Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[O:10][CH:11]([CH3:14])[CH2:12][F:13])[CH2:3][CH2:2]1.[N+:15]1([O-])C=CC=C[CH:16]=1.CN(C)C(Cl)=O.C[Si](C#N)(C)C>ClCCl>[CH:1]1([C:4]2[C:9]([O:10][CH:11]([CH3:14])[CH2:12][F:13])=[CH:8][C:7]([C:16]#[N:15])=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(CF)Oc1ccncc1C1CC1
Reactant: [O-][n+]1ccccc1
Agent: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Product: CC(CF)Oc1cc(C#N)ncc1C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.2 %

Procedure:
To a solution of 3-cyclopropyl-4-(2-fluoro-1-methyl-ethoxy)pyridine (example 287b, 6.26 g, 32.1 mmole) in dichloromethane (100 mL) was added m-cpba 77% (10.8 g, 48.1 mmole) and the reaction was stirred at room temperature for 16 hours. Reaction mixture was diluted with dichloromethane and extracted with a 1M aqueous solution of sodium bicarbonate. Organic phase was collected and the aqueous phase was back-extracted with dichloromethane. Combined organic phases were dried over magnesium sulfate and evaporated down to dryness. The crude pyridine-oxide intermediate (6.97 g) was used without any purification. To a solution of the crude pyridine-oxide (6.97 g, 33.0 mmole) in dichloromethane (110 mL) was added dimethylcarbamoylchloride (CAN 79-44-7, 5.32 g, 4.55 mL, 49.5 mmole) and trimethylsilylcyanide (8.18 g, 10.3 mL, 82.5 mmole). The reaction mixture was stirred at room temperature for 16 hours and the reaction was quenched by addition of a 1M aqueous solution of sodium bicarbonate. The bi-phasic mixture was vigorously stirred for 10 minutes and then poured into a separatory funnel. The organic phase was extracted and collected. The aqueous phase was back-extracted with dichloromethane. Combined organic phases were dried over magnesium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a gradient of heptane and ethyl acetate to yield the title compound (1.5 g, 21%). MS (ESI, m/z): 221.6 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Li]CCCC.[CH3:16][N:17]1[C:21]([CH:22]=[O:23])=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:19]=[N:18]1>C1COCC1>[OH:23][CH:22]([C:21]1[N:17]([CH3:16])[N:18]=[N:19][C:20]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH2:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: Cn1nnc(-c2ccccn2)c1C=O
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(CC(O)c2c(-c3ccccn3)nnn2C)sc1C(=O)O
Temperature: -75 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a suspension of 2,4-dimethylthiazole-5-carboxylic acid (157 mg, 1.0 mmol) in THF (8 mL) was added dropwise n-BuLi (1.6 M in hexanes, 1.25 mL, 2.0 mmol) under Ar at −75° C. The brown suspension was stirred at −75° C. for 2 h and then a solution of 3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazole-4-carbaldehyde (188 mg, 1.0 mmol) in THF (3 mL) was added at −75° C. and the brown suspension was stirred at −75° C. for 2 h. The mixture was then quenched with an aqueous solution of citric acid (5%, 10 mL), allowed to warm to room temperature. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by recrystallisation from ethylacetate-heptane afforded the title compound (288 mg, 83%) as a light red solid. MS: m/e=344.0 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([OH:9])[N:3]=1.C(O[Na])(C)=O.Br[CH:16]([CH:20]([CH3:22])[CH3:21])[CH2:17]C=O>CC#N.O>[NH2:1][C:2]1[NH:3][C:4](=[O:9])[C:5]2[C:16]([CH:20]([CH3:22])[CH3:21])=[CH:17][NH:8][C:6]=2[N:7]=1
Reactant: Nc1cc(O)nc(N)n1
Reactant: CC(C)C(Br)CC=O
Agent: CC(=O)O[Na]
Solvent: CC#N
Solvent: O
Product: CC(C)c1c[nH]c2nc(N)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A suspension of 2,4-diamino-6-hydroxypyrimidine (6.68 g, 50 mmol), AcONa (8.3 g 100 mmol) and 3-bromo-4-methyl-pentanal (8.76 g, 50 mmol) in CH3CN (100 mL) and H2O (100 mL) was stirred at 25° C. overnight whereupon the starting materials gradually dissolved and the desired pyrrolo[2,3-d]pyrimidine precipitated. The precipitate was collected by filtration and washed with MeOH to give 2-amino-5-isopropyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (3.80 g, 40%). HPLC Rt: 4.408 min. 1H-NMR (DMSO-d6): δ 10.58 (s, 1H), 10.10 (s, 1H), 6.30 (s, 1H), 5.97 (s, 2H), 3.03 (7, 1H), 1.20 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][C:3]=1[CH:10]1[S:14](=[O:16])(=[O:15])[NH:13][C:12](=[O:17])[CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>O1CCOCC1.C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:38])[CH:5]=[CH:4][C:3]=1[CH:10]1[S:14](=[O:16])(=[O:15])[NH:13][C:12](=[O:17])[CH2:11]1
