Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)=[CH:4][CH:3]=1.[CH3:37][C:38]([CH3:42])([CH3:41])[CH:39]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([CH2:37][C:38]([CH3:42])([CH3:41])[CH3:39])[CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:33])([F:32])[F:34])[CH:24]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Reactant: CC(C)(C)C=O
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(CC(C)(C)C)CC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 104, the title compound N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(2,2-dimethyl-propyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using trimethylacetaldehyde (75% in tert butanol) instead of acetone and was obtained as a light brown oil. MS m/e: 594.3 [M]+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[C:8]2=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(=CC)C.CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[C:8]2=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cccc(CC2CCN(C3CCCCC3)C2=O)c1
Agent: CC=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C1C(Cc2cccc(O)c2)CCN1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.2 %

Procedure:
Dissolve 1-cyclohexyl-3-(3-methoxy-benzyl)-pyrrolidin-2-one (example 67) (440 mg, 1.5 mmol) in methylene chloride (50 ml) and add 2-methyl 2-butene (0.97 ml, 9.2 mmol) followed by borontribromide (0.43 ml, 4.6 mmol) and stir at room temperature for 20 minutes. Pour reaction mixture into an ice, methanol, sodium bicarbonate mixture and stir for 5 minutes. Separate layers wash organic with brine dry over sodium sulfate, filter and concentrate. Purify by silica gel (10-20% ethyl acetate in hexanes) to yield 165 mg (39%) of the title compound: Mass spectrum (apci) m/z=274 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:22][CH2:21][C@@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19]3)=[CH:11][C:10]=2[O:26][CH3:27])=[N:6][CH:7]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)=[N:4][C:5]([NH:8][C:9]2[C:10]([O:26][CH3:27])=[CH:11][C:12]([N:18]3[CH2:22][CH2:21][C@@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19]3)=[C:13]([NH2:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 83.5 %

Procedure:
A mixture of 5-chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 19, 145 mg, 0.28 mmol), iron (95 mg, 1.71 mmol) and NH4Cl (11.4 mg, 0.21 mmol) was heated at reflux in ethanol (6 mL) and water (2 mL) for 1.5 h. The mixture was then cooled and concentrated in vacuo. The resulting residue was triturated using 10% CH3OH in CH2Cl2 (15 mL) for 15 minutes and the mixture was then filtered. The residues were triturated again using 10% CH3OH in CH2Cl2 (15 mL) and the mixture was filtered. The combined filtrates were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (112 mg, 82%) as a yellow gum; 1H NMR: (CDCl3) 1.83-1.96 (1H, m), 2.08-2.23 (1H, m), 2.30 (6H, s), 2.82-2.92 (1H, m), 2.99-3.13 (2H, m), 3.17-3.28 (2H, m), 3.65 (2H, s), 3.84 (3H, s), 6.72 (1H, s), 6.96 (1H, td), 7.38 (1H, ddd), 7.52 (1H, s), 7.90 (1H, s), 8.36 (1H, s), 8.55-8.60 (1H, m), 8.65 (1H, dd), 8.94 (1H, s); m/z: ES+ MH+ 479.5.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:14][CH2:13][CH2:12][C:7]3([CH2:11][CH2:10][CH2:9][CH2:8]3)[C:6]2=[O:15])[CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[CH2:18]1[C:22]2(CCCC3(CCCC3)[CH:23]2[OH:32])[CH2:21]CC1>[OH-].[Na+].C1(C)C=CC=CC=1.O1CCCC1.O.CO>[C:23]([O:15][CH:6]1[C:5]2([CH2:1][CH2:2][CH2:3][CH2:4]2)[CH2:14][CH2:13][CH2:12][C:7]21[CH2:11][CH2:10][CH2:9][CH2:8]2)(=[O:32])[C:22]([CH3:18])=[CH2:21]
Reactant: O=C1C2(CCCC2)CCCC12CCCC2
Reactant: OC1C2(CCCC2)CCCC12CCCC2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: C=C(C)C(=O)OC1C2(CCCC2)CCCC12CCCC2
Yield: 99 %

Procedure:
