Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]=O)=[CH:28][C:23]=2[CH2:22][CH2:21]1>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:28][C:23]=2[CH2:22][CH2:21]1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc5c(c4)CCO5)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2,3-dihydro-1-benzofuran-5-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(2,3-dihydro-1-benzofuran-5-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([C:13]3[C:14](OC)=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[CH:11][N:10]=[C:9]([NH2:23])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>N1C=CC=CC=1>[CH:1]1([N:6]2[C:7]3[N:8]=[C:9]([NH2:23])[N:10]=[CH:11][C:12]=3[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[N:15][C:14]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cnc(N)nc2NC2CCCC2)c(OC)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc2c3cnc(N)nc3n(C3CCCC3)c2n1
Temperature: 150 °C
Yield: 62.2 %

Procedure:
A 10 mL reaction vessel was charged with N4-cyclopentyl-5-(2,6-dimethoxypyridin-3-yl)pyrimidine-2,4-diamine (267) (50.0 mg, 159 μmol) dissolved in dry pyridine (1 mL) under argon. Sodium bis(trimethylsilyl)amide in THF (1.0M, 0.349 mL, 349 μmol) was added and the reaction heated with microwave energy (300 W) for 12 minutes at 150° C. The solvent was removed in vacuo. Silica gel chromatography of the residue (gradient elution dichloromethane/0-5% methanol) afforded compound 268 as an off-white solid (28 mg, 62%)
Reaction SMILES: [NH2:1][CH:2]([C:12]1[C:20]2[O:19][C:18]([F:22])([F:21])[O:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[CH:5]=1.Cl[CH2:24][CH2:25][N:26]=[C:27]=[S:28]>C(OCC)C>[S:28]1[CH2:24][CH2:25][N:26]=[C:27]1[N:26]1[CH2:25][CH2:24][S:28][C:27]1=[N:1][CH:2]([C:12]1[C:20]2[O:19][C:18]([F:22])([F:21])[O:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[CH:5]=1
Reactant: Cc1cc(C)cc(CC(N)c2cccc3c2OC(F)(F)O3)c1
Reactant: S=C=NCCCl
Solvent: CCOCC
Product: Cc1cc(C)cc(CC(N=C2SCCN2C2=NCCS2)c2cccc3c2OC(F)(F)O3)c1
Reaction time: 5 h
Yield: 32 %

Procedure:
A solution of 1-amino-1-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-(3,5-dimethylphenyl)-ethane (0.39 g) in diethyl ether was treated at 0° C. with 2-chloroethyl isothiocyanate (0.16 g) and stirring was continued for 5 h at this temperature. The mixture was quenched with an aqueous sodium hydroxide solution (1 M, 4 ml) and water (15 ml) and stirred for 15 minutes. The organic phase was washed with water, the aqueous phase was extracted with diethyl ether, the combined organic phases were dried over sodium sulphate and the solvent was removed in vacuo. The remainder was purified by column chromatography to yield 0.1 g of the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6](C)(C)[NH:5]2.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:22]([N:5]1[C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[NH:8][C:7](=[O:12])[CH2:6]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)Nc2cc(F)ccc2NC1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CN(C(=O)c2ccccc2)c2ccccc2N1
Reaction time: 0.5 h

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoxalin-2-one (IV, EXAMPLE 1, 0.593 g) and triethylamine (0.725 ml) in THF (5 ml) is cooled at 0°. To this is added benzoyl chloride (0.56 ml). After the addition is complete, the ice bath is removed and additional THF (5 ml) is added. The reaction is stirred for 30 min and then partitioned between ethyl acetate, aq. sodium bicarbonate, and saline. The organic phases are separated and the organic phase is dried over magnesium sulfate and concentrated. The crude product is recrystallized from methanol/dichloromethane/hexane to give the title compound, mp 208.0°-208.5°; MS (m/z) at 252; IR (mineral oil) 1684, 1666, 1502, 757 and 1362 cm-1 ; NMR (CDCl3) 4.58, 6.7, 6.79, 6.98, 7.10, 7.34 and 7.40 δ.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([CH:19]([CH2:23][CH3:24])[C:20]([OH:22])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[CH:32][N:31]([CH2:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][C:36]=3[O:45][CH3:46])[C:30]=2[CH:47]=1>ClCCl>[CH3:46][O:45][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:35]=1[CH2:34][N:31]1[C:30]2[CH:47]=[C:26]([NH:25][C:20](=[O:22])[CH:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:23][CH3:24])[CH:27]=[CH:28][C:29]=2[N:33]=[CH:32]1)[C:39]([O:41][CH3:42])=[O:40]
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: COC(=O)c1ccc(Cn2cnc3ccc(N)cc32)c(OC)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCC(C(=O)Nc1ccc2ncn(Cc3ccc(C(=O)OC)cc3OC)c2c1)c1ccccc1
Yield: 24.9 %

