Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[CH2:21]1[C:24]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23][C:22]1=[CH:30][C:31]#[N:32]>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:22]4([CH2:30][C:31]#[N:32])[CH2:23][C:24]5([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)[CH2:21]4)[CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Reactant: N#CC=C1CC2(CCCCC2)C1
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CC5(CCCCC5)C4)c3)n2)cn1
Yield: 37.3 %

Procedure:
This was prepared from 7-(1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (100 mg; 0.377 mmol) and 2-(spiro[3.5]nonan-2-ylidene)acetonitrile (91 mg; 0.565 mmol) using the procedure described in Example 148, Step D to give the desired product (60 mg). MS (apci) m/z=427.2 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]4[CH:21]=3)=[CH:8][CH:7]=2)=[CH:25][CH:24]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1ccn2cc(-c3ccc(OCCCCl)cc3)nc2c1
Product: Cc1ccn2cc(-c3ccc(OCCCNCc4ccc(F)cc4)cc3)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C, Example 8 (160 mg) and 4-fluorobenzylamine (1.0 mL) were heated at 100° C. for 40 minutes. The reaction was cooled to ambient temperature and purified via silica gel chromatography (methanol/dichloromethane) to yield the title compound (16 mg) in approximately 80% purity. 1HNMR (CDCl3): δ 7.97 (d, J=7.0 Hz, 1H), 7.85 (m, 2H), 7.69 (s, 1H), 7.36 (br s, 1H), 7.28 (m, 2H), 6.96 (m, 4H), 6.59 (dd, J=7.0 Hz, J=1.5 Hz, 1H), 4.09 (t, J=6.0 Hz, 2H), 3.78 (s, 2H), 2.83 (t, J=7.0 Hz, 2H), 2.39 (s, 3H), 2.00 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[NH:6][C:5]=1[Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19].[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[N:24]([CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[NH:6][C:5]=1[Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C(F)(F)F)cc2c1CCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2ccc(C(F)(F)F)cc2c1CCN=[N+]=[N-]
Temperature: 70 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
A mixture of 3-(2-bromoethyl)-2-(triethylsilyl)-5-(trifluoromethyl)-1H-indole (0.448 g; 1.10 mmol) and sodium azide (0.215 g; 3.31 mmol) in DMF (10 mL) was stirred at 70° C. for 4 hours and concentrated under reduced pressure. The residue was diluted in ethyl acetate, washed with brine, dried and concentrated under reduced pressure to give 0.402 g (99%) of the title compound as a brown oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:18]([CH2:19][CH:20]=[CH2:21])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[CH2:22][CH:23]=[CH2:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>C(O)C>[Si:1]([O:8][C:9]1[C:10]([CH2:22][CH2:23][CH3:24])=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][C:18]=1[CH2:19][CH2:20][CH3:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CCc1cc(C(=O)OC)cc(CC=C)c1O[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Solvent: CCO
Product: CCCc1cc(C(=O)OC)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Yield: 89.8 %

Procedure:
A solution of 5.0 g (14.45 mmol) of the product of Step C in 250 mL ethanol containing 5% Rh/C (0.25 g) was shaken under a 40 psi pressure of hydrogen. Upon completion of reduction, the mixture was filtered through Celite, the filter cake was washed with methanol and dichloromethane. Removal of solvents afforded 4.55 g (90%) of the title compound.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:38])[C@H:7]([CH3:37])[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:11][C@@H:12]([CH:25]([CH3:27])[CH3:26])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([OH:24])[CH:15]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:45]([O:47][C:48](=[O:51])[CH2:49]I)[CH3:46]>CC(C)=O>[CH2:1]([NH:5][C:6](=[O:38])[C@H:7]([CH3:37])[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:11][C@@H:12]([CH:25]([CH3:26])[CH3:27])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([O:24][CH2:49][C:48]([O:47][CH2:45][CH3:46])=[O:51])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(O)c1)C(C)C)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(OCC(=O)OCC)c1)C(C)C)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
A mixture of 52 mg of N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide (Example 5a), 47.5 mg of caesium carbonate, 0.012 ml of iodoacetic acid ethyl ester and 5 ml of acetone is stirred for 3 hours under reflux and then concentrated by evaporation. The residue is partitioned between diethyl ether and water. The organic phases are dried and combined and then concentrated by evaporation, yielding the title compound in the form of the crude product: Rf (dichloromethane/diethyl ether=8:2)=0.28.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[C:14]([CH3:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:9]([CH:20](Cl)[CH3:21])=[CH:8]2.CN(C=O)C.[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>>[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[C:14]([CH3:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:9]([CH:20]([N:32]1[C:28](=[O:38])[C:29]3[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31]1=[O:33])[CH3:21])=[CH:8]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ncccc1-c1nc2c(Cl)cccc2cc1C(C)Cl
Agent: Cl
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1ncccc1-c1nc2c(Cl)cccc2cc1C(C)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a stirring solution of 8-chloro-3-(1-chloroethyl)-2-(2-methylpyridin-3-yl)-quinoline hydrochloride (1.3130 g, 3.712 mmol) in DMF (18.56 mL, 3.712 mmol) at 100° C. was added potassium phthalimide (1.719 g, 9.281 mmol) at 100° C. and the mixture was stirred at 100° C. After 1.5 h, the mixture was concentrated under reduced pressure and triturated with water (50 mL). The resulting solid was filtered and washed with 2 N NaOH (50 mL) and then with water (500 mL), and air-dried to give 2-(1-(8-chloro-2-(2-methylpyridin-3-yl)quinolin-3-yl)ethyl)-isoindoline-1,3-dione as a tan solid: LC-MS (ESI) m/z 428.0 [M+H]+. The impure product was carried on crude without purification for the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[N+:6]([O-:26])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(F)cn1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(F)c[n+]1[O-]
Reaction time: 4.5 h
Yield: 88.6 %

