Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][C:18]([S:20]([C:23]([CH3:29])([CH3:28])[C:24](OC)=[O:25])(=[O:22])=[O:21])=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:9][CH2:8]1.[F-].[K+].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH:7]1([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][C:18]([S:20]([C:23]([CH3:28])([CH3:29])[CH2:24][OH:25])(=[O:22])=[O:21])=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:8][CH2:9]1
Reactant: COC(=O)C(C)(C)S(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)CO)ccc2n1CC1CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a suspension of lithium aluminum hydride (46 mg, 1.22 mmol) in tetrahydrofuran (5 mL) was added a solution of methyl 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoate (Step G, 452 mg, 1.11 mmol) in tetrahydrofuran (5 mL) at 0° C. After stirring for 3 h at 0° C., the mixture was quenched with potassium fluoride (210 mg, 3.66 mmol) and sodium sulfate decahydrate (1.57 g, 4.88 mmol) at 0° C. The resulting mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1 as eluent) to afford the title compound (388 mg, 92%) as a white amorphous.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:16].CC(C)([O-])C.[K+].[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Cl>C1COCC1>[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][C:9]=2/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[C:5]([CH3:16])=[CH:6]1
Reactant: Cc1c[nH]c2c(C=CC(=O)O)cc(F)cc12
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cn(Cc2ccc(Cl)cc2Cl)c2c(/C=C/C(=O)O)cc(F)cc12
Reaction time: 24 h
Yield: 70 %

Procedure:
To a solution of 3-(5-fluoro-3-methylindol-7-yl)acrylic acid, prepared as in Example 3 (20 g, 92 mmol) in 200 mL THF was added potassium t-butoxide (24.4 g, 206 mmol) in portions over approximately 10 min, while keeping the internal temperature below 18° C. with an ice-water bath. 2,4-Dichlorobenzyl chloride (21.7 g, 110 mmol) was added over a period of 5 min, after which the cooling bath was removed. The reaction mixture was stirred for 24 h, then quenched with 200 mL water, followed by dilution with 200 mL MTBE and 200 mL heptanes. After stirring for 10 min, the layers were separated, and the aqueous layer was filtered through a celite pad. The pad was rinsed with 50 mL water, and the aqueous filtrate was acidified to pH of 1-2 with 2 M HCl. The suspension was diluted with 200 mL MTBE and 100 mL heptanes, stirred for 5 min, then the solids were collected on a fritted glass funnel and rinsed with heptanes. The solids were dried under reduced pressure overnight at 58° C. to afford 24.4 g (70% yield) of the title compound: 1H-NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 5.55 (s, 2H), 6.21 (d, 1H, J=8.4 Hz), 6.24 (d, 1H, J=15.6 Hz), 7.22 (dd, 1H, J=10.4, 2.4 Hz), 7.28 (dd, 1H, J=8.6, 2.0 Hz), 7.34 (s, 1H), 7.43 (dd, 1H, J=8.6, 2.4 Hz), 7.66 (d, 1H, J=15.6 Hz), 7.67 (d, 1H, J=2.4 Hz), 12.29 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:3]=1[CH3:19].[CH3:20][C:21]1([CH3:36])[C:25]2=[N:26][CH:27]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:29]=[C:24]2[NH:23][CH2:22]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[CH3:20][C:21]1([CH3:36])[C:25]2=[N:26][CH:27]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:29]=[C:24]2[N:23]([C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:3]=2[CH3:19])[CH2:22]1
