 60% dispersion in mineral oil) at 0° C. After 30 min iodomethane (0.97 mL) was added and the mixture stirred for 22 h. The mixture was diluted with ethyl acetate and washed with water, brine and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to give 4-(2-methoxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (724 mg). To a solution of 4-(2-methoxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (284 mg) in DCM (5 mL) was added 2M hydrogen chloride in diethyl ether (5.0 mL) and the mixture stirred for 21 h. The solvent was evaporated to give the desired amine as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=1)=[O:10]>CCOCC.ClCCl>[Br:17][C:13]1[CH:12]=[C:11]([C:9](=[O:10])[CH2:8][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:16]=[CH:15][CH:14]=1
Reactant: C1COCCN1
Reactant: O=C(CBr)c1cccc(Br)c1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CN1CCOCC1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
To a solution of morpholine (4.72 mL, 54.0 mmol) in ether (40 mL) cooled at 0° C., was added dropwise 2-bromo-1-(3-bromophenyl)ethanone (7.53 g, 27.0 mmol) in a mixture of ether (100 mL) and dichloromethane (100 mL). The reaction mixture was then warmed to room temperature, stirred at room temperature for 1 h, and concentrated under reduced pressure to give white solid. The white solid was dissolved in dichloromethane (200 mL) and washed with 5% NaHCO3 (200 mL) and brine (200 mL). The organic layer was dried (MgSO4) and concentrated to yield 1-(3-bromophenyl)-2-(4-morpholinyl)ethanone 7.8 g (100%) as a white solid, which was used without purification. MS (ESI): 284.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.[C:33]([N:36]1[CH2:40][CH2:39][CH2:38][C@@H:37]1[C:41](O)=[O:42])(=[O:35])[CH3:34].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[C:33]([N:36]1[CH2:40][CH2:39][CH2:38][C@@H:37]1[C:41]([N:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)=[O:42])(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCC[C@@H]1C(=O)O
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC[C@@H]1C(=O)N1CCC(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
The mixture of compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (50 mg, 0.11 mmol), (R)-acetyl-pyrrolidine-2-carboxylic acid (35 mg, 0.22 mmol), DIEA (180 μL, 1.1 mmol) in 4 mL NMP was stirred at RT. To it was added BOP (210 mg, 0.55 mmol). The mixture was stirred for overnight, quenched with TFA, and subjected to reverse phase preparative HPLC to isolate the title compound (65 mg). MS found for C31H34F2N6O3 as (M+H)+ 577.5. UV: λ=259 nm. 1H NMR (a pair of rotomers): (CD3OD) δ 8.13 (with 8.15, 1H, s), 7.36 (with 7.32, 2H, d, J=8.8 Hz), 7.25 (1H, m), 7.16 (1H, m), 7.13-7.07 (3H, m), 5.83 (with 5.79, 1H, s), 4.95 (1H, m), 4.65 (1H, m), 4.56 (with 4.55, 2H, s), 4.20 (1H, m), 3.66 (2H, m), 3.30 (1H, m), 2.92 (1H, m), 2.79 (1H, m), 2.27 (1H, m), 2.12 (with 2.10, 3H, s), 2.07-1.85 (5H, m), 1.68 (2H, m) ppm.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:29][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=1)[CH2:18][C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:33][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)cc(C(F)(F)F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)cc(C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine-1-carboxylate (2.52 g, 5.81 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. Sodium hydroxide (0.246 g, 6.15 mmol) dissolved in water (2.2 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.38 mL, 6.20 mmol) was added over 1 min and stirring continued at −40° C. for 2 h 20 min. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (40 mL, 240.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-35% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.52 g, 65%) was isolated as a colorless foam. 1H NMR (600 MHz, cdcl3) δ 1.87-2.10 (m, 4H), 2.61-2.67 (m, 1H), 2.80-2.87 (m, 1H), 2.97-3.04 (m, 1H), 3.13-3.21 (m, 1H), 3.60 (s, 3H), 3.96-4.04 (m, 1H), 4.26-4.32 (m, 1H), 5.74 (s, 1H), 7.00 (d, 1H), 7.11-7.16 (m, 2H). MS m/z 403 (M+H)+
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:36]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=1[C:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH3:51])=[O:44].[O:52]1[CH2:57][CH2:56][N:55]([C:58]2[C:59]([NH2:77])=[N:60][C:61]3[C:66]([CH:67]=2)=[CH:65][C:64](B2OC(C)(C)C(C)(C)O2)=[CH:63][CH:62]=3)[CH2:54][CH2:53]1.O1CCOCC1>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].O>[NH2:77][C:59]1[C:58]([N:55]2[CH2:56][CH2:57][O:52][CH2:53][CH2:54]2)=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[C:64]([C:36]3[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=3[C:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[CH3:51])=[O:44])[CH:65]=2)[N:60]=1