Reactant: BrC(Br)(Br)Br
Reactant: O=C1CC(c2ccc(CO)cc2Br)S(=O)(=O)N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C1CC(c2ccc(CBr)cc2Br)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-[2-bromo-4-(hydroxymethyl)phenyl]isothiazolidin-3-one 1,1-dioxide (54.0 mg, 0.169 mmol) in 1,4-dioxane (5 mL) was added triphenylphosphine (49 mg, 0.18 mmol) and carbon tetrabromide (62 mg, 0.18 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with acetonitrile and purified by preparative LCMS to give the product as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH3:7][C:8]([S-:11])([CH3:10])[CH3:9].[Na+]>CN(C=O)C>[CH3:7][C:8]([S:11][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[S-]
Reactant: BrCCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)SCCCCBr
Temperature: 70 °C
Yield: 21 %

Procedure:
A solution of 1,4-dibromobutane (commercially available, for example, from Aldrich) (4.7 ml, 40 mmol) in DMF (10 ml) was treated with sodium 2-methyl-2-propanethiolate (commercially available, for example, from Aldrich) (3.36 g, 30 mmol) and the mixture was heated for 23 h at 70° C. The mixture was allowed to cool to room temperature, and partitioned between water and EtOAc. The organic solution was washed with water (×4), aqueous sodium bicarbonate solution, brine, dried (MgSO4), and evaporated. The residue was purified by flash column chromatography on silica (200 g) eluting with 0-50% EtOAc-cyclohexane to give the title compound (1.4 g, 21%): 1H NMR δ (CDCl3) 3.46 (2H, t, J=7 Hz), 2.96 (2H, t, J=7 Hz), 2.15-2.03 (4H, m), 1.44 (9H, s).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C(N(CC)C(C)C)(C)C.[CH2:30]([NH:34][CH2:35][C:36]1[CH:48]=[CH:47][C:39]([O:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:38]([CH3:49])[CH:37]=1)[CH2:31][CH2:32][CH3:33]>C(Cl)Cl>[CH2:30]([N:34]([CH2:35][C:36]1[CH:48]=[CH:47][C:39]([O:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:38]([CH3:49])[CH:37]=1)[C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CS(=O)(=O)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C
Yield: 21.9 %

Procedure:
A mixture of 2-(methylsulfonyl)-4-[4-(trifluoromethyl)phenyl]pyrimidine (0.3 g, 1 mmol), N,N-diisopropylethylamine (0.18 mL, 1 mmol) and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (0.424 g, 1.53 mmol) was heated at 100° C. in a sealed reactivial for 18 h. The residue was dissolved in CH2Cl2 and purified by Biotage™ chromatography (Silica, 40 g) eluting 3:97 EtOAc:cyclohexane to afford the title compound as a pale yellow oil (110 mg).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:23](=O)[CH3:24])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].[NH2:26]/[C:27](/[CH3:36])=[CH:28]\[C:29]([O:31][CH:32]1[CH2:35][CH2:34][CH2:33]1)=[O:30]>C(O)C>[C:15]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:28]([C:29]([O:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:30])=[C:27]([CH3:36])[NH:26][C:23]=1[CH3:24])(=[O:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C/C(N)=C/C(=O)OC1CCC1
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)c1ccccc1
Solvent: CCO
Product: CC1=C(C(=O)OC2CCC2)C(c2cccc3c(=O)cc(C)oc23)C(C(=O)c2ccccc2)=C(C)N1

Procedure:
