Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1C(F)=NC(F)=NC=1[F:22].N1C=CC=CC=1>C(Cl)Cl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([F:22])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)F

Procedure:
BOC-Phe (1 mmole) in dry CH2Cl2 under nitrogen is treated with cyanuric fluoride (8 mmol) and pyridine (1 mmole) to form the above-identified product.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[CH3:14][CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][NH:17][CH2:16]1>C1COCC1>[CH3:14][CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][N:17]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=2)[CH2:16]1
Reactant: CC1CNCC(C)C1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CC1CC(C)CN(c2ncc([N+](=O)[O-])cc2[N+](=O)[O-])C1
Temperature: 60 °C
Yield: 92.6 %

Procedure:
2 g (9.82 mmol) of 2-chloro-3,5-dinitropyridine, 10 ml of THF and 20 mmol of 3,5-dimethylpiperidine were placed in a round-bottomed flask. he mixture was maintained at 60° C. for 15 hours with stirring and was then poured into a mixture of ice-water with stirring. The precipitate formed was filtered off by suction and dried under vacuum to constant weight. 2.55 g of yellow powder were obtained.
Reaction SMILES: [Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[NH2:10][C@@H:11]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([F:34])([F:33])[F:32])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([NH:10][C@@H:11]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:32])[F:33])[CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[O:9])[CH:3]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O)c1coc(Br)c1
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of 5-bromo-3-furancarboxylic acid (0.30 g, 1.57 mmol) [prepared according to J. Org. Chem. 1976, 41, 2350.], 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (0.60 g, 1.73 mmol) [from Preparation 5] and diisopropylethyl amine (0.82 mL, 4.7 mmol) in DCM (50 mL) at 25° C. was added PyBrOP (1.09 g, 2.36 mmol) in one portion. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, hexanes/EtOAc, 1:1) affording the title compound (0.45 g, 55%) as a white solid: LC-MS (ES) m/z=521 (WH)+.
Reaction SMILES: [ClH:1].Cl.C([S:6][CH:7]1[CH2:12][CH2:11][N:10]([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH2:9]/[C:8]/1=[CH:26]\[C:27]1[N:31]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[N:30]=[N:29][CH:28]=1)(=O)C.[CH2:38](O)C>>[ClH:1].[CH:16]1([C:14](=[O:15])[CH:13]([N:10]2[CH2:11][CH2:12][CH:7]([SH:6])/[C:8](=[CH:26]/[C:27]3[N:31]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:30]=[N:29][CH:28]=3)/[CH2:9]2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:18][CH2:17]1
Reactant: CCO
Reactant: COC(=O)CCn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1SC(C)=O
Agent: Cl
Product: CCOC(=O)CCn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Hydrogen chloride was passed through a solution of (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({1-[2-(methoxycarbonyl)ethyl]-1H-1,2,3-triazol-5-yl}methylidene)piperidine hydrochloride (2.0 g) in ethanol (5.0 ml) with stirring at 0° C. for one hour, and the resulting mixture was stirred at room temperature under tightly sealed condition for 4 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified using preparative HPLC [YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N aqueous hydrochloric acid solution (33:67, v/v)]. The eluate was treated with hydrogen chloride (4 N dioxane solution, 2 ml). The solvent and excess hydrogen chloride were removed under reduced pressure to afford the title compound (1.29 g, yield: 68%) as a colourless amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>O>[C:16]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:8])[CH3:9])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1sc(C(C)(C)C)cc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(C(C)(C)C)cc1NC(=O)OCc1ccccc1
Reaction time: 18 h