Procedure:
To a solution of tert-butyl [(1R)-1-(5-fluoropyridin-2-yl)ethyl]carbamate (5.77 g, 24.0 mmol) in dichloromethane (96 mL) was added 3-chloroperbenzoic acid (6.51 g, 26.4 mmol). After 4.5 h, excess 3-chloroperbenzoic acid (0.59 g, 2.6 mmol) was added. After 72 h, saturated aqueous sodium sulfite was added. After 1 h, saturated aqueous sodium bicarbonate was added. The organic layer was isolated and the aqueous layer was extracted with dichloromethane (2×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol with 1% ammonium hydroxide) gave the title compound (5.45 g). MS 257.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.CO.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)OC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.7 %

Procedure:
Commercially available 6-nitro-1(3H)-isobenzofuranone (9.9 g, 55 mmol) was dissolved in a mixed solvent of tetrahydrofuran (20 ml)-methanol (60 ml), then 5% palladium-charcoal catalyst (1.5 g) was added thereto, and the mixture was stirred at room temperature for 20 hours under an atmosphere of hydrogen gas. The reaction mixture was filtered, and the solid was washed successively with ethyl acetate and methanol. The filtrate and washings were combined, and the resulting solution was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (6.21 g) as a crystalline solid. The washings were concentrated, and the residue was crystallized from a mixed solvent of ethyl acetate-hexane to give an additional amount of the title compound (0.95 g, total yield 87%).
Reaction SMILES: [CH:1]1([C:6]2[CH:33]=[CH:32][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]5=[CH:15][C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:34]([F:37])([F:36])[F:35])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:38]N1C(=O)CCC1=O>C(Cl)Cl>[CH:1]1([C:6]2[CH:33]=[CH:32][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[C:16]5=[C:15]([I:38])[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:34]([F:37])([F:35])[F:36])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC1CCn2c1c(I)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of tert-butyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (100 mg, 0.195 mmol) in DCM (2 mL) was added 1-iodopyrrolidine-2,5-dione (43.8 mg, 0.195 mmol) at 0° C. and the reaction was allowed to continue at 0° C. for 30 min in a 20 mL sealed scintillation vial. After 30 min, the reaction mixture was diluted with DCM, washed with water (3×10 mL), sodium thiolsulfate pentahydrate (aq) (2×10 mL), dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound as an off-white solid (118 mg). LCMS m/z=640.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (s, 9H), 1.55-1.73 (m, 4H), 1.79-1.89 (m, 2H), 1.95-2.05 (m, 2H), 2.26-2.38 (m, 1H), 2.51-2.56 (m, 1H), 2.77-2.88 (m, 1H), 2.94 (dd, J=15.92, 3.41 Hz, 1H), 3.20-3.28 (m, 1H), 3.50-3.60 (m, 1H), 3.99-4.08 (m, 1H), 4.12-4.21 (m, 1H), 5.18 (s, 2H), 6.79 (d, J=2.27 Hz, 1H), 6.87 (dd, J=8.78, 2.46 Hz, 1H), 7.26 (d, J=8.84 Hz, 1H), 7.63 (d, J=8.59 Hz, 1H), 7.70-7.77 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(F)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To 3-chloro-4-fluoroaniline (100 g) was slowly added acetic anhydride (200 ml). After allowed to stand for 30 minutes, the reaction mixture was poured into water (1 litter). The resulting precipitate was collected by filtration and recrystallized from aqueous ethanol to give the title compound (119.4 g), mp 118°-119° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([C:22](O)=[O:23])=[CH:20][N:21]=3)[CH2:13][C@H:12]2[O:25][CH3:26])=[O:9])[NH:5][C:6]=1[CH3:7].[CH3:27][O:28][NH2:29].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([C:22]([NH:29][O:28][CH3:27])=[O:23])=[CH:20][N:21]=3)[CH2:13][C@H:12]2[O:25][CH3:26])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CON
Reactant: CO[C@@H]1CN(c2ncc(C(=O)O)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(C)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CONC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(C)[nH]3)[C@H](OC)C2)s1
Yield: 18 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-methyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid obtained by the method described in Example (5f) (17 mg, 0.045 mmol), O-methylhydroxylamine (15 mg, 0.18 mmol), WSC hydrochloride (0.46 g, 0.24 mmol) and DMAP (5 mg, 0.042 mmol), to obtain 3.5 mg of the title compound as a white solid (18%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:16])[CH:12]=2)[CH:7]=1)[CH3:2].C1C(=O)N([Br:25])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][Br:25])[CH:12]=2)[CH:7]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1ccc2cc(C)ccc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1ccc2cc(CBr)ccc2c1
Temperature: 82 °C

