Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[C:14]([C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[OH:25])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[C:26]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.Cl>>[C:26]1([C:12]2[CH:13]=[C:14]([C:16]([CH3:17])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH:15]=[C:10]([C:2]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)([CH3:1])[CH3:3])[C:11]=2[OH:25])[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: O=C1CCCCC1
Reactant: CC(C)(c1ccccc1)c1ccc(O)c(C(C)(C)c2ccccc2)c1
Agent: Cl
Product: CC(C)(c1ccccc1)c1cc(C2=CCCCC2)c(O)c(C(C)(C)c2ccccc2)c1
Reaction time: 19 h
Yield: 3.2 %

Procedure:
A mixture consisting of 66.1 g (0.20 mol) of 2,4-bis(1-methyl-1-phenylethyl)phenol and 9.8 g (0.10 mol) of cyclohexanone is melted together and is then saturated, with stirring, with hydrochloric acid gas at 40-45° C. After 19 hours, another 9.8 g (0.10 mol) of cyclohexanone are added. The reaction mixture is saturated again with hydrochloric acid gas and is then stirred for 21 hours. The reaction mixture is diluted with petroleum ether and washed with water. The organic phase is dried over magnesium sulfate and concentrated on a rotary evaporator. The residue is chromatographed over silica gel using the solvent system hexane/ethyl acetate=39:1, giving 1.3 g (2%) of 2-cyclohexen-1-yl-4,6-bis(1-methyl-1-phenylethyl)phenol as a thick yellowish oil (compound (110), Table 1).
Reaction SMILES: [Br:1]Br.[CH2:3]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH2:4][CH2:5][CH3:6]>C(Cl)(Cl)Cl>[Br:1][C:9]1[S:8][C:7]([CH2:3][CH2:4][CH2:5][CH3:6])=[CH:11][CH:10]=1
Reactant: CCCCc1cccs1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Bromine, 5 ml (15.63 g or 0.0977 mol), was added to a solution of 15.2 g (0.108 mol) of 2-butylthiophene in 400 ml of chloroform. Following the addition, the mixture was stirred for 10 minutes at room temperature and was then washed with 10% aqueous sodium carbonate solution. The organic layer was separated, dried and evaporated and the remaining oil was distilled under high vacuum to yield a colorless oil. Nmr (CDCl3): 0.89 ppm (t, 3, J=7.5 Hz, CH3), 1.2-1.7 (m, 4, CH2CH2), 2.7 (t, 2, J=7.5 Hz, CH2), 6.47 (d, 1, J=4 Hz, C4-H), 6.78 (d, 1, J=4 Hz, C3-H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:13]2[C:21]3[C:16](=[C:17]([CH:22]=[O:23])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:35][CH3:36]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([CH:22]=[O:23])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:35][CH3:36])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(C=O)cccc21
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(C=O)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(4-chlorophenyl)-2-(4-formyl-1H-indol-1-yl)acetate (2.34 g, 7.17 mmol) in THF (60 mL) and HMPA (15 mL) was added LiHMDS (1 M in THF, 11.0 mL, 11 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 30 min before adding iodoethane (1.23 g, 7.88 mmol). After stirring for another 30 min at 0° C., the mixture was diluted with EtOAc (120 mL) and then quenched with water (20 mL). The organic layer was separated and washed with brine (20 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified via column chromatography (0-15% EtOAc/hexanes) to provide the title compound.
Reaction SMILES: [C-:1]1([C:6]([CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12])=[O:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19]>C1(C)C=C(C)C=C(C)C=1.[Cl-].[Al+3].[Cl-].[Cl-]>[C:16]1([CH3:15])[CH:17]=[C:18]([CH3:14])[CH:5]=[C:1]([CH3:6])[C:2]=1[C:11]([CH2:10][CH2:9][CH2:8][C:6]([C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)=[O:7])=[O:12].[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Fe+2:19]
Reactant: O=C(Cl)CCCC(=O)[c-]1cccc1
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1cc(C)cc(C)c1
Product: Cc1cc(C)c(C(=O)CCCC(=O)[c-]2cccc2)c(C)c1
Reaction time: 0.67 h
Yield: 12.2 %