Procedure:
A solution of methyl 3-amino-5-tert-butylthiophene-2-carboxylate (20.0 g, 93.9 mmol), benzyl chloroformate (80.4 mL, 563 mmol), Na2CO3 (1.10 g, 9.93 mmol), toluene (400 mL) and water (50 mL) was heated at the reflux temp. for 18 h. Volatiles were removed under reduced pressure. The resulting oil was dissolved in EtOAc, washed with water and a concentrated NaCl solution, dried (MgSO4) and concentrated under reduced pressure to afford methyl 3-(N-carbobenzyloxyamino)-5-tert-butylthiophene-2-carboxylate as a crude oil in quantitative yield.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]([CH2:25][C:26]2[CH:34]=[C:33]([Cl:35])[C:32]([OH:36])=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:44][C:45]([O:47]C)=[O:46]>CN(C=O)C.CCOC(C)=O>[C:1]1([S:7]([NH:10][CH:11]([C:12](=[O:13])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][C:26]2[CH:34]=[C:33]([Cl:35])[C:32]([O:36][CH2:44][C:45]([OH:47])=[O:46])=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCCCc1ccccc1)C(Cc1cc(Cl)c(O)c2[nH]ncc12)NS(=O)(=O)c1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)COc1c(Cl)cc(CC(NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)c2cn[nH]c12
Reaction time: 36 h

Procedure:
2-Benzenesulfonylamino-3-(6-chloro-7-hydroxy-1H-indazol-4-yl)-N-(4-phenyl-butyl)-propionamide (30 mg, 0.057 mmol) is dissolved in DMF (1 mL) and K2CO3 is added followed by a slight excess of methyl bromoacetate (11 mg, 0.072 mmol). The reaction is allowed to stir for 36 h. The reaction is worked-up by diluting with EtOAc and washing with NH4Cl, 0.5 N HCl, water and brine. The solution is dried with MgSO4 and concentrated to provide a mixture of the intermediate ester and desired acid product as observed by LC/MS. The acid is purified by chromatography using a 10 g C18 sep-pak column (CH3CN/H2O) to provide {4-[2-benzenesulfonylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-6-chloro-1H-indazol-7-yloxy}-acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.17 (d, 1H), 8.29 (bs, 1H), 7.94 (dd, 1H), 7.46 (d, 2H), 7.42 (dd, 1H), 7.28–7.24 (m, 4H), 7.16–7.14 (m, 3H), 6.84 (s, 1H), 4.59 (bs, 2H), 4.19–4.15 (m, 1H), 4.01–3.95 (m, 1H), 3.03–2.97 (m, 1H), 2.90–2.79 (m, 3H), 2.50 (obs, 2H), 1.43–1.38 (m, 2H), 1.22–1.17 (m, 2H); MS (ESI+) m/z 585 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[N:7]=1.[CH3:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][C:36]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[F:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[N:21]1[C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]4[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]4)[CH2:10][CH2:9]3)[N:7]=[C:2]([C:36]3[CH:37]=[C:38]([CH:42]=[CH:43][C:35]=3[CH3:34])[C:39]([OH:41])=[O:40])[C:3]=2[CH:24]=[CH:23][C:22]1=[O:25]
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC1CCN(C2CCN(c3nc(Cl)c4ccc(=O)n(-c5c(F)cccc5F)c4n3)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 150 °C
Yield: 68 %

Procedure:
To the compound 4-chloro-8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (47.5 mg, 0.1 mmol) in dioxane (3 mL) and water (1 mL) were added 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (38.4 mg, 0.15 mol), potassium carbonate (83 mg, 0.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.6 mL, 0.005 mmol). The mixture was heated with microwave at about 150° C. for about 15 min. The mixture was concentrated & then mixed with DMSO (0.75 mL) and water (0.25 mL). Separation by HPLC afforded the title compound (39 mg, 68%). LC-MS m/z 574 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:15]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]2)=[C:16]=[O:17]>C(OCC)C>[CH:23]1[C:24]2[C:19](=[C:18]([NH:15][C:16]([NH:12][CH2:11][C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:14][CH:13]=3)=[O:17])[CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][N:22]=1
Reactant: O=C=Nc1cccc2cnccc12
Reactant: NCc1ccc(N2CCOCC2)cc1
Solvent: CCOCC
Product: O=C(NCc1ccc(N2CCOCC2)cc1)Nc1cccc2cnccc12