Procedure:
To a solution of the product of Step 1, above (50) (3.07 mmol), in 6 ml of CCl4 was added NBS (3.07 mmol) and azobisisobutyronitrile (0.09 mmol) and the mixture was heated to 82° C. for 2 hours. The reaction was cooled to ambient temperature and filtered through celite, washing the cake thoroughly with CCl4. The organics were then concentrated to dryness to obtain the title compound (51).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NC[C@@H](O)CO
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC[C@@H](O)CO)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (2R)-3-aminopropane-1,2-diol. MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=7.83, 1.26 Hz, 1 H), 7.89 (d, J=7.33 Hz, 1 H), 7.63 (td, J=7.45, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.50-7.35 (m, 2 H), 7.29 (dd, J=8.59, 1.77 Hz, 1 H), 6.13 (s, 1 H), 5.14 (s, 2 H), 4.55 (brs, 2 H), 4.04-3.89 (m, 1 H), 3.69 (d, J=5.56 Hz, 2 H), 3.64-3.49 (m, 4 H), 2.41 (s, 3 H).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13](OCC)=[O:14].[Na].O>C(OCC)C>[CH:13]([CH:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:1]([O:10][CH2:11][CH3:12])=[O:9])=[O:14]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: CCOC=O
Agent: [Na]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CC(C=O)C(=O)OCC
Reaction time: 17 h

Procedure:
A mixture of diethyl succinate (26.1 g, 25.0 mL, 0.150 mol) and ethyl formate (I1.1 g, 12.1 mL, 0.150 mol) was added drop wise over 1.5 hours to a stirred suspension of sodium (3.40 g, 0.150 mol) in diethyl ether (120 mL) at 0° C. under nitrogen. On completion of addition, stirring was continued at room temperature for 17 hours. Water (120 mL) was cautiously added to the resulting suspension and stirring continued until all the solids were dissolved. The layers were separated and the aqueous layer was washed with diethyl ether (100 mL). The aqueous layer was then acidified to pH 5 using 11 N HCl and extracted with diethyl ether (3×100 mL), the ethereal extracts of the acidified layer were combined, dried (Na2SO4) then evaporated to dryness under reduced pressure to give the title compound (I105) (16.5 g) as a yellow mobile liquid. The crude product was not purified further and was used directly in the following step.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:8]2([NH:16][S:17]([CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])(=[O:19])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.[OH2:33]>CCOC(C)=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:8]2([NH:16][S:17]([CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])(=[O:18])=[O:19])[C:11]([O:13][CH2:14][CH3:15])=[O:33])=[CH:4][CH:3]=1
Reactant: O
Reactant: C=C(OCC)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of NaIO4 (5.9503 g, 27.82 mmol) in water (40 mL) was added RuCl3 hydrate (0.0526 g, 0.25 mmol) followed by a solution of crude N-(6′-bromo-1′-(1-ethoxyvinyl)-4-methoxy-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-1′-yl)-2-(trimethylsilyl)ethanesulfonamide (9) (1.0894 g), obtained as described above, in EtOAc (60 mL). The resulting mixture was vigorously stirred at room temperature for 30 min and LC-MS indicated the disappearance of starting material. The organic layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers was dried over Na2SO4, filtered and evaporated. The residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford ethyl 6′-bromo-4-methoxy-1′-(2-(trimethylsilyl)ethylsulfonamido)-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-1′-carboxylate (10) (0.5329 g, 50% in two steps). LC-MS tR=2.27 min in 3 min chromatography, m/z 568, 570 (MNa+), 333, 335; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.12 (d, J=8.2 Hz, 1H), 4.41-4.25 (m, 2H), 3.32 (s, 3H), 3.08-3.02 (m, 2H), 2.80 (d, J=15.8 Hz, 1H), 2.16-2.04 (m, 3H), 1.91-1.87 (m, 2H), 1.80-1.72 (m, 1H), 1.40-1.22 (m, 7H), 0.95-0.88 (m, 1H), 0.80-0.72 (m, 1H), 0.65-0.57 (m, 1H), −0.17 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.13, 142.21, 140.91, 132.97, 132.25, 126.52, 119.45, 78.49, 75.10, 61.87, 55.79, 53.06, 50.92, 38.15, 28.64, 28.38, 28.33, 27.82, 14.18, 9.98, −2.28.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].I[C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:9](=[O:18])[NH:10]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:4][CH2:1][C:2]#[C:3][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:9](=[O:18])[NH:10]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(C#CCO)c21