Procedure:
A solution of 1,1'-carbonyldiimidazole (0.23 g.) and 2-phenylbutyric acid (0.22 g.) in dichloromethane (3 ml.) was heated under reflux for 30 minutes and then treated with a solution of (J) (0.41 g.) in dichloromethane (3 ml.). The mixture was heated under reflux for an additional 10 minutes and then diluted with dichloromethane. This mixture was washed successively with 10% v/v hydrochloric acid, water, and brine, then dried (MgSO4) and evaporated. The resultant residue was purified by flash chromatography on a 5×25 cm. silica gel column using 3:97 v/v methanol:dichloromethane as the eluent to give the title compound (0.15 g., 25%): partial NMR: 2.0(br m,2H, CH3CH2), 3.4(t,1H, CH2CH), 7.3(s,5H, Ar).
Reaction SMILES: [C:1]1([C:11]2[CH:15]=[C:14]([NH2:16])[NH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:17](OC)(=O)[CH2:18][C:19](OC)=O.C(O)C.C[O-].[Na+].CO>>[C:1]1([C:11]2[CH:15]=[C:14]3[N:16]=[CH:17][CH:18]=[CH:19][N:13]3[N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cc(-c2cccc3ccccc23)n[nH]1
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: c1ccc2c(-c3cc4ncccn4n3)cccc2c1
Temperature: 120 °C

Procedure:
To a solution of 3-(1-naphthyl)-1H-pyrazol-5-amine (654 mg, 3.12 mmol) and dimethyl malonate (0.394 mL, 3.44 mmol) in anhydrous ethanol (9.44 mL, 162 mmol) is added 0.5 M sodium methoxide in methanol (12.5 mL, 6.25 mmol). The mixture is heated at 120° C. under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature and the solvent is removed in vacuo. The residue is suspended in water and the precipitate is collected in a Buchner funnel to provide 2-(1-naphthyl)pyrazolo[1,5-a]pyrimidine, 7-diol (534 mg, yield 62%). LCMS: (AA) M+1 278; 1H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 8.73 (dd, J=8.2, 4.8 Hz, 1H), 7.99-7.88 (m, 2H), 7.72 (dd, J=7.1, 1.1 Hz, 1H), 7.58-7.49 (m, 4H), 5.83 (s, 1H), 4.14 (s, 1H).
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([CH2:22][C:23]([NH2:25])=[O:24])=[CH:16][NH:17]2.C[O:27][C:28](=O)[C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[N:38]([CH3:40])[CH:37]=[CH:36]2)=O>CN(C=O)C>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([C:22]1[C:23](=[O:24])[NH:25][C:28](=[O:27])[C:29]=1[C:31]1[CH:32]=[CH:33][CH:34]=[C:35]3[C:39]=1[N:38]([CH3:40])[CH:37]=[CH:36]3)=[CH:16][NH:17]2
Reactant: NC(=O)Cc1c[nH]c2cccc(F)c12
Reactant: COC(=O)C(=O)c1cccc2ccn(C)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5cccc(F)c45)C(=O)NC3=O)c21
Reaction time: 4 h
Yield: 54.6 %