Procedure:
The product from Example 172B (285 mg, 1.48 mmol) in diethyl ether (10 mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline, causing a white precipitate to form. This precipitate was collected by filtration and purified by chromatography (95:5 CH2Cl2-MeOH, eluant) to provide the title compound. The corresponding di-hydrochloride salt was prepared using methanolic HCl to afford a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.67 (s, 1H), 8.52-8.55 (m, 1H), 8.32 (dd, J=7.8 Hz, 1.1 Hz, 1H), 7.92 (d, J=6.1 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.60 (m, 1H), 7.23 (d, J=8.8 Hz, 2H), 6.92-6.96 (m, 3H), 4.26 (d, 5.4 Hz, 2H), 3.72-3.75 (m, 4H), 3.06-3.12 (m, 4H); MS (ESI+) m/z 363 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[NH2:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[CH:37]=[CH:36][C:34](=[O:35])[NH:33][C:31]2=[O:32])[CH2:27][C@@H:26]1[OH:38]>N1C=CC=CC=1>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:23][CH2:24][C@H:25]2[O:29][C@@H:28]([N:30]3[CH:37]=[CH:36][C:34](=[O:35])[NH:33][C:31]3=[O:32])[CH2:27][C@@H:26]2[OH:38])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Solvent: c1ccncc1
Product: N#Cc1ccc(C(NC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 74.3 %

Procedure:
4-Cyanotrityl chloride (0.406 g, 1.34 mmol) was added to a solution of 5′-amino-2′,5′-dideoxyuridine (0.239 g, 1.05 mmol) in dry pyridine (5 mL). The reaction mixture was stirred at 40° C. for 48 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. Purification was carried out using flash column chromatography eluting the column (ISOLUTE SI) with a gradient of 0→5% CH3OH in CHCl3. The fractions with Rf=0.31 (10% CH3OH/CHCl3) afforded the title compound as a white crystalline solid (0.386 g, 37%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:6].CC(C)=O.[CH3:21][N:22]=[C:23]=[O:24]>C(N(CC)CC)C>[CH3:21][NH:22][C:23](=[O:24])[NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:6]
Reactant: CN=C=O
Reactant: Nc1cccc(C(=O)Nc2ccccn2)c1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1cccc(C(=O)Nc2ccccn2)c1
Yield: 85 %

Procedure:
A mixture of the 3-amino-N-2-pyridylbenzamide (6.4 g), acetone (60 ml), methyl isocyanate (1.8 ml) and a catalytic amount of triethylamine were stirred at room temperature for 24 hours. The resulting crystal was collected by filtration and recrystallized from acetone to provide 6.9 g of 3-(3-methylureido)-N-2-pyridylbenzamide as a colorless acicular crystal (compound 37) (yield: 85%, m.p. 163°-164° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Li]CCCC.[CH:15](N1CCCCC1)=[O:16]>C1COCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH:7]=1)[CH:15]=[O:16]
Reactant: Cc1ccc(Cl)cc1Br
Reactant: O=CN1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1C=O
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-chlorotoluene (20.0 g; 97.3 mmol) in 300 mL of THF at −78° C. was added dropwise a 2.5 M solution of n-BuLi (102.2 mmol). After 30 min of stirring at that temperature, 1-formylpiperidine (11.4 mL) in 10 mL of THF was added and the solution left for 1 h. It was brought to 0° C. , quenched with NH4OAc (25%) and diluted with EtOAc. The organic phase was dried over Na2SO4, filtered and the solvent removed to yield 13.3 g of the title compound.
Reaction SMILES: C(OC[CH:10]1[CH2:15][O:14][CH:13]([N:16]2[CH:23]=[CH:22][C:20]([NH2:21])=[N:19][C:17]2=[O:18])[CH2:12][S:11]1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.C(Cl)Cl.[C:33](=O)(O)[O-:34].[Na+]>C(Cl)Cl>[OH:34][CH2:33][SH:11]1[CH2:10][CH2:15][O:14][CH:13]([N:16]2[CH:23]=[CH:22][C:20]([NH2:21])=[N:19][C:17]2=[O:18])[CH2:12]1
Reactant: Nc1ccn(C2CSC(COCc3ccccc3)CO2)c(=O)n1
Reactant: O=C([O-])O
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccn(C2C[SH](CO)CCO2)c(=O)n1
Temperature: -78 °C