Reactant: Cc1c(-c2cccc(F)c2)nc2ncccc2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: Cl[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(-c2cccc(F)c2)nc2ncccc2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 4-chloro-2-(3-fluorophenyl)-3-methyl-1,8-naphthyridine (70.1 mg, 0.257 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (60 mg, 0.257 mmol), sodium tert-butoxide (49.4 mg, 0.514 mmol) and XPhos precatalyst (18.9 mg, 0.026 mmol) in toluene (4 mL) for 2 hours at 110° C. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(3-fluorophenyl)-3-methyl-1,8-naphthyridine. 1H NMR (400 MHz, chloroform-d) δ ppm 9.12 (1H, dd, J=4.3, 2.0 Hz), 8.17 (1H, dd, J=8.4, 2.0 Hz), 7.64 (1H, d, J=2.3 Hz), 7.42-7.54 (4H, m), 7.13-7.23 (1H, m), 5.79 (1H, d, J=2.3 Hz), 3.86-3.91 (1H, m), 3.80-3.84 (1H, m), 3.72-3.79 (4H, m), 2.94-3.05 (4H, m), 2.37 (3H, s), 1.58 (3H, s), 1.53 (3H, s). Mass Spectrum (ESI) m/e=470.2 (M+1)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[NH:15]1[CH2:18][CH:17]([N:19]2[CH:23]=[CH:22][C:21]([C:24]3[N:36]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=4)[C:27]4[CH:28]=[CH:29][C:30]5[N:31]([C:32]([CH3:35])=[N:33][N:34]=5)[C:26]=4[CH:25]=3)=[N:20]2)[CH2:16]1.C(N(CC)CC)C.[CH3:52][N:53]([CH3:58])[S:54](Cl)(=[O:56])=[O:55]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:44][C:40]1[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=1)[CH2:37][N:36]1[C:27]2[CH:28]=[CH:29][C:30]3[N:31]([C:32]([CH3:35])=[N:33][N:34]=3)[C:26]=2[CH:25]=[C:24]1[C:21]1[CH:22]=[CH:23][N:19]([CH:17]2[CH2:16][N:15]([S:54]([N:53]([CH3:58])[CH3:52])(=[O:56])=[O:55])[CH2:18]2)[N:20]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5CNC5)n4)n3Cc3cccc(Cl)c3)n12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5CN(S(=O)(=O)N(C)C)C5)n4)n3Cc3cccc(Cl)c3)n12
Reaction time: 0.58 h

Procedure:
A solution of 7-(1-azetidin-3-yl-1H-pyrazol-3-yl)-6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine bis(trifluoroacetate) salt (10.2 mg, 0.0158 mmol, prepared as in Example 156) in DCM (0.56 mL) was treated with triethylamine (11 μL, 0.079 mmol) and dimethylsulfamoyl chloride (2.5 μL, 0.024 mmol, Aldrich) and stirred for 35 minutes. Additional triethylamine (4.4 μL, 0.032 mmol) and dimethylsulfamoyl chloride (1.0 μL, 0.0093 mmol) were added. When the reaction was complete as determined by HPLC-MS, the product was purified via preparative HPLC-MS (Waters SunFire C18, eluting with a gradient of MeCN/H2O containing 0.1% TFA). Yield: (6.3 mg, 90%).
Reaction SMILES: [P:1]([O-:37])([O:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34])([O:3][CH2:4][CH:5]([OH:29])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:2].[CH3:38][N:39]=[C:40]=[O:41]>N1C=CC=CC=1>[P:1]([O-:37])([O:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34])([O:3][CH2:4][CH:5]([O:29][C:40](=[O:41])[NH:39][CH3:38])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(O)COP(=O)([O-])OCC[N+](C)(C)C
Reactant: CN=C=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCC[N+](C)(C)C)OC(=O)NC
Temperature: 50 °C

Procedure:
The hydroxy compound (300 mg) obtained in Example 28 and 1.5 ml of methyl isocyanate were dissolved in 7 ml of pyridine, and the solution was warmed at 50° C. for 5 hours. The solvent was then distilled off and the residue was purified by silica gel column chromatography [silica gel: 10 g; eluent: chloroform-methanol-water (65:25:4)] to give 298 mg of the above-identified compound.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][N:7]3[C:16]=2I)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:20]=[CH:21][C:22]2=[C:23]([CH:39]=1)[O:24][CH2:25][C:26]1[CH:36]=[C:35]([CH:37]=[O:38])[CH:34]=[CH:33][C:27]=1/[C:28]/2=[C:29](/[CH3:32])\[C:30]#[N:31]>>[CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][N:7]3[C:16]=2[CH:37]([OH:38])[C:35]2[CH:34]=[CH:33][C:27]3/[C:28](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:22]4[CH:21]=[CH:20][C:19]([F:18])=[CH:39][C:23]=4[O:24][CH2:25][C:26]=3[CH:36]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cccn2c(I)c(C3CC3)nc12
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C4CC4)nc4c(C(F)(F)F)cccn34)cc2COc2cc(F)ccc21
Yield: 100.8 %

Procedure:
[step 3] Using 2-cyclopropyl-3-iodo-8-(trifluoromethyl)imidazo[1,2-a]pyridine (480 mg, 1.36 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (200 mg, 0.68 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8A, step 3, (E)-2-(8-{[2-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl](hydroxy)methyl}-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (356 mg) was obtained quantitatively.