Procedure:
A 1.0 M solution of KOtBu in THF (10.6 mL, 10.6 mmol) was added to a solution of 2-(4-fluoro-1H-indol-3-yl)-acetamide (595 mg, 3.10 mmol) and (1-methyl-1H-indol-7-yl)-oxo-acetic acid methyl ester (646 mg, 2.98 mmol) in DMF (40 mL). The initially light yellow solution turned red-orange over 4 h and was then stirred 4 h at 60–70° C. The heating bath was removed, 1N HCl added and the mixture poured into EtOAc. The EtOAc layer was separated and washed with water (2×), saturated aq NaHCO3 (2×) and brine (3×), dried (MgSO4), filtered and concentrated onto SiO2. Flash chromatography (1:1 EtOAc:hexanes) afforded a red glass that was dried at 70° C. overnight giving the title compound (585 mg, 55%) as a bright red solid. 1H NMR (400 MHz, DMSO-6) 11.83 (br s, 1H), 11.21 (s, 1H), 7.53 (dd, J=7, 1 Hz, 1H), 7.40 (d, J=3 Hz, 1H), 7.25 (d, J=3 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 7.0–7.08 (m, 1H), 7.86–7.04 (m, 2H), 6.65 (dd, J=11, 8 Hz, 1H), 6.44 (d, J=3 Hz, 1H), 3.71 (s, 3H). IR (CHCl3, cm−1) 1726. MS (electrospray, m/z) 360 (M++1), 358 (M−−1).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH3:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31].O>CN(C)C=O>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([N:5]3[CH:6]([CH2:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]3=[O:3])=[N:15]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CCCCC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(=O)CC1c2ccccc2C(=O)N1c1ccc2ccc(OC)nc2n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
An oily suspension (50% by weight; 3.1 g) of sodium hydride is added in small portions at a temperature in the region of -5° C. to a solution, maintained under a nitrogen atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (10 g) in anhydrous dimethylformamide (195 cc), and the suspension obtained is stirred for 30 minutes at a temperature in the region of -5° C. A solution of 2-hexanone (6.5 g) in anhydrous dimethylformamide (5 cc) is then added and stirring is continued for 8 hours at a temperature in the region of 0° C. and then for 16 hours at a temperature in the region of 20° C. The reaction mixture is then poured into water (1.5 litres). The solid obtained is separated by filtration, washed with water and dried in the air. After recrystallization in ethanol, 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(2-oxohexyl)-1-isoindolinone (3.6 g), m.p. 161° C., is obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH:21]=[CH:20][CH:19]=[CH:18]3)=[CH:14][CH:15]=2)[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:9]1[C:28](O)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:34][C:35](=[O:45])[C@H:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[NH2:37])C>O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH:18]=[CH:19][CH:20]=[CH:21]3)=[CH:14][CH:15]=2)[C:10]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:9]1[C:28]([NH:37][C@H:36]([C:35]([OH:34])=[O:45])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(-n3cccc3)ccc2n1Cc1ccccc1
Agent: Cl
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1c(-c2ccccc2)c2cc(-n3cccc3)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from 1-benzyl-3-phenyl-5-(1H-pyrrol-1-yl)-1H-indole-2-carboxylic acid and L-phenylalanine ethyl ester hydrochloride followed the procedure of Example 2 Step 4 as an off-white solid: 1H NMR (DMSO-d6) δ 2.90 (dd, J=13.8, 10.7 Hz, 1 H), 3.17 (dd, J=13.8, 4.3 Hz, 1H), 4.65-4.75 (m, 1 H), 5.23 (d, J=16.2 Hz, 1 H), 5.53 (d, J=16.2 Hz, 1 H), 6.21 (t, J=3.9 Hz, 2 H), 7.10-7.50 (m, 18 H), 7.57 (d, J=9.8 Hz, 1 H), 7.64 (d, J=1.9 Hz, 1 H), 9.09 (d, J=8.0 Hz, 1 H), 12.93 (br s, 1 H); MS (ESI) m/z 540 (MH+); MS (ESI) m/z 538 ([M-H]−); HRMS calcd for C35H30N3O3: 540.2288; found (ESI+): 540.2277; Anal. calcd for C35H29N3O3.0.4 H2O: C, 76.88; H, 5.49; N, 7.68. Found: C, 76.68; H, 5.24; N, 7.87.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[S-:16][C:17]#[N:18].[NH4+].ClCl>CO>[CH3:12][C:11]([C:7]1[CH:8]=[C:9]([S:16][C:17]#[N:18])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])[CH3:13]
Reactant: N#C[S-]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: ClCl
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)c1cc(SC#N)cc(C(C)(C)C)c1O
Temperature: 0 °C