With stirring under nitrogen atmosphere under ice cooling, 80 g of dispiro[4.1.4.3]tetradecan-6-one and 73 g of tetrahydrofuran were added to a mixture of 14.5 g of sodium borohydride, 145 g of methanol, 0.3 g of 25% sodium hydroxide aqueous solution, 8 g of water, and 73 g of tetrahydrofuran. The reaction mixture was stirred overnight at room temperature, and 300 ml of toluene was added thereto, whereupon the organic layer was separated. Through ordinary work-up of extraction, washing and drying, and subsequent concentration under reduced pressure, there was obtained 81.0 g (yield 99%) of the target compound, dispiro[4.1.4.3]-tetradecan-6-ol. This compound had a purity high enough to use in the subsequent step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=C(O)C=[C:6]([OH:9])[C:7]=1[CH3:8].[ClH:11].[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[ClH:11].[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]2[C:3]3[C:2]([OH:1])=[C:7]([CH3:8])[C:6]([OH:9])=[CH:30][C:29]=3[O:28][C:26](=[O:27])[C:21]=2[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(O)cc(O)cc1O
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Product: Cc1c(O)cc2oc(=O)c3c(c2c1O)CCN(Cc1ccccc1)C3
Yield: 24 %

Procedure:
Prepared by the procedure of Example 1 from 3,5-dihydroxy-4-methylphenol and ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride. The crude product was converted to the hydrochloride salt. Yield 24%; mp 293°-299° C.
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[C:7]2[C:11](=[O:12])[N:10]([C:13]3([CH3:21])[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]3=[O:20])[C:9](=[O:22])[C:8]=12)([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CC(C)=O.O>[NH2:1][C:4]1[S:5][CH:6]=[C:7]2[C:11](=[O:12])[N:10]([C:13]3([CH3:21])[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]3=[O:20])[C:9](=[O:22])[C:8]=12
Reactant: CC1(N2C(=O)c3csc([N+](=O)[O-])c3C2=O)CCC(=O)NC1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(N2C(=O)c3csc(N)c3C2=O)CCC(=O)NC1=O
Yield: 53.2 %

Procedure:
0.323 g of 1-nitro-5-(3-methyl-2,6-dioxopiperidin-3-yl)-5H-thieno(3,4-c)pyrrole-4,6-dione was dissolved in 10 mL of acetone, and a solution obtained by dissolving 0.783 g Na2S2O4 in 100 mL of water was added. The reaction mixture was refluxed for 2 h, cooled, and 100 mL of water were added. The aqueous phase was extracted with ethyl acetate (3×50 mL), the organic phases were combined and washed with 40 mL of water and 40 mL of brine, dried over anhydrous MgSO4, filtered, and evaporated to dryness. The remaining residue was purified on silica gel column chromatography to obtain a solid (0.156 g). MS (m/z): 292 (M−1)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)([OH:26])[CH2:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:36].[Na+]>CO.O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:28]=[CH:29][C:30]([S:33]([CH3:34])=[O:36])=[CH:31][CH:32]=2)([OH:26])[CH2:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc(C(O)(CC2CCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)c1ccc(C(O)(CC2CCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred solution of 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclobutyl-1-(4-methylsulfanyl-phenyl)-ethanol (500 mg, 1 mmol) in methanol (50 mL) and water (10 mL) was added sodium metaperiodate (440 mg, 2 mmol) at room temperature. The resulting mixture was stirred at room temperature for 8 h, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclobutyl-1-(4-methylsulfinyl-phenyl)-ethanol (512 mg, quant.) as a light yellow solid: LC/MS m/e calcd for C26H25FN2O4S2 [M+H]+ 513.63, observed 512.8.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[CH:41]=[CH:40][C:26]([C:27]([NH:29][CH:30]2[CH2:37][C@H:36]3[N:38]([CH3:39])[C@H:32]([CH2:33][CH2:34][CH2:35]3)[CH2:31]2)=[O:28])=[CH:25][C:24]=1[F:42].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:41]=[CH:40][C:26]([C:27]([NH:29][CH:30]5[CH2:37][C@H:36]6[N:38]([CH3:39])[C@H:32]([CH2:33][CH2:34][CH2:35]6)[CH2:31]5)=[O:28])=[CH:25][C:24]=4[F:42])=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1[C@@H]2CCC[C@H]1CC(NC(=O)c1ccc(N)c(F)c1)C2