Procedure:
Ferrocenoylbutyrylchloride (obtained from above and assumed to be 40 m mole) was dissolved in mesitylene (150 ml) and aluminium chloride (5.34g; 40 m mole added). The mixture was stirred at 80° for 40 minutes. The tan-like material which was insoluble in mesitylene was separated, taken up in benzene, and washed with water, 2N HCl, saturated sodium bicarbonate and water, and dried (sodium sulphate) to yield a dark oil which was recrystallised from petroleum ether (bp 40°-60°) to yield 2.05g (12.2%) of pure mesitoylbutyryl ferrocene as a brown soild mp 75°-6°.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([OH:7])=O)[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:21][CH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[C:25](=[O:42])[N:26]([CH:34]1[CH2:39][CH2:38][C:37](=[O:40])[NH:36][C:35]1=[O:41])[C:27]([CH3:33])=[N:28]2>CN(C=O)C>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]([NH:21][CH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[C:25](=[O:42])[N:26]([CH:34]1[CH2:39][CH2:38][C:37](=[O:40])[NH:36][C:35]1=[O:41])[C:27]([CH3:33])=[N:28]2)=[O:7]
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: CN(C)CC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc(CNC(=O)CN(C)C)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a stirred solution of dimethylamino-acetic acid (0.27 g, 1.9 mmol) in DMF in a 40° C. oil bath (8 mL), was added 1,1′ carbonyldiimidazole (0.35 g, 2.1 mmol) and stirred for one hour. Then 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.65 g, 1.9 mmol) was added and stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 2-dimethylamino-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-acetamide as a light yellow solid (340 mg, 46% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 05/95 CH3CN/0.1% H3PO4, 7.29 min (99.8%); mp, 275° C. (decomposed); 1HNMR (DMSO-d6) 2.16-2.19 (m, 7H, CHH and NMe2), 2.63-2.91 (m, 8H, CHCH2, CH3 and NCH2), 4.74-4.76 (m, 2H, CH2NH), 5.25 (dd, J=6, 12 Hz, 1H, CH), 7.31-7.76 (m, 3H, Ar), 8.26 (t, J=6 Hz, 1H, CH2NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.68, 23.31, 30.59, 41.62, 45.54, 56.51, 62.81, 117.69, 125.53, 125.74, 133.96, 140.54, 148.52, 154.82, 161.03, 169.42, 169.63, 172.63. LCMS MH=386; Anal Calcd For C19H23N5O4: C, 59.21; H, 6.01; N, 18.17. Found: C, 58.95; H, 6.05; N, 17.79.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.COC(C1C=NC(OCC2C(C3C=CC(Cl)=CC=3)=NOC=2)=CN=1)=O>>[CH3:19][C:18]1[O:17][N:16]=[C:15]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)[C:14]=1[CH2:13][O:12][C:9]1[N:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccncn3)noc2C)nn1
Agent: COC(=O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Product: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)nn1
Yield: 92.2 %

Procedure:
As described for example 112a, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (616 mg, 1.8 mmol) was converted, instead of 5-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester, to the title compound (520 mg, 92%) which was obtained as a white solid. MS: m/e=312.3 [M−H]−.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:17][C@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([NH2:21])=[O:20])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)#[N:2].C([O-])([O-])=[O:27].[K+].[K+]>CO.OO>[NH2:21][C:19](=[O:20])[C@H:18]([NH:17][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)[C:3]([C:1]([NH2:2])=[O:27])=[N:4][CH:5]=1)[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(Nc2nc(N[C@H](CC(C)C)C(N)=O)cnc2C#N)c1
Agent: OO
Agent: [K+]
Solvent: CO
Product: Cc1cccc(Nc2nc(N[C@H](CC(C)C)C(N)=O)cnc2C(N)=O)c1