Procedure:
1-(5-benzyloxymethyl-1,4-oxathian-2-yl)cytosine (0.12 g) was dissolved in methylene chloride (10 ml), and the solution was cooled to -78° C. To the solution, 1M boron trichloride solution (3.7 ml) was added dropwise, and the resultant mixture was stirred at the same temperature for 4 hours. Mixed solvent of methanol-methylene chloride (1/1, 8 ml) was added thereto, and sodium bicarbonate was added to neutralize the reaction mixture. Upon raising the temperature of the reaction mixture to room temperature, the solvent was distilled off under reduced pressure to obtain white solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([O:25][C:26]1[CH:27]=[C:28]([CH:34]=[C:35]([CH3:37])[CH:36]=1)[O:29][CH2:30][CH2:31][CH2:32][OH:33])(=[O:24])=[O:23])([O-:15])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:58]1[C:62](=[O:63])[C:61]2=[CH:64][CH:65]=[CH:66][CH:67]=[C:60]2[C:59]1=[O:68]>O1CCCC1>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([O:25][C:26]1[CH:27]=[C:28]([CH:34]=[C:35]([CH3:37])[CH:36]=1)[O:29][CH2:30][CH2:31][CH2:32][O:33][N:58]1[C:59](=[O:68])[C:60]2=[CH:67][CH:66]=[CH:65][CH:64]=[C:61]2[C:62]1=[O:63])(=[O:24])=[O:23])([O-:15])=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCCCON2C(=O)c3ccccc3C2=O)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
Diethyl azodicarboxylate (910 μL, 5.78 mmol) was slowly added to a solution of 3-[3-(2-nitrophenylsulfonyloxy)-5-methylphenoxy]propanol (1.77 g, 4.82 mmol), as prepared in the preceding step, triphenylphosphine (1.52 g, 5.80 mmol), and N-hydroxyphthalimide (864 mg, 530 mmol) in tetrahydrofuran (10 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the product purified by flash chromatography (dichloromethane) to give 2.33 g (95%) of the title compound as an oil. 1H-NMR (300 MHz, CDCl3) δ7.98 (dd, 1H, J=7, 1 Hz), 7.67-7.88 (m, 7H), 6.67 (s, 1H), 6.64 (m, 1H), 6.55 (t, 1H, J=2 Hz), 4.36 (t, 2H, J=6 Hz), 4.12 (t, 2H, J=6 Hz), 2.28 (s, 3H), 2.18 (pentet, 2H, J=6 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid) calcd. for C24H20N2O9S: 535.1 (M+Na). Found 535.0.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][N:5]1[C@@H:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:22])([CH3:21])[C@H:10]1[OH:23])#[N:2].[CH2:24](Br)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:3]=[C:4]1[N:8]([CH2:24][CH3:25])[CH2:7][CH2:6][N:5]1[C@@H:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:21])([CH3:22])[C@H:10]1[OH:23])#[N:2]
Reactant: CCBr
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCNC2=NC#N)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)C1=NC#N
Temperature: 63 °C
Yield: 68.2 %

Procedure:
A mixture of trans-4-(2-cyanoiminoimidazolidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6carbonitrile (0.78 g), ethyl bromide (1.08 g) and potassium carbonate (1.38 g) in N,N-dimethylformamide (7.8 ml) was heated for 3 hours at 63° C. The reaction mixture was poured into ice-water (50 ml), and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was recrystallized from ethanol to give trans-4-(2-cyanoimino-3-ethylimidazolidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.58 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(O)C>[CH2:13]([NH:20][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: NCc1ccccc1
Solvent: CCO
Solvent: O
Product: Clc1cc(NCc2ccccc2)c2ccccc2n1
Yield: 34.8 %

