Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl-].[Cl-].[Cl-].[Al+3].[CH2:15]([C:18]1[N:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]2=[CH:20][N:19]=1)[CH2:16][CH3:17]>ClCCCl>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:20]1[N:19]=[C:18]([CH2:15][CH2:16][CH3:17])[N:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=12)=[O:6]
Reactant: CCCc1ncc2ccccn12
Reactant: O=C(O)c1ccccc1I
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCc1nc(C(=O)c2ccccc2I)c2ccccn12
Reaction time: 0.17 h
Yield: 14.7 %

Procedure:
To a solution of 2-iodobenzoic acid (487 mg, 1.83 mmol) in 1,2-dichloroethane (20 mL) was added aluminum trichloride (266 mg, 2.00 mmol). The mixture was allowed to stir for 10 min. then a solution of 3-propyl-imidazo[1,5-a]pyridine (139 mg, 0.87 mmol) in 1,2-dichloroethane (5 mL) was added. The mixture was stirred at ambient temperature for 30 min. then washed with saturated aqueous sodium bicarbonate and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (50 mg, 15%). 1H NMR (DMSO-d6) δ 8.54 (1H), 8.10 (1H), 7.92 (1H), 7.50 (1H), 7.41 (2H), 7.22 (1H), 7.10 (1H), 3.00 (2H), 1.70 (2H), 0.94 (3H); m/z (M+H)=391.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.[CH3:17][O:18][CH2:19][CH2:20]Br>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH2:20][CH2:19][O:18][CH3:17])[C:6]=2[CH:16]=1
Reactant: COCCBr
Reactant: O=c1[nH]c2cc(Cl)ccc2c2ccncc12
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1c(=O)c2cnccc2c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a stirred solution of 8-chlorobenzo[c][2,7]naphthyridin-5(6H)-one (0.150 g, 0.650 mmol) in anhydrous DMF (2 mL) at 0° C. was added 2-bromoethyl methyl ether (0.090 g, 0.650 mmol) under nitrogen. The reaction mixture was allowed to warm to RT and stirred for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford 8-chloro-6-(2-methoxyethyl)benzo[c][2,7]naphthyridin-5(6H)-one (150 mg, 0.520 mmol, 80% yield). LC/MS (ESI) m/e 289.1 [(M+H)+, calcd for C15H13ClN2O2 289.1]; LC/MS retention time (method A): tR=1.65 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14]CC)=O)=[CH:5]2.[CH3:17][N:18]1C2C(=CC=CC=2)C=C1C(OCC)=O>>[CH3:17][NH:18][C:12]([C:6]1[N:7]([CH3:11])[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)=[O:14]
Reactant: CCOC(=O)c1cc2ccccc2n1C
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1C
Product: CNC(=O)c1cc2cc(F)ccc2n1C
Yield: 68 %

Procedure:
According to the procedure of Preparation 1(b), except substituting ethyl 5-fluoro-1-methyl-1H-indole-2-carboxylate for the ethyl 1-methyl-1H-indole-2-carboxylate, the title compound (2.1 g, 68%) was prepared as a white solid: MS (ES) m/e 207 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:11])[CH2:6][C:7]([CH2:9][Cl:10])=[O:8])[CH2:2][CH3:3]>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5](=[O:11])[CH2:6][C@@H:7]([OH:8])[CH2:9][Cl:10])[CH2:2][CH3:3]
Reactant: CCCOC(=O)CC(=O)CCl
Solvent: ClC(Cl)Cl
Product: CCCOC(=O)C[C@@H](O)CCl

Procedure:
The procedure of example 375 was repeated using n-propyl-4-chloroacetoacetate as the substrate to afford n-propyl-4-chloro-3(R)-hydroxybutyrate, [α]D23 +21.5° (c, 5.0, CHCl3).