Procedure:
A mixture of 2,6-di-tert-butylphenol (474g, 2.30 mole) and ammonium thiocyanate (76.12g, 4.83 mole) in methanol (1200ml) was stirred with cooling at 0° C. While the temperature was maintained at 0°to 10° C., chlorine gas was slowly bubbled through the mixture for about 1 hour, during which time the reaction mixture became a heterogeneous yellow color. Ammonia was then bubbled through the mixture for about 1.5 hours, during which time the reaction mixture was maintained at a temperature of between 0°to 10° C. The reaction was stirred for an additional hour at 0° C., poured into 2 liters of cold distilled water and refrigerated overnight. The aqueous phase was decanted, and the solid was taken up in methanol, precipitated by addition of water, filtered, and dried for 2 days over phosphorus pentoxide. The resulting gummy yellow solid was recrystallized from pentane and dried in vacuo to yield the product as a white powder, m.p. 61.5°-63° C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[CH3:27][O:28][C:29](=[O:40])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=1>ClCCl>[CH3:27][O:28][C:29](=[O:40])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][I:25])[CH:33]=1
Reactant: COC(=O)COc1cccc(CO)c1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)COc1cccc(CI)c1
Reaction time: 0.08 h
Yield: 92.7 %

Procedure:
Dichloromethane (85 mL) was added to Ph3P (4.942 g, 18.8 mmol), imidazole (1.311 g, 19.3 mmol) and I2 (4.735 g, 18.7 mmol). The mixture was stirred for 5 min. and then a solution of 12-2 (2.937 g, 15.0 mmol) in 15 mL dichloromethane was added by cannula. The reaction was stirred for 3 h, silica gel was added and the mixture evaporated. The residue was purified by flash chromatography on silica gel (10%→20%→30% ethyl acetate/hexanes) to give 12-3 (4.246 g, 13.9 mmol, 93%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])C(C)(C)C.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C(#N)C>[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH2:11][NH:1][CH2:2][C:7]([O:9][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
To a solution of t-butylglycine (1.40 g, 10.67 mmol) in acetonitrile (20 mL) cooled to 0° C. was added ethyldisopropylamine (1.86 mL, 10.67 mmol) and t-butyl bromoacetate (1.57 mL, 10.67 mmol). The resulting solution was stirred for 24 h at room temperature. The mixture was concentrated to dryness in vacuo, water was added and the solution was extracted with dichloromethane (3×70 mL). The combined organic phases were washed with brine (70 mL), dried over Na2SO4 and concentrated to dryness in vacuo. The crude material was purified by silica gel chromatography (20-80% EtOAc in hexanes) to give the compound 14 (0.88 g, 33.6%). 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 18H), 3.30 (s, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 2-fluorobenzene boronic acid according to the general procedure B. Obtained as a yellow solid (1.48 g).
Reaction SMILES: C[O:2][C:3](=[O:41])[C@H:4]([O:12][C:13]1[C:18]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:17][C:16]([C:24]2[C:36]3[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=3[C:31]([Br:39])=[C:30]3[C:25]=2[CH:26]=[CH:27][CH:28]=[CH:29]3)=[CH:15][C:14]=1[Br:40])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[K+]>O1CCCC1.CO>[Br:40][C:14]1[CH:15]=[C:16]([C:24]2[C:36]3[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=3[C:31]([Br:39])=[C:30]3[C:25]=2[CH:26]=[CH:27][CH:28]=[CH:29]3)[CH:17]=[C:18]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:13]=1[O:12][C@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:41])=[O:2]
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O[C@H](Cc4ccccc4)C(=O)O)c(C4CCCC4)c3)c2c1C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
To a solution of (2R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-cyclopentyl-phenoxy]-3-phenyl-propionic acid methyl ester (1.0 g, 1.5 mmol) in tetrahydrofuran (30 mL) and methanol (10 mL) at room temperature was added dropwise aqueous potassium hydroxide (3.0 mL of a 1 N solution, 3.0 mmol). After 4 h the reaction mixture was concentrated under reduced pressure. The residue was taken up in water (100 mL) and acidified with aqueous 10% hydrochloric acid. After stirring for 15 min the solid was filtered and washed with water:methanol (95:5). The solid was dried under a vacuum at 50° C. for 18 h to yield the title compound as a white solid (0.99 g, 100%): Opt. Rot. [a]25/D=+38.44° (9.624 mg/mL, MeOH); NMR (DMSO-d6): δ13.01 (broad s, 1H), 8.19 (d, 1H), 7.67-7.62 (m, 1H), 7.54-7.22 (m, 9H), 4.92 (m, 1H), 3.46 (m, 1H), 3.34 (m, 2H), 2.42 and 2.41 (two singlets 3H, rotational isomers), 1.99 (m, 1H), 1.98 (m, 1H), 1.72-1.27 (m containing two s at δ1.57 and 1.53 (rotational isomers), 6H); MS(−ESI): [M−H], 2 bromine isotope pattern, 675 (72%), 677 (100%), 679 (66%); Anal. Calc. for C34H30Br2O3S: C, 60.19; H, 4.46; N, 0.00. Found: C, 59.53; H, 4.35; N, −0.04.
Reaction SMILES: C(OC([NH:8][N:9]([C:11]([C@@H:13]1[CH2:17][C@@H:16]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:15][N:14]1[S:28]([C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)(=[O:30])=[O:29])=[O:12])[CH3:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:10][N:9]([C:11]([C@@H:13]1[CH2:17][C@@H:16]([S:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:15][N:14]1[S:28]([C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)(=[O:29])=[O:30])=[O:12])[NH2:8]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C(=O)N(C)NC(=O)OC(C)(C)C)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CS[C@@H]2C[C@@H](C(=O)N(C)N)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Yield: 101.1 %

