Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Br[C:34]1C=CC(C(OCC)=O)=C[CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:19]=[C:20]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([O:32][CH2:34][CH3:35])=[O:31])=[CH:28][CH:29]=4)[CH:21]=[CH:22][CH:23]=3)[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCO
Product: CCOC(=O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of NAPHTHYRIDINONE 3 (1 eq), ethyl 4-bromobenzoate (3 eq), Na2CO3 (3.5eq.; 2M in H2O), Pd(PPh3)4 (0.15eq.) in n-propanol-DMF (1:1, 0.1M) was stirred at 80° C. for 2 h. The mixture was cooled to rt, quenched with brine and diluted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was triturated in ether/EtOAc and then isolated by filtration to afford the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([OH:22])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][S:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[C:38]([OH:45])[C:37]=1[CH2:46][CH2:47][CH3:48]>CC(C)=O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:32][CH2:33][CH2:34][S:35][C:36]2[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[C:38]([OH:45])[C:37]=2[CH2:46][CH2:47][CH3:48])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(O)ccc(C(C)=O)c1OCCCC(=O)OCC
Reactant: CCCc1c(SCCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(SCCCOc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
To a stirred mixture of ethyl 4-(6-acetyl-3-hydroxy-2-propylphenoxy)butyrate (1.6 g), potassium iodide (0.5 g) and potassium carbonate (1.45 g) in acetone (30 ml) was added drop wise a solution of 4-(3-bromopropylthio)-2-hydroxy-3-propylphenyl-ethanone (1.9 g) in acetone (10 ml) with heating to reflux. After refluxing six hours the mixture was cooled to room temperature and inorganic materials were separated by filtration. The filtrate was concentrated and the residue was separated and purified by silica-gel column chromatography (eluting with benzene:ethyl acetate=9:1) to give the title compound as crude crystals (2.1 g, 72.4%) which were recrystallized from ethanol to give colorless crystals, mp 65-66° C.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][S:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1.[I:22]N1C(=O)CCC1=O.O>CN(C)C=O>[I:22][C:18]1[O:17][C:16]([S:15][CH2:14][C:5]2[C:6]([C:10]([F:12])([F:13])[F:11])=[N:7][N:8]([CH3:9])[C:4]=2[O:3][CH:2]([F:1])[F:21])=[N:20][CH:19]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1nc(C(F)(F)F)c(CSc2ncco2)c1OC(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)c(CSc2ncc(I)o2)c1OC(F)F

Procedure:
2-({[5-(Difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfanyl)-1,3-oxazole (0.700 g, 2 mmol) is initially charged in 10 ml of dimethylformamide. N-Iodosuccinimide (0.750 g, 3.3 mmol) is then added a little at a time with stirring. The mixture is stirred at 40° C. for a further 16 hours. For work-up, the reaction mixture is added to water and extracted twice with dichloromethane, and the extracts are then washed with water and finally with saturated NaCl solution. The combined organic phases are dried over magnesium sulfate, filtered off and concentrated. The crude product is purified chromatographically (heptane:ethyl acetate, gradient 10:0 to 8:2). This gives 0.25 g of product (24.5% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH2:20])[N:3]=1.[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[O:13][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:4]([NH2:20])[N:3]=1
Reactant: CCCCCCCCCBr
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Yield: 39.4 %

Procedure:
2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) was treated with sodium hydride (8.8 g, 220 mmol) and bromononane (59 g, 54.4 ml, 285 mmol) in DMF (700 ml) as per the procedure of Example 2 (the diamino compound in DMF was cooled in an ice bath during the addition of NaH) to yield 83 g of crude product. 50 g of crude product was purified by silica gel chromatography. Fraction containing 2'-O-nonyl and 3'-O-nonyl product were combined to give a 77:23 mixture (29 g) of the 2' and 3' product. Pure 2'-O-nonyl product is obtained by chromatography. 1H NMR (DMSO-d6) δ 0.95 (t, 3, CH3); 1.17 [m, 12, O--CH2 --CH2 --(CH2)6 ]; 1.42 [m, 2, O--CH2CH2 (CH2)6 ]; 3.27-3.70 (m, 2, H-5'); 3.50-3.70 [m, 2, O--CH2 (CH2)7 ]; 3.95 (m, 1, H-4'), 4.24 (m, 1, H-3'); 4.40 (m, 1, H-2'); 5.10 (d, 1, 3'-OH, J=5 Hz); 5.50 (t, 1, 5'-OH, J=6 Hz); 5.76 (s, 2, 2-NH2); 5.83 (d, 1, H-1', J=6.0 Hz); 6.81 (s, 2, 6-NH2); and 7.96 (s, 1, 8-H).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C@@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][OH:11])=[O:7])=[C:4]([F:20])[CH:3]=1.[NH2:21][C:22]1[N:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)=[CH:24][C:23]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C>[NH2:21][C:22]1[C:23]([C:2]2[CH:19]=[CH:18][C:5]([C:6]([NH:8][C@@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][OH:11])=[O:7])=[C:4]([F:20])[CH:3]=2)=[CH:24][C:25]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:26][N:27]=1
Reactant: O=C(N[C@H](CO)c1ccccc1)c1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(N)c(B3OC(C)(C)C(C)(C)O3)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1ncc(C2CCNCC2)cc1-c1ccc(C(=O)N[C@H](CO)c2ccccc2)c(F)c1
Temperature: 120 °C
Yield: 20.9 %