Procedure:
2,4-Dichloroquinoline (0.70 g, 3.53 mmole) and benzylamine (3.79 g, 35.3 mmole) in ethanol (2 mL) were stirred at 110° C. in a microwave oven for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phases were washed with saturated NaCl solution, dried and concentrated. The residue thus obtained was purified using silica gel chromatography, eluting with dichloromethane:methanol 95:5 to give a white solid (330 mg, 35%).
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](CNC=O)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[C:32]([C@@H:34]1[CH:51]2[C@:46]([CH3:53])([CH2:47][CH2:48][C:49](=[O:52])[CH2:50]2)[C@@H:45]2[C@H:36]([C@H:37]3[C@@:41]([CH2:43][CH2:44]2)([CH3:42])[C:40](=[O:54])[CH2:39][CH2:38]3)[CH2:35]1)#[N:33]>>[CH:1]([NH:33][CH2:32][C@@H:34]1[CH:51]2[C@:46]([CH3:53])([CH2:47][CH2:48][C:49](=[O:52])[CH2:50]2)[C@@H:45]2[C@H:36]([C@H:37]3[C@@:41]([CH2:43][CH2:44]2)([CH3:42])[C:40](=[O:54])[CH2:39][CH2:38]3)[CH2:35]1)=[O:2]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CCCCC1[C@@H](CNC=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1[C@@H](CNC=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 92 %

Procedure:
The title compound II-bl was prepared in 92% yield from 3,3:17,17-bis(ethylendioxy)-6α-formamidomethylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). 1H-NMR (300 MHz, DMSO, ppm from TMS): δ 7.99 (0.9H, s), 7.94 (0.9H, m), 7.88 (0.1H, d), 7.67 (0.1H, m), 3.15 (1H, m), 2.87 (1H, m), 2.40-1.00 (21H, m), 0.98 (3H, s), 0.79 (3H, s).
Reaction SMILES: [CH2:1]([N:5]1[CH2:11][CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].Br.Br.[NH2:24][CH2:25][C:26]([NH2:28])=[NH:27]>>[NH2:28][C:26]1[CH:25]=[N:24][C:9]2[CH2:10][CH2:11][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][C:8]=2[N:27]=1
Reactant: CCCCN1CCC(O[Si](C)(C)C)=C(O[Si](C)(C)C)CC1
Reactant: N=C(N)CN
Agent: Br
Product: CCCCN1CCc2ncc(N)nc2CC1

Procedure:
This compound was prepared analogous to Example 3 from 1-butyl-2,3,6,7-tetrahydro-4,5-bis(trimethylsilyloxy)-azepine and 2-amino-acetamidine dihydrobromide.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[Br:12])=[O:21]
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1Br
Yield: 46.5 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-bromophenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(530 mg, 47%). EI-MS m/z 350(M-H)-
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[CH2:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[NH:15][C:12]2=[N:13][CH:14]=1)([CH3:7])[CH3:6])C.[OH-].[Li+]>O1CCCC1.O>[CH:20]1([CH:19]=[C:18]([C:16]2[NH:15][C:12]3=[N:13][CH:14]=[C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:35])=[O:3])[CH:10]=[C:11]3[CH:17]=2)[C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)C(C)(C)Oc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Oc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1)C(=O)O
Reaction time: 12 h
Yield: 53.4 %

Procedure:
To a stirred solution of 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-2-methyl-propionic acid ethyl ester (prepared as in Example 26, 120 mg, 0.24 mmol) in tetrahydrofuran (10 mL) and water (2.5 mL) was added lithium hydroxide (48 mg, 2 mmol) at room temperature and the mixture was stirred for 12 h. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-2-methyl-propionic acid (60 mg, 92.3%) as a white solid: LC/MS m/e calcd for C25H30N2O5S [M+H]+ 471.59, observed 471.6; 1H NMR (400 MHz, CD3OD) δ ppm 1.24 (m, 2H), 1.51 (m, 2H), 1.57 (s, 6H), 1.60-1.88 (m, 5 H, H), 2.13 (m, 1H), 2.27 (m, 1H), 3.08 (s, 3H), 4.32 (t, J=7.8 Hz, 1H), 6.50 (s, 1H), 7.59 (d, J=8.3 Hz, 2H), 7.85 (d, J=2.3 Hz, 1H), 7.89 (d, J=8.3 Hz, 2H), 7.97 (br. d., 1H).