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(C)CC(C)O
Solvent: O
Product: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4C[C@H]5CCC[C@@H](C4)N5C)cc3F)ncc21
Temperature: 160 °C
Yield: 27.5 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 108 mg, 0.35 mmol) and 4-amino-3-fluoro-N-(9-methyl-9-azabicyclo[3.3.1]non-7-yl)benzamide (Intermediate 162; 102 mg, 0.35 mmol) were combined with p-toluenesulphonic acid monohydrate (167 mg, 0.88 mmol) in 4-methyl-2-pentanol (2 mL) and heated by microwave irradiation for 25 minutes at 160° C. The cooled reaction mixture was diluted with methanol (10 mL) and loaded onto an SCX-3 cartridge (5 g) pre-wet with methanol. The cartridge was washed with methanol (2×5 mL) and eluted with 7 N methanolic ammonia (10 mL). Product containing fractions were evaporated and the resultant material purified by base modified reverse phase preparative HPLC to give the title compound as a white solid (54 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:17]CC4C=CC=CC=4)[CH:12]=3)[NH:7][C:6]=2[C:5]([N+:25]([O-:27])=[O:26])=[CH:4][CH:3]=1.CS(O)(=O)=O>C(O)(=O)C>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=3)[NH:7][C:6]=2[C:5]([N+:25]([O-:27])=[O:26])=[CH:4][CH:3]=1
Reactant: O=c1c2cc(OCc3ccccc3)ccc2[nH]c2c([N+](=O)[O-])ccc(Cl)c12
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Product: O=c1c2cc(O)ccc2[nH]c2c([N+](=O)[O-])ccc(Cl)c12
Reaction time: 7 h

Procedure:
To a stirred and boiling mixture of 26.7 g of 1-chloro-4-nitro-7-(phenylmethoxy)-9(10H)-acridinone in 1.9 l of glacial acetic acid was added 13.0 ml of methanesulfonic acid. Heating and stirring were continued for seven hours and the mixture was filtered. The precipitate was suspended in 250 ml of boiling glacial acetic acid, cooled to 60°, collected, washed with water and then methanol, and dried providing the title compound, mp above 325° C.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:38]=[CH:37][C:6]([CH2:7][N:8]2[CH2:36][CH2:35][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH:21][CH:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[O:20])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:48]([C:50]1[CH:55]=[CH:54][C:53]([S:56](Cl)(=[O:58])=[O:57])=[CH:52][CH:51]=1)#[N:49].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:48]([C:50]1[CH:51]=[CH:52][C:53]([S:56]([N:25]2[CH2:26][CH2:27][CH:22]([NH:21][C:19]([C:16]3[CH:15]=[CH:14][C:13]4[NH:12][C:11]5[CH2:35][CH2:36][N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([C:2]([F:40])([F:1])[F:39])=[CH:38][CH:37]=6)[CH2:9][C:10]=5[C:18]=4[CH:17]=3)=[O:20])[CH2:23][CH2:24]2)(=[O:58])=[O:57])=[CH:54][CH:55]=1)#[N:49]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CN(Cc2ccc(C(F)(F)F)cc2)CC4)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCC(NC(=O)c3ccc4[nH]c5c(c4c3)CN(Cc3ccc(C(F)(F)F)cc3)CC5)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of tert-butyl 4-(2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (9, 50 mg, 90 μmol) in DCM (1.0 mL), TFA (1.0 mL) was added. After allowing the reaction mixture to stir at room temperature for 2 h, the volatiles were evaporated, DCM and toluene (10 mL) were added and the volatiles evaporated (2×). The resulting residue was dissolved in DMF (2.0 mL) and triethylamine (0.5 mL, 0.36 g, 3.6 mmol) and 4-cyanobenzenesulfonyl chloride (22 mg, 110 μmol) were added. The resulting reaction mixture was allowed to stir at room temperature overnight, poured into saturated sodium bicarbonate solution (20 mL) to give a tan solid which was triturated with ethyl ether to provide N-(1-(4-cyanophenylsulfonyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide (Compound 21, 54 mg, 97%). 