Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:21]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH2:21])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
The crude material 18a (3.0 g, 8.0 mmol) was dissolved in ethanol (20 mL) and 300 mg of 10% Pd/C was added. The system was evacuated under vacuum and placed under 1 atm of hydrogen gas via balloon with vigorous stirring, and repeated 4 times to ensure a pure hydrogen atmosphere. The reaction was then stirred overnight at room temperature. TLC showed that the reaction was complete after 16 hrs. The crude reaction was passed through a short pad of celite rinsing with ethyl acetate. The solvent was removed and the amine purified on silica gel using a mixture of 15% methanol and 2.5% triethylamine in methylene chloride as the eluant to give 2.3 g (85% yield) of the desired amine 19a (FIG. 8). 1H NMR: 1.36 (s, 9H), 2.27 (br s., 2H), 2.42 (t, 2H, J=6.4 Hz), 2.80 (t, 2H, J=5.2 Hz), 3.45 (d, 2H, J=5.2 Hz), 3.51-3.59 (m, 12H), 3.63 (d, 2H, J=6.4 Hz). MS: m/z Calculated: 322.21, Found: 321.97.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.NCC1C=NC(CCC(C)(C)C)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:15][C:12]([F:13])([F:14])[C:11]([N:8]1[CH2:7][CH2:6][C:5]2[CH:17]=[CH:18][CH:2]=[CH:3][C:4]=2[CH2:10][CH2:9]1)=[O:16]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)CCc1ccc(CN)cn1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccccc2CC1)C(F)(F)F
Temperature: 100 °C
Yield: 157.1 %

Procedure:
Use a method similar to the General Procedure 5-2 to react 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (166 mg, 0.39 mmol), tris(dibenzylideneacetone)dipalladium(0) (71 mg, 0.078 mmol), BINAP (103 mg, 0.156 mmol), 3-aminomethyl-6-(3,3-dimethyl-butyl)-pyridine (150 mg, 0.78 mmol) and cesium carbonate (178 mg, 0.546 mmol) in degassed toluene (20 mL). Degas the mixture with vacuum/nitrogen purge and heat to 100° C. for 14 h. Cool the mixture to room temperature, dilute with EtOAc and filter through Celite®. Purify the crude mixture by chromatography on silica gel eluting with hexane and then hexane/EtOAc (19:1, 9:1 and 4:1) to obtain 7-chloro-6,6-(3,3-dimethyl-butyl)-pyridin-3-yl-methylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (149 mg, 82%). MS (ES+) m/z: 468 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:10]([NH:22][C:23]2[N:28]=[C:27](SC#N)[C:26]([N+:32]([O-:34])=[O:33])=[CH:25][N:24]=2)[CH:9]=1.[OH:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH2:42])[CH2:38][CH2:37]1>C(#N)C.C(Cl)Cl>[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[C:10]([NH:22][C:23]2[N:28]=[C:27]([NH:42][C@H:39]3[CH2:40][CH2:41][C@H:36]([OH:35])[CH2:37][CH2:38]3)[C:26]([N+:32]([O-:34])=[O:33])=[CH:25][N:24]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@H]2CC[C@H](O)CC2)n1
Reaction time: 16 h

Procedure:
Potassium carbonate (105 mg) was added to a stirred mixture of tert-butyl 4-fluoro-2-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)phenyl-carbamate (101 mg) in acetonitrile (5 ml) followed by the addition of trans-4-hydroxycyclohexylamine (44 mg). The reaction mixture was stirred for 16 hours, then diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide 110 mg of the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:59][C:60]1[CH:61]=[C:62](B(O)O)[CH:63]=[CH:64][C:65]=1[O:66][CH3:67]>>[F:59][C:60]1[CH:61]=[C:62]([C:2]2[C:3](=[O:32])[C:4]3[C:9]([C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH2:27]2)[CH:5]=3)[CH:63]=[CH:64][C:65]=1[O:66][CH3:67]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(F)cc2F)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1F
Yield: 68 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}-1H-inden-1-one obtained in Step 1 of Example 116 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 3-fluoro-4-methoxyphenylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (68%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:23][CH:24]1[CH2:26][CH2:25]1)[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:23][CH:24]1[CH2:26][CH2:25]1)(=[O:21])[NH2:22]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)CC1CC1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and (S)-α-amino-cyclopropanepropanamide (CAN 156077-93-9) as starting materials, and isolated (22 mg, 30%) as light yellow oil; LC-MS (UV peak area, ESI) 100%, 345.1929 (M+H).
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[C:25]([O:32][CH3:33])[CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[C:25]([O:32][CH3:33])[CH:24]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Reactant: CCOc1ccc(C(N)CC(=O)O)cc1OC
Product: CCOc1ccc(C(N)CC(=O)OC)cc1OC