Reactant: Cc1ccccc1C(=O)c1cccc(C)c1Br
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1C(=O)c1cccc(C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 140 °C

Procedure:
A mixture of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.013 g, 0.028 mmol), (2-bromo-3-methylphenyl)(o-tolyl)methanone (0.16 g, 0.563 mmol), 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.050 g, 0.141 mmol), Pd2(dba)3 (6.44 mg, 7.04 μmol) were treated with dioxane (0.94 mL) and water (0.47 mL) in a medium-sized Smith synthesizer vial. The mixture was heated to 140° C. for 12 min in a microwave reactor. The reaction mixture was filtered then partitioned between EtOAc and water. The organic layer was washed with water and brine and then concentrated in vacuo. The crude product was purified first by column chromatography (1-10% MeOH:DCM) and then by HPLC (10-90% CH3CN/H2O; TFA modifier). A single fraction was treated with NH4OH, concentrated, filtered and air-dried to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(o-tolyl)methanone. MS (ESI, pos. ion) m/z: 438 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][C:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:36]([C:33]2([CH2:32][CH2:31][CH2:30][O:29][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:35][CH2:34]2)(=[O:38])=[O:37])=[C:3]2[O:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Reactant: O=S(=O)(Cl)C1(CCCOCc2ccccc2)CC1
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CCCOCc3ccccc3)CC2)c2n(c1=O)CCO2
Yield: 28.2 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 7A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 0.5 g, 1.246 mmol) in pyridine (5 ml) was reacted with 1-(3-benzyloxy-propyl)-cyclopropanesulfonyl chloride (0.39 mg, 1.371 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 0.23 g of the product (28% yield). LCMS: 93.01%, m/z=654.0 (M+1). HPLC: 74.6%
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][O:3]1.CN(C)C=O.[Br-:28].[Li+]>O>[Br:28][CH2:10][CH2:9][CH2:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:22])([CH3:1])[O:6]1
Reactant: Cc1ccc(S(=O)(=O)OCCCCC2COC(C)(C)O2)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCCCBr)O1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a stirred solution of 220 g. of 2,2-dimethyl-4-(4-p-toluenesulfonyloxybutyl)-1,3-dioxolane in 800 ml. of dimethylformamide at 0° C. is added 115 g. of anhydrous lithium bromide in portions during 5 minutes. The resulting mixture is stirred at ambient temperature for 22 hours, diluted with water, and extracted with ehter. The extract is washed with sodium bicarbonate solution, water, and brine; dried over magnesium sulfate; and concentrated. The residue is distilled to give a colorless liquid, b.p. 71°-74° C. (0.2 mm.).
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][N:28]=[C:29]=[O:30]>ClCCl>[CH3:27][NH:28][C:29]([N:12]1[CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[CH:16][CH:15]=2)[CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:30]
Reactant: CN=C=O
Reactant: Clc1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Solvent: ClCCl
Product: CNC(=O)N1CCN(Cc2ccc(-c3ccccc3Cl)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound could be made in the following manner: 100 mg of 3-phenyl-1-(2′-chloro-biphenyl-4-ylmethyl)-piperazine would be dissolved in dichloromethane, 1.1 equiv. methylisocyanate would be added. The reaction would be stirred at room temperature under nitrogen overnight. Aminomethylpolystyrene (loading 1.6 mmol/g) could be added and the reaction would be shaken for further 6 h. The polymer could be separated by filtration and rinsed with dichloromethane. The filtrate could be concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:39])[C:35](=[O:38])[CH2:36]C)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:39])[C:35](=[O:38])[CH3:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)C(=O)CC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CCO
Product: CCCCc1nc2ccc(N(C)C(C)=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
tert.butyl 4'-[(2-n-butyl-6-(N-propionyl-methylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.65 (Silica gel: methylene chloride/ethanol=19:1)
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:33])([CH3:32])[O:6][CH2:7][C@@H:8]([CH3:31])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([C:17]([CH3:30])([CH3:29])[C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)([CH3:4])[CH3:3].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>N1C=CC=CC=1>[C:34]([O:28][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:8]([CH3:31])[CH2:7][O:6][Si:5]([C:2]([CH3:3])([CH3:1])[CH3:4])([CH3:32])[CH3:33])[C:17]1([CH3:30])[CH3:29])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