340 mg (1.02 mmol) of 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-1-phenylbutane-1,3-dione are dissolved with 156 mg (1.8 mmol) of cyclobutyl 3-aminocrotonate in 5 ml of ethanol and heated under reflux under argon for 24 h. The reaction solution is purified by preparative HPLC. Concentration of the product fractions and crystallization from ethyl acetate result in 206 mg (43% of theory) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.C(N(C(C)C)CC)(C)C.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1.[OH-].[Na+]>C1COCC1>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:38](=[O:39])[C:37]5[CH:41]=[CH:42][C:34]([F:33])=[CH:35][CH:36]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccc(F)cc4)nc3cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol), diisopropylethylamine (0.36 ml, 2.01 mmol) in THF (0.8 ml), 4-fluorobenzoyl chloride (114 μL, 0.97 mmol) was slowly added at rt. The mixture was stirred overnight at rt. Aqueous NaOH (2 mL, 1M) was added and the solvent was evaporated. Water (25 ml) was added and the mixture was extracted three times with ethyl acetate (3×25 ml). The combined organic layers were washed with brine, dried and evaporated to afford a residue which precipitated after addition of methanol. The precipitate was suspended in MeOH/CH3CN (1:1, 6 mL) and refluxed for 2 hours in aqueous KOH (0.50 mL, 5M). After evaporation of the solvent and addition of water, a white solid was isolated and dried under high vacuum. The title compound was obtained (77 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:14])=[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=1)=[O:3].C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH:40]1([C:43]([CH:45]2[CH2:47][CH2:46]2)=O)[CH2:42][CH2:41]1>C(Cl)Cl>[C:15]([C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[C:43]([CH:45]2[CH2:47][CH2:46]2)[CH:40]2[CH2:42][CH2:41]2)[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[C:7]=1[OH:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C(C1CC1)C1CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)C=C(C2CC2)C2CC2)cc(C(C)(C)C)c1O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 4 g of 3,5-di-tert-butyl-4-hydroxyacetophenone in 250 ml of dry methylene chloride is cooled to -78° C. and 7.3 ml di-iso-propyl ethylamine (i-Pr2EtN) is added followed by 8.1 ml of trimethylsilyl trifluoromethanesulphonate (TMSOTf). The mixture is stirred at -78° C. for 10 minutes and is allowed to warm to ambient temperature over 1 hour. The mixture is cooled again to -78° C., and 3.6 ml of dicyclopropylketone is added followed by 32 ml of 1M titanum tetrachloride solution in methylene chloride. After stirring for 1 hr, the mixture is washed with 1N aqueous hydrochloric acid and the solvents are removed under reduced pressure. The residue is dissolved in 50 ml of methanol-1N aqueous hydrochloric acid and stirred for 1 hr at room temperature. The mixture is concentrated under reduced pressure and partitioned between methylene chloride and water. The organic phase is washed with aqueous sodium bicarbonate, brine and dried over sodium sulphate. The solvents are evaporated and the residue is purified by flash chromatography (10% ethyl acetate in hexane), and the product is recrystallized from hexane to give 1-(3,5-di-tert-butyl-4-hydroxyphenyl-3,3-dicyclopropylprop-2-en-1-one as an orange solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:17][CH2:18]Br>CS(C)=O.CN(C)C=O>[F:17][CH2:18][O:7][N:8]=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: FCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)=NOCF
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
Potassium carbonate (110.6 g, 0.8 ml) was added to ethyl 2-hydroxyimino-cyanoacetate (56.8 g, 0.4 mol) in dimethylsulfoxide (200 ml) under ice-cooling, and the mixture was stirred for 10 mins, and then Fluoromethyl bromide (48.8 g, 0.4 mol) in N,N-dimethylformamide (40 ml) was added dropwise to the mixture under ice-cooling. The mixture was stirred at an internal temperature of 20° to 30° C. for 2.5 hrs. The reaction solution was dispersed in ice water (1 L), and it was extracted with ethyl acetate (800 ml, 500 ml, and 500 ml). The combined extracts were washed twice with saturated brine (300 ml) and dried over sodium sulfate, and then concentrated to give a concentrate (66.4 g) which was purified by column chromatography using silica gel (60 g) to give ethyl 2-fluoromethoxyimino-cyanoacetate (46.6 g, yield: 66.9%) as an oily substance.