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)propionic acid was substituted with 3-amino-3-(3-methoxy-4-ethoxy-phenyl)propionic acid. 1H NMR (CDCl3): δ 6.79-6.90 (m, 3H), 4.37 (q, 1H, J=5 Hz), 4.06 (q, 2H, J=5 Hz), 3.86 (s, 3H), 3.67 (s, 3H), 2.63 (d, 2H, J=5 Hz), 1.80 (s, 2H), 1.43 (t, 3H, J=5 Hz).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[N:17]1[CH2:21][CH:20]([CH3:22])[CH2:19][C:18]1=[O:23])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[N:17]1[CH2:21][CH:20]([CH3:22])[CH2:19][C:18]1=[O:23]
Reactant: CC1CC(=O)N([C@@H]2CCCC[C@H]2NC(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1CC(=O)N([C@@H]2CCCC[C@H]2N)C1

Procedure:
To a solution of trans-[2-(4-methyl-2-oxo-pyrrolidin-1-yl)-cydohexyl]-carbamic acid benzyl ester (34 mg) in absolute ethanol (4.0 ml) was added 10% Pd on charcoal (5 mg). A hydrogen atmosphere was introduced by repeated evacuation/gas introduction. The suspension was vigorously stirred over night. The catalyst was removed by filtration through dicalite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2/MeOH/NH3 93/7/0.5) to give the product as a 1:1 mixture of epimers as a colorless liquid (15 mg). MS (ESI): 197.3 (M+H+).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:23])[C:8]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl>>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:23])[C:8]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc2n1C
Solvent: ClCCl
Product: COC(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)O)cc2n1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.9 %

Procedure:
To a solution of tert-butyl 3-cyclohexyl-2-(2-(2-methoxy-2-oxoethoxy)phenyl)-1-methyl-1H-indole-6-carboxylate 26 (0.7 g, 1.46 mmol), in dichloromethane 50 mL tri-fluoro-acetic acid (4.2 g, 36.6 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. The solvent was removed then the residue was purified by column chromatography using dichloromethane/methanol to yield 0.59 g (96%) of 3-cyclohexyl-2-[2-(2-methoxy-2-oxoethoxy)phenyl]-1-methyl-1H-indole-6-carboxylic acid 27: m/z=422 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH2:15]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH:15][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1]
Reactant: NCc1cccc(Cl)c1
Reactant: COC(=O)C(OC)OC
Product: COC(OC)C(=O)NCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Into a vial were added methyl dimethoxyacetate (1.9 g, 14 mmol) and 3-chlorobenzylamine (2.0 g, 14 mmol), this mixture was stirred at room temperature over two days. The product was triturated with hexane (3×) and re-crystallized from hexane, affording the desired product as oil that solidified over time. 1H NMR (400 MHz, CDCl3): δ=3.43 (s, 6H), 4.47 (d, J=6.1 Hz, 2H), 4.77 (s, 1H), 6.91 (br. s., 1H), 7.15-7.21 (m, 1H), 7.25-7.30 (m, 3H). MS (ES+): m/z=243.93/245.81 [MH+]. HPLC: tR=2.80 min (ZQ2, polar—5 min).
Reaction SMILES: NCCC(O)=O.[NH:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH:12]=O.[C:14]([CH2:16][C:17]([NH:19][CH:20]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][O:32][CH3:33])=[CH:26][CH:25]=1)[CH2:21][CH2:22][CH3:23])=[O:18])#[N:15]>C(O)C.O.CCOC(C)=O.CCCCCC>[C:14](/[C:16](=[CH:12]\[C:8]1[NH:7][CH:11]=[CH:10][N:9]=1)/[C:17]([NH:19][CH:20]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][O:32][CH3:33])=[CH:28][CH:29]=1)[CH2:21][CH2:22][CH3:23])=[O:18])#[N:15]
Reactant: O=Cc1ncc[nH]1
Reactant: CCCC(NC(=O)CC#N)c1ccc(OCOC)cc1
Agent: NCCC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCC(NC(=O)/C(C#N)=C/c1ncc[nH]1)c1ccc(OCOC)cc1
Yield: 155.2 %