Procedure:
Using Method C above, propargyl alcohol (0.11 g, 1.95 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (0.32 g, 0.78 mmol) (Starting Material 2 above) using (Ph3P)2PdCl2 (27.4 mg) and Cul (7.4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one. (Yield 0.12 g, 46%).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)C.Br[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])=[CH:25][CH:24]=1>>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][CH2:19][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:15][CH3:16])[C:4]([OH:3])=[O:17])=[CH:8][C:9]=2[CH3:14])=[CH:28][CH:27]=1)(=[O:30])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(c1ccccc1)c1ccc(OCCCBr)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(C)c1)OC
Product: COC(Cc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)c(C)c1)C(=O)O

Procedure:
A mixture of 3-(4-Hydroxy-3-methyl-phenyl)-2-methoxy-propionic acid ethyl ester and from Example 162, Step E and [4-(3-Bromo-propoxy)-phenyl]-phenyl-methanone were treated under standard condition I to give the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].F[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[O:10][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C=O)c(Cl)c2)cc1
Temperature: 130 °C
Yield: 13.3 %

Procedure:
Dissolve 2-chloro-4-hydroxy-benzaldehyde (1.09 g, 7.01 mmol) in DMF (10 mL), add K2CO3 (1.06 g, 7.7 mmol) and 4-fluorobenzonitrile (932 mg, 7.7 mmol), heat the mixture at 130° C. overnight. Add water and extract the aqueous layer with EtOAc. Combine organic layers and dry over Na2SO4. Eliminate the solvent and purify by flash chromatography on silica gel (eluent: EtOAc/hexane 15/85) to give the title compound (240 mg, 14%), 1H-NMR (CDCl3, 300 MHz): 10.40 (s, 1H), 7.98 (d, 1H, J=8.6 Hz), 7.74-7.71 (m, 2H), 7.17-7.00 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]([NH:16][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([OH:23])[CH:25]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)NC(=O)c3cccc(O)c3)c2c1N

Procedure:
Prepared as in Example 24a from (R)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate (Example 86b) and 3-hydroxybenzoic acid as brown solid (36%). MS 424 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][C@@H:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.CO>O1CCOCC1.O=[Mn]=O>[CH3:13][O:12][C:10]([C:7]1[N:6]=[CH:5][C:4]2[N:3]=[CH:2][NH:1][C:9]=2[CH:8]=1)=[O:11]
Reactant: COC(=O)[C@@H]1Cc2[nH]cnc2CN1
Agent: O=[Mn]=O
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cc2[nH]cnc2cn1

Procedure:
A mixture of 59.9 g methyl (6S)-4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine-6-carboxylate and 172.5 g MnO2 in 2 l anhydrous 1,4-dioxane is refluxed for 4 hours. The reaction mixture is allowed to come to 60-70° C. whereupon 1 l methanol is slowly added. The suspension is filtered hot and the filtrate is concentrated under reduced pressure to give a first batch of the title product. The filter cake is washed with hot methanol (2 l) and concentrated under reduced pressure to a volume of about 50 ml. 80 ml 1,4-dioxane is added whereupon precipitation takes place. After filtration a second batch of the title product is obtained. The washing procedure of the initial filter cakes is repeated once again to give a third batch of the title product.