Reaction SMILES: CCO[CH:4]([O:13]CC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1.[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([NH2:24])=[C:19]([NH2:25])[CH:18]=1.C1(=O)C=CC(=O)C=C1>C(O)C>[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]2[N:24]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([CH:4]=[O:13])=[CH:10][CH:9]=3)[NH:25][C:19]=2[CH:18]=1
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: O=C1C=CC(=O)C=C1
Solvent: CCO
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a mixture of terephthalaldehyde mono-(diethyl acetal) (2.0 mL, 10 mmol), 4,5-dichloro-1,2-phenylenediamine (1.77 g, 10 mmol) and 1,4-benzoquinone (1.08 g, 10 mmol) in ethanol (50 mL) was heated to reflux for 6 h. The solvent was removed under reduced pressure. To the residue were added tetrahydrofuran (50 mL) and hydrochloric acid (1 mol/L, 10 mL), and the mixture was stirred at room temperature for 2 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was triturated with ether to afford 5,6-dichloro-2-(4-formylphenyl)benzimidazole (2.80 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1.C([O-])=O.[NH4+:16].Cl>CO.C[C]1[C](C)[C](C)[C](C)[C]1C.C[C]1[C](C)[C](C)[C](C)[C]1C.Cl[Rh]Cl.Cl[Rh]Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:16])[CH:5]=[N:6][CH:7]=1
Reactant: CCCC(=O)c1cncc(C)c1
Reactant: [NH4+]
Agent: Cl[Rh]Cl
Agent: C[C]1[C](C)[C](C)[C](C)[C]1C
Agent: Cl
Solvent: CO
Product: Cc1cncc(CCCCN)c1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of 1-(5-methylpyridin-3-yl)butan-1-one (800 mg, 4.9 mmol) and ammonium formate (1.55 g, 24.5 mmol) in methanol (5 mL) under nitrogen was added dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer (45 mg, 0.074 mmol). The solution was heated at reflux for 8 h. after which time the solution was cooled to room temperature and acidified to pH ˜2 with 2M HCl. The mixture was washed with dichloromethane (3×15 mL) and the aqueous phase then basified to pH ˜12 by addition of solid KOH. The aqueous phase was extracted with dichloromethane (3×15 mL) and the combined organic layers washed with brine, dried (Na2SO4) and concentrated to give a pure product (620 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11]([Cl:14])(=[O:13])=[O:12].[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.S(Cl)(Cl)(=O)=O.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:7])=[CH:4][C:3]=1[S:11]([Cl:14])(=[O:13])=[O:12]
Reactant: OCCN1CCOCC1
Reactant: O=C(Cl)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: O=C(OCCN1CCOCC1)c1ccc(Cl)c(S(=O)(=O)Cl)c1

Procedure:
To a solution of 4-chloro-3-(chlorosulfonyl)benzoyl chloride (1.0 g, 3.6 mmol) in DCM (10 ml) was added a solution of hydroxy ethyl morpholine (443 μl, 3.6 mmol) in DCM (1 ml). The reaction mixture was stirred for 12 h after which time no sulfonyl chloride was observed by LC-MS. Upon concentration of the crude reaction mixture a solid was isolated, which was trituated with ether to afford the desired compound as a brown solid. (1.54 g, 100%) IR (neat) vmax/cm−1 1724, 1174, 1450; 6H (500 MHz, DMSO-d6) 8.49 (1H, d, 1.8 Hz), 7.97 (1H, dd, 8.2, 1.9 Hz), 7.56 (1H, d, 8.2 Hz), 4.38-5.00 (2H, m), 3.88-4.07 (2H, m), 3.76-3.83 (2H, m), 3.56-3.62 (2H, m), 3.36-3.54 (2H, m), 3.14-3.28 (2H, m).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH:11]1[C:20](Cl)=[O:21].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:3]1([CH2:2][CH2:1][NH:9][C:20]([CH:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10]2)=[O:21])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)C1CCc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)C1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