Procedure:
β-Alanine (71.3 mg, 0.8 mmol) and 1H-imidazole-2-carbaldehyde (19.2 mg, 0.2 mmol) were added successively to a stirred solution of 2-cyano-N-(1-(4-(methoxymethoxy)phenyl)butyl)acetamide (5; 27.6 mg, 0.1 mmol) in ethanol/water (2.0 mL/0.8 mL) at room temp. After 72 hours TLC (in 50% EtOAc/Hexane) showed a single product formed. The mixture was partitioned between aqueous sodium bicarbonate and ethyl acetate. The separated organic layer was washed with sat. brine and dried with sodium sulfate and concentrated to give a light amber oil (55 mg) as crude product. The crude material was purified by column chromatography to afford the titled compound as a yellow oil (23 mg) in 65% yield. 1H NMR (500 MHz, CDCl3) δ 10.59 (s, 1H), 8.14 (s, 1H), 7.42 (s, 1H), 7.23 (s, 1H), 7.17-7.13 (m, 2H), 7.12-7.07 (m, 2H), 5.22 (s, 2H), 3.86-3.75 (m, 2H), 3.51 (s, 3H), 1.64-1.53 (m, 2H), 1.36 (m, 2H), 0.93 (t, J=7.3, 3H). Mass spec ES+, m/z=355.1 (m+H+).
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1.[Si](I)(C)(C)C>C(Cl)Cl>[CH3:12][N:11]1[C:6]2[CH:5]=[C:4]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:3](=[O:2])[NH:8][C:7]=2[CH:9]=[CH:10]1
Reactant: COc1nc2ccn(C)c2cc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: Cn1ccc2[nH]c(=O)c(C3CCNCC3)cc21
Temperature: 60 °C
Yield: 93.4 %

Procedure:
To tert-butyl 4-(5-methoxy-1-methyl-1H-pyrrolo [3,2-b]pyridin-6-yl)piperidine-1-carboxylate (104 mg, 0.301 mmol) in CH2Cl2 (3 mL) was added TMS-I (123 μl, 0.903 mmol) at rt. The resulting brown solution was stirred at 60° C. over night. Partial of the solvent was removed on rotary vacuo, the residue was purified on reverse phase PrepHPLC to afford the expected product, 1-methyl-6-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridin-5(4H)-one (65 mg, 94%). 1H-NMR (400 MHz, MeOD) δ ppm 2.05 (s, 3 H) 2.13 (s, 3 H) 3.20 (s, 4 H) 3.55 (s, 3 H) 6.25 (s, 1 H) 7.35 (s, 1 H) 8.01 (s, 1 H); Mass spec 232.19 Calc for C13H17N3O 231.14.
Reaction SMILES: [F:1][C:2]1[C:14]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[NH:17][C:16]2=[O:26])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.S(OC)(O[CH3:31])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[F:1][C:2]1[C:14]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[N:17]=[C:16]2[O:26][CH3:31])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: C#CCn1c(=O)sc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCn1c(=O)sc2cc(F)c(-n3c(OC)nc(C(F)(F)F)cc3=O)cc21
Reaction time: 1.5 h

Procedure:
A mixture of 27.50 g of 3-[6-fluoro-2-oxo-3-(2-propynyl)-5-benzothiazolinyl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (see Example 1), 10.80 g of dimethyl sulphate and 9.08 g of sodium carbonate in 250 ml of acetone is heated at the boiling temperature while stirring for 1.5 hours. After cooling the solid constituent is filtered off under suction and washed with acetone. The filtrate is then evaporated to dryness under reduced pressure, the residue is dissolved in 350 ml of ethyl acetate and the solution is washed three times with 300 ml of water each time. Subsequently, the organic phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure, and the resinous residue is purified by chromatography on 1.5 g of silica gel using ethyl acetate/n-hexane (1:3) as the eluent. The first fraction is recrystallized from ethyl acetate/diethyl ether (1:1), whereby there is obtained 6-fluoro-5-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-3-(2-propynyl)-2-benzothiazolinone, m.p. 191°-192° C. The 2nd fraction is recrystallized from diethyl ether/n-hexane (1:1) and there is thus obtained 3-[6-fluoro-2-oxo-3-(2-propynyl)-5-benzothiazolinyl]-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 190°-192° C.
Reaction SMILES: CS(O[CH:6]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)=O.[C:33]([C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34].C(OCC)(=O)C.Cl>CN(C=O)C>[C:33]([C:37]1[CH:38]=[CH:39][C:40]([N:41]2[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[CH2:8][CH2:7][CH:6]2[C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[CH:42][CH:43]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(N2C(c3ccc([N+](=O)[O-])cc3)CCC2c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.17 h

Procedure:
The product from Example 1C (3.67 g, 7.51 mmol) and 4-tert-butylaniline (11.86 ml, 75 mmol) in DMF (40 ml) was stirred under nitrogen at 50° C. for 4 h. The resulting mixture was diluted into ethyl acetate, treated with 1M HCl, stirred for 10 minutes and filtered to remove solids. The filtrate organic layer was washed twice with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (5% to 30%) to give a solid. The solid was triturated in a minimal volume of 1:9 ethyl acetate/hexane to give a light yellow solid as a mixture of trans and cis isomers (1.21 g, 36%).
Reaction SMILES: OC1CCCCCCCCC=CCCCCCCCCC1=O.[OH:23][CH:24]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH:37]=[CH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=[O:48]>>[OH:48][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:24]1=[O:23]
Reactant: O=C1CCCCCCCCCCC=CCCCCCCCCCCC1O
Agent: O=C1CCCCCCCCC=CCCCCCCCCC1O
Product: O=C1CCCCCCCCCCCCCCCCCCCCCCC1O
Yield: 99.4 %