1H NMR (DMSO-d6, 300 MHZ) 11.04 (br s, 1H), 8.12 (d, J=8.5 Hz, 2H), 8.04 (d, J=7.7 Hz, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.79 (s, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.62 (d, J=7.7 Hz, 2H), 7.51 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 3.86 (s, 2H), 3.82-3.72 (m, 1H), 3.70-3.59 (m, 4H), 2.90-2.78 (m, 4H), 2.56-2.44 (m, 2H), 1.90-1.80 (m, 2H), 1.64-1.48 (m, 2H) ppm; MS (ES) 622 (M+H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br/[CH:41]=[CH:42]\[CH2:43][C:44]([CH2:55][CH3:56])([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH2:45][CH3:46].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24]/[CH:41]=[CH:42]\[CH2:43][C:44]([CH2:55][CH3:56])([O:47][Si:48]([CH2:53][CH3:54])([CH2:49][CH3:50])[CH2:51][CH3:52])[CH2:45][CH3:46])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(CC)(C/C=C\Br)O[Si](CC)(CC)CC
Reactant: CC(C)(O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(C/C=C\OC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Yield: 71.7 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene (100 mg, 0.175 mmol), 1-bromo-4-ethyl-4-triethylsilyloxy-(2Z)-hexene (224 mg, 0.697 mmol), sodium hydride (60% in oil, 42 mg, 1.05 mmol), 15-crown-5 (38 mg, 0.173 mmol) and tetrahydrofuran (3 ml) were subjected to reaction using a procedure similar to that of Example 5(1) (reflux under heating for 17 hours), worked up and purified by column chromatography (hexane:toluene=2:1) to give the titled compound (102 mg, 72%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9](=[O:29])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21](=[O:28])[NH:20][N:19]=2)[CH:12]=1)([CH3:7])[C:3]([O:5]C)=O.[OH-].[Na+].Cl>CN(C=O)C>[CH3:7][C:2]1([CH3:1])[NH:8][C:9](=[O:29])[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]3[C:27]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=4[C:21](=[O:28])[NH:20][N:19]=3)[CH:12]=2)[C:3]1=[O:5]
Reactant: COC(=O)C(C)(C)NC(=O)Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(c2cccc(Cc3n[nH]c(=O)c4c3CCCC4)c2)C1=O
Reaction time: 5 h

Procedure:
To a solution of methyl 2-methyl-2-[[3-[(4-oxo-5,6,7,8-tetrahydro-3H-phthalazin-1-yl)methyl]phenyl]carbamoylamino]propanoate (14) (44 mg, 0.11 mmol) in dry DMF (2 mL) was added finely powdered sodium hydroxide (4 mg, 0.072 mmol). The reaction mixture was immersed in a preheated oil bath at 50° C. for 5 hours, before being neutralized by addition of 1M HCl The desired product was isolated from the resultant solution by preparative chromatography to yield a solid (3.6 mg, 98% purity). M/z (LC-MS, ESP), RT=7.69 mins (M+H 367.1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH:19][C:20](=[O:35])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH:33]=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N:29]5[CH:33]=[CH:32][N:31]=[N:30]5)[CH:24]=4)[CH2:21][C:20](=[O:35])[NH:19][C:9]=3[CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-pyrrol-1-yl-phenyl}-carbamic acid tert.-butyl ester (Example M20) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (36 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:15]3[C:31](=[O:38])[C:32]4[CH:33]=[CH:34][N:35]=[CH:36][C:37]=4[C:13]([C:14]=23)=[N:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]([O:43][C:44]([NH:46][CH2:47][CH2:48][NH2:49])=[O:45])([CH3:42])([CH3:41])[CH3:40]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16]([NH:49][CH2:48][CH2:47][NH:46][C:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:45])=[C:15]3[C:31](=[O:38])[C:32]4[CH:33]=[CH:34][N:35]=[CH:36][C:37]=4[C:13]([C:14]=23)=[N:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c4c(nn3CCNC(=O)OC(C)(C)C)-c3cnccc3C(=O)c24)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCNc1ccc2c3c(nn2CCNC(=O)OC(C)(C)C)-c2cnccc2C(=O)c13