Procedure:
To a mixture of (R)-2-(5-cyano-6-(m-tolylamino)pyrazin-2-ylamino)-4-methylpentanamide in methanol (1 ml) was added K2CO3 (excess)) and H2O2 (50%, a few drops). After completion, it was concentrated and purified by preparative HPLC to give (R)-5-(1-amino-4-methyl-1-oxopentan-2-ylamino)-3-(m-tolylamino)pyrazine-2-carboxamide (6 mg). MS found for C18H24N6O2 as (M+H)+357.3, UV: λ=253.4, 304.5.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:23][C:24]1[CH:25]=[CH:26][C:27]([N+:31]([O-:33])=[O:32])=[C:28](O)[CH:29]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:26]1[CH:25]=[C:24]([F:23])[CH:29]=[CH:28][C:27]=1[N+:31]([O-:33])=[O:32])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethanol (4.2 ml) in tetrahydrofuran (65 ml) was added a solution of triphenylphosphine (13 g) and 5-fluoro-2-nitrophenol (10 g) in tetrahydrofuran (65 ml). To this solution was added diethyl azodicarboxylate (10 ml) under ice-cooling and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure and diisopropyl ether was added. The precipitated crystals were collected by filtration and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography (developing solvent; hexane:ethyl acetate=4:1) to give a yellow oil. To this oil was added ethyl acetate, washed with an aqueous sodium hydroxide solution, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (9.6 g) as a yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:8]2[C:9](=[O:26])[N:10]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:7]=2[N:6]([CH3:27])[C:5]=1[C:28]([NH:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:29].C(N(CC)CC)C.[C:45]([O:48][CH2:49][C:50](Cl)=[O:51])(=[O:47])[CH3:46]>C1COCC1.C(=O)([O-])O.[Na+]>[C:45]([O:48][CH2:49][C:50]([N:35]1[CH2:34][CH2:33][CH:32]([CH2:31][NH:30][C:28]([C:5]2[N:6]([CH3:27])[C:7]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]([CH2:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:9](=[O:26])[C:8]=3[C:4]=2[O:3][CH3:2])=[O:29])[CH2:37][CH2:36]1)=[O:51])(=[O:47])[CH3:46]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1c(C(=O)NCC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(C(=O)NCC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of the compound of Example 542 (400 mg, 0.76 mmol) and triethylamine (0.29 mL, 2.1 mmol) in THF (17 mL) was added acetoxyacetyl chloride (0.10 mL, 0.95 mmol) under ice-cooling, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was combined, washed with saturated brine, dried over magnesium sulfate, and filtered through aminosilica gel. The filtrate was concentrated, and the residue was recrystallized from ethanol-hexane to give the title compound (321 mg, 71%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][OH:15])[CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][OH:15])[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(CCO)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(N)cc(CCO)c1

Procedure:
3,5-Dinitro-(2-hydroxyethyl)benzene (0.18 g, 0.85 mmol) was dissolved in methanol (50 ml) and hydrogenated over Pd/c (10%) in a Parr apparatus at 60 psi. After complete hydrogen uptake the catalyst was filtered off and the solvent was evaporated which gave a solid residue of 0.10 g (81%).
Reaction SMILES: I[C:2]12[CH2:6][C:4]([CH3:7])([CH2:5]1)[CH2:3]2.C([Li])(C)(C)C.[C:13](=[O:15])=[O:14]>C(OCC)C>[CH3:7][C:4]12[CH2:6][C:2]([C:13]([OH:15])=[O:14])([CH2:5]1)[CH2:3]2
Reactant: O=C=O
Reactant: CC12CC(I)(C1)C2
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC12CC(C(=O)O)(C1)C2
Temperature: 25 °C
Yield: 50.9 %

Procedure:
To a solution of 1-iodo-3-methylbicyclo[1.1.1]pentane (1.62 g, 7.79 mmol; prepared according to Eur. J. Org. Chem. 1137-1155 (2000)) in diethyl ether (26 mL), a solution of tert-butyllithium (9.16 mL, 15.57 mmol, 1.7 M in pentane) was added over a period of 40 min at −78° C. After stirring the reaction mixture for 1 h at this temperature, carbon dioxide gas was bubbled through the reaction mixture for 5 min and then the mixture was allowed to warm to room temperature. The reaction mixture was extracted twice with a 5% aqueous sodium bicarbonate solution. The combined aqueous phases were acidified to pH 2-3 with concentrated hydrochloric acid at 0° C., saturated with sodium chloride, and extracted with diethyl ether. The combined organic phases were dried and, after evaporation of the solvent under reduced pressure, purified by column chromatography (0-20% ethyl acetate in hexanes) to afford 3-methylbicyclo[1.1.1]pentane-1-carboxylic acid (0.5 g, 3.96 mmol, 50.9% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.21 (s, 1H), 1.82 (s, 6H), 1.14 (s, 3H).
Reaction SMILES: Br.Br.[CH2:3]([NH:6][CH:7]1[CH2:16][CH2:15][C:10]2[N:11]=[C:12](N)[S:13][C:9]=2[CH2:8]1)[CH2:4][CH3:5].N([O-])=O.P(P(O)(O)=O)(O)(O)=O.[OH-].[Na+]>Cl>[CH2:3]([NH:6][CH:7]1[CH2:16][CH2:15][C:10]2[N:11]=[CH:12][S:13][C:9]=2[CH2:8]1)[CH2:4][CH3:5]
Reactant: CCCNC1CCc2nc(N)sc2C1
Agent: Br
Agent: Cl
Agent: O=N[O-]
Product: CCCNC1CCc2ncsc2C1
Temperature: -30 °C
Reaction time: 8 h