Reaction SMILES: C([O:8][C:9](=[O:58])[C@H:10]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[NH:11][C:12](=[O:50])[CH2:13][CH:14]([O:30][C:31](=[O:49])[CH2:32][NH:33][C:34](=[O:48])[CH2:35][NH:36][C:37](=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])C1C=CC=CC=1>O1CCCC1.CO>[C:37]([NH:36][CH2:35][C:34]([NH:33][CH2:32][C:31]([O:30][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:13][C:12]([NH:11][C@H:10]([C:9]([OH:58])=[O:8])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:50])=[O:49])=[O:48])(=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCCC(CC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OC(=O)CNC(=O)CNC(=O)CCCCCCCCC
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCCCCC(CC(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC(=O)CNC(=O)CNC(=O)CCCCCCCCC
Yield: 101.3 %

Procedure:
300 mg of the formed ester compound as above was dissolved in a mixture of 20 ml of tetrahydrofuran and 10 ml of methanol. By following the same procedure as in Example 23-(iv), 270 mg of N-[3-(N-decanoylglycylglycyloxy)octadecanoyl]-L-phenylalanine was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]5[CH:37]=[CH:36][C:35]([CH2:38][C:39]6[CH:44]=[CH:43][C:42]([N+:45]([O-])=O)=[CH:41][CH:40]=6)=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]5[CH:37]=[CH:36][C:35]([CH2:38][C:39]6[CH:40]=[CH:41][C:42]([NH2:45])=[CH:43][CH:44]=6)=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(Cc3ccc(Cc4ccc(Cc5ccc(Cc6ccc([N+](=O)[O-])cc6)cc5)cc4)cc3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Cc2ccc(Cc3ccc(Cc4ccc(Cc5ccc(Cc6ccc(N)cc6)cc5)cc4)cc3)cc2)cc1

Procedure:
In a 1-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 16.4 g of 1,1-bis(4-(4-(4-nitrophenylmethyl)phenylmethyl)phenyl)methane was dissolved in 500 milliliters of tetrahydrofuran, 1.7 g of a Pd-C catalyst (a 5% product, containing 54.8% of water) was added and contacted with hydrogen gas while cooled with water at a normal pressure and then stirred. After absorption of hydrogen was stopped, the catalyst was filtered off and the objective product adhered to a residual layer of the catalyst was washed with chloroform thoroughly and then the filtrate was concentrated. By recrystallizing the concentrate from a chloroform solvent, 11.0 g of a diamino compound according to the invention, that is, 1,1-bis(4-(4-(4-aminophenylmethyl)phenylmethyl)phenyl)methane was obtained as crystals. Melting point was from 192.0° to 193.0° C.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1[C:28]([C:29]2C=CC=CC=2)=[CH:27]SC=1C(OC)=O.C(OCC)(OCC)OCC.C(C1CCC(N)CC1)(C)(C)C>C(O)(=O)C>[C:28]([CH:4]1[CH2:5][CH2:6][CH:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:2][CH2:3]1)([CH3:29])([CH3:24])[CH3:27]
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: CC(C)(C)C1CCC(N)CC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: CC(C)(C)C1CCC(n2cnc3c(-c4ccccc4)csc3c2=O)CC1
Yield: 65.4 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1 ml), 4-t-butylcyclohexylamine (0.161 ml, 0.90 mmol), and acetic acid (0.1 ml) were used to give 103.1 mg (0.28 mmol, 65.4% yield) of the title compound.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClC(Cl)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:24](=[O:25])[CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: CC(Cl)Cl