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A suspension of 2-[2-(N-tert-butoxycarbonylamino)ethyl]-5-(p-toluenesulfonyl oxy)isoquino[8,7,6cd]indazole-6(2H)-one Example 3 (0.535 g) and N-(tert-butoxycarbonyl)ethylenediamine (1.12 g) in dry pyridine (5.35 mL) is heated at 80° C. The dark solution obtained is held at this temperature for 5 hours, then it is concentrated to dryness and partitioned between brine (30 mL) and ethyl acetate (2×25 mL). The orange-red solid insoluble in the biphasic mixture is separated by suction filtration and dried at 40° C. under vacuum (0.43 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH2:14][CH2:13][C:12](=[O:15])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25](Cl)[N:26]=[C:27]=[O:28])=[CH:21][N:20]=1>ClCCl>[Cl:18][C:19]1[N:20]=[CH:21][C:22]([CH:25]2[NH:26][C:27](=[O:28])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:4]=3)[C:10]3[CH2:14][CH2:13][C:12](=[O:15])[C:11]2=3)=[CH:23][CH:24]=1
Reactant: O=C=NC(Cl)c1ccc(Cl)nc1
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CC1
Solvent: ClCCl
Product: O=C1CCC2=C1C(c1ccc(Cl)nc1)NC(=O)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-(3-(trifluoromethyl)phenylamino)cyclopent-2-enone (900 mg, 3.73 mmol) in dichloromethane (8 mL) is added dropweise to a solution of 2-chloro-5-(chloro(iso-cyanato)methyl)pyridine (intermediate 10, 757 mg, 3.73 mmol) in dichloromethane (7 mL). The mixture is stirred at room temperature for 2 h and concentrated, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 160 mg; ESI mass spectrum [M+H]+=408; Retention time HPLC: 0.98 min (V011_S01).
Reaction SMILES: C[O:2][C:3](=[O:63])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH2:61])=[N:58][C:57]=1[CH3:62])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C([N:71]1[CH2:78][CH2:77][CH2:76][C@H:72]1[C:73]([OH:75])=O)(OC(C)(C)C)=O>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([NH:20][C:21]([CH:23]3[CH2:32][C:31]4[CH:30]=[C:29]5[O:33][CH2:34][C@H:35]([C:37]6[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]7[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=7)=[CH:41][CH:42]=6)[O:36][C:28]5=[CH:27][C:26]=4[CH2:25][N:24]3[S:53]([C:56]3[S:60][C:59]([NH:61][C:73]([C@@H:72]4[CH2:76][CH2:77][CH2:78][NH:71]4)=[O:75])=[N:58][C:57]=3[CH3:62])(=[O:54])=[O:55])=[O:22])[C:3]([OH:63])=[O:2])=[CH:11][CH:10]=2)=[CH:17][CH:16]=1)#[N:19]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: Cc1nc(NC(=O)[C@@H]2CCCN2)sc1S(=O)(=O)N1Cc2cc3c(cc2CC1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound (18 mg) was prepared from (S)-2-({(S)-7-(2-Amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester and boc-L-proline according to General Procedures L, C, and B. LCMS (m/z): 1008.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10](O)(=[O:13])[CH2:11][CH3:12].FC(F)(F)S(O)(=O)=O>>[CH3:1][C:2]1[CH:7]=[C:6]([C:10](=[O:13])[CH2:11][CH3:12])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cccc(C)c1O
Reactant: CCC(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC(=O)c1cc(C)c(O)c(C)c1
Temperature: 80 °C

Procedure:
A mixture of 2,6-dimethylphenol (10.5 g, 85.95 mmol), propionic acid (4.64 mL, 86.81 mmol), and trifluoromethanesulfonic acid (59 g) was heated to 80° C. for 48 h, then poured onto ice. The mixture was extracted with chloroform and this organic phase was washed with aqueous bicarbonate and brine. The organic layer was dried and concentrated to a dark orange oily solid. The residue was kugelrohr distilled at 1.5 mm Hg and the following fractions were collected: 23-105° C. (pot temperature), discarded forerun; 105-135° C., 11.2 g (73%) of 2,6-dimethyl-4-propionylphenol as a yellow-white solid which had NMR identical to that of preparation 15.