Procedure:
To a suspension of (S)-4-bromo-2-fluoro-N-(2-hydroxy-1-phenylethyl)benzamide (67.1 mg, 0.20 mmol) in DME (5 mL) was added tert-butyl 4-(6-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperidine-1-carboxylate (40 mg, 0.099 mmol) and sodium carbonate (0.24 mL, 0.49 mmol). The mixture was purged with nitrogen for 10 min, then PdCl2(dppf)-CH2Cl2Adduct (12.15 mg, 0.015 mmol) was added. The reaction mixture was heated to 120° C. in an oil bath for 3 h. The reaction mixture was diluted with ethyl acetate. The organic solution was washed with water, brine, dried over sodium sulfate and concentrated. The resulting residue was treated with 30% TFA in DCM (20 mL) for 15 min. The reaction mixture was concentrated and the crude product was purified by HPLC to give (S)-4-(2-amino-5-(piperidin-4-yl)pyridin-3-yl)-2-fluoro-N-(2-hydroxy-1-phenylethyl)benzamide (9 mg, 20.8%) as TFA salt. LCMS (m/z): 435 (MH+), 0.44 min; 1H NMR (300 MHz, CD3OD) δ ppm 8.63 (br. s., 1H) 7.90 (t, J=7.77 Hz, 1H) 7.84 (s, 2H) 7.47-7.24 (m, 7H), 5.27-5.17 (m, 1H) 3.93-3.79 (m, 2H) 3.52 (d, J=12.60 Hz, 2H) 3.21-3.05 (m, 2H) 2.96 (t, J=12.31 Hz, 1H) 2.15 (d, J=14.07 Hz, 2H) 1.96-1.78 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[CH:11][C:10]=2[C:17]([F:20])([F:19])[F:18])=[O:5])[CH3:2].C1(C)C=CC=CC=1.O=P(Cl)(Cl)[Cl:30].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:30])=[CH:13][CH:12]=[CH:11][C:10]=2[C:17]([F:20])([F:19])[F:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1Cl
Temperature: 0 °C

Procedure:
4-Hydroxy-8-(trifluoromethyl)-3-quinolinecarboxylic acid ethyl ester (compound of formula (V)), 11.27 g, 39.55 mmol) was taken into toluene (125 mL), then POCl3 (7.4 mL, 79.08 mmol) was added and the mixture was refluxed for 1.5 hours. The reaction was carefully poured into ice-water with vigorous stirring, then added carefully added saturated NaHCO3 until the solution was neutral. Dilute with ethyl acetate and separate the layers. The organic layer was dried over MgSO4, filtered and concentrated. The resulting material was passed through a short silica gel plug using 10% ethyl acetate in hexane. Concentration and drying under high vacuum yielded 9.93 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](O)=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22].C(N1C=CN=C1)([N:25]1C=CN=C1)=O.C(=O)=O.N>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:25])=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Agent: N
Agent: O=C=O
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
40 g (124 mmol) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid were suspended in 190 ml of N,N-dimethylformamide and treated portionwise at room temperature with 21 g (129.5 mmol) of 1,1'-carbonyldiimidazole. After completion of the CO2 evolution the clear brown solution was stirred at 50° for 30 min., cooled and treated dropwise with 30 ml of conc. ammonia at a temperature below 25° within about 10 min. After stirring for 30 minutes the suspension obtained was poured into 700 ml of ice-water, stirred at room temperature for 30 min. and filtered, whereupon the crystals were rinsed with a small amount of water. After drying there were obtained 31.36 g (78%) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide of m.p. 296°-298°.
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[Na+].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[NH2:30][C:31]1[S:32][CH:33]=[C:34]([O:38][CH2:39][CH3:40])[C:35]=1[C:36]#[N:37]>O>[C:1]([NH:30][C:31]1[S:32][CH:33]=[C:34]([O:38][CH2:39][CH3:40])[C:35]=1[C:36]#[N:37])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOc1csc(N)c1C#N
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [Na+]
Solvent: O
Product: CCOc1csc(NC(C)=O)c1C#N