Product: O=C(Cc1ccccc1)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 81.5 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.20 g, 0.92 mmol), phenylacetyl chloride (0.14 mL, 1.0 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (12 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)-2-phenylacetamide (0.25 g). MS (ESI) m/z 334.3 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:35]([NH2:40])(=[O:39])[CH2:36][CH2:37][CH3:38].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(Cl)Cl>[C:35]([NH:40][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1)(=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: CCCC(N)=O
Reactant: O=C(Nc1cc2ccccc2cn1)c1ccccc1NCc1ccnc(Br)c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCC(=O)Nc1cc(CNc2ccccc2C(=O)Nc2cc3ccccc3cn2)ccn1
Yield: 44.5 %

Procedure:
100 mg (0.23 mmol) of 2-[(2-bromopyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamide is heated in 1 ml of dioxane with 89 mg (0.28 mmol) of cesium carbonate, 24 mg (0.69 mmol) of butyramide, 4.7 mg (0.0046 mmol) of dipalladium-tribenzylidene acetone and 7.9 mg (0.014 mmol) of Xanthphos under a cover gas and in a moisture-free environment for 25 hours to a bath temperature of 90° C. It is then mixed with 20 ml of methylene chloride, suctioned off and concentrated by evaporation. The residue is chromatographed on silica gel first with hexane, then with hexane:ethyl acetate=8:2 and then with hexane:ethyl acetate=1:1 as an eluant. 45 mg (42% of theory) of 2-[(2-butyrylamino-pyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamide with a melting point of 173° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([S:18](Cl)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[Cl:17]>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([NH:8][S:18]([C:13]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([CH3:10])[CH:12]=2)(=[O:19])=[O:20])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)cnc1Br
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl
Reaction time: 18 h

Procedure:
To a stirred solution of 2-bromo-5-chloro-pyridin-3-ylamine (4.12 g, 20 mmol) in anhydrous pyridine (100 mL) was added 3-methyl-4-chlorobenzenesulfonyl chloride (6.35 g, 26 mmol) and the progress of the reaction was followed by LCMS. The reaction mixture was stirred overnight (18 h), then concentrated to remove as much of the pyridine as possible. The residue was dissolved in THF and was stirred 18 h with aqueous sodium hydroxide (20 mL) in THF to cleave the bis-sulfonamide. The reaction mixture was subsequently neutralized with aqueous HCl and extracted with EtOAc; the organic phase was washed with water (2×100 mL), brine, and then dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using EtOAc-hexane to provide N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-methyl-benzenesulfonamide as a white crystalline solid. MS m/z 397.1 (M+H).
Reaction SMILES: [F:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:32])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(Cn3cnc4cc(F)c(F)cc43)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(F)c(F)cc43)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a stirred solution of 6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (0.55 g, 1.58 mmol) from the previous step in DCM (20 mL) at 0° C. was added a solution of meta-chloroperbenzoic acid (0.32 g, 1.58 mmol) in DCM (3 mL). After stirring for 2 h at 0° C., the mixture was diluted with EtOAc (100 mL) and washed sequentially with saturated aq Na2S2O3, saturated aq NaHCO3, and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (0.50 g, 88%) as a white solid, which was not purified further. 1H NMR (300 MHz, CDCl3) δ 8.02-8.06 (m, 2H), 7.77 (s, 1H), 7.61 (m, 1H), 7.37 (dd, J=8.4, 1.5 Hz, 1H), 7.01 (m, 1H), 5.48 (s, 2H), 3.07 (s, 3H); LCMS (ESI) m/z 364 (M+H)+.