The solution of phenethylamine (344 mg, 2.84 mmol) in 20 ml of CH2Cl2 was first treated with the solution of 1,2,3,4-tetrahydro-2-naphthoyl chloride (2.83 mmol) in 2 ml of CH2Cl2 followed by treatment with 10 ml 10% K2CO3 solution. After stirred at r.t. overnight, the organic layer was separated and washed with 2N HCl, water, sat'd brine and dried over Na2SO4. Filtration and removal of solvent gave N-(2-phenylethyl) 1,2,3,4-tetrahydro-2-naphthoic amide as a white powder (793 mg, 100%); mp 86°-87° C.; Calcd for C19H21NO: C 81.67, H 7.59, N 5.01; Found: C 82.00, H 7.27, N 4.77.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7](Br)[C:8]2[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]=2[CH:15]=1)=[O:4].C(N(CC)CC)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[B]1OC(C)(C)C(C)(C)O1.Br[C:60]1[CH:61]=[C:62]([CH:65]=[CH:66][C:67]=1[O:68][C:69]([F:72])([F:71])[F:70])[CH:63]=[O:64]>O1CCOCC1.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]([C:60]2[CH:61]=[C:62]([CH:63]=[O:64])[CH:65]=[CH:66][C:67]=2[O:68][C:69]([F:70])([F:72])[F:71])[C:8]2[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]=2[CH:15]=1)=[O:4]
Reactant: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Reactant: CN(C)C(=O)c1cc(Br)c2c(c1)C(C)(C)CO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)O[B]OC1(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C(=O)c1cc(-c2cc(C=O)ccc2OC(F)(F)F)c2c(c1)C(C)(C)CO2
Temperature: 80 °C
Yield: 44.4 %

Procedure:
To a solution of 7-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-5-carboxylic acid dimethylamide (437 mg, 1.46 mmol) in dioxane (4 mL), were added under argon, triethylamine (0.82 mL, 5.86 mmol), Pd(OAc)2 (16 mg, 0.07 mmol), 2-(dicyclohexylphosphino)biphenyl (103 mg, 0.29 mmol) and pinacolborane (0.64 mL, 4.40 mmol) dropwise. The mixture was heated at 80° C. under argon for 2 hrs then cooled to room temperature. Water (0.5 mL) was added dropwise, then Ba(OH)2.8H2O (1.38 g, 4.40 mmol) followed by 3-bromo-4-trifluoromethoxy benzaldehyde (473 mg, 1.76 mmol) dissolved in dioxane (1.2 mL). The mixture was refluxed for 4 hours then cooled to room temperature, diluted with ethyl acetate and filtered over celite. The solution was further washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (5% methanol in dichloromethane) to give 264 mg of 7-[5-formyl-2-trifluoromethoxy-phenyl]-3,3-dimethyl-2,3-dihydro-benzofuran-5-carboxylic acid dimethylamide (containing 50% of 3,3-dimethyl-2,3-dihydro-benzofuran-5-carboxylic acid dimethylamide as determined by 1H NMR) use as this in the next step.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]([NH:18][C:19]([NH2:21])=[NH:20])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O>CN(C=O)C>[NH2:21][C:19]1[N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[N:20]=1
Reactant: CC(C)(C)OC(=O)NC(=N)N
Reactant: CCCCCCC(=O)CBr
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reaction time: 48 h
Yield: 57.3 %

Procedure:
1-bromooctan-2-one (1.00 g, 4.83 mmol) was placed in a 50 mL round bottomed flask with a stir bar and dissolved in 10 mL of DMF. Boc guanidine (2.31 g, 14.89 mmol) was then added to the reaction mixture and it was allowed to stir for 48 hours. Water was then added to the reaction mixture and it was placed in a separatory funnel. The mixture was then extracted twice with ethyl acetate, washed twice with water, washed twice with brine, concentrated de vacuo and then purified via column chromatography (5% methanol/95% dichloromethane) to provide tert-butyl 2-amino-4-hexyl-1H-imidazole-1-carboxylate as a hygroscopic light yellow solid (0.74 g, 57% yield). 1H NMR (300 MHz, CDCl3) δ 6.69 (s, 2H), δ 6.34 (s, 1H), δ 2.20 (t, J=7.5 Hz, 2H), δ 1.44 (bs, 11H), 1.17 (s, 6H), δ 0.76 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 151.1, 149.6, 139.3, 105.7, 84.1, 31.8, 29.2, 28.4, 28.3, 28.0, 22.7, 14.2 ppm; IR νmax (cm−1) 3421, 2109, 1644, 1442, 1204, 1142; HRMS (ESI) calcd for C14H25N3O2 (M+) 267.1946, found 267.1940. Then, tert-butyl 2-amino-4-hexyl-1H-imidazole-1-carboxylate was dissolved in a 1:4 mixture of trifluoroacetic acid/dichloromethane and allowed to stir for five hours and then concentrated de vacuo. The sample was then dissolved with a dilute HCl/methanol (5 drops HCl/50 mL of methanol) and then concentrated in vacuo to provide 4-(5phenylpentyl)-1H)-imidazol-2-amine hydrochloride as a hygroscopic light yellow solid (0.57 g, 57% overall yield). 1H NMR (300 MHz, CD3OD) δ 6.34 (bs, 3H), δ 2.41 (t, J=7.5 Hz, 2H), δ1.56 (m, 2H), δ 1.28 (bs, 6H), δ 0.82 (t, J=6.6 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 151.4, 131.9, 111.9, 35.3, 32.4, 31.9, 28.3, 26.3, 17.1 ppm; IR νmax (cm−1) 3411, 2099, 1638; HRMS (ESI) calcd for C9H17N3 (M+) 167.1422, found 167.1416.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][C:9](=[O:11])[CH3:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C>[O:1]([C@H:2]([CH2:8][C:9](=[O:11])[CH3:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: COC(=O)C[C@H](O)CC(C)=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](CC(C)=O)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