Procedure:
100 parts of anhydrous sodium acetate are introduced into 400 parts by volume of acetic anhydrice, 168 parts of 2-amino-3-cyano-4-ethoxythiophene are added and the mixture is refluxed for 4 hours. Thereafter, 800 parts of water are added dropwise to the hot mixture, the mixture is left to cool and the product is filtered off under suction, washed with water and dried to give 194 parts of 2-acetylamino-3-cyano-4-ethoxythiophene of melting point 242°-243° C. (from acetic acid).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([O:23]C)=[O:22])(=[O:14])=[O:13].[OH-].[Li+]>O1CCCC1.CO>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([OH:23])=[O:22])(=[O:14])=[O:13]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1Br
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1Br
Temperature: 77.5 °C
Yield: 34.6 %

Procedure:
To a solution of 97 (330.0 mg; 0.74 mmol) in tetrahydrofuran (8 mL) and methanol (2 mL) was added aqueous lithium hydroxide (4 mL; 2M). The reaction mixture was heated at 75-80° C. for 6 hours, allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL; 2N). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to afford the title compound as a white solid (110 mg).
Reaction SMILES: [S:1]1[C:5]([CH:6]([NH:8][C:9]2[C:10]([CH3:21])=[N:11][O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH3:7])=[CH:4][C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2.[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:17]3[CH:18]=[CH:19][C:14]([C:13]4[O:12][N:11]=[C:10]([CH3:21])[C:9]=4[NH:8][CH:6]([C:5]4[S:1][C:2]5[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=5[CH:4]=4)[CH3:7])=[CH:15][CH:16]=3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)c1cc2ccccc2s1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)c4cc5ccccc5s4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using (1-benzo[b]thiophen-2-yl-ethyl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][OH:17])[N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[CH:21]=[C:22](O)[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27]>>[C:1]([O:5][C:6](=[O:18])[N:7]([CH3:8])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][O:17][C:22]2[CH:23]=[CH:24][C:25]([N+:26]([O-:28])=[O:27])=[C:20]([CH3:19])[CH:21]=2)[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(CCO)n1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Product: Cc1cc(OCCc2cccc(N(C)C(=O)OC(C)(C)C)n2)ccc1[N+](=O)[O-]
Yield: 81 %

Procedure:
The title compound was synthesized from [6-(2-hydroxy-ethyl)-pyridin-2-yl]-methyl-carbamic acid tert-butyl ester and the commercially available 3-methyl-4-nitro-phenol using the procedure described in Example 16, step (b), in 81% yield. 1H NMR (Cl3CD), δ: 1.52 (s, 9H), 2.62 (s, 3H), 3.21 (t, 2H, J=8.00 Hz), 3.36 (s, 3H), 4.44 (t, 2H, J=8.00 Hz), 6.80 (m, 2H), 6.94 (dd, 1H, J=2.4, 5.6 Hz), 7.55 (m, 2H), 8.05 (d, 1H, J=8.8 Hz).
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.[C:49]([OH:55])(=O)[CH2:50][CH:51]([CH3:53])[CH3:52]>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][N:46]([C:49](=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:47][CH2:48]1)[CH2:4][CH2:3]2
Reactant: CC(C)CC(=O)O
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)CC(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound (3.3 mg) was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure as described above using isovaleric acid as the acylating agent. LCMS: m/e 726.8 (M+H)+, 3.71 min (method 14). 1H NMR (500 MHz, METHANOL-d4) δ 7.89 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 5.30 (d, J=4.9 Hz, 1H), 4.79 (s, 1H), 4.69 (s, 1H), 3.77-3.55 (m, 4H), 3.09-3.02 (m, 1H), 2.91 (br. s., 1H), 2.86-2.72 (m, 2H), 2.71-2.60 (m, 3H), 2.59-2.52 (m, 1H), 2.52-2.43 (m, 1H), 2.31 (d, J=7.3 Hz, 2H), 2.21-1.80 (m, 7H), 1.76 (s, 3H), 1.73-1.08 (m, 16H), 1.22 (s, 3H), 1.11 (s, 3H), 1.05 (s, 3H), 0.99 (d, J=6.4 Hz, 6H), 0.97 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([CH3:15])[CH:8]=1)=O.Cl.[NH:20]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][N:23]=1)[NH2:21]>C(O)C>[CH3:15][C:9]1[CH:8]=[C:7]([C:5]2[N:20]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][N:23]=3)[N:21]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Reactant: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)cn2)cc1C
Temperature: 25 °C
Yield: 43.3 %