Reaction SMILES: C1(=O)[N:5]([C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)C(=O)C2=CC=CC=C12.[H][H].O.NN>CO.[Pt]=O>[Cl:18][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH2:5])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C1c2ccccc2C(=O)N1C#CCCCCc1cccc(Cl)c1
Reactant: [H][H]
Agent: O=[Pt]
Agent: NN
Solvent: CO
Solvent: O
Product: NCCCCCCc1cccc(Cl)c1
Reaction time: 72 h

Procedure:
A suspension of 1-(phthalimido)-6-(3-chlorophenyl)hex-1-yne (10 g, 30 mmol) in methanol (100 ml) was treated with platinum oxide (250 mg) and the mixture hydrogenated at 50 psi for 72 h. Further quantities of catalyst were added at intervals and when the theoretical uptake of hydrogen was complete, the mixture was filtered and the filtrate evaporated to a brown oil (9.5 g, 96%). This was dissolved in ethanol (100 ml) and treated with hydrazine hydrate (2.8 g, 56 mmol) under reflux for 16 h. The mixture was cooled to 5°
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:10]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pt]=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH:14]([OH:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:10]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(=O)c2ccccc21
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(O)c2ccccc21
Reaction time: 2 h

Procedure:
A solution of 3-(S)-t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2,5-dione (8.0 g) in ethanol (500 ml) containing platinum oxide (800 mg) was hydrogenated at atmospheric pressure and at room temperature for two hours. The catalyst was filtered off and the filtrate evaporated to give 3-(S)-t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, [α]D =-173° (c=1.8 in DMF).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([CH3:11])=[N:8][C:5]2=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23])[C:9]([CH3:11])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc2ncc(Br)cc2[nH]1
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2ncc(Br)cc2n1C(=O)OCC(C)C
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution of 6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (3.40 g, 16.0 mmol) and diisopropylethylamine (6.5 mL, 65 mmol) in N,N-dimethylformamide (20 mL) cooled in an ice bath was added dropwise isobutyl chloroformate (2.51 mL, 19.2 mmol) and the mixture was warmed to room temperature. After 1 hour the reaction was diluted with ethyl acetate (80 mL) and washed with water (60 mL), 10% aqueous citric acid (40 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to a slurry. The residue was triturated diethyl ether (100 mL) and the solid isolated by filtration to give isobutyl 6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine-1-carboxylate (2.3 g, 46% yield). MS (EI) for C12H14BrN3O2: 313 (MH+).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15]O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(S(F)(=O)=O)(F)(F)F.[CH:30]1([Li])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31]1>C1(C)C=CC=CC=1.CCCCCC.C(OCC)C>[CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][CH:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]C1C=Cc2ccccc21
Reactant: OCCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)(F)C(F)(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: C1=CC(CCC2c3ccccc3-c3ccccc32)c2ccccc21
Reaction time: 6 h

Procedure:
To a solution of 21.0 g 2-(9-fluorenyl)ethanol, in 495 mL toluene was added dropwise with stirring 40 mL of a 2.5M solution of n-butyllithium in hexane. The resulting solution of Li{flu-CH2—CH2—O} was cooled to below −25° C. Then, 16.7 g CF3SO2F was condensed into the reaction mixture. The temperature was allowed to rise to 25° C. and the reaction mixture was stirred for 6 h. Unreacted CF3SO2F was removed by pumping about 10 mL of liquid into a dry ice-cooled trap. To the solution of flu-CH2—CH2—OSO2CF3 thus obtained was added a solution of 0.1 mole indenyllithium in 100 mL diethyl ether. After stirring for 12 h, solvents were removed under vacuum and the residue recrystallized in air from boiling heptane. The yield of white microcrystalline solid, mp 79-80° C., was 8.9 g (29%). Spectroscopic and chemical analysis confirmed the identity of the desired 5 compound.