v)—A solution of the alcohol 6 (132.5 g) obtained in the previous step in dry pyridine (1310 ml) was cooled to 0° C. Benzoyl chloride (65.7 ml) was added in 5 min. and the reaction mixture was stirred for 1 h at room temperature. Then it was poured into ice-water (6650 ml) and the resulting suspension was stirred over-night. The precipitate was collected by filtration and washed with water (40-50° C.). The residue was dried and purified by crystallization from acetone to give (3β,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,20-trimethylpregn-5-en-3-ol benzoate (7) (113.6 g).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:16]([OH:18])=O)[N:12]=[CH:13]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:52]1[CH:56]=[CH:55][N:54]=[C:53]1[NH:57][C:58]([C:60]1[C:68]2[NH:67][C:66]([NH2:69])=[N:65][C:64]=2[CH:63]=[CH:62][CH:61]=1)=[O:59]>CN(C=O)C>[NH:54]1[CH:55]=[CH:56][N:52]=[C:53]1[NH:57][C:58]([C:60]1[C:68]2[NH:67][C:66]([NH:69][C:16]([C:11]3[N:12]=[CH:13][C:14]4[C:9]([CH:10]=3)=[CH:8][CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:15]=4)=[O:18])=[N:65][C:64]=2[CH:63]=[CH:62][CH:61]=1)=[O:59]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: CS(=O)(=O)Nc1ccc2cc(C(=O)O)ncc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc2cc(C(=O)Nc3nc4cccc(C(=O)Nc5ncc[nH]5)c4[nH]3)ncc2c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 10.2 %

Procedure:
To a solution of 30 mg (0.11 mmol) of 7-methanesulfonylamino-isoquinoline-3-carboxylic acid in DMF (0.8 mL) was added 60 mg (0.15 mmol) of HBTU and DIEA (0.1 mL). The mixture was stirred for 10 min and then 24 mg (0.1 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (intermediate B) was added. The reaction was heated at 80° C. for 1 h. After usual work up, the residue was purified by column chromatography eluting with DCM/methanol (v/v=10:1 to 8:1) to afford 5 mg (9%) of 7-methanesulfonylamino-isoquinoline-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 491 (M+1)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:36]=[CH:35][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[O:34]=[S:30]1(=[O:33])[CH2:31][CH2:32][N:27]([CH2:26][C:25]2[CH:35]=[CH:36][C:22]([NH:20][C:18]3[N:19]=[C:12]4[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)=[CH:16][CH:15]=[CH:14][N:13]4[N:17]=3)=[CH:23][CH:24]=2)[CH2:28][CH2:29]1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(CN5CCS(=O)(=O)CC5)cc4)nc23)cc1

Procedure:
N-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-8-[4-(methylsulfonyl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(4-bromo-benzyl)-thiomorpholine 1,1-dioxide (90.0 mg, 0.296 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.039 g, 29%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.7 Hz, 1H), 8.23 (d, J=7.4 Hz, 2H), 8.09 (d, J=8.0 Hz, 2H), 7.67 (d, J=6.9 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H), 7.29 (d, J=7.8 Hz, 2H), 7.04 (t, J=7.2 Hz, 1H), 6.94 (s, 1H), 3.62 (s, 2H), 3.10 (s, 3H), 3.08-3.03 (m, 4H), 3.02-2.97 (m, 4H). MS=512 (MH)+.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=2)=[CH:18][C:17]=1[NH:37][C:38](=[O:46])[C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1.O[CH:48]1[CH2:52][CH2:51][O:50][CH2:49]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=2)=[CH:18][C:17]=1[NH:37][C:38](=[O:46])[C:39]1[CH:40]=[CH:41][C:42]([O:45][CH:48]2[CH2:52][CH2:51][O:50][CH2:49]2)=[CH:43][CH:44]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1ccc(O)cc1
Reactant: OC1CCOC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1ccc(OC2CCOC2)cc1
Temperature: 5 °C
Yield: 298.2 %

Procedure:
Di-isopropyl azodicarboxylate (0.21 ml) was added to a stirred mixture of N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-4-hydroxybenzamide (0.15 g), 3-hydroxytetrahydrofuran (0.31 g), triphenyl phosphine (0.275 g) and methylene chloride (5 ml) which had been cooled to 5° C. The resultant mixture was stirred at ambient temperature for 18 hours. The mixture was poured onto a pre-wetted (methylene chloride) ion-exchange column (isolute SCX 5 g column from International Sorbent Technology Limited) and eluted in turn with methylene chloride (40 ml), with methylene chloride (40 ml) containing 20% methanol and with methylene chloride containing 20% methanol and 3% of a saturated aqueous ammonium hydroxide solution. The product so obtained was further purified by column chromatography on silica using a 4:1 mixture of ethyl acetate and methanol as eluent. There was thus obtained the title compound as a solid (0.52 g); Mass Spectrum: M+H+ 502.