Methyl(3R)-3-hydroxy-5-oxohexanoate (6) (10 g, 0.062 mol) was dissolved in dry DMF (110 mL) and the solution was cooled down to 0° C. Imidazole (8.5 g, 0.124 mol) and tert-butyldimethylsilyl chloride (11.3 g, 0.0744 mol) were added. The reaction mixture was stirred at 25° C. for 12 h and then quenched with a 10% NaHCO3 solution. After the extraction with toluene (3×150 mL), the collected organic phase was dried under vacuum and the resulted oil was purified via by fractional distillation. Methyl(3R)-3-(tert-butyldimethylsiloxy)-5-oxohexanoate was obtained as a yellow oil the compound of formula (II-R, PG=TDBMS, Z=OMe)(11.3 g; molar yield 66%).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:17](=[O:33])[CH:18]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:17]([NH:16][C@@H:13]2[C@@H:11]3[C@@H:10]([CH2:9][NH:8][CH2:12]3)[CH2:15][CH2:14]2)=[O:33])=[CH:27][CH:28]=1
Reactant: O=C(N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(N[C@H]1CC[C@@H]2CNC[C@@H]21)C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
N-((3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-2,2-bis(4-fluorophenyl)acetamide (150 mg, 0.336 mmol) from Example 228 and ethanol (20 mL) were added to 20% Pd(OH)2 on carbon, wet (30.0 mg, 0.214 mmol) in a 50 mL pressure bottle and stirred for 2 hours under 30 psi hydrogen at 50° C. The mixture was filtered and the solvent was removed in vacuo to give 2,2-bis(4-fluorophenyl)-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.09 (d, J=7.1, 1H), 7.60-7.55 (m, 4H), 7.13 (q, J=8.2, 4H), 5.26 (s, 1H), 4.36-4.27 (m, 1H), 3.06 (dd, J=10.9, 2.7, 1H), 2.92 (dd, J=10.9, 7.0, 1H), 2.81 (dd, J=10.7, 7.0, 1H), 2.59 (dd, J=10.8, 2.8, 1H), 2.52-2.41 (m, 2H), 2.33-2.25 (m, 1H), 2.06-1.96 (m, 1H), 1.83 (td, J=12.7, 6.9, 1H), 1.65-1.52 (m, 1H), 1.26 (ddt, J=12.3, 8.7, 6.1, 1H); MS (ESI+) m/z 357 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[NH:36]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:36]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: C1CCCNCC1
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N2CCCCCC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 73 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (50 mg, 0.10 mmol) in DCM (5 mL) was added hexahydro-1H-azepine (0.034 mL, 0.30 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (39 mg, 73%). LC-MS m/z 535 (M+H)+; 1H-NMR (MeOD) δ 1.27 (d, 6H), 1.47 (m, 6H), 1.70 (m, 2H), 2.31 (s, 3H), 3.32 (m, 2H), 3.68 (m, 2H), 4.11 (m, 2H), 4.23 (m, 1H), 7.13 (t, 2H), 7.44 (d, 1H), 7.48 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[C:18]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:14]
Reactant: CCOC(=O)C=Cc1ccccn1
Reactant: COc1n[nH]c2cc(Br)ccc12
Product: CCOC(=O)C=C(c1ccc2c(OC)n[nH]c2c1)c1ccccn1

Procedure:
3-(3-Methoxy-1H-indazol-6-yl)-3-pyridin-2yl-acrylic acid ethyl ester CCXLIII was prepared from 6-bromo-3-methoxy-1H-indazole and 3-pyridin-2-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl esterLVIII (Example 14).