Procedure:
4,4,4-Trifluoro-1-(3-methyl-4-methoxylphenyl)-1,3-butanedione (0.78 g, 3 mmol) and 2-hydrazino-5-(methylsulfonyl)pyridine hydrochloride (0.671 g, 3 mmol) were mixed in ethanol (60 ml), and the resulting reaction mixture was heated at reflux temperature for 72 hours. The reaction mixture was then cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in EtOAc (250 ml), and the organic layer was washed with saturated NaHCO3 solution, brine, dried (MgSO4), and concentrated in vacuo. The residue was purified first by flash chromatography using 40% hexane in methylene chloride to and then by recrystallization from 3:1 of isooctane:methylene chloride to give the title compound (535 mg, 43%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:18]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:1][C:2]2[C:3]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=3)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=2)=[O:27])=[CH:29][CH:30]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1nccnc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(C(=O)Nc2nccnc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 55 °C
Reaction time: 36 h

Procedure:
To a mixture of the above 3-amino-N-(5-chloropyridin-2-yl)pyrazine-2-carboxamide (255 mg, 1 mmol) in pyridine (20 mL) was added 4-tert-butylbenzoyl chloride (402 mg, 86 mmol). The mixture was stirred for 36 hours at 55° C. It was cooled to room temperature then concentrated to dryness in vacuo. The residue was mixed with CH2Cl2 and purified by radial chromatography from which was recovered 85 mg (21%) of product.
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[O:24][C:23]([C:25]([NH:27][C:28]2[CH:29]=[N:30][C:31]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[CH:32][CH:33]=2)=[O:26])=[N:22][N:21]=1.[C:40](O)(=[O:43])[CH2:41][OH:42].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[O:24][C:23]([C:25]([NH:27][C:28]2[CH:29]=[N:30][C:31]([N:34]3[CH2:39][CH2:38][N:37]([C:41](=[O:42])[CH2:40][OH:43])[CH2:36][CH2:35]3)=[CH:32][CH:33]=2)=[O:26])=[N:22][N:21]=1
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nnc(Nc2ccccc2F)o1
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCN(C(=O)CO)CC2)nc1)c1nnc(Nc2ccccc2F)o1
Reaction time: 16 h
Yield: 65 %

Procedure:
EDAC (60 mg, 0.31 mmol) was added to a stirred mixture of 5-[(2-fluorophenyl)amino]-N-(6-piperazin-1-ylpyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide (Intermediate 41, 100 mg, 0.26 mmol), glycolic acid (20 mg (0.26 mmol) and HOBt (42 mg, 0.31 mmol) in 3 mL of DMF and stirring was continued for 16 h. Water (10 mL) was added and the resultant precipitate was collected by filtration, washed with water then ether and dried in vacuo to give the title compound (75 mg, 65%) as a solid; 1H NMR δ 10.94 (1H, s), 10.70 (1H, s), 8.50 (1H, s), 8.05 (1H, t), 7.90 (1H, d), 7.35-7.20 (2H, m), 7.20-7.10 (1H, m), 6.90 (1H, d), 4.60 (1H, t), 4.10 (2H, d), 3.60-3.4 (8H, m); MS m/e MH+ 442.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:2].O.[CH2:13]1[CH2:17]OC[CH2:14]1>C(OCC)C.[Ti]>[CH2:14]=[CH:13][CH2:17][C@@H:1]([OH:2])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C1CCOC1
Reactant: CCCCCCCCCC=O
Agent: [Ti]
Solvent: O
Solvent: CCOCC
Product: C=CC[C@@H](O)CCCCCCCCC
Temperature: -74 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A solution of 1.25 mmol of the titanium compound of Example 2b in 60 ml of diethyl ether is cooled to -74° C. and 0.19 ml (0.1 mmol) of freshly distilled capraldehyde is added. The slightly yellow, clear solution is stirred for a further 2 hours at -74° C. and 5 ml of a 5N H2O/THF solution are added and the mixture is warmed to RT, stirred for a further hour at this temperature, filtered with suction and evaporated on a rotary evaporator. The crude product (1.13 g of clear, colourless oil) is flash-chromatographed (60 g of silica gel, 35 cm long, cross-section 2 cm, 5 ml/fraction, 0.4 bar, 10:1 toluene/ethanol) and is then distilled in a bulb tube (b.p.: ≈120-130 at 0.104 mbar). 0.141 g of product is obtained. Yield: 71%, ee: 95%.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][CH2:10][CH3:11])[CH2:7][C:6](=O)[NH:5][C:3]1=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:1][C:2]1([CH2:9][CH2:10][CH3:11])[CH2:7][CH2:6][NH:5][CH2:3]1
Reactant: CCCC1(C)CC(=O)NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC1(C)CCNC1
Reaction time: 0.08 h
Yield: 62.9 %

Procedure:
α-Methyl-α-propyl-succinimide (310 mg, 2 mmol) was dissolved in THF and to the solution was added 84 mg LiAlH4 (2.2 mmol) in three small portions. The reaction was proceeded at 0° C. for 5 min, then room temp for 2 h. Cold water was added to quench the reduction. The solution was filtered through celite. The filtrates were combined and evaporated under vacuum. The product (160 mg, Yield 63%) was ready for use.