Procedure:
To a solution of 14.5 g (38.9 mmol) N6-propyl-4,5,6,7-tetrahydro-benzothiazole-2,6-diamine dihydrobromide in 220 mL concentrated aqueous hydrochloric acid at −30° C. is drop wise added 66.3 mL of an aqueous 1N solution nitrite over the course of 30 minutes. After further stirring for 1 hour at the same temperature 5.44 ml (52.5 mmol) of a 50% aqueous solution hypophosphoric acid is added. The reaction mixture is stored at 4° C. overnight. After having cooled down the solution again to −30° C. the mixture is slowly basified with 40% aqueous sodium hydroxide solution while temperature is kept at −30° C. The resulting mixture is warmed up to room temperature and extracted with chloroform/ethanol 5:1 (3×250 mL). The solution is dried over anhydrous sodium sulfate and concentrated in vacuum. The brown oil obtained is chromatographically purified over silica gel, eluting with dichloromethane/methanol 97:3 under ammonia atmosphere.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide to yield a white solid (20%). LCMS: m/z=495.23 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.87 (d, 3H, J=0.76 Hz), 7.66 (bs, 1H), 7.51 (m, 2H), 7.27 (m, 1H), 7.13 (m, 1H), 6.30 (m, 2H), 6.17 (bs, 1H), 5.97 (bs, 1H), 4.33 (t, 1H, J=8.1 Hz), 3.81 (m, 2H), 3.06 (s, 1H), 2.89 (s, 1H), 2.51 (d, 1H, J=8.1 Hz), 2.27 (m, 3H), 2.03 (m, 2H), 1.62 (d, 1H, J=8.9 Hz), 1.30 (m, 9H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([CH3:16])[C:5]=1[OH:17].Cl[C:19]1[N:24]=[C:23]([Cl:25])[N:22]=[C:21]2[NH:26][N:27]=[CH:28][C:20]=12>>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:7]=[C:6]([CH3:16])[C:5]=1[O:17][C:19]1[N:24]=[C:23]([Cl:25])[N:22]=[C:21]2[NH:26][N:27]=[CH:28][C:20]=12
Reactant: Clc1nc(Cl)c2cn[nH]c2n1
Reactant: Cc1cc(-c2ccncc2)cc(C)c1O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(-c2ccncc2)cc(C)c1Oc1nc(Cl)nc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.2 eq) is added to 2,6-dimethyl-4-(pyridin-4-yl)phenol (prepared according to literature procedures, see Combellas et al., Tetrahedron Letters, 1992, 33, 4923) (1.2 eq) in 1-methyl-2-pyrridone (2 ml/mmol) at 0° C. The reaction mixture is stirred at room temperature for 30 min and a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (1 eq) in 1-methyl-2-pyrridone (1 ml/mmol) is added. The resulting mixture is heated to 100° C. for 16 h, cooled to room temperature, poured into ice water and extracted with CHCl3 (×3). The combined organic layers are washed with water and brine, dried (Na2SO4), concentrated to dryness and purified by silica gel chromatography.
Reaction SMILES: [C:1]1(=[O:13])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[O-]CC.[Na+]>C(O)C>[C:14]([CH:2]1[C:3]2[C:12]3[C:7]([CH:6]=[CH:5][CH:4]=2)=[CH:8][CH:9]=[CH:10][C:11]=3[C:1]1=[O:13])([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:20]
Reactant: O=C1Cc2cccc3cccc1c23
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)C1C(=O)c2cccc3cccc1c23