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]=4[NH2:41])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:24])[CH2:18][N:19](C)[C:20](=O)O)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.CCOC(C)=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]2=[C:8]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]=4[NH2:41])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:24])[CH2:18][NH:19][CH3:20])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CN(CC(=O)N1CCC(c2cc(-c3ccc4c(N)n(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNCC(=O)N1CCC(c2cc(-c3ccc4c(N)n(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a suspension of (2-(4-[4-Amino-5-(3-amino-2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-piperidin-1-yl)-2-oxo-ethyl)-methyl-carbamic acid tart-butyl ester (30 mg, 0.049 mmol) in anhydrous DCM (1.0 mL) was added trifluoroacetic acid (1.0 mL), and the reaction mixture was stirred at rt. After 1 h, the mixture was poured into EtOAc (75 mL), and the organic phase was washed with aqueous, saturated NaHCO3 solution (3×25 mL), water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Trituration with DCM-hexane afforded the title compound (24.7 mg, 98.5%) as a pink solid. 1H NMR (300 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.71 (d, 1H), 7.34 to 7.29 (m, 2H), 7.27 to 7.21 (m, 3H), 7.15 (s, 1H), 6.73 (dd, 1H), 6.54 (s, 1H), 6.37 (broad s, 2H), 5.38 (s, 2H), 4.50 (d, 1H), 3.90 (d, 1H), 3.42 to 3.27 (m, 3H), 3.13 (t, 1H), 2.76 to 2.66 (m, 1H), 2.26 (s, 3H), 2.05 to 1.99 (m, 3H), 1.68 to 1.49 (m, 2H); ES-MS m/z 510.1 [M+H]+, RT (min) 1.56.
Reaction SMILES: [C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30](F)=[C:29]([N+:34]([O-:36])=[O:35])[CH:28]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:13]=2[CH3:37])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN.[CH3:42][N:43]1CCCC1=O.O>C1COCC1>[C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([NH:43][CH3:42])=[C:29]([N+:34]([O-:36])=[O:35])[CH:28]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:13]=2[CH3:37])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCCC1=O
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(F)c([N+](=O)[O-])c2)n1
Agent: CN
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn(C)c2=O)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of give 4-tert-butyl-N-{3-[6-(4-fluoro-3-nitro-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide (2) (600 mg; 1.13 mmol), methylamine (5 mL of a 2M solution in THF), and 1-methyl-2-pyrollidinone (10 mL) was heated at 60 degrees in a sealed pressure vessel for 16 hr. The mixture was cooled to room temperature, treated with water (30 mL) and filtered to give 4-tert-butyl-N-{2-methyl-3-[4-methyl-6-(4-methylamino-3-nitro-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide (3) as a red solid (501 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22].Cl.[OH-].[Na+]>O.C(O)C>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: COc1ccc(OC)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(OC)c(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)c1
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol), 2,5-dimethoxyaniline and aqueous 2N HCl (150 μl) in water:ethanol (1:1, 10 ml) was refluxed for 48 h. The mixture was cooled to room temperature and then basified with aqueous 2N NaOH to pH 10–12. The resulting precipitate was filtered, washed with water, water:ethanol (2:1) and isolated as a green-yellow solid (46 mg, 64%). 1H NMR (CDCl3): 9.74 (d, J=1.5 Hz, 1H), 8.79 (dd, J=1.8, 2.4 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H), 7.80 (bs, 1H), 7.70 (s, 1H), 7.07 (s, 1H), 6.91 (d, J=9.3 Hz, 1H), 6.72 (dd, J=3.0, 9.0 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: C([O:4][C@@H:5]1[CH:24]=[CH:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=O)C.C(=O)(O)[O-].[K+]>CO>[OH:4][C@@H:5]1[CH:24]=[CH:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1
Reactant: CC(=O)O[C@@H]1C=C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)C=C[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 23.4 %

Procedure:
A solution of 3α-acetoxy-5α-pregn-1-ene-11,20-dione (7.9 g.) in dry methanol (225 mg.) was treated with potassium bicarbonate (8.5 g.), and the mixture was refluxed under nitrogen for 11/2 hr. The reaction mixture was concentrated in vacuo, then poured into water, and the product was extracted with methylene chloride. The extract was washed with water, dried (Na2SO4), and evaporated in vacuo. The residue (6.0 g.) was purified by preparative t.l.c. and crystallisation from methyl acetate/petroleum ether to give the title compound (1.64 g.), m.p. 119°-121°, [α]D + 56.8°.