Procedure:
(Step 22) 2 g (3.4 mmol) (2S,4R)-N′-[4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-N′-methyl-hydrazinecarboxylic acid tert-butyl ester in 9 ml CH2Cl2 were treated with 3.4 ml TFA for 2 h. The solution was concentrated, redissolved in toluene and evaporated. The residue was dissolved in ethyl acetate and sat. aq. NaHCO3, the layers were separated and the inorganic one was extracted with ethyl acetate, the combined organic ones were washed wit brine, dried over Na2SO4 and concentrated yielding 1.67 g (quant) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid N-methyl-hydrazide as white solid, MS: 486 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([Si:19]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(F)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
To a solution of (4-fluoro-phenyl)-methanol (12.16 g, 96.4 mmol, 1.0 equiv) in anhydrous DMF (50 mL) at 0° C. under Ar was added imidazole (7.22 g, 106.1 mmol, 1.1 equiv) and tert-butyl-chloro-dimethyl-silane (15.99 g, 106.1 mmol, 1.1 equiv). After the addition was completed the cooling bath was removed and the reaction stirred for 18 h at rt. The reaction mixture was poured on ice, extracted with ethyl acetate (2×100 mL) and the combined organic phases washed with a sat. solution of Na2CO3 (2×100 mL) and NaCl (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure yielding a brown oil that was purified by high vacuum destillation (bp 32-35° C. at 0.1 mbar) to give 23.0 g (99%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 0.00 (s, 6H), 0.84 (s, 9H), 4.60 (s, 2H), 6.89-6.94 (m, 2H), 7.16-7.20 (m, 2H). MS (EI): 183.1 [M-tert-Bu]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[C:24]1[C:25]([NH2:32])=[N:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>COCCOC.O.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>[CH3:31][O:30][C:29]1[CH:28]=[CH:27][N:26]=[C:25]([NH2:32])[C:24]=1[C:17]1[CH:18]=[CH:19][C:14]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: COc1ccnc(N)c1I
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: O
Solvent: COCCOC
Product: COc1ccnc(N)c1-c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A mixture of sodium carbonate (122 mg), tetrakis(triphenylphosphine)palladium(0) (33.2 mg), 4-phenoxyphenylboronic acid (160 mg) and 3-iodo-4-methoxypyridin-2-amine (144 mg) in DME (10 mL) and water (3 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (124 mg) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[C:18]1([CH2:24][C:25](O)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:25](=[O:26])[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(Cc1ccccc1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 72.5 %

Procedure:
A mixture of Intermediate 1 (0.028 g) and phenylacetic acid (0.015 g) was treated with 1-methyl-2-pyrrolidinone (0.015 ml) then heated in a 600 W microwave oven, at full power, for 4 min. The crude mixture was purified by chromatography on silica gel (Varian Bond-Elut, 1 g) eluting with cyclohexane/ethyl acetate (4:1 followed by 2:1) to give the title compound as a colourless gum (0.029 g).