Reaction SMILES: C(OC([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13](Cl)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26].Cl.[OH-].[Na+]>CC(O)C.O1CCOCC1.ClCCl.CO.C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:13]2[C:12]3[C:11]4[CH2:10][CH2:9][NH:8][CH2:20][C:19]=4[S:18][C:17]=3[N:16]=[CH:15][N:14]=2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCNC4)cc1Cl
Temperature: 82.5 °C
Yield: 94 %

Procedure:
To a mixture of 4-Chloro-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluorene-7-carboxylic acid tert-butyl ester (6.86 g, 0.021 mol) and 3-chloro-4-fluoroaniline (3.2 g, 0.022 mol) in 2-propanol (96 ml) was added 4 N HCl in Dioxane (0.27 ml) and the mixture heated to 80-85° C. overnight. LCMS and TLC (5% MeOH/DCM) indicate that no SM (Boc-protected SM) present. 4 N HCl in Dioxane (10.5 ml, 0.042 mol) added and the heating continued until LCMS indicates no Boc-protected product present. Cooled to RT and conc. to dryness. The mixture was then suspended in dichloromethane (200 ml) and stirred with 1N NaOH (200 ml) for 30 min. Clear biphasic layers obtained. Layers separated and the aqueous washed with dichloromethane (100 ml). Combined organic layers washed with water (2×100 ml), then with brine (100 ml). Dried the organic layer with sodium sulfate, filtered and conc. to dryness. Dried under vacuum at to give 6.61 g (94%) of the product as indicated by LCMS and HNMR. 1H NMR (DMSO-d6) δ 8.41 (s, 1H), 8.24 (s, 1H), 7.92 (m, 1H), 7.64 (m, 1H), 7.39 (t, J=9.4 Hz, 1H), 3.94 (broad s, 1H), 3.32 (m, 2H), 3.05 (m, 2H), 3.01 (m, 2H); LCMS RT=2.13 min, [M+H]+=335.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.[CH3:52][NH:53][CH2:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=1>ClCCl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:9])[C@@H:10]([C:11](=[O:13])[N:53]([CH3:52])[CH2:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Reactant: CNCCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCc1ccccn1)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-phenylpropionic acid (11.2 g, 40 mmol), 1-hydroxy-7-azabenzotriazole (5.4 g, 40 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.7 g, 40 mmol) were dissolved in dichloromethane (100 mL). The reaction mixture was stirred for 15 min. Ethyidiisopropylamine (6.85 mL, 40 mmol) and 2-(2-methylaminoethyl)pyridine (5.54 mL, 40 mmol) were added. The reaction mixture was stirred for 16 h. The reaction mixture was washed with sat. aqueous sodium hydrogen carbonate solution (3×150 mL). The organic layer was dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using ethyl acetate as eluent, to give 10.9 g of N-methyl-N{(1R)-1-[N-methyl-N-(2-(2-pyridyl)ethyl)carbamoyl]-2-phenylethyl}carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCCC2)c(C#N)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N4CCCCC4)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-cyano-5-piperidin-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J33) (316 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (420 mg, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:23][CH3:24])=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:5][CH:4]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(N(CC(C)C)CC(C)C)C(C)C.C(OC(Cl)=O)C(C)C.[CH3:67][NH:68][CH2:69][CH2:70][CH2:71][CH3:72]>CC(C)=O.O.C(Cl)Cl.C(O)(C)C>[CH2:69]([N:68]([CH3:67])[C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH2:23][CH3:24])[CH2:70][CH2:71][CH3:72]