Procedure:
Acenaphthen-1-one (JACS, 62, 432, 1940) (4.1 g) is reacted with diethyl oxalate (4.2 g) in anhydrous ethanol (280 ml) containing sodium ethoxide (from 0.66 g of sodium) at room temperature for 2 hours. The precipitate is filtered and washed with hexane, then is dissolved in water. The aqueous solution is acidified to pH 4 with citric acid and the precipitate is filtered and washed with water. Crystallization from chloroform-hexane gives 2-ethoxalylacenaphthen-1-one, m.p. 101°-103° C. (5.1 g), which is reacted with methylhydrazide (1.3 g) in acetic acid (110 ml) at 60° C. for 4 hours. After cooling the reaction mixture is diluted with ice water and extracted with ethyl acetate.
Reaction SMILES: Cl[C:2]([C:11]1[S:12][CH:13]=[C:14]([CH3:17])[C:15]=1[Cl:16])=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[CH3:19][NH:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23].C(N(CC)CC)C>C(#N)C>[Cl:16][C:15]1[C:14]([CH3:17])=[CH:13][S:12][C:11]=1/[C:2](/[NH:23][C@H:22]([CH3:24])[C:21]([NH:20][CH3:19])=[O:25])=[C:3](\[C:9]#[N:10])/[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CNC(=O)[C@H](C)N
Reactant: CCOC(=O)C(C#N)=C(Cl)c1scc(C)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)/C(C#N)=C(\N[C@H](C)C(=O)NC)c1scc(C)c1Cl
Yield: 60.4 %

Procedure:
To a solution of ethyl 3-chloro-3-(3-chloro-4-methyl-2-thienyl)-2-cyanoacrylate (0.351 g, 1.21 mmol, 1 eq.) in 3 ml of acetonitrile was added N-methyl-L-alaninamide hydrochloride (0.201 g, 1.45 mmol, 1.2 eq.) followed by triethylamine (TEA) (0.490 g, 4.84 mmol, 4 eq.). The reaction was microwaved (130° C., 300 s, fixed hold, high absorption) and the solvent evaporated. The residual oil was triturated in ethyl acetate and the white solid removed by filtration. After concentration under vacuum, the residual oil was subjected to column chromatography to give ethyl (2Z)-3-(3-chloro-4-methyl-2-thienyl)-2-cyano-3-{[(2R)-1-(methylamino)-1-oxopropan-2-yl]amino}acrylate (0.26 g, 57% yield) as a mixture of atropoisomers.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:44][C:45]([OH:48])([CH3:47])[CH3:46])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([C:17](N(OC)C)=[O:18])=[CH:12][C:11]=3[N:10]=[C:9]([NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:8]=2[N:43]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+].O>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:44][C:45]([OH:48])([CH3:47])[CH3:46])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([CH:17]=[O:18])=[CH:12][C:11]=3[N:10]=[C:9]([NH:23][C:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:8]=2[N:43]=1)[CH3:2]
Reactant: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(C(=O)N(C)OC)ccc3c2n1CC(C)(C)O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(C=O)ccc3c2n1CC(C)(C)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.7 %

Procedure:
To a solution of 2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-N-methoxy-N-methyl-4-(tritylamino)-1H-imidazo[4,5-c]quinoline-7-carboxamide (520 mg, 808 μmol) in THF (7 mL) in an inert atmosphere was added with stirring at 0° C. a solution of lithium aluminum hydride in THF (1 M, 404 μl, 404 μmol). The mixture was stirred 1 h at 0° C., saturated ammonium chloride solution (10 mL) was added slowly and finally water (20 mL) and ethyl acetate (30 mL) were added. The phases were separated, the water layer was extracted with ethyl acetate (30 mL), and the organic phases were washed with water (20 mL), combined, dried with MgSO4, and concentrated in vacuo to give the title compound (0.49 g, quant.) as white foam (LC-MS (UV peak area, ESI) 83%, 585.4 (MH+)) that was used in the next step without further purification.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C@@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][CH:60]1[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C@@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:59][CH:60]5[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: C=C[C@]1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C=C[C@]1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from (S)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 4-amino 1-N-methyl piperidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.93 (m, 2 H) 1.18-1.31 (m, 2 H) 1.50-1.80 (m, 6 H) 1.83-2.00 (m, 4 H) 2.17 (s, 3 H) 2.71-2.95 (m, 2 H) 3.29 (s, 3 H) 3.67-3.87 (m, 3 H) 3.94 (s, 3 H) 4.89 (d, J=8.59 Hz, 1 H) 5.30-5.47 (m, 2 H) 6.01 (ddd, J=17.49, 12.69, 10.74 Hz, 1 H) 7.41-7.54 (m, 2 H) 7.82 (s, 1 H) 8.12 (s, 2 H) 8.30 (d, J=8.34 Hz, 1 H) [M+H] calc'd for C29H38FN7O3, 552; found 552.