Procedure:
2-Hydroxy-11-cycloeicosenone of Synthesis Example 7 was replaced by 2-hydroxy-13-cyclotetracosenone (0.70 g, 1.92 mmol). The latter was subjected to a hydrogenation reaction and subsequent treatment under the same conditions as in Synthesis Example 7, to give 0.70 g of 2-hydroxycyclotetracosanone (quantitative yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl.N1C=CC=CC=1.ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C@H:12]3[CH2:13][CH2:14][C@H:15]([NH:18][C:19](=[O:21])[CH3:20])[CH2:16][CH2:17]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(=O)Cl
Reactant: N[C@H]1CC[C@H](Oc2ccc3cnccc3c2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N[C@H]1CC[C@H](Oc2ccc3cnccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.4 g (34.7 mmol) of 4-(isoquinolin-6-yloxy)-cyclohexylamine (15) were dissolved in 100 ml of dichloromethane/pyridine (4:1). At 0° C. a solution of 3.27 g (41.6 mmol) of acetyl chloride in 10 ml of dichloromethane was added and the reaction mixture was stirred at room temperature. After 2 h, the solution was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. After washing twice with 2 N HCl, the product was transferred to the aqueous phase. The HCl-layers were adjusted to alkaline pH by addition of solid NaOH and extracted three times with dichloromethane. Drying the organic layers with magnesium sulfate and evaporation of the solvent gave 7.69 g of the crude product. After silica gel chromatography 4.48 g of the title compound were isolated. Rt=0.87 min (Method A). Detected mass: 285.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:34][CH3:35])=[C:16]([CH:23]4[CH2:26][N:25]([C:27]([NH:29]C(C)(C)C)=[O:28])[CH2:24]4)[C:17]([C:21]#[N:22])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12>FC(F)(F)C(O)=O.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:34][CH3:35])=[C:16]([CH:23]4[CH2:26][N:25]([C:27]([NH2:29])=[O:28])[CH2:24]4)[C:17]([C:21]#[N:22])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(=O)NC(C)(C)C)C1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(N)=O)C1
Yield: 49.6 %

Procedure:
A solution of 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N-(tert-butyl)azetidine-1-carboxamide (chiral intermediate from Example 292) (16 mg, 0.032 mmol) in trifluoroacetic acid (2 mL) was heated in the microwave at 120° C. for 10 min. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (7 mg, 50%). The product was isolated as a single enantiomer.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20]C)[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:22][CH3:23])[CH3:2].CO.Cl>O1CCCC1.O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:22][CH3:23])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2OC)CC(OC)=CC4
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC
Yield: 26.2 %

Procedure:
Add 13β-ethyl-3, 17β-dimethoxy-gona-2,5(10)-diene (0.8 g.) in tetrahydrofuran (5 cc.) to methanol (72 cc.) in an atmosphere of nitrogen and add a mixture of hydrochloric acid (4.8 cc.) and water (3.2 cc.). Add a further 10 cc. of tetrahydrofuran and after 1 hour dilute the solution with water and extract with ether. Wash, dry and evaporate the ethereal extracts and chromatograph the residue on neutral alumina. Remove impurities by elution with benzene. Wash the column with ether, evaporate the eluate and recrystallize the residue from hexane to obtain the title compound (0.2 g.), m.p. 117°-119°; ultraviolet absorption ξ max. 240 mμ (ε15,800); infrared spectrum (KBr disc) 6.0, 6.2, 8.8, 9.05 μ.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][NH:16][C:15](=[O:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][CH2:12]1.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>CN(C)C=O>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:15](=[O:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Reactant: BrCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2ccccn2)C1=O
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 30 mg, 1.175 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (160 mg, 0.470 mmol) in N,N-dimethylformamide (6 mL) at 0° C. After 30 min, 2-bromomethylpyridine (0.125 mg, 0.494 mmol) was added. After 1 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (202 mg). MS 432.2 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH:11]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:13])[CH3:12]>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH:11]([CH3:13])[CH3:12])=[CH:21][CH:20]=1)=[O:7]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CC(C)Oc1ccc(N)cc1
Product: CC(C)Oc1ccc(NC(=O)c2cccc(I)c2)cc1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-iodobenzoic acid and 4-isopropoxyaniline as the starting materials.