Reactant: CCCCNC
Reactant: CCC(C(=CCCCCCCCCCCO)c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: O=[Cr](=O)=O
Agent: CC(C)CN(CC(C)C)CC(C)C
Agent: CC(C)COC(=O)Cl
Solvent: CC(C)O
Solvent: O
Solvent: ClCCl
Product: CCCCN(C)C(=O)CCCCCCCCCC=C(c1ccc(OC)cc1)C(CC)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a cooled solution of alcohol 3 (710 mg, 1.56 mmol) in acetone (17 ml) was added Jones' reagent (8N-chromic acid solution, 0.77 ml). After 30 minutes, isopropanol (5 ml) was added and the mixture was poured in water and extracted three times with ethyl acetate. The organic layer was washed twice with brine, dried over magnesium sulfate and evaporated to dryness. The crude 12,13Bis(4-methoxyphenyl)-11-pantadecenoic acid was used in the next step without purification. To its solution in anhydrous methylene chloride (4 ml) at -10° C. was added, under stirring, triisobutylamine (470 μl , 1.96 mmol) and isobutylchloroformate (280 μl, 2.1 mmol). After 40 minutes, N-methylbutylamine (1.5 ml) was added and the mixture was stirred at room temperature during 1 hour. Methylene chloride (50 ml) was added. The organic solution was washed with 1N HCl, saturated sodium bicarbonate solution and water (3×), dried on magnesium sulfate and evaporated to dryness. The residue was purified by "Flash chromatography" on silica gel (Kieselgel 60, Merck, under 0.063 mm, 50 g). Elution with a mixture of hexane-ethyl acetate (4:1 v/v) gave N-butyl,N-methyl-12,13-Bis(4-methoxyphenyl)-11-pentadecenoic amide (4) (549 mg, 68%) colorless oil; IR νmax (neat), 1640, 1600 cm-1 ; UV γmax (log ε)=230, (4.39) nm; 1H-NMR (δ, CDCl3), 0.85-0.98 (6H, m, 2CH2CH3), 2.27 (2H, t, J=7.1 Hz, CH2CON), 2.91 and 2.96 (3H, 2s, --NCH3), 3.25-3.36 (3H, m, --NCH2 and CH3CH2CH--), 3.77 and 3.78 (6H, 2s, OCH3), 5.50 (1H, J=7.1 Hz, --C=CH--) and 6.69-7.01 (8H, m, H--Ar) ppm; MS m/e=521 (M+).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH3:5][C:6](=[C:8]([CH3:10])[CH3:9])[CH3:7].S(=O)(=O)(O)O.[OH-].[Na+]>O.C(O)(=O)C>[CH3:5][C:6]([NH:1][C:2]([NH2:4])=[O:3])([CH:8]([CH3:10])[CH3:9])[CH3:7]
Reactant: CC(C)=C(C)C
Reactant: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(C)(C)NC(N)=O
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To the mixture of 288 mL glacial acetic acid, 412 g (6.86 mole) urea and 288 g (3.43 mole) 2,3-dimethyl-2-butene, the solution of 412 mL concentrated sulfuric acid and 412 mL of glacial acetic acid was added dropwise under stirring, while maintaining the reaction temperature at the range of 45° C. to 50° C., then stirred for 5 hours at the temperature of 50-55° C. The mixture stood overnight. Next day, the mixture was reacted for another 7 hours at the temperature of 50-55° C., then poured into the solution of 1200 g (30 mole) sodium hydroxide in 8 L glacial water. The resulting solid was filtered, washed with water (200 mL×5) and dried to give 404 g (yield 81.8%) N-(2,3-dimethyl-2-butyl)urea as white solid, mp 175-176° C. Elemental analysis for C7H16N2O(%): Calculated C, 58.30; H, 11.18; N, 19.42. Found C, 58.70; H, 11.54; N, 19.25. 1H-NMR(CDCl3, ppm) 0.88-0.91(d, 6H, 2×CH3), 1.26(s, 6H, 2×CH3), 2.20-2.26(m, 1H, CH), 4,45(br, 2H), 4.65(br, 1H). MS(m/z) 145.0, 144.0(M+), 143.0, 129.1, 101.0, 86.1, 